Urine drug tests (UDTs) are useful clinical tools for assessing and monitoring the risk of misuse, abuse, and diversion when prescribing controlled substances, or for monitoring abstinence in patients with substance use disorders (SUDs). However, UDTs have been underutilized, and have been used without systematic documentation of reasons and results.^1,2 In addition, many clinicians may lack the knowledge needed to effectively interpret test results.^3,4 Although the reported use of UDTs is much higher among clinicians who are members of American Society of Addiction Medicine (ASAM), there is still a need for improved education.⁵

The appropriate use of UDTs strengthens the therapeutic relationship and promotes healthy behaviors and patients’ recovery. On the other hand, incorrect interpretation of test results may lead to missing potential aberrant behaviors, or inappropriate consequences for patients, such as discontinuing necessary medications or discharging them from care secondary to a perceived violation of a treatment contract due to unexpected positive or negative drug screening results.⁶ In this article, we review the basic concepts of UDTs and provide an algorithm to determine when to order these tests, how to interpret the results, and how to modify treatment accordingly.

Urine drug tests 101

Urine drug tests include rapid urine drug screening (UDS) and confirmatory tests. Urine drug screenings are usually based on various types of immunoassays. They are fast, sensitive, and cost-effective. Because immunoassays are antibody-mediated, they have significant false-positive and false-negative rates due to cross-reactivity and sensitivity of antibodies.⁷ For example, antibodies used in immunoassays to detect opioids are essentially morphine antibodies, and are not able to detect semisynthetic opioids or synthetic opioids (except hydrocodone).⁷ However, immunoassays specifically developed to detect oxycodone, buprenorphine, fentanyl, and methadone are available. On the other hand, antibodies can cross-react with molecules unrelated to proto-medicines or drug metabolites, but with similar antigenic determinants. For example, amphetamine immunoassays have high false-positive rates with many different classes of medications or substances.⁷

Urine drug tests based on mass spectrometry, gas chromatography/mass spectrometry (GC/MS), and liquid chromatography/mass spectrometry (LC/MS) are gold standards to confirm toxicology results. They are highly sensitive and specific, with accurate quantitative measurement. However, they are more expensive than UDS and usually need to be sent to a laboratory with capacity to perform GC/MS or LC/MS, with a turnaround time of up to 1 week.⁸ In clinical practice, we usually start with UDS tests and order confirmatory tests when needed.

When to order UDTs in outpatient psychiatry

On December 12, 2013, the ASAM released a white paper that suggests the use of drug testing as a primary prevention, diagnostic, and monitoring tool in the management of addiction or drug misuse and its application in a wide variety of medical settings.⁹ Many clinicians use treatment contracts when prescribing controlled substances as a part of a risk-mitigation strategy, and these contracts often include the use of UDTs. Urine drug tests provide objective evidence to support or negate self-report, because many people may underreport their use.¹⁰ The literature has shown significant “abnormal” urine test results, ranging from 9% to 53%, in patients receiving chronic opioid therapy.^2,11

The CDC and the American Academy of Pain Medicine recommend UDS before initiating any controlled substance for pain therapy.^12,13 They also suggest random drug testing at least once or twice a year for low-risk patients, and more frequent screening for high-risk patients, such as those with a history of addiction.^12,13 For example, for patients with opioid use disorder who participate in a methadone program, weekly UDTs are mandated for the first 90 days, and at least 8 UDTs a year are required after that.

However, UDTs carry significant stigma due to their association with SUDs. Talking with patients from the start of treatment helps to reduce this stigma, and makes it easier to have further discussions when patients have unexpected results during treatment. For example, clinicians can explain to patients that monitoring UDTs when prescribing controlled substances is similar to monitoring thyroid function with lithium use because treatment with a controlled substance carries an inherent risk of misuse, abuse, and diversion. For patients with SUDs, clinicians can explain that using UDTs to monitor their abstinence is similar to monitoring HbA_1c for glucose control in patients with diabetes.

Continue to: Factors that can affect UDT results

In addition to knowing when to order UDT, it is critical to know how to interpret the results of UDS and follow up with confirmatory tests when needed. Other than the limitations of the tests, the following factors could contribute to unexpected UDT results:

• the drug itself, including its half-life, metabolic pathways, and potential interactions with other medications
• how patients take their medications, including dose, frequency, and pattern of drug use
• all the medications that patients are taking, including prescription, over-the-counter, and herbal and supplemental preparations
• when the last dose of a prescribed controlled substance was taken. Always ask when the patient’s last dose was taken before you consider ordering a UDT.

To help better understand UDT results, Figure 1¹⁴ and Figure 2¹⁵ demonstrate metabolic pathways of commonly used benzodiazepines and opioids, respectively. There are several comprehensive reviews on commonly seen false positives and negatives for each drug or each class of drugs in immunoassays.^16-21 Confirmatory tests are usually very accurate. However, chiral analysis is needed to differentiate enantiomers, such as methamphetamine (active R-enantiomer) and selegiline, which is metabolized into L-methamphetamine (inactive S-enantiomer).²² In addition, detection of tetrahydrocannabivarin (THCV), an ingredient of the cannabis plant, via GC/MS can be used to distinguish between consumption of dronabinol and natural cannabis products.²³ The Table^16-21 summarizes the proto­type agents, other detectable agents in the same class, and false positives and negatives in immunoassays.

Interpreting UDT results and management strategies

Our Algorithm outlines how to interpret UDT results, and management strategies to consider based on whether the results are as expected or unexpected, with a few key caveats as described below.

Expected results

If there are no concerns based on the patient’s clinical presentation or collateral information, simply continue the current treatment. However, for patients taking medications that are undetectable by UDS (for example, regular use of clonazepam or oxycodone), consider ordering confirmatory tests at least once to ensure compliance, even when UDS results are negative.

Unexpected positive results, including the presence of illicit drugs and/or unprescribed licit drugs

Drug misuse, abuse, or dependence. The first step is to talk with the patient, who may acknowledge drug misuse, abuse, or dependence. Next, consider modifying the treatment plan; this may include more frequent monitoring and visits, limiting or discontinuing prescribed controlled substances, or referring the patient to inpatient or outpatient SUD treatment, as appropriate.

Continue to: Interference from medications or diet

Interference from medications or diets. One example of a positive opioid screening result due to interference from diet is the consumption of foods that contain poppy seeds. Because of this potential interference, the cutoff value for a positive opioid immunoassay in workplace drug testing was increased from 300 to 2,000 ug/L.²⁴ Educating patients regarding medication and lifestyle choices can help them avoid any interference with drug monitoring. Confirmatory tests can be ordered at the clinician’s discretion. The same principle applies to medication choice when prescribing. For example, a patient taking bupropion may experience a false positive result on a UDS for amphetamines, and a different antidepressant might be a better choice (Box 1).

Box 1

Urine sample tampering. Consider the possibility that urine samples could be substituted, especially when there are signs or indications of tampering, such as a positive pregnancy test for a male patient, or the presence of multiple prescription medications not prescribed to the patient. If there is high suspicion of urine sample tampering, consider observed urine sample collection.

When to order confirmatory tests for unexpected positive results.

Order a confirmatory test if a patient adamantly denies taking the substance(s) for which he/she has screened positive, and there’s no other explanation for the positive result. Continue the patient’s current treatment if the confirmatory test is negative. However, if the confirmatory test is positive, then modify the treatment plan (Algorithm).

Special circumstances.

A positive opioid screen in a patient who has been prescribed a synthetic or semisynthetic opioid indicates the patient is likely using opioids other than the one he/she has been prescribed. Similarly, clonazepam is expected to be negative in a benzodiazepine immunoassay. If such testing is positive, consider the possibility that the patient is taking other benzodiazepines, such as diazepam. The results of UDTs can also be complicated by common metabolites in the same class of drugs. For example, the presence of hydromorphone for patients taking hydrocodone does not necessarily indicate the use of hydromorphone, because hydromorphone is a metabolite of hydrocodone (Figure 2¹⁵).

Unexpected negative results

Prescribed medications exist in low concentration that are below the UDS detection threshold. This unexpected UDS result could occur if patients:

• take their medications less often than prescribed (because of financial difficulties or the patient feels better and does not think he/she needs it, etc.)
• hydrate too much (intentionally or unintentionally), are pregnant, or are fast metabolizers (Box 2)
• take other medications that increase the metabolism of the prescribed medication.

Box 2

Continue to: Further inquiry will...

Further inquiry will clarify these concerns. Clinicians should educate patients and manage accordingly. Confirmatory tests may be ordered upon clinicians’ discretion.

Urine sample tampering. Dilution or substitution of urine samples may lead to unexpected negative results. Usually, the urine sample will have abnormal parameters, including temperature, pH, specific gravity, urine creatinine level, or detection of adulterants. If needed, consider observed urine sample collection. Jaffee et al²⁵ reviewed tampering methods in urine drug testing.

Diversion or binge use of medications. If patients adamantly deny diverting or binge using their medication, order confirmatory tests. If the confirmatory test also is negative, modify the treatment plan accordingly, and consider the following options:

• adjust the medication dosage or frequency
• discontinue the medication
• conduct pill counts for more definitive evidence of diversion or misuse, especially if discontinuation may lead to potential harm (for example, for patients prescribed buprenorphine for opioid use disorder).

When to order confirmatory tests for unexpected negative results.

Because confirmatory tests also measure drug concentrations, clinicians sometimes order serial confirmatory testing to monitor lipophilic drugs after a patient reports discontinuation, such as in the case of a patient using marijuana, ketamine, or alprazolam. The level of a lipophilic drug, such as these 3, should continue to decline if the patient has discontinued using it. However, because the drug level is affected by how concentrated the urine samples are, it is necessary to compare the ratios of drug levels over urine creatinine levels.²⁶ Another use for confirmatory-quantitative testing is to detect “urine spiking,”^27,28 when a patient adds an unconsumed drug to his/her urine sample to produce a positive result without actually taking the drug (Box 3).

Box 3

When to consult lab specialists

Because many clinicians may find it challenging to stay abreast of all of the factors necessary to properly interpret UDT results, consulting with qualified laboratory professionals is appropriate when needed. For example, a patient was prescribed codeine, and his UDTs showed morphine as anticipated; however, the prescribing clinician suspected that the patient was also using heroin. In this case, consultation with a specialist may be warranted to look for 6-mono-acetylemorphine (6-MAM, a unique heroin metabolite) and/or the ratio of morphine to codeine.

Continue to: In summary...

In summary, UDTs are important tools to use in general psychiatry practice, especially when prescribing controlled substances. To use UDTs effectively, it is essential to possess knowledge of drug metabolism and the limitations of these tests. All immunoassay results should be considered as presumptive, and confirmatory tests are often needed for making treatment decisions. Many clinicians are unlikely to possess all the knowledge needed to correctly interpret UDTs, and in some cases, communication with qualified laboratory professionals may be necessary. In addition, the patient’s history and clinical presentation, collateral information, and data from prescription drug monitoring programs are all important factors to consider.

The cost of UDTs, variable insurance coverage, and a lack of on-site laboratory services can be deterrents to implementing UDTs as recommended. These factors vary significantly across regions, facilities, and insurance providers (see Related Resources). If faced with these issues and you expect to often need UDTs in your practice, consider using point-of-care UDTs as an alternative to improve access, convenience, and possibly cost.

Bottom Line

Urine drug tests (UDTs) should be standard clinical practice when prescribing controlled substances and treating patients with substance use disorders in the outpatient setting. Clinicians need to be knowledgeable about the limitations of UDTs, drug metabolism, and relevant patient history to interpret UDTs proficiently for optimal patient care. Consult laboratory specialists when needed to help interpret the results.

Related Resources

• Islam FA, Choudhry Z. Urine drug screens: Not just for job applicants. Current Psychiatry. 2018;17(12):43-44.
• HealthCare.gov. Health benefits & coverage: Mental health & substance abuse coverage. www.healthcare.gov/coverage/mental-health-substance-abuse-coverage/.

Drug Brand Names

Alprazolam • Xanax
Amphetamine • Adderall
Atomoxetine • Strattera
Buprenorphine • Subutex
Buprenorphine/naloxone • Suboxone, Zubsolv
Bupropion • Wellbutrin, Zyban
Chlordiazepoxide • Librium
Chlorpromazine • Thorazine
Clonazepam • Klonopin
Desipramine • Norpramin
Dextroamphetamine • Dexedrine, ProCentra
Diazepam • Valium
Doxepin • Silenor
Dronabinol • Marinol
Efavirenz • Sustiva
Ephedrine • Akovaz
Fentanyl • Actiq, Duragesic
Flurazepam • Dalmane
Hydrocodone • Hysingla, Zohydro ER
Hydromorphone • Dilaudid, Exalgo
Labetalol • Normodyne, Trandate
Lamotrigine • Lamictal
Lisdexamfetamine • Vyvanse
Lithium • Eskalith, Lithobid
Lorazepam • Ativan
Meperidine • Demerol
Metformin • Fortamet, Glucophage
Methadone • Dolophine, Methadose
Methylphenidate • Ritalin
Midazolam • Versed
Morphine • Kadian, MorphaBond
Nabilone • Cesamet
Naltrexone • Vivitrol
Oxaprozin • Daypro
Oxazepam • Serax
Oxycodone • Oxycontin
Oxymorphone • Opana
Phentermine • Adipex-P, Ionamin
Promethazine • Phenergan
Quetiapine • Seroquel
Ranitidine • Zantac
Rifampicin • Rifadin
Selegiline • Eldepryl, Zelapar
Sertraline • Zoloft
Temazepam • Restoril
Thioridazine • Mellaril
Tramadol • Conzip, Ultram
Trazodone • Desyrel
Triazolam • Halcion
Venlafaxine • Effexor
Verapamil • Calan, Verelan
Zolpidem • Ambien

Urine drug tests (UDTs) are useful clinical tools for assessing and monitoring the risk of misuse, abuse, and diversion when prescribing controlled substances, or for monitoring abstinence in patients with substance use disorders (SUDs). However, UDTs have been underutilized, and have been used without systematic documentation of reasons and results.^1,2 In addition, many clinicians may lack the knowledge needed to effectively interpret test results.^3,4 Although the reported use of UDTs is much higher among clinicians who are members of American Society of Addiction Medicine (ASAM), there is still a need for improved education.⁵

The appropriate use of UDTs strengthens the therapeutic relationship and promotes healthy behaviors and patients’ recovery. On the other hand, incorrect interpretation of test results may lead to missing potential aberrant behaviors, or inappropriate consequences for patients, such as discontinuing necessary medications or discharging them from care secondary to a perceived violation of a treatment contract due to unexpected positive or negative drug screening results.⁶ In this article, we review the basic concepts of UDTs and provide an algorithm to determine when to order these tests, how to interpret the results, and how to modify treatment accordingly.

