Evidence-Based Reviews

The use of pharmacogenetic testing to help drive decisions for medication management of patients with psychiatric illnesses is growing. It’s becoming increasingly common for patients or the parents of pediatric patients to request pharmacogenetic testing or to bring the results of prior testing to their appointment. In these situations, patients may ask clinicians to consider the recommendations from these testing reports, which rarely provide guidance specific to pediatric patients. However, this can be difficult for clinicians who did not receive education in pharmacogenetics and may not be familiar with the evidence or options for pharmacogenetic testing. Many of the pharmacogenetic associations identified thus far have been discovered in adults, but studies in pediatric patients are relatively rare. This article reviews pharmacogenetic testing and the evidence supporting it, and describes implementation of routine pharmacogenetics testing at a children’s hospital.

CASE
Testing leads to dose adjustment, improvement

Ms. R, age 16, presents with treatment-resistant major depressive disorder that is characterized by a significant neurovegetative burden and prominent anhedonia, as well as intermittent suicidal ideation without intent or plan. She reportedly did not improve after multiple medication trials, including citalopram (maximum dose 30 mg/d, treatment duration 8 weeks, good compliance), sertraline (maximum dose 150 mg/d, treatment duration 10 weeks, good compliance), fluoxetine (maximum dose 40 mg/d, treatment duration 8 weeks, good compliance, mild improvement in neurovegetative symptoms and depressed mood), and duloxetine (maximum dose 90 mg/d, treatment duration 6 weeks, good compliance, mild benefit but intolerable nausea).

Augmentation strategies included risperidone, 1 mg/d at bedtime, but it failed to ameliorate her depressive symptoms. At the time of pharmacogenetic testing, she is taking aripiprazole, 2 mg/d at bedtime, and venlafaxine ER, 37.5 mg/d. Some benefit was noted, but her symptoms recrudesced within several weeks. Because both of these medications are metabolized by the cytochrome P450 (CYP) 2D6 enzyme, Ms. R is tested for CYP2D6 variants and is determined to be a CYP2D6 ultra-rapid metabolizer. Her venlafaxine ER is quickly titrated from 37.5 to 112.5 mg/d and aripiprazole is titrated from 2 to 10 mg/d. The patient’s anergia, amotivation, and mood improve.

_

Drug metabolism and genetic variants

It is common for patients with psychiatric disorders to receive trials of multiple psychotropic medications prior to identifying one that reduces symptom burden without producing intolerable adverse effects. Due to the high frequency of toxicity-related adverse effects (observed in 20% to 70% of patients),¹ these medications are frequently initiated at low doses and titrated slowly until the patient either experiences an intolerable adverse effect or achieves symptomatic remission.^1,2 The practice of slow titration at the start of treatment increases the risk of undertreatment in many patients, and may ultimately lead to a medication change due to the lack of response.

Many of the medications used to treat psychiatric illnesses are primarily metabolized by 2 CYP enzymes expressed in the liver, encoded by the CYP2D6 and CYP2C19 genes³ (Table 1^3-7 and Table 2^3,6,7). These drug-metabolizing enzymes affect the pharmacokinetics of many medications. Some medications are converted to an active form by these enzymes, and some are inactivated. The contributions of CYP enzymes to the pharmacokinetics of neuro­psychiatric medications have been well-described; however, there is less evidence on whether variants in these genes are associated with treatment efficacy, especially in pediatric patients.^8,9 CYP2D6 enzyme activity reaches adult levels soon after birth, but children may have higher CYP2C19 activity than adults.⁴ CYP3A4 also contributes to the metabolism of many medications; however, there is only weak evidence that genetic variants in CYP3A4 contribute to variability in the pharmacokinetics of these medications, and there are currently no dosing guidelines based on pharmacogenetics available for this gene.¹⁰

As is common in the pharmacogenetic field, genotypes are denoted with a “star allele” (eg, *2) rather than positional nomenclature (eg, c.681G>A). The normal allele is usually designated as *1, and this result is given in the absence of the tested alleles. There is no consensus on the minimum set of alleles to be tested for most genes,¹¹ so commercially available tests vary widely in what alleles are tested (and therefore what they exclude before calling a normal allele).¹² The metabolizer phenotype for a patient is determined by taking into account the activity of each of the patient’s 2 alleles (eg, *1/*2). A patient is categorized as a poor-, intermediate-, normal- (extensive-), or ultra-rapid metabolizer. Generally, the allele definitions are widely agreed upon (what genetic variant or variants comprise the *2 allele) due to nomenclature committees for each gene; however, because there are no standards for interpretation, the interpretation of the activity of the alleles and conversion to metabolizer phenotype varies among clinics.¹³

Continue to: Guidelines help with genotype-guided dosing

Each CPIC guideline specifically addresses use in pediatric patients, indicating that there are relatively few studies in pediatrics, but “it may be appropriate to extrapolate these recommendations to adolescents or possibly younger children with close monitoring.”⁴ The DPWG guidelines do not mention whether or not the recommendations are applicable to children. Neither CPIC nor the DPWG provides guidance on when to test; however, the French National Network of Pharmacogenetics (Réseau national de pharmacogénétique) recommends CYP2D6 and CYP2C19 genotyping before initiating antidepressant treatment, especially in patients with a high risk of toxicity.¹⁶

In the case above, Ms. R was determined to be a CYP2D6 ultra-rapid metabolizer. Because she showed some initial response to aripiprazole and venlafaxine ER, which are both metabolized by CYP2D6, these medications were very quickly titrated up, and the increased dosages produced the desired response. Venlafaxine is metabolized to the active metabolite O-desmethylvenlafaxine by CYP2D6. The DPWG recommends increasing the dose of venlafaxine in CYP2D6 ultra-rapid metabolizers to 150% of the normal dose based on the decreased serum concentrations of venlafaxine and O-desmethylvenlafaxine in these patients.⁶ Aripiprazole is also metabolized by CYP2D6; however, the FDA and DPWG give no recommendations for ultra-rapid metabolizers, but do recommend reducing the dose of aripiprazole in CYP2D6 poor metabolizers.

Multiple studies in adults have analyzed the association between pharmacokinetic (CYP2D6 and CYP2C19) or pharmacodynamic genes (SLC6A4, HTR2A, and GRIK4) and outcomes,¹⁷ including some large clinical trials that conducted genome-wide association studies^18-20 and meta-analyses across multiple studies.^21,22 Most pharmacogenetic studies in psychiatric patients are small, and very few have included pediatric patients. However, with more interest in neuropsychiatric pharmacogenetics, these studies are becoming more common.^23-26

Continue to: Limited evidence from studies of commercially available tests

Several pharmacogenetic tests are commercially available, including some that focus on providing information that can be used specifically when prescribing psychiatric medications, such as the GeneSight Psychotropic test, CNSdose, Genomind, and Neuropharmagen.

In an industry-sponsored, nonrandomized clinical trial that included patients for whom prescribing decisions were made based on the GeneSight test, outcomes in adults were improved compared with treatment as usual,²⁷ inpatient stays were shorter,²⁸ and pharmacy costs were reduced.²⁹ In one of these studies, the authors noted that the traditional, single-gene analysis was not associated with improved outcomes, whereas the multiple gene combination (pharmacokinetic and pharmacodynamic genes) was associated with improved outcomes among patients with depression.²⁷ However, when GeneSightwas compared with treatment as usual in a small randomized trial, there was not a significant association between use of the test and improved outcomes among patients with treatment-resistant depression.³⁰ The results of a much larger randomized trial (N = 1,167) are available³¹ and expected to be published, but patients younger than age 18 were excluded from this study.³² A retrospective study conducted in adult psychiatric patients found that patients whose treatment followed recommendations of a pharmacogenetic test including 20 genes were almost 4 times more likely to improve than patients whose treatment did not follow the recommendations.³³

Pharmacogenetic testing at our pediatric inpatient unit

The Cincinnati Children’s Division of Child and Adolescent Psychiatry is the largest psychiatric inpatient service in a U.S. pediatric hospital. Starting in 2004, we adopted pharmacogenetically-guided dosing of psychiatric medications.³⁴ CYP2D6 and CYP2C19 were chosen for testing because the enzymes encoded by these genes metabolize many of the antidepressants and antipsychotics that patients admitted to our unit will receive, and the clinicians wanted all available tools to help improve the care of these patients. To date, the Genetic Pharmacology Service (GPS) has performed >25,000 tests for variants in CYP2D6 and CYP2C19 as part of inpatient care. Patients provide a specimen (blood or buccal swab) at the time of admission to inpatient psychiatry, genotyping is performed onsite by the Molecular Genetics Laboratory (certified by the College of American Pathologists [CAP]/Clinical Laboratory Improvement Amendments [CLIA]) and the results are posted to the medical record within 2 business days. The report contains the patient’s alleles for CYP2D6 and CYP2C19, the genotype-predicted metabolizer phenotype, and dosing recommendations for 19 drugs (provided as a percentage of the standard dose). Insurance is billed for the test, and reimbursement is usually received when the test is performed as part of an inpatient stay.

The GPS team performed a retrospective chart review after the first panel was implemented in 2005.²³ The study included 279 patients who were receiving a medication metabolized by one of the 2 genes tested. The poor metabolizers had the highest efficacy and highest number of adverse drug reactions, while ultra-rapid metabolizers had the lowest efficacy and lowest number of adverse reactions during their initial inpatient stay. In patients not treated with medications metabolized by CYP2D6 or CYP2C19, there was no association between metabolizer status and efficacy or adverse drug reactions. In this retrospective study, there was no association between metabolizer status and length of stay.

Overcoming the challenges

One challenge with many of the pharmacogenetic tests is interpretation of the results. The reports can span more than 20 pages, and clinicians may not have time to thoroughly read and understand how best to use all of this information. Sometimes the reports can make it seem like the first-line medication for the patient’s condition is not the best choice, but it could work well when dosed appropriately based on the patient’s genotype. Each commercially available test has a different way of presenting results,¹³ so when choosing a pharmacogenetic test, one should be sure to see a sample report. Vo et al³⁵ recently reviewed factors to consider when choosing a pharmacogenetic test.

Continue to: Because patients and families also have difficulty understanding the reports...

Because patients and families also have difficulty understanding the reports, we created patient education sheets,³⁶ written at an eighth grade level with feedback from parents and modeled on those provided by St. Jude Children’s Research Hospital.³⁷ St. Jude Children’s Research Hospital also has pharmacogenetic competencies that pharmacists and nurses must pass.^38,39 The following is a sample explanation that one of our nurses uses to educate parents on what is being tested and what effect the results will have on the treatment plan.

“During your child’s stay we will be completing a genetic test to help us understand how he/she processes the types of medications that we may be likely to start during their hospitalization. This does not tell us which medication will be best—unfortunately within the field of psychiatry there is still some unavoidable trial and error; rather, what it will do is tell us how to make sure that the dosing is at a level that would be safe for the way your child’s body breaks down the medicine, so that he/she can get the intended benefit of the medicine’s effects, while decreasing the risk of uncomfortable side effects, where possible.”

Other challenges in pharmacogenetic testing are the cost, disease risk, and concern about how genetic information will be used. Because these tests are often not covered by health insurance, some commercial pharmacogenetic testing companies offer an out-of-pocket maximum in the $250 to $350 range to reduce the cost to the patient. Some pharmacogenetic testing companies also test for genes associated with disease, so if a clinician orders the test, he or she may be responsible for sharing that information with the patient. For most pharmacogenetic testing companies, the turn-around time is 2 to 10 days. Genetic information is protected by federal laws, including Genetic Information Nondiscrimination Act (GINA) and Health Insurance Portability and Accountability Act (HIPAA).

The choice of psychotropic medication is complex, and although we would like pharmacogenetics to be the only answer to why every patient does or does not respond to a medication, it is not. Response to medication is influenced by age, comorbidities, illness severity, illness duration, compliance, gender, concomitant medications, and potentially more.⁴⁰ Pharmacogenetics is another tool at the clinician’s disposal to help in choosing a medication and dose. There is a clear association between CYP2D6 and CYP2C19 and exposure to many antidepressants and antipsychotics (reviewed by Stingl et al³); however, the link between exposure and response is much weaker. It may be strengthened by the inclusion of pharmacodynamic information (the level of expression of the drug target), which can be influenced by genetic variants.⁴¹ At the present time, the most evidence exists for testing CYP2D6 and CYP2C19, and the CPIC^4,5,15 and DWPG⁶ guidelines provide evidence-based recommendations for how to adjust medication dosages based on the results.

There is clearly much more research that needs to be done in the field of neuropsychi­atric pharmacogenetics, especially in pediatric populations. As we see increased utilization of pharmacogenetic tests in psychiatry, there is also a need for pharmaco­genetic education of patients, families, nurses, pharmacists, and psychiatrists. Several good pharmacogenetic resources that contain up-to-date summaries of the available evidence linking pharmacogenetic variants to medication response, implementation resources, and educational resources are available. These include CPIC (www.cpicpgx.org), PharmGKB (www.pharmgkb.org), and the IGNITE Spark Toolbox (https://ignite-genomics.org/spark-toolbox/clinicians/).

Acknowledgements

The author thanks Jen Milau, APRN, for the case study and sample explanation, and Jeffrey Strawn, MD, FAACP, Ethan Poweleit, and Stacey Aldrich, MS, for help with preparing this manuscript.

The use of pharmacogenetic testing to help drive decisions for medication management of patients with psychiatric illnesses is growing. It’s becoming increasingly common for patients or the parents of pediatric patients to request pharmacogenetic testing or to bring the results of prior testing to their appointment. In these situations, patients may ask clinicians to consider the recommendations from these testing reports, which rarely provide guidance specific to pediatric patients. However, this can be difficult for clinicians who did not receive education in pharmacogenetics and may not be familiar with the evidence or options for pharmacogenetic testing. Many of the pharmacogenetic associations identified thus far have been discovered in adults, but studies in pediatric patients are relatively rare. This article reviews pharmacogenetic testing and the evidence supporting it, and describes implementation of routine pharmacogenetics testing at a children’s hospital.

CASE
Testing leads to dose adjustment, improvement

Ms. R, age 16, presents with treatment-resistant major depressive disorder that is characterized by a significant neurovegetative burden and prominent anhedonia, as well as intermittent suicidal ideation without intent or plan. She reportedly did not improve after multiple medication trials, including citalopram (maximum dose 30 mg/d, treatment duration 8 weeks, good compliance), sertraline (maximum dose 150 mg/d, treatment duration 10 weeks, good compliance), fluoxetine (maximum dose 40 mg/d, treatment duration 8 weeks, good compliance, mild improvement in neurovegetative symptoms and depressed mood), and duloxetine (maximum dose 90 mg/d, treatment duration 6 weeks, good compliance, mild benefit but intolerable nausea).

Augmentation strategies included risperidone, 1 mg/d at bedtime, but it failed to ameliorate her depressive symptoms. At the time of pharmacogenetic testing, she is taking aripiprazole, 2 mg/d at bedtime, and venlafaxine ER, 37.5 mg/d. Some benefit was noted, but her symptoms recrudesced within several weeks. Because both of these medications are metabolized by the cytochrome P450 (CYP) 2D6 enzyme, Ms. R is tested for CYP2D6 variants and is determined to be a CYP2D6 ultra-rapid metabolizer. Her venlafaxine ER is quickly titrated from 37.5 to 112.5 mg/d and aripiprazole is titrated from 2 to 10 mg/d. The patient’s anergia, amotivation, and mood improve.

_

Drug metabolism and genetic variants

It is common for patients with psychiatric disorders to receive trials of multiple psychotropic medications prior to identifying one that reduces symptom burden without producing intolerable adverse effects. Due to the high frequency of toxicity-related adverse effects (observed in 20% to 70% of patients),¹ these medications are frequently initiated at low doses and titrated slowly until the patient either experiences an intolerable adverse effect or achieves symptomatic remission.^1,2 The practice of slow titration at the start of treatment increases the risk of undertreatment in many patients, and may ultimately lead to a medication change due to the lack of response.

Many of the medications used to treat psychiatric illnesses are primarily metabolized by 2 CYP enzymes expressed in the liver, encoded by the CYP2D6 and CYP2C19 genes³ (Table 1^3-7 and Table 2^3,6,7). These drug-metabolizing enzymes affect the pharmacokinetics of many medications. Some medications are converted to an active form by these enzymes, and some are inactivated. The contributions of CYP enzymes to the pharmacokinetics of neuro­psychiatric medications have been well-described; however, there is less evidence on whether variants in these genes are associated with treatment efficacy, especially in pediatric patients.^8,9 CYP2D6 enzyme activity reaches adult levels soon after birth, but children may have higher CYP2C19 activity than adults.⁴ CYP3A4 also contributes to the metabolism of many medications; however, there is only weak evidence that genetic variants in CYP3A4 contribute to variability in the pharmacokinetics of these medications, and there are currently no dosing guidelines based on pharmacogenetics available for this gene.¹⁰

As is common in the pharmacogenetic field, genotypes are denoted with a “star allele” (eg, *2) rather than positional nomenclature (eg, c.681G>A). The normal allele is usually designated as *1, and this result is given in the absence of the tested alleles. There is no consensus on the minimum set of alleles to be tested for most genes,¹¹ so commercially available tests vary widely in what alleles are tested (and therefore what they exclude before calling a normal allele).¹² The metabolizer phenotype for a patient is determined by taking into account the activity of each of the patient’s 2 alleles (eg, *1/*2). A patient is categorized as a poor-, intermediate-, normal- (extensive-), or ultra-rapid metabolizer. Generally, the allele definitions are widely agreed upon (what genetic variant or variants comprise the *2 allele) due to nomenclature committees for each gene; however, because there are no standards for interpretation, the interpretation of the activity of the alleles and conversion to metabolizer phenotype varies among clinics.¹³

Continue to: Guidelines help with genotype-guided dosing

Each CPIC guideline specifically addresses use in pediatric patients, indicating that there are relatively few studies in pediatrics, but “it may be appropriate to extrapolate these recommendations to adolescents or possibly younger children with close monitoring.”⁴ The DPWG guidelines do not mention whether or not the recommendations are applicable to children. Neither CPIC nor the DPWG provides guidance on when to test; however, the French National Network of Pharmacogenetics (Réseau national de pharmacogénétique) recommends CYP2D6 and CYP2C19 genotyping before initiating antidepressant treatment, especially in patients with a high risk of toxicity.¹⁶

In the case above, Ms. R was determined to be a CYP2D6 ultra-rapid metabolizer. Because she showed some initial response to aripiprazole and venlafaxine ER, which are both metabolized by CYP2D6, these medications were very quickly titrated up, and the increased dosages produced the desired response. Venlafaxine is metabolized to the active metabolite O-desmethylvenlafaxine by CYP2D6. The DPWG recommends increasing the dose of venlafaxine in CYP2D6 ultra-rapid metabolizers to 150% of the normal dose based on the decreased serum concentrations of venlafaxine and O-desmethylvenlafaxine in these patients.⁶ Aripiprazole is also metabolized by CYP2D6; however, the FDA and DPWG give no recommendations for ultra-rapid metabolizers, but do recommend reducing the dose of aripiprazole in CYP2D6 poor metabolizers.

Multiple studies in adults have analyzed the association between pharmacokinetic (CYP2D6 and CYP2C19) or pharmacodynamic genes (SLC6A4, HTR2A, and GRIK4) and outcomes,¹⁷ including some large clinical trials that conducted genome-wide association studies^18-20 and meta-analyses across multiple studies.^21,22 Most pharmacogenetic studies in psychiatric patients are small, and very few have included pediatric patients. However, with more interest in neuropsychiatric pharmacogenetics, these studies are becoming more common.^23-26

Continue to: Limited evidence from studies of commercially available tests

Several pharmacogenetic tests are commercially available, including some that focus on providing information that can be used specifically when prescribing psychiatric medications, such as the GeneSight Psychotropic test, CNSdose, Genomind, and Neuropharmagen.

In an industry-sponsored, nonrandomized clinical trial that included patients for whom prescribing decisions were made based on the GeneSight test, outcomes in adults were improved compared with treatment as usual,²⁷ inpatient stays were shorter,²⁸ and pharmacy costs were reduced.²⁹ In one of these studies, the authors noted that the traditional, single-gene analysis was not associated with improved outcomes, whereas the multiple gene combination (pharmacokinetic and pharmacodynamic genes) was associated with improved outcomes among patients with depression.²⁷ However, when GeneSightwas compared with treatment as usual in a small randomized trial, there was not a significant association between use of the test and improved outcomes among patients with treatment-resistant depression.³⁰ The results of a much larger randomized trial (N = 1,167) are available³¹ and expected to be published, but patients younger than age 18 were excluded from this study.³² A retrospective study conducted in adult psychiatric patients found that patients whose treatment followed recommendations of a pharmacogenetic test including 20 genes were almost 4 times more likely to improve than patients whose treatment did not follow the recommendations.³³

Pharmacogenetic testing at our pediatric inpatient unit

The Cincinnati Children’s Division of Child and Adolescent Psychiatry is the largest psychiatric inpatient service in a U.S. pediatric hospital. Starting in 2004, we adopted pharmacogenetically-guided dosing of psychiatric medications.³⁴ CYP2D6 and CYP2C19 were chosen for testing because the enzymes encoded by these genes metabolize many of the antidepressants and antipsychotics that patients admitted to our unit will receive, and the clinicians wanted all available tools to help improve the care of these patients. To date, the Genetic Pharmacology Service (GPS) has performed >25,000 tests for variants in CYP2D6 and CYP2C19 as part of inpatient care. Patients provide a specimen (blood or buccal swab) at the time of admission to inpatient psychiatry, genotyping is performed onsite by the Molecular Genetics Laboratory (certified by the College of American Pathologists [CAP]/Clinical Laboratory Improvement Amendments [CLIA]) and the results are posted to the medical record within 2 business days. The report contains the patient’s alleles for CYP2D6 and CYP2C19, the genotype-predicted metabolizer phenotype, and dosing recommendations for 19 drugs (provided as a percentage of the standard dose). Insurance is billed for the test, and reimbursement is usually received when the test is performed as part of an inpatient stay.

The GPS team performed a retrospective chart review after the first panel was implemented in 2005.²³ The study included 279 patients who were receiving a medication metabolized by one of the 2 genes tested. The poor metabolizers had the highest efficacy and highest number of adverse drug reactions, while ultra-rapid metabolizers had the lowest efficacy and lowest number of adverse reactions during their initial inpatient stay. In patients not treated with medications metabolized by CYP2D6 or CYP2C19, there was no association between metabolizer status and efficacy or adverse drug reactions. In this retrospective study, there was no association between metabolizer status and length of stay.

Overcoming the challenges

One challenge with many of the pharmacogenetic tests is interpretation of the results. The reports can span more than 20 pages, and clinicians may not have time to thoroughly read and understand how best to use all of this information. Sometimes the reports can make it seem like the first-line medication for the patient’s condition is not the best choice, but it could work well when dosed appropriately based on the patient’s genotype. Each commercially available test has a different way of presenting results,¹³ so when choosing a pharmacogenetic test, one should be sure to see a sample report. Vo et al³⁵ recently reviewed factors to consider when choosing a pharmacogenetic test.

Continue to: Because patients and families also have difficulty understanding the reports...

Because patients and families also have difficulty understanding the reports, we created patient education sheets,³⁶ written at an eighth grade level with feedback from parents and modeled on those provided by St. Jude Children’s Research Hospital.³⁷ St. Jude Children’s Research Hospital also has pharmacogenetic competencies that pharmacists and nurses must pass.^38,39 The following is a sample explanation that one of our nurses uses to educate parents on what is being tested and what effect the results will have on the treatment plan.

“During your child’s stay we will be completing a genetic test to help us understand how he/she processes the types of medications that we may be likely to start during their hospitalization. This does not tell us which medication will be best—unfortunately within the field of psychiatry there is still some unavoidable trial and error; rather, what it will do is tell us how to make sure that the dosing is at a level that would be safe for the way your child’s body breaks down the medicine, so that he/she can get the intended benefit of the medicine’s effects, while decreasing the risk of uncomfortable side effects, where possible.”

Other challenges in pharmacogenetic testing are the cost, disease risk, and concern about how genetic information will be used. Because these tests are often not covered by health insurance, some commercial pharmacogenetic testing companies offer an out-of-pocket maximum in the $250 to $350 range to reduce the cost to the patient. Some pharmacogenetic testing companies also test for genes associated with disease, so if a clinician orders the test, he or she may be responsible for sharing that information with the patient. For most pharmacogenetic testing companies, the turn-around time is 2 to 10 days. Genetic information is protected by federal laws, including Genetic Information Nondiscrimination Act (GINA) and Health Insurance Portability and Accountability Act (HIPAA).

The choice of psychotropic medication is complex, and although we would like pharmacogenetics to be the only answer to why every patient does or does not respond to a medication, it is not. Response to medication is influenced by age, comorbidities, illness severity, illness duration, compliance, gender, concomitant medications, and potentially more.⁴⁰ Pharmacogenetics is another tool at the clinician’s disposal to help in choosing a medication and dose. There is a clear association between CYP2D6 and CYP2C19 and exposure to many antidepressants and antipsychotics (reviewed by Stingl et al³); however, the link between exposure and response is much weaker. It may be strengthened by the inclusion of pharmacodynamic information (the level of expression of the drug target), which can be influenced by genetic variants.⁴¹ At the present time, the most evidence exists for testing CYP2D6 and CYP2C19, and the CPIC^4,5,15 and DWPG⁶ guidelines provide evidence-based recommendations for how to adjust medication dosages based on the results.

There is clearly much more research that needs to be done in the field of neuropsychi­atric pharmacogenetics, especially in pediatric populations. As we see increased utilization of pharmacogenetic tests in psychiatry, there is also a need for pharmaco­genetic education of patients, families, nurses, pharmacists, and psychiatrists. Several good pharmacogenetic resources that contain up-to-date summaries of the available evidence linking pharmacogenetic variants to medication response, implementation resources, and educational resources are available. These include CPIC (www.cpicpgx.org), PharmGKB (www.pharmgkb.org), and the IGNITE Spark Toolbox (https://ignite-genomics.org/spark-toolbox/clinicians/).

Acknowledgements

The author thanks Jen Milau, APRN, for the case study and sample explanation, and Jeffrey Strawn, MD, FAACP, Ethan Poweleit, and Stacey Aldrich, MS, for help with preparing this manuscript.

The use of pharmacogenetic testing to help drive decisions for medication management of patients with psychiatric illnesses is growing. It’s becoming increasingly common for patients or the parents of pediatric patients to request pharmacogenetic testing or to bring the results of prior testing to their appointment. In these situations, patients may ask clinicians to consider the recommendations from these testing reports, which rarely provide guidance specific to pediatric patients. However, this can be difficult for clinicians who did not receive education in pharmacogenetics and may not be familiar with the evidence or options for pharmacogenetic testing. Many of the pharmacogenetic associations identified thus far have been discovered in adults, but studies in pediatric patients are relatively rare. This article reviews pharmacogenetic testing and the evidence supporting it, and describes implementation of routine pharmacogenetics testing at a children’s hospital.

CASE
Testing leads to dose adjustment, improvement

Ms. R, age 16, presents with treatment-resistant major depressive disorder that is characterized by a significant neurovegetative burden and prominent anhedonia, as well as intermittent suicidal ideation without intent or plan. She reportedly did not improve after multiple medication trials, including citalopram (maximum dose 30 mg/d, treatment duration 8 weeks, good compliance), sertraline (maximum dose 150 mg/d, treatment duration 10 weeks, good compliance), fluoxetine (maximum dose 40 mg/d, treatment duration 8 weeks, good compliance, mild improvement in neurovegetative symptoms and depressed mood), and duloxetine (maximum dose 90 mg/d, treatment duration 6 weeks, good compliance, mild benefit but intolerable nausea).

Augmentation strategies included risperidone, 1 mg/d at bedtime, but it failed to ameliorate her depressive symptoms. At the time of pharmacogenetic testing, she is taking aripiprazole, 2 mg/d at bedtime, and venlafaxine ER, 37.5 mg/d. Some benefit was noted, but her symptoms recrudesced within several weeks. Because both of these medications are metabolized by the cytochrome P450 (CYP) 2D6 enzyme, Ms. R is tested for CYP2D6 variants and is determined to be a CYP2D6 ultra-rapid metabolizer. Her venlafaxine ER is quickly titrated from 37.5 to 112.5 mg/d and aripiprazole is titrated from 2 to 10 mg/d. The patient’s anergia, amotivation, and mood improve.

_

Drug metabolism and genetic variants

It is common for patients with psychiatric disorders to receive trials of multiple psychotropic medications prior to identifying one that reduces symptom burden without producing intolerable adverse effects. Due to the high frequency of toxicity-related adverse effects (observed in 20% to 70% of patients),¹ these medications are frequently initiated at low doses and titrated slowly until the patient either experiences an intolerable adverse effect or achieves symptomatic remission.^1,2 The practice of slow titration at the start of treatment increases the risk of undertreatment in many patients, and may ultimately lead to a medication change due to the lack of response.

Many of the medications used to treat psychiatric illnesses are primarily metabolized by 2 CYP enzymes expressed in the liver, encoded by the CYP2D6 and CYP2C19 genes³ (Table 1^3-7 and Table 2^3,6,7). These drug-metabolizing enzymes affect the pharmacokinetics of many medications. Some medications are converted to an active form by these enzymes, and some are inactivated. The contributions of CYP enzymes to the pharmacokinetics of neuro­psychiatric medications have been well-described; however, there is less evidence on whether variants in these genes are associated with treatment efficacy, especially in pediatric patients.^8,9 CYP2D6 enzyme activity reaches adult levels soon after birth, but children may have higher CYP2C19 activity than adults.⁴ CYP3A4 also contributes to the metabolism of many medications; however, there is only weak evidence that genetic variants in CYP3A4 contribute to variability in the pharmacokinetics of these medications, and there are currently no dosing guidelines based on pharmacogenetics available for this gene.¹⁰

As is common in the pharmacogenetic field, genotypes are denoted with a “star allele” (eg, *2) rather than positional nomenclature (eg, c.681G>A). The normal allele is usually designated as *1, and this result is given in the absence of the tested alleles. There is no consensus on the minimum set of alleles to be tested for most genes,¹¹ so commercially available tests vary widely in what alleles are tested (and therefore what they exclude before calling a normal allele).¹² The metabolizer phenotype for a patient is determined by taking into account the activity of each of the patient’s 2 alleles (eg, *1/*2). A patient is categorized as a poor-, intermediate-, normal- (extensive-), or ultra-rapid metabolizer. Generally, the allele definitions are widely agreed upon (what genetic variant or variants comprise the *2 allele) due to nomenclature committees for each gene; however, because there are no standards for interpretation, the interpretation of the activity of the alleles and conversion to metabolizer phenotype varies among clinics.¹³

Continue to: Guidelines help with genotype-guided dosing

Each CPIC guideline specifically addresses use in pediatric patients, indicating that there are relatively few studies in pediatrics, but “it may be appropriate to extrapolate these recommendations to adolescents or possibly younger children with close monitoring.”⁴ The DPWG guidelines do not mention whether or not the recommendations are applicable to children. Neither CPIC nor the DPWG provides guidance on when to test; however, the French National Network of Pharmacogenetics (Réseau national de pharmacogénétique) recommends CYP2D6 and CYP2C19 genotyping before initiating antidepressant treatment, especially in patients with a high risk of toxicity.¹⁶

In the case above, Ms. R was determined to be a CYP2D6 ultra-rapid metabolizer. Because she showed some initial response to aripiprazole and venlafaxine ER, which are both metabolized by CYP2D6, these medications were very quickly titrated up, and the increased dosages produced the desired response. Venlafaxine is metabolized to the active metabolite O-desmethylvenlafaxine by CYP2D6. The DPWG recommends increasing the dose of venlafaxine in CYP2D6 ultra-rapid metabolizers to 150% of the normal dose based on the decreased serum concentrations of venlafaxine and O-desmethylvenlafaxine in these patients.⁶ Aripiprazole is also metabolized by CYP2D6; however, the FDA and DPWG give no recommendations for ultra-rapid metabolizers, but do recommend reducing the dose of aripiprazole in CYP2D6 poor metabolizers.

Multiple studies in adults have analyzed the association between pharmacokinetic (CYP2D6 and CYP2C19) or pharmacodynamic genes (SLC6A4, HTR2A, and GRIK4) and outcomes,¹⁷ including some large clinical trials that conducted genome-wide association studies^18-20 and meta-analyses across multiple studies.^21,22 Most pharmacogenetic studies in psychiatric patients are small, and very few have included pediatric patients. However, with more interest in neuropsychiatric pharmacogenetics, these studies are becoming more common.^23-26

Continue to: Limited evidence from studies of commercially available tests

Several pharmacogenetic tests are commercially available, including some that focus on providing information that can be used specifically when prescribing psychiatric medications, such as the GeneSight Psychotropic test, CNSdose, Genomind, and Neuropharmagen.

In an industry-sponsored, nonrandomized clinical trial that included patients for whom prescribing decisions were made based on the GeneSight test, outcomes in adults were improved compared with treatment as usual,²⁷ inpatient stays were shorter,²⁸ and pharmacy costs were reduced.²⁹ In one of these studies, the authors noted that the traditional, single-gene analysis was not associated with improved outcomes, whereas the multiple gene combination (pharmacokinetic and pharmacodynamic genes) was associated with improved outcomes among patients with depression.²⁷ However, when GeneSightwas compared with treatment as usual in a small randomized trial, there was not a significant association between use of the test and improved outcomes among patients with treatment-resistant depression.³⁰ The results of a much larger randomized trial (N = 1,167) are available³¹ and expected to be published, but patients younger than age 18 were excluded from this study.³² A retrospective study conducted in adult psychiatric patients found that patients whose treatment followed recommendations of a pharmacogenetic test including 20 genes were almost 4 times more likely to improve than patients whose treatment did not follow the recommendations.³³

Pharmacogenetic testing at our pediatric inpatient unit

The Cincinnati Children’s Division of Child and Adolescent Psychiatry is the largest psychiatric inpatient service in a U.S. pediatric hospital. Starting in 2004, we adopted pharmacogenetically-guided dosing of psychiatric medications.³⁴ CYP2D6 and CYP2C19 were chosen for testing because the enzymes encoded by these genes metabolize many of the antidepressants and antipsychotics that patients admitted to our unit will receive, and the clinicians wanted all available tools to help improve the care of these patients. To date, the Genetic Pharmacology Service (GPS) has performed >25,000 tests for variants in CYP2D6 and CYP2C19 as part of inpatient care. Patients provide a specimen (blood or buccal swab) at the time of admission to inpatient psychiatry, genotyping is performed onsite by the Molecular Genetics Laboratory (certified by the College of American Pathologists [CAP]/Clinical Laboratory Improvement Amendments [CLIA]) and the results are posted to the medical record within 2 business days. The report contains the patient’s alleles for CYP2D6 and CYP2C19, the genotype-predicted metabolizer phenotype, and dosing recommendations for 19 drugs (provided as a percentage of the standard dose). Insurance is billed for the test, and reimbursement is usually received when the test is performed as part of an inpatient stay.

The GPS team performed a retrospective chart review after the first panel was implemented in 2005.²³ The study included 279 patients who were receiving a medication metabolized by one of the 2 genes tested. The poor metabolizers had the highest efficacy and highest number of adverse drug reactions, while ultra-rapid metabolizers had the lowest efficacy and lowest number of adverse reactions during their initial inpatient stay. In patients not treated with medications metabolized by CYP2D6 or CYP2C19, there was no association between metabolizer status and efficacy or adverse drug reactions. In this retrospective study, there was no association between metabolizer status and length of stay.

Overcoming the challenges

One challenge with many of the pharmacogenetic tests is interpretation of the results. The reports can span more than 20 pages, and clinicians may not have time to thoroughly read and understand how best to use all of this information. Sometimes the reports can make it seem like the first-line medication for the patient’s condition is not the best choice, but it could work well when dosed appropriately based on the patient’s genotype. Each commercially available test has a different way of presenting results,¹³ so when choosing a pharmacogenetic test, one should be sure to see a sample report. Vo et al³⁵ recently reviewed factors to consider when choosing a pharmacogenetic test.

Continue to: Because patients and families also have difficulty understanding the reports...

Because patients and families also have difficulty understanding the reports, we created patient education sheets,³⁶ written at an eighth grade level with feedback from parents and modeled on those provided by St. Jude Children’s Research Hospital.³⁷ St. Jude Children’s Research Hospital also has pharmacogenetic competencies that pharmacists and nurses must pass.^38,39 The following is a sample explanation that one of our nurses uses to educate parents on what is being tested and what effect the results will have on the treatment plan.

“During your child’s stay we will be completing a genetic test to help us understand how he/she processes the types of medications that we may be likely to start during their hospitalization. This does not tell us which medication will be best—unfortunately within the field of psychiatry there is still some unavoidable trial and error; rather, what it will do is tell us how to make sure that the dosing is at a level that would be safe for the way your child’s body breaks down the medicine, so that he/she can get the intended benefit of the medicine’s effects, while decreasing the risk of uncomfortable side effects, where possible.”

Other challenges in pharmacogenetic testing are the cost, disease risk, and concern about how genetic information will be used. Because these tests are often not covered by health insurance, some commercial pharmacogenetic testing companies offer an out-of-pocket maximum in the $250 to $350 range to reduce the cost to the patient. Some pharmacogenetic testing companies also test for genes associated with disease, so if a clinician orders the test, he or she may be responsible for sharing that information with the patient. For most pharmacogenetic testing companies, the turn-around time is 2 to 10 days. Genetic information is protected by federal laws, including Genetic Information Nondiscrimination Act (GINA) and Health Insurance Portability and Accountability Act (HIPAA).

The choice of psychotropic medication is complex, and although we would like pharmacogenetics to be the only answer to why every patient does or does not respond to a medication, it is not. Response to medication is influenced by age, comorbidities, illness severity, illness duration, compliance, gender, concomitant medications, and potentially more.⁴⁰ Pharmacogenetics is another tool at the clinician’s disposal to help in choosing a medication and dose. There is a clear association between CYP2D6 and CYP2C19 and exposure to many antidepressants and antipsychotics (reviewed by Stingl et al³); however, the link between exposure and response is much weaker. It may be strengthened by the inclusion of pharmacodynamic information (the level of expression of the drug target), which can be influenced by genetic variants.⁴¹ At the present time, the most evidence exists for testing CYP2D6 and CYP2C19, and the CPIC^4,5,15 and DWPG⁶ guidelines provide evidence-based recommendations for how to adjust medication dosages based on the results.

There is clearly much more research that needs to be done in the field of neuropsychi­atric pharmacogenetics, especially in pediatric populations. As we see increased utilization of pharmacogenetic tests in psychiatry, there is also a need for pharmaco­genetic education of patients, families, nurses, pharmacists, and psychiatrists. Several good pharmacogenetic resources that contain up-to-date summaries of the available evidence linking pharmacogenetic variants to medication response, implementation resources, and educational resources are available. These include CPIC (www.cpicpgx.org), PharmGKB (www.pharmgkb.org), and the IGNITE Spark Toolbox (https://ignite-genomics.org/spark-toolbox/clinicians/).

Acknowledgements

The author thanks Jen Milau, APRN, for the case study and sample explanation, and Jeffrey Strawn, MD, FAACP, Ethan Poweleit, and Stacey Aldrich, MS, for help with preparing this manuscript.

The term “dual diagnosis” describes the clinically challenging comorbidity of a substance use disorder (SUD) along with another major mental illness. Based on data from the Epidemiologic Catchment Area study, the lifetime prevalence of SUDs among patients with mental illness is approximately 30%, and is higher among patients with certain mental disorders, such as schizophrenia (47%), bipolar disorder (61%), and antisocial personality disorder (84%).¹ These statistics highlight that addiction is often the rule rather than the exception among those with severe mental illness.¹ Not surprisingly, the combined effects of having an SUD along with another mental illness are uniformly negative (Table 1^2-4).

Based on outcomes research, the core tenets of evidence-based dual-diagnosis treatment include the importance of integrated (rather than parallel) and simultaneous (rather than sequential) care, which means an ideal treatment program includes a unified, multidisciplinary team whose coordinated efforts focus on treating both disorders concurrently.² Evidence-based psychotherapies for addiction, including motivational interviewing, cognitive-behavioral therapy, relapse prevention, contingency management, skills training, and/or case management, are a necessity,^3,5 and must be balanced with rational and appropriate pharmacotherapy targeting both the SUD as well as the other disorder (Table 2^2,3,5-9).

3 ‘Real-world’ clinical challenges

Ideal vs real-world treatment

Treating patients with co-occurring disorders (CODs) within integrated dual-disorder treatment (IDDT) programs sounds straightforward. However, implementing evidence-based “best practice” treatment is a significant challenge in the real world for several reasons. First, individuals with CODs often struggle with poor insight, low motivation to change, and lack of access to health care. According to the Substance Abuse and Mental Health Services Administration (SAMHSA), 52% of individuals with CODs in the U.S. received no treatment at all in 2016.¹⁰ For patients with dual disorders who do seek care, most are not given access to specialty SUD treatment¹⁰ and may instead find themselves treated by psychiatrists with limited SUD training who fail to provide evidence-based psychotherapies and underutilize pharmacotherapies for SUDs.¹¹ In the setting of CODs, the “harm reduction model” can be conflated with therapeutic nihilism, resulting in the neglect of SUD issues, with clinicians expecting patients to seek SUD treatment on their own, through self-help groups such as Alcoholics Anonymous or in other community treatment programs staffed by nonprofessionals that often are not tailored to the unique needs of patients with dual disorders. Psychiatrists working with other mental health professionals who provide psychotherapy for SUDs often do so in parallel rather than in an evidence-based, integrated fashion.

IDDT programs are not widely available. One study found that fewer than 20% of addiction treatment programs and fewer than 10% of mental health programs in the U.S. met criteria for dual diagnosis–capable services.¹² Getting treatment programs to become dual diagnosis–capable is possible, but it is a time-consuming and costly endeavor that, once achieved, requires continuous staff training and programmatic adaptations to interruptions in funding.^13-16 With myriad barriers to the establishment and maintenance of IDDTs, many patients with dual disorders are left without access to the most effective and comprehensive care; as few as 4% of individuals with CODs are treated within integrated programs.¹⁷

Diagnostic dilemmas

Establishing whether or not a patient with an active SUD has another serious mental illness (SMI) is a crucial first step for optimizing treatment, but diagnostic reliability can prove challenging and requires careful clinical assessment (Table 3). As always in psychiatry, accurate diagnosis is limited to careful clinical assessment¹⁸ and, in the case of possible dual disorders, is complicated by the fact that both SUDs as well as non-SUDs can result in the same psychiatric symptoms (eg, insomnia, anxiety, depression, manic behaviors, and psychosis). Clinicians must therefore distinguish between:

• Symptoms of substance intoxication or withdrawal vs independent symptoms of an underlying psychiatric disorder (that persist beyond a month after cessation of intoxication or withdrawal)
• Subclinical symptoms vs threshold mental illness, keeping in mind that some mood and anxiety states can be normal given social situations and stressors (eg, turmoil in relationships, employment difficulties, homelessness, etc.)
• Any mental illness (AMI) vs SMI. The latter is defined by SAMHSA as AMI that substantially interferes with or limits ≥1 major life activities.¹⁰

With these distinctions in mind, data from the 2016 National Survey on Drug Use and Health indicate that dual-diagnosis comorbidity was higher when the thres­hold for mental illness was lower—among the 19 million adults in the U.S. with SUDs, the past-year prevalence was 43% for AMI and 14% for SMI.¹⁰ Looking at substance-induced disorders vs “independent” disorders, the 2001-2002 National Epidemiologic Survey on Alcohol and Related Conditions found that for individuals with SUDs, the past-year prevalence of an independent mood or anxiety disorder was 35% and 26%, respectively.¹⁹ Taken together, these findings illustrate the substantial rate of dual-diagnosis comorbidity, the diagnostic heterogeneity and range of severity of CODs,²⁰ and the potential for both false negatives (eg, diagnosing a substance-induced syndrome when in fact a patient has an underlying disorder) and false positives (diagnosing a full-blown mental illness when symptoms are subclinical or substance-induced) when performing diagnostic assessments in the setting of known SUDs.

Continue to: False positives are more likely...

False positives are more likely when patients seeking treatment for non-SUDs don’t disclose active drug use, even when asked. Both patients and their treating clinicians may also be prone to underestimating the significant potential for morbidity associated with SUDs, such that substance-induced symptoms may be misattributed to a dual disorder. Diagnostic questioning and thorough chart review that includes careful assessment of whether psychiatric symptoms preceded the onset of substance use, and whether they persisted in the setting of extended sobriety, is therefore paramount for minimizing false positives when assessing for dual diagnoses.^18,21 Likewise, random urine toxicology testing can be invaluable in verifying claims regarding sobriety.

Another factor that can complicate diagnosis is that there are often considerable secondary gains (eg, disability income, hospitalization, housing, access to prescription medications, and mitigation of the blame and stigma associated with addiction) associated with having a dual disorder as opposed to having “just” a SUD. As a result, for some patients, obtaining a non-SUD diagnosis can be highly incentivized.^22,23 Clinicians must therefore be savvy about the high potential for malingering, embellishment, and mislabeling of symptoms when conducting diagnostic interviews. For example, in assessing for psychosis, the frequent endorsement of “hearing voices” in patients with SUDs often results in a diagnosis of schizophrenia or unspecified psychotic disorder,²² despite the fact that this symptom can occur during substance intoxication and withdrawal, is well documented among people without mental illness as well as those with non-psychotic disorders,²⁴ and can resolve without medications or with non-antipsychotic pharmacotherapy.²⁵

When assessing for dual disorders, diagnostic false positives and false negatives can both contribute to inappropriate treatment and unrealistic expectations for recovery, and therefore underscore the importance of careful diagnostic assessment. Even with diligent assessment, however, diagnostic clarity can prove elusive due to inadequate sobriety, inconsistent reporting, and poor memory.²⁶ Therefore, for patients with known SUDs but diagnostic uncertainty about a dual disorder, the work-up should include a trial of prospective observation, with completion of appropriate detoxification, throughout a 1-month period of sobriety and in the absence of psychiatric medications, to determine if there are persistent symptoms that would justify a dual diagnosis. In research settings, such observations have revealed that most of depressive symptoms among alcoholics who present for substance abuse treatment resolve after a month of abstinence.²⁷ A similar time course for resolution has been noted for anxiety, distress, fatigue, and depressive symptoms among individuals with cocaine dependence.²⁸ These findings support the guideline established in DSM-IV that symptoms persisting beyond a month of sobriety “should be considered to be manifestations of an independent, non-substance-induced mental disorder,”²⁹ while symptoms occurring within that month may well be substance-induced. Unfortunately, in real-world clinical practice, and particularly in outpatient settings, it can be quite difficult to achieve the requisite period of sobriety for reliable diagnosis, and patients are often prematurely prescribed medications (eg, an antidepressant, antipsychotic, or mood stabilizer) that can confound the cause of symptomatic resolution. Such prescriptions are driven by compelling pressures from patients to relieve their acute suffering, as well as the predilection of some clinicians to give patients “the benefit of doubt” in assessing for dual diagnoses. However, whether an inappropriate diagnosis or a prescription for an unnecessary medication represents a benefit is debatable at best.

Pharmacotherapy

A third real-world challenge in managing patients with dual disorders involves optimizing pharmacotherapy. Unfortunately, because patients with SUDs often are excluded from clinical trials, evidence-based guidance for patients with dual disorders is lacking. In addition, medications for both CODs often remain inaccessible to patients with dual disorders for 3 reasons:

• SUDs negatively impact medication adherence among patients with dual disorders, who sometimes point out that “it says right here on the bottle not to take this medication with drugs or alcohol!”
• Some self-help groups still espouse blanket opposition of any “psychotropic” medications, even when clearly indicated for patients with COD. Groups that recognize the importance of pharmacotherapy, such as Dual Diagnosis Anonymous (DDA), have emerged, but are not yet widely available.³⁰
• Although there are increasing options for FDA-approved medications for SUDs, they are limited to the treatment of alcohol, opioid, and nicotine use disorders³¹; are often restricted due to hospital and health insurance formularies³²; and remain underprescribed for patients with dual disorders.¹¹

Continue to: Although underutilization of pharmacotherapy is...

Although underutilization of pharmacotherapy is a pitfall to be avoided in the treatment of patients with dual disorders, medication overutilization can be just as problematic. Patients with dual disorders are sometimes singularly focused on resolving acute anxiety, depression, or psychosis at the expense of working towards sobriety.³³ Although the “self-medication hypothesis” is frequently invoked by patients and clinicians alike to suggest that substance use occurs in the service of “treating” underlying disorders,³⁴ this theory has not been well supported in studies.^35-37 Some patients may pledge dedication to abstinence, but still pressure physicians for a pharmacologic solution to their suffering. With expanding legalization of cannabis for both recreational and medical purposes, patients are increasingly seeking doctors’ recommendations for “medical marijuana” for a wide range of complaints, despite the fact that data supporting a therapeutic role for cannabis in the treatment of mental illness is sparse,³⁸ whereas the potential harm in terms of either causing or worsening psychosis is well established.^39,40 Clinicians must be knowledgeable about the abuse potential of prescribed medications, ranging from sleep aids, analgesics, and muscle relaxants to antidepressants and antipsychotics, while also being mindful of the psychological meaningfulness of seeking, prescribing, and not prescribing medications.⁴¹

Although the simultaneous treatment of patients with dual disorders that includes pharmacotherapy for both SUDs and CODs is vital for optimizing clinical outcomes, clinicians should strive for diagnostic accuracy and use medications judiciously. In addition, although pharmacotherapy often is necessary to deliver evidence-based treatment for patients with dual disorders, it is inadequate as standalone treatment and should be administered along with psychosocial interventions within an integrated, multidisciplinary treatment setting.

The keys to optimal outcomes

The treatment of patients with dual disorders can be challenging, to say the least. Ideal, evidence-based therapy in the form of an IDDT program can be difficult for clinicians to implement and for patients to access. Best efforts to perform meticulous clinical assessment to clarify diagnoses, use pharmacotherapy judiciously, work collaboratively in a multidisciplinary setting, and optimize treatment given available resources are keys to clinical success.

Bottom Line

Ideal treatment of patients with dual disorders consists of simultaneous, integrated interventions delivered by a multidisciplinary team. However, in the real world, limited resources, diagnostic challenges, and both over- and underutilization of pharmacotherapy often hamper optimal treatment.

Related Resources

• Substance Abuse and Mental Health Services Administration. Co-occurring disorders. https://www.samhsa.gov/disorders/co-occurring.
• National Alliance on Mental Illness. Dual diagnosis. https://www.nami.org/Learn-More/Mental-Health-Conditions/Related-Conditions/Dual-Diagnosis.
• Foundations Recovery Network. Dual diagnosis support groups. http://www.dualdiagnosis.org/resource/ddrn/self-helpsupport-groups/support-groups.
• Substance Abuse and Mental Health Services Administration. Integrated treatment for co-occurring disorders evidence-based practices (EBP) KIT. https://store.samhsa.gov/product/Integrated-Treatment-for-Co-Occurring-Disorders-Evidence-Based-Practices-EBP-KIT/SMA08-4367.
• Substance Abuse and Mental Health Services Administration. Substance abuse treatment for persons with co-occurring disorders. https://store.samhsa.gov/shin/content/SMA13-3992/SMA13-3992.pdf.

The term “dual diagnosis” describes the clinically challenging comorbidity of a substance use disorder (SUD) along with another major mental illness. Based on data from the Epidemiologic Catchment Area study, the lifetime prevalence of SUDs among patients with mental illness is approximately 30%, and is higher among patients with certain mental disorders, such as schizophrenia (47%), bipolar disorder (61%), and antisocial personality disorder (84%).¹ These statistics highlight that addiction is often the rule rather than the exception among those with severe mental illness.¹ Not surprisingly, the combined effects of having an SUD along with another mental illness are uniformly negative (Table 1^2-4).

Based on outcomes research, the core tenets of evidence-based dual-diagnosis treatment include the importance of integrated (rather than parallel) and simultaneous (rather than sequential) care, which means an ideal treatment program includes a unified, multidisciplinary team whose coordinated efforts focus on treating both disorders concurrently.² Evidence-based psychotherapies for addiction, including motivational interviewing, cognitive-behavioral therapy, relapse prevention, contingency management, skills training, and/or case management, are a necessity,^3,5 and must be balanced with rational and appropriate pharmacotherapy targeting both the SUD as well as the other disorder (Table 2^2,3,5-9).

3 ‘Real-world’ clinical challenges

Ideal vs real-world treatment

Treating patients with co-occurring disorders (CODs) within integrated dual-disorder treatment (IDDT) programs sounds straightforward. However, implementing evidence-based “best practice” treatment is a significant challenge in the real world for several reasons. First, individuals with CODs often struggle with poor insight, low motivation to change, and lack of access to health care. According to the Substance Abuse and Mental Health Services Administration (SAMHSA), 52% of individuals with CODs in the U.S. received no treatment at all in 2016.¹⁰ For patients with dual disorders who do seek care, most are not given access to specialty SUD treatment¹⁰ and may instead find themselves treated by psychiatrists with limited SUD training who fail to provide evidence-based psychotherapies and underutilize pharmacotherapies for SUDs.¹¹ In the setting of CODs, the “harm reduction model” can be conflated with therapeutic nihilism, resulting in the neglect of SUD issues, with clinicians expecting patients to seek SUD treatment on their own, through self-help groups such as Alcoholics Anonymous or in other community treatment programs staffed by nonprofessionals that often are not tailored to the unique needs of patients with dual disorders. Psychiatrists working with other mental health professionals who provide psychotherapy for SUDs often do so in parallel rather than in an evidence-based, integrated fashion.

IDDT programs are not widely available. One study found that fewer than 20% of addiction treatment programs and fewer than 10% of mental health programs in the U.S. met criteria for dual diagnosis–capable services.¹² Getting treatment programs to become dual diagnosis–capable is possible, but it is a time-consuming and costly endeavor that, once achieved, requires continuous staff training and programmatic adaptations to interruptions in funding.^13-16 With myriad barriers to the establishment and maintenance of IDDTs, many patients with dual disorders are left without access to the most effective and comprehensive care; as few as 4% of individuals with CODs are treated within integrated programs.¹⁷

Diagnostic dilemmas

Establishing whether or not a patient with an active SUD has another serious mental illness (SMI) is a crucial first step for optimizing treatment, but diagnostic reliability can prove challenging and requires careful clinical assessment (Table 3). As always in psychiatry, accurate diagnosis is limited to careful clinical assessment¹⁸ and, in the case of possible dual disorders, is complicated by the fact that both SUDs as well as non-SUDs can result in the same psychiatric symptoms (eg, insomnia, anxiety, depression, manic behaviors, and psychosis). Clinicians must therefore distinguish between:

• Symptoms of substance intoxication or withdrawal vs independent symptoms of an underlying psychiatric disorder (that persist beyond a month after cessation of intoxication or withdrawal)
• Subclinical symptoms vs threshold mental illness, keeping in mind that some mood and anxiety states can be normal given social situations and stressors (eg, turmoil in relationships, employment difficulties, homelessness, etc.)
• Any mental illness (AMI) vs SMI. The latter is defined by SAMHSA as AMI that substantially interferes with or limits ≥1 major life activities.¹⁰

With these distinctions in mind, data from the 2016 National Survey on Drug Use and Health indicate that dual-diagnosis comorbidity was higher when the thres­hold for mental illness was lower—among the 19 million adults in the U.S. with SUDs, the past-year prevalence was 43% for AMI and 14% for SMI.¹⁰ Looking at substance-induced disorders vs “independent” disorders, the 2001-2002 National Epidemiologic Survey on Alcohol and Related Conditions found that for individuals with SUDs, the past-year prevalence of an independent mood or anxiety disorder was 35% and 26%, respectively.¹⁹ Taken together, these findings illustrate the substantial rate of dual-diagnosis comorbidity, the diagnostic heterogeneity and range of severity of CODs,²⁰ and the potential for both false negatives (eg, diagnosing a substance-induced syndrome when in fact a patient has an underlying disorder) and false positives (diagnosing a full-blown mental illness when symptoms are subclinical or substance-induced) when performing diagnostic assessments in the setting of known SUDs.

Continue to: False positives are more likely...

False positives are more likely when patients seeking treatment for non-SUDs don’t disclose active drug use, even when asked. Both patients and their treating clinicians may also be prone to underestimating the significant potential for morbidity associated with SUDs, such that substance-induced symptoms may be misattributed to a dual disorder. Diagnostic questioning and thorough chart review that includes careful assessment of whether psychiatric symptoms preceded the onset of substance use, and whether they persisted in the setting of extended sobriety, is therefore paramount for minimizing false positives when assessing for dual diagnoses.^18,21 Likewise, random urine toxicology testing can be invaluable in verifying claims regarding sobriety.

Another factor that can complicate diagnosis is that there are often considerable secondary gains (eg, disability income, hospitalization, housing, access to prescription medications, and mitigation of the blame and stigma associated with addiction) associated with having a dual disorder as opposed to having “just” a SUD. As a result, for some patients, obtaining a non-SUD diagnosis can be highly incentivized.^22,23 Clinicians must therefore be savvy about the high potential for malingering, embellishment, and mislabeling of symptoms when conducting diagnostic interviews. For example, in assessing for psychosis, the frequent endorsement of “hearing voices” in patients with SUDs often results in a diagnosis of schizophrenia or unspecified psychotic disorder,²² despite the fact that this symptom can occur during substance intoxication and withdrawal, is well documented among people without mental illness as well as those with non-psychotic disorders,²⁴ and can resolve without medications or with non-antipsychotic pharmacotherapy.²⁵

When assessing for dual disorders, diagnostic false positives and false negatives can both contribute to inappropriate treatment and unrealistic expectations for recovery, and therefore underscore the importance of careful diagnostic assessment. Even with diligent assessment, however, diagnostic clarity can prove elusive due to inadequate sobriety, inconsistent reporting, and poor memory.²⁶ Therefore, for patients with known SUDs but diagnostic uncertainty about a dual disorder, the work-up should include a trial of prospective observation, with completion of appropriate detoxification, throughout a 1-month period of sobriety and in the absence of psychiatric medications, to determine if there are persistent symptoms that would justify a dual diagnosis. In research settings, such observations have revealed that most of depressive symptoms among alcoholics who present for substance abuse treatment resolve after a month of abstinence.²⁷ A similar time course for resolution has been noted for anxiety, distress, fatigue, and depressive symptoms among individuals with cocaine dependence.²⁸ These findings support the guideline established in DSM-IV that symptoms persisting beyond a month of sobriety “should be considered to be manifestations of an independent, non-substance-induced mental disorder,”²⁹ while symptoms occurring within that month may well be substance-induced. Unfortunately, in real-world clinical practice, and particularly in outpatient settings, it can be quite difficult to achieve the requisite period of sobriety for reliable diagnosis, and patients are often prematurely prescribed medications (eg, an antidepressant, antipsychotic, or mood stabilizer) that can confound the cause of symptomatic resolution. Such prescriptions are driven by compelling pressures from patients to relieve their acute suffering, as well as the predilection of some clinicians to give patients “the benefit of doubt” in assessing for dual diagnoses. However, whether an inappropriate diagnosis or a prescription for an unnecessary medication represents a benefit is debatable at best.

Pharmacotherapy

A third real-world challenge in managing patients with dual disorders involves optimizing pharmacotherapy. Unfortunately, because patients with SUDs often are excluded from clinical trials, evidence-based guidance for patients with dual disorders is lacking. In addition, medications for both CODs often remain inaccessible to patients with dual disorders for 3 reasons:

• SUDs negatively impact medication adherence among patients with dual disorders, who sometimes point out that “it says right here on the bottle not to take this medication with drugs or alcohol!”
• Some self-help groups still espouse blanket opposition of any “psychotropic” medications, even when clearly indicated for patients with COD. Groups that recognize the importance of pharmacotherapy, such as Dual Diagnosis Anonymous (DDA), have emerged, but are not yet widely available.³⁰
• Although there are increasing options for FDA-approved medications for SUDs, they are limited to the treatment of alcohol, opioid, and nicotine use disorders³¹; are often restricted due to hospital and health insurance formularies³²; and remain underprescribed for patients with dual disorders.¹¹

Continue to: Although underutilization of pharmacotherapy is...

Although underutilization of pharmacotherapy is a pitfall to be avoided in the treatment of patients with dual disorders, medication overutilization can be just as problematic. Patients with dual disorders are sometimes singularly focused on resolving acute anxiety, depression, or psychosis at the expense of working towards sobriety.³³ Although the “self-medication hypothesis” is frequently invoked by patients and clinicians alike to suggest that substance use occurs in the service of “treating” underlying disorders,³⁴ this theory has not been well supported in studies.^35-37 Some patients may pledge dedication to abstinence, but still pressure physicians for a pharmacologic solution to their suffering. With expanding legalization of cannabis for both recreational and medical purposes, patients are increasingly seeking doctors’ recommendations for “medical marijuana” for a wide range of complaints, despite the fact that data supporting a therapeutic role for cannabis in the treatment of mental illness is sparse,³⁸ whereas the potential harm in terms of either causing or worsening psychosis is well established.^39,40 Clinicians must be knowledgeable about the abuse potential of prescribed medications, ranging from sleep aids, analgesics, and muscle relaxants to antidepressants and antipsychotics, while also being mindful of the psychological meaningfulness of seeking, prescribing, and not prescribing medications.⁴¹

Although the simultaneous treatment of patients with dual disorders that includes pharmacotherapy for both SUDs and CODs is vital for optimizing clinical outcomes, clinicians should strive for diagnostic accuracy and use medications judiciously. In addition, although pharmacotherapy often is necessary to deliver evidence-based treatment for patients with dual disorders, it is inadequate as standalone treatment and should be administered along with psychosocial interventions within an integrated, multidisciplinary treatment setting.

The keys to optimal outcomes

The treatment of patients with dual disorders can be challenging, to say the least. Ideal, evidence-based therapy in the form of an IDDT program can be difficult for clinicians to implement and for patients to access. Best efforts to perform meticulous clinical assessment to clarify diagnoses, use pharmacotherapy judiciously, work collaboratively in a multidisciplinary setting, and optimize treatment given available resources are keys to clinical success.

Bottom Line

Ideal treatment of patients with dual disorders consists of simultaneous, integrated interventions delivered by a multidisciplinary team. However, in the real world, limited resources, diagnostic challenges, and both over- and underutilization of pharmacotherapy often hamper optimal treatment.

Related Resources

• Substance Abuse and Mental Health Services Administration. Co-occurring disorders. https://www.samhsa.gov/disorders/co-occurring.
• National Alliance on Mental Illness. Dual diagnosis. https://www.nami.org/Learn-More/Mental-Health-Conditions/Related-Conditions/Dual-Diagnosis.
• Foundations Recovery Network. Dual diagnosis support groups. http://www.dualdiagnosis.org/resource/ddrn/self-helpsupport-groups/support-groups.
• Substance Abuse and Mental Health Services Administration. Integrated treatment for co-occurring disorders evidence-based practices (EBP) KIT. https://store.samhsa.gov/product/Integrated-Treatment-for-Co-Occurring-Disorders-Evidence-Based-Practices-EBP-KIT/SMA08-4367.
• Substance Abuse and Mental Health Services Administration. Substance abuse treatment for persons with co-occurring disorders. https://store.samhsa.gov/shin/content/SMA13-3992/SMA13-3992.pdf.

The term “dual diagnosis” describes the clinically challenging comorbidity of a substance use disorder (SUD) along with another major mental illness. Based on data from the Epidemiologic Catchment Area study, the lifetime prevalence of SUDs among patients with mental illness is approximately 30%, and is higher among patients with certain mental disorders, such as schizophrenia (47%), bipolar disorder (61%), and antisocial personality disorder (84%).¹ These statistics highlight that addiction is often the rule rather than the exception among those with severe mental illness.¹ Not surprisingly, the combined effects of having an SUD along with another mental illness are uniformly negative (Table 1^2-4).

Based on outcomes research, the core tenets of evidence-based dual-diagnosis treatment include the importance of integrated (rather than parallel) and simultaneous (rather than sequential) care, which means an ideal treatment program includes a unified, multidisciplinary team whose coordinated efforts focus on treating both disorders concurrently.² Evidence-based psychotherapies for addiction, including motivational interviewing, cognitive-behavioral therapy, relapse prevention, contingency management, skills training, and/or case management, are a necessity,^3,5 and must be balanced with rational and appropriate pharmacotherapy targeting both the SUD as well as the other disorder (Table 2^2,3,5-9).

3 ‘Real-world’ clinical challenges

Ideal vs real-world treatment

Treating patients with co-occurring disorders (CODs) within integrated dual-disorder treatment (IDDT) programs sounds straightforward. However, implementing evidence-based “best practice” treatment is a significant challenge in the real world for several reasons. First, individuals with CODs often struggle with poor insight, low motivation to change, and lack of access to health care. According to the Substance Abuse and Mental Health Services Administration (SAMHSA), 52% of individuals with CODs in the U.S. received no treatment at all in 2016.¹⁰ For patients with dual disorders who do seek care, most are not given access to specialty SUD treatment¹⁰ and may instead find themselves treated by psychiatrists with limited SUD training who fail to provide evidence-based psychotherapies and underutilize pharmacotherapies for SUDs.¹¹ In the setting of CODs, the “harm reduction model” can be conflated with therapeutic nihilism, resulting in the neglect of SUD issues, with clinicians expecting patients to seek SUD treatment on their own, through self-help groups such as Alcoholics Anonymous or in other community treatment programs staffed by nonprofessionals that often are not tailored to the unique needs of patients with dual disorders. Psychiatrists working with other mental health professionals who provide psychotherapy for SUDs often do so in parallel rather than in an evidence-based, integrated fashion.

IDDT programs are not widely available. One study found that fewer than 20% of addiction treatment programs and fewer than 10% of mental health programs in the U.S. met criteria for dual diagnosis–capable services.¹² Getting treatment programs to become dual diagnosis–capable is possible, but it is a time-consuming and costly endeavor that, once achieved, requires continuous staff training and programmatic adaptations to interruptions in funding.^13-16 With myriad barriers to the establishment and maintenance of IDDTs, many patients with dual disorders are left without access to the most effective and comprehensive care; as few as 4% of individuals with CODs are treated within integrated programs.¹⁷

Diagnostic dilemmas

Establishing whether or not a patient with an active SUD has another serious mental illness (SMI) is a crucial first step for optimizing treatment, but diagnostic reliability can prove challenging and requires careful clinical assessment (Table 3). As always in psychiatry, accurate diagnosis is limited to careful clinical assessment¹⁸ and, in the case of possible dual disorders, is complicated by the fact that both SUDs as well as non-SUDs can result in the same psychiatric symptoms (eg, insomnia, anxiety, depression, manic behaviors, and psychosis). Clinicians must therefore distinguish between:

• Symptoms of substance intoxication or withdrawal vs independent symptoms of an underlying psychiatric disorder (that persist beyond a month after cessation of intoxication or withdrawal)
• Subclinical symptoms vs threshold mental illness, keeping in mind that some mood and anxiety states can be normal given social situations and stressors (eg, turmoil in relationships, employment difficulties, homelessness, etc.)
• Any mental illness (AMI) vs SMI. The latter is defined by SAMHSA as AMI that substantially interferes with or limits ≥1 major life activities.¹⁰

With these distinctions in mind, data from the 2016 National Survey on Drug Use and Health indicate that dual-diagnosis comorbidity was higher when the thres­hold for mental illness was lower—among the 19 million adults in the U.S. with SUDs, the past-year prevalence was 43% for AMI and 14% for SMI.¹⁰ Looking at substance-induced disorders vs “independent” disorders, the 2001-2002 National Epidemiologic Survey on Alcohol and Related Conditions found that for individuals with SUDs, the past-year prevalence of an independent mood or anxiety disorder was 35% and 26%, respectively.¹⁹ Taken together, these findings illustrate the substantial rate of dual-diagnosis comorbidity, the diagnostic heterogeneity and range of severity of CODs,²⁰ and the potential for both false negatives (eg, diagnosing a substance-induced syndrome when in fact a patient has an underlying disorder) and false positives (diagnosing a full-blown mental illness when symptoms are subclinical or substance-induced) when performing diagnostic assessments in the setting of known SUDs.

Continue to: False positives are more likely...

False positives are more likely when patients seeking treatment for non-SUDs don’t disclose active drug use, even when asked. Both patients and their treating clinicians may also be prone to underestimating the significant potential for morbidity associated with SUDs, such that substance-induced symptoms may be misattributed to a dual disorder. Diagnostic questioning and thorough chart review that includes careful assessment of whether psychiatric symptoms preceded the onset of substance use, and whether they persisted in the setting of extended sobriety, is therefore paramount for minimizing false positives when assessing for dual diagnoses.^18,21 Likewise, random urine toxicology testing can be invaluable in verifying claims regarding sobriety.

Another factor that can complicate diagnosis is that there are often considerable secondary gains (eg, disability income, hospitalization, housing, access to prescription medications, and mitigation of the blame and stigma associated with addiction) associated with having a dual disorder as opposed to having “just” a SUD. As a result, for some patients, obtaining a non-SUD diagnosis can be highly incentivized.^22,23 Clinicians must therefore be savvy about the high potential for malingering, embellishment, and mislabeling of symptoms when conducting diagnostic interviews. For example, in assessing for psychosis, the frequent endorsement of “hearing voices” in patients with SUDs often results in a diagnosis of schizophrenia or unspecified psychotic disorder,²² despite the fact that this symptom can occur during substance intoxication and withdrawal, is well documented among people without mental illness as well as those with non-psychotic disorders,²⁴ and can resolve without medications or with non-antipsychotic pharmacotherapy.²⁵

When assessing for dual disorders, diagnostic false positives and false negatives can both contribute to inappropriate treatment and unrealistic expectations for recovery, and therefore underscore the importance of careful diagnostic assessment. Even with diligent assessment, however, diagnostic clarity can prove elusive due to inadequate sobriety, inconsistent reporting, and poor memory.²⁶ Therefore, for patients with known SUDs but diagnostic uncertainty about a dual disorder, the work-up should include a trial of prospective observation, with completion of appropriate detoxification, throughout a 1-month period of sobriety and in the absence of psychiatric medications, to determine if there are persistent symptoms that would justify a dual diagnosis. In research settings, such observations have revealed that most of depressive symptoms among alcoholics who present for substance abuse treatment resolve after a month of abstinence.²⁷ A similar time course for resolution has been noted for anxiety, distress, fatigue, and depressive symptoms among individuals with cocaine dependence.²⁸ These findings support the guideline established in DSM-IV that symptoms persisting beyond a month of sobriety “should be considered to be manifestations of an independent, non-substance-induced mental disorder,”²⁹ while symptoms occurring within that month may well be substance-induced. Unfortunately, in real-world clinical practice, and particularly in outpatient settings, it can be quite difficult to achieve the requisite period of sobriety for reliable diagnosis, and patients are often prematurely prescribed medications (eg, an antidepressant, antipsychotic, or mood stabilizer) that can confound the cause of symptomatic resolution. Such prescriptions are driven by compelling pressures from patients to relieve their acute suffering, as well as the predilection of some clinicians to give patients “the benefit of doubt” in assessing for dual diagnoses. However, whether an inappropriate diagnosis or a prescription for an unnecessary medication represents a benefit is debatable at best.

Pharmacotherapy

A third real-world challenge in managing patients with dual disorders involves optimizing pharmacotherapy. Unfortunately, because patients with SUDs often are excluded from clinical trials, evidence-based guidance for patients with dual disorders is lacking. In addition, medications for both CODs often remain inaccessible to patients with dual disorders for 3 reasons:

• SUDs negatively impact medication adherence among patients with dual disorders, who sometimes point out that “it says right here on the bottle not to take this medication with drugs or alcohol!”
• Some self-help groups still espouse blanket opposition of any “psychotropic” medications, even when clearly indicated for patients with COD. Groups that recognize the importance of pharmacotherapy, such as Dual Diagnosis Anonymous (DDA), have emerged, but are not yet widely available.³⁰
• Although there are increasing options for FDA-approved medications for SUDs, they are limited to the treatment of alcohol, opioid, and nicotine use disorders³¹; are often restricted due to hospital and health insurance formularies³²; and remain underprescribed for patients with dual disorders.¹¹

Continue to: Although underutilization of pharmacotherapy is...

Although underutilization of pharmacotherapy is a pitfall to be avoided in the treatment of patients with dual disorders, medication overutilization can be just as problematic. Patients with dual disorders are sometimes singularly focused on resolving acute anxiety, depression, or psychosis at the expense of working towards sobriety.³³ Although the “self-medication hypothesis” is frequently invoked by patients and clinicians alike to suggest that substance use occurs in the service of “treating” underlying disorders,³⁴ this theory has not been well supported in studies.^35-37 Some patients may pledge dedication to abstinence, but still pressure physicians for a pharmacologic solution to their suffering. With expanding legalization of cannabis for both recreational and medical purposes, patients are increasingly seeking doctors’ recommendations for “medical marijuana” for a wide range of complaints, despite the fact that data supporting a therapeutic role for cannabis in the treatment of mental illness is sparse,³⁸ whereas the potential harm in terms of either causing or worsening psychosis is well established.^39,40 Clinicians must be knowledgeable about the abuse potential of prescribed medications, ranging from sleep aids, analgesics, and muscle relaxants to antidepressants and antipsychotics, while also being mindful of the psychological meaningfulness of seeking, prescribing, and not prescribing medications.⁴¹

Although the simultaneous treatment of patients with dual disorders that includes pharmacotherapy for both SUDs and CODs is vital for optimizing clinical outcomes, clinicians should strive for diagnostic accuracy and use medications judiciously. In addition, although pharmacotherapy often is necessary to deliver evidence-based treatment for patients with dual disorders, it is inadequate as standalone treatment and should be administered along with psychosocial interventions within an integrated, multidisciplinary treatment setting.

The keys to optimal outcomes

The treatment of patients with dual disorders can be challenging, to say the least. Ideal, evidence-based therapy in the form of an IDDT program can be difficult for clinicians to implement and for patients to access. Best efforts to perform meticulous clinical assessment to clarify diagnoses, use pharmacotherapy judiciously, work collaboratively in a multidisciplinary setting, and optimize treatment given available resources are keys to clinical success.

Bottom Line

Ideal treatment of patients with dual disorders consists of simultaneous, integrated interventions delivered by a multidisciplinary team. However, in the real world, limited resources, diagnostic challenges, and both over- and underutilization of pharmacotherapy often hamper optimal treatment.

Related Resources

• Substance Abuse and Mental Health Services Administration. Co-occurring disorders. https://www.samhsa.gov/disorders/co-occurring.
• National Alliance on Mental Illness. Dual diagnosis. https://www.nami.org/Learn-More/Mental-Health-Conditions/Related-Conditions/Dual-Diagnosis.
• Foundations Recovery Network. Dual diagnosis support groups. http://www.dualdiagnosis.org/resource/ddrn/self-helpsupport-groups/support-groups.
• Substance Abuse and Mental Health Services Administration. Integrated treatment for co-occurring disorders evidence-based practices (EBP) KIT. https://store.samhsa.gov/product/Integrated-Treatment-for-Co-Occurring-Disorders-Evidence-Based-Practices-EBP-KIT/SMA08-4367.
• Substance Abuse and Mental Health Services Administration. Substance abuse treatment for persons with co-occurring disorders. https://store.samhsa.gov/shin/content/SMA13-3992/SMA13-3992.pdf.

Major depressive disorder (MDD) has a devastating impact on individuals and society because of its high prevalence, its recurrent nature, its frequent comorbidity with other disorders, and the functional impairment it causes. Compared with other chronic diseases, such as arthritis, asthma, and diabetes, MDD produces the greatest decrement in health worldwide.¹ The goals in treating MDD should be not just to reduce symptom severity but also to achieve continuing remission and lower the risk for relapse.²

Antidepressants are the most common treatment for depression.³ Among psychotherapies used to treat MDD, cognitive-behavioral therapy (CBT) has been identified as an effective treatment.⁴ Collaborative care models have been reported to manage MDD more effectively.⁵ In this article, we review the evidence supporting the use of CBT as monotherapy and in combination with antidepressants for acute and long-term treatment of MDD.

Acute treatment: Not too soon for CBT

Mild to moderate depression

Research has indicated that for the treatment of mild MDD, antidepressants are unlikely to be more effective than placebo.^6,7 Studies also have reported that response to anti­depressants begins to outpace response to placebo only when symptoms are no longer mild. Using antidepressants for patients with mild depression could therefore place them at risk of overtreatment.⁸ In keeping with these findings, the American Psychiatric Association (APA) has recommended the use of evidence-based psychotherapies, such as CBT, as an initial treatment choice for patients with mild to moderate MDD.⁹

Two recent studies have suggested that the combination of CBT plus antidepressants could boost improvement in psychosocial functioning for patients with mild MDD.^10,11 However, neither study included a group of patients who received only CBT to evaluate if CBT alone could have also produced similar effects. Other limitations include the lack of a control group in one study and small sample sizes in both studies. However, both studies had a long follow-up period and specifically studied the impact on psychosocial functioning.