Urine drug tests 101

Urine drug tests include rapid urine drug screening (UDS) and confirmatory tests. Urine drug screenings are usually based on various types of immunoassays. They are fast, sensitive, and cost-effective. Because immunoassays are antibody-mediated, they have significant false-positive and false-negative rates due to cross-reactivity and sensitivity of antibodies.⁷ For example, antibodies used in immunoassays to detect opioids are essentially morphine antibodies, and are not able to detect semisynthetic opioids or synthetic opioids (except hydrocodone).⁷ However, immunoassays specifically developed to detect oxycodone, buprenorphine, fentanyl, and methadone are available. On the other hand, antibodies can cross-react with molecules unrelated to proto-medicines or drug metabolites, but with similar antigenic determinants. For example, amphetamine immunoassays have high false-positive rates with many different classes of medications or substances.⁷

Urine drug tests based on mass spectrometry, gas chromatography/mass spectrometry (GC/MS), and liquid chromatography/mass spectrometry (LC/MS) are gold standards to confirm toxicology results. They are highly sensitive and specific, with accurate quantitative measurement. However, they are more expensive than UDS and usually need to be sent to a laboratory with capacity to perform GC/MS or LC/MS, with a turnaround time of up to 1 week.⁸ In clinical practice, we usually start with UDS tests and order confirmatory tests when needed.

When to order UDTs in outpatient psychiatry

On December 12, 2013, the ASAM released a white paper that suggests the use of drug testing as a primary prevention, diagnostic, and monitoring tool in the management of addiction or drug misuse and its application in a wide variety of medical settings.⁹ Many clinicians use treatment contracts when prescribing controlled substances as a part of a risk-mitigation strategy, and these contracts often include the use of UDTs. Urine drug tests provide objective evidence to support or negate self-report, because many people may underreport their use.¹⁰ The literature has shown significant “abnormal” urine test results, ranging from 9% to 53%, in patients receiving chronic opioid therapy.^2,11

The CDC and the American Academy of Pain Medicine recommend UDS before initiating any controlled substance for pain therapy.^12,13 They also suggest random drug testing at least once or twice a year for low-risk patients, and more frequent screening for high-risk patients, such as those with a history of addiction.^12,13 For example, for patients with opioid use disorder who participate in a methadone program, weekly UDTs are mandated for the first 90 days, and at least 8 UDTs a year are required after that.

However, UDTs carry significant stigma due to their association with SUDs. Talking with patients from the start of treatment helps to reduce this stigma, and makes it easier to have further discussions when patients have unexpected results during treatment. For example, clinicians can explain to patients that monitoring UDTs when prescribing controlled substances is similar to monitoring thyroid function with lithium use because treatment with a controlled substance carries an inherent risk of misuse, abuse, and diversion. For patients with SUDs, clinicians can explain that using UDTs to monitor their abstinence is similar to monitoring HbA_1c for glucose control in patients with diabetes.

Continue to: Factors that can affect UDT results

In addition to knowing when to order UDT, it is critical to know how to interpret the results of UDS and follow up with confirmatory tests when needed. Other than the limitations of the tests, the following factors could contribute to unexpected UDT results:

• the drug itself, including its half-life, metabolic pathways, and potential interactions with other medications
• how patients take their medications, including dose, frequency, and pattern of drug use
• all the medications that patients are taking, including prescription, over-the-counter, and herbal and supplemental preparations
• when the last dose of a prescribed controlled substance was taken. Always ask when the patient’s last dose was taken before you consider ordering a UDT.

To help better understand UDT results, Figure 1¹⁴ and Figure 2¹⁵ demonstrate metabolic pathways of commonly used benzodiazepines and opioids, respectively. There are several comprehensive reviews on commonly seen false positives and negatives for each drug or each class of drugs in immunoassays.^16-21 Confirmatory tests are usually very accurate. However, chiral analysis is needed to differentiate enantiomers, such as methamphetamine (active R-enantiomer) and selegiline, which is metabolized into L-methamphetamine (inactive S-enantiomer).²² In addition, detection of tetrahydrocannabivarin (THCV), an ingredient of the cannabis plant, via GC/MS can be used to distinguish between consumption of dronabinol and natural cannabis products.²³ The Table^16-21 summarizes the proto­type agents, other detectable agents in the same class, and false positives and negatives in immunoassays.

Interpreting UDT results and management strategies

Our Algorithm outlines how to interpret UDT results, and management strategies to consider based on whether the results are as expected or unexpected, with a few key caveats as described below.

Expected results

If there are no concerns based on the patient’s clinical presentation or collateral information, simply continue the current treatment. However, for patients taking medications that are undetectable by UDS (for example, regular use of clonazepam or oxycodone), consider ordering confirmatory tests at least once to ensure compliance, even when UDS results are negative.

Unexpected positive results, including the presence of illicit drugs and/or unprescribed licit drugs

Drug misuse, abuse, or dependence. The first step is to talk with the patient, who may acknowledge drug misuse, abuse, or dependence. Next, consider modifying the treatment plan; this may include more frequent monitoring and visits, limiting or discontinuing prescribed controlled substances, or referring the patient to inpatient or outpatient SUD treatment, as appropriate.

Continue to: Interference from medications or diet

Interference from medications or diets. One example of a positive opioid screening result due to interference from diet is the consumption of foods that contain poppy seeds. Because of this potential interference, the cutoff value for a positive opioid immunoassay in workplace drug testing was increased from 300 to 2,000 ug/L.²⁴ Educating patients regarding medication and lifestyle choices can help them avoid any interference with drug monitoring. Confirmatory tests can be ordered at the clinician’s discretion. The same principle applies to medication choice when prescribing. For example, a patient taking bupropion may experience a false positive result on a UDS for amphetamines, and a different antidepressant might be a better choice (Box 1).

Box 1

Urine sample tampering. Consider the possibility that urine samples could be substituted, especially when there are signs or indications of tampering, such as a positive pregnancy test for a male patient, or the presence of multiple prescription medications not prescribed to the patient. If there is high suspicion of urine sample tampering, consider observed urine sample collection.

When to order confirmatory tests for unexpected positive results.

Order a confirmatory test if a patient adamantly denies taking the substance(s) for which he/she has screened positive, and there’s no other explanation for the positive result. Continue the patient’s current treatment if the confirmatory test is negative. However, if the confirmatory test is positive, then modify the treatment plan (Algorithm).

Special circumstances.

A positive opioid screen in a patient who has been prescribed a synthetic or semisynthetic opioid indicates the patient is likely using opioids other than the one he/she has been prescribed. Similarly, clonazepam is expected to be negative in a benzodiazepine immunoassay. If such testing is positive, consider the possibility that the patient is taking other benzodiazepines, such as diazepam. The results of UDTs can also be complicated by common metabolites in the same class of drugs. For example, the presence of hydromorphone for patients taking hydrocodone does not necessarily indicate the use of hydromorphone, because hydromorphone is a metabolite of hydrocodone (Figure 2¹⁵).

Unexpected negative results

Prescribed medications exist in low concentration that are below the UDS detection threshold. This unexpected UDS result could occur if patients:

• take their medications less often than prescribed (because of financial difficulties or the patient feels better and does not think he/she needs it, etc.)
• hydrate too much (intentionally or unintentionally), are pregnant, or are fast metabolizers (Box 2)
• take other medications that increase the metabolism of the prescribed medication.

Box 2

Continue to: Further inquiry will...

Further inquiry will clarify these concerns. Clinicians should educate patients and manage accordingly. Confirmatory tests may be ordered upon clinicians’ discretion.

Urine sample tampering. Dilution or substitution of urine samples may lead to unexpected negative results. Usually, the urine sample will have abnormal parameters, including temperature, pH, specific gravity, urine creatinine level, or detection of adulterants. If needed, consider observed urine sample collection. Jaffee et al²⁵ reviewed tampering methods in urine drug testing.

Diversion or binge use of medications. If patients adamantly deny diverting or binge using their medication, order confirmatory tests. If the confirmatory test also is negative, modify the treatment plan accordingly, and consider the following options:

• adjust the medication dosage or frequency
• discontinue the medication
• conduct pill counts for more definitive evidence of diversion or misuse, especially if discontinuation may lead to potential harm (for example, for patients prescribed buprenorphine for opioid use disorder).

When to order confirmatory tests for unexpected negative results.

Because confirmatory tests also measure drug concentrations, clinicians sometimes order serial confirmatory testing to monitor lipophilic drugs after a patient reports discontinuation, such as in the case of a patient using marijuana, ketamine, or alprazolam. The level of a lipophilic drug, such as these 3, should continue to decline if the patient has discontinued using it. However, because the drug level is affected by how concentrated the urine samples are, it is necessary to compare the ratios of drug levels over urine creatinine levels.²⁶ Another use for confirmatory-quantitative testing is to detect “urine spiking,”^27,28 when a patient adds an unconsumed drug to his/her urine sample to produce a positive result without actually taking the drug (Box 3).

Box 3

When to consult lab specialists

Because many clinicians may find it challenging to stay abreast of all of the factors necessary to properly interpret UDT results, consulting with qualified laboratory professionals is appropriate when needed. For example, a patient was prescribed codeine, and his UDTs showed morphine as anticipated; however, the prescribing clinician suspected that the patient was also using heroin. In this case, consultation with a specialist may be warranted to look for 6-mono-acetylemorphine (6-MAM, a unique heroin metabolite) and/or the ratio of morphine to codeine.

Continue to: In summary...

In summary, UDTs are important tools to use in general psychiatry practice, especially when prescribing controlled substances. To use UDTs effectively, it is essential to possess knowledge of drug metabolism and the limitations of these tests. All immunoassay results should be considered as presumptive, and confirmatory tests are often needed for making treatment decisions. Many clinicians are unlikely to possess all the knowledge needed to correctly interpret UDTs, and in some cases, communication with qualified laboratory professionals may be necessary. In addition, the patient’s history and clinical presentation, collateral information, and data from prescription drug monitoring programs are all important factors to consider.

The cost of UDTs, variable insurance coverage, and a lack of on-site laboratory services can be deterrents to implementing UDTs as recommended. These factors vary significantly across regions, facilities, and insurance providers (see Related Resources). If faced with these issues and you expect to often need UDTs in your practice, consider using point-of-care UDTs as an alternative to improve access, convenience, and possibly cost.

Bottom Line

Urine drug tests (UDTs) should be standard clinical practice when prescribing controlled substances and treating patients with substance use disorders in the outpatient setting. Clinicians need to be knowledgeable about the limitations of UDTs, drug metabolism, and relevant patient history to interpret UDTs proficiently for optimal patient care. Consult laboratory specialists when needed to help interpret the results.

Related Resources

• Islam FA, Choudhry Z. Urine drug screens: Not just for job applicants. Current Psychiatry. 2018;17(12):43-44.
• HealthCare.gov. Health benefits & coverage: Mental health & substance abuse coverage. www.healthcare.gov/coverage/mental-health-substance-abuse-coverage/.

Drug Brand Names

Alprazolam • Xanax
Amphetamine • Adderall
Atomoxetine • Strattera
Buprenorphine • Subutex
Buprenorphine/naloxone • Suboxone, Zubsolv
Bupropion • Wellbutrin, Zyban
Chlordiazepoxide • Librium
Chlorpromazine • Thorazine
Clonazepam • Klonopin
Desipramine • Norpramin
Dextroamphetamine • Dexedrine, ProCentra
Diazepam • Valium
Doxepin • Silenor
Dronabinol • Marinol
Efavirenz • Sustiva
Ephedrine • Akovaz
Fentanyl • Actiq, Duragesic
Flurazepam • Dalmane
Hydrocodone • Hysingla, Zohydro ER
Hydromorphone • Dilaudid, Exalgo
Labetalol • Normodyne, Trandate
Lamotrigine • Lamictal
Lisdexamfetamine • Vyvanse
Lithium • Eskalith, Lithobid
Lorazepam • Ativan
Meperidine • Demerol
Metformin • Fortamet, Glucophage
Methadone • Dolophine, Methadose
Methylphenidate • Ritalin
Midazolam • Versed
Morphine • Kadian, MorphaBond
Nabilone • Cesamet
Naltrexone • Vivitrol
Oxaprozin • Daypro
Oxazepam • Serax
Oxycodone • Oxycontin
Oxymorphone • Opana
Phentermine • Adipex-P, Ionamin
Promethazine • Phenergan
Quetiapine • Seroquel
Ranitidine • Zantac
Rifampicin • Rifadin
Selegiline • Eldepryl, Zelapar
Sertraline • Zoloft
Temazepam • Restoril
Thioridazine • Mellaril
Tramadol • Conzip, Ultram
Trazodone • Desyrel
Triazolam • Halcion
Venlafaxine • Effexor
Verapamil • Calan, Verelan
Zolpidem • Ambien

Urine drug tests (UDTs) are useful clinical tools for assessing and monitoring the risk of misuse, abuse, and diversion when prescribing controlled substances, or for monitoring abstinence in patients with substance use disorders (SUDs). However, UDTs have been underutilized, and have been used without systematic documentation of reasons and results.^1,2 In addition, many clinicians may lack the knowledge needed to effectively interpret test results.^3,4 Although the reported use of UDTs is much higher among clinicians who are members of American Society of Addiction Medicine (ASAM), there is still a need for improved education.⁵

The appropriate use of UDTs strengthens the therapeutic relationship and promotes healthy behaviors and patients’ recovery. On the other hand, incorrect interpretation of test results may lead to missing potential aberrant behaviors, or inappropriate consequences for patients, such as discontinuing necessary medications or discharging them from care secondary to a perceived violation of a treatment contract due to unexpected positive or negative drug screening results.⁶ In this article, we review the basic concepts of UDTs and provide an algorithm to determine when to order these tests, how to interpret the results, and how to modify treatment accordingly.