Moderate to severe depression

Earlier depression treatment guidelines suggested that antidepressants should be used to treat more severe depression, while psychotherapy should be used mainly for mild depression.¹² This recommendation was influenced by the well-known National Institute of Mental Health (NIMH) Treatment of Depression Collaborative Research Program, a multicenter randomized controlled trial (RCT) that used a placebo control.¹³ In this study, CBT was compared with antidepressants and found to be no more effective than placebo for more severely depressed patients.¹³ However, this finding was not consistent across the 3 sites where the study was conducted; at the site where CBT was provided by more experienced CBT therapists, patients with more severe depression who received CBT fared as well as patients treated with antidepressants.¹⁴ A later double-blind RCT that used experienced therapists found that CBT was as effective as antidepressants (monoamine oxidase inhibitors), and both treatments were superior to placebo in reducing symptoms of atypical depression.¹⁵

Another placebo-controlled RCT conducted at 2 sites found that CBT was as effective as antidepressants in the treatment of moderately to severely depressed patients. As in the NIMH Treatment of Depression Collaborative Research Program trial,¹³ in this study, there were indications that the results were dependent on therapist experience.¹⁶ These findings suggest that the experience of the therapist is an important factor.

A recent meta-analysis of treatments of the acute phase of MDD compared 11 RCTs of CBT and second-generation antidepressants (selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and other medications with related mechanisms of action).¹⁷ It found that as a first-step treatment, CBT and antidepressants had a similar impact on symptom relief in patients with moderate to severe depression. Patients treated with antidepressants also had a higher risk of experiencing adverse events or discontinuing treatment because of adverse events. However, this meta-analysis included trials that had methodological shortcomings, which reduces the strength of these conclusions.

Continue to: Patients with MDD and comorbid personality disorders have been...

Patients with MDD and comorbid personality disorders have been reported to have poorer outcomes, regardless of the treatment used.¹⁸ Fournier et al¹⁹ examined the impact of antidepressants and CBT in moderately to severely depressed patients with and without a personality disorder. They found that a combination of antidepressants and CBT was suitable for patients with personality disorders because antidepressants would boost the initial response and CBT would help sustain improvement in the long term.

Presently, the APA suggests that the combination of psychotherapy and antidepressants may be used as an initial treatment for patients with moderate to severe MDD.⁹ As research brings to light other factors that affect treatment outcomes, these guidelines could change.

Table 1^10,11,15,16 summarizes the findings of select studies evaluating the use of CBT for the acute treatment of depression.

CBT’s role in long-term treatment

Recurrence and relapse are major problems associated with MDD. The large majority of individuals who experience an episode of depression go on to experience more episodes of depression,²⁰ and the risk of recurrence increases after each successive episode.²¹

To reduce the risk of relapse and the return of symptoms, it is recommended that patients treated with antidepressants continue pharmacotherapy for 4 to 9 months after remission.⁹ Maintenance pharmacotherapy, which involves keeping patients on antidepressants beyond the point of recovery, is intended to reduce the risk of recurrence, and is standard treatment for patients with chronic or recurrent MDD.²² However, this preventive effect exists only while the patient continues to take the medication. Rates of symptom recurrence following medication withdrawal are often high regardless of how long patients have taken medications.²³

Continue to: Studies examining CBT as a maintenance treatment...

Studies examining CBT as a maintenance treatment—provided alone or in combination with or sequentially with antidepressants—have found it has an enduring effect that extends beyond the end of treatment and equals the impact of continuing antidepressants.^24-27 A recent meta-analysis of 10 trials where CBT had been provided to patients after acute treatment found that the risk of relapse was reduced by 21% in the first year and by 28% in the first 2 years.²⁸

Studies have compared the prophylactic impact of maintenance CBT and antidepressants. In an early study, 40 patients who had been successfully treated with antidepressants but had residual symptoms were randomly assigned to 20 weeks of CBT or to clinical management.²⁹ By the end of 20 weeks, patients were tapered off their antidepressant. All patients were then followed for 2 years, during which time they received no treatment. At the 2-year follow-up, the CBT group had a relapse rate of 25%, compared with 80% in the antidepressant group.²⁹ Weaknesses of this study include a small sample size, and the fact that a single therapist provided the CBT.

This study was extended to a 6-year follow-up; antidepressants were prescribed only to patients who relapsed. The CBT group continued to have a significantly lower relapse rate (40%) compared with the antidepressant group (90%).³⁰

In another RCT, patients with depression who had recovered with CBT or medication continued with the same treatment during a maintenance phase.²⁶ The CBT group received 3 booster sessions during the next year and antidepressant group received medication. At the end of the second year (without CBT or medication) CBT patients were less likely to relapse compared with patients receiving antidepressants. The adjusted relapse rates were 17.3% for CBT and 53.6% for antidepressants.²⁶

An RCT that included 452 patients with severe depression used a long intervention period (up to 42 weeks) and a flexible treatment algorithm to more closely model the strategies used in clinical practice.³¹ Patients were randomly assigned to antidepressants only or in combination with CBT. At the end of 12 months, outcome assessment by blinded interviewers indicated that patients with more severe depression were more likely to benefit from the combination of antidepressants and CBT (76.9% vs 60.3%) and those with severe, non-chronic depression received the most benefit (79.5% vs 62.8%). The lack of a CBT-only group limits the generalizability of these findings. Neither patients nor clinicians were blinded to the treatment assignment, which is a common limitation in psychotherapy studies but could have contributed to the finding that combined treatment was more effective.

Continue to: Some evidence suggests...

Some evidence suggests that augmenting treatment as usual (TAU) with CBT can have a resilient protective impact that also intensifies with the number of depressive episodes experienced. In an RCT, 172 patients with depression in remission were randomly assigned to TAU or to TAU augmented with CBT.³² The time to recurrence was assessed over the course of 10 years. Augmenting TAU with CBT had a significant protective impact that was greater for patients who had >3 previous episodes.³²

Another long-term study assessed the longitudinal course of 158 patients who received CBT, medication, and clinical management, or medication and clinical management alone.³³ Patients were followed 6 years after randomization (4.5 years after completion of CBT). Researchers found the effects of CBT in preventing relapse and recurrence persisted for several years.³³

Table 2^24,26,29-32 summarizes the findings of select studies evaluating the use of CBT for the long-term treatment of depression.

Limitations of long-term studies

Studies that have examined the efficacy of adding CBT to antidepressants in the continuation and maintenance treatment of patients with MDD have had some limitations. The definitions of relapse and recurrence have not always been clearly delineated in all studies. This is important because recurrence rates tend to be lower, and long-term follow-up would be needed to detect multiple recurrences so that their incidence is not underestimated. In addition, the types of CBT interventions utilized has varied across studies. Some studies have employed standard interventions such as cognitive restructuring, while others have added strategies that focus on enhancing memories for positive experiences or interventions to encourage medication adherence. Despite these limitations, research has shown promising results and suggests that adding CBT to the maintenance treatment of patients with depression—with or without antidepressants—is likely to reduce the rate of relapse and recurrence.

Consider CBT for all depressed patients

Research indicates that CBT can be the preferred treatment for patients with mild to moderate MDD. Antidepressants significantly reduce depressive symptoms in patients with moderate to severe MDD. Some research suggests that CBT can be as effective as antidepressants for moderate and severe MDD. However, as the severity and chronicity of depression increase, other moderating factors need to be considered. The expertise of the CBT therapist has an impact on outcomes. Treatment protocols that utilize CBT plus antidepressants are likely to be more effective than CBT or antidepressants alone. Incorporating CBT in the acute phase of depression treatment, with or without antidepressants, can have a long-term impact. For maintenance treatment, CBT alone and CBT plus antidepressants have been found to help sustain remission.

Continue to: Bottom Line

Cognitive-behavioral therapy (CBT) can be an effective treatment for patients with major depressive disorder, regardless of symptom severity. The expertise of the clinician who provides CBT has a substantial impact on outcomes. Combination treatment with CBT plus antidepressants is more likely to be effective than either treatment alone.

Related Resources

• Flynn HA, Warren R. Using CBT effectively for treating depression and anxiety. Current Psychiatry. 2014;13(6):45-53.
• Ijaz S, Davies P, Williams CJ, et al. Psychological therapies for treatment-resistant depression in adults. Cochrane Database Syst Rev. 2018;5:CD010558.

Major depressive disorder (MDD) has a devastating impact on individuals and society because of its high prevalence, its recurrent nature, its frequent comorbidity with other disorders, and the functional impairment it causes. Compared with other chronic diseases, such as arthritis, asthma, and diabetes, MDD produces the greatest decrement in health worldwide.¹ The goals in treating MDD should be not just to reduce symptom severity but also to achieve continuing remission and lower the risk for relapse.²

Antidepressants are the most common treatment for depression.³ Among psychotherapies used to treat MDD, cognitive-behavioral therapy (CBT) has been identified as an effective treatment.⁴ Collaborative care models have been reported to manage MDD more effectively.⁵ In this article, we review the evidence supporting the use of CBT as monotherapy and in combination with antidepressants for acute and long-term treatment of MDD.

Acute treatment: Not too soon for CBT

Mild to moderate depression

Research has indicated that for the treatment of mild MDD, antidepressants are unlikely to be more effective than placebo.^6,7 Studies also have reported that response to anti­depressants begins to outpace response to placebo only when symptoms are no longer mild. Using antidepressants for patients with mild depression could therefore place them at risk of overtreatment.⁸ In keeping with these findings, the American Psychiatric Association (APA) has recommended the use of evidence-based psychotherapies, such as CBT, as an initial treatment choice for patients with mild to moderate MDD.⁹

Two recent studies have suggested that the combination of CBT plus antidepressants could boost improvement in psychosocial functioning for patients with mild MDD.^10,11 However, neither study included a group of patients who received only CBT to evaluate if CBT alone could have also produced similar effects. Other limitations include the lack of a control group in one study and small sample sizes in both studies. However, both studies had a long follow-up period and specifically studied the impact on psychosocial functioning.

Moderate to severe depression

Earlier depression treatment guidelines suggested that antidepressants should be used to treat more severe depression, while psychotherapy should be used mainly for mild depression.¹² This recommendation was influenced by the well-known National Institute of Mental Health (NIMH) Treatment of Depression Collaborative Research Program, a multicenter randomized controlled trial (RCT) that used a placebo control.¹³ In this study, CBT was compared with antidepressants and found to be no more effective than placebo for more severely depressed patients.¹³ However, this finding was not consistent across the 3 sites where the study was conducted; at the site where CBT was provided by more experienced CBT therapists, patients with more severe depression who received CBT fared as well as patients treated with antidepressants.¹⁴ A later double-blind RCT that used experienced therapists found that CBT was as effective as antidepressants (monoamine oxidase inhibitors), and both treatments were superior to placebo in reducing symptoms of atypical depression.¹⁵

Another placebo-controlled RCT conducted at 2 sites found that CBT was as effective as antidepressants in the treatment of moderately to severely depressed patients. As in the NIMH Treatment of Depression Collaborative Research Program trial,¹³ in this study, there were indications that the results were dependent on therapist experience.¹⁶ These findings suggest that the experience of the therapist is an important factor.

A recent meta-analysis of treatments of the acute phase of MDD compared 11 RCTs of CBT and second-generation antidepressants (selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and other medications with related mechanisms of action).¹⁷ It found that as a first-step treatment, CBT and antidepressants had a similar impact on symptom relief in patients with moderate to severe depression. Patients treated with antidepressants also had a higher risk of experiencing adverse events or discontinuing treatment because of adverse events. However, this meta-analysis included trials that had methodological shortcomings, which reduces the strength of these conclusions.

Continue to: Patients with MDD and comorbid personality disorders have been...

Patients with MDD and comorbid personality disorders have been reported to have poorer outcomes, regardless of the treatment used.¹⁸ Fournier et al¹⁹ examined the impact of antidepressants and CBT in moderately to severely depressed patients with and without a personality disorder. They found that a combination of antidepressants and CBT was suitable for patients with personality disorders because antidepressants would boost the initial response and CBT would help sustain improvement in the long term.

Presently, the APA suggests that the combination of psychotherapy and antidepressants may be used as an initial treatment for patients with moderate to severe MDD.⁹ As research brings to light other factors that affect treatment outcomes, these guidelines could change.

Table 1^10,11,15,16 summarizes the findings of select studies evaluating the use of CBT for the acute treatment of depression.

CBT’s role in long-term treatment

Recurrence and relapse are major problems associated with MDD. The large majority of individuals who experience an episode of depression go on to experience more episodes of depression,²⁰ and the risk of recurrence increases after each successive episode.²¹

To reduce the risk of relapse and the return of symptoms, it is recommended that patients treated with antidepressants continue pharmacotherapy for 4 to 9 months after remission.⁹ Maintenance pharmacotherapy, which involves keeping patients on antidepressants beyond the point of recovery, is intended to reduce the risk of recurrence, and is standard treatment for patients with chronic or recurrent MDD.²² However, this preventive effect exists only while the patient continues to take the medication. Rates of symptom recurrence following medication withdrawal are often high regardless of how long patients have taken medications.²³

Continue to: Studies examining CBT as a maintenance treatment...

Studies examining CBT as a maintenance treatment—provided alone or in combination with or sequentially with antidepressants—have found it has an enduring effect that extends beyond the end of treatment and equals the impact of continuing antidepressants.^24-27 A recent meta-analysis of 10 trials where CBT had been provided to patients after acute treatment found that the risk of relapse was reduced by 21% in the first year and by 28% in the first 2 years.²⁸

Studies have compared the prophylactic impact of maintenance CBT and antidepressants. In an early study, 40 patients who had been successfully treated with antidepressants but had residual symptoms were randomly assigned to 20 weeks of CBT or to clinical management.²⁹ By the end of 20 weeks, patients were tapered off their antidepressant. All patients were then followed for 2 years, during which time they received no treatment. At the 2-year follow-up, the CBT group had a relapse rate of 25%, compared with 80% in the antidepressant group.²⁹ Weaknesses of this study include a small sample size, and the fact that a single therapist provided the CBT.

This study was extended to a 6-year follow-up; antidepressants were prescribed only to patients who relapsed. The CBT group continued to have a significantly lower relapse rate (40%) compared with the antidepressant group (90%).³⁰

In another RCT, patients with depression who had recovered with CBT or medication continued with the same treatment during a maintenance phase.²⁶ The CBT group received 3 booster sessions during the next year and antidepressant group received medication. At the end of the second year (without CBT or medication) CBT patients were less likely to relapse compared with patients receiving antidepressants. The adjusted relapse rates were 17.3% for CBT and 53.6% for antidepressants.²⁶

An RCT that included 452 patients with severe depression used a long intervention period (up to 42 weeks) and a flexible treatment algorithm to more closely model the strategies used in clinical practice.³¹ Patients were randomly assigned to antidepressants only or in combination with CBT. At the end of 12 months, outcome assessment by blinded interviewers indicated that patients with more severe depression were more likely to benefit from the combination of antidepressants and CBT (76.9% vs 60.3%) and those with severe, non-chronic depression received the most benefit (79.5% vs 62.8%). The lack of a CBT-only group limits the generalizability of these findings. Neither patients nor clinicians were blinded to the treatment assignment, which is a common limitation in psychotherapy studies but could have contributed to the finding that combined treatment was more effective.

Continue to: Some evidence suggests...

Some evidence suggests that augmenting treatment as usual (TAU) with CBT can have a resilient protective impact that also intensifies with the number of depressive episodes experienced. In an RCT, 172 patients with depression in remission were randomly assigned to TAU or to TAU augmented with CBT.³² The time to recurrence was assessed over the course of 10 years. Augmenting TAU with CBT had a significant protective impact that was greater for patients who had >3 previous episodes.³²

Another long-term study assessed the longitudinal course of 158 patients who received CBT, medication, and clinical management, or medication and clinical management alone.³³ Patients were followed 6 years after randomization (4.5 years after completion of CBT). Researchers found the effects of CBT in preventing relapse and recurrence persisted for several years.³³

Table 2^24,26,29-32 summarizes the findings of select studies evaluating the use of CBT for the long-term treatment of depression.

Limitations of long-term studies

Studies that have examined the efficacy of adding CBT to antidepressants in the continuation and maintenance treatment of patients with MDD have had some limitations. The definitions of relapse and recurrence have not always been clearly delineated in all studies. This is important because recurrence rates tend to be lower, and long-term follow-up would be needed to detect multiple recurrences so that their incidence is not underestimated. In addition, the types of CBT interventions utilized has varied across studies. Some studies have employed standard interventions such as cognitive restructuring, while others have added strategies that focus on enhancing memories for positive experiences or interventions to encourage medication adherence. Despite these limitations, research has shown promising results and suggests that adding CBT to the maintenance treatment of patients with depression—with or without antidepressants—is likely to reduce the rate of relapse and recurrence.

Consider CBT for all depressed patients

Research indicates that CBT can be the preferred treatment for patients with mild to moderate MDD. Antidepressants significantly reduce depressive symptoms in patients with moderate to severe MDD. Some research suggests that CBT can be as effective as antidepressants for moderate and severe MDD. However, as the severity and chronicity of depression increase, other moderating factors need to be considered. The expertise of the CBT therapist has an impact on outcomes. Treatment protocols that utilize CBT plus antidepressants are likely to be more effective than CBT or antidepressants alone. Incorporating CBT in the acute phase of depression treatment, with or without antidepressants, can have a long-term impact. For maintenance treatment, CBT alone and CBT plus antidepressants have been found to help sustain remission.

Continue to: Bottom Line

Cognitive-behavioral therapy (CBT) can be an effective treatment for patients with major depressive disorder, regardless of symptom severity. The expertise of the clinician who provides CBT has a substantial impact on outcomes. Combination treatment with CBT plus antidepressants is more likely to be effective than either treatment alone.

Related Resources

• Flynn HA, Warren R. Using CBT effectively for treating depression and anxiety. Current Psychiatry. 2014;13(6):45-53.
• Ijaz S, Davies P, Williams CJ, et al. Psychological therapies for treatment-resistant depression in adults. Cochrane Database Syst Rev. 2018;5:CD010558.

Major depressive disorder (MDD) has a devastating impact on individuals and society because of its high prevalence, its recurrent nature, its frequent comorbidity with other disorders, and the functional impairment it causes. Compared with other chronic diseases, such as arthritis, asthma, and diabetes, MDD produces the greatest decrement in health worldwide.¹ The goals in treating MDD should be not just to reduce symptom severity but also to achieve continuing remission and lower the risk for relapse.²

Antidepressants are the most common treatment for depression.³ Among psychotherapies used to treat MDD, cognitive-behavioral therapy (CBT) has been identified as an effective treatment.⁴ Collaborative care models have been reported to manage MDD more effectively.⁵ In this article, we review the evidence supporting the use of CBT as monotherapy and in combination with antidepressants for acute and long-term treatment of MDD.

Acute treatment: Not too soon for CBT

Mild to moderate depression

Research has indicated that for the treatment of mild MDD, antidepressants are unlikely to be more effective than placebo.^6,7 Studies also have reported that response to anti­depressants begins to outpace response to placebo only when symptoms are no longer mild. Using antidepressants for patients with mild depression could therefore place them at risk of overtreatment.⁸ In keeping with these findings, the American Psychiatric Association (APA) has recommended the use of evidence-based psychotherapies, such as CBT, as an initial treatment choice for patients with mild to moderate MDD.⁹

Two recent studies have suggested that the combination of CBT plus antidepressants could boost improvement in psychosocial functioning for patients with mild MDD.^10,11 However, neither study included a group of patients who received only CBT to evaluate if CBT alone could have also produced similar effects. Other limitations include the lack of a control group in one study and small sample sizes in both studies. However, both studies had a long follow-up period and specifically studied the impact on psychosocial functioning.

Moderate to severe depression

Earlier depression treatment guidelines suggested that antidepressants should be used to treat more severe depression, while psychotherapy should be used mainly for mild depression.¹² This recommendation was influenced by the well-known National Institute of Mental Health (NIMH) Treatment of Depression Collaborative Research Program, a multicenter randomized controlled trial (RCT) that used a placebo control.¹³ In this study, CBT was compared with antidepressants and found to be no more effective than placebo for more severely depressed patients.¹³ However, this finding was not consistent across the 3 sites where the study was conducted; at the site where CBT was provided by more experienced CBT therapists, patients with more severe depression who received CBT fared as well as patients treated with antidepressants.¹⁴ A later double-blind RCT that used experienced therapists found that CBT was as effective as antidepressants (monoamine oxidase inhibitors), and both treatments were superior to placebo in reducing symptoms of atypical depression.¹⁵

Another placebo-controlled RCT conducted at 2 sites found that CBT was as effective as antidepressants in the treatment of moderately to severely depressed patients. As in the NIMH Treatment of Depression Collaborative Research Program trial,¹³ in this study, there were indications that the results were dependent on therapist experience.¹⁶ These findings suggest that the experience of the therapist is an important factor.

A recent meta-analysis of treatments of the acute phase of MDD compared 11 RCTs of CBT and second-generation antidepressants (selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and other medications with related mechanisms of action).¹⁷ It found that as a first-step treatment, CBT and antidepressants had a similar impact on symptom relief in patients with moderate to severe depression. Patients treated with antidepressants also had a higher risk of experiencing adverse events or discontinuing treatment because of adverse events. However, this meta-analysis included trials that had methodological shortcomings, which reduces the strength of these conclusions.

Continue to: Patients with MDD and comorbid personality disorders have been...

Patients with MDD and comorbid personality disorders have been reported to have poorer outcomes, regardless of the treatment used.¹⁸ Fournier et al¹⁹ examined the impact of antidepressants and CBT in moderately to severely depressed patients with and without a personality disorder. They found that a combination of antidepressants and CBT was suitable for patients with personality disorders because antidepressants would boost the initial response and CBT would help sustain improvement in the long term.

Presently, the APA suggests that the combination of psychotherapy and antidepressants may be used as an initial treatment for patients with moderate to severe MDD.⁹ As research brings to light other factors that affect treatment outcomes, these guidelines could change.

Table 1^10,11,15,16 summarizes the findings of select studies evaluating the use of CBT for the acute treatment of depression.

CBT’s role in long-term treatment

Recurrence and relapse are major problems associated with MDD. The large majority of individuals who experience an episode of depression go on to experience more episodes of depression,²⁰ and the risk of recurrence increases after each successive episode.²¹

To reduce the risk of relapse and the return of symptoms, it is recommended that patients treated with antidepressants continue pharmacotherapy for 4 to 9 months after remission.⁹ Maintenance pharmacotherapy, which involves keeping patients on antidepressants beyond the point of recovery, is intended to reduce the risk of recurrence, and is standard treatment for patients with chronic or recurrent MDD.²² However, this preventive effect exists only while the patient continues to take the medication. Rates of symptom recurrence following medication withdrawal are often high regardless of how long patients have taken medications.²³

Continue to: Studies examining CBT as a maintenance treatment...

Studies examining CBT as a maintenance treatment—provided alone or in combination with or sequentially with antidepressants—have found it has an enduring effect that extends beyond the end of treatment and equals the impact of continuing antidepressants.^24-27 A recent meta-analysis of 10 trials where CBT had been provided to patients after acute treatment found that the risk of relapse was reduced by 21% in the first year and by 28% in the first 2 years.²⁸

Studies have compared the prophylactic impact of maintenance CBT and antidepressants. In an early study, 40 patients who had been successfully treated with antidepressants but had residual symptoms were randomly assigned to 20 weeks of CBT or to clinical management.²⁹ By the end of 20 weeks, patients were tapered off their antidepressant. All patients were then followed for 2 years, during which time they received no treatment. At the 2-year follow-up, the CBT group had a relapse rate of 25%, compared with 80% in the antidepressant group.²⁹ Weaknesses of this study include a small sample size, and the fact that a single therapist provided the CBT.

This study was extended to a 6-year follow-up; antidepressants were prescribed only to patients who relapsed. The CBT group continued to have a significantly lower relapse rate (40%) compared with the antidepressant group (90%).³⁰

In another RCT, patients with depression who had recovered with CBT or medication continued with the same treatment during a maintenance phase.²⁶ The CBT group received 3 booster sessions during the next year and antidepressant group received medication. At the end of the second year (without CBT or medication) CBT patients were less likely to relapse compared with patients receiving antidepressants. The adjusted relapse rates were 17.3% for CBT and 53.6% for antidepressants.²⁶

An RCT that included 452 patients with severe depression used a long intervention period (up to 42 weeks) and a flexible treatment algorithm to more closely model the strategies used in clinical practice.³¹ Patients were randomly assigned to antidepressants only or in combination with CBT. At the end of 12 months, outcome assessment by blinded interviewers indicated that patients with more severe depression were more likely to benefit from the combination of antidepressants and CBT (76.9% vs 60.3%) and those with severe, non-chronic depression received the most benefit (79.5% vs 62.8%). The lack of a CBT-only group limits the generalizability of these findings. Neither patients nor clinicians were blinded to the treatment assignment, which is a common limitation in psychotherapy studies but could have contributed to the finding that combined treatment was more effective.

Continue to: Some evidence suggests...

Some evidence suggests that augmenting treatment as usual (TAU) with CBT can have a resilient protective impact that also intensifies with the number of depressive episodes experienced. In an RCT, 172 patients with depression in remission were randomly assigned to TAU or to TAU augmented with CBT.³² The time to recurrence was assessed over the course of 10 years. Augmenting TAU with CBT had a significant protective impact that was greater for patients who had >3 previous episodes.³²

Another long-term study assessed the longitudinal course of 158 patients who received CBT, medication, and clinical management, or medication and clinical management alone.³³ Patients were followed 6 years after randomization (4.5 years after completion of CBT). Researchers found the effects of CBT in preventing relapse and recurrence persisted for several years.³³

Table 2^24,26,29-32 summarizes the findings of select studies evaluating the use of CBT for the long-term treatment of depression.

Limitations of long-term studies

Studies that have examined the efficacy of adding CBT to antidepressants in the continuation and maintenance treatment of patients with MDD have had some limitations. The definitions of relapse and recurrence have not always been clearly delineated in all studies. This is important because recurrence rates tend to be lower, and long-term follow-up would be needed to detect multiple recurrences so that their incidence is not underestimated. In addition, the types of CBT interventions utilized has varied across studies. Some studies have employed standard interventions such as cognitive restructuring, while others have added strategies that focus on enhancing memories for positive experiences or interventions to encourage medication adherence. Despite these limitations, research has shown promising results and suggests that adding CBT to the maintenance treatment of patients with depression—with or without antidepressants—is likely to reduce the rate of relapse and recurrence.

Consider CBT for all depressed patients

Research indicates that CBT can be the preferred treatment for patients with mild to moderate MDD. Antidepressants significantly reduce depressive symptoms in patients with moderate to severe MDD. Some research suggests that CBT can be as effective as antidepressants for moderate and severe MDD. However, as the severity and chronicity of depression increase, other moderating factors need to be considered. The expertise of the CBT therapist has an impact on outcomes. Treatment protocols that utilize CBT plus antidepressants are likely to be more effective than CBT or antidepressants alone. Incorporating CBT in the acute phase of depression treatment, with or without antidepressants, can have a long-term impact. For maintenance treatment, CBT alone and CBT plus antidepressants have been found to help sustain remission.

Continue to: Bottom Line

Cognitive-behavioral therapy (CBT) can be an effective treatment for patients with major depressive disorder, regardless of symptom severity. The expertise of the clinician who provides CBT has a substantial impact on outcomes. Combination treatment with CBT plus antidepressants is more likely to be effective than either treatment alone.

Related Resources

• Flynn HA, Warren R. Using CBT effectively for treating depression and anxiety. Current Psychiatry. 2014;13(6):45-53.
• Ijaz S, Davies P, Williams CJ, et al. Psychological therapies for treatment-resistant depression in adults. Cochrane Database Syst Rev. 2018;5:CD010558.

The loss of a loved one to suicide is often experienced as “devastating.”¹ While survivors of suicide loss may be able to move through the grief process without clinical support,² the traumatic and stigmatizing nature of suicide is likely to make its aftermath more challenging to navigate than other types of loss. Sanford et al³ found that more than two-thirds of suicide loss survivors sought therapy after their loss. Further, when individuals facing these challenges present for treatment, clinicians often face challenges of their own.

Very few clinicians are trained in general grief processes,⁴ and even those specifically trained in grief and loss have been shown to “miss” several of the common clinical features that are unique to suicide loss.³ In my professional experience, the intensity and duration of suicide grief are often greater than they are for other losses, and many survivors of suicide loss have reported that others, including clinicians, have “pathologized” this, rather than having understood it as normative under the circumstances.

Although there is extensive literature on the aftermath of suicide for surviving loved ones, very few controlled studies have assessed interventions specifically for this population. Yet the U.S. Guidelines for Suicide Postvention⁵ explicitly call for improved training for those who work with suicide loss survivors, as well as research on these interventions. Jordan and McGann⁶ noted, “Without a full knowledge of suicide and its aftermath, it is very possible to make clinical errors which can hamper treatment.” This article summarizes what is currently known about the general experience of suicide bereavement and optimal interventions in treatment.

What makes suicide loss unique?

Suicide bereavement is distinct from other types of loss in 3 significant ways⁷:

• the thematic content of the grief
• the social processes surrounding the survivor
• the impact that suicide has on family systems.

Additionally, the perceived intentionality and preventability of a suicide death, as well as its stigmatized and traumatic nature, differentiate it from other types of traumatic loss.⁷ These elements are all likely to affect the nature, intensity, and duration of the grief.

Stigma and suicide. Stigma associated with suicide is well documented.⁸ Former U.S. Surgeon General David Satcher⁹ specifically described stigma toward suicide as one of the biggest barriers to prevention. In addition, researchers have found that the stigma associated with suicide “spills over” to the bereaved family members. Doka^10,11 refers to “disenfranchised grief,” in which bereaved individuals receive the message that their grief is not legitimate, and as a result, they are likely to internalize this view. Studies have shown that individuals bereaved by suicide are also stigmatized, and are believed to be more psychologically disturbed, less likable, more blameworthy, more ashamed, and more in need of professional help than other bereaved individuals.^8,12-20

These judgments often mirror suicide loss survivors’ self-punitive assessments, which then become exacerbated by and intertwined with both externally imposed and internalized stigma. Thus, it is not uncommon for survivors of suicide loss to question their own right to grieve, to report low expectations of social support, and to feel compelled to deny or hide the mode of death. To the extent that they are actively grieving, survivors of suicide loss often feel that they must do so in isolation. Thus, the perception of stigma, whether external or internalized, can have a profound effect on decisions about disclosure, requesting support, and ultimately on one’s ability to integrate the loss. Indeed, Feigelman et al²¹ found that stigmatization after suicide was specifically associated with ongoing grief difficulties, depression, and suicidal ideation.

Continue to: Traumatic nature of suicide

Traumatic nature of suicide. Suicide loss is also quite traumatic, and posttraumatic stress disorder (PTSD) symptoms such as shock, horror, disbelief, and intrusive/perseverative thoughts and questions, particularly in the earlier stages of grief, are common. Sanford et al³ found that the higher the level of “perceived closeness” to the deceased, the more likely that survivors of suicide loss would experience PTSD symptoms. In addition, the dramatic loss of social support following a suicide loss may itself be traumatic, which can serve to compound these difficulties. Notably, Sanford et al³ found that even for those survivors of suicide loss in treatment who endorsed PTSD symptoms, many of their treating clinicians did not assess or diagnose this disorder, thus missing an important component for treatment.

Increased risk for suicidality. Studies have shown that individuals who have lost a loved one to suicide are themselves at heightened risk for suicidal ideation and behaviors.^22-27 Therefore, an assessment for suicide risk is always advisable. However, it is important to note that suicidal ideation is not uncommon and can serve different functions for survivors of suicide loss without necessarily progressing to a plan for acting on such ideations. Survivors of suicide loss may wish to “join” their loved one; to understand or identify with the mental state of the deceased; to punish themselves for failing to prevent the suicide; or to end their own pain through death. Therefore, it is crucial to assess the nature and function of expressed ideation (in addition to the presence or absence of plans) before assigning the level of risk.

Elements of suicide grief

After the loss of a loved one to suicide, the path to healing is often complex, with survivors of suicide loss enduring the following challenges:

Existential assumptions are shattered. Several authors^28-30 have found that suicide loss is also likely to shatter survivors’ existential assumptions regarding their worldviews, roles, and identities, as well as religious and spiritual beliefs. As one survivor of suicide loss in my practice noted, “The world is gone, nothing is predictable anymore, and it’s no longer safe to assume anything.” Others have described feeling “fragmented” in ways they had never before experienced, and many have reported difficulties in “trusting” their own judgment, the stability of the world, and relationships. “Why?” becomes an emergent and insistent question in the survivor’s efforts to understand the suicide and (ideally) reassemble a coherent narrative around the loss.

Increased duration and intensity of grief. The duration of the grief process is likely to be affected by the traumatic nature of suicide loss, the differential social support accorded to its survivors, and the difficulty in finding systems that can validate and normalize the unique elements in suicide bereavement. The stigmatized reactions of others, particularly when internalized, can present barriers to the processing of grief. In addition, the intensity of the trauma and existential impact, as well as the perseverative nature of several of the unique themes (Box 1), can also prolong the processing and increase the intensity of suicide grief. Clinicians would do well to recognize the relatively “normative” nature of the increased duration and intensity, rather than seeing it as immediately indicative of a DSM diagnosis of complicated/prolonged grief disorder.

Box 1
Common themes in the suicide grief process

Continue to: Family disruption

Family disruption. It is not uncommon for a suicide loss to result in family disruption.^6,31-32 This may manifest in the blaming of family members for “sins of omission or commission,”⁶ conflicts around the disclosure of the suicide both within and outside of the family, discordant grieving styles, and difficulties in understanding and attending to the needs of one’s children while grieving oneself.

Despite the common elements often seen in suicide grief, it is crucial to recognize that this process is not “one size fits all.” Not only are there individual variants, but Grad et al³³ found gender-based differences in grieving styles, and cultural issues such as the “meanings” assigned to suicide, and culturally sanctioned grief rituals and behaviors that are also likely to affect how grief is experienced and expressed. In addition, personal variants such as closeness/conflicts with the deceased, histories of previous trauma or loss, pre-existing psychiatric disorders, and attachment orientation³⁴ are likely to impact the grief process.

Losing close friends and colleagues may be similarly traumatic, but these survivors of suicide loss often receive even less social support than those who have kinship losses. Finally, when a suicide loss occurs in a professional capacity (such as the loss of a patient), this is likely to have many additional implications for one’s professional functions and identity.³⁵

Interventions to help survivors

Several goals and “tasks” are involved in the suicide bereavement process (Box 2^1,6,30,36-40). These can be achieved through the following interventions: Support groups. Many survivors find that support groups that focus on suicide loss are extremely helpful, and research has supported this.^1,4,41-44 Interactions with other suicide loss survivors provide hope, connection, and an “antidote” to stigma and shame. Optimally, group facilitators provide education, validation and normalization of the grief trajectory, and facilitate the sharing of both loss experiences and current functioning between group members. As a result, group participants often report renewed connections, increased efficacy in giving and accepting support, and decreased distress (including reductions in PTSD and depressive symptoms). The American Association of Suicidology (www.suicidology.org) and American Foundation of Suicide Prevention (www.afsp.org) provide contact information for suicide loss survivor groups (by geographical area) as well as information about online support groups.

Box 2
Goals and 'tasks' in suicide bereavement

Individual treatment. The limited research on individual treatment for suicide loss survivors suggests that while most participants find it generally helpful, a significant number of others report that their therapists lack knowledge of suicide grief and endorse stigmatizing attitudes toward suicide and suicide loss survivors.^45-46 In addition, Sanford et al³ found that survivors of suicide loss who endorsed PTSD symptoms were not assessed, diagnosed, or treated for these symptoms.

Continue to: This speaks to the importance of understanding what is...

This speaks to the importance of understanding what is “normative” for survivors of suicide loss. In general, “normalization” and psychoeducation about the suicide grief trajectory can play an important role in work with survivors of suicide loss, even in the presence of diagnosable disorders. While PTSD, depressive symptoms, and suicidal ideation are not uncommon in suicide loss survivors, and certainly may warrant clinical assessment and treatment, it can be helpful (and less stigmatizing) for your patients to know that these diagnoses are relatively common and understandable in the context of this devastating experience. For instance, survivors of suicide loss often report feeling relieved when clinicians explain the connections between traumatic loss and PTSD and/or depressive symptoms, and this can also help to relieve secondary anxiety about “going crazy.” Many survivors of suicide loss also describe feeling as though they are functioning on “autopilot” in the earlier stages of grief; it can help them understand the “function” of compartmentalization as potentially adaptive in the short run.

Suicide loss survivors may also find it helpful to learn about suicidal states of mind and their relationships to any types of mental illness their loved ones had struggled with.⁴⁷

Your role: Help survivors integrate the loss

Before beginning treatment with an individual who has lost a loved one to suicide, clinicians should thoroughly explore their own understanding of and experience with suicide, including assumptions around causation, internalized stigma about suicidal individuals and survivors of suicide loss, their own history of suicide loss or suicidality, cultural/religious attitudes, and anxiety/defenses associated with the topic of suicide. These factors, particularly when unexamined, are likely to impact the treatment relationship and one’s clinical efficacy.

In concert with the existing literature, consider the potential goals and tasks involved in the integration of the individual’s suicide loss, along with any individual factors/variants that may impact the grief trajectory. Kosminsky and Jordon³⁴ described the role of the clinician in this situation as a “transitional attachment figure” who facilitates the management and integration of the loss into the creation of what survivors of suicide loss have termed a “new normal.”

Because suicide loss is often associated with PTSD and other psychiatric illnesses (eg, depression, suicidality, substance abuse), it is essential to balance the assessment and treatment of these issues with attention to grief issues as needed. Again, to the extent that such issues have arisen primarily in the wake of the suicide loss, it can be helpful for patients to understand their connection to the context of the loss.

Continue to: Ideally, the clinician should...

Ideally, the clinician should be “present” with the patient’s pain, normative guilt, and rumination, without attempting to quickly eliminate or “fix” it or provide premature reassurance that the survivor of suicide loss “did nothing wrong.” Rather, as Jordan⁶ suggests, the clinician should act to promote a “fair trial” with respect to the patient’s guilt and blame, with an understanding of the “tyranny of hindsight.” The promotion of ambiguity tolerance should also play a role in coming to terms with many questions that may remain unanswered.

Optimally, clinicians should encourage patients to attend to their ongoing relationship with the deceased, particularly in the service of resolving “unfinished business,” ultimately integrating the loss into memories of the whole person. In line with this, survivors of suicide loss may be encouraged to create a narrative of the loss that incorporates both complexity and ambiguity. In the service of supporting the suicide loss survivor’s reinvestment in life, it is often helpful to facilitate their ability to anticipate and cope with triggers, such as anniversaries, birthdays, or holidays, as well as to develop and use skills for managing difficult or stigmatizing social or cultural reactions.