Urine drug tests 101

Urine drug tests include rapid urine drug screening (UDS) and confirmatory tests. Urine drug screenings are usually based on various types of immunoassays. They are fast, sensitive, and cost-effective. Because immunoassays are antibody-mediated, they have significant false-positive and false-negative rates due to cross-reactivity and sensitivity of antibodies.⁷ For example, antibodies used in immunoassays to detect opioids are essentially morphine antibodies, and are not able to detect semisynthetic opioids or synthetic opioids (except hydrocodone).⁷ However, immunoassays specifically developed to detect oxycodone, buprenorphine, fentanyl, and methadone are available. On the other hand, antibodies can cross-react with molecules unrelated to proto-medicines or drug metabolites, but with similar antigenic determinants. For example, amphetamine immunoassays have high false-positive rates with many different classes of medications or substances.⁷

Urine drug tests based on mass spectrometry, gas chromatography/mass spectrometry (GC/MS), and liquid chromatography/mass spectrometry (LC/MS) are gold standards to confirm toxicology results. They are highly sensitive and specific, with accurate quantitative measurement. However, they are more expensive than UDS and usually need to be sent to a laboratory with capacity to perform GC/MS or LC/MS, with a turnaround time of up to 1 week.⁸ In clinical practice, we usually start with UDS tests and order confirmatory tests when needed.

When to order UDTs in outpatient psychiatry

On December 12, 2013, the ASAM released a white paper that suggests the use of drug testing as a primary prevention, diagnostic, and monitoring tool in the management of addiction or drug misuse and its application in a wide variety of medical settings.⁹ Many clinicians use treatment contracts when prescribing controlled substances as a part of a risk-mitigation strategy, and these contracts often include the use of UDTs. Urine drug tests provide objective evidence to support or negate self-report, because many people may underreport their use.¹⁰ The literature has shown significant “abnormal” urine test results, ranging from 9% to 53%, in patients receiving chronic opioid therapy.^2,11

The CDC and the American Academy of Pain Medicine recommend UDS before initiating any controlled substance for pain therapy.^12,13 They also suggest random drug testing at least once or twice a year for low-risk patients, and more frequent screening for high-risk patients, such as those with a history of addiction.^12,13 For example, for patients with opioid use disorder who participate in a methadone program, weekly UDTs are mandated for the first 90 days, and at least 8 UDTs a year are required after that.

However, UDTs carry significant stigma due to their association with SUDs. Talking with patients from the start of treatment helps to reduce this stigma, and makes it easier to have further discussions when patients have unexpected results during treatment. For example, clinicians can explain to patients that monitoring UDTs when prescribing controlled substances is similar to monitoring thyroid function with lithium use because treatment with a controlled substance carries an inherent risk of misuse, abuse, and diversion. For patients with SUDs, clinicians can explain that using UDTs to monitor their abstinence is similar to monitoring HbA_1c for glucose control in patients with diabetes.

Continue to: Factors that can affect UDT results

In addition to knowing when to order UDT, it is critical to know how to interpret the results of UDS and follow up with confirmatory tests when needed. Other than the limitations of the tests, the following factors could contribute to unexpected UDT results:

• the drug itself, including its half-life, metabolic pathways, and potential interactions with other medications
• how patients take their medications, including dose, frequency, and pattern of drug use
• all the medications that patients are taking, including prescription, over-the-counter, and herbal and supplemental preparations
• when the last dose of a prescribed controlled substance was taken. Always ask when the patient’s last dose was taken before you consider ordering a UDT.

To help better understand UDT results, Figure 1¹⁴ and Figure 2¹⁵ demonstrate metabolic pathways of commonly used benzodiazepines and opioids, respectively. There are several comprehensive reviews on commonly seen false positives and negatives for each drug or each class of drugs in immunoassays.^16-21 Confirmatory tests are usually very accurate. However, chiral analysis is needed to differentiate enantiomers, such as methamphetamine (active R-enantiomer) and selegiline, which is metabolized into L-methamphetamine (inactive S-enantiomer).²² In addition, detection of tetrahydrocannabivarin (THCV), an ingredient of the cannabis plant, via GC/MS can be used to distinguish between consumption of dronabinol and natural cannabis products.²³ The Table^16-21 summarizes the proto­type agents, other detectable agents in the same class, and false positives and negatives in immunoassays.

Interpreting UDT results and management strategies

Our Algorithm outlines how to interpret UDT results, and management strategies to consider based on whether the results are as expected or unexpected, with a few key caveats as described below.

Expected results

If there are no concerns based on the patient’s clinical presentation or collateral information, simply continue the current treatment. However, for patients taking medications that are undetectable by UDS (for example, regular use of clonazepam or oxycodone), consider ordering confirmatory tests at least once to ensure compliance, even when UDS results are negative.

Unexpected positive results, including the presence of illicit drugs and/or unprescribed licit drugs

Drug misuse, abuse, or dependence. The first step is to talk with the patient, who may acknowledge drug misuse, abuse, or dependence. Next, consider modifying the treatment plan; this may include more frequent monitoring and visits, limiting or discontinuing prescribed controlled substances, or referring the patient to inpatient or outpatient SUD treatment, as appropriate.

Continue to: Interference from medications or diet

Interference from medications or diets. One example of a positive opioid screening result due to interference from diet is the consumption of foods that contain poppy seeds. Because of this potential interference, the cutoff value for a positive opioid immunoassay in workplace drug testing was increased from 300 to 2,000 ug/L.²⁴ Educating patients regarding medication and lifestyle choices can help them avoid any interference with drug monitoring. Confirmatory tests can be ordered at the clinician’s discretion. The same principle applies to medication choice when prescribing. For example, a patient taking bupropion may experience a false positive result on a UDS for amphetamines, and a different antidepressant might be a better choice (Box 1).

Box 1

Urine sample tampering. Consider the possibility that urine samples could be substituted, especially when there are signs or indications of tampering, such as a positive pregnancy test for a male patient, or the presence of multiple prescription medications not prescribed to the patient. If there is high suspicion of urine sample tampering, consider observed urine sample collection.

When to order confirmatory tests for unexpected positive results.

Order a confirmatory test if a patient adamantly denies taking the substance(s) for which he/she has screened positive, and there’s no other explanation for the positive result. Continue the patient’s current treatment if the confirmatory test is negative. However, if the confirmatory test is positive, then modify the treatment plan (Algorithm).

Special circumstances.

A positive opioid screen in a patient who has been prescribed a synthetic or semisynthetic opioid indicates the patient is likely using opioids other than the one he/she has been prescribed. Similarly, clonazepam is expected to be negative in a benzodiazepine immunoassay. If such testing is positive, consider the possibility that the patient is taking other benzodiazepines, such as diazepam. The results of UDTs can also be complicated by common metabolites in the same class of drugs. For example, the presence of hydromorphone for patients taking hydrocodone does not necessarily indicate the use of hydromorphone, because hydromorphone is a metabolite of hydrocodone (Figure 2¹⁵).

Unexpected negative results

Prescribed medications exist in low concentration that are below the UDS detection threshold. This unexpected UDS result could occur if patients:

• take their medications less often than prescribed (because of financial difficulties or the patient feels better and does not think he/she needs it, etc.)
• hydrate too much (intentionally or unintentionally), are pregnant, or are fast metabolizers (Box 2)
• take other medications that increase the metabolism of the prescribed medication.

Box 2

Continue to: Further inquiry will...

Further inquiry will clarify these concerns. Clinicians should educate patients and manage accordingly. Confirmatory tests may be ordered upon clinicians’ discretion.

Urine sample tampering. Dilution or substitution of urine samples may lead to unexpected negative results. Usually, the urine sample will have abnormal parameters, including temperature, pH, specific gravity, urine creatinine level, or detection of adulterants. If needed, consider observed urine sample collection. Jaffee et al²⁵ reviewed tampering methods in urine drug testing.

Diversion or binge use of medications. If patients adamantly deny diverting or binge using their medication, order confirmatory tests. If the confirmatory test also is negative, modify the treatment plan accordingly, and consider the following options:

• adjust the medication dosage or frequency
• discontinue the medication
• conduct pill counts for more definitive evidence of diversion or misuse, especially if discontinuation may lead to potential harm (for example, for patients prescribed buprenorphine for opioid use disorder).

When to order confirmatory tests for unexpected negative results.

Because confirmatory tests also measure drug concentrations, clinicians sometimes order serial confirmatory testing to monitor lipophilic drugs after a patient reports discontinuation, such as in the case of a patient using marijuana, ketamine, or alprazolam. The level of a lipophilic drug, such as these 3, should continue to decline if the patient has discontinued using it. However, because the drug level is affected by how concentrated the urine samples are, it is necessary to compare the ratios of drug levels over urine creatinine levels.²⁶ Another use for confirmatory-quantitative testing is to detect “urine spiking,”^27,28 when a patient adds an unconsumed drug to his/her urine sample to produce a positive result without actually taking the drug (Box 3).

Box 3

When to consult lab specialists

Because many clinicians may find it challenging to stay abreast of all of the factors necessary to properly interpret UDT results, consulting with qualified laboratory professionals is appropriate when needed. For example, a patient was prescribed codeine, and his UDTs showed morphine as anticipated; however, the prescribing clinician suspected that the patient was also using heroin. In this case, consultation with a specialist may be warranted to look for 6-mono-acetylemorphine (6-MAM, a unique heroin metabolite) and/or the ratio of morphine to codeine.

Continue to: In summary...

In summary, UDTs are important tools to use in general psychiatry practice, especially when prescribing controlled substances. To use UDTs effectively, it is essential to possess knowledge of drug metabolism and the limitations of these tests. All immunoassay results should be considered as presumptive, and confirmatory tests are often needed for making treatment decisions. Many clinicians are unlikely to possess all the knowledge needed to correctly interpret UDTs, and in some cases, communication with qualified laboratory professionals may be necessary. In addition, the patient’s history and clinical presentation, collateral information, and data from prescription drug monitoring programs are all important factors to consider.

The cost of UDTs, variable insurance coverage, and a lack of on-site laboratory services can be deterrents to implementing UDTs as recommended. These factors vary significantly across regions, facilities, and insurance providers (see Related Resources). If faced with these issues and you expect to often need UDTs in your practice, consider using point-of-care UDTs as an alternative to improve access, convenience, and possibly cost.

Bottom Line

Urine drug tests (UDTs) should be standard clinical practice when prescribing controlled substances and treating patients with substance use disorders in the outpatient setting. Clinicians need to be knowledgeable about the limitations of UDTs, drug metabolism, and relevant patient history to interpret UDTs proficiently for optimal patient care. Consult laboratory specialists when needed to help interpret the results.

Related Resources

• Islam FA, Choudhry Z. Urine drug screens: Not just for job applicants. Current Psychiatry. 2018;17(12):43-44.
• HealthCare.gov. Health benefits & coverage: Mental health & substance abuse coverage. www.healthcare.gov/coverage/mental-health-substance-abuse-coverage/.

Drug Brand Names

Alprazolam • Xanax
Amphetamine • Adderall
Atomoxetine • Strattera
Buprenorphine • Subutex
Buprenorphine/naloxone • Suboxone, Zubsolv
Bupropion • Wellbutrin, Zyban
Chlordiazepoxide • Librium
Chlorpromazine • Thorazine
Clonazepam • Klonopin
Desipramine • Norpramin
Dextroamphetamine • Dexedrine, ProCentra
Diazepam • Valium
Doxepin • Silenor
Dronabinol • Marinol
Efavirenz • Sustiva
Ephedrine • Akovaz
Fentanyl • Actiq, Duragesic
Flurazepam • Dalmane
Hydrocodone • Hysingla, Zohydro ER
Hydromorphone • Dilaudid, Exalgo
Labetalol • Normodyne, Trandate
Lamotrigine • Lamictal
Lisdexamfetamine • Vyvanse
Lithium • Eskalith, Lithobid
Lorazepam • Ativan
Meperidine • Demerol
Metformin • Fortamet, Glucophage
Methadone • Dolophine, Methadose
Methylphenidate • Ritalin
Midazolam • Versed
Morphine • Kadian, MorphaBond
Nabilone • Cesamet
Naltrexone • Vivitrol
Oxaprozin • Daypro
Oxazepam • Serax
Oxycodone • Oxycontin
Oxymorphone • Opana
Phentermine • Adipex-P, Ionamin
Promethazine • Phenergan
Quetiapine • Seroquel
Ranitidine • Zantac
Rifampicin • Rifadin
Selegiline • Eldepryl, Zelapar
Sertraline • Zoloft
Temazepam • Restoril
Thioridazine • Mellaril
Tramadol • Conzip, Ultram
Trazodone • Desyrel
Triazolam • Halcion
Venlafaxine • Effexor
Verapamil • Calan, Verelan
Zolpidem • Ambien

Attention-deficit/hyperactivity disorder (ADHD) is the most common childhood neurodevelopmental disorder, affecting 8% to 12% of school-aged children in the United States^1-3 with significant impairments that often persist into adulthood.^4-8 Current guidelines recommend stimulant medication and/or behavioral therapies as first-line treatments for ADHD.^9,10 There is a wealth of evidence on the efficacy of stimulants in ADHD, with the most significant effects noted on core ADHD symptoms.^11,12 Additional evidence links stimulants to decreased long-term negative outcomes, including reduced school absences and grade retention,¹³ as well as modestly but significantly improved reading and math scores.¹⁴ Other studies have reported that individuals with ADHD who receive medication have decreased criminality,^15,16 motor vehicle accidents,^17,18 injuries,¹⁹ substance abuse,^20-22 and risk for subsequent and concurrent depression.²³ Therefore, the evidence suggests that consistent medication treatment helps improve outcomes for individuals with ADHD.

Adherence is defined as “the extent to which a person’s behavior (eg, taking medication) corresponds with agreed recommendations from a clinician.”²⁴ Unfortunately, pediatric ADHD medication adherence has been found to be poor (approximately 64%).^25-30 Nonadherence to ADHD medication has been linked to multiple factors, including caregiver/family and child/adolescent factors (Table 1), medication-related factors (Table 2), and health care/system factors (Table 3). Understanding and addressing these factors is essential to maximizing long-term outcomes. In this article, we review the factors associated with nonadherence to ADHD medication, and outline strategies to improve adherence.

Caregiver/family characteristics

Caregiver beliefs about ADHD and their attitudes toward treatment have been associated with the initiation of and adherence to ADHD medication. For example, caregivers who view a child’s difficulties as a medical disorder that requires a biologic intervention are more likely to accept and adhere to medication.³¹ Similarly, caregivers who perceive ADHD medication as safe, effective, and socially acceptable are more likely to be treatment-adherent.^32-35Other caregiver-related factors associated with improved ADHD medication adherence include:

• increased caregiver knowledge about ADHD³³
• receiving an ADHD diagnosis based on a thorough diagnostic process (ie, comprehensive psychological testing)³⁶
• satisfaction with information about medicine
• comfort with the treatment plan.³⁴

Socioeconomic status, family functioning, and caregiver mental health diagnoses (eg, ADHD, depression) have also been linked to ADHD medication adherence. Several studies, including the Multimodal Treatment Study of Children with ADHD,¹¹ a landmark study of stimulant medication for children with ADHD, have found an association between low income and decreased likelihood of receiving ADHD medication.^2,37-39 Further, Gau et al⁴⁰ found that negative caregiver-child relationships and family dysfunction were associated with poor medication adherence in children with ADHD.⁹ Prior studies have also shown that mothers of children with ADHD are more likely to have depression and/or anxiety,^41,42 and that caregivers with a history of mental health diagnoses are more accepting of initiating medication treatment for their children.⁴³ However, additional studies have found that caregiver mental health diagnoses decreased the likelihood of ADHD medication adherence.^40,44

Child characteristics

Child characteristics associated with decreased ADHD medication adherence include older age (eg, adolescents vs school-aged children),^{29,30,34,40,45-47} non-White race, Hispanic ethnicity,^29,33,48-51 female gender,^29,33,52 lower baseline ADHD symptom severity,^30,37 and child unwillingness to take medications.³⁴ However, prior studies have not been completely consistent about the relationship between child comorbid conditions (eg, oppositional defiant disorder [ODD], conduct disorder) and ADHD medication adherence. A few studies found that child comorbid conditions, especially ODD, mediate poor ADHD medication adherence, possibly secondary to an increased caregiver-child conflict.^30,53,54 However, other studies have reported that the presence of comorbid ODD, depression, and anxiety predicted increased adherence to ADHD medications.^37,46

Medication-related factors

Adverse effects of medications are the most commonly cited reason for ADHD medication nonadherence.^5,33,54-56 The adverse effects most often linked to nonadherence are reduced weight/appetite, increased aggressive behavior/irritability, and sleep difficulties.^54,57 Studies comparing methylphenidates and amphetamines, including 2 recent meta-analyses, suggest that amphetamines may be less well-tolerated on average, particularly with regard to emotional lability and irritability.^45,58,59 Therefore, clinicians might consider using methylphenidate-based preparations as first-line psychopharmacologic interventions in children with ADHD, as is consistent with the findings and conclusions drawn by a recent systematic review and meta-analysis of the comparative efficacy and tolerability of ADHD medications.⁶⁰

On the other hand, increased ADHD medication effectiveness has been associated with improved medication adherence.^5,34,54-56 Medication titration and dosing factors have also been shown to affect adherence. Specifically, adherence has been improved when ADHD medications are titrated in a systematic manner soon after starting treatment, and when families have an early first contact with a physician after starting medication (within 3 months).²⁸ In addition, use of a simplified dose regimen has been linked to better adherence: patients who are prescribed long-acting stimulants are more likely to adhere to treatment compared with patients who take short-acting formulations.^{26,40,49,61-63} It is possible that long-acting stimulants increase adherence because they produce more even and sustained effects on ADHD symptoms throughout the day, compared with short-acting formulations.⁶⁴ Furthermore, the inconvenience of taking multiple doses throughout the day, as well as the potential social stigma of mid-school day dosing, may negatively impact adherence to short-acting formulations.¹⁰

Continue to: Health care/system factors

Several studies have investigated the influence of health services factors on ADHD medication adherence. Specifically, limited transportation services and lack of mental health providers in the community have been linked to decreased ADHD medication adherence.^47,65,66 Furthermore, limited insurance coverage and higher costs of ADHD medications, which lead to substantial out-of-pocket payments for families, have been associated with decreased likelihood of ADHD medication adherence.^29,67

Clinician-related factors also can affect ADHD medication adherence. For example, a clinician’s lack knowledge of ADHD care can negatively impact ADHD medication adherence.⁶⁸ Two studies have documented improved ADHD medication adherence when treatment is provided by specialists (eg, child psychiatrists) rather than by community primary care providers, possibly because specialists are more likely to provide close stimulant titration and monitoring (ie, ≥ 3 visits in the first 90 days) and use higher maximum doses.^62,69 Furthermore, ADHD medication initiation and adherence are increased when patients have a strong working alliance with their clinician and trust the health care system,^31,34,35 as well as when there is a match between the caregiver’s and clinician’s perception of the cause, course, and best treatment practices for a child’s ADHD.⁶⁵

Strategies to improve medication adherence

A number of strategies to improve ADHD medication adherence can be derived from our knowledge of the factors that influence adherence.

Patient/family education. Unanswered questions about ADHD diagnosis, etiology, and medication adverse effects can negatively impact the ADHD treatment process. Therefore, patient/family education regarding ADHD and its management is necessary to improve medication adherence, because it helps families attain the knowledge, confidence, and motivation to manage their child’s condition.

Clinicians have an important role in educating patients about⁷⁰:

• the medications they are taking
• why they are taking them
• what the medications look like
• the time of medication administration
• the potential adverse effects
• what to do if adverse effects occur
• what regular testing/monitoring is necessary.

Clinicians can provide appropriate psychoeducation by sharing written materials and trusted websites with families (see Related Resources).

Behavioral strategies. Behavioral interventions have been among the most effective strategies for improving medication adherence in other chronic conditions.⁷¹ Behavioral strategies are likely to be particularly important for families of children with ADHD and comorbid conditions such as ODD because these families experience considerable caregiver-child conflict.⁷² Moreover, parents of children with ADHD are at higher risk for having ADHD and depression themselves,⁷³ both of which may interfere with a parent’s ability to obtain and administer medications consistently. Thus, for these families, using a combination of psychoeducation and behavioral strategies will be necessary to affect change in attitude and behavior. Behavioral strategies that can be used to improve medication adherence include:

• Technology-based interventions can reduce the impact of environmental barriers to adherence. For example, pharmacy automatic prescription renewal systems can reduce the likelihood of families failing to obtain ADHD medication refills. Pill reminder boxes, smartphone alerts, and setting various alarms can effectively prompt caregivers/patients to administer medication. In particular, these methods can be crucial in families for which multiple members have ADHD and its attendant difficulties with organization and task completion.
• Caregiver training may assist families in developing specific behavioral management skills that support adherence. This training can be as straightforward as instructing caregivers on the use of positive reinforcement when teaching their children to swallow pills. It may also encompass structured behavioral interventions aimed at training caregivers to utilize rewards and consequences in order to maximize medication adherence.⁷⁴

Continue to: Clinician interventions

Clinician interventions. Clinicians can use decision aids to help inform families about treatment options, promote shared decision making, and decrease uncertainty about the treatment plan⁷⁵ (see Related Resources). Early titration of ADHD medications and early first contact (within months of starting medication treatment) between caregivers and clinicians, whether via in-person visit, telephone, or email, have also been related to improved adherence.²⁸ Furthermore, clinicians can improve adherence by prescribing a simplified medication regimen (ie, long-acting formulations that provide full-day coverage). To address the negative impact of high out-of-pocket ADHD medication costs on adherence, clinicians can also prescribe generic preparations and/or “preferred” medications options on an individual patient’s formulary.

Because clinician knowledge and expertise in ADHD care has been linked to improved patient medication adherence,⁶⁸ clinicians are encouraged to use the American Academy of Pediatrics (AAP) guideline for diagnosis and treatment of ADHD, which includes a supplemental process of care algorithm (last published in 2011,¹⁰ with an updated guideline anticipated in 2019), as well as the AAP/National Institute for Children’s Health Quality (NICHQ) ADHD Toolkit,⁷⁶ which includes items helpful for ADHD diagnosis and treatment. The Society for Developmental and Behavioral Pediatrics is also developing a clinical practice guideline for the diagnosis and treatment of complex ADHD (ie, ADHD complicated by coexisting mental health, developmental, and/or psychosocial conditions or issues), with publication anticipated in 2019. Primary care providers can also improve their expertise in ADHD care by pursuing additional mental health–related trainings (such as those conducted by the REACH Institute).⁷⁷

Because receiving ADHD care from a specialist has been shown to improve medication initiation and adherence,^62,69 other strategies to address the short supply of child psychiatrists include offering incentives to medical students to pursue a career in child psychiatry (eg, loan forgiveness). Telepsychiatry and co-location of mental health specialists and primary care providers are additional innovative ways in which ADHD specialty care can be delivered to more patients.⁶⁴

Finally, providing culturally-sensitive care can strengthen the clinician-caregiver relationship and promote adherence to treatment. For example, clinicians can partner with local groups to increase their understanding of how different racial/ethnic groups perceive ADHD and its treatment.⁶⁴

Peer support models. Peers are credible role models who have a valued role in facilitating the use of mental health services by empowering families and enhancing service satisfaction.⁷⁸ In several communities in the United States, peer models using family advocates have been introduced.⁷⁹ Family advocates are typically caregivers of children who have special needs or have been involved in the mental health system. Their perspective—as peers and first-hand consumers of the health care and/or mental health system—can make them powerful and effective coaches to families of children with ADHD. By helping families to navigate ADHD care systems successfully, family advocates can play an important role in enhancing ADHD medication adherence, although further investigation is needed. In addition, the stigma around ADHD medication use, which adversely impacts adherence, can be mitigated if caregivers participate in organized ADHD-related support groups (eg, Children and Adults with ADHD [CHADD]).

Continue to: Health disparity-reducing interventions

Health disparity-reducing interventions. Successful health disparity-reducing interventions—such as those developed to enhance care of other chronic disorders including asthma and diabetes—can be applied to improve ADHD care. These interventions, which include medical-legal partnerships (eg, between clinicians, social workers, legal advocates, and community partners) in primary care centers, have been shown to improve health insurance coverage and therefore health care access.^80,81 Although some hardships linked to nonadherence (eg, low socioeconomic status) may not be amenable to health care–related interventions, screening for these hardships can identify children who are most at risk for poor adherence. This would alert clinicians to proactively identify barriers to adherence and implement mitigation strategies. This might include developing more streamlined, easier-to-follow management plans for these patients, such as those that can be delivered through pharmacist-physician collaborative programs⁸² and school-based therapy programs.^83-85

Bottom Line

Suboptimal adherence to medications for attention-deficit/hyperactivity disorder (ADHD) can be addressed through patient/family education, behavioral strategies, clinician interventions, peer support models, and health disparity-reducing interventions. By improving ADHD treatment adherence, these interventions have the potential to maximize long-term outcomes.

Related Resources

• Cohen Children’s Medical Center Northwell Health. The ADHD Medication Guide. www.ADHDMedicationGuide.com. Revised December 31, 2017.
• Cincinnati Children’s Hospital Medical Center. Decision aids to facilitate shared decision making in practice. www.cincinnatichildrens.org/service/j/anderson-center/ evidence-based-care/decision-aids.
• CHADD. Children and Adults with attention-deficit/ hyperactivity disorder. www.chadd.org.

Drug Brand Name

Methylphenidate • Concerta, Ritalin

Attention-deficit/hyperactivity disorder (ADHD) is the most common childhood neurodevelopmental disorder, affecting 8% to 12% of school-aged children in the United States^1-3 with significant impairments that often persist into adulthood.^4-8 Current guidelines recommend stimulant medication and/or behavioral therapies as first-line treatments for ADHD.^9,10 There is a wealth of evidence on the efficacy of stimulants in ADHD, with the most significant effects noted on core ADHD symptoms.^11,12 Additional evidence links stimulants to decreased long-term negative outcomes, including reduced school absences and grade retention,¹³ as well as modestly but significantly improved reading and math scores.¹⁴ Other studies have reported that individuals with ADHD who receive medication have decreased criminality,^15,16 motor vehicle accidents,^17,18 injuries,¹⁹ substance abuse,^20-22 and risk for subsequent and concurrent depression.²³ Therefore, the evidence suggests that consistent medication treatment helps improve outcomes for individuals with ADHD.

Adherence is defined as “the extent to which a person’s behavior (eg, taking medication) corresponds with agreed recommendations from a clinician.”²⁴ Unfortunately, pediatric ADHD medication adherence has been found to be poor (approximately 64%).^25-30 Nonadherence to ADHD medication has been linked to multiple factors, including caregiver/family and child/adolescent factors (Table 1), medication-related factors (Table 2), and health care/system factors (Table 3). Understanding and addressing these factors is essential to maximizing long-term outcomes. In this article, we review the factors associated with nonadherence to ADHD medication, and outline strategies to improve adherence.

Caregiver/family characteristics

Caregiver beliefs about ADHD and their attitudes toward treatment have been associated with the initiation of and adherence to ADHD medication. For example, caregivers who view a child’s difficulties as a medical disorder that requires a biologic intervention are more likely to accept and adhere to medication.³¹ Similarly, caregivers who perceive ADHD medication as safe, effective, and socially acceptable are more likely to be treatment-adherent.^32-35Other caregiver-related factors associated with improved ADHD medication adherence include:

• increased caregiver knowledge about ADHD³³
• receiving an ADHD diagnosis based on a thorough diagnostic process (ie, comprehensive psychological testing)³⁶
• satisfaction with information about medicine
• comfort with the treatment plan.³⁴

Socioeconomic status, family functioning, and caregiver mental health diagnoses (eg, ADHD, depression) have also been linked to ADHD medication adherence. Several studies, including the Multimodal Treatment Study of Children with ADHD,¹¹ a landmark study of stimulant medication for children with ADHD, have found an association between low income and decreased likelihood of receiving ADHD medication.^2,37-39 Further, Gau et al⁴⁰ found that negative caregiver-child relationships and family dysfunction were associated with poor medication adherence in children with ADHD.⁹ Prior studies have also shown that mothers of children with ADHD are more likely to have depression and/or anxiety,^41,42 and that caregivers with a history of mental health diagnoses are more accepting of initiating medication treatment for their children.⁴³ However, additional studies have found that caregiver mental health diagnoses decreased the likelihood of ADHD medication adherence.^40,44

Child characteristics

Child characteristics associated with decreased ADHD medication adherence include older age (eg, adolescents vs school-aged children),^{29,30,34,40,45-47} non-White race, Hispanic ethnicity,^29,33,48-51 female gender,^29,33,52 lower baseline ADHD symptom severity,^30,37 and child unwillingness to take medications.³⁴ However, prior studies have not been completely consistent about the relationship between child comorbid conditions (eg, oppositional defiant disorder [ODD], conduct disorder) and ADHD medication adherence. A few studies found that child comorbid conditions, especially ODD, mediate poor ADHD medication adherence, possibly secondary to an increased caregiver-child conflict.^30,53,54 However, other studies have reported that the presence of comorbid ODD, depression, and anxiety predicted increased adherence to ADHD medications.^37,46