Any disruptions in family functioning should also be addressed. Psychoeducation about discordant grieving styles (particularly around gender) and the support of children’s grief may be helpful, and referrals to family or couples therapists should be considered as needed. Finally, the facilitation of suicide loss survivors’ creation of memorializations or rituals can help promote healing and make their loss meaningful.

Bottom Line

Losing a loved one to suicide is often a devastating and traumatic experience, but with optimal support, most survivors are ultimately able to integrate the loss and grow as a result. Understanding the suicide grief trajectory, as well as general guidelines for treatment, will facilitate healing and growth in the aftermath of suicide loss.

Related Resources

• Jordan JR, McIntosh JL. Grief after suicide: understanding the consequences and caring for the survivors. New York, NY: Routledge/Taylor & Francis Group; 2011.
• American Association of Suicidology. http://www.suicidology.org/. 
• American Foundation for Suicide Prevention. https://afsp.org/.

The loss of a loved one to suicide is often experienced as “devastating.”¹ While survivors of suicide loss may be able to move through the grief process without clinical support,² the traumatic and stigmatizing nature of suicide is likely to make its aftermath more challenging to navigate than other types of loss. Sanford et al³ found that more than two-thirds of suicide loss survivors sought therapy after their loss. Further, when individuals facing these challenges present for treatment, clinicians often face challenges of their own.

Very few clinicians are trained in general grief processes,⁴ and even those specifically trained in grief and loss have been shown to “miss” several of the common clinical features that are unique to suicide loss.³ In my professional experience, the intensity and duration of suicide grief are often greater than they are for other losses, and many survivors of suicide loss have reported that others, including clinicians, have “pathologized” this, rather than having understood it as normative under the circumstances.

Although there is extensive literature on the aftermath of suicide for surviving loved ones, very few controlled studies have assessed interventions specifically for this population. Yet the U.S. Guidelines for Suicide Postvention⁵ explicitly call for improved training for those who work with suicide loss survivors, as well as research on these interventions. Jordan and McGann⁶ noted, “Without a full knowledge of suicide and its aftermath, it is very possible to make clinical errors which can hamper treatment.” This article summarizes what is currently known about the general experience of suicide bereavement and optimal interventions in treatment.

What makes suicide loss unique?

Suicide bereavement is distinct from other types of loss in 3 significant ways⁷:

• the thematic content of the grief
• the social processes surrounding the survivor
• the impact that suicide has on family systems.

Additionally, the perceived intentionality and preventability of a suicide death, as well as its stigmatized and traumatic nature, differentiate it from other types of traumatic loss.⁷ These elements are all likely to affect the nature, intensity, and duration of the grief.

Stigma and suicide. Stigma associated with suicide is well documented.⁸ Former U.S. Surgeon General David Satcher⁹ specifically described stigma toward suicide as one of the biggest barriers to prevention. In addition, researchers have found that the stigma associated with suicide “spills over” to the bereaved family members. Doka^10,11 refers to “disenfranchised grief,” in which bereaved individuals receive the message that their grief is not legitimate, and as a result, they are likely to internalize this view. Studies have shown that individuals bereaved by suicide are also stigmatized, and are believed to be more psychologically disturbed, less likable, more blameworthy, more ashamed, and more in need of professional help than other bereaved individuals.^8,12-20

These judgments often mirror suicide loss survivors’ self-punitive assessments, which then become exacerbated by and intertwined with both externally imposed and internalized stigma. Thus, it is not uncommon for survivors of suicide loss to question their own right to grieve, to report low expectations of social support, and to feel compelled to deny or hide the mode of death. To the extent that they are actively grieving, survivors of suicide loss often feel that they must do so in isolation. Thus, the perception of stigma, whether external or internalized, can have a profound effect on decisions about disclosure, requesting support, and ultimately on one’s ability to integrate the loss. Indeed, Feigelman et al²¹ found that stigmatization after suicide was specifically associated with ongoing grief difficulties, depression, and suicidal ideation.

Continue to: Traumatic nature of suicide

Traumatic nature of suicide. Suicide loss is also quite traumatic, and posttraumatic stress disorder (PTSD) symptoms such as shock, horror, disbelief, and intrusive/perseverative thoughts and questions, particularly in the earlier stages of grief, are common. Sanford et al³ found that the higher the level of “perceived closeness” to the deceased, the more likely that survivors of suicide loss would experience PTSD symptoms. In addition, the dramatic loss of social support following a suicide loss may itself be traumatic, which can serve to compound these difficulties. Notably, Sanford et al³ found that even for those survivors of suicide loss in treatment who endorsed PTSD symptoms, many of their treating clinicians did not assess or diagnose this disorder, thus missing an important component for treatment.

Increased risk for suicidality. Studies have shown that individuals who have lost a loved one to suicide are themselves at heightened risk for suicidal ideation and behaviors.^22-27 Therefore, an assessment for suicide risk is always advisable. However, it is important to note that suicidal ideation is not uncommon and can serve different functions for survivors of suicide loss without necessarily progressing to a plan for acting on such ideations. Survivors of suicide loss may wish to “join” their loved one; to understand or identify with the mental state of the deceased; to punish themselves for failing to prevent the suicide; or to end their own pain through death. Therefore, it is crucial to assess the nature and function of expressed ideation (in addition to the presence or absence of plans) before assigning the level of risk.

Elements of suicide grief

After the loss of a loved one to suicide, the path to healing is often complex, with survivors of suicide loss enduring the following challenges:

Existential assumptions are shattered. Several authors^28-30 have found that suicide loss is also likely to shatter survivors’ existential assumptions regarding their worldviews, roles, and identities, as well as religious and spiritual beliefs. As one survivor of suicide loss in my practice noted, “The world is gone, nothing is predictable anymore, and it’s no longer safe to assume anything.” Others have described feeling “fragmented” in ways they had never before experienced, and many have reported difficulties in “trusting” their own judgment, the stability of the world, and relationships. “Why?” becomes an emergent and insistent question in the survivor’s efforts to understand the suicide and (ideally) reassemble a coherent narrative around the loss.

Increased duration and intensity of grief. The duration of the grief process is likely to be affected by the traumatic nature of suicide loss, the differential social support accorded to its survivors, and the difficulty in finding systems that can validate and normalize the unique elements in suicide bereavement. The stigmatized reactions of others, particularly when internalized, can present barriers to the processing of grief. In addition, the intensity of the trauma and existential impact, as well as the perseverative nature of several of the unique themes (Box 1), can also prolong the processing and increase the intensity of suicide grief. Clinicians would do well to recognize the relatively “normative” nature of the increased duration and intensity, rather than seeing it as immediately indicative of a DSM diagnosis of complicated/prolonged grief disorder.

Box 1
Common themes in the suicide grief process

Continue to: Family disruption

Family disruption. It is not uncommon for a suicide loss to result in family disruption.^6,31-32 This may manifest in the blaming of family members for “sins of omission or commission,”⁶ conflicts around the disclosure of the suicide both within and outside of the family, discordant grieving styles, and difficulties in understanding and attending to the needs of one’s children while grieving oneself.

Despite the common elements often seen in suicide grief, it is crucial to recognize that this process is not “one size fits all.” Not only are there individual variants, but Grad et al³³ found gender-based differences in grieving styles, and cultural issues such as the “meanings” assigned to suicide, and culturally sanctioned grief rituals and behaviors that are also likely to affect how grief is experienced and expressed. In addition, personal variants such as closeness/conflicts with the deceased, histories of previous trauma or loss, pre-existing psychiatric disorders, and attachment orientation³⁴ are likely to impact the grief process.

Losing close friends and colleagues may be similarly traumatic, but these survivors of suicide loss often receive even less social support than those who have kinship losses. Finally, when a suicide loss occurs in a professional capacity (such as the loss of a patient), this is likely to have many additional implications for one’s professional functions and identity.³⁵

Interventions to help survivors

Several goals and “tasks” are involved in the suicide bereavement process (Box 2^1,6,30,36-40). These can be achieved through the following interventions: Support groups. Many survivors find that support groups that focus on suicide loss are extremely helpful, and research has supported this.^1,4,41-44 Interactions with other suicide loss survivors provide hope, connection, and an “antidote” to stigma and shame. Optimally, group facilitators provide education, validation and normalization of the grief trajectory, and facilitate the sharing of both loss experiences and current functioning between group members. As a result, group participants often report renewed connections, increased efficacy in giving and accepting support, and decreased distress (including reductions in PTSD and depressive symptoms). The American Association of Suicidology (www.suicidology.org) and American Foundation of Suicide Prevention (www.afsp.org) provide contact information for suicide loss survivor groups (by geographical area) as well as information about online support groups.

Box 2
Goals and 'tasks' in suicide bereavement

Individual treatment. The limited research on individual treatment for suicide loss survivors suggests that while most participants find it generally helpful, a significant number of others report that their therapists lack knowledge of suicide grief and endorse stigmatizing attitudes toward suicide and suicide loss survivors.^45-46 In addition, Sanford et al³ found that survivors of suicide loss who endorsed PTSD symptoms were not assessed, diagnosed, or treated for these symptoms.

Continue to: This speaks to the importance of understanding what is...

This speaks to the importance of understanding what is “normative” for survivors of suicide loss. In general, “normalization” and psychoeducation about the suicide grief trajectory can play an important role in work with survivors of suicide loss, even in the presence of diagnosable disorders. While PTSD, depressive symptoms, and suicidal ideation are not uncommon in suicide loss survivors, and certainly may warrant clinical assessment and treatment, it can be helpful (and less stigmatizing) for your patients to know that these diagnoses are relatively common and understandable in the context of this devastating experience. For instance, survivors of suicide loss often report feeling relieved when clinicians explain the connections between traumatic loss and PTSD and/or depressive symptoms, and this can also help to relieve secondary anxiety about “going crazy.” Many survivors of suicide loss also describe feeling as though they are functioning on “autopilot” in the earlier stages of grief; it can help them understand the “function” of compartmentalization as potentially adaptive in the short run.

Suicide loss survivors may also find it helpful to learn about suicidal states of mind and their relationships to any types of mental illness their loved ones had struggled with.⁴⁷

Your role: Help survivors integrate the loss

Before beginning treatment with an individual who has lost a loved one to suicide, clinicians should thoroughly explore their own understanding of and experience with suicide, including assumptions around causation, internalized stigma about suicidal individuals and survivors of suicide loss, their own history of suicide loss or suicidality, cultural/religious attitudes, and anxiety/defenses associated with the topic of suicide. These factors, particularly when unexamined, are likely to impact the treatment relationship and one’s clinical efficacy.

In concert with the existing literature, consider the potential goals and tasks involved in the integration of the individual’s suicide loss, along with any individual factors/variants that may impact the grief trajectory. Kosminsky and Jordon³⁴ described the role of the clinician in this situation as a “transitional attachment figure” who facilitates the management and integration of the loss into the creation of what survivors of suicide loss have termed a “new normal.”

Because suicide loss is often associated with PTSD and other psychiatric illnesses (eg, depression, suicidality, substance abuse), it is essential to balance the assessment and treatment of these issues with attention to grief issues as needed. Again, to the extent that such issues have arisen primarily in the wake of the suicide loss, it can be helpful for patients to understand their connection to the context of the loss.

Continue to: Ideally, the clinician should...

Ideally, the clinician should be “present” with the patient’s pain, normative guilt, and rumination, without attempting to quickly eliminate or “fix” it or provide premature reassurance that the survivor of suicide loss “did nothing wrong.” Rather, as Jordan⁶ suggests, the clinician should act to promote a “fair trial” with respect to the patient’s guilt and blame, with an understanding of the “tyranny of hindsight.” The promotion of ambiguity tolerance should also play a role in coming to terms with many questions that may remain unanswered.

Optimally, clinicians should encourage patients to attend to their ongoing relationship with the deceased, particularly in the service of resolving “unfinished business,” ultimately integrating the loss into memories of the whole person. In line with this, survivors of suicide loss may be encouraged to create a narrative of the loss that incorporates both complexity and ambiguity. In the service of supporting the suicide loss survivor’s reinvestment in life, it is often helpful to facilitate their ability to anticipate and cope with triggers, such as anniversaries, birthdays, or holidays, as well as to develop and use skills for managing difficult or stigmatizing social or cultural reactions.

Any disruptions in family functioning should also be addressed. Psychoeducation about discordant grieving styles (particularly around gender) and the support of children’s grief may be helpful, and referrals to family or couples therapists should be considered as needed. Finally, the facilitation of suicide loss survivors’ creation of memorializations or rituals can help promote healing and make their loss meaningful.

Bottom Line

Losing a loved one to suicide is often a devastating and traumatic experience, but with optimal support, most survivors are ultimately able to integrate the loss and grow as a result. Understanding the suicide grief trajectory, as well as general guidelines for treatment, will facilitate healing and growth in the aftermath of suicide loss.

Related Resources

• Jordan JR, McIntosh JL. Grief after suicide: understanding the consequences and caring for the survivors. New York, NY: Routledge/Taylor & Francis Group; 2011.
• American Association of Suicidology. http://www.suicidology.org/. 
• American Foundation for Suicide Prevention. https://afsp.org/.

The loss of a loved one to suicide is often experienced as “devastating.”¹ While survivors of suicide loss may be able to move through the grief process without clinical support,² the traumatic and stigmatizing nature of suicide is likely to make its aftermath more challenging to navigate than other types of loss. Sanford et al³ found that more than two-thirds of suicide loss survivors sought therapy after their loss. Further, when individuals facing these challenges present for treatment, clinicians often face challenges of their own.

Very few clinicians are trained in general grief processes,⁴ and even those specifically trained in grief and loss have been shown to “miss” several of the common clinical features that are unique to suicide loss.³ In my professional experience, the intensity and duration of suicide grief are often greater than they are for other losses, and many survivors of suicide loss have reported that others, including clinicians, have “pathologized” this, rather than having understood it as normative under the circumstances.

Although there is extensive literature on the aftermath of suicide for surviving loved ones, very few controlled studies have assessed interventions specifically for this population. Yet the U.S. Guidelines for Suicide Postvention⁵ explicitly call for improved training for those who work with suicide loss survivors, as well as research on these interventions. Jordan and McGann⁶ noted, “Without a full knowledge of suicide and its aftermath, it is very possible to make clinical errors which can hamper treatment.” This article summarizes what is currently known about the general experience of suicide bereavement and optimal interventions in treatment.

What makes suicide loss unique?

Suicide bereavement is distinct from other types of loss in 3 significant ways⁷:

• the thematic content of the grief
• the social processes surrounding the survivor
• the impact that suicide has on family systems.

Additionally, the perceived intentionality and preventability of a suicide death, as well as its stigmatized and traumatic nature, differentiate it from other types of traumatic loss.⁷ These elements are all likely to affect the nature, intensity, and duration of the grief.

Stigma and suicide. Stigma associated with suicide is well documented.⁸ Former U.S. Surgeon General David Satcher⁹ specifically described stigma toward suicide as one of the biggest barriers to prevention. In addition, researchers have found that the stigma associated with suicide “spills over” to the bereaved family members. Doka^10,11 refers to “disenfranchised grief,” in which bereaved individuals receive the message that their grief is not legitimate, and as a result, they are likely to internalize this view. Studies have shown that individuals bereaved by suicide are also stigmatized, and are believed to be more psychologically disturbed, less likable, more blameworthy, more ashamed, and more in need of professional help than other bereaved individuals.^8,12-20

These judgments often mirror suicide loss survivors’ self-punitive assessments, which then become exacerbated by and intertwined with both externally imposed and internalized stigma. Thus, it is not uncommon for survivors of suicide loss to question their own right to grieve, to report low expectations of social support, and to feel compelled to deny or hide the mode of death. To the extent that they are actively grieving, survivors of suicide loss often feel that they must do so in isolation. Thus, the perception of stigma, whether external or internalized, can have a profound effect on decisions about disclosure, requesting support, and ultimately on one’s ability to integrate the loss. Indeed, Feigelman et al²¹ found that stigmatization after suicide was specifically associated with ongoing grief difficulties, depression, and suicidal ideation.

Continue to: Traumatic nature of suicide

Traumatic nature of suicide. Suicide loss is also quite traumatic, and posttraumatic stress disorder (PTSD) symptoms such as shock, horror, disbelief, and intrusive/perseverative thoughts and questions, particularly in the earlier stages of grief, are common. Sanford et al³ found that the higher the level of “perceived closeness” to the deceased, the more likely that survivors of suicide loss would experience PTSD symptoms. In addition, the dramatic loss of social support following a suicide loss may itself be traumatic, which can serve to compound these difficulties. Notably, Sanford et al³ found that even for those survivors of suicide loss in treatment who endorsed PTSD symptoms, many of their treating clinicians did not assess or diagnose this disorder, thus missing an important component for treatment.

Increased risk for suicidality. Studies have shown that individuals who have lost a loved one to suicide are themselves at heightened risk for suicidal ideation and behaviors.^22-27 Therefore, an assessment for suicide risk is always advisable. However, it is important to note that suicidal ideation is not uncommon and can serve different functions for survivors of suicide loss without necessarily progressing to a plan for acting on such ideations. Survivors of suicide loss may wish to “join” their loved one; to understand or identify with the mental state of the deceased; to punish themselves for failing to prevent the suicide; or to end their own pain through death. Therefore, it is crucial to assess the nature and function of expressed ideation (in addition to the presence or absence of plans) before assigning the level of risk.

Elements of suicide grief

After the loss of a loved one to suicide, the path to healing is often complex, with survivors of suicide loss enduring the following challenges:

Existential assumptions are shattered. Several authors^28-30 have found that suicide loss is also likely to shatter survivors’ existential assumptions regarding their worldviews, roles, and identities, as well as religious and spiritual beliefs. As one survivor of suicide loss in my practice noted, “The world is gone, nothing is predictable anymore, and it’s no longer safe to assume anything.” Others have described feeling “fragmented” in ways they had never before experienced, and many have reported difficulties in “trusting” their own judgment, the stability of the world, and relationships. “Why?” becomes an emergent and insistent question in the survivor’s efforts to understand the suicide and (ideally) reassemble a coherent narrative around the loss.

Increased duration and intensity of grief. The duration of the grief process is likely to be affected by the traumatic nature of suicide loss, the differential social support accorded to its survivors, and the difficulty in finding systems that can validate and normalize the unique elements in suicide bereavement. The stigmatized reactions of others, particularly when internalized, can present barriers to the processing of grief. In addition, the intensity of the trauma and existential impact, as well as the perseverative nature of several of the unique themes (Box 1), can also prolong the processing and increase the intensity of suicide grief. Clinicians would do well to recognize the relatively “normative” nature of the increased duration and intensity, rather than seeing it as immediately indicative of a DSM diagnosis of complicated/prolonged grief disorder.

Box 1
Common themes in the suicide grief process

Continue to: Family disruption

Family disruption. It is not uncommon for a suicide loss to result in family disruption.^6,31-32 This may manifest in the blaming of family members for “sins of omission or commission,”⁶ conflicts around the disclosure of the suicide both within and outside of the family, discordant grieving styles, and difficulties in understanding and attending to the needs of one’s children while grieving oneself.

Despite the common elements often seen in suicide grief, it is crucial to recognize that this process is not “one size fits all.” Not only are there individual variants, but Grad et al³³ found gender-based differences in grieving styles, and cultural issues such as the “meanings” assigned to suicide, and culturally sanctioned grief rituals and behaviors that are also likely to affect how grief is experienced and expressed. In addition, personal variants such as closeness/conflicts with the deceased, histories of previous trauma or loss, pre-existing psychiatric disorders, and attachment orientation³⁴ are likely to impact the grief process.

Losing close friends and colleagues may be similarly traumatic, but these survivors of suicide loss often receive even less social support than those who have kinship losses. Finally, when a suicide loss occurs in a professional capacity (such as the loss of a patient), this is likely to have many additional implications for one’s professional functions and identity.³⁵

Interventions to help survivors

Several goals and “tasks” are involved in the suicide bereavement process (Box 2^1,6,30,36-40). These can be achieved through the following interventions: Support groups. Many survivors find that support groups that focus on suicide loss are extremely helpful, and research has supported this.^1,4,41-44 Interactions with other suicide loss survivors provide hope, connection, and an “antidote” to stigma and shame. Optimally, group facilitators provide education, validation and normalization of the grief trajectory, and facilitate the sharing of both loss experiences and current functioning between group members. As a result, group participants often report renewed connections, increased efficacy in giving and accepting support, and decreased distress (including reductions in PTSD and depressive symptoms). The American Association of Suicidology (www.suicidology.org) and American Foundation of Suicide Prevention (www.afsp.org) provide contact information for suicide loss survivor groups (by geographical area) as well as information about online support groups.

Box 2
Goals and 'tasks' in suicide bereavement

Individual treatment. The limited research on individual treatment for suicide loss survivors suggests that while most participants find it generally helpful, a significant number of others report that their therapists lack knowledge of suicide grief and endorse stigmatizing attitudes toward suicide and suicide loss survivors.^45-46 In addition, Sanford et al³ found that survivors of suicide loss who endorsed PTSD symptoms were not assessed, diagnosed, or treated for these symptoms.

Continue to: This speaks to the importance of understanding what is...

This speaks to the importance of understanding what is “normative” for survivors of suicide loss. In general, “normalization” and psychoeducation about the suicide grief trajectory can play an important role in work with survivors of suicide loss, even in the presence of diagnosable disorders. While PTSD, depressive symptoms, and suicidal ideation are not uncommon in suicide loss survivors, and certainly may warrant clinical assessment and treatment, it can be helpful (and less stigmatizing) for your patients to know that these diagnoses are relatively common and understandable in the context of this devastating experience. For instance, survivors of suicide loss often report feeling relieved when clinicians explain the connections between traumatic loss and PTSD and/or depressive symptoms, and this can also help to relieve secondary anxiety about “going crazy.” Many survivors of suicide loss also describe feeling as though they are functioning on “autopilot” in the earlier stages of grief; it can help them understand the “function” of compartmentalization as potentially adaptive in the short run.

Suicide loss survivors may also find it helpful to learn about suicidal states of mind and their relationships to any types of mental illness their loved ones had struggled with.⁴⁷

Your role: Help survivors integrate the loss

Before beginning treatment with an individual who has lost a loved one to suicide, clinicians should thoroughly explore their own understanding of and experience with suicide, including assumptions around causation, internalized stigma about suicidal individuals and survivors of suicide loss, their own history of suicide loss or suicidality, cultural/religious attitudes, and anxiety/defenses associated with the topic of suicide. These factors, particularly when unexamined, are likely to impact the treatment relationship and one’s clinical efficacy.

In concert with the existing literature, consider the potential goals and tasks involved in the integration of the individual’s suicide loss, along with any individual factors/variants that may impact the grief trajectory. Kosminsky and Jordon³⁴ described the role of the clinician in this situation as a “transitional attachment figure” who facilitates the management and integration of the loss into the creation of what survivors of suicide loss have termed a “new normal.”

Because suicide loss is often associated with PTSD and other psychiatric illnesses (eg, depression, suicidality, substance abuse), it is essential to balance the assessment and treatment of these issues with attention to grief issues as needed. Again, to the extent that such issues have arisen primarily in the wake of the suicide loss, it can be helpful for patients to understand their connection to the context of the loss.

Continue to: Ideally, the clinician should...

Ideally, the clinician should be “present” with the patient’s pain, normative guilt, and rumination, without attempting to quickly eliminate or “fix” it or provide premature reassurance that the survivor of suicide loss “did nothing wrong.” Rather, as Jordan⁶ suggests, the clinician should act to promote a “fair trial” with respect to the patient’s guilt and blame, with an understanding of the “tyranny of hindsight.” The promotion of ambiguity tolerance should also play a role in coming to terms with many questions that may remain unanswered.

Optimally, clinicians should encourage patients to attend to their ongoing relationship with the deceased, particularly in the service of resolving “unfinished business,” ultimately integrating the loss into memories of the whole person. In line with this, survivors of suicide loss may be encouraged to create a narrative of the loss that incorporates both complexity and ambiguity. In the service of supporting the suicide loss survivor’s reinvestment in life, it is often helpful to facilitate their ability to anticipate and cope with triggers, such as anniversaries, birthdays, or holidays, as well as to develop and use skills for managing difficult or stigmatizing social or cultural reactions.

Any disruptions in family functioning should also be addressed. Psychoeducation about discordant grieving styles (particularly around gender) and the support of children’s grief may be helpful, and referrals to family or couples therapists should be considered as needed. Finally, the facilitation of suicide loss survivors’ creation of memorializations or rituals can help promote healing and make their loss meaningful.

Bottom Line

Losing a loved one to suicide is often a devastating and traumatic experience, but with optimal support, most survivors are ultimately able to integrate the loss and grow as a result. Understanding the suicide grief trajectory, as well as general guidelines for treatment, will facilitate healing and growth in the aftermath of suicide loss.

Related Resources

• Jordan JR, McIntosh JL. Grief after suicide: understanding the consequences and caring for the survivors. New York, NY: Routledge/Taylor & Francis Group; 2011.
• American Association of Suicidology. http://www.suicidology.org/. 
• American Foundation for Suicide Prevention. https://afsp.org/.

Xenomelia, literally meaning “foreign limb,” is a neuropsychiatric condition in which nonpsychotic individuals have an intense, persistent belief that one or more of their limbs does not belong to their body; instead they regard it as an alien appendage that should be discarded.¹ This unwavering, fixed belief resembles a delusion and is often debilitating to the point where the affected person strongly desires amputation of the unwanted limb. Traditionally, such requests often are denied by the medical community, which may cause an individual who has xenomelia to attempt risky self-amputation, or to injure the limb in a manner that makes subsequent amputation medically necessary.¹

The name for this condition has evolved over the years, depending on the emphasis given to specific characteristics. It was once called apotemnophilia, meaning “love of amputation,” when the condition was believed to be a fetish involving sexual gratification derived from being an amputee.^2,3 The term “body integrity identity disorder” (BIID) was introduced several decades later to incorporate the condition into a broader spectrum of accepted psychiatric pathologies, reasoning that it was the cause of a mismatch between objective and subjective body schema, similar to anorexia nervosa or body dysmorphic disorder.^4,5 This name also served to draw parallels between this condition and gender identity disorder. However, unlike these other disorders, individuals with this condition have sufficient factual insight to know they appear “normal” to others. The newest term, xenomelia, was established to acknowledge the neurologic component of the condition after neuroimaging studies showed structural changes to the right parietal lobe in individuals who desired amputation of their left lower limb, thus linking the part of the brain that processes sensory input from the affected limb.⁶

While particular nuances in symptomatology were modified in formulating these older names, certain hallmark features of xenomelia have remained the same.⁷ The condition starts in early childhood, prior to puberty. Those who have it feel intense distress, and are resigned to the notion that nothing but amputation can alleviate their distress. Xenomelia is overwhelmingly more common in males than females. It is accompanied by nontraditional attitudes about disability, including admiration of amputees and complete apathy and disregard toward the impairment that amputation would cause.

While the data are insufficient to draw a definitive conclusion, the trend in the published literature suggests in xenomelia, the lower left leg is predominantly the limb implicated in the condition, in right-handed individuals.¹

Here, we describe the case of a young man, Mr. H, with xenomelia who contacted us after reading about this condition in a review we recently published.¹ He agreed to allow us to anonymously describe his history and symptoms so that clinicians can recognize and help other individuals with xenomelia. His history may also help stimulate exploration of etiological factors and novel treatment strategies for xenomelia, other than amputation of a healthy limb.

CASE

‘I have this limb that should not be’

Mr. H, age 31, is a white male of Eastern European descent who was born, raised, and resides in a major metropolitan area in the western United States. He is married, college-educated, and currently works as a computer programmer for a prominent technology company. During our conversation via telephone, he exhibits above-average intelligence, appears to be in euthymic mood, and speaks with broad affect. Mr. H displays no psychotic symptoms such as overt delusions, hallucinations, reality distortion, or response to internal stimuli. His past psychiatric history includes attention-deficit/hyperactivity disorder (ADHD), which was diagnosed at age 6 and treated with appropriate medication under the care of a psychiatrist until age 18, when Mr. H decided to discontinue treatment. He no longer endorses symptoms of ADHD. He has no chronic medical conditions other than season allergies, for which he sometimes takes antihistamines, and occasional exacerbation of sciatica, for which he takes an over-the-counter nonsteroidal anti-inflammatory medication. Mr. H also has episodic insomnia, which he attributes to job-related stress and working odd hours. He was treated for meningitis as an infant, and underwent a bilateral myringotomy as a young child to treat recurrent ear infections. He has no other surgical history. He was raised in a middle-class Christian household that included both parents, who are still alive, still together, and have no significant psychiatric or medical history. He has no siblings.

Although he lives an ostensibly normal life, Mr. H suffers in silence and secrecy with xenomelia. According to him, there was never a time in his life when he didn’t feel that his left leg was “too long” and he was “walking on a stilt.” He says, “It takes a daily toll on my health and well-being.” He can clearly recall being 4 years old and playing games in which he would pretend to injure his left leg. He says, “When we played ‘make believe,’ the game would always end with something ‘happening’ to [my left leg].” He enjoys outdoor sports like snowboarding and mountain biking, and although he denies self-injurious behavior, he says in the event of an accident, he would prefer to land on his left leg, because it is the part of his body that he considers most “expendable.” One of his most vivid memories of childhood was going shopping with his parents and seeing an older man with only one leg standing on crutches in the parking lot outside the entrance. He remembers feeling “jealous” of this man.

Continue to: Although his parents were not particularly wealthy...

Although his parents were not particularly wealthy, they sent him to a private Christian school for most of his childhood. Mr. H admits that while there he didn’t fit in and felt like an outcast, in part because he didn’t come from the level of wealth of his classmates, and because having ADHD left him isolative and avoidant. “I was always the one going away to take medication,” he explains, and he also developed a hostile attitude. He was suspended from school multiple times for fighting. These years left him tremendously anxious and depressed, and he would often find it therapeutic to sit with his left leg bent underneath him, so as to hide its undesired portion. It was common for him to tie his leg up and stare at himself in the mirror for minutes to hours as a form of stress reduction.

Most of Mr. H’s social circle is composed of friends he has known since childhood, none of whom are aware of his condition. He acknowledges that his feelings are “bizarre in nature” and so he has kept this secret on a “need-to-know” basis out of “fear of rejection, mockery, and damage to my reputation.” Through the years, he has sought out and encountered others with this condition, first anonymously on the internet, then in-person once he gets to know and trust them. He claims to know and be friendly with several people with xenomelia in his own city, some of whom have undergone amputation and are extremely happy with the results. According to Mr. H, there is a community aspect to xenomelia in his city, and people with the condition often meet each other socially. He has revealed his secret to 2 women he dated, including his present wife, who he told 3 years into their relationship. “I was prepared for her to leave me,” he recalls. Although he has never connected the desire for amputation with sexuality, he certainly believes that amputating his left leg would enhance his sex life. “Do I find amputees sexy?” he asks, “I would say yes.” On a 10-point scale, he considers his sex life to be a “7 or 8,” and it would reach 10 if he underwent amputation.

Mr. H has a calendar on which he keeps track of the days when he feels “impaired” by his xenomelia. He marks each day as either “red” or “green.” So far, he does not recognize a pattern of exacerbation. “I have my good days, then I have my bad days,” he laments. “On good days, I think about amputation and where my leg should actually end, but it is something I can quickly push off. On my bad days, I am constantly reminded in one way or another that, yes, I have this limb that should not be.” While he has never sought treatment for this condition from a health care professional, he developed his own therapeutic regimen that includes yoga, hiking, and daily use of cannabis, which “helps take the edge off.” He used alcohol in the past as self-medication, but stopped drinking to excess when it started to disrupt other aspects of his life. According to Mr. H, the goal is to distract himself from the condition, which provides temporary relief. “I find if my mind is more engaged, the amputation thoughts are fewer and less in intensity.” He reports that the months leading up to his wedding were particularly therapeutic because wedding planning provided an excellent distraction.

Overall, his current desire for amputation is steadily increasing. “Lately it has become more of a roller coaster,” he says. “If there’s a safe way to do it, I’ll do it.” An amputation would allow him to “feel good, complete, grounded, and content.” If he were to undergo amputation, he would use a prosthetic in order to retain mobility and keep his physique as discreet as possible. He has made initial inquiries into getting an amputation, saying, “I have heard of rumors of surgeons willing to perform the surgery, for a price. However, I have not completed the ‘vetting process’ to actually come into contact with the surgeons themselves.” Similar to others with xenomelia, he is easily able to draw a line on his leg, exactly where the desired amputation should occur.⁸ For most of his life, that line would have been 2 inches above his knee, but in recent years, the line has drifted lower, to 2 inches below the knee. However, he “wouldn’t mind either” line of amputation. He indicates the area below the desired line is less sensitive to pain than the corresponding part of his right leg, particularly his toes.

Mr. H’s wife is extremely supportive and understanding of her husband’s condition, but is opposed to the possibility of amputation (Box).

Box
Xenomelia: A spouse's perspective

Continue to: Much left to be learned about xenomelia

Much left to be learned about xenomelia

What remains to be discovered about xenomelia falls into 2 areas:

• the possible usefulness of various neuroimaging modalities (morphological MRI, functional MRI, magnetic resonance spectroscopy, and diffusion tensor imaging) to identify and localize anomalous neural pathways or neuroanatomical foci associated with this condition, such as an aberrantly developed or poorly myelinated right parietal lobe, which houses the limb’s physical proprioception
• a biopsychosocial inquiry into whether there exists a specific combination of a given individual’s organic brain, mind, and environmental interactions that may give rise to this condition, and whether we might detect a prodrome that arises in early childhood. The objective of any research into this condition would be to minimize its effects, if not prevent them altogether.¹

As this case illustrates, xenomelia begins in early childhood, with symptoms being reported in children as young as age 3.⁷ However, no published literature has investigated these early stages. We’ve learned that individuals with xenomelia often can point to key childhood experiences or memories related to seeing people with amputated limbs. They remember feeling a sense of wonder, fascination, or other strong emotion. It may be in this memory that xenomelia is permanently imprinted. This was definitely true for Mr. H, who never knew a time when he didn’t endure some level of debilitation from xenomelia, and distinctly remembers feeling jealous upon seeing a man with the amputated leg standing on crutches in a store parking lot. Although he has come across many amputees in his life, Mr. H says he vividly remembers everything about that particular man in that particular moment, adding “I can still see the clothes he was wearing. I can still see the cars in the parking lot.” That was likely his moment of vivid and powerful imprinting.

Particularly influential changes occur in adolescence, not just in the course of physical development, but in the formulation of self-identity, which involves the inevitable comparison of one’s own appearance to that of others, with heightened awareness of what others might perceive. This phenomenon is known as “the imaginary audience,” and it is often overemphasized in the minds of individuals with xenomelia.⁷ Mr. H is a textbook example of someone acutely aware of his “audience,” suffering from the embarrassment that came from being less wealthy than others at his school, and having to manage his ADHD in plain sight of his classmates, who knew that he required medication. It is no surprise that he felt like an outcast and got suspended for fighting. He would relieve anxiety by tying his leg up and staring at himself in the mirror, finding refuge in front of an audience of one that understood and sympathized with his suffering.

Among the most notorious aspects of this condition is investigation into the possibility of there being a sexual component to the desire for amputation. The notion that the desire is a fetish employed for the purpose of sexual arousal was first propagated by Penthouse magazine in the 1970s.⁹ Learning that xenomelia exists in a child long before sexual maturation—and in an older adult long after sexual drive peaks—suggests the condition is independent of sexuality. However, this aspect of xenomelia continues to be investigated. A recent study found that >70% of individuals with xenomelia are at least partially motivated by the perceived enhancement in sexual gratification.¹⁰ Individuals with this motivation are predominantly male, homosexual, come from a religious background, and are far more likely to self-amputate.¹⁰ Mr. H admitted that he is sexually attracted to amputees, and while he had no complaints about his sex life, he felt it could only reach the highest levels of gratification if he were an amputee.

It is reasonable to posit that there is a genetic mechanism that creates a cortical template of one’s body, and this template connects with the limbic system, encoding a visual preference for and attraction to one’s own idealized and preferred body morphology that includes an amputated limb.¹¹ Therefore, if Mr. H sees himself as an amputee, it would be reasonable for him to identify with and be attracted to other amputees. However, Mr. H is clearly not preoccupied with sexuality, and believes that heightened sexual gratification would be an ancillary bonus, and not the main objective, of amputation.

Continue to: Most individuals who have particpated in research studies about xenomelia tend to...

Most individuals who have participated in research studies about xenomelia tend to be older, mainly in their 60s. This is particularly true of individuals who go through with amputation. At some point, the need for a person to invoke their autonomy, alleviate their debilitation, and fulfill their desire may supersede their aversion to physical disability and social ridicule. At this stage in his life, Mr. H can’t commit to going forward with the amputation. However, he regards the likelihood of undergoing amputation to be quite high. He made initial inquiries to find a surgeon who would be willing to perform the procedure. Given that he has found people with xenomelia who have undergone amputation, he will likely will be able find a surgeon to perform the procedure. Mr. H reports that just about everyone he has ever known with xenomelia who underwent amputation is completely satisfied with their decision, even years later. He has come across only one person who regretted the amputation, and he believes that person was likely suffering from other psychiatric issues, and did not have true xenomelia.

In the mind of an individual with xenomelia, the desire for amputation is separate from a desire to be disabled. Mr. H is mindful of the assumed irrationality of removing a healthy but “alien” limb to replace it with a prosthetic limb that is equally alien. The perceived irony is not lost on him. He values his mobility, and has no desire to use crutches, a wheelchair, or any other ambulatory tool. This is consistent with most individuals with xenomelia, who are neither motived by the desire to flaunt their amputated limb, nor by the sympathy they might receive from others by endorsing impaired mobility. They don’t consider themselves disabled. On the contrary, for them, amputation is a much-desired enhancement to their health and well-being.

Increased opportunities for research

The internet, social media, and even peer-reviewed medical journals offer ever-increasing opportunities for individuals with xenomelia, such as Mr. H, to have their story told, regardless of whether they choose to identify themselves or remain anonymous. There are no published data about the prevalence of xenomelia, but it is almost certainly rare. However, if Mr. H was able to meet multiple people with xeno­melia in his own city and form a supportive community with them, then perhaps it isn’t exactly as rare as one might initially assume. People with xenomelia may tend to look for each other, hoping those with the same condition might show them the greatest empathy.

From Mr. H’s experience, it appears that it would be possible to locate a sufficient number of individuals with xenomelia for the purposes of conducting research, which might allow for results with acceptable statistical power. There are plenty of individual patient stories, and by documenting these stories in published literature, it is likely that patterns would emerge and causality might be determined. Such data might be bolstered by a possible strong neurologic corroboration based on what is found via neuroimaging.

Informed research into xenomelia is still in the early stages, and it is clear that there is much left to discover. It is vital that, moving forward, investigation into this condition be thorough and objective, with the goal of alleviating this secretive and debilitating neuropsychiatric condition.