Medication-related factors

Adverse effects of medications are the most commonly cited reason for ADHD medication nonadherence.^5,33,54-56 The adverse effects most often linked to nonadherence are reduced weight/appetite, increased aggressive behavior/irritability, and sleep difficulties.^54,57 Studies comparing methylphenidates and amphetamines, including 2 recent meta-analyses, suggest that amphetamines may be less well-tolerated on average, particularly with regard to emotional lability and irritability.^45,58,59 Therefore, clinicians might consider using methylphenidate-based preparations as first-line psychopharmacologic interventions in children with ADHD, as is consistent with the findings and conclusions drawn by a recent systematic review and meta-analysis of the comparative efficacy and tolerability of ADHD medications.⁶⁰

On the other hand, increased ADHD medication effectiveness has been associated with improved medication adherence.^5,34,54-56 Medication titration and dosing factors have also been shown to affect adherence. Specifically, adherence has been improved when ADHD medications are titrated in a systematic manner soon after starting treatment, and when families have an early first contact with a physician after starting medication (within 3 months).²⁸ In addition, use of a simplified dose regimen has been linked to better adherence: patients who are prescribed long-acting stimulants are more likely to adhere to treatment compared with patients who take short-acting formulations.^{26,40,49,61-63} It is possible that long-acting stimulants increase adherence because they produce more even and sustained effects on ADHD symptoms throughout the day, compared with short-acting formulations.⁶⁴ Furthermore, the inconvenience of taking multiple doses throughout the day, as well as the potential social stigma of mid-school day dosing, may negatively impact adherence to short-acting formulations.¹⁰

Continue to: Health care/system factors

Several studies have investigated the influence of health services factors on ADHD medication adherence. Specifically, limited transportation services and lack of mental health providers in the community have been linked to decreased ADHD medication adherence.^47,65,66 Furthermore, limited insurance coverage and higher costs of ADHD medications, which lead to substantial out-of-pocket payments for families, have been associated with decreased likelihood of ADHD medication adherence.^29,67

Clinician-related factors also can affect ADHD medication adherence. For example, a clinician’s lack knowledge of ADHD care can negatively impact ADHD medication adherence.⁶⁸ Two studies have documented improved ADHD medication adherence when treatment is provided by specialists (eg, child psychiatrists) rather than by community primary care providers, possibly because specialists are more likely to provide close stimulant titration and monitoring (ie, ≥ 3 visits in the first 90 days) and use higher maximum doses.^62,69 Furthermore, ADHD medication initiation and adherence are increased when patients have a strong working alliance with their clinician and trust the health care system,^31,34,35 as well as when there is a match between the caregiver’s and clinician’s perception of the cause, course, and best treatment practices for a child’s ADHD.⁶⁵

Strategies to improve medication adherence

A number of strategies to improve ADHD medication adherence can be derived from our knowledge of the factors that influence adherence.

Patient/family education. Unanswered questions about ADHD diagnosis, etiology, and medication adverse effects can negatively impact the ADHD treatment process. Therefore, patient/family education regarding ADHD and its management is necessary to improve medication adherence, because it helps families attain the knowledge, confidence, and motivation to manage their child’s condition.

Clinicians have an important role in educating patients about⁷⁰:

• the medications they are taking
• why they are taking them
• what the medications look like
• the time of medication administration
• the potential adverse effects
• what to do if adverse effects occur
• what regular testing/monitoring is necessary.

Clinicians can provide appropriate psychoeducation by sharing written materials and trusted websites with families (see Related Resources).

Behavioral strategies. Behavioral interventions have been among the most effective strategies for improving medication adherence in other chronic conditions.⁷¹ Behavioral strategies are likely to be particularly important for families of children with ADHD and comorbid conditions such as ODD because these families experience considerable caregiver-child conflict.⁷² Moreover, parents of children with ADHD are at higher risk for having ADHD and depression themselves,⁷³ both of which may interfere with a parent’s ability to obtain and administer medications consistently. Thus, for these families, using a combination of psychoeducation and behavioral strategies will be necessary to affect change in attitude and behavior. Behavioral strategies that can be used to improve medication adherence include:

• Technology-based interventions can reduce the impact of environmental barriers to adherence. For example, pharmacy automatic prescription renewal systems can reduce the likelihood of families failing to obtain ADHD medication refills. Pill reminder boxes, smartphone alerts, and setting various alarms can effectively prompt caregivers/patients to administer medication. In particular, these methods can be crucial in families for which multiple members have ADHD and its attendant difficulties with organization and task completion.
• Caregiver training may assist families in developing specific behavioral management skills that support adherence. This training can be as straightforward as instructing caregivers on the use of positive reinforcement when teaching their children to swallow pills. It may also encompass structured behavioral interventions aimed at training caregivers to utilize rewards and consequences in order to maximize medication adherence.⁷⁴

Continue to: Clinician interventions

Clinician interventions. Clinicians can use decision aids to help inform families about treatment options, promote shared decision making, and decrease uncertainty about the treatment plan⁷⁵ (see Related Resources). Early titration of ADHD medications and early first contact (within months of starting medication treatment) between caregivers and clinicians, whether via in-person visit, telephone, or email, have also been related to improved adherence.²⁸ Furthermore, clinicians can improve adherence by prescribing a simplified medication regimen (ie, long-acting formulations that provide full-day coverage). To address the negative impact of high out-of-pocket ADHD medication costs on adherence, clinicians can also prescribe generic preparations and/or “preferred” medications options on an individual patient’s formulary.

Because clinician knowledge and expertise in ADHD care has been linked to improved patient medication adherence,⁶⁸ clinicians are encouraged to use the American Academy of Pediatrics (AAP) guideline for diagnosis and treatment of ADHD, which includes a supplemental process of care algorithm (last published in 2011,¹⁰ with an updated guideline anticipated in 2019), as well as the AAP/National Institute for Children’s Health Quality (NICHQ) ADHD Toolkit,⁷⁶ which includes items helpful for ADHD diagnosis and treatment. The Society for Developmental and Behavioral Pediatrics is also developing a clinical practice guideline for the diagnosis and treatment of complex ADHD (ie, ADHD complicated by coexisting mental health, developmental, and/or psychosocial conditions or issues), with publication anticipated in 2019. Primary care providers can also improve their expertise in ADHD care by pursuing additional mental health–related trainings (such as those conducted by the REACH Institute).⁷⁷

Because receiving ADHD care from a specialist has been shown to improve medication initiation and adherence,^62,69 other strategies to address the short supply of child psychiatrists include offering incentives to medical students to pursue a career in child psychiatry (eg, loan forgiveness). Telepsychiatry and co-location of mental health specialists and primary care providers are additional innovative ways in which ADHD specialty care can be delivered to more patients.⁶⁴

Finally, providing culturally-sensitive care can strengthen the clinician-caregiver relationship and promote adherence to treatment. For example, clinicians can partner with local groups to increase their understanding of how different racial/ethnic groups perceive ADHD and its treatment.⁶⁴

Peer support models. Peers are credible role models who have a valued role in facilitating the use of mental health services by empowering families and enhancing service satisfaction.⁷⁸ In several communities in the United States, peer models using family advocates have been introduced.⁷⁹ Family advocates are typically caregivers of children who have special needs or have been involved in the mental health system. Their perspective—as peers and first-hand consumers of the health care and/or mental health system—can make them powerful and effective coaches to families of children with ADHD. By helping families to navigate ADHD care systems successfully, family advocates can play an important role in enhancing ADHD medication adherence, although further investigation is needed. In addition, the stigma around ADHD medication use, which adversely impacts adherence, can be mitigated if caregivers participate in organized ADHD-related support groups (eg, Children and Adults with ADHD [CHADD]).

Continue to: Health disparity-reducing interventions

Health disparity-reducing interventions. Successful health disparity-reducing interventions—such as those developed to enhance care of other chronic disorders including asthma and diabetes—can be applied to improve ADHD care. These interventions, which include medical-legal partnerships (eg, between clinicians, social workers, legal advocates, and community partners) in primary care centers, have been shown to improve health insurance coverage and therefore health care access.^80,81 Although some hardships linked to nonadherence (eg, low socioeconomic status) may not be amenable to health care–related interventions, screening for these hardships can identify children who are most at risk for poor adherence. This would alert clinicians to proactively identify barriers to adherence and implement mitigation strategies. This might include developing more streamlined, easier-to-follow management plans for these patients, such as those that can be delivered through pharmacist-physician collaborative programs⁸² and school-based therapy programs.^83-85

Bottom Line

Suboptimal adherence to medications for attention-deficit/hyperactivity disorder (ADHD) can be addressed through patient/family education, behavioral strategies, clinician interventions, peer support models, and health disparity-reducing interventions. By improving ADHD treatment adherence, these interventions have the potential to maximize long-term outcomes.

Related Resources

• Cohen Children’s Medical Center Northwell Health. The ADHD Medication Guide. www.ADHDMedicationGuide.com. Revised December 31, 2017.
• Cincinnati Children’s Hospital Medical Center. Decision aids to facilitate shared decision making in practice. www.cincinnatichildrens.org/service/j/anderson-center/ evidence-based-care/decision-aids.
• CHADD. Children and Adults with attention-deficit/ hyperactivity disorder. www.chadd.org.

Drug Brand Name

Methylphenidate • Concerta, Ritalin

Attention-deficit/hyperactivity disorder (ADHD) is the most common childhood neurodevelopmental disorder, affecting 8% to 12% of school-aged children in the United States^1-3 with significant impairments that often persist into adulthood.^4-8 Current guidelines recommend stimulant medication and/or behavioral therapies as first-line treatments for ADHD.^9,10 There is a wealth of evidence on the efficacy of stimulants in ADHD, with the most significant effects noted on core ADHD symptoms.^11,12 Additional evidence links stimulants to decreased long-term negative outcomes, including reduced school absences and grade retention,¹³ as well as modestly but significantly improved reading and math scores.¹⁴ Other studies have reported that individuals with ADHD who receive medication have decreased criminality,^15,16 motor vehicle accidents,^17,18 injuries,¹⁹ substance abuse,^20-22 and risk for subsequent and concurrent depression.²³ Therefore, the evidence suggests that consistent medication treatment helps improve outcomes for individuals with ADHD.

Adherence is defined as “the extent to which a person’s behavior (eg, taking medication) corresponds with agreed recommendations from a clinician.”²⁴ Unfortunately, pediatric ADHD medication adherence has been found to be poor (approximately 64%).^25-30 Nonadherence to ADHD medication has been linked to multiple factors, including caregiver/family and child/adolescent factors (Table 1), medication-related factors (Table 2), and health care/system factors (Table 3). Understanding and addressing these factors is essential to maximizing long-term outcomes. In this article, we review the factors associated with nonadherence to ADHD medication, and outline strategies to improve adherence.

Caregiver/family characteristics

Caregiver beliefs about ADHD and their attitudes toward treatment have been associated with the initiation of and adherence to ADHD medication. For example, caregivers who view a child’s difficulties as a medical disorder that requires a biologic intervention are more likely to accept and adhere to medication.³¹ Similarly, caregivers who perceive ADHD medication as safe, effective, and socially acceptable are more likely to be treatment-adherent.^32-35Other caregiver-related factors associated with improved ADHD medication adherence include:

• increased caregiver knowledge about ADHD³³
• receiving an ADHD diagnosis based on a thorough diagnostic process (ie, comprehensive psychological testing)³⁶
• satisfaction with information about medicine
• comfort with the treatment plan.³⁴

Socioeconomic status, family functioning, and caregiver mental health diagnoses (eg, ADHD, depression) have also been linked to ADHD medication adherence. Several studies, including the Multimodal Treatment Study of Children with ADHD,¹¹ a landmark study of stimulant medication for children with ADHD, have found an association between low income and decreased likelihood of receiving ADHD medication.^2,37-39 Further, Gau et al⁴⁰ found that negative caregiver-child relationships and family dysfunction were associated with poor medication adherence in children with ADHD.⁹ Prior studies have also shown that mothers of children with ADHD are more likely to have depression and/or anxiety,^41,42 and that caregivers with a history of mental health diagnoses are more accepting of initiating medication treatment for their children.⁴³ However, additional studies have found that caregiver mental health diagnoses decreased the likelihood of ADHD medication adherence.^40,44

Child characteristics

Child characteristics associated with decreased ADHD medication adherence include older age (eg, adolescents vs school-aged children),^{29,30,34,40,45-47} non-White race, Hispanic ethnicity,^29,33,48-51 female gender,^29,33,52 lower baseline ADHD symptom severity,^30,37 and child unwillingness to take medications.³⁴ However, prior studies have not been completely consistent about the relationship between child comorbid conditions (eg, oppositional defiant disorder [ODD], conduct disorder) and ADHD medication adherence. A few studies found that child comorbid conditions, especially ODD, mediate poor ADHD medication adherence, possibly secondary to an increased caregiver-child conflict.^30,53,54 However, other studies have reported that the presence of comorbid ODD, depression, and anxiety predicted increased adherence to ADHD medications.^37,46

Medication-related factors

Adverse effects of medications are the most commonly cited reason for ADHD medication nonadherence.^5,33,54-56 The adverse effects most often linked to nonadherence are reduced weight/appetite, increased aggressive behavior/irritability, and sleep difficulties.^54,57 Studies comparing methylphenidates and amphetamines, including 2 recent meta-analyses, suggest that amphetamines may be less well-tolerated on average, particularly with regard to emotional lability and irritability.^45,58,59 Therefore, clinicians might consider using methylphenidate-based preparations as first-line psychopharmacologic interventions in children with ADHD, as is consistent with the findings and conclusions drawn by a recent systematic review and meta-analysis of the comparative efficacy and tolerability of ADHD medications.⁶⁰

On the other hand, increased ADHD medication effectiveness has been associated with improved medication adherence.^5,34,54-56 Medication titration and dosing factors have also been shown to affect adherence. Specifically, adherence has been improved when ADHD medications are titrated in a systematic manner soon after starting treatment, and when families have an early first contact with a physician after starting medication (within 3 months).²⁸ In addition, use of a simplified dose regimen has been linked to better adherence: patients who are prescribed long-acting stimulants are more likely to adhere to treatment compared with patients who take short-acting formulations.^{26,40,49,61-63} It is possible that long-acting stimulants increase adherence because they produce more even and sustained effects on ADHD symptoms throughout the day, compared with short-acting formulations.⁶⁴ Furthermore, the inconvenience of taking multiple doses throughout the day, as well as the potential social stigma of mid-school day dosing, may negatively impact adherence to short-acting formulations.¹⁰

Continue to: Health care/system factors

Several studies have investigated the influence of health services factors on ADHD medication adherence. Specifically, limited transportation services and lack of mental health providers in the community have been linked to decreased ADHD medication adherence.^47,65,66 Furthermore, limited insurance coverage and higher costs of ADHD medications, which lead to substantial out-of-pocket payments for families, have been associated with decreased likelihood of ADHD medication adherence.^29,67

Clinician-related factors also can affect ADHD medication adherence. For example, a clinician’s lack knowledge of ADHD care can negatively impact ADHD medication adherence.⁶⁸ Two studies have documented improved ADHD medication adherence when treatment is provided by specialists (eg, child psychiatrists) rather than by community primary care providers, possibly because specialists are more likely to provide close stimulant titration and monitoring (ie, ≥ 3 visits in the first 90 days) and use higher maximum doses.^62,69 Furthermore, ADHD medication initiation and adherence are increased when patients have a strong working alliance with their clinician and trust the health care system,^31,34,35 as well as when there is a match between the caregiver’s and clinician’s perception of the cause, course, and best treatment practices for a child’s ADHD.⁶⁵

Strategies to improve medication adherence

A number of strategies to improve ADHD medication adherence can be derived from our knowledge of the factors that influence adherence.

Patient/family education. Unanswered questions about ADHD diagnosis, etiology, and medication adverse effects can negatively impact the ADHD treatment process. Therefore, patient/family education regarding ADHD and its management is necessary to improve medication adherence, because it helps families attain the knowledge, confidence, and motivation to manage their child’s condition.

Clinicians have an important role in educating patients about⁷⁰:

• the medications they are taking
• why they are taking them
• what the medications look like
• the time of medication administration
• the potential adverse effects
• what to do if adverse effects occur
• what regular testing/monitoring is necessary.

Clinicians can provide appropriate psychoeducation by sharing written materials and trusted websites with families (see Related Resources).

Behavioral strategies. Behavioral interventions have been among the most effective strategies for improving medication adherence in other chronic conditions.⁷¹ Behavioral strategies are likely to be particularly important for families of children with ADHD and comorbid conditions such as ODD because these families experience considerable caregiver-child conflict.⁷² Moreover, parents of children with ADHD are at higher risk for having ADHD and depression themselves,⁷³ both of which may interfere with a parent’s ability to obtain and administer medications consistently. Thus, for these families, using a combination of psychoeducation and behavioral strategies will be necessary to affect change in attitude and behavior. Behavioral strategies that can be used to improve medication adherence include:

• Technology-based interventions can reduce the impact of environmental barriers to adherence. For example, pharmacy automatic prescription renewal systems can reduce the likelihood of families failing to obtain ADHD medication refills. Pill reminder boxes, smartphone alerts, and setting various alarms can effectively prompt caregivers/patients to administer medication. In particular, these methods can be crucial in families for which multiple members have ADHD and its attendant difficulties with organization and task completion.
• Caregiver training may assist families in developing specific behavioral management skills that support adherence. This training can be as straightforward as instructing caregivers on the use of positive reinforcement when teaching their children to swallow pills. It may also encompass structured behavioral interventions aimed at training caregivers to utilize rewards and consequences in order to maximize medication adherence.⁷⁴

Continue to: Clinician interventions

Clinician interventions. Clinicians can use decision aids to help inform families about treatment options, promote shared decision making, and decrease uncertainty about the treatment plan⁷⁵ (see Related Resources). Early titration of ADHD medications and early first contact (within months of starting medication treatment) between caregivers and clinicians, whether via in-person visit, telephone, or email, have also been related to improved adherence.²⁸ Furthermore, clinicians can improve adherence by prescribing a simplified medication regimen (ie, long-acting formulations that provide full-day coverage). To address the negative impact of high out-of-pocket ADHD medication costs on adherence, clinicians can also prescribe generic preparations and/or “preferred” medications options on an individual patient’s formulary.

Because clinician knowledge and expertise in ADHD care has been linked to improved patient medication adherence,⁶⁸ clinicians are encouraged to use the American Academy of Pediatrics (AAP) guideline for diagnosis and treatment of ADHD, which includes a supplemental process of care algorithm (last published in 2011,¹⁰ with an updated guideline anticipated in 2019), as well as the AAP/National Institute for Children’s Health Quality (NICHQ) ADHD Toolkit,⁷⁶ which includes items helpful for ADHD diagnosis and treatment. The Society for Developmental and Behavioral Pediatrics is also developing a clinical practice guideline for the diagnosis and treatment of complex ADHD (ie, ADHD complicated by coexisting mental health, developmental, and/or psychosocial conditions or issues), with publication anticipated in 2019. Primary care providers can also improve their expertise in ADHD care by pursuing additional mental health–related trainings (such as those conducted by the REACH Institute).⁷⁷

Because receiving ADHD care from a specialist has been shown to improve medication initiation and adherence,^62,69 other strategies to address the short supply of child psychiatrists include offering incentives to medical students to pursue a career in child psychiatry (eg, loan forgiveness). Telepsychiatry and co-location of mental health specialists and primary care providers are additional innovative ways in which ADHD specialty care can be delivered to more patients.⁶⁴

Finally, providing culturally-sensitive care can strengthen the clinician-caregiver relationship and promote adherence to treatment. For example, clinicians can partner with local groups to increase their understanding of how different racial/ethnic groups perceive ADHD and its treatment.⁶⁴

Peer support models. Peers are credible role models who have a valued role in facilitating the use of mental health services by empowering families and enhancing service satisfaction.⁷⁸ In several communities in the United States, peer models using family advocates have been introduced.⁷⁹ Family advocates are typically caregivers of children who have special needs or have been involved in the mental health system. Their perspective—as peers and first-hand consumers of the health care and/or mental health system—can make them powerful and effective coaches to families of children with ADHD. By helping families to navigate ADHD care systems successfully, family advocates can play an important role in enhancing ADHD medication adherence, although further investigation is needed. In addition, the stigma around ADHD medication use, which adversely impacts adherence, can be mitigated if caregivers participate in organized ADHD-related support groups (eg, Children and Adults with ADHD [CHADD]).

Continue to: Health disparity-reducing interventions

Health disparity-reducing interventions. Successful health disparity-reducing interventions—such as those developed to enhance care of other chronic disorders including asthma and diabetes—can be applied to improve ADHD care. These interventions, which include medical-legal partnerships (eg, between clinicians, social workers, legal advocates, and community partners) in primary care centers, have been shown to improve health insurance coverage and therefore health care access.^80,81 Although some hardships linked to nonadherence (eg, low socioeconomic status) may not be amenable to health care–related interventions, screening for these hardships can identify children who are most at risk for poor adherence. This would alert clinicians to proactively identify barriers to adherence and implement mitigation strategies. This might include developing more streamlined, easier-to-follow management plans for these patients, such as those that can be delivered through pharmacist-physician collaborative programs⁸² and school-based therapy programs.^83-85

Bottom Line

Suboptimal adherence to medications for attention-deficit/hyperactivity disorder (ADHD) can be addressed through patient/family education, behavioral strategies, clinician interventions, peer support models, and health disparity-reducing interventions. By improving ADHD treatment adherence, these interventions have the potential to maximize long-term outcomes.

Related Resources

• Cohen Children’s Medical Center Northwell Health. The ADHD Medication Guide. www.ADHDMedicationGuide.com. Revised December 31, 2017.
• Cincinnati Children’s Hospital Medical Center. Decision aids to facilitate shared decision making in practice. www.cincinnatichildrens.org/service/j/anderson-center/ evidence-based-care/decision-aids.
• CHADD. Children and Adults with attention-deficit/ hyperactivity disorder. www.chadd.org.

Drug Brand Name

Methylphenidate • Concerta, Ritalin

For many people, artificial intelligence (AI) brings to mind some form of humanoid robot that speaks and acts like a human. However, AI is much more than merely robotics and machines. Professor John McCarthy of Stanford University, who first coined the term “artificial intelligence” in the early 1950s, defined it as “the science and engineering of making intelligent machines, especially intelligent computer programs”; he defined intelligence as “the computational part of the ability to achieve goals.^”1 Artificial intelligence also is commonly defined as the development of computer systems able to perform tasks that normally require human intelligence.² English Mathematician Alan Turing is considered one of the forefathers of AI research, and devised the first test to determine if a computer program was intelligent (Box 1³). Today, AI has established itself as an integral part of medicine and psychiatry.

Box 1

The semantics of AI

Two subsets of AI are machine learning and deep learning.^4,5 Machine learning is defined as a set of methods that can automatically detect patterns in data and then use the uncovered pattern to predict future data.⁴ Deep learning is a form of machine learning that enables computers to learn from experience and understand the world in terms of a hierarchy of concepts.⁵

Machine learning can be supervised, semi-supervised, or unsupervised. The majority of practical machine learning uses supervised learning, where all data are labeled and an algorithm is used to learn the mapping function from the input to the output. In unsupervised learning, all data are unlabeled and the algorithm models the underlying structure of the data by itself. Semi-supervised learning is a mixture of both.⁶

Many researchers also categorize AI into 2 types: general or “strong” AI, and narrow or “weak” AI. Strong AI is defined as computers that can think on a level at least equal to humans and are able to experience emotions and even consciousness.⁷ Weak AI includes adding “thinking-like” features to computers to make them more useful tools. Almost all AI technologies available today are considered to be weak AI.

AI in medicine

AI is being developed for a broad range of applications in medicine. This includes informatics approaches, including learning in health management systems such as electronic health records, and actively guiding physicians in their treatment decisions.⁸

AI has been applied to assist administrative workflows that reach beyond automated non-patient care activities such as chart documentation and placing orders. One example is the Judy Reitz Capacity Command Center, which was designed and built with GE Healthcare Partners.⁹ It combines AI technology in the form of systems engineering and predictive analytics to better manage multiple workflows in different administrative settings, including patient safety, volume, flow, and access to care.⁹

In April 2018, Intel Corporation surveyed 200 health-care decision makers in the United States regarding their use of AI in practice and their attitudes toward it.¹⁰ Overall, 37% of respondents reported using AI and 54% expected to increase their use of AI in the next 5 years. Clinical use of AI (77%) was more common than administrative use (41%) or financial use (26 %).¹⁰

Continue to: Box 2

Box 2^11-19 describes studies that evaluated the clinical use of AI in specialties other than psychiatry.

Box 2

How can AI be used in psychiatry?

Artificially intelligent technologies have been used in psychiatry for several decades. One of the earliest examples is ELIZA, a computer program published by Professor Joseph Weizenbaum of the Massachusetts Institute of Technology in 1966.²⁰ ELIZA consisted of a language analyzer and a script or a set of rules to improvise around a certain theme; the script DOCTOR was used to simulate a Rogerian psychotherapist.²⁰

The application of AI in psychiatry has come a long way since the pioneering work of Weizenbaum. A recent study examined AI’s ability to distinguish between an individual who had suicidal ideation vs a control group. Machine-learning algorithms were used to evaluate functional MRI scans of 34 participants (17 who had suicidal ideation and 17 controls) to identify certain neural signatures of concepts related to life and death.²¹ The machine-learning algorithms were able to distinguish between these 2 groups with 91% accuracy. They also were able to distinguish between individuals who attempted suicide and those who did not with 94% accuracy.²¹

A study from the University of Cincinnati looked at using machine learning and natural language processing to distinguish genuine suicide notes from “fake” suicide notes that had been written by a healthy control group.²² Sixty-six notes were evaluated and categorized by 11 mental health professionals (psychiatrists, social workers, and emergency medicine physicians) and 31 PGY-3 residents. The accuracy of their results was compared with that of 9 machine-learning algorithms.²² The best machine-learning algorithm accurately classified the notes 78% of the time, compared with 63% of the time for the mental health professionals and 49% of the time for the residents.²²

Researchers at Vanderbilt University examined using machine learning to predict suicide risk.²³ They developed algorithms to scan electronic health records of 5,167 adults, 3,250 of whom had attempted suicide. In a review of the patients’ data from 1 week to 2 years before the attempt, the algorithms looked for certain predictors of suicide attempts, including recurrent depression, psychotic disorder, and substance use. The algorithm was 80% accurate at predicting whether a patient would attempt suicide within the next 2 years, and 84% accurate at predicting an attempt within the next week.²³

Continue to: In a prospective study...

In a prospective study, researchers at Cincinnati Children’s Hospital used a machine-learning algorithm to evaluate 379 patients who were categorized into 3 groups: suicidal, mentally ill but not suicidal, or controls.²⁴ All participants completed a standardized behavioral rating scale and participated in a semi-structured interview. Based on the participants’ linguistic and acoustic characteristics, the algorithm was able to classify them into the 3 groups with 85% accuracy.²⁴

Many studies have looked at using language analysis to predicting the risk of psychosis in at-risk individuals. In one study, researchers evaluated individuals known to be at high risk for developing psychosis, some of whom eventually did develop psychosis.²⁵ Participants were asked to retell a story and to answer questions about that story. Researchers fed the transcripts of these interviews into a language analysis program that looked at semantic coherence, syntactic complexity, and other factors. The algorithm was able to predict the future occurrence of psychosis with 82% accuracy. Participants who converted to psychosis had decreased semantic coherence and reduced syntactic complexity.²⁵

A similar study looked at 34 at-risk youth in an attempt to predict who would develop psychosis based on speech pattern analysis.²⁶ The participants underwent baseline interviews and were assessed quarterly for 2.5 years. The algorithm was able to predict who would develop psychosis with 100% accuracy.²⁶

Challenges and limitations

The amount of research about applying machine learning to various fields of psychiatry continues to grow. With this increased interest, there have been reports of bias and human influence in the various stages of machine learning. Therefore, being aware of these challenges and engaging in practices to minimize their effects are necessary. Such practices include providing more details on data collection and processing, and constantly evaluating machine learning models for their relevance and utility to the research question proposed.²⁷

As is the case with most innovative, fast-growing technologies, AI has its fair share of criticisms and concerns. Critics have focused on the potential threat of privacy issues, medical errors, and ethical concerns. Researchers at the Stanford Center for Biomedical Ethics emphasize the importance of being aware of the different types of bias that humans and algorithm designs can introduce into health data.²⁸

Continue to: The Nuffield Council on Bioethics...