Continue to: Bottom Line

Individuals with xenomelia have the persistent belief that one or more of their limbs does not belong to their body but is an alien appendage that should be removed. Patients with this condition may resort to self-amputation or self-mutilation that requires subsequent surgical amputation. Xenomelia may be related to anomalous brain development, with a lack of neural representation of a limb in the right parietal lobe.

Related Resources

• Hilti LM, Hänggi J, Vitacco DA, et al. The desire for healthy limb amputation: structural brain correlates and clinical features of xenomelia. Brain. 2013;136(pt 1):318-329.
• Brugger P, Lenggenhager B, Giummarra MJ. Xenomelia: a social neuroscience view of altered bodily self-consciousness. Front Psychol. 2013;4:204. doi:10.3389/fpsyg.2013.00204.

Xenomelia, literally meaning “foreign limb,” is a neuropsychiatric condition in which nonpsychotic individuals have an intense, persistent belief that one or more of their limbs does not belong to their body; instead they regard it as an alien appendage that should be discarded.¹ This unwavering, fixed belief resembles a delusion and is often debilitating to the point where the affected person strongly desires amputation of the unwanted limb. Traditionally, such requests often are denied by the medical community, which may cause an individual who has xenomelia to attempt risky self-amputation, or to injure the limb in a manner that makes subsequent amputation medically necessary.¹

The name for this condition has evolved over the years, depending on the emphasis given to specific characteristics. It was once called apotemnophilia, meaning “love of amputation,” when the condition was believed to be a fetish involving sexual gratification derived from being an amputee.^2,3 The term “body integrity identity disorder” (BIID) was introduced several decades later to incorporate the condition into a broader spectrum of accepted psychiatric pathologies, reasoning that it was the cause of a mismatch between objective and subjective body schema, similar to anorexia nervosa or body dysmorphic disorder.^4,5 This name also served to draw parallels between this condition and gender identity disorder. However, unlike these other disorders, individuals with this condition have sufficient factual insight to know they appear “normal” to others. The newest term, xenomelia, was established to acknowledge the neurologic component of the condition after neuroimaging studies showed structural changes to the right parietal lobe in individuals who desired amputation of their left lower limb, thus linking the part of the brain that processes sensory input from the affected limb.⁶

While particular nuances in symptomatology were modified in formulating these older names, certain hallmark features of xenomelia have remained the same.⁷ The condition starts in early childhood, prior to puberty. Those who have it feel intense distress, and are resigned to the notion that nothing but amputation can alleviate their distress. Xenomelia is overwhelmingly more common in males than females. It is accompanied by nontraditional attitudes about disability, including admiration of amputees and complete apathy and disregard toward the impairment that amputation would cause.

While the data are insufficient to draw a definitive conclusion, the trend in the published literature suggests in xenomelia, the lower left leg is predominantly the limb implicated in the condition, in right-handed individuals.¹

Here, we describe the case of a young man, Mr. H, with xenomelia who contacted us after reading about this condition in a review we recently published.¹ He agreed to allow us to anonymously describe his history and symptoms so that clinicians can recognize and help other individuals with xenomelia. His history may also help stimulate exploration of etiological factors and novel treatment strategies for xenomelia, other than amputation of a healthy limb.

CASE

‘I have this limb that should not be’

Mr. H, age 31, is a white male of Eastern European descent who was born, raised, and resides in a major metropolitan area in the western United States. He is married, college-educated, and currently works as a computer programmer for a prominent technology company. During our conversation via telephone, he exhibits above-average intelligence, appears to be in euthymic mood, and speaks with broad affect. Mr. H displays no psychotic symptoms such as overt delusions, hallucinations, reality distortion, or response to internal stimuli. His past psychiatric history includes attention-deficit/hyperactivity disorder (ADHD), which was diagnosed at age 6 and treated with appropriate medication under the care of a psychiatrist until age 18, when Mr. H decided to discontinue treatment. He no longer endorses symptoms of ADHD. He has no chronic medical conditions other than season allergies, for which he sometimes takes antihistamines, and occasional exacerbation of sciatica, for which he takes an over-the-counter nonsteroidal anti-inflammatory medication. Mr. H also has episodic insomnia, which he attributes to job-related stress and working odd hours. He was treated for meningitis as an infant, and underwent a bilateral myringotomy as a young child to treat recurrent ear infections. He has no other surgical history. He was raised in a middle-class Christian household that included both parents, who are still alive, still together, and have no significant psychiatric or medical history. He has no siblings.

Although he lives an ostensibly normal life, Mr. H suffers in silence and secrecy with xenomelia. According to him, there was never a time in his life when he didn’t feel that his left leg was “too long” and he was “walking on a stilt.” He says, “It takes a daily toll on my health and well-being.” He can clearly recall being 4 years old and playing games in which he would pretend to injure his left leg. He says, “When we played ‘make believe,’ the game would always end with something ‘happening’ to [my left leg].” He enjoys outdoor sports like snowboarding and mountain biking, and although he denies self-injurious behavior, he says in the event of an accident, he would prefer to land on his left leg, because it is the part of his body that he considers most “expendable.” One of his most vivid memories of childhood was going shopping with his parents and seeing an older man with only one leg standing on crutches in the parking lot outside the entrance. He remembers feeling “jealous” of this man.

Continue to: Although his parents were not particularly wealthy...

Although his parents were not particularly wealthy, they sent him to a private Christian school for most of his childhood. Mr. H admits that while there he didn’t fit in and felt like an outcast, in part because he didn’t come from the level of wealth of his classmates, and because having ADHD left him isolative and avoidant. “I was always the one going away to take medication,” he explains, and he also developed a hostile attitude. He was suspended from school multiple times for fighting. These years left him tremendously anxious and depressed, and he would often find it therapeutic to sit with his left leg bent underneath him, so as to hide its undesired portion. It was common for him to tie his leg up and stare at himself in the mirror for minutes to hours as a form of stress reduction.

Most of Mr. H’s social circle is composed of friends he has known since childhood, none of whom are aware of his condition. He acknowledges that his feelings are “bizarre in nature” and so he has kept this secret on a “need-to-know” basis out of “fear of rejection, mockery, and damage to my reputation.” Through the years, he has sought out and encountered others with this condition, first anonymously on the internet, then in-person once he gets to know and trust them. He claims to know and be friendly with several people with xenomelia in his own city, some of whom have undergone amputation and are extremely happy with the results. According to Mr. H, there is a community aspect to xenomelia in his city, and people with the condition often meet each other socially. He has revealed his secret to 2 women he dated, including his present wife, who he told 3 years into their relationship. “I was prepared for her to leave me,” he recalls. Although he has never connected the desire for amputation with sexuality, he certainly believes that amputating his left leg would enhance his sex life. “Do I find amputees sexy?” he asks, “I would say yes.” On a 10-point scale, he considers his sex life to be a “7 or 8,” and it would reach 10 if he underwent amputation.

Mr. H has a calendar on which he keeps track of the days when he feels “impaired” by his xenomelia. He marks each day as either “red” or “green.” So far, he does not recognize a pattern of exacerbation. “I have my good days, then I have my bad days,” he laments. “On good days, I think about amputation and where my leg should actually end, but it is something I can quickly push off. On my bad days, I am constantly reminded in one way or another that, yes, I have this limb that should not be.” While he has never sought treatment for this condition from a health care professional, he developed his own therapeutic regimen that includes yoga, hiking, and daily use of cannabis, which “helps take the edge off.” He used alcohol in the past as self-medication, but stopped drinking to excess when it started to disrupt other aspects of his life. According to Mr. H, the goal is to distract himself from the condition, which provides temporary relief. “I find if my mind is more engaged, the amputation thoughts are fewer and less in intensity.” He reports that the months leading up to his wedding were particularly therapeutic because wedding planning provided an excellent distraction.

Overall, his current desire for amputation is steadily increasing. “Lately it has become more of a roller coaster,” he says. “If there’s a safe way to do it, I’ll do it.” An amputation would allow him to “feel good, complete, grounded, and content.” If he were to undergo amputation, he would use a prosthetic in order to retain mobility and keep his physique as discreet as possible. He has made initial inquiries into getting an amputation, saying, “I have heard of rumors of surgeons willing to perform the surgery, for a price. However, I have not completed the ‘vetting process’ to actually come into contact with the surgeons themselves.” Similar to others with xenomelia, he is easily able to draw a line on his leg, exactly where the desired amputation should occur.⁸ For most of his life, that line would have been 2 inches above his knee, but in recent years, the line has drifted lower, to 2 inches below the knee. However, he “wouldn’t mind either” line of amputation. He indicates the area below the desired line is less sensitive to pain than the corresponding part of his right leg, particularly his toes.

Mr. H’s wife is extremely supportive and understanding of her husband’s condition, but is opposed to the possibility of amputation (Box).

Box
Xenomelia: A spouse's perspective

Continue to: Much left to be learned about xenomelia

Much left to be learned about xenomelia

What remains to be discovered about xenomelia falls into 2 areas:

• the possible usefulness of various neuroimaging modalities (morphological MRI, functional MRI, magnetic resonance spectroscopy, and diffusion tensor imaging) to identify and localize anomalous neural pathways or neuroanatomical foci associated with this condition, such as an aberrantly developed or poorly myelinated right parietal lobe, which houses the limb’s physical proprioception
• a biopsychosocial inquiry into whether there exists a specific combination of a given individual’s organic brain, mind, and environmental interactions that may give rise to this condition, and whether we might detect a prodrome that arises in early childhood. The objective of any research into this condition would be to minimize its effects, if not prevent them altogether.¹

As this case illustrates, xenomelia begins in early childhood, with symptoms being reported in children as young as age 3.⁷ However, no published literature has investigated these early stages. We’ve learned that individuals with xenomelia often can point to key childhood experiences or memories related to seeing people with amputated limbs. They remember feeling a sense of wonder, fascination, or other strong emotion. It may be in this memory that xenomelia is permanently imprinted. This was definitely true for Mr. H, who never knew a time when he didn’t endure some level of debilitation from xenomelia, and distinctly remembers feeling jealous upon seeing a man with the amputated leg standing on crutches in a store parking lot. Although he has come across many amputees in his life, Mr. H says he vividly remembers everything about that particular man in that particular moment, adding “I can still see the clothes he was wearing. I can still see the cars in the parking lot.” That was likely his moment of vivid and powerful imprinting.

Particularly influential changes occur in adolescence, not just in the course of physical development, but in the formulation of self-identity, which involves the inevitable comparison of one’s own appearance to that of others, with heightened awareness of what others might perceive. This phenomenon is known as “the imaginary audience,” and it is often overemphasized in the minds of individuals with xenomelia.⁷ Mr. H is a textbook example of someone acutely aware of his “audience,” suffering from the embarrassment that came from being less wealthy than others at his school, and having to manage his ADHD in plain sight of his classmates, who knew that he required medication. It is no surprise that he felt like an outcast and got suspended for fighting. He would relieve anxiety by tying his leg up and staring at himself in the mirror, finding refuge in front of an audience of one that understood and sympathized with his suffering.

Among the most notorious aspects of this condition is investigation into the possibility of there being a sexual component to the desire for amputation. The notion that the desire is a fetish employed for the purpose of sexual arousal was first propagated by Penthouse magazine in the 1970s.⁹ Learning that xenomelia exists in a child long before sexual maturation—and in an older adult long after sexual drive peaks—suggests the condition is independent of sexuality. However, this aspect of xenomelia continues to be investigated. A recent study found that >70% of individuals with xenomelia are at least partially motivated by the perceived enhancement in sexual gratification.¹⁰ Individuals with this motivation are predominantly male, homosexual, come from a religious background, and are far more likely to self-amputate.¹⁰ Mr. H admitted that he is sexually attracted to amputees, and while he had no complaints about his sex life, he felt it could only reach the highest levels of gratification if he were an amputee.

It is reasonable to posit that there is a genetic mechanism that creates a cortical template of one’s body, and this template connects with the limbic system, encoding a visual preference for and attraction to one’s own idealized and preferred body morphology that includes an amputated limb.¹¹ Therefore, if Mr. H sees himself as an amputee, it would be reasonable for him to identify with and be attracted to other amputees. However, Mr. H is clearly not preoccupied with sexuality, and believes that heightened sexual gratification would be an ancillary bonus, and not the main objective, of amputation.

Continue to: Most individuals who have particpated in research studies about xenomelia tend to...

Most individuals who have participated in research studies about xenomelia tend to be older, mainly in their 60s. This is particularly true of individuals who go through with amputation. At some point, the need for a person to invoke their autonomy, alleviate their debilitation, and fulfill their desire may supersede their aversion to physical disability and social ridicule. At this stage in his life, Mr. H can’t commit to going forward with the amputation. However, he regards the likelihood of undergoing amputation to be quite high. He made initial inquiries to find a surgeon who would be willing to perform the procedure. Given that he has found people with xenomelia who have undergone amputation, he will likely will be able find a surgeon to perform the procedure. Mr. H reports that just about everyone he has ever known with xenomelia who underwent amputation is completely satisfied with their decision, even years later. He has come across only one person who regretted the amputation, and he believes that person was likely suffering from other psychiatric issues, and did not have true xenomelia.

In the mind of an individual with xenomelia, the desire for amputation is separate from a desire to be disabled. Mr. H is mindful of the assumed irrationality of removing a healthy but “alien” limb to replace it with a prosthetic limb that is equally alien. The perceived irony is not lost on him. He values his mobility, and has no desire to use crutches, a wheelchair, or any other ambulatory tool. This is consistent with most individuals with xenomelia, who are neither motived by the desire to flaunt their amputated limb, nor by the sympathy they might receive from others by endorsing impaired mobility. They don’t consider themselves disabled. On the contrary, for them, amputation is a much-desired enhancement to their health and well-being.

Increased opportunities for research

The internet, social media, and even peer-reviewed medical journals offer ever-increasing opportunities for individuals with xenomelia, such as Mr. H, to have their story told, regardless of whether they choose to identify themselves or remain anonymous. There are no published data about the prevalence of xenomelia, but it is almost certainly rare. However, if Mr. H was able to meet multiple people with xeno­melia in his own city and form a supportive community with them, then perhaps it isn’t exactly as rare as one might initially assume. People with xenomelia may tend to look for each other, hoping those with the same condition might show them the greatest empathy.

From Mr. H’s experience, it appears that it would be possible to locate a sufficient number of individuals with xenomelia for the purposes of conducting research, which might allow for results with acceptable statistical power. There are plenty of individual patient stories, and by documenting these stories in published literature, it is likely that patterns would emerge and causality might be determined. Such data might be bolstered by a possible strong neurologic corroboration based on what is found via neuroimaging.

Informed research into xenomelia is still in the early stages, and it is clear that there is much left to discover. It is vital that, moving forward, investigation into this condition be thorough and objective, with the goal of alleviating this secretive and debilitating neuropsychiatric condition.

Continue to: Bottom Line

Individuals with xenomelia have the persistent belief that one or more of their limbs does not belong to their body but is an alien appendage that should be removed. Patients with this condition may resort to self-amputation or self-mutilation that requires subsequent surgical amputation. Xenomelia may be related to anomalous brain development, with a lack of neural representation of a limb in the right parietal lobe.

Related Resources

• Hilti LM, Hänggi J, Vitacco DA, et al. The desire for healthy limb amputation: structural brain correlates and clinical features of xenomelia. Brain. 2013;136(pt 1):318-329.
• Brugger P, Lenggenhager B, Giummarra MJ. Xenomelia: a social neuroscience view of altered bodily self-consciousness. Front Psychol. 2013;4:204. doi:10.3389/fpsyg.2013.00204.

Xenomelia, literally meaning “foreign limb,” is a neuropsychiatric condition in which nonpsychotic individuals have an intense, persistent belief that one or more of their limbs does not belong to their body; instead they regard it as an alien appendage that should be discarded.¹ This unwavering, fixed belief resembles a delusion and is often debilitating to the point where the affected person strongly desires amputation of the unwanted limb. Traditionally, such requests often are denied by the medical community, which may cause an individual who has xenomelia to attempt risky self-amputation, or to injure the limb in a manner that makes subsequent amputation medically necessary.¹

The name for this condition has evolved over the years, depending on the emphasis given to specific characteristics. It was once called apotemnophilia, meaning “love of amputation,” when the condition was believed to be a fetish involving sexual gratification derived from being an amputee.^2,3 The term “body integrity identity disorder” (BIID) was introduced several decades later to incorporate the condition into a broader spectrum of accepted psychiatric pathologies, reasoning that it was the cause of a mismatch between objective and subjective body schema, similar to anorexia nervosa or body dysmorphic disorder.^4,5 This name also served to draw parallels between this condition and gender identity disorder. However, unlike these other disorders, individuals with this condition have sufficient factual insight to know they appear “normal” to others. The newest term, xenomelia, was established to acknowledge the neurologic component of the condition after neuroimaging studies showed structural changes to the right parietal lobe in individuals who desired amputation of their left lower limb, thus linking the part of the brain that processes sensory input from the affected limb.⁶

While particular nuances in symptomatology were modified in formulating these older names, certain hallmark features of xenomelia have remained the same.⁷ The condition starts in early childhood, prior to puberty. Those who have it feel intense distress, and are resigned to the notion that nothing but amputation can alleviate their distress. Xenomelia is overwhelmingly more common in males than females. It is accompanied by nontraditional attitudes about disability, including admiration of amputees and complete apathy and disregard toward the impairment that amputation would cause.

While the data are insufficient to draw a definitive conclusion, the trend in the published literature suggests in xenomelia, the lower left leg is predominantly the limb implicated in the condition, in right-handed individuals.¹

Here, we describe the case of a young man, Mr. H, with xenomelia who contacted us after reading about this condition in a review we recently published.¹ He agreed to allow us to anonymously describe his history and symptoms so that clinicians can recognize and help other individuals with xenomelia. His history may also help stimulate exploration of etiological factors and novel treatment strategies for xenomelia, other than amputation of a healthy limb.

CASE

‘I have this limb that should not be’

Mr. H, age 31, is a white male of Eastern European descent who was born, raised, and resides in a major metropolitan area in the western United States. He is married, college-educated, and currently works as a computer programmer for a prominent technology company. During our conversation via telephone, he exhibits above-average intelligence, appears to be in euthymic mood, and speaks with broad affect. Mr. H displays no psychotic symptoms such as overt delusions, hallucinations, reality distortion, or response to internal stimuli. His past psychiatric history includes attention-deficit/hyperactivity disorder (ADHD), which was diagnosed at age 6 and treated with appropriate medication under the care of a psychiatrist until age 18, when Mr. H decided to discontinue treatment. He no longer endorses symptoms of ADHD. He has no chronic medical conditions other than season allergies, for which he sometimes takes antihistamines, and occasional exacerbation of sciatica, for which he takes an over-the-counter nonsteroidal anti-inflammatory medication. Mr. H also has episodic insomnia, which he attributes to job-related stress and working odd hours. He was treated for meningitis as an infant, and underwent a bilateral myringotomy as a young child to treat recurrent ear infections. He has no other surgical history. He was raised in a middle-class Christian household that included both parents, who are still alive, still together, and have no significant psychiatric or medical history. He has no siblings.

Although he lives an ostensibly normal life, Mr. H suffers in silence and secrecy with xenomelia. According to him, there was never a time in his life when he didn’t feel that his left leg was “too long” and he was “walking on a stilt.” He says, “It takes a daily toll on my health and well-being.” He can clearly recall being 4 years old and playing games in which he would pretend to injure his left leg. He says, “When we played ‘make believe,’ the game would always end with something ‘happening’ to [my left leg].” He enjoys outdoor sports like snowboarding and mountain biking, and although he denies self-injurious behavior, he says in the event of an accident, he would prefer to land on his left leg, because it is the part of his body that he considers most “expendable.” One of his most vivid memories of childhood was going shopping with his parents and seeing an older man with only one leg standing on crutches in the parking lot outside the entrance. He remembers feeling “jealous” of this man.

Continue to: Although his parents were not particularly wealthy...

Although his parents were not particularly wealthy, they sent him to a private Christian school for most of his childhood. Mr. H admits that while there he didn’t fit in and felt like an outcast, in part because he didn’t come from the level of wealth of his classmates, and because having ADHD left him isolative and avoidant. “I was always the one going away to take medication,” he explains, and he also developed a hostile attitude. He was suspended from school multiple times for fighting. These years left him tremendously anxious and depressed, and he would often find it therapeutic to sit with his left leg bent underneath him, so as to hide its undesired portion. It was common for him to tie his leg up and stare at himself in the mirror for minutes to hours as a form of stress reduction.

Most of Mr. H’s social circle is composed of friends he has known since childhood, none of whom are aware of his condition. He acknowledges that his feelings are “bizarre in nature” and so he has kept this secret on a “need-to-know” basis out of “fear of rejection, mockery, and damage to my reputation.” Through the years, he has sought out and encountered others with this condition, first anonymously on the internet, then in-person once he gets to know and trust them. He claims to know and be friendly with several people with xenomelia in his own city, some of whom have undergone amputation and are extremely happy with the results. According to Mr. H, there is a community aspect to xenomelia in his city, and people with the condition often meet each other socially. He has revealed his secret to 2 women he dated, including his present wife, who he told 3 years into their relationship. “I was prepared for her to leave me,” he recalls. Although he has never connected the desire for amputation with sexuality, he certainly believes that amputating his left leg would enhance his sex life. “Do I find amputees sexy?” he asks, “I would say yes.” On a 10-point scale, he considers his sex life to be a “7 or 8,” and it would reach 10 if he underwent amputation.

Mr. H has a calendar on which he keeps track of the days when he feels “impaired” by his xenomelia. He marks each day as either “red” or “green.” So far, he does not recognize a pattern of exacerbation. “I have my good days, then I have my bad days,” he laments. “On good days, I think about amputation and where my leg should actually end, but it is something I can quickly push off. On my bad days, I am constantly reminded in one way or another that, yes, I have this limb that should not be.” While he has never sought treatment for this condition from a health care professional, he developed his own therapeutic regimen that includes yoga, hiking, and daily use of cannabis, which “helps take the edge off.” He used alcohol in the past as self-medication, but stopped drinking to excess when it started to disrupt other aspects of his life. According to Mr. H, the goal is to distract himself from the condition, which provides temporary relief. “I find if my mind is more engaged, the amputation thoughts are fewer and less in intensity.” He reports that the months leading up to his wedding were particularly therapeutic because wedding planning provided an excellent distraction.

Overall, his current desire for amputation is steadily increasing. “Lately it has become more of a roller coaster,” he says. “If there’s a safe way to do it, I’ll do it.” An amputation would allow him to “feel good, complete, grounded, and content.” If he were to undergo amputation, he would use a prosthetic in order to retain mobility and keep his physique as discreet as possible. He has made initial inquiries into getting an amputation, saying, “I have heard of rumors of surgeons willing to perform the surgery, for a price. However, I have not completed the ‘vetting process’ to actually come into contact with the surgeons themselves.” Similar to others with xenomelia, he is easily able to draw a line on his leg, exactly where the desired amputation should occur.⁸ For most of his life, that line would have been 2 inches above his knee, but in recent years, the line has drifted lower, to 2 inches below the knee. However, he “wouldn’t mind either” line of amputation. He indicates the area below the desired line is less sensitive to pain than the corresponding part of his right leg, particularly his toes.

Mr. H’s wife is extremely supportive and understanding of her husband’s condition, but is opposed to the possibility of amputation (Box).

Box
Xenomelia: A spouse's perspective

Continue to: Much left to be learned about xenomelia

Much left to be learned about xenomelia

What remains to be discovered about xenomelia falls into 2 areas:

• the possible usefulness of various neuroimaging modalities (morphological MRI, functional MRI, magnetic resonance spectroscopy, and diffusion tensor imaging) to identify and localize anomalous neural pathways or neuroanatomical foci associated with this condition, such as an aberrantly developed or poorly myelinated right parietal lobe, which houses the limb’s physical proprioception
• a biopsychosocial inquiry into whether there exists a specific combination of a given individual’s organic brain, mind, and environmental interactions that may give rise to this condition, and whether we might detect a prodrome that arises in early childhood. The objective of any research into this condition would be to minimize its effects, if not prevent them altogether.¹

As this case illustrates, xenomelia begins in early childhood, with symptoms being reported in children as young as age 3.⁷ However, no published literature has investigated these early stages. We’ve learned that individuals with xenomelia often can point to key childhood experiences or memories related to seeing people with amputated limbs. They remember feeling a sense of wonder, fascination, or other strong emotion. It may be in this memory that xenomelia is permanently imprinted. This was definitely true for Mr. H, who never knew a time when he didn’t endure some level of debilitation from xenomelia, and distinctly remembers feeling jealous upon seeing a man with the amputated leg standing on crutches in a store parking lot. Although he has come across many amputees in his life, Mr. H says he vividly remembers everything about that particular man in that particular moment, adding “I can still see the clothes he was wearing. I can still see the cars in the parking lot.” That was likely his moment of vivid and powerful imprinting.

Particularly influential changes occur in adolescence, not just in the course of physical development, but in the formulation of self-identity, which involves the inevitable comparison of one’s own appearance to that of others, with heightened awareness of what others might perceive. This phenomenon is known as “the imaginary audience,” and it is often overemphasized in the minds of individuals with xenomelia.⁷ Mr. H is a textbook example of someone acutely aware of his “audience,” suffering from the embarrassment that came from being less wealthy than others at his school, and having to manage his ADHD in plain sight of his classmates, who knew that he required medication. It is no surprise that he felt like an outcast and got suspended for fighting. He would relieve anxiety by tying his leg up and staring at himself in the mirror, finding refuge in front of an audience of one that understood and sympathized with his suffering.

Among the most notorious aspects of this condition is investigation into the possibility of there being a sexual component to the desire for amputation. The notion that the desire is a fetish employed for the purpose of sexual arousal was first propagated by Penthouse magazine in the 1970s.⁹ Learning that xenomelia exists in a child long before sexual maturation—and in an older adult long after sexual drive peaks—suggests the condition is independent of sexuality. However, this aspect of xenomelia continues to be investigated. A recent study found that >70% of individuals with xenomelia are at least partially motivated by the perceived enhancement in sexual gratification.¹⁰ Individuals with this motivation are predominantly male, homosexual, come from a religious background, and are far more likely to self-amputate.¹⁰ Mr. H admitted that he is sexually attracted to amputees, and while he had no complaints about his sex life, he felt it could only reach the highest levels of gratification if he were an amputee.

It is reasonable to posit that there is a genetic mechanism that creates a cortical template of one’s body, and this template connects with the limbic system, encoding a visual preference for and attraction to one’s own idealized and preferred body morphology that includes an amputated limb.¹¹ Therefore, if Mr. H sees himself as an amputee, it would be reasonable for him to identify with and be attracted to other amputees. However, Mr. H is clearly not preoccupied with sexuality, and believes that heightened sexual gratification would be an ancillary bonus, and not the main objective, of amputation.

Continue to: Most individuals who have particpated in research studies about xenomelia tend to...

Most individuals who have participated in research studies about xenomelia tend to be older, mainly in their 60s. This is particularly true of individuals who go through with amputation. At some point, the need for a person to invoke their autonomy, alleviate their debilitation, and fulfill their desire may supersede their aversion to physical disability and social ridicule. At this stage in his life, Mr. H can’t commit to going forward with the amputation. However, he regards the likelihood of undergoing amputation to be quite high. He made initial inquiries to find a surgeon who would be willing to perform the procedure. Given that he has found people with xenomelia who have undergone amputation, he will likely will be able find a surgeon to perform the procedure. Mr. H reports that just about everyone he has ever known with xenomelia who underwent amputation is completely satisfied with their decision, even years later. He has come across only one person who regretted the amputation, and he believes that person was likely suffering from other psychiatric issues, and did not have true xenomelia.

In the mind of an individual with xenomelia, the desire for amputation is separate from a desire to be disabled. Mr. H is mindful of the assumed irrationality of removing a healthy but “alien” limb to replace it with a prosthetic limb that is equally alien. The perceived irony is not lost on him. He values his mobility, and has no desire to use crutches, a wheelchair, or any other ambulatory tool. This is consistent with most individuals with xenomelia, who are neither motived by the desire to flaunt their amputated limb, nor by the sympathy they might receive from others by endorsing impaired mobility. They don’t consider themselves disabled. On the contrary, for them, amputation is a much-desired enhancement to their health and well-being.

Increased opportunities for research

The internet, social media, and even peer-reviewed medical journals offer ever-increasing opportunities for individuals with xenomelia, such as Mr. H, to have their story told, regardless of whether they choose to identify themselves or remain anonymous. There are no published data about the prevalence of xenomelia, but it is almost certainly rare. However, if Mr. H was able to meet multiple people with xeno­melia in his own city and form a supportive community with them, then perhaps it isn’t exactly as rare as one might initially assume. People with xenomelia may tend to look for each other, hoping those with the same condition might show them the greatest empathy.

From Mr. H’s experience, it appears that it would be possible to locate a sufficient number of individuals with xenomelia for the purposes of conducting research, which might allow for results with acceptable statistical power. There are plenty of individual patient stories, and by documenting these stories in published literature, it is likely that patterns would emerge and causality might be determined. Such data might be bolstered by a possible strong neurologic corroboration based on what is found via neuroimaging.

Informed research into xenomelia is still in the early stages, and it is clear that there is much left to discover. It is vital that, moving forward, investigation into this condition be thorough and objective, with the goal of alleviating this secretive and debilitating neuropsychiatric condition.

Continue to: Bottom Line

Individuals with xenomelia have the persistent belief that one or more of their limbs does not belong to their body but is an alien appendage that should be removed. Patients with this condition may resort to self-amputation or self-mutilation that requires subsequent surgical amputation. Xenomelia may be related to anomalous brain development, with a lack of neural representation of a limb in the right parietal lobe.

Related Resources

• Hilti LM, Hänggi J, Vitacco DA, et al. The desire for healthy limb amputation: structural brain correlates and clinical features of xenomelia. Brain. 2013;136(pt 1):318-329.
• Brugger P, Lenggenhager B, Giummarra MJ. Xenomelia: a social neuroscience view of altered bodily self-consciousness. Front Psychol. 2013;4:204. doi:10.3389/fpsyg.2013.00204.

Is catatonia a rare condition that belongs in the history books, or is it more prevalent than we think? If we think we don’t see it often, how will we recognize it? And how do we treat it? This article reviews the evolution of our understanding of the phenomenology and therapy of this interesting and complex condition.

History of the concept

In 1874, Kahlbaum^1,2 was the first to propose a syndrome of motor dysfunction characterized by mutism, immobility, staring gaze, negativism, stereotyped behavior, waxy flexibility, and verbal stereotypies that he called catatonia. Kahlbaum conceptualized catatonia as a distinct disorder,³ but Kraepelin reformulated it as a feature of dementia praecox.⁴ Although Bleuler felt that catatonia could occur in other psychiatric disorders and in normal people,⁴ he also included catatonia as a marker of schizophrenia, where it remained from DSM-I through DSM-IV.³ As was believed to be true of schizophrenia, Kraepelin considered catatonia to be characterized by poor prognosis, whereas Bleuler eliminated poor prognosis as a criterion for catatonia.³

In DSM-IV, catatonia was still a subtype of schizophrenia, but for the first time it was expanded diagnostically to become both a specifier in mood disorders, and a syndrome resulting from a general medical condition.^5,6 In DSM-5, catatonic schizophrenia was deleted, and catatonia became a specifier for 10 disorders, including schizophrenia, mood disorders, and general medical conditions.^3,5-9 In ICD-10, however, catatonia is still associated primarily with schizophrenia.¹⁰

A wide range of presentations

Catatonia is a cyclical syndrome characterized by alterations in motor, behavioral, and vocal signs occurring in the context of medical, neurologic, and psychiatric disorders.⁸ The most common features are immobility, waxy flexibility, stupor, mutism, negativism, echolalia, echopraxia, peculiarities of voluntary movement, and rigidity.^7,11 Features of catatonia that have been repeatedly described through the years are summarized in Table 1.^8,12,13 In general, presentations of catatonia are not specific to any psychiatric or medical etiology.^13,14

Catatonia often is described along a continuum from retarded/stuporous to excited,^14,15 and from benign to malignant.¹³ Examples of these ranges of presentation include^{5,12,13,15-19}:

Stuporous/retarded catatonia (Kahlbaum syndrome) is a primarily negative syndrome in which stupor, mutism, negativism, obsessional slowness, and posturing predominate. Akinetic mutism and coma vigil are sometimes considered to be types of stuporous catatonia, as occasionally are locked-in syndrome and abulia caused by anterior cingulate lesions.

Excited catatonia (hyperkinetic variant, Bell’s mania, oneirophrenia, oneroid state/syndrome, catatonia raptus) is characterized by agitation, combativeness, verbigeration, stereotypies, grimacing, and echo phenomena (echopraxia and echolalia).

Continue to: Malignant (lethal) catatonia

Several specific subtypes of catatonia that may exist anywhere along dimensions of activity and severity also have been described:

Periodic catatonia. In 1908, Kraepelin described a form of periodic catatonia, with rapid shifts from excitement to stupor.⁴ Later, Gjessing described periodic catatonia in schizophrenia and reported success treating it with high doses of thyroid hormone.⁴ Today, periodic catatonia refers to the rapid onset of recurrent, brief hypokinetic or hyperkinetic episodes lasting 4 to 10 days and recurring during the course of weeks to years. Patients often are asymptomatic between episodes except for grimacing, stereotypies, and negativism later in the course.^13,15 At least some forms of periodic catatonia are familial,⁴ with autosomal dominant transmission possibly linked to chromosome 15q15.¹³

A familial form of catatonia has been described that has a poor response to standard therapies (benzodiazepines and electroconvulsive therapy [ECT]), but in view of the high comorbidity of catatonia and bipolar disorder, it is difficult to determine whether this is a separate condition, or a group of patients with bipolar disorder.⁵

Late (ie, late-onset) catatonia is well described in the Japanese literature.¹⁰ Reported primarily in women without a known medical illness or brain disorder, late catatonia begins with prodromal hypochondriacal or depressive symptoms during a stressful situation, followed by unprovoked anxiety and agitation. Some patients develop hallucinations, delusions, and recurrent excitement, along with anxiety and agitation. The next stage involves typical catatonic features (mainly excitement, retardation, negativism, and autonomic disturbance), progressing to stupor, mutism, verbal stereotypies, and negativism, including refusal of food. Most patients have residual symptoms following improvement. A few cases have been noted to remit with ECT, with relapse when treatment was discontinued. Late catatonia has been thought to be associated with late-onset schizophrenia or bipolar disorder, or to be an independent entity.

Continue to: Untreated catatonia can have...

Not as rare as you might think

With the shift from inpatient to outpatient care driven by deinstitutionalization, longitudinal close observation became less common, and clinicians got the impression that the dramatic catatonia that was common in the hospital had become rare.³ The impression that catatonia was unimportant was strengthened by expanding industry promotion of antipsychotic medications while ignoring catatonia, for which the industry had no specific treatment.³ With recent research, however, catatonia has been reported in 7% to 38% of adult psychiatric patients, including 9% to 25% of inpatients, 20% to 25% of patients with mania,^3,5 and 20% of patients with major depressive episodes.⁷ Catatonia has been noted in .6% to 18% of adolescent psychiatric inpatients (especially in communication and social disorders programs),^5,8,22 some children,⁵ and 6% to 18% of adult and juvenile patients with autism spectrum disorder (ASD).²³ In the medical setting, catatonia occurs in 12% to 37% of patients with delirium,^{8,14,17,18,20,24} 7% to 45% of medically ill patients, including those with no psychiatric history,^12,13 and 4% of ICU patients.¹² Several substances have been linked to catatonia; these are discussed later.¹¹ Contrary to earlier impressions, catatonia is more common in mood disorders, particularly mixed bipolar disorder, especially mania,⁵ than in schizophrenia.^7,8,17,25

Pathophysiology/etiology

Conditions associated with catatonia have different features that act through a final common pathway,⁷ possibly related to the neurobiology of an extreme fear response called tonic immobility that has been conserved through evolution.⁸ This mechanism may be mediated by decreased dopamine signaling in basal ganglia, orbitofrontal, and limbic systems, including the hypothalamus and basal forebrain.^3,17,20 Subcortical reduction of dopaminergic neurotransmission appears to be related to reduced GABA_A receptor signaling and dysfunction of N-methyl-d-aspartate (NMDA) receptors with glutaminergic excess in striato-cortical or frontal cortico-cortical systems.^13,20,26,27

Up to one-quarter of cases of catatonia are secondary to medical (mostly neurologic) factors or substances.¹⁵Table 2^5,13,15 lists common medical and neurological causes. Medications and substances known to cause catatonia are noted in Table 3.^5,8,13,16,26

Catatonia can be a specifier, or a separate condition

DSM-5 criteria for catatonia are summarized in Table 4.²⁸ With these features, catatonia can be a specifier for depressive, bipolar, or psychotic disorders; a complication of a medical disorder; or another separate diagnosis.⁸ The diagnosis of catatonia in DSM-5 is made when the clinical picture is dominated by ≥3 of the following core features^8,15:

• motoric immobility as evidenced by catalepsy (including waxy flexibility) or stupor
• excessive purposeless motor activity that is not influenced by external stimuli
• extreme negativism or mutism
• peculiarities of voluntary movement such as posturing, stereotyped movements, prominent mannerisms, or prominent grimacing
• echolalia or echopraxia.

Continue to: DSM-5 criteria for the diagnosis of catatonia are more...

DSM-5 criteria for the diagnosis of catatonia are more restrictive than DSM-IV criteria. As a result, they exclude a significant number of patients who would be considered catatonic in other systems.²⁹ For example, DSM-5 criteria do not include common features noted in Table 1,^8,12,13 such as rigidity and staring.^14,29 If the diagnosis is not obvious, it might be suspected in the presence of >1 of posturing, automatic obedience, or waxy flexibility, or >2 of echopraxia/echolalia, gegenhalten, negativism, mitgehen, or stereotypy/vergiberation.¹² Clues to catatonia that are not included in formal diagnostic systems and are easily confused with features of psychosis include whispered or robotic speech, uncharacteristic foreign accent, tiptoe walking, hopping, rituals, and odd mannerisms.⁵

There are several catatonia rating scales containing between 14 and 40 items that are useful in diagnosing and following treatment response in catatonia (Table 5^8,13,15,29). Of these, the Kanner Scale is primarily applied in neuropsychiatric settings, while the Bush-Francis Catatonia Rating Scale (BFCRS) has had the most widespread use. The BFCRS consists of 23 items, the first 14 of which are used as a screening instrument. It requires 2 of its first 14 items to diagnose catatonia, while DSM-5 requires 3 of 12 signs.²⁹ If the diagnosis remains in doubt, a benzodiazepine agonist test can be instructive.^9,12 The presence of catatonia is suggested by significant improvement, ideally assessed prospectively by improvement of BFCRS scores, shortly after administration of a single dose of 1 to 2 mg lorazepam or 5 mg diazepam IV, or 10 mg zolpidem orally. Further evaluation generally consists of a careful medical and psychiatric histories of patient and family, review of all medications, history of substance use with toxicology as indicated, physical examination focusing on autonomic dysregulation, examination for delirium, and laboratory tests as suggested by the history and examination that may include complete blood count, creatine kinase, serum iron, blood urea nitrogen, electrolytes, creatinine, prolactin, anti-NMDA antibodies, thyroid function tests, serology, metabolic panel, human immunodeficiency virus testing, EEG, and neuroimaging.^8,15,16

A complex differential diagnosis

Manifestations of numerous psychiatric and neurologic disorders can mimic or be identical to those of catatonia. The differential diagnosis is complicated by the fact that some of these disorders can cause catatonia, which is then masked by the primary disorder; some disorders (eg, NMS) are forms of catatonia. Table 6^{5,8,12,19,26,30} lists conditions to consider.

Some of these conditions warrant discussion. ASD may have catatonia-like features such as echolalia, echopraxia, excitement, combativeness, grimacing, mutism, logorrhea, verbigeration, catalepsy, mannerisms, rigidity, staring and withdrawal.⁸ Catatonia may also be a stage of deterioration of autism, in which case it is characterized by increases in slowness of movement and speech, reliance on physical or verbal prompting from others, passivity, and lack of motivation.²³ At the same time, catatonic features such as mutism, stereotypic speech, repetitive behavior, echolalia, posturing, mannerisms, purposeless agitation, and rigidity in catatonia can be misinterpreted as signs of ASD.⁸ Catatonia should be suspected as a complication of longstanding ASD in the presence of a consistent, marked change in motor behavior, such as immobility, decreased speech, stupor, excitement, or mixtures or alternations of stupor and excitement.⁸ Freezing while doing something, difficulty crossing lines, or uncharacteristic persistence of a particular behavior may also herald the presence of catatonia with ASD.⁸

Catatonia caused by a neurologic or metabolic factor or a substance can be difficult to distinguish from delirium complicated by catatonia. Delirium may be identified in patients with catatonia by the presence of a waxing and waning level of consciousness (vs fluctuating behavior in catatonia) and slowing of the EEG.^12,15 Antipsychotic medications can improve delirium but worsen catatonia, while benzodiazepines can improve catatonia but worsen delirium.

Continue to: Among other neurologic syndromes...

Benzodiazepines, ECT are the usual treatments

Experience dictates that the general principles of treatment noted in Table 7^12,15,23,31 apply to all patients with catatonia. Since the first reported improvement of catatonia with amobarbital in 1930,⁶ there have been no controlled studies of specific treatments of catatonia.¹³ Meaningful treatment trials are either naturalistic, or have been performed only for NMS and malignant catatonia.⁵ However, multiple case reports and case series suggest that treatments with agents that have anticonvulsant properties (benzodiazepines, barbiturates) and ECT are effective.⁵

Benzodiazepines and related compounds. Case series have suggested a 60% to 80% remission rate of catatonia with benzodiazepines, the most commonly utilized of which has been lorazepam.^7,13,32 Treatment begins with a lorazepam challenge test of 1 to 2 mg in adults and 0.5 to 1 mg in children and geriatric patients,^9,15 administered orally (including via nasogastric tube), IM, or IV. Following a response (≥50% improvement), the dose is increased to 2 mg 3 times per day. The dose is further increased to 6 to 16 mg/d, and sometimes up to 30 mg/d.^9,11 Oral is less effective than sublingual or IM administration.¹¹ Diazepam can be helpful at doses 5 times the lorazepam dose.^9,17 A zolpidem challenge test of 10 mg orally or via nasogastric tube has also been utilized.¹⁵ Response is brief and is usually followed by lorazepam, although zolpidem up to 40 mg/d has been used for ongoing treatment.⁹

One alternative benzodiazepine protocol utilizes an initial IV dose of 2 mg lorazepam, repeated 3 to 5 times per day; the dose is increased to 10 to 12 mg/d if the first doses are partially effective.¹⁶ A lorazepam/diazepam approach involves a combination of IM lorazepam and IV diazepam.¹¹ The protocol begins with 2 mg of IM lorazepam. If there is no effect within 2 hours, a second 2 mg dose is administered, followed by an IV infusion of 10 mg diazepam in 500 ml of normal saline at 1.25 mg/hour until catatonia remits.

An Indian study of 107 patients (mean age 26) receiving relatively low doses of lorazepam (3 to 6 mg/d for at least 3 days) found that factors suggesting a robust response include a shorter duration of catatonia and waxy flexibility, while passivity, mutism, and auditory hallucinations describing the patient in the third person were associated with a poorer acute response.³¹ Catatonia with marked retardation and mutism complicating schizophrenia, especially with chronic negative symptoms, may be associated with a lower response rate to benzodiazepines.^20,33 Maintenance lorazepam has been effective in reducing relapse and recurrence.¹¹ There are no controlled studies of maintenance treatment with benzodiazepines, but clinical reports suggest that doses in the range of 4 to 10 mg/d are effective.³²

Continue to: ECT was used for catatonia in 1934...

ECT was first used for catatonia in 1934, when Laszlo Meduna used chemically induced seizures in catatonic patients who had been on tube feeding for months and no longer needed it after treatment.^6,7 As was true for other disorders, this approach was replaced by ECT.⁷ In various case series, the effectiveness of ECT in catatonia has been 53% to 100%.^7,13,15 Right unilateral ECT has been reported to be effective with 1 treatment.²¹ However, the best-established approach is with bitemporal ECT with a suprathreshold stimulus,⁹ usually with an acute course of 6 to 20 treatments.²⁰ ECT has been reported to be equally safe and effective in adolescents and adults.³⁴ Continued ECT is usually necessary until the patient has returned to baseline.⁹

ECT usually is recommended within 24 hours for treatment-resistant malignant catatonia or refusal to eat or drink, and within 2 to 3 days if medications are not sufficiently effective in other forms of catatonia.^12,15,20 If ECT is initiated after a benzodiazepine trial, the benzodiazepine antagonist flumazenil is administered first to reverse the anticonvulsant effect.⁹ Some experts recommend using a muscle relaxant other than succinylcholine in the presence of evidence of muscle damage.⁷

Alternatives to benzodiazepines and ECT. Based on case reports, the treatments described in Table 8^{13,15,17,20,25} have been used for patients with catatonia who do not tolerate or respond to standard treatments. The largest number of case reports have been with NMDA antagonists, while the presumed involvement of reduced dopamine signaling suggests that dopaminergic medications should be helpful. Dantrolene, which blocks release of calcium from intracellular stores and has been used to treat malignant hyperthermia, is sometimes used for NMS, often with disappointing results.

Whereas first-generation antipsychotics definitely increase the risk of catatonia and second-generation antipsychotics (SGAs) probably do so, SGAs are sometimes necessary to treat persistent psychosis in patients with schizophrenia who develop catatonia. Of these medications, clozapine may be most desirable because of low potency for dopamine receptor blockade and modulation of glutamatergic signaling. Partial dopamine agonism by aripiprazole, and the potential for increased subcortical prefrontal dopamine release resulting from serotonin 5HT2A antagonism and 5HT1A agonism by other SGAs, could also be helpful or at least not harmful in catatonia. Lorazepam is usually administered along with these medications to ameliorate treatment-emergent exacerbation of catatonia.

There are no controlled studies of any of these treatments. Based on case reports, most experts would recommend initiating treatment of catatonia with lorazepam, followed by ECT if necessary or in the presence of life-threatening catatonia. If ECT is not available, ineffective, or not tolerated, the first alternatives to be considered would be an NMDA antagonist or an anticonvulsant.²⁰

Continue to: Course varies by patient, underlying cause

Course varies by patient, underlying cause

The response to benzodiazepines or ECT can vary from episode to episode¹¹ and is similar in adults and younger patients.²² Many patients recover completely after a single episode, while relapse after remission occurs repeatedly in periodic catatonia, which involves chronic alternating stupor and excitement waxing and waning over years.¹¹ Relapses may occur frequently, or every few years.¹¹ Some cases of catatonia initially have an episodic course and become chronic and deteriorating, possibly paralleling the original descriptions of the natural history of untreated catatonia, while malignant catatonia can be complicated by medical morbidity or death.⁴ The long-term prognosis generally depends on the underlying cause of catatonia.⁵

Bottom Line

Much more common than many clinicians realize, catatonia can be overlooked because symptoms can mimic or overlap with features of an underlying medical or neurologic disorder. Suspect catatonia when one of these illnesses has an unexpected course or an inadequate treatment response. Be alert to characteristic changes in behavior and speech. A benzodiazepine challenge can be used to diagnose and begin treatment of catatonia. Consider electroconvulsive therapy sooner rather than later, especially for severely ill patients.

Related Resources

• Gibson RC, Walcott G. Benzodiazepines for catatonia in people with schizophrenia and other serious mental illnesses. Cochrane Database Syst Rev. 2008;(4):CD006570. 
• Newcastle University. Catatonia. https://youtu.be/_s1lzxHRO4U.

Drug Brand Names

Amantadine • Symmetrel
Amobarbital • Amytal
Aripiprazole • Abilify
Azithromycin • Zithromax
Baclofen • Lioresal
Benztropine • Cogentin
Carbamazepine • Carbatrol, Tegretol
Carbidopa/levodopa • Sinemet
Ciprofloxacin • Cipro
Clozapine • Clozaril
Dantrolene • Dantrium
Dexamethasone • Decadron
Dextromethorphan/quinidine • Neudexta
Diazepam • Valium
Disulfiram • Antabuse
Flumazenil • Romazicon
Fluoxetine • Prozac
Fluvoxamine • Luvox
Levetiracetam • Keppra
Lithium • Eskalith, Lithobid
Lorazepam • Ativan
Memantine • Namenda
Methylphenidate • Ritalin
Minocycline • Minocin
Olanzapine • Zyprexa
Risperidone • Risperdal
Succinylcholine • Anectine
Topiramate • Topamax
Trihexyphenidyl • Artane
Valproate • Depakote
Ziprasidone • Geodon
Zolpidem • Ambien

Is catatonia a rare condition that belongs in the history books, or is it more prevalent than we think? If we think we don’t see it often, how will we recognize it? And how do we treat it? This article reviews the evolution of our understanding of the phenomenology and therapy of this interesting and complex condition.

History of the concept

In 1874, Kahlbaum^1,2 was the first to propose a syndrome of motor dysfunction characterized by mutism, immobility, staring gaze, negativism, stereotyped behavior, waxy flexibility, and verbal stereotypies that he called catatonia. Kahlbaum conceptualized catatonia as a distinct disorder,³ but Kraepelin reformulated it as a feature of dementia praecox.⁴ Although Bleuler felt that catatonia could occur in other psychiatric disorders and in normal people,⁴ he also included catatonia as a marker of schizophrenia, where it remained from DSM-I through DSM-IV.³ As was believed to be true of schizophrenia, Kraepelin considered catatonia to be characterized by poor prognosis, whereas Bleuler eliminated poor prognosis as a criterion for catatonia.³

In DSM-IV, catatonia was still a subtype of schizophrenia, but for the first time it was expanded diagnostically to become both a specifier in mood disorders, and a syndrome resulting from a general medical condition.^5,6 In DSM-5, catatonic schizophrenia was deleted, and catatonia became a specifier for 10 disorders, including schizophrenia, mood disorders, and general medical conditions.^3,5-9 In ICD-10, however, catatonia is still associated primarily with schizophrenia.¹⁰

A wide range of presentations

Catatonia is a cyclical syndrome characterized by alterations in motor, behavioral, and vocal signs occurring in the context of medical, neurologic, and psychiatric disorders.⁸ The most common features are immobility, waxy flexibility, stupor, mutism, negativism, echolalia, echopraxia, peculiarities of voluntary movement, and rigidity.^7,11 Features of catatonia that have been repeatedly described through the years are summarized in Table 1.^8,12,13 In general, presentations of catatonia are not specific to any psychiatric or medical etiology.^13,14

Catatonia often is described along a continuum from retarded/stuporous to excited,^14,15 and from benign to malignant.¹³ Examples of these ranges of presentation include^{5,12,13,15-19}:

Stuporous/retarded catatonia (Kahlbaum syndrome) is a primarily negative syndrome in which stupor, mutism, negativism, obsessional slowness, and posturing predominate. Akinetic mutism and coma vigil are sometimes considered to be types of stuporous catatonia, as occasionally are locked-in syndrome and abulia caused by anterior cingulate lesions.

Excited catatonia (hyperkinetic variant, Bell’s mania, oneirophrenia, oneroid state/syndrome, catatonia raptus) is characterized by agitation, combativeness, verbigeration, stereotypies, grimacing, and echo phenomena (echopraxia and echolalia).

Continue to: Malignant (lethal) catatonia

Several specific subtypes of catatonia that may exist anywhere along dimensions of activity and severity also have been described:

Periodic catatonia. In 1908, Kraepelin described a form of periodic catatonia, with rapid shifts from excitement to stupor.⁴ Later, Gjessing described periodic catatonia in schizophrenia and reported success treating it with high doses of thyroid hormone.⁴ Today, periodic catatonia refers to the rapid onset of recurrent, brief hypokinetic or hyperkinetic episodes lasting 4 to 10 days and recurring during the course of weeks to years. Patients often are asymptomatic between episodes except for grimacing, stereotypies, and negativism later in the course.^13,15 At least some forms of periodic catatonia are familial,⁴ with autosomal dominant transmission possibly linked to chromosome 15q15.¹³

A familial form of catatonia has been described that has a poor response to standard therapies (benzodiazepines and electroconvulsive therapy [ECT]), but in view of the high comorbidity of catatonia and bipolar disorder, it is difficult to determine whether this is a separate condition, or a group of patients with bipolar disorder.⁵

Late (ie, late-onset) catatonia is well described in the Japanese literature.¹⁰ Reported primarily in women without a known medical illness or brain disorder, late catatonia begins with prodromal hypochondriacal or depressive symptoms during a stressful situation, followed by unprovoked anxiety and agitation. Some patients develop hallucinations, delusions, and recurrent excitement, along with anxiety and agitation. The next stage involves typical catatonic features (mainly excitement, retardation, negativism, and autonomic disturbance), progressing to stupor, mutism, verbal stereotypies, and negativism, including refusal of food. Most patients have residual symptoms following improvement. A few cases have been noted to remit with ECT, with relapse when treatment was discontinued. Late catatonia has been thought to be associated with late-onset schizophrenia or bipolar disorder, or to be an independent entity.

Continue to: Untreated catatonia can have...

Not as rare as you might think

With the shift from inpatient to outpatient care driven by deinstitutionalization, longitudinal close observation became less common, and clinicians got the impression that the dramatic catatonia that was common in the hospital had become rare.³ The impression that catatonia was unimportant was strengthened by expanding industry promotion of antipsychotic medications while ignoring catatonia, for which the industry had no specific treatment.³ With recent research, however, catatonia has been reported in 7% to 38% of adult psychiatric patients, including 9% to 25% of inpatients, 20% to 25% of patients with mania,^3,5 and 20% of patients with major depressive episodes.⁷ Catatonia has been noted in .6% to 18% of adolescent psychiatric inpatients (especially in communication and social disorders programs),^5,8,22 some children,⁵ and 6% to 18% of adult and juvenile patients with autism spectrum disorder (ASD).²³ In the medical setting, catatonia occurs in 12% to 37% of patients with delirium,^{8,14,17,18,20,24} 7% to 45% of medically ill patients, including those with no psychiatric history,^12,13 and 4% of ICU patients.¹² Several substances have been linked to catatonia; these are discussed later.¹¹ Contrary to earlier impressions, catatonia is more common in mood disorders, particularly mixed bipolar disorder, especially mania,⁵ than in schizophrenia.^7,8,17,25

Pathophysiology/etiology

Conditions associated with catatonia have different features that act through a final common pathway,⁷ possibly related to the neurobiology of an extreme fear response called tonic immobility that has been conserved through evolution.⁸ This mechanism may be mediated by decreased dopamine signaling in basal ganglia, orbitofrontal, and limbic systems, including the hypothalamus and basal forebrain.^3,17,20 Subcortical reduction of dopaminergic neurotransmission appears to be related to reduced GABA_A receptor signaling and dysfunction of N-methyl-d-aspartate (NMDA) receptors with glutaminergic excess in striato-cortical or frontal cortico-cortical systems.^13,20,26,27

Up to one-quarter of cases of catatonia are secondary to medical (mostly neurologic) factors or substances.¹⁵Table 2^5,13,15 lists common medical and neurological causes. Medications and substances known to cause catatonia are noted in Table 3.^5,8,13,16,26

Catatonia can be a specifier, or a separate condition

DSM-5 criteria for catatonia are summarized in Table 4.²⁸ With these features, catatonia can be a specifier for depressive, bipolar, or psychotic disorders; a complication of a medical disorder; or another separate diagnosis.⁸ The diagnosis of catatonia in DSM-5 is made when the clinical picture is dominated by ≥3 of the following core features^8,15:

• motoric immobility as evidenced by catalepsy (including waxy flexibility) or stupor
• excessive purposeless motor activity that is not influenced by external stimuli
• extreme negativism or mutism
• peculiarities of voluntary movement such as posturing, stereotyped movements, prominent mannerisms, or prominent grimacing
• echolalia or echopraxia.

Continue to: DSM-5 criteria for the diagnosis of catatonia are more...

DSM-5 criteria for the diagnosis of catatonia are more restrictive than DSM-IV criteria. As a result, they exclude a significant number of patients who would be considered catatonic in other systems.²⁹ For example, DSM-5 criteria do not include common features noted in Table 1,^8,12,13 such as rigidity and staring.^14,29 If the diagnosis is not obvious, it might be suspected in the presence of >1 of posturing, automatic obedience, or waxy flexibility, or >2 of echopraxia/echolalia, gegenhalten, negativism, mitgehen, or stereotypy/vergiberation.¹² Clues to catatonia that are not included in formal diagnostic systems and are easily confused with features of psychosis include whispered or robotic speech, uncharacteristic foreign accent, tiptoe walking, hopping, rituals, and odd mannerisms.⁵

There are several catatonia rating scales containing between 14 and 40 items that are useful in diagnosing and following treatment response in catatonia (Table 5^8,13,15,29). Of these, the Kanner Scale is primarily applied in neuropsychiatric settings, while the Bush-Francis Catatonia Rating Scale (BFCRS) has had the most widespread use. The BFCRS consists of 23 items, the first 14 of which are used as a screening instrument. It requires 2 of its first 14 items to diagnose catatonia, while DSM-5 requires 3 of 12 signs.²⁹ If the diagnosis remains in doubt, a benzodiazepine agonist test can be instructive.^9,12 The presence of catatonia is suggested by significant improvement, ideally assessed prospectively by improvement of BFCRS scores, shortly after administration of a single dose of 1 to 2 mg lorazepam or 5 mg diazepam IV, or 10 mg zolpidem orally. Further evaluation generally consists of a careful medical and psychiatric histories of patient and family, review of all medications, history of substance use with toxicology as indicated, physical examination focusing on autonomic dysregulation, examination for delirium, and laboratory tests as suggested by the history and examination that may include complete blood count, creatine kinase, serum iron, blood urea nitrogen, electrolytes, creatinine, prolactin, anti-NMDA antibodies, thyroid function tests, serology, metabolic panel, human immunodeficiency virus testing, EEG, and neuroimaging.^8,15,16

A complex differential diagnosis

Manifestations of numerous psychiatric and neurologic disorders can mimic or be identical to those of catatonia. The differential diagnosis is complicated by the fact that some of these disorders can cause catatonia, which is then masked by the primary disorder; some disorders (eg, NMS) are forms of catatonia. Table 6^{5,8,12,19,26,30} lists conditions to consider.

Some of these conditions warrant discussion. ASD may have catatonia-like features such as echolalia, echopraxia, excitement, combativeness, grimacing, mutism, logorrhea, verbigeration, catalepsy, mannerisms, rigidity, staring and withdrawal.⁸ Catatonia may also be a stage of deterioration of autism, in which case it is characterized by increases in slowness of movement and speech, reliance on physical or verbal prompting from others, passivity, and lack of motivation.²³ At the same time, catatonic features such as mutism, stereotypic speech, repetitive behavior, echolalia, posturing, mannerisms, purposeless agitation, and rigidity in catatonia can be misinterpreted as signs of ASD.⁸ Catatonia should be suspected as a complication of longstanding ASD in the presence of a consistent, marked change in motor behavior, such as immobility, decreased speech, stupor, excitement, or mixtures or alternations of stupor and excitement.⁸ Freezing while doing something, difficulty crossing lines, or uncharacteristic persistence of a particular behavior may also herald the presence of catatonia with ASD.⁸

Catatonia caused by a neurologic or metabolic factor or a substance can be difficult to distinguish from delirium complicated by catatonia. Delirium may be identified in patients with catatonia by the presence of a waxing and waning level of consciousness (vs fluctuating behavior in catatonia) and slowing of the EEG.^12,15 Antipsychotic medications can improve delirium but worsen catatonia, while benzodiazepines can improve catatonia but worsen delirium.

Continue to: Among other neurologic syndromes...

Benzodiazepines, ECT are the usual treatments

Experience dictates that the general principles of treatment noted in Table 7^12,15,23,31 apply to all patients with catatonia. Since the first reported improvement of catatonia with amobarbital in 1930,⁶ there have been no controlled studies of specific treatments of catatonia.¹³ Meaningful treatment trials are either naturalistic, or have been performed only for NMS and malignant catatonia.⁵ However, multiple case reports and case series suggest that treatments with agents that have anticonvulsant properties (benzodiazepines, barbiturates) and ECT are effective.⁵

Benzodiazepines and related compounds. Case series have suggested a 60% to 80% remission rate of catatonia with benzodiazepines, the most commonly utilized of which has been lorazepam.^7,13,32 Treatment begins with a lorazepam challenge test of 1 to 2 mg in adults and 0.5 to 1 mg in children and geriatric patients,^9,15 administered orally (including via nasogastric tube), IM, or IV. Following a response (≥50% improvement), the dose is increased to 2 mg 3 times per day. The dose is further increased to 6 to 16 mg/d, and sometimes up to 30 mg/d.^9,11 Oral is less effective than sublingual or IM administration.¹¹ Diazepam can be helpful at doses 5 times the lorazepam dose.^9,17 A zolpidem challenge test of 10 mg orally or via nasogastric tube has also been utilized.¹⁵ Response is brief and is usually followed by lorazepam, although zolpidem up to 40 mg/d has been used for ongoing treatment.⁹

One alternative benzodiazepine protocol utilizes an initial IV dose of 2 mg lorazepam, repeated 3 to 5 times per day; the dose is increased to 10 to 12 mg/d if the first doses are partially effective.¹⁶ A lorazepam/diazepam approach involves a combination of IM lorazepam and IV diazepam.¹¹ The protocol begins with 2 mg of IM lorazepam. If there is no effect within 2 hours, a second 2 mg dose is administered, followed by an IV infusion of 10 mg diazepam in 500 ml of normal saline at 1.25 mg/hour until catatonia remits.

An Indian study of 107 patients (mean age 26) receiving relatively low doses of lorazepam (3 to 6 mg/d for at least 3 days) found that factors suggesting a robust response include a shorter duration of catatonia and waxy flexibility, while passivity, mutism, and auditory hallucinations describing the patient in the third person were associated with a poorer acute response.³¹ Catatonia with marked retardation and mutism complicating schizophrenia, especially with chronic negative symptoms, may be associated with a lower response rate to benzodiazepines.^20,33 Maintenance lorazepam has been effective in reducing relapse and recurrence.¹¹ There are no controlled studies of maintenance treatment with benzodiazepines, but clinical reports suggest that doses in the range of 4 to 10 mg/d are effective.³²

Continue to: ECT was used for catatonia in 1934...

ECT was first used for catatonia in 1934, when Laszlo Meduna used chemically induced seizures in catatonic patients who had been on tube feeding for months and no longer needed it after treatment.^6,7 As was true for other disorders, this approach was replaced by ECT.⁷ In various case series, the effectiveness of ECT in catatonia has been 53% to 100%.^7,13,15 Right unilateral ECT has been reported to be effective with 1 treatment.²¹ However, the best-established approach is with bitemporal ECT with a suprathreshold stimulus,⁹ usually with an acute course of 6 to 20 treatments.²⁰ ECT has been reported to be equally safe and effective in adolescents and adults.³⁴ Continued ECT is usually necessary until the patient has returned to baseline.⁹

ECT usually is recommended within 24 hours for treatment-resistant malignant catatonia or refusal to eat or drink, and within 2 to 3 days if medications are not sufficiently effective in other forms of catatonia.^12,15,20 If ECT is initiated after a benzodiazepine trial, the benzodiazepine antagonist flumazenil is administered first to reverse the anticonvulsant effect.⁹ Some experts recommend using a muscle relaxant other than succinylcholine in the presence of evidence of muscle damage.⁷

Alternatives to benzodiazepines and ECT. Based on case reports, the treatments described in Table 8^{13,15,17,20,25} have been used for patients with catatonia who do not tolerate or respond to standard treatments. The largest number of case reports have been with NMDA antagonists, while the presumed involvement of reduced dopamine signaling suggests that dopaminergic medications should be helpful. Dantrolene, which blocks release of calcium from intracellular stores and has been used to treat malignant hyperthermia, is sometimes used for NMS, often with disappointing results.

Whereas first-generation antipsychotics definitely increase the risk of catatonia and second-generation antipsychotics (SGAs) probably do so, SGAs are sometimes necessary to treat persistent psychosis in patients with schizophrenia who develop catatonia. Of these medications, clozapine may be most desirable because of low potency for dopamine receptor blockade and modulation of glutamatergic signaling. Partial dopamine agonism by aripiprazole, and the potential for increased subcortical prefrontal dopamine release resulting from serotonin 5HT2A antagonism and 5HT1A agonism by other SGAs, could also be helpful or at least not harmful in catatonia. Lorazepam is usually administered along with these medications to ameliorate treatment-emergent exacerbation of catatonia.

There are no controlled studies of any of these treatments. Based on case reports, most experts would recommend initiating treatment of catatonia with lorazepam, followed by ECT if necessary or in the presence of life-threatening catatonia. If ECT is not available, ineffective, or not tolerated, the first alternatives to be considered would be an NMDA antagonist or an anticonvulsant.²⁰

Continue to: Course varies by patient, underlying cause

Course varies by patient, underlying cause

The response to benzodiazepines or ECT can vary from episode to episode¹¹ and is similar in adults and younger patients.²² Many patients recover completely after a single episode, while relapse after remission occurs repeatedly in periodic catatonia, which involves chronic alternating stupor and excitement waxing and waning over years.¹¹ Relapses may occur frequently, or every few years.¹¹ Some cases of catatonia initially have an episodic course and become chronic and deteriorating, possibly paralleling the original descriptions of the natural history of untreated catatonia, while malignant catatonia can be complicated by medical morbidity or death.⁴ The long-term prognosis generally depends on the underlying cause of catatonia.⁵

Bottom Line

Much more common than many clinicians realize, catatonia can be overlooked because symptoms can mimic or overlap with features of an underlying medical or neurologic disorder. Suspect catatonia when one of these illnesses has an unexpected course or an inadequate treatment response. Be alert to characteristic changes in behavior and speech. A benzodiazepine challenge can be used to diagnose and begin treatment of catatonia. Consider electroconvulsive therapy sooner rather than later, especially for severely ill patients.

Related Resources

• Gibson RC, Walcott G. Benzodiazepines for catatonia in people with schizophrenia and other serious mental illnesses. Cochrane Database Syst Rev. 2008;(4):CD006570. 
• Newcastle University. Catatonia. https://youtu.be/_s1lzxHRO4U.

Drug Brand Names

Amantadine • Symmetrel
Amobarbital • Amytal
Aripiprazole • Abilify
Azithromycin • Zithromax
Baclofen • Lioresal
Benztropine • Cogentin
Carbamazepine • Carbatrol, Tegretol
Carbidopa/levodopa • Sinemet
Ciprofloxacin • Cipro
Clozapine • Clozaril
Dantrolene • Dantrium
Dexamethasone • Decadron
Dextromethorphan/quinidine • Neudexta
Diazepam • Valium
Disulfiram • Antabuse
Flumazenil • Romazicon
Fluoxetine • Prozac
Fluvoxamine • Luvox
Levetiracetam • Keppra
Lithium • Eskalith, Lithobid
Lorazepam • Ativan
Memantine • Namenda
Methylphenidate • Ritalin
Minocycline • Minocin
Olanzapine • Zyprexa
Risperidone • Risperdal
Succinylcholine • Anectine
Topiramate • Topamax
Trihexyphenidyl • Artane
Valproate • Depakote
Ziprasidone • Geodon
Zolpidem • Ambien

Is catatonia a rare condition that belongs in the history books, or is it more prevalent than we think? If we think we don’t see it often, how will we recognize it? And how do we treat it? This article reviews the evolution of our understanding of the phenomenology and therapy of this interesting and complex condition.

History of the concept

In 1874, Kahlbaum^1,2 was the first to propose a syndrome of motor dysfunction characterized by mutism, immobility, staring gaze, negativism, stereotyped behavior, waxy flexibility, and verbal stereotypies that he called catatonia. Kahlbaum conceptualized catatonia as a distinct disorder,³ but Kraepelin reformulated it as a feature of dementia praecox.⁴ Although Bleuler felt that catatonia could occur in other psychiatric disorders and in normal people,⁴ he also included catatonia as a marker of schizophrenia, where it remained from DSM-I through DSM-IV.³ As was believed to be true of schizophrenia, Kraepelin considered catatonia to be characterized by poor prognosis, whereas Bleuler eliminated poor prognosis as a criterion for catatonia.³

In DSM-IV, catatonia was still a subtype of schizophrenia, but for the first time it was expanded diagnostically to become both a specifier in mood disorders, and a syndrome resulting from a general medical condition.^5,6 In DSM-5, catatonic schizophrenia was deleted, and catatonia became a specifier for 10 disorders, including schizophrenia, mood disorders, and general medical conditions.^3,5-9 In ICD-10, however, catatonia is still associated primarily with schizophrenia.¹⁰

A wide range of presentations

Catatonia is a cyclical syndrome characterized by alterations in motor, behavioral, and vocal signs occurring in the context of medical, neurologic, and psychiatric disorders.⁸ The most common features are immobility, waxy flexibility, stupor, mutism, negativism, echolalia, echopraxia, peculiarities of voluntary movement, and rigidity.^7,11 Features of catatonia that have been repeatedly described through the years are summarized in Table 1.^8,12,13 In general, presentations of catatonia are not specific to any psychiatric or medical etiology.^13,14

Catatonia often is described along a continuum from retarded/stuporous to excited,^14,15 and from benign to malignant.¹³ Examples of these ranges of presentation include^{5,12,13,15-19}:

Stuporous/retarded catatonia (Kahlbaum syndrome) is a primarily negative syndrome in which stupor, mutism, negativism, obsessional slowness, and posturing predominate. Akinetic mutism and coma vigil are sometimes considered to be types of stuporous catatonia, as occasionally are locked-in syndrome and abulia caused by anterior cingulate lesions.

Excited catatonia (hyperkinetic variant, Bell’s mania, oneirophrenia, oneroid state/syndrome, catatonia raptus) is characterized by agitation, combativeness, verbigeration, stereotypies, grimacing, and echo phenomena (echopraxia and echolalia).

Continue to: Malignant (lethal) catatonia

Several specific subtypes of catatonia that may exist anywhere along dimensions of activity and severity also have been described:

Periodic catatonia. In 1908, Kraepelin described a form of periodic catatonia, with rapid shifts from excitement to stupor.⁴ Later, Gjessing described periodic catatonia in schizophrenia and reported success treating it with high doses of thyroid hormone.⁴ Today, periodic catatonia refers to the rapid onset of recurrent, brief hypokinetic or hyperkinetic episodes lasting 4 to 10 days and recurring during the course of weeks to years. Patients often are asymptomatic between episodes except for grimacing, stereotypies, and negativism later in the course.^13,15 At least some forms of periodic catatonia are familial,⁴ with autosomal dominant transmission possibly linked to chromosome 15q15.¹³

A familial form of catatonia has been described that has a poor response to standard therapies (benzodiazepines and electroconvulsive therapy [ECT]), but in view of the high comorbidity of catatonia and bipolar disorder, it is difficult to determine whether this is a separate condition, or a group of patients with bipolar disorder.⁵

Late (ie, late-onset) catatonia is well described in the Japanese literature.¹⁰ Reported primarily in women without a known medical illness or brain disorder, late catatonia begins with prodromal hypochondriacal or depressive symptoms during a stressful situation, followed by unprovoked anxiety and agitation. Some patients develop hallucinations, delusions, and recurrent excitement, along with anxiety and agitation. The next stage involves typical catatonic features (mainly excitement, retardation, negativism, and autonomic disturbance), progressing to stupor, mutism, verbal stereotypies, and negativism, including refusal of food. Most patients have residual symptoms following improvement. A few cases have been noted to remit with ECT, with relapse when treatment was discontinued. Late catatonia has been thought to be associated with late-onset schizophrenia or bipolar disorder, or to be an independent entity.

Continue to: Untreated catatonia can have...

Not as rare as you might think

With the shift from inpatient to outpatient care driven by deinstitutionalization, longitudinal close observation became less common, and clinicians got the impression that the dramatic catatonia that was common in the hospital had become rare.³ The impression that catatonia was unimportant was strengthened by expanding industry promotion of antipsychotic medications while ignoring catatonia, for which the industry had no specific treatment.³ With recent research, however, catatonia has been reported in 7% to 38% of adult psychiatric patients, including 9% to 25% of inpatients, 20% to 25% of patients with mania,^3,5 and 20% of patients with major depressive episodes.⁷ Catatonia has been noted in .6% to 18% of adolescent psychiatric inpatients (especially in communication and social disorders programs),^5,8,22 some children,⁵ and 6% to 18% of adult and juvenile patients with autism spectrum disorder (ASD).²³ In the medical setting, catatonia occurs in 12% to 37% of patients with delirium,^{8,14,17,18,20,24} 7% to 45% of medically ill patients, including those with no psychiatric history,^12,13 and 4% of ICU patients.¹² Several substances have been linked to catatonia; these are discussed later.¹¹ Contrary to earlier impressions, catatonia is more common in mood disorders, particularly mixed bipolar disorder, especially mania,⁵ than in schizophrenia.^7,8,17,25

Pathophysiology/etiology

Conditions associated with catatonia have different features that act through a final common pathway,⁷ possibly related to the neurobiology of an extreme fear response called tonic immobility that has been conserved through evolution.⁸ This mechanism may be mediated by decreased dopamine signaling in basal ganglia, orbitofrontal, and limbic systems, including the hypothalamus and basal forebrain.^3,17,20 Subcortical reduction of dopaminergic neurotransmission appears to be related to reduced GABA_A receptor signaling and dysfunction of N-methyl-d-aspartate (NMDA) receptors with glutaminergic excess in striato-cortical or frontal cortico-cortical systems.^13,20,26,27

Up to one-quarter of cases of catatonia are secondary to medical (mostly neurologic) factors or substances.¹⁵Table 2^5,13,15 lists common medical and neurological causes. Medications and substances known to cause catatonia are noted in Table 3.^5,8,13,16,26

Catatonia can be a specifier, or a separate condition

DSM-5 criteria for catatonia are summarized in Table 4.²⁸ With these features, catatonia can be a specifier for depressive, bipolar, or psychotic disorders; a complication of a medical disorder; or another separate diagnosis.⁸ The diagnosis of catatonia in DSM-5 is made when the clinical picture is dominated by ≥3 of the following core features^8,15:

• motoric immobility as evidenced by catalepsy (including waxy flexibility) or stupor
• excessive purposeless motor activity that is not influenced by external stimuli
• extreme negativism or mutism
• peculiarities of voluntary movement such as posturing, stereotyped movements, prominent mannerisms, or prominent grimacing
• echolalia or echopraxia.

Continue to: DSM-5 criteria for the diagnosis of catatonia are more...

DSM-5 criteria for the diagnosis of catatonia are more restrictive than DSM-IV criteria. As a result, they exclude a significant number of patients who would be considered catatonic in other systems.²⁹ For example, DSM-5 criteria do not include common features noted in Table 1,^8,12,13 such as rigidity and staring.^14,29 If the diagnosis is not obvious, it might be suspected in the presence of >1 of posturing, automatic obedience, or waxy flexibility, or >2 of echopraxia/echolalia, gegenhalten, negativism, mitgehen, or stereotypy/vergiberation.¹² Clues to catatonia that are not included in formal diagnostic systems and are easily confused with features of psychosis include whispered or robotic speech, uncharacteristic foreign accent, tiptoe walking, hopping, rituals, and odd mannerisms.⁵

There are several catatonia rating scales containing between 14 and 40 items that are useful in diagnosing and following treatment response in catatonia (Table 5^8,13,15,29). Of these, the Kanner Scale is primarily applied in neuropsychiatric settings, while the Bush-Francis Catatonia Rating Scale (BFCRS) has had the most widespread use. The BFCRS consists of 23 items, the first 14 of which are used as a screening instrument. It requires 2 of its first 14 items to diagnose catatonia, while DSM-5 requires 3 of 12 signs.²⁹ If the diagnosis remains in doubt, a benzodiazepine agonist test can be instructive.^9,12 The presence of catatonia is suggested by significant improvement, ideally assessed prospectively by improvement of BFCRS scores, shortly after administration of a single dose of 1 to 2 mg lorazepam or 5 mg diazepam IV, or 10 mg zolpidem orally. Further evaluation generally consists of a careful medical and psychiatric histories of patient and family, review of all medications, history of substance use with toxicology as indicated, physical examination focusing on autonomic dysregulation, examination for delirium, and laboratory tests as suggested by the history and examination that may include complete blood count, creatine kinase, serum iron, blood urea nitrogen, electrolytes, creatinine, prolactin, anti-NMDA antibodies, thyroid function tests, serology, metabolic panel, human immunodeficiency virus testing, EEG, and neuroimaging.^8,15,16

A complex differential diagnosis

Manifestations of numerous psychiatric and neurologic disorders can mimic or be identical to those of catatonia. The differential diagnosis is complicated by the fact that some of these disorders can cause catatonia, which is then masked by the primary disorder; some disorders (eg, NMS) are forms of catatonia. Table 6^{5,8,12,19,26,30} lists conditions to consider.