The Nuffield Council on Bioethics also emphasizes the importance of identifying the ethical issues raised by using AI in health care. Concerns include erroneous decisions made by AI and determining who is responsible for such errors, difficulty in validating the outputs of AI systems, and the potential for AI to be used for malicious purposes.²⁹

For clinicians who are considering implementing AI into their practice, it is vital to recognize where this technology belongs in a workflow and in the decision-making process. Jeffery Axt, a researcher on the clinical applications of AI, encourages clinicians to view using AI as a consulting tool to eliminate the element of fear associated with not having control over diagnostics and management.³⁰

What’s on the horizon

Research into using AI in psychiatry has drawn the attention of large companies. IBM is building an automated speech analysis application that uses machine learning to provide a real-time overview of a patient’s mental health.³¹ Social media platforms are also starting to incorporate AI technologies to scan posts for language and image patterns suggestive of suicidal thoughts or behavior.³²

“Chat bots”—AI that can conduct a conversation in natural language—are becoming popular as well. Woebot is a cognitive-behavioral therapy–based chat bot designed by a Stanford psychologist that can be accessed through Facebook Messenger. In a 2-week study, 70 young adults (age 18 to 28) with depression were randomly assigned to use Woebot or to read mental health e-books.³³ Participants who used Woebot experienced a significant reduction in depressive symptoms as measured by change in score on the Patient Health Questionnaire-9, while those assigned to the reading group did not.³³

Other researchers have focused on identifying patterns of inattention, hyperactivity, and impulsivity in children using AI technologies such as computer vision, machine learning, and data mining. For example, researchers at the University of Texas at Arlington and Yale University are analyzing data from watching children perform certain tasks involving attention, decision making, and emotion management.³⁴ There have been several advances in using AI to note abnormalities in a child’s gaze pattern that might suggest autism.³⁵

Continue to: A project at...

A project at the University of Southern California called SimSensei/Multisense uses software to track real-time behavior descriptors such as facial expressions, body postures, and acoustic features that can help identify psychological distress.³⁶ This software is combined with a virtual human platform that communicates with the patient as a therapist would.³⁶

The future of AI in health care appears to have great possibilities. Putting aside irrational fears of being replaced by computers one day, AI may someday be highly transformative, leading to vast improvements in patient care.

Bottom Line

Artificial intelligence (AI) —the development of computer systems able to perform tasks that normally require human intelligence—is being developed for use in a wide range of medical specialties. Potential uses in psychiatry include predicting a patient’s risk for suicide or psychosis. Privacy concerns, ethical issues, and the potential for medical errors are among the challenges of AI use in psychiatry.

Related Resources

• Durstewitz D, Koppe G, Meyer-Lindenberg A. Deep neural networks in psychiatry. Mol Psychiatry. 2019. doi:10.1038/s41380-019-0365-9.
• Kretzschmar K, Tyroll H, Pavarini G, et al; NeurOx Young People’s Advisory Group. Can your phone be your therapist? Young people’s ethical perspectives on the use of fully automated conversational agents (chatbots) in mental health support. Biomed Inform Insights. 2019;11:1178222619829083. doi: 10.1177/1178222619829083.

For many people, artificial intelligence (AI) brings to mind some form of humanoid robot that speaks and acts like a human. However, AI is much more than merely robotics and machines. Professor John McCarthy of Stanford University, who first coined the term “artificial intelligence” in the early 1950s, defined it as “the science and engineering of making intelligent machines, especially intelligent computer programs”; he defined intelligence as “the computational part of the ability to achieve goals.^”1 Artificial intelligence also is commonly defined as the development of computer systems able to perform tasks that normally require human intelligence.² English Mathematician Alan Turing is considered one of the forefathers of AI research, and devised the first test to determine if a computer program was intelligent (Box 1³). Today, AI has established itself as an integral part of medicine and psychiatry.

Box 1

The semantics of AI

Two subsets of AI are machine learning and deep learning.^4,5 Machine learning is defined as a set of methods that can automatically detect patterns in data and then use the uncovered pattern to predict future data.⁴ Deep learning is a form of machine learning that enables computers to learn from experience and understand the world in terms of a hierarchy of concepts.⁵

Machine learning can be supervised, semi-supervised, or unsupervised. The majority of practical machine learning uses supervised learning, where all data are labeled and an algorithm is used to learn the mapping function from the input to the output. In unsupervised learning, all data are unlabeled and the algorithm models the underlying structure of the data by itself. Semi-supervised learning is a mixture of both.⁶

Many researchers also categorize AI into 2 types: general or “strong” AI, and narrow or “weak” AI. Strong AI is defined as computers that can think on a level at least equal to humans and are able to experience emotions and even consciousness.⁷ Weak AI includes adding “thinking-like” features to computers to make them more useful tools. Almost all AI technologies available today are considered to be weak AI.

AI in medicine

AI is being developed for a broad range of applications in medicine. This includes informatics approaches, including learning in health management systems such as electronic health records, and actively guiding physicians in their treatment decisions.⁸

AI has been applied to assist administrative workflows that reach beyond automated non-patient care activities such as chart documentation and placing orders. One example is the Judy Reitz Capacity Command Center, which was designed and built with GE Healthcare Partners.⁹ It combines AI technology in the form of systems engineering and predictive analytics to better manage multiple workflows in different administrative settings, including patient safety, volume, flow, and access to care.⁹

In April 2018, Intel Corporation surveyed 200 health-care decision makers in the United States regarding their use of AI in practice and their attitudes toward it.¹⁰ Overall, 37% of respondents reported using AI and 54% expected to increase their use of AI in the next 5 years. Clinical use of AI (77%) was more common than administrative use (41%) or financial use (26 %).¹⁰

Continue to: Box 2

Box 2^11-19 describes studies that evaluated the clinical use of AI in specialties other than psychiatry.

Box 2

How can AI be used in psychiatry?

Artificially intelligent technologies have been used in psychiatry for several decades. One of the earliest examples is ELIZA, a computer program published by Professor Joseph Weizenbaum of the Massachusetts Institute of Technology in 1966.²⁰ ELIZA consisted of a language analyzer and a script or a set of rules to improvise around a certain theme; the script DOCTOR was used to simulate a Rogerian psychotherapist.²⁰

The application of AI in psychiatry has come a long way since the pioneering work of Weizenbaum. A recent study examined AI’s ability to distinguish between an individual who had suicidal ideation vs a control group. Machine-learning algorithms were used to evaluate functional MRI scans of 34 participants (17 who had suicidal ideation and 17 controls) to identify certain neural signatures of concepts related to life and death.²¹ The machine-learning algorithms were able to distinguish between these 2 groups with 91% accuracy. They also were able to distinguish between individuals who attempted suicide and those who did not with 94% accuracy.²¹

A study from the University of Cincinnati looked at using machine learning and natural language processing to distinguish genuine suicide notes from “fake” suicide notes that had been written by a healthy control group.²² Sixty-six notes were evaluated and categorized by 11 mental health professionals (psychiatrists, social workers, and emergency medicine physicians) and 31 PGY-3 residents. The accuracy of their results was compared with that of 9 machine-learning algorithms.²² The best machine-learning algorithm accurately classified the notes 78% of the time, compared with 63% of the time for the mental health professionals and 49% of the time for the residents.²²

Researchers at Vanderbilt University examined using machine learning to predict suicide risk.²³ They developed algorithms to scan electronic health records of 5,167 adults, 3,250 of whom had attempted suicide. In a review of the patients’ data from 1 week to 2 years before the attempt, the algorithms looked for certain predictors of suicide attempts, including recurrent depression, psychotic disorder, and substance use. The algorithm was 80% accurate at predicting whether a patient would attempt suicide within the next 2 years, and 84% accurate at predicting an attempt within the next week.²³

Continue to: In a prospective study...

In a prospective study, researchers at Cincinnati Children’s Hospital used a machine-learning algorithm to evaluate 379 patients who were categorized into 3 groups: suicidal, mentally ill but not suicidal, or controls.²⁴ All participants completed a standardized behavioral rating scale and participated in a semi-structured interview. Based on the participants’ linguistic and acoustic characteristics, the algorithm was able to classify them into the 3 groups with 85% accuracy.²⁴

Many studies have looked at using language analysis to predicting the risk of psychosis in at-risk individuals. In one study, researchers evaluated individuals known to be at high risk for developing psychosis, some of whom eventually did develop psychosis.²⁵ Participants were asked to retell a story and to answer questions about that story. Researchers fed the transcripts of these interviews into a language analysis program that looked at semantic coherence, syntactic complexity, and other factors. The algorithm was able to predict the future occurrence of psychosis with 82% accuracy. Participants who converted to psychosis had decreased semantic coherence and reduced syntactic complexity.²⁵

A similar study looked at 34 at-risk youth in an attempt to predict who would develop psychosis based on speech pattern analysis.²⁶ The participants underwent baseline interviews and were assessed quarterly for 2.5 years. The algorithm was able to predict who would develop psychosis with 100% accuracy.²⁶

Challenges and limitations

The amount of research about applying machine learning to various fields of psychiatry continues to grow. With this increased interest, there have been reports of bias and human influence in the various stages of machine learning. Therefore, being aware of these challenges and engaging in practices to minimize their effects are necessary. Such practices include providing more details on data collection and processing, and constantly evaluating machine learning models for their relevance and utility to the research question proposed.²⁷

As is the case with most innovative, fast-growing technologies, AI has its fair share of criticisms and concerns. Critics have focused on the potential threat of privacy issues, medical errors, and ethical concerns. Researchers at the Stanford Center for Biomedical Ethics emphasize the importance of being aware of the different types of bias that humans and algorithm designs can introduce into health data.²⁸

Continue to: The Nuffield Council on Bioethics...

The Nuffield Council on Bioethics also emphasizes the importance of identifying the ethical issues raised by using AI in health care. Concerns include erroneous decisions made by AI and determining who is responsible for such errors, difficulty in validating the outputs of AI systems, and the potential for AI to be used for malicious purposes.²⁹

For clinicians who are considering implementing AI into their practice, it is vital to recognize where this technology belongs in a workflow and in the decision-making process. Jeffery Axt, a researcher on the clinical applications of AI, encourages clinicians to view using AI as a consulting tool to eliminate the element of fear associated with not having control over diagnostics and management.³⁰

What’s on the horizon

Research into using AI in psychiatry has drawn the attention of large companies. IBM is building an automated speech analysis application that uses machine learning to provide a real-time overview of a patient’s mental health.³¹ Social media platforms are also starting to incorporate AI technologies to scan posts for language and image patterns suggestive of suicidal thoughts or behavior.³²

“Chat bots”—AI that can conduct a conversation in natural language—are becoming popular as well. Woebot is a cognitive-behavioral therapy–based chat bot designed by a Stanford psychologist that can be accessed through Facebook Messenger. In a 2-week study, 70 young adults (age 18 to 28) with depression were randomly assigned to use Woebot or to read mental health e-books.³³ Participants who used Woebot experienced a significant reduction in depressive symptoms as measured by change in score on the Patient Health Questionnaire-9, while those assigned to the reading group did not.³³

Other researchers have focused on identifying patterns of inattention, hyperactivity, and impulsivity in children using AI technologies such as computer vision, machine learning, and data mining. For example, researchers at the University of Texas at Arlington and Yale University are analyzing data from watching children perform certain tasks involving attention, decision making, and emotion management.³⁴ There have been several advances in using AI to note abnormalities in a child’s gaze pattern that might suggest autism.³⁵

Continue to: A project at...

A project at the University of Southern California called SimSensei/Multisense uses software to track real-time behavior descriptors such as facial expressions, body postures, and acoustic features that can help identify psychological distress.³⁶ This software is combined with a virtual human platform that communicates with the patient as a therapist would.³⁶

The future of AI in health care appears to have great possibilities. Putting aside irrational fears of being replaced by computers one day, AI may someday be highly transformative, leading to vast improvements in patient care.

Bottom Line

Artificial intelligence (AI) —the development of computer systems able to perform tasks that normally require human intelligence—is being developed for use in a wide range of medical specialties. Potential uses in psychiatry include predicting a patient’s risk for suicide or psychosis. Privacy concerns, ethical issues, and the potential for medical errors are among the challenges of AI use in psychiatry.

Related Resources

• Durstewitz D, Koppe G, Meyer-Lindenberg A. Deep neural networks in psychiatry. Mol Psychiatry. 2019. doi:10.1038/s41380-019-0365-9.
• Kretzschmar K, Tyroll H, Pavarini G, et al; NeurOx Young People’s Advisory Group. Can your phone be your therapist? Young people’s ethical perspectives on the use of fully automated conversational agents (chatbots) in mental health support. Biomed Inform Insights. 2019;11:1178222619829083. doi: 10.1177/1178222619829083.

For many people, artificial intelligence (AI) brings to mind some form of humanoid robot that speaks and acts like a human. However, AI is much more than merely robotics and machines. Professor John McCarthy of Stanford University, who first coined the term “artificial intelligence” in the early 1950s, defined it as “the science and engineering of making intelligent machines, especially intelligent computer programs”; he defined intelligence as “the computational part of the ability to achieve goals.^”1 Artificial intelligence also is commonly defined as the development of computer systems able to perform tasks that normally require human intelligence.² English Mathematician Alan Turing is considered one of the forefathers of AI research, and devised the first test to determine if a computer program was intelligent (Box 1³). Today, AI has established itself as an integral part of medicine and psychiatry.

Box 1

The semantics of AI

Two subsets of AI are machine learning and deep learning.^4,5 Machine learning is defined as a set of methods that can automatically detect patterns in data and then use the uncovered pattern to predict future data.⁴ Deep learning is a form of machine learning that enables computers to learn from experience and understand the world in terms of a hierarchy of concepts.⁵

Machine learning can be supervised, semi-supervised, or unsupervised. The majority of practical machine learning uses supervised learning, where all data are labeled and an algorithm is used to learn the mapping function from the input to the output. In unsupervised learning, all data are unlabeled and the algorithm models the underlying structure of the data by itself. Semi-supervised learning is a mixture of both.⁶

Many researchers also categorize AI into 2 types: general or “strong” AI, and narrow or “weak” AI. Strong AI is defined as computers that can think on a level at least equal to humans and are able to experience emotions and even consciousness.⁷ Weak AI includes adding “thinking-like” features to computers to make them more useful tools. Almost all AI technologies available today are considered to be weak AI.