Some of these conditions warrant discussion. ASD may have catatonia-like features such as echolalia, echopraxia, excitement, combativeness, grimacing, mutism, logorrhea, verbigeration, catalepsy, mannerisms, rigidity, staring and withdrawal.⁸ Catatonia may also be a stage of deterioration of autism, in which case it is characterized by increases in slowness of movement and speech, reliance on physical or verbal prompting from others, passivity, and lack of motivation.²³ At the same time, catatonic features such as mutism, stereotypic speech, repetitive behavior, echolalia, posturing, mannerisms, purposeless agitation, and rigidity in catatonia can be misinterpreted as signs of ASD.⁸ Catatonia should be suspected as a complication of longstanding ASD in the presence of a consistent, marked change in motor behavior, such as immobility, decreased speech, stupor, excitement, or mixtures or alternations of stupor and excitement.⁸ Freezing while doing something, difficulty crossing lines, or uncharacteristic persistence of a particular behavior may also herald the presence of catatonia with ASD.⁸

Catatonia caused by a neurologic or metabolic factor or a substance can be difficult to distinguish from delirium complicated by catatonia. Delirium may be identified in patients with catatonia by the presence of a waxing and waning level of consciousness (vs fluctuating behavior in catatonia) and slowing of the EEG.^12,15 Antipsychotic medications can improve delirium but worsen catatonia, while benzodiazepines can improve catatonia but worsen delirium.

Continue to: Among other neurologic syndromes...

Benzodiazepines, ECT are the usual treatments

Experience dictates that the general principles of treatment noted in Table 7^12,15,23,31 apply to all patients with catatonia. Since the first reported improvement of catatonia with amobarbital in 1930,⁶ there have been no controlled studies of specific treatments of catatonia.¹³ Meaningful treatment trials are either naturalistic, or have been performed only for NMS and malignant catatonia.⁵ However, multiple case reports and case series suggest that treatments with agents that have anticonvulsant properties (benzodiazepines, barbiturates) and ECT are effective.⁵

Benzodiazepines and related compounds. Case series have suggested a 60% to 80% remission rate of catatonia with benzodiazepines, the most commonly utilized of which has been lorazepam.^7,13,32 Treatment begins with a lorazepam challenge test of 1 to 2 mg in adults and 0.5 to 1 mg in children and geriatric patients,^9,15 administered orally (including via nasogastric tube), IM, or IV. Following a response (≥50% improvement), the dose is increased to 2 mg 3 times per day. The dose is further increased to 6 to 16 mg/d, and sometimes up to 30 mg/d.^9,11 Oral is less effective than sublingual or IM administration.¹¹ Diazepam can be helpful at doses 5 times the lorazepam dose.^9,17 A zolpidem challenge test of 10 mg orally or via nasogastric tube has also been utilized.¹⁵ Response is brief and is usually followed by lorazepam, although zolpidem up to 40 mg/d has been used for ongoing treatment.⁹

One alternative benzodiazepine protocol utilizes an initial IV dose of 2 mg lorazepam, repeated 3 to 5 times per day; the dose is increased to 10 to 12 mg/d if the first doses are partially effective.¹⁶ A lorazepam/diazepam approach involves a combination of IM lorazepam and IV diazepam.¹¹ The protocol begins with 2 mg of IM lorazepam. If there is no effect within 2 hours, a second 2 mg dose is administered, followed by an IV infusion of 10 mg diazepam in 500 ml of normal saline at 1.25 mg/hour until catatonia remits.

An Indian study of 107 patients (mean age 26) receiving relatively low doses of lorazepam (3 to 6 mg/d for at least 3 days) found that factors suggesting a robust response include a shorter duration of catatonia and waxy flexibility, while passivity, mutism, and auditory hallucinations describing the patient in the third person were associated with a poorer acute response.³¹ Catatonia with marked retardation and mutism complicating schizophrenia, especially with chronic negative symptoms, may be associated with a lower response rate to benzodiazepines.^20,33 Maintenance lorazepam has been effective in reducing relapse and recurrence.¹¹ There are no controlled studies of maintenance treatment with benzodiazepines, but clinical reports suggest that doses in the range of 4 to 10 mg/d are effective.³²

Continue to: ECT was used for catatonia in 1934...

ECT was first used for catatonia in 1934, when Laszlo Meduna used chemically induced seizures in catatonic patients who had been on tube feeding for months and no longer needed it after treatment.^6,7 As was true for other disorders, this approach was replaced by ECT.⁷ In various case series, the effectiveness of ECT in catatonia has been 53% to 100%.^7,13,15 Right unilateral ECT has been reported to be effective with 1 treatment.²¹ However, the best-established approach is with bitemporal ECT with a suprathreshold stimulus,⁹ usually with an acute course of 6 to 20 treatments.²⁰ ECT has been reported to be equally safe and effective in adolescents and adults.³⁴ Continued ECT is usually necessary until the patient has returned to baseline.⁹

ECT usually is recommended within 24 hours for treatment-resistant malignant catatonia or refusal to eat or drink, and within 2 to 3 days if medications are not sufficiently effective in other forms of catatonia.^12,15,20 If ECT is initiated after a benzodiazepine trial, the benzodiazepine antagonist flumazenil is administered first to reverse the anticonvulsant effect.⁹ Some experts recommend using a muscle relaxant other than succinylcholine in the presence of evidence of muscle damage.⁷

Alternatives to benzodiazepines and ECT. Based on case reports, the treatments described in Table 8^{13,15,17,20,25} have been used for patients with catatonia who do not tolerate or respond to standard treatments. The largest number of case reports have been with NMDA antagonists, while the presumed involvement of reduced dopamine signaling suggests that dopaminergic medications should be helpful. Dantrolene, which blocks release of calcium from intracellular stores and has been used to treat malignant hyperthermia, is sometimes used for NMS, often with disappointing results.

Whereas first-generation antipsychotics definitely increase the risk of catatonia and second-generation antipsychotics (SGAs) probably do so, SGAs are sometimes necessary to treat persistent psychosis in patients with schizophrenia who develop catatonia. Of these medications, clozapine may be most desirable because of low potency for dopamine receptor blockade and modulation of glutamatergic signaling. Partial dopamine agonism by aripiprazole, and the potential for increased subcortical prefrontal dopamine release resulting from serotonin 5HT2A antagonism and 5HT1A agonism by other SGAs, could also be helpful or at least not harmful in catatonia. Lorazepam is usually administered along with these medications to ameliorate treatment-emergent exacerbation of catatonia.

There are no controlled studies of any of these treatments. Based on case reports, most experts would recommend initiating treatment of catatonia with lorazepam, followed by ECT if necessary or in the presence of life-threatening catatonia. If ECT is not available, ineffective, or not tolerated, the first alternatives to be considered would be an NMDA antagonist or an anticonvulsant.²⁰

Continue to: Course varies by patient, underlying cause

Course varies by patient, underlying cause

The response to benzodiazepines or ECT can vary from episode to episode¹¹ and is similar in adults and younger patients.²² Many patients recover completely after a single episode, while relapse after remission occurs repeatedly in periodic catatonia, which involves chronic alternating stupor and excitement waxing and waning over years.¹¹ Relapses may occur frequently, or every few years.¹¹ Some cases of catatonia initially have an episodic course and become chronic and deteriorating, possibly paralleling the original descriptions of the natural history of untreated catatonia, while malignant catatonia can be complicated by medical morbidity or death.⁴ The long-term prognosis generally depends on the underlying cause of catatonia.⁵

Bottom Line

Much more common than many clinicians realize, catatonia can be overlooked because symptoms can mimic or overlap with features of an underlying medical or neurologic disorder. Suspect catatonia when one of these illnesses has an unexpected course or an inadequate treatment response. Be alert to characteristic changes in behavior and speech. A benzodiazepine challenge can be used to diagnose and begin treatment of catatonia. Consider electroconvulsive therapy sooner rather than later, especially for severely ill patients.

Related Resources

• Gibson RC, Walcott G. Benzodiazepines for catatonia in people with schizophrenia and other serious mental illnesses. Cochrane Database Syst Rev. 2008;(4):CD006570. 
• Newcastle University. Catatonia. https://youtu.be/_s1lzxHRO4U.

Drug Brand Names

Amantadine • Symmetrel
Amobarbital • Amytal
Aripiprazole • Abilify
Azithromycin • Zithromax
Baclofen • Lioresal
Benztropine • Cogentin
Carbamazepine • Carbatrol, Tegretol
Carbidopa/levodopa • Sinemet
Ciprofloxacin • Cipro
Clozapine • Clozaril
Dantrolene • Dantrium
Dexamethasone • Decadron
Dextromethorphan/quinidine • Neudexta
Diazepam • Valium
Disulfiram • Antabuse
Flumazenil • Romazicon
Fluoxetine • Prozac
Fluvoxamine • Luvox
Levetiracetam • Keppra
Lithium • Eskalith, Lithobid
Lorazepam • Ativan
Memantine • Namenda
Methylphenidate • Ritalin
Minocycline • Minocin
Olanzapine • Zyprexa
Risperidone • Risperdal
Succinylcholine • Anectine
Topiramate • Topamax
Trihexyphenidyl • Artane
Valproate • Depakote
Ziprasidone • Geodon
Zolpidem • Ambien

Antipsychotic agents are the mainstay of treatment for patients with schizophrenia,^1-3 and when taken regularly, they can greatly improve patient outcomes. Unfortunately, many studies have documented poor adherence to antipsychotic regimens in patients with schizophrenia, which often leads to an exacerbation of symptoms and preventable hospitalizations.^4-8 In order to improve adherence, many clinicians prescribe long-acting injectable antipsychotics (LAIAs).

LAIAs help improve adherence, but these benefits are seen only in patients who receive their injections within a specific time frame.^9-11 LAIAs administered outside of this time frame (missed doses) can lead to reoccurrence or exacerbation of symptoms. This article explains how to adequately manage missed LAIA doses.

First-generation long-acting injectable antipsychotics

Two first-generation antipsychotics are available as a long-acting injectable formulation: haloperidol decanoate and fluphenazine decanoate. Due to the increased risk of extrapyramidal symptoms, use of these agents have decreased, and they are often less preferred than second-generation LAIAs. Furthermore, unlike many of the newer second-generation LAIAs, first-generation LAIAs lack literature on how to manage missed doses. Therefore, clinicians should analyze the pharmacokinetic properties of these agents (Table 1^12-28), as well as the patient’s medical history and clinical presentation, in order to determine how best to address missed doses.

Haloperidol decanoate plasma concentrations peak approximately 6 days after the injection.¹² The medication has a half-life of 3 weeks. One study found that haloperidol plasma concentrations were detectable 13 weeks after the discontinuation of haloperidol decanoate.¹⁷ This same study also found that the change in plasma levels from 3 to 6 weeks after the last dose was minimal.¹⁷ Based on these findings, Figure 1 summarizes our recommendations for addressing missed haloperidol decanoate doses.

Fluphenazine decanoate levels peak 24 hours after the injection.¹⁸ An estimated therapeutic range for fluphenazine is 0.2 to 2 ng/mL.^21-25 One study that evaluated fluphenazine decanoate levels following discontinuation after reaching steady state found there was no significant difference in plasma levels 6 weeks after the last dose of fluphenazine, but a significant decrease in levels 8 to 12 weeks after the last dose.²⁶ Other studies found that fluphenazine levels were detectable 21 to 24 weeks following fluphenazine decanoate discontinuation.^27,28 Based on these findings, Figure 2 summarizes our recommendations for addressing missed fluphenazine decanoate doses.

Continue to: Second-generation LAIAs

Six second-generation LAIAs are available in the United States. Compared with the first-generation LAIAs, second-generation LAIAs have more extensive guidance on how to address missed doses.

Risperidone long-acting injection. When addressing missed doses of risperidone long-acting injection, first determine whether the medication has reached steady state. Steady state occurs approximately after the fourth consecutive injection (approximately 2 months).²⁹

If a patient missed a dose but has not reached steady state, he or she should receive the next dose as well as oral antipsychotic supplementation for 3 weeks.³⁰ If the patient has reached steady state and if it has been ≤6 weeks since the last injection, give the next injection as soon as possible. However, if steady state has been reached and it has been >6 weeks since the last injection, give the next injection, along with 3 weeks of oral antipsychotic supplementation (Figure 3).

Paliperidone palmitate monthly long-acting injection. Once the initiation dosing phase of paliperidone palmitate monthly long-acting injection (PP1M) is completed, the maintenance dose is administered every 4 weeks. When addressing missed doses of PP1M, first determine whether the patient is in the initiation or maintenance dosing phase.³¹

Initiation phase. Patients are in the initiation dosing phase during the first 2 injections of PP1M. During the initiation phase, the patient first receives 234 mg and then 156 mg 1 week later, both in the deltoid muscle. One month later, the patient receives a maintenance dose of PP1M (in the deltoid or gluteal muscle). The second initiation injection may be given 4 days before or after the scheduled administration date. The initiation doses should be adjusted in patients with mild renal function (creatinine clearance 50 to 80 mL/min).³¹ Figure 4 summarizes the guidance for addressing a missed or delayed second injection during the initiation phase.

Continue to: Maintenance phase

Maintenance phase. During the maintenance phase, PP1M can be administered 7 days before or after the monthly due date. If the patient has missed a maintenance injection and it has been <6 weeks since the last dose, the maintenance injection can be given as soon as possible (Figure 5).³¹ If it has been 6 weeks to 6 months since the last injection, the patient should receive their prescribed maintenance dose as soon as possible and the same dose 1 week later, with both injections in the deltoid muscle. Following the second dose, the patient can resume their regular monthly maintenance schedule, in either the deltoid or gluteal muscle. For example, if the patient was maintained on 117 mg of PP1M and it had been 8 weeks since the last injection, the patient should receive 117 mg immediately, then 117 mg 1 week later, then 117 mg 1 month later. An exception to this is if a patient’s maintenance dose is 234 mg monthly. In this case, the patient should receive 156 mg of PP1M immediately, then 156 mg 1 week later, and then 234 mg 1 month later.³¹ If it has been >6 months since the last dose, the patient should start the initiation schedule as if he or she were receiving a new medication.³¹

Paliperidone palmitate 3-month long-acting injection (PP3M) should be administered every 3 months. This injection can be given 2 weeks before or after the date of the scheduled dose.³²

If the patient missed an injection and it has been <4 months since the last dose, the next scheduled dose should be given as soon as possible.³² If it has been 4 to 9 months since the last dose, the patient must return to PP1M for 2 booster injections 1 week apart. The dose of these PP1M booster injections depends on the dose of PP3M that the patient had been stabilized on:

• 78 mg if stabilized on 273 mg
• 117 mg if stabilized on 410 mg
• 156 mg if stabilized on 546 mg or 819 mg.³²

After the second booster dose, PP3M can be restarted 1 month later.³² If it has been >9 months since the last PP3M dose, the patient should be restarted on PP1M. PP3M can be reconsidered once the patient has been stabilized on PP1M for ≥4 months (Figure 6).³²

Continue to: Aripiprazole long-acting injection

Aripiprazole long-acting injection is administered every 4 weeks. If a patient misses an injection, first determine how many consecutive doses he or she has received.³³ If the patient has missed the second or third injection, and it has been <5 weeks since the last dose, give the next injection as soon as possible. If it has been >5 weeks, give the next injection as soon as possible, plus oral aripiprazole supplementation for 2 weeks (Figure 7).

If the patient has received ≥4 consecutive doses and misses a dose and it has been <6 weeks since the last dose, administer an injection as soon as possible. If it has been >6 weeks since the last dose, give the next injection as soon as possible, plus with oral aripiprazole supplementation for 2 weeks.

Aripiprazole lauroxil long-acting injection. Depending on the dose, aripiprazole lauroxil can be administered monthly, every 6 weeks, or every 2 months. Aripiprazole lauroxil can be administered 14 days before or after the scheduled dose.³⁴

The guidance for addressing missed or delayed doses of aripiprazole lauroxil differs depending on the dose the patient is stabilized on, and how long it has been since the last injection. Figure 8 summarizes how missed injections should be managed. When oral aripiprazole supplementation is needed, the following doses should be used:

• 10 mg/d if stabilized on 441 mg every month
• 15 mg/d if stabilized on 662 mg every month, 882 mg every 6 weeks, or 1,064 mg every 2 months
• 20 mg/d if stabilized on 882 mg every month.³⁴

Olanzapine pamoate long-acting injection is a unique LAIA because it requires prescribers and patients to participate in a risk evaluation and mitigation strategies (REMS) program due the risk of post-injection delirium/sedation syndrome. It is administered every 2 to 4 weeks, with loading doses given for the first 2 months of treatment (Table 2³⁵). After 2 months, the patient can proceed to the maintenance dosing regimen.

Continue to: Currently, there is no concrete guidance...

Currently, there is no concrete guidance on how to address missed doses of olanzapine long-acting injection; however, the pharmacokinetics of this formulation allow flexibility in dosing intervals. Therapeutic levels are present after the first injection, and the medication reaches steady-state levels in 3 months.^35-37 As a result of its specific formulation, olanzapine pamoate long-acting injection provides sustained olanzapine pamoate plasma concentrations between injections, and has a half-life of 30 days.³⁵ Consequently, therapeutic levels of the medication are still present 2 to 4 weeks after an injection.³⁷ Additionally, clinically relevant plasma concentrations may be present 2 to 3 months after the last injection.³⁶

In light of this information, if a patient has not reached steady state and has missed an injection, he or she should receive the recommended loading dose schedule. If the patient has reached steady state and it has been ≤2 months since the last dose, he or she should receive the next dose as soon as possible. If steady state has been reached and it has been >2 months since the last injection, the patient should receive the recommended loading dosing for 2 months (Figure 9). Because of the risk of post-injection delirium/sedation syndrome, and because therapeutic levels are achieved after the first injection, oral olanzapine supplementation is not recommended.

Use a stepwise approach

In general, clinicians can use a stepwise approach to managing missed doses of LAIAs (Figure 10). First, establish the number of LAIA doses the patient had received prior to the last dose, and whether these injections were administered on schedule. This will help you determine if the patient is in the initiation or maintenance phase and/or has reached steady state. The second step is to establish the date of the last injection. Use objective tools, such as pharmacy records or the medical chart, to determine the date of the last injection, rather than relying on patient reporting. For the third step, calculate the time that has passed since the last LAIA dose. Once you have completed these steps, use the specific medication recommendations described in this article to address the missed dose.

Continue to: Address barriers to adherence

When addressing missed LAIA doses, be sure to identify any barriers that may have led to a missed injection. These might include:

• bothersome adverse effects
• transportation difficulties
• issues with insurance/medication coverage
• comorbidities (ie, alcohol/substance use disorders)
• cognitive and functional impairment caused by the patient’s illness
• difficulty with keeping track of appointments.

Clinicians can work closely with patients and/or caregivers to address any barriers to ensure that patients receive their injections in a timely fashion.

The goal: Reducing relapse

LAIAs improve medication adherence. Although nonadherence is less frequent with LAIAs than with oral antipsychotics, when a LAIA dose is missed, it is important to properly follow a stepwise approach based on the unique properties of the specific LAIA prescribed. Proper management of LAIA missed doses can prevent relapse and reoccurrence of schizophrenia symptoms, thus possibly avoiding future hospitalizations.

Acknowledgments

The authors thank Brian Tschosik, JD, Mary Collen O’Rourke, MD, and Amanda Holloway, MD, for their assistance with this article.

Bottom Line

Although long-acting injectable antipsychotics (LAIAs) greatly assist with adherence, these agents are effective only when missed doses are avoided. When addressing missed LAIA doses, use a stepwise approach that takes into consideration the unique properties of the specific LAIA prescribed.

Related Resources

• Haddad P, Lambert T, Lauriello J, eds. Antipsychotic long-acting injections. 2nd ed. Oxford, UK: Oxford University Press; 2016.  
• Diefenderfer LA. When should you consider combining 2 long-acting injectable antipsychotics? Current Psychiatry. 2017;16(10):42-46.

Drug Brand Names 

Aripiprazole long-acting injection • Abilify Maintena
Aripiprazole lauroxil long-acting injection • Aristada
Fluphenazine decanoate • Prolixin decanoate  
Haloperidol decanoate • Haldol decanoate
Olanzapine pamoate long-acting injection • Zyprexa Relprevv
Paliperidone palmitate monthly long-acting injection • Invega Sustenna
Paliperidone palmitate 3-month long-acting injection • Invega Trinza  
Risperidone long-acting injection • Risperdal Consta

Antipsychotic agents are the mainstay of treatment for patients with schizophrenia,^1-3 and when taken regularly, they can greatly improve patient outcomes. Unfortunately, many studies have documented poor adherence to antipsychotic regimens in patients with schizophrenia, which often leads to an exacerbation of symptoms and preventable hospitalizations.^4-8 In order to improve adherence, many clinicians prescribe long-acting injectable antipsychotics (LAIAs).

LAIAs help improve adherence, but these benefits are seen only in patients who receive their injections within a specific time frame.^9-11 LAIAs administered outside of this time frame (missed doses) can lead to reoccurrence or exacerbation of symptoms. This article explains how to adequately manage missed LAIA doses.

First-generation long-acting injectable antipsychotics

Two first-generation antipsychotics are available as a long-acting injectable formulation: haloperidol decanoate and fluphenazine decanoate. Due to the increased risk of extrapyramidal symptoms, use of these agents have decreased, and they are often less preferred than second-generation LAIAs. Furthermore, unlike many of the newer second-generation LAIAs, first-generation LAIAs lack literature on how to manage missed doses. Therefore, clinicians should analyze the pharmacokinetic properties of these agents (Table 1^12-28), as well as the patient’s medical history and clinical presentation, in order to determine how best to address missed doses.

Haloperidol decanoate plasma concentrations peak approximately 6 days after the injection.¹² The medication has a half-life of 3 weeks. One study found that haloperidol plasma concentrations were detectable 13 weeks after the discontinuation of haloperidol decanoate.¹⁷ This same study also found that the change in plasma levels from 3 to 6 weeks after the last dose was minimal.¹⁷ Based on these findings, Figure 1 summarizes our recommendations for addressing missed haloperidol decanoate doses.

Fluphenazine decanoate levels peak 24 hours after the injection.¹⁸ An estimated therapeutic range for fluphenazine is 0.2 to 2 ng/mL.^21-25 One study that evaluated fluphenazine decanoate levels following discontinuation after reaching steady state found there was no significant difference in plasma levels 6 weeks after the last dose of fluphenazine, but a significant decrease in levels 8 to 12 weeks after the last dose.²⁶ Other studies found that fluphenazine levels were detectable 21 to 24 weeks following fluphenazine decanoate discontinuation.^27,28 Based on these findings, Figure 2 summarizes our recommendations for addressing missed fluphenazine decanoate doses.

Continue to: Second-generation LAIAs

Six second-generation LAIAs are available in the United States. Compared with the first-generation LAIAs, second-generation LAIAs have more extensive guidance on how to address missed doses.

Risperidone long-acting injection. When addressing missed doses of risperidone long-acting injection, first determine whether the medication has reached steady state. Steady state occurs approximately after the fourth consecutive injection (approximately 2 months).²⁹

If a patient missed a dose but has not reached steady state, he or she should receive the next dose as well as oral antipsychotic supplementation for 3 weeks.³⁰ If the patient has reached steady state and if it has been ≤6 weeks since the last injection, give the next injection as soon as possible. However, if steady state has been reached and it has been >6 weeks since the last injection, give the next injection, along with 3 weeks of oral antipsychotic supplementation (Figure 3).

Paliperidone palmitate monthly long-acting injection. Once the initiation dosing phase of paliperidone palmitate monthly long-acting injection (PP1M) is completed, the maintenance dose is administered every 4 weeks. When addressing missed doses of PP1M, first determine whether the patient is in the initiation or maintenance dosing phase.³¹

Initiation phase. Patients are in the initiation dosing phase during the first 2 injections of PP1M. During the initiation phase, the patient first receives 234 mg and then 156 mg 1 week later, both in the deltoid muscle. One month later, the patient receives a maintenance dose of PP1M (in the deltoid or gluteal muscle). The second initiation injection may be given 4 days before or after the scheduled administration date. The initiation doses should be adjusted in patients with mild renal function (creatinine clearance 50 to 80 mL/min).³¹ Figure 4 summarizes the guidance for addressing a missed or delayed second injection during the initiation phase.

Continue to: Maintenance phase

Maintenance phase. During the maintenance phase, PP1M can be administered 7 days before or after the monthly due date. If the patient has missed a maintenance injection and it has been <6 weeks since the last dose, the maintenance injection can be given as soon as possible (Figure 5).³¹ If it has been 6 weeks to 6 months since the last injection, the patient should receive their prescribed maintenance dose as soon as possible and the same dose 1 week later, with both injections in the deltoid muscle. Following the second dose, the patient can resume their regular monthly maintenance schedule, in either the deltoid or gluteal muscle. For example, if the patient was maintained on 117 mg of PP1M and it had been 8 weeks since the last injection, the patient should receive 117 mg immediately, then 117 mg 1 week later, then 117 mg 1 month later. An exception to this is if a patient’s maintenance dose is 234 mg monthly. In this case, the patient should receive 156 mg of PP1M immediately, then 156 mg 1 week later, and then 234 mg 1 month later.³¹ If it has been >6 months since the last dose, the patient should start the initiation schedule as if he or she were receiving a new medication.³¹

Paliperidone palmitate 3-month long-acting injection (PP3M) should be administered every 3 months. This injection can be given 2 weeks before or after the date of the scheduled dose.³²

If the patient missed an injection and it has been <4 months since the last dose, the next scheduled dose should be given as soon as possible.³² If it has been 4 to 9 months since the last dose, the patient must return to PP1M for 2 booster injections 1 week apart. The dose of these PP1M booster injections depends on the dose of PP3M that the patient had been stabilized on:

• 78 mg if stabilized on 273 mg
• 117 mg if stabilized on 410 mg
• 156 mg if stabilized on 546 mg or 819 mg.³²

After the second booster dose, PP3M can be restarted 1 month later.³² If it has been >9 months since the last PP3M dose, the patient should be restarted on PP1M. PP3M can be reconsidered once the patient has been stabilized on PP1M for ≥4 months (Figure 6).³²

Continue to: Aripiprazole long-acting injection

Aripiprazole long-acting injection is administered every 4 weeks. If a patient misses an injection, first determine how many consecutive doses he or she has received.³³ If the patient has missed the second or third injection, and it has been <5 weeks since the last dose, give the next injection as soon as possible. If it has been >5 weeks, give the next injection as soon as possible, plus oral aripiprazole supplementation for 2 weeks (Figure 7).

If the patient has received ≥4 consecutive doses and misses a dose and it has been <6 weeks since the last dose, administer an injection as soon as possible. If it has been >6 weeks since the last dose, give the next injection as soon as possible, plus with oral aripiprazole supplementation for 2 weeks.

Aripiprazole lauroxil long-acting injection. Depending on the dose, aripiprazole lauroxil can be administered monthly, every 6 weeks, or every 2 months. Aripiprazole lauroxil can be administered 14 days before or after the scheduled dose.³⁴

The guidance for addressing missed or delayed doses of aripiprazole lauroxil differs depending on the dose the patient is stabilized on, and how long it has been since the last injection. Figure 8 summarizes how missed injections should be managed. When oral aripiprazole supplementation is needed, the following doses should be used:

• 10 mg/d if stabilized on 441 mg every month
• 15 mg/d if stabilized on 662 mg every month, 882 mg every 6 weeks, or 1,064 mg every 2 months
• 20 mg/d if stabilized on 882 mg every month.³⁴

Olanzapine pamoate long-acting injection is a unique LAIA because it requires prescribers and patients to participate in a risk evaluation and mitigation strategies (REMS) program due the risk of post-injection delirium/sedation syndrome. It is administered every 2 to 4 weeks, with loading doses given for the first 2 months of treatment (Table 2³⁵). After 2 months, the patient can proceed to the maintenance dosing regimen.

Continue to: Currently, there is no concrete guidance...

Currently, there is no concrete guidance on how to address missed doses of olanzapine long-acting injection; however, the pharmacokinetics of this formulation allow flexibility in dosing intervals. Therapeutic levels are present after the first injection, and the medication reaches steady-state levels in 3 months.^35-37 As a result of its specific formulation, olanzapine pamoate long-acting injection provides sustained olanzapine pamoate plasma concentrations between injections, and has a half-life of 30 days.³⁵ Consequently, therapeutic levels of the medication are still present 2 to 4 weeks after an injection.³⁷ Additionally, clinically relevant plasma concentrations may be present 2 to 3 months after the last injection.³⁶

In light of this information, if a patient has not reached steady state and has missed an injection, he or she should receive the recommended loading dose schedule. If the patient has reached steady state and it has been ≤2 months since the last dose, he or she should receive the next dose as soon as possible. If steady state has been reached and it has been >2 months since the last injection, the patient should receive the recommended loading dosing for 2 months (Figure 9). Because of the risk of post-injection delirium/sedation syndrome, and because therapeutic levels are achieved after the first injection, oral olanzapine supplementation is not recommended.

Use a stepwise approach

In general, clinicians can use a stepwise approach to managing missed doses of LAIAs (Figure 10). First, establish the number of LAIA doses the patient had received prior to the last dose, and whether these injections were administered on schedule. This will help you determine if the patient is in the initiation or maintenance phase and/or has reached steady state. The second step is to establish the date of the last injection. Use objective tools, such as pharmacy records or the medical chart, to determine the date of the last injection, rather than relying on patient reporting. For the third step, calculate the time that has passed since the last LAIA dose. Once you have completed these steps, use the specific medication recommendations described in this article to address the missed dose.

Continue to: Address barriers to adherence

When addressing missed LAIA doses, be sure to identify any barriers that may have led to a missed injection. These might include:

• bothersome adverse effects
• transportation difficulties
• issues with insurance/medication coverage
• comorbidities (ie, alcohol/substance use disorders)
• cognitive and functional impairment caused by the patient’s illness
• difficulty with keeping track of appointments.

Clinicians can work closely with patients and/or caregivers to address any barriers to ensure that patients receive their injections in a timely fashion.

The goal: Reducing relapse

LAIAs improve medication adherence. Although nonadherence is less frequent with LAIAs than with oral antipsychotics, when a LAIA dose is missed, it is important to properly follow a stepwise approach based on the unique properties of the specific LAIA prescribed. Proper management of LAIA missed doses can prevent relapse and reoccurrence of schizophrenia symptoms, thus possibly avoiding future hospitalizations.

Acknowledgments

The authors thank Brian Tschosik, JD, Mary Collen O’Rourke, MD, and Amanda Holloway, MD, for their assistance with this article.

Bottom Line

Although long-acting injectable antipsychotics (LAIAs) greatly assist with adherence, these agents are effective only when missed doses are avoided. When addressing missed LAIA doses, use a stepwise approach that takes into consideration the unique properties of the specific LAIA prescribed.

Related Resources

• Haddad P, Lambert T, Lauriello J, eds. Antipsychotic long-acting injections. 2nd ed. Oxford, UK: Oxford University Press; 2016.  
• Diefenderfer LA. When should you consider combining 2 long-acting injectable antipsychotics? Current Psychiatry. 2017;16(10):42-46.

Drug Brand Names 

Aripiprazole long-acting injection • Abilify Maintena
Aripiprazole lauroxil long-acting injection • Aristada
Fluphenazine decanoate • Prolixin decanoate  
Haloperidol decanoate • Haldol decanoate
Olanzapine pamoate long-acting injection • Zyprexa Relprevv
Paliperidone palmitate monthly long-acting injection • Invega Sustenna
Paliperidone palmitate 3-month long-acting injection • Invega Trinza  
Risperidone long-acting injection • Risperdal Consta

Antipsychotic agents are the mainstay of treatment for patients with schizophrenia,^1-3 and when taken regularly, they can greatly improve patient outcomes. Unfortunately, many studies have documented poor adherence to antipsychotic regimens in patients with schizophrenia, which often leads to an exacerbation of symptoms and preventable hospitalizations.^4-8 In order to improve adherence, many clinicians prescribe long-acting injectable antipsychotics (LAIAs).

LAIAs help improve adherence, but these benefits are seen only in patients who receive their injections within a specific time frame.^9-11 LAIAs administered outside of this time frame (missed doses) can lead to reoccurrence or exacerbation of symptoms. This article explains how to adequately manage missed LAIA doses.

First-generation long-acting injectable antipsychotics

Two first-generation antipsychotics are available as a long-acting injectable formulation: haloperidol decanoate and fluphenazine decanoate. Due to the increased risk of extrapyramidal symptoms, use of these agents have decreased, and they are often less preferred than second-generation LAIAs. Furthermore, unlike many of the newer second-generation LAIAs, first-generation LAIAs lack literature on how to manage missed doses. Therefore, clinicians should analyze the pharmacokinetic properties of these agents (Table 1^12-28), as well as the patient’s medical history and clinical presentation, in order to determine how best to address missed doses.

Haloperidol decanoate plasma concentrations peak approximately 6 days after the injection.¹² The medication has a half-life of 3 weeks. One study found that haloperidol plasma concentrations were detectable 13 weeks after the discontinuation of haloperidol decanoate.¹⁷ This same study also found that the change in plasma levels from 3 to 6 weeks after the last dose was minimal.¹⁷ Based on these findings, Figure 1 summarizes our recommendations for addressing missed haloperidol decanoate doses.

Fluphenazine decanoate levels peak 24 hours after the injection.¹⁸ An estimated therapeutic range for fluphenazine is 0.2 to 2 ng/mL.^21-25 One study that evaluated fluphenazine decanoate levels following discontinuation after reaching steady state found there was no significant difference in plasma levels 6 weeks after the last dose of fluphenazine, but a significant decrease in levels 8 to 12 weeks after the last dose.²⁶ Other studies found that fluphenazine levels were detectable 21 to 24 weeks following fluphenazine decanoate discontinuation.^27,28 Based on these findings, Figure 2 summarizes our recommendations for addressing missed fluphenazine decanoate doses.

Continue to: Second-generation LAIAs

Six second-generation LAIAs are available in the United States. Compared with the first-generation LAIAs, second-generation LAIAs have more extensive guidance on how to address missed doses.

Risperidone long-acting injection. When addressing missed doses of risperidone long-acting injection, first determine whether the medication has reached steady state. Steady state occurs approximately after the fourth consecutive injection (approximately 2 months).²⁹

If a patient missed a dose but has not reached steady state, he or she should receive the next dose as well as oral antipsychotic supplementation for 3 weeks.³⁰ If the patient has reached steady state and if it has been ≤6 weeks since the last injection, give the next injection as soon as possible. However, if steady state has been reached and it has been >6 weeks since the last injection, give the next injection, along with 3 weeks of oral antipsychotic supplementation (Figure 3).

Paliperidone palmitate monthly long-acting injection. Once the initiation dosing phase of paliperidone palmitate monthly long-acting injection (PP1M) is completed, the maintenance dose is administered every 4 weeks. When addressing missed doses of PP1M, first determine whether the patient is in the initiation or maintenance dosing phase.³¹

Initiation phase. Patients are in the initiation dosing phase during the first 2 injections of PP1M. During the initiation phase, the patient first receives 234 mg and then 156 mg 1 week later, both in the deltoid muscle. One month later, the patient receives a maintenance dose of PP1M (in the deltoid or gluteal muscle). The second initiation injection may be given 4 days before or after the scheduled administration date. The initiation doses should be adjusted in patients with mild renal function (creatinine clearance 50 to 80 mL/min).³¹ Figure 4 summarizes the guidance for addressing a missed or delayed second injection during the initiation phase.

Continue to: Maintenance phase

Maintenance phase. During the maintenance phase, PP1M can be administered 7 days before or after the monthly due date. If the patient has missed a maintenance injection and it has been <6 weeks since the last dose, the maintenance injection can be given as soon as possible (Figure 5).³¹ If it has been 6 weeks to 6 months since the last injection, the patient should receive their prescribed maintenance dose as soon as possible and the same dose 1 week later, with both injections in the deltoid muscle. Following the second dose, the patient can resume their regular monthly maintenance schedule, in either the deltoid or gluteal muscle. For example, if the patient was maintained on 117 mg of PP1M and it had been 8 weeks since the last injection, the patient should receive 117 mg immediately, then 117 mg 1 week later, then 117 mg 1 month later. An exception to this is if a patient’s maintenance dose is 234 mg monthly. In this case, the patient should receive 156 mg of PP1M immediately, then 156 mg 1 week later, and then 234 mg 1 month later.³¹ If it has been >6 months since the last dose, the patient should start the initiation schedule as if he or she were receiving a new medication.³¹

Paliperidone palmitate 3-month long-acting injection (PP3M) should be administered every 3 months. This injection can be given 2 weeks before or after the date of the scheduled dose.³²

If the patient missed an injection and it has been <4 months since the last dose, the next scheduled dose should be given as soon as possible.³² If it has been 4 to 9 months since the last dose, the patient must return to PP1M for 2 booster injections 1 week apart. The dose of these PP1M booster injections depends on the dose of PP3M that the patient had been stabilized on:

• 78 mg if stabilized on 273 mg
• 117 mg if stabilized on 410 mg
• 156 mg if stabilized on 546 mg or 819 mg.³²

After the second booster dose, PP3M can be restarted 1 month later.³² If it has been >9 months since the last PP3M dose, the patient should be restarted on PP1M. PP3M can be reconsidered once the patient has been stabilized on PP1M for ≥4 months (Figure 6).³²

Continue to: Aripiprazole long-acting injection

Aripiprazole long-acting injection is administered every 4 weeks. If a patient misses an injection, first determine how many consecutive doses he or she has received.³³ If the patient has missed the second or third injection, and it has been <5 weeks since the last dose, give the next injection as soon as possible. If it has been >5 weeks, give the next injection as soon as possible, plus oral aripiprazole supplementation for 2 weeks (Figure 7).

If the patient has received ≥4 consecutive doses and misses a dose and it has been <6 weeks since the last dose, administer an injection as soon as possible. If it has been >6 weeks since the last dose, give the next injection as soon as possible, plus with oral aripiprazole supplementation for 2 weeks.

Aripiprazole lauroxil long-acting injection. Depending on the dose, aripiprazole lauroxil can be administered monthly, every 6 weeks, or every 2 months. Aripiprazole lauroxil can be administered 14 days before or after the scheduled dose.³⁴

The guidance for addressing missed or delayed doses of aripiprazole lauroxil differs depending on the dose the patient is stabilized on, and how long it has been since the last injection. Figure 8 summarizes how missed injections should be managed. When oral aripiprazole supplementation is needed, the following doses should be used:

• 10 mg/d if stabilized on 441 mg every month
• 15 mg/d if stabilized on 662 mg every month, 882 mg every 6 weeks, or 1,064 mg every 2 months
• 20 mg/d if stabilized on 882 mg every month.³⁴

Olanzapine pamoate long-acting injection is a unique LAIA because it requires prescribers and patients to participate in a risk evaluation and mitigation strategies (REMS) program due the risk of post-injection delirium/sedation syndrome. It is administered every 2 to 4 weeks, with loading doses given for the first 2 months of treatment (Table 2³⁵). After 2 months, the patient can proceed to the maintenance dosing regimen.

Continue to: Currently, there is no concrete guidance...

Currently, there is no concrete guidance on how to address missed doses of olanzapine long-acting injection; however, the pharmacokinetics of this formulation allow flexibility in dosing intervals. Therapeutic levels are present after the first injection, and the medication reaches steady-state levels in 3 months.^35-37 As a result of its specific formulation, olanzapine pamoate long-acting injection provides sustained olanzapine pamoate plasma concentrations between injections, and has a half-life of 30 days.³⁵ Consequently, therapeutic levels of the medication are still present 2 to 4 weeks after an injection.³⁷ Additionally, clinically relevant plasma concentrations may be present 2 to 3 months after the last injection.³⁶

In light of this information, if a patient has not reached steady state and has missed an injection, he or she should receive the recommended loading dose schedule. If the patient has reached steady state and it has been ≤2 months since the last dose, he or she should receive the next dose as soon as possible. If steady state has been reached and it has been >2 months since the last injection, the patient should receive the recommended loading dosing for 2 months (Figure 9). Because of the risk of post-injection delirium/sedation syndrome, and because therapeutic levels are achieved after the first injection, oral olanzapine supplementation is not recommended.

Use a stepwise approach

In general, clinicians can use a stepwise approach to managing missed doses of LAIAs (Figure 10). First, establish the number of LAIA doses the patient had received prior to the last dose, and whether these injections were administered on schedule. This will help you determine if the patient is in the initiation or maintenance phase and/or has reached steady state. The second step is to establish the date of the last injection. Use objective tools, such as pharmacy records or the medical chart, to determine the date of the last injection, rather than relying on patient reporting. For the third step, calculate the time that has passed since the last LAIA dose. Once you have completed these steps, use the specific medication recommendations described in this article to address the missed dose.

Continue to: Address barriers to adherence

When addressing missed LAIA doses, be sure to identify any barriers that may have led to a missed injection. These might include:

• bothersome adverse effects
• transportation difficulties
• issues with insurance/medication coverage
• comorbidities (ie, alcohol/substance use disorders)
• cognitive and functional impairment caused by the patient’s illness
• difficulty with keeping track of appointments.

Clinicians can work closely with patients and/or caregivers to address any barriers to ensure that patients receive their injections in a timely fashion.

The goal: Reducing relapse

LAIAs improve medication adherence. Although nonadherence is less frequent with LAIAs than with oral antipsychotics, when a LAIA dose is missed, it is important to properly follow a stepwise approach based on the unique properties of the specific LAIA prescribed. Proper management of LAIA missed doses can prevent relapse and reoccurrence of schizophrenia symptoms, thus possibly avoiding future hospitalizations.

Acknowledgments

The authors thank Brian Tschosik, JD, Mary Collen O’Rourke, MD, and Amanda Holloway, MD, for their assistance with this article.

Bottom Line

Although long-acting injectable antipsychotics (LAIAs) greatly assist with adherence, these agents are effective only when missed doses are avoided. When addressing missed LAIA doses, use a stepwise approach that takes into consideration the unique properties of the specific LAIA prescribed.

Related Resources

• Haddad P, Lambert T, Lauriello J, eds. Antipsychotic long-acting injections. 2nd ed. Oxford, UK: Oxford University Press; 2016.  
• Diefenderfer LA. When should you consider combining 2 long-acting injectable antipsychotics? Current Psychiatry. 2017;16(10):42-46.

Drug Brand Names 

Aripiprazole long-acting injection • Abilify Maintena
Aripiprazole lauroxil long-acting injection • Aristada
Fluphenazine decanoate • Prolixin decanoate  
Haloperidol decanoate • Haldol decanoate
Olanzapine pamoate long-acting injection • Zyprexa Relprevv
Paliperidone palmitate monthly long-acting injection • Invega Sustenna
Paliperidone palmitate 3-month long-acting injection • Invega Trinza  
Risperidone long-acting injection • Risperdal Consta

More than 5 million older Americans are living with Alzheimer’s disease and related dementias—and this number is estimated to rise to almost 14 million by 2050.¹ Dementia is associated with high costs for the patient, family, and society. In 2017, nearly 16.1 million caregivers assisted older adults with dementia, devoting more than 18.2 billion hours per year in care.¹ In the United States, the cost of caring for individuals with dementia is expected to reach $277 billion in 2018. Additionally, Medicare and Medicaid are expected to pay 67% of the estimated 2018 cost, and 22% is expected to come out of the pockets of patients and their caregivers.¹

Although dementia is often viewed as a memory loss disease, neuropsychiatric symptoms (NPS) are common. NPS includes distressing behaviors, such as aggression and wandering, that increase caregiver burden, escalate the cost of care, and contribute to premature institutionalization. This article examines the evidence for the use of a combination of a cholinesterase inhibitor and memantine vs use of either medication alone for treating NPS of Alzheimer’s disease and other types of dementia.

First, rule out reversible causes of NPS

There are no disease-modifying treatments for dementia¹; therefore, clinicians focus on decreasing patients’ suffering and improving their quality of life. Nearly all patients with dementia will develop at least one NPS. These commonly include auditory and visual hallucinations, delusions, depression, anxiety, psychosis, psychomotor agitation, aggression, apathy, repetitive questioning, wandering, socially or sexually inappropriate behaviors, and sleep disturbances.² The underlying cause of these behaviors may be neurobiological,³ an acute medical condition, unmet needs or a pre-existing personality disorder, or other psychiatric illness.² Because of this complexity, there is no specific treatment for NPS of dementia. Treatment should begin with an assessment to rule out potentially reversible causes of NPS, such as a urinary tract infection, environmental triggers, unmet needs, or untreated psychiatric illness. For mild to moderate NPS, short-term behavioral interventions, followed by pharmacologic interventions, are used. For moderate to severe NPS, pharmacologic interventions and behavioral interventions are often used simultaneously.

Pharmacologic options for treating NPS

The classes of medications frequently used to treat NPS include antidepressants, antipsychotics, mood stabilizers, and memory-enhancing, dementia-specific agents (cholinesterase inhibitors and the N-methyl-D-aspartate [NMDA] agonist memantine). Use of these medications to treat medical, psychiatric, or neurological illnesses in patients who do not have dementia is not covered in this article.

Serotonergic antidepressants are the recommended first-line antidepressant class for NPS in older adults who have dementia because they are generally well-tolerated. Of the serotonergic agents (sertraline, fluoxetine, citalopram, and trazodone), only citalopram has some limited evidence of benefit for patients with NPS.⁴

Antipsychotic medications are typically reserved for treating specific non-cognitive NPS, such as psychosis and/or severe agitated behavior that causes significant distress. Atypical antipsychotics, such as risperidone, aripiprazole, and olanzapine, currently have the best evidence for efficacy in this population. The effects are modest and use of these medications may be associated with an increased risk of stroke.^4,5

The mood stabilizers valproate and carbamazepine have been studied for treating NPS, but available evidence suggests that neither medication provides significant benefit for patients with NPS. Furthermore, there is evidence of significant harm with valproate.⁴ There are no known studies evaluating the use of lithium for NPS.

Continue to: Evidence for dementia-specific medications

Evidence for dementia-specific medications

An alternative to the above pharmacologic options is treatment with a cholinesterase inhibitor and/or memantine. Among cholinesterase inhibitors in the United States, donepezil is approved to treat mild, moderate, and severe dementia, while rivastigmine and galantamine are approved for the treatment of mild to moderate dementia. Memantine is the only NMDA receptor agonist approved in the United States for moderate to severe dementia. The Table^6-10 highlights potential dosing regimens for each of these 4 medications.

Few randomized controlled trials (RCTs) of cholinesterase inhibitors or memantine have focused on improvement of NPS as a primary outcome measure, but some RCTs have used treatment of NPS as a secondary outcome.⁴ Most RCT data for using medications for NPS have come from small studies that lasted 17 days to 28 weeks and had design limitations. Most meta-analyses and review articles exclude trials if they do not evaluate NPS as a primary outcome, and most RCTs have only included NPS as a secondary outcome. We hypothesize that this is because NPS is conceptualized as a psychiatric condition, while dementia is codified as a neurologic condition. The reality is that dementia is a neuropsychiatric condition. This artificial divergence complicates both the evaluation and treatment of patients with dementia, who almost always have NPS. Medication trials focused on the neurologic components for primary outcomes contribute to the confusion and difficulty of building an evidence base around the treatment of NPS in Alzheimer’s disease. Patients with severe NPS are seldom included in RCTs.

A cholinesterase inhibitor, memantine, or both?

In a large, pooled area-under-the-curve analysis, Atri et al¹¹ examined data from 1,408 individuals with moderate to severe Alzheimer’s disease who were enrolled in four 6-month RCTs of memantine with or without donepezil add-on therapy; some participants received donepezil only. This analysis found positive benefits for cognition, function, and behavior among those who received a combination of memantine and donepezil compared with those who received either medication alone. This study was limited to 6 months, it used a measure of cognition without executive function, and most participants were white females. However, 6 months is far longer than most medication trials.

In the absence of extended RCTs, attention turns to the opinions of panels of experts examining available data. There are no recent guidelines from any U.S.-based specialty society that address the use of combination cholinesterase/memantine treatment for NPS of dementia. Since 2013, there has been emerging awareness of the evidence for efficacy and cost effectiveness to support the use of a cholinesterase inhibitor and/or memantine for patients demonstrating cognitive and functional decline due to Alzheimer’s disease, Lewy body dementia, and dementia due to Parkinson’s disease.

The 2012 Fourth Canadian Consensus Conference on the Diagnosis and Treatment of Dementia¹² recommended a trial of a cholinesterase inhibitor in most patients with Alzheimer’s disease or Alzheimer’s disease combined with another type of dementia. The panel did not find enough evidence to recommend for or against the use of cholinesterase inhibitors and/or memantine for the treatment of NPS as a primary indication. However, they warned of the risks of discontinuing a cholinesterase inhibitor and suggested a slow taper and monitoring, with consideration of restarting the medication if there is notable functional or behavioral decline.

Continue to: In 2015, the European Neurological Society and the European Federation of Neurological Societies...

In 2015, the European Neurological Society and the European Federation of Neurological Societies (now combined into the European Academy of Neurology) found a moderate benefit for using cholinesterase inhibitors to treat problematic behaviors in patients with Alzheimer’s disease.¹³ They found the evidence weak only when they included consideration of cognitive benefits. For patients with moderate to severe Alzheimer’s disease, the Academy endorsed the combination of cholinesterase inhibitors and memantine.¹³

The United Kingdom National Institute for Clinical Excellence (NICE) guideline on dementia is updated every 1 to 3 years based on evolving evidence for the treatment of Alzheimer’s disease and related symptoms. In 2016, NICE updated its guideline to recommend the use of a cholinesterase inhibitor for patients with mild to severe Alzheimer’s disease and memantine for those with severe Alzheimer’s disease.¹⁴ NICE specifically noted that it could not endorse the use of a cholinesterase inhibitor for severe dementia because that indication is not approved in the United Kingdom, even though there is evidence for this use. The NICE guidelines recommend use of cholinesterase inhibitors for the non-cognitive and/or behavioral symptoms of Alzheimer’s disease, vascular dementia, or mixed dementia after failure or intolerance of an antipsychotic medication. They recommend memantine if there is a failure to respond or intolerance of a cholinesterase inhibitor. The NICE guideline did not address concomitant use of a cholinesterase inhibitor with memantine.

The 2017 guideline published by the British Association for Psychopharmacology states that combination therapy (a cholinesterase inhibitor plus memantine) “may” be beneficial. The group noted that while studies were well-designed, sample sizes were small and not based on clinically representative samples.¹⁵

Both available evidence and published guidelines suggest that combination treatment for moderate to severe Alzheimer’s disease may slow the worsening of symptoms or prevent the emergence of NPS better than either medication could accomplish alone. Slowing symptom progression could potentially decrease the cost of in-home care and delay institutionalization.

For a patient prescribed combination therapy, the cost of treatment with generics (as of June 2018) could range from approximately $120 per year for donepezil, 10 mg/d, and approximately $180 per year for memantine, 10 mg twice daily, taken by mouth.¹⁶ The cost of a once-daily capsule that contains a combination pill of donepezil and memantine is much more because this product is not available generically.

The Donepezil and Memantine in Moderate to Severe Alzheimer’s disease (DOMINO-AD) trial assessed the effect of combination therapy on cognition, activities of daily living, and health-related quality of life, as well as the cost efficacy of the combined treatment.¹⁷ In the 52-week study, researchers found that combined donepezil and memantine was not more cost-effective than donepezil alone. However, a post hoc analysis of the DOMINO-AD data combined with the Memantine Clinical Trial Program data found benefits across multiple clinical domains.¹⁸

Continue to: Don't overlook nonpharmacologic interventions

Don’t overlook nonpharmacologic interventions

Families caring for a loved one with Alzheimer’s disease face many decisions. Regardless of when in the course of the disease the diagnosis occurs, its pronouncement is followed by a complex and often emotional negotiation process that includes identifying community resources, making care arrangements, and legal and financial planning. This work may take place concurrently with the exhausting physical care that often comes with the job of a caregiver. As the disease progresses, the physical, emotional, and financial stress on the family increases.

Because they may be pressed for time, have limited staff support, or have limited knowledge of community resources, physicians unfamiliar with the treatment of Alzheimer’s disease may focus on prescribing pharmacologic interventions rather than providing education, resources, and referrals. This approach may lead caregivers to unrealistic expectations of medications in lieu of beneficial environmental and behavioral interventions for NPS. For a family attempting to provide home care for a patient with Alzheimer’s disease, improved behavior may lead to improved quality of life—both for those with dementia and their caregivers. Further, environmental and behavioral interventions could also slow the speed of functional decline and decrease NPS.

Despite the quality of the small studies we examined, without replication in diverse populations that reflect patients seen in everyday clinical practice, it is difficult to know which patients will benefit from combination therapy. The goal of evidence-based medicine is to use evidence gathered from patients who are similar to those that the physician is treating. To evaluate the evidence base around the use of dementia-specific medications and the impact on patients with dementia, additional RCTs, longitudinal data, and secondary outcomes are needed. However, even without this evidence, currently available data should not be ignored. This is part of the evolution of the evidence base.

Bottom Line

For treatment of neuropsychiatric symptoms (NPS) in patients with dementia, evidence supports monotherapy with a cholinesterase inhibitor for patients with mild to moderate dementia, and memantine for those with moderate to severe dementia. The use of these agents results in moderate improvements in NPS. Combination of a cholinesterase inhibitor and memantine increasingly appears to offer benefit.

Related Resources

• Steffens DC, Blazer DG, Thakur ME. The American Psychiatric Publishing textbook of geriatric psychiatry, 5th ed. Arlington, Virginia: American Psychiatric Association; 2015.  
• Jacobson SA. Clinical manual of geriatric psychopharmacology, 2nd ed. Washington, DC: American Psychiatric Publishing; 2014.
• Fitzpatrick JL. Cruising through caregiving. Austin, Texas: Greenleaf Book Press; 2016.
• Snow T. Positive approach to care. Techniques and training for families and professionals working with persons with cognitive impairment. www.teepasnow.com. 

Drug Brand Names

Aripiprazole • Abilify
Carbamazepine • Tegretol
Citalopram • Celexa
Donepezil • Aricept
Donepezil/memantine • Namzaric
Fluoxetine • Prozac, Sarafem
Galantamine • Razadyne
Lithium • Eskalith, Lithobid
Memantine • Namenda
Olanzapine • Zyprexa
Risperidone • Risperdal
Rivastigmine • Exelon
Sertraline • Zoloft
Trazodone • Desyrel, Oleptro
Valproate • Depakote

More than 5 million older Americans are living with Alzheimer’s disease and related dementias—and this number is estimated to rise to almost 14 million by 2050.¹ Dementia is associated with high costs for the patient, family, and society. In 2017, nearly 16.1 million caregivers assisted older adults with dementia, devoting more than 18.2 billion hours per year in care.¹ In the United States, the cost of caring for individuals with dementia is expected to reach $277 billion in 2018. Additionally, Medicare and Medicaid are expected to pay 67% of the estimated 2018 cost, and 22% is expected to come out of the pockets of patients and their caregivers.¹

Although dementia is often viewed as a memory loss disease, neuropsychiatric symptoms (NPS) are common. NPS includes distressing behaviors, such as aggression and wandering, that increase caregiver burden, escalate the cost of care, and contribute to premature institutionalization. This article examines the evidence for the use of a combination of a cholinesterase inhibitor and memantine vs use of either medication alone for treating NPS of Alzheimer’s disease and other types of dementia.

First, rule out reversible causes of NPS

There are no disease-modifying treatments for dementia¹; therefore, clinicians focus on decreasing patients’ suffering and improving their quality of life. Nearly all patients with dementia will develop at least one NPS. These commonly include auditory and visual hallucinations, delusions, depression, anxiety, psychosis, psychomotor agitation, aggression, apathy, repetitive questioning, wandering, socially or sexually inappropriate behaviors, and sleep disturbances.² The underlying cause of these behaviors may be neurobiological,³ an acute medical condition, unmet needs or a pre-existing personality disorder, or other psychiatric illness.² Because of this complexity, there is no specific treatment for NPS of dementia. Treatment should begin with an assessment to rule out potentially reversible causes of NPS, such as a urinary tract infection, environmental triggers, unmet needs, or untreated psychiatric illness. For mild to moderate NPS, short-term behavioral interventions, followed by pharmacologic interventions, are used. For moderate to severe NPS, pharmacologic interventions and behavioral interventions are often used simultaneously.

Pharmacologic options for treating NPS

The classes of medications frequently used to treat NPS include antidepressants, antipsychotics, mood stabilizers, and memory-enhancing, dementia-specific agents (cholinesterase inhibitors and the N-methyl-D-aspartate [NMDA] agonist memantine). Use of these medications to treat medical, psychiatric, or neurological illnesses in patients who do not have dementia is not covered in this article.

Serotonergic antidepressants are the recommended first-line antidepressant class for NPS in older adults who have dementia because they are generally well-tolerated. Of the serotonergic agents (sertraline, fluoxetine, citalopram, and trazodone), only citalopram has some limited evidence of benefit for patients with NPS.⁴

Antipsychotic medications are typically reserved for treating specific non-cognitive NPS, such as psychosis and/or severe agitated behavior that causes significant distress. Atypical antipsychotics, such as risperidone, aripiprazole, and olanzapine, currently have the best evidence for efficacy in this population. The effects are modest and use of these medications may be associated with an increased risk of stroke.^4,5

The mood stabilizers valproate and carbamazepine have been studied for treating NPS, but available evidence suggests that neither medication provides significant benefit for patients with NPS. Furthermore, there is evidence of significant harm with valproate.⁴ There are no known studies evaluating the use of lithium for NPS.

Continue to: Evidence for dementia-specific medications

Evidence for dementia-specific medications

An alternative to the above pharmacologic options is treatment with a cholinesterase inhibitor and/or memantine. Among cholinesterase inhibitors in the United States, donepezil is approved to treat mild, moderate, and severe dementia, while rivastigmine and galantamine are approved for the treatment of mild to moderate dementia. Memantine is the only NMDA receptor agonist approved in the United States for moderate to severe dementia. The Table^6-10 highlights potential dosing regimens for each of these 4 medications.

Few randomized controlled trials (RCTs) of cholinesterase inhibitors or memantine have focused on improvement of NPS as a primary outcome measure, but some RCTs have used treatment of NPS as a secondary outcome.⁴ Most RCT data for using medications for NPS have come from small studies that lasted 17 days to 28 weeks and had design limitations. Most meta-analyses and review articles exclude trials if they do not evaluate NPS as a primary outcome, and most RCTs have only included NPS as a secondary outcome. We hypothesize that this is because NPS is conceptualized as a psychiatric condition, while dementia is codified as a neurologic condition. The reality is that dementia is a neuropsychiatric condition. This artificial divergence complicates both the evaluation and treatment of patients with dementia, who almost always have NPS. Medication trials focused on the neurologic components for primary outcomes contribute to the confusion and difficulty of building an evidence base around the treatment of NPS in Alzheimer’s disease. Patients with severe NPS are seldom included in RCTs.

A cholinesterase inhibitor, memantine, or both?

In a large, pooled area-under-the-curve analysis, Atri et al¹¹ examined data from 1,408 individuals with moderate to severe Alzheimer’s disease who were enrolled in four 6-month RCTs of memantine with or without donepezil add-on therapy; some participants received donepezil only. This analysis found positive benefits for cognition, function, and behavior among those who received a combination of memantine and donepezil compared with those who received either medication alone. This study was limited to 6 months, it used a measure of cognition without executive function, and most participants were white females. However, 6 months is far longer than most medication trials.

In the absence of extended RCTs, attention turns to the opinions of panels of experts examining available data. There are no recent guidelines from any U.S.-based specialty society that address the use of combination cholinesterase/memantine treatment for NPS of dementia. Since 2013, there has been emerging awareness of the evidence for efficacy and cost effectiveness to support the use of a cholinesterase inhibitor and/or memantine for patients demonstrating cognitive and functional decline due to Alzheimer’s disease, Lewy body dementia, and dementia due to Parkinson’s disease.

The 2012 Fourth Canadian Consensus Conference on the Diagnosis and Treatment of Dementia¹² recommended a trial of a cholinesterase inhibitor in most patients with Alzheimer’s disease or Alzheimer’s disease combined with another type of dementia. The panel did not find enough evidence to recommend for or against the use of cholinesterase inhibitors and/or memantine for the treatment of NPS as a primary indication. However, they warned of the risks of discontinuing a cholinesterase inhibitor and suggested a slow taper and monitoring, with consideration of restarting the medication if there is notable functional or behavioral decline.

Continue to: In 2015, the European Neurological Society and the European Federation of Neurological Societies...

In 2015, the European Neurological Society and the European Federation of Neurological Societies (now combined into the European Academy of Neurology) found a moderate benefit for using cholinesterase inhibitors to treat problematic behaviors in patients with Alzheimer’s disease.¹³ They found the evidence weak only when they included consideration of cognitive benefits. For patients with moderate to severe Alzheimer’s disease, the Academy endorsed the combination of cholinesterase inhibitors and memantine.¹³

The United Kingdom National Institute for Clinical Excellence (NICE) guideline on dementia is updated every 1 to 3 years based on evolving evidence for the treatment of Alzheimer’s disease and related symptoms. In 2016, NICE updated its guideline to recommend the use of a cholinesterase inhibitor for patients with mild to severe Alzheimer’s disease and memantine for those with severe Alzheimer’s disease.¹⁴ NICE specifically noted that it could not endorse the use of a cholinesterase inhibitor for severe dementia because that indication is not approved in the United Kingdom, even though there is evidence for this use. The NICE guidelines recommend use of cholinesterase inhibitors for the non-cognitive and/or behavioral symptoms of Alzheimer’s disease, vascular dementia, or mixed dementia after failure or intolerance of an antipsychotic medication. They recommend memantine if there is a failure to respond or intolerance of a cholinesterase inhibitor. The NICE guideline did not address concomitant use of a cholinesterase inhibitor with memantine.

The 2017 guideline published by the British Association for Psychopharmacology states that combination therapy (a cholinesterase inhibitor plus memantine) “may” be beneficial. The group noted that while studies were well-designed, sample sizes were small and not based on clinically representative samples.¹⁵

Both available evidence and published guidelines suggest that combination treatment for moderate to severe Alzheimer’s disease may slow the worsening of symptoms or prevent the emergence of NPS better than either medication could accomplish alone. Slowing symptom progression could potentially decrease the cost of in-home care and delay institutionalization.

For a patient prescribed combination therapy, the cost of treatment with generics (as of June 2018) could range from approximately $120 per year for donepezil, 10 mg/d, and approximately $180 per year for memantine, 10 mg twice daily, taken by mouth.¹⁶ The cost of a once-daily capsule that contains a combination pill of donepezil and memantine is much more because this product is not available generically.

The Donepezil and Memantine in Moderate to Severe Alzheimer’s disease (DOMINO-AD) trial assessed the effect of combination therapy on cognition, activities of daily living, and health-related quality of life, as well as the cost efficacy of the combined treatment.¹⁷ In the 52-week study, researchers found that combined donepezil and memantine was not more cost-effective than donepezil alone. However, a post hoc analysis of the DOMINO-AD data combined with the Memantine Clinical Trial Program data found benefits across multiple clinical domains.¹⁸

Continue to: Don't overlook nonpharmacologic interventions

Don’t overlook nonpharmacologic interventions

Families caring for a loved one with Alzheimer’s disease face many decisions. Regardless of when in the course of the disease the diagnosis occurs, its pronouncement is followed by a complex and often emotional negotiation process that includes identifying community resources, making care arrangements, and legal and financial planning. This work may take place concurrently with the exhausting physical care that often comes with the job of a caregiver. As the disease progresses, the physical, emotional, and financial stress on the family increases.

Because they may be pressed for time, have limited staff support, or have limited knowledge of community resources, physicians unfamiliar with the treatment of Alzheimer’s disease may focus on prescribing pharmacologic interventions rather than providing education, resources, and referrals. This approach may lead caregivers to unrealistic expectations of medications in lieu of beneficial environmental and behavioral interventions for NPS. For a family attempting to provide home care for a patient with Alzheimer’s disease, improved behavior may lead to improved quality of life—both for those with dementia and their caregivers. Further, environmental and behavioral interventions could also slow the speed of functional decline and decrease NPS.

Despite the quality of the small studies we examined, without replication in diverse populations that reflect patients seen in everyday clinical practice, it is difficult to know which patients will benefit from combination therapy. The goal of evidence-based medicine is to use evidence gathered from patients who are similar to those that the physician is treating. To evaluate the evidence base around the use of dementia-specific medications and the impact on patients with dementia, additional RCTs, longitudinal data, and secondary outcomes are needed. However, even without this evidence, currently available data should not be ignored. This is part of the evolution of the evidence base.

Bottom Line

For treatment of neuropsychiatric symptoms (NPS) in patients with dementia, evidence supports monotherapy with a cholinesterase inhibitor for patients with mild to moderate dementia, and memantine for those with moderate to severe dementia. The use of these agents results in moderate improvements in NPS. Combination of a cholinesterase inhibitor and memantine increasingly appears to offer benefit.

Related Resources

• Steffens DC, Blazer DG, Thakur ME. The American Psychiatric Publishing textbook of geriatric psychiatry, 5th ed. Arlington, Virginia: American Psychiatric Association; 2015.  
• Jacobson SA. Clinical manual of geriatric psychopharmacology, 2nd ed. Washington, DC: American Psychiatric Publishing; 2014.
• Fitzpatrick JL. Cruising through caregiving. Austin, Texas: Greenleaf Book Press; 2016.
• Snow T. Positive approach to care. Techniques and training for families and professionals working with persons with cognitive impairment. www.teepasnow.com. 

Drug Brand Names

Aripiprazole • Abilify
Carbamazepine • Tegretol
Citalopram • Celexa
Donepezil • Aricept
Donepezil/memantine • Namzaric
Fluoxetine • Prozac, Sarafem
Galantamine • Razadyne
Lithium • Eskalith, Lithobid
Memantine • Namenda
Olanzapine • Zyprexa
Risperidone • Risperdal
Rivastigmine • Exelon
Sertraline • Zoloft
Trazodone • Desyrel, Oleptro
Valproate • Depakote

More than 5 million older Americans are living with Alzheimer’s disease and related dementias—and this number is estimated to rise to almost 14 million by 2050.¹ Dementia is associated with high costs for the patient, family, and society. In 2017, nearly 16.1 million caregivers assisted older adults with dementia, devoting more than 18.2 billion hours per year in care.¹ In the United States, the cost of caring for individuals with dementia is expected to reach $277 billion in 2018. Additionally, Medicare and Medicaid are expected to pay 67% of the estimated 2018 cost, and 22% is expected to come out of the pockets of patients and their caregivers.¹

Although dementia is often viewed as a memory loss disease, neuropsychiatric symptoms (NPS) are common. NPS includes distressing behaviors, such as aggression and wandering, that increase caregiver burden, escalate the cost of care, and contribute to premature institutionalization. This article examines the evidence for the use of a combination of a cholinesterase inhibitor and memantine vs use of either medication alone for treating NPS of Alzheimer’s disease and other types of dementia.

First, rule out reversible causes of NPS

There are no disease-modifying treatments for dementia¹; therefore, clinicians focus on decreasing patients’ suffering and improving their quality of life. Nearly all patients with dementia will develop at least one NPS. These commonly include auditory and visual hallucinations, delusions, depression, anxiety, psychosis, psychomotor agitation, aggression, apathy, repetitive questioning, wandering, socially or sexually inappropriate behaviors, and sleep disturbances.² The underlying cause of these behaviors may be neurobiological,³ an acute medical condition, unmet needs or a pre-existing personality disorder, or other psychiatric illness.² Because of this complexity, there is no specific treatment for NPS of dementia. Treatment should begin with an assessment to rule out potentially reversible causes of NPS, such as a urinary tract infection, environmental triggers, unmet needs, or untreated psychiatric illness. For mild to moderate NPS, short-term behavioral interventions, followed by pharmacologic interventions, are used. For moderate to severe NPS, pharmacologic interventions and behavioral interventions are often used simultaneously.

Pharmacologic options for treating NPS

The classes of medications frequently used to treat NPS include antidepressants, antipsychotics, mood stabilizers, and memory-enhancing, dementia-specific agents (cholinesterase inhibitors and the N-methyl-D-aspartate [NMDA] agonist memantine). Use of these medications to treat medical, psychiatric, or neurological illnesses in patients who do not have dementia is not covered in this article.

Serotonergic antidepressants are the recommended first-line antidepressant class for NPS in older adults who have dementia because they are generally well-tolerated. Of the serotonergic agents (sertraline, fluoxetine, citalopram, and trazodone), only citalopram has some limited evidence of benefit for patients with NPS.⁴

Antipsychotic medications are typically reserved for treating specific non-cognitive NPS, such as psychosis and/or severe agitated behavior that causes significant distress. Atypical antipsychotics, such as risperidone, aripiprazole, and olanzapine, currently have the best evidence for efficacy in this population. The effects are modest and use of these medications may be associated with an increased risk of stroke.^4,5

The mood stabilizers valproate and carbamazepine have been studied for treating NPS, but available evidence suggests that neither medication provides significant benefit for patients with NPS. Furthermore, there is evidence of significant harm with valproate.⁴ There are no known studies evaluating the use of lithium for NPS.

Continue to: Evidence for dementia-specific medications

Evidence for dementia-specific medications

An alternative to the above pharmacologic options is treatment with a cholinesterase inhibitor and/or memantine. Among cholinesterase inhibitors in the United States, donepezil is approved to treat mild, moderate, and severe dementia, while rivastigmine and galantamine are approved for the treatment of mild to moderate dementia. Memantine is the only NMDA receptor agonist approved in the United States for moderate to severe dementia. The Table^6-10 highlights potential dosing regimens for each of these 4 medications.

Few randomized controlled trials (RCTs) of cholinesterase inhibitors or memantine have focused on improvement of NPS as a primary outcome measure, but some RCTs have used treatment of NPS as a secondary outcome.⁴ Most RCT data for using medications for NPS have come from small studies that lasted 17 days to 28 weeks and had design limitations. Most meta-analyses and review articles exclude trials if they do not evaluate NPS as a primary outcome, and most RCTs have only included NPS as a secondary outcome. We hypothesize that this is because NPS is conceptualized as a psychiatric condition, while dementia is codified as a neurologic condition. The reality is that dementia is a neuropsychiatric condition. This artificial divergence complicates both the evaluation and treatment of patients with dementia, who almost always have NPS. Medication trials focused on the neurologic components for primary outcomes contribute to the confusion and difficulty of building an evidence base around the treatment of NPS in Alzheimer’s disease. Patients with severe NPS are seldom included in RCTs.

A cholinesterase inhibitor, memantine, or both?

In a large, pooled area-under-the-curve analysis, Atri et al¹¹ examined data from 1,408 individuals with moderate to severe Alzheimer’s disease who were enrolled in four 6-month RCTs of memantine with or without donepezil add-on therapy; some participants received donepezil only. This analysis found positive benefits for cognition, function, and behavior among those who received a combination of memantine and donepezil compared with those who received either medication alone. This study was limited to 6 months, it used a measure of cognition without executive function, and most participants were white females. However, 6 months is far longer than most medication trials.

In the absence of extended RCTs, attention turns to the opinions of panels of experts examining available data. There are no recent guidelines from any U.S.-based specialty society that address the use of combination cholinesterase/memantine treatment for NPS of dementia. Since 2013, there has been emerging awareness of the evidence for efficacy and cost effectiveness to support the use of a cholinesterase inhibitor and/or memantine for patients demonstrating cognitive and functional decline due to Alzheimer’s disease, Lewy body dementia, and dementia due to Parkinson’s disease.

The 2012 Fourth Canadian Consensus Conference on the Diagnosis and Treatment of Dementia¹² recommended a trial of a cholinesterase inhibitor in most patients with Alzheimer’s disease or Alzheimer’s disease combined with another type of dementia. The panel did not find enough evidence to recommend for or against the use of cholinesterase inhibitors and/or memantine for the treatment of NPS as a primary indication. However, they warned of the risks of discontinuing a cholinesterase inhibitor and suggested a slow taper and monitoring, with consideration of restarting the medication if there is notable functional or behavioral decline.

Continue to: In 2015, the European Neurological Society and the European Federation of Neurological Societies...

In 2015, the European Neurological Society and the European Federation of Neurological Societies (now combined into the European Academy of Neurology) found a moderate benefit for using cholinesterase inhibitors to treat problematic behaviors in patients with Alzheimer’s disease.¹³ They found the evidence weak only when they included consideration of cognitive benefits. For patients with moderate to severe Alzheimer’s disease, the Academy endorsed the combination of cholinesterase inhibitors and memantine.¹³

The United Kingdom National Institute for Clinical Excellence (NICE) guideline on dementia is updated every 1 to 3 years based on evolving evidence for the treatment of Alzheimer’s disease and related symptoms. In 2016, NICE updated its guideline to recommend the use of a cholinesterase inhibitor for patients with mild to severe Alzheimer’s disease and memantine for those with severe Alzheimer’s disease.¹⁴ NICE specifically noted that it could not endorse the use of a cholinesterase inhibitor for severe dementia because that indication is not approved in the United Kingdom, even though there is evidence for this use. The NICE guidelines recommend use of cholinesterase inhibitors for the non-cognitive and/or behavioral symptoms of Alzheimer’s disease, vascular dementia, or mixed dementia after failure or intolerance of an antipsychotic medication. They recommend memantine if there is a failure to respond or intolerance of a cholinesterase inhibitor. The NICE guideline did not address concomitant use of a cholinesterase inhibitor with memantine.

The 2017 guideline published by the British Association for Psychopharmacology states that combination therapy (a cholinesterase inhibitor plus memantine) “may” be beneficial. The group noted that while studies were well-designed, sample sizes were small and not based on clinically representative samples.¹⁵

Both available evidence and published guidelines suggest that combination treatment for moderate to severe Alzheimer’s disease may slow the worsening of symptoms or prevent the emergence of NPS better than either medication could accomplish alone. Slowing symptom progression could potentially decrease the cost of in-home care and delay institutionalization.

For a patient prescribed combination therapy, the cost of treatment with generics (as of June 2018) could range from approximately $120 per year for donepezil, 10 mg/d, and approximately $180 per year for memantine, 10 mg twice daily, taken by mouth.¹⁶ The cost of a once-daily capsule that contains a combination pill of donepezil and memantine is much more because this product is not available generically.

The Donepezil and Memantine in Moderate to Severe Alzheimer’s disease (DOMINO-AD) trial assessed the effect of combination therapy on cognition, activities of daily living, and health-related quality of life, as well as the cost efficacy of the combined treatment.¹⁷ In the 52-week study, researchers found that combined donepezil and memantine was not more cost-effective than donepezil alone. However, a post hoc analysis of the DOMINO-AD data combined with the Memantine Clinical Trial Program data found benefits across multiple clinical domains.¹⁸

Continue to: Don't overlook nonpharmacologic interventions

Don’t overlook nonpharmacologic interventions

Families caring for a loved one with Alzheimer’s disease face many decisions. Regardless of when in the course of the disease the diagnosis occurs, its pronouncement is followed by a complex and often emotional negotiation process that includes identifying community resources, making care arrangements, and legal and financial planning. This work may take place concurrently with the exhausting physical care that often comes with the job of a caregiver. As the disease progresses, the physical, emotional, and financial stress on the family increases.

Because they may be pressed for time, have limited staff support, or have limited knowledge of community resources, physicians unfamiliar with the treatment of Alzheimer’s disease may focus on prescribing pharmacologic interventions rather than providing education, resources, and referrals. This approach may lead caregivers to unrealistic expectations of medications in lieu of beneficial environmental and behavioral interventions for NPS. For a family attempting to provide home care for a patient with Alzheimer’s disease, improved behavior may lead to improved quality of life—both for those with dementia and their caregivers. Further, environmental and behavioral interventions could also slow the speed of functional decline and decrease NPS.

Despite the quality of the small studies we examined, without replication in diverse populations that reflect patients seen in everyday clinical practice, it is difficult to know which patients will benefit from combination therapy. The goal of evidence-based medicine is to use evidence gathered from patients who are similar to those that the physician is treating. To evaluate the evidence base around the use of dementia-specific medications and the impact on patients with dementia, additional RCTs, longitudinal data, and secondary outcomes are needed. However, even without this evidence, currently available data should not be ignored. This is part of the evolution of the evidence base.

Bottom Line

For treatment of neuropsychiatric symptoms (NPS) in patients with dementia, evidence supports monotherapy with a cholinesterase inhibitor for patients with mild to moderate dementia, and memantine for those with moderate to severe dementia. The use of these agents results in moderate improvements in NPS. Combination of a cholinesterase inhibitor and memantine increasingly appears to offer benefit.

Related Resources

• Steffens DC, Blazer DG, Thakur ME. The American Psychiatric Publishing textbook of geriatric psychiatry, 5th ed. Arlington, Virginia: American Psychiatric Association; 2015.  
• Jacobson SA. Clinical manual of geriatric psychopharmacology, 2nd ed. Washington, DC: American Psychiatric Publishing; 2014.
• Fitzpatrick JL. Cruising through caregiving. Austin, Texas: Greenleaf Book Press; 2016.
• Snow T. Positive approach to care. Techniques and training for families and professionals working with persons with cognitive impairment. www.teepasnow.com. 

Drug Brand Names

Aripiprazole • Abilify
Carbamazepine • Tegretol
Citalopram • Celexa
Donepezil • Aricept
Donepezil/memantine • Namzaric
Fluoxetine • Prozac, Sarafem
Galantamine • Razadyne
Lithium • Eskalith, Lithobid
Memantine • Namenda
Olanzapine • Zyprexa
Risperidone • Risperdal
Rivastigmine • Exelon
Sertraline • Zoloft
Trazodone • Desyrel, Oleptro
Valproate • Depakote