AI in medicine

AI is being developed for a broad range of applications in medicine. This includes informatics approaches, including learning in health management systems such as electronic health records, and actively guiding physicians in their treatment decisions.⁸

AI has been applied to assist administrative workflows that reach beyond automated non-patient care activities such as chart documentation and placing orders. One example is the Judy Reitz Capacity Command Center, which was designed and built with GE Healthcare Partners.⁹ It combines AI technology in the form of systems engineering and predictive analytics to better manage multiple workflows in different administrative settings, including patient safety, volume, flow, and access to care.⁹

In April 2018, Intel Corporation surveyed 200 health-care decision makers in the United States regarding their use of AI in practice and their attitudes toward it.¹⁰ Overall, 37% of respondents reported using AI and 54% expected to increase their use of AI in the next 5 years. Clinical use of AI (77%) was more common than administrative use (41%) or financial use (26 %).¹⁰

Continue to: Box 2

Box 2^11-19 describes studies that evaluated the clinical use of AI in specialties other than psychiatry.

Box 2

How can AI be used in psychiatry?

Artificially intelligent technologies have been used in psychiatry for several decades. One of the earliest examples is ELIZA, a computer program published by Professor Joseph Weizenbaum of the Massachusetts Institute of Technology in 1966.²⁰ ELIZA consisted of a language analyzer and a script or a set of rules to improvise around a certain theme; the script DOCTOR was used to simulate a Rogerian psychotherapist.²⁰

The application of AI in psychiatry has come a long way since the pioneering work of Weizenbaum. A recent study examined AI’s ability to distinguish between an individual who had suicidal ideation vs a control group. Machine-learning algorithms were used to evaluate functional MRI scans of 34 participants (17 who had suicidal ideation and 17 controls) to identify certain neural signatures of concepts related to life and death.²¹ The machine-learning algorithms were able to distinguish between these 2 groups with 91% accuracy. They also were able to distinguish between individuals who attempted suicide and those who did not with 94% accuracy.²¹

A study from the University of Cincinnati looked at using machine learning and natural language processing to distinguish genuine suicide notes from “fake” suicide notes that had been written by a healthy control group.²² Sixty-six notes were evaluated and categorized by 11 mental health professionals (psychiatrists, social workers, and emergency medicine physicians) and 31 PGY-3 residents. The accuracy of their results was compared with that of 9 machine-learning algorithms.²² The best machine-learning algorithm accurately classified the notes 78% of the time, compared with 63% of the time for the mental health professionals and 49% of the time for the residents.²²

Researchers at Vanderbilt University examined using machine learning to predict suicide risk.²³ They developed algorithms to scan electronic health records of 5,167 adults, 3,250 of whom had attempted suicide. In a review of the patients’ data from 1 week to 2 years before the attempt, the algorithms looked for certain predictors of suicide attempts, including recurrent depression, psychotic disorder, and substance use. The algorithm was 80% accurate at predicting whether a patient would attempt suicide within the next 2 years, and 84% accurate at predicting an attempt within the next week.²³

Continue to: In a prospective study...

In a prospective study, researchers at Cincinnati Children’s Hospital used a machine-learning algorithm to evaluate 379 patients who were categorized into 3 groups: suicidal, mentally ill but not suicidal, or controls.²⁴ All participants completed a standardized behavioral rating scale and participated in a semi-structured interview. Based on the participants’ linguistic and acoustic characteristics, the algorithm was able to classify them into the 3 groups with 85% accuracy.²⁴

Many studies have looked at using language analysis to predicting the risk of psychosis in at-risk individuals. In one study, researchers evaluated individuals known to be at high risk for developing psychosis, some of whom eventually did develop psychosis.²⁵ Participants were asked to retell a story and to answer questions about that story. Researchers fed the transcripts of these interviews into a language analysis program that looked at semantic coherence, syntactic complexity, and other factors. The algorithm was able to predict the future occurrence of psychosis with 82% accuracy. Participants who converted to psychosis had decreased semantic coherence and reduced syntactic complexity.²⁵

A similar study looked at 34 at-risk youth in an attempt to predict who would develop psychosis based on speech pattern analysis.²⁶ The participants underwent baseline interviews and were assessed quarterly for 2.5 years. The algorithm was able to predict who would develop psychosis with 100% accuracy.²⁶

Challenges and limitations

The amount of research about applying machine learning to various fields of psychiatry continues to grow. With this increased interest, there have been reports of bias and human influence in the various stages of machine learning. Therefore, being aware of these challenges and engaging in practices to minimize their effects are necessary. Such practices include providing more details on data collection and processing, and constantly evaluating machine learning models for their relevance and utility to the research question proposed.²⁷

As is the case with most innovative, fast-growing technologies, AI has its fair share of criticisms and concerns. Critics have focused on the potential threat of privacy issues, medical errors, and ethical concerns. Researchers at the Stanford Center for Biomedical Ethics emphasize the importance of being aware of the different types of bias that humans and algorithm designs can introduce into health data.²⁸

Continue to: The Nuffield Council on Bioethics...

The Nuffield Council on Bioethics also emphasizes the importance of identifying the ethical issues raised by using AI in health care. Concerns include erroneous decisions made by AI and determining who is responsible for such errors, difficulty in validating the outputs of AI systems, and the potential for AI to be used for malicious purposes.²⁹

For clinicians who are considering implementing AI into their practice, it is vital to recognize where this technology belongs in a workflow and in the decision-making process. Jeffery Axt, a researcher on the clinical applications of AI, encourages clinicians to view using AI as a consulting tool to eliminate the element of fear associated with not having control over diagnostics and management.³⁰

What’s on the horizon

Research into using AI in psychiatry has drawn the attention of large companies. IBM is building an automated speech analysis application that uses machine learning to provide a real-time overview of a patient’s mental health.³¹ Social media platforms are also starting to incorporate AI technologies to scan posts for language and image patterns suggestive of suicidal thoughts or behavior.³²

“Chat bots”—AI that can conduct a conversation in natural language—are becoming popular as well. Woebot is a cognitive-behavioral therapy–based chat bot designed by a Stanford psychologist that can be accessed through Facebook Messenger. In a 2-week study, 70 young adults (age 18 to 28) with depression were randomly assigned to use Woebot or to read mental health e-books.³³ Participants who used Woebot experienced a significant reduction in depressive symptoms as measured by change in score on the Patient Health Questionnaire-9, while those assigned to the reading group did not.³³

Other researchers have focused on identifying patterns of inattention, hyperactivity, and impulsivity in children using AI technologies such as computer vision, machine learning, and data mining. For example, researchers at the University of Texas at Arlington and Yale University are analyzing data from watching children perform certain tasks involving attention, decision making, and emotion management.³⁴ There have been several advances in using AI to note abnormalities in a child’s gaze pattern that might suggest autism.³⁵

Continue to: A project at...

A project at the University of Southern California called SimSensei/Multisense uses software to track real-time behavior descriptors such as facial expressions, body postures, and acoustic features that can help identify psychological distress.³⁶ This software is combined with a virtual human platform that communicates with the patient as a therapist would.³⁶

The future of AI in health care appears to have great possibilities. Putting aside irrational fears of being replaced by computers one day, AI may someday be highly transformative, leading to vast improvements in patient care.

Bottom Line

Artificial intelligence (AI) —the development of computer systems able to perform tasks that normally require human intelligence—is being developed for use in a wide range of medical specialties. Potential uses in psychiatry include predicting a patient’s risk for suicide or psychosis. Privacy concerns, ethical issues, and the potential for medical errors are among the challenges of AI use in psychiatry.

Related Resources

• Durstewitz D, Koppe G, Meyer-Lindenberg A. Deep neural networks in psychiatry. Mol Psychiatry. 2019. doi:10.1038/s41380-019-0365-9.
• Kretzschmar K, Tyroll H, Pavarini G, et al; NeurOx Young People’s Advisory Group. Can your phone be your therapist? Young people’s ethical perspectives on the use of fully automated conversational agents (chatbots) in mental health support. Biomed Inform Insights. 2019;11:1178222619829083. doi: 10.1177/1178222619829083.

“A leader is someone who helps improve the lives of other people or improve the system they live under.”

— Sam Houston

If my motivation to become a doctor was ever the supposed glamour and prestige conferred once “MD” is added to your name, that delusion was quickly wiped away on my first day of residency; not at work, but on my way there.

I live in New York City—a city that relies on buses and subways, where the wealthy and elite go to work using the same modes of transportation as everyone else. Unfortunately, because the shelter system in New York isn’t nearly large enough to accommodate the vast homeless population, many homeless people sleep in the subway at night. It’s not uncommon to see a still-sleeping homeless person on the subway in the early hours of the morning, and I encountered one on my first official day of work as a doctor.

There I was, dressed for the occasion in a new, freshly ironed white button-down shirt and black slacks. There he was, haggard, disheveled, and smelling of alcohol, lying on a subway bench with an empty bottle of vodka tucked into his pants pocket. Out of both pity and fear of what he might do if someone attempted to wake him, people allowed him to sleep, and politely stood around him as the train proceeded on its route. The homeless man had his legs tucked in the fetal position, and I saw there was enough space on the bench for someone to sit. I wondered why nobody else chose to use that space by his feet, and I saw no harm in sitting there, so I did.

Within seconds of sitting down, the man extended one of his legs and kicked me in the chest while still asleep. Not hard enough to cause pain or injury, but enough to leave a dirty boot print on my shirt. I had to wear that shirt for the rest of the day, and so I spent my first day of residency explaining to hospital staff and patients alike how I was branded by a drunk homeless man on the subway as he slept.

As time wore on in my first year of residency, I learned that encounters with individuals like these were not rare. The majority of the patients I see are people like that man on the subway. “I sleep on the subway” is often the answer when I ask a patient about their living conditions. “I’m on public assistance” is what I hear when questioning what a patient does for money. “I don’t have money to take the bus” is a typical explanation for why they missed their doctor’s appointments and ran out of medicine. And, sadly, “Because I’m lonely” is the main excuse for why patients engage in self-defeating habits such as drug and alcohol abuse.

I didn’t anticipate this part of psychiatry when I applied for residency in this specialty. My notion of this profession was far more romanticized. I was enthralled with the science of neurotransmitters, the parameters of DSM criteria, the interpersonal skills required to elicit information from a patient during an interview, the deliberation in arriving at a diagnosis, and the ever-changing nature of psychopharmacology. That’s the psychiatry I expected to learn when I got on the subway for my first day of residency. It wasn’t until later that I truly considered the human toll that psychiatric illness takes on the individual who suffers from it. To that person, the science behind their illness and the suffering they endure isn’t romantic at all; it’s a burden to be lifted.

Continue to: We use the term...

We use the term “underserved” to identify challenging patient populations, but there are categories of patients that fall below the threshold of merely underserved. I am mortified to know that one-third of homeless people in the United States have a serious and untreated mental illness. Individuals discharged from psychiatric hospitals are 3 times more likely to obtain food from garbage. They are also far more likely to be the victim of a crime than perpetrators of it. As I’ve discovered since starting residency, if a patient doesn’t have a place to live, food to eat, and some semblance of a support system, then it’s often meaningless for them to take pills, regardless of how those pills work in theory.

No definition of sound mental health is complete unless it gives deference to those who lack basic human needs. This is a realization that was literally kicked into me, and one I hope will guide me in the years ahead.

“A leader is someone who helps improve the lives of other people or improve the system they live under.”

— Sam Houston

If my motivation to become a doctor was ever the supposed glamour and prestige conferred once “MD” is added to your name, that delusion was quickly wiped away on my first day of residency; not at work, but on my way there.

I live in New York City—a city that relies on buses and subways, where the wealthy and elite go to work using the same modes of transportation as everyone else. Unfortunately, because the shelter system in New York isn’t nearly large enough to accommodate the vast homeless population, many homeless people sleep in the subway at night. It’s not uncommon to see a still-sleeping homeless person on the subway in the early hours of the morning, and I encountered one on my first official day of work as a doctor.

There I was, dressed for the occasion in a new, freshly ironed white button-down shirt and black slacks. There he was, haggard, disheveled, and smelling of alcohol, lying on a subway bench with an empty bottle of vodka tucked into his pants pocket. Out of both pity and fear of what he might do if someone attempted to wake him, people allowed him to sleep, and politely stood around him as the train proceeded on its route. The homeless man had his legs tucked in the fetal position, and I saw there was enough space on the bench for someone to sit. I wondered why nobody else chose to use that space by his feet, and I saw no harm in sitting there, so I did.

Within seconds of sitting down, the man extended one of his legs and kicked me in the chest while still asleep. Not hard enough to cause pain or injury, but enough to leave a dirty boot print on my shirt. I had to wear that shirt for the rest of the day, and so I spent my first day of residency explaining to hospital staff and patients alike how I was branded by a drunk homeless man on the subway as he slept.

As time wore on in my first year of residency, I learned that encounters with individuals like these were not rare. The majority of the patients I see are people like that man on the subway. “I sleep on the subway” is often the answer when I ask a patient about their living conditions. “I’m on public assistance” is what I hear when questioning what a patient does for money. “I don’t have money to take the bus” is a typical explanation for why they missed their doctor’s appointments and ran out of medicine. And, sadly, “Because I’m lonely” is the main excuse for why patients engage in self-defeating habits such as drug and alcohol abuse.

I didn’t anticipate this part of psychiatry when I applied for residency in this specialty. My notion of this profession was far more romanticized. I was enthralled with the science of neurotransmitters, the parameters of DSM criteria, the interpersonal skills required to elicit information from a patient during an interview, the deliberation in arriving at a diagnosis, and the ever-changing nature of psychopharmacology. That’s the psychiatry I expected to learn when I got on the subway for my first day of residency. It wasn’t until later that I truly considered the human toll that psychiatric illness takes on the individual who suffers from it. To that person, the science behind their illness and the suffering they endure isn’t romantic at all; it’s a burden to be lifted.

Continue to: We use the term...

We use the term “underserved” to identify challenging patient populations, but there are categories of patients that fall below the threshold of merely underserved. I am mortified to know that one-third of homeless people in the United States have a serious and untreated mental illness. Individuals discharged from psychiatric hospitals are 3 times more likely to obtain food from garbage. They are also far more likely to be the victim of a crime than perpetrators of it. As I’ve discovered since starting residency, if a patient doesn’t have a place to live, food to eat, and some semblance of a support system, then it’s often meaningless for them to take pills, regardless of how those pills work in theory.

No definition of sound mental health is complete unless it gives deference to those who lack basic human needs. This is a realization that was literally kicked into me, and one I hope will guide me in the years ahead.

“A leader is someone who helps improve the lives of other people or improve the system they live under.”

— Sam Houston

If my motivation to become a doctor was ever the supposed glamour and prestige conferred once “MD” is added to your name, that delusion was quickly wiped away on my first day of residency; not at work, but on my way there.

I live in New York City—a city that relies on buses and subways, where the wealthy and elite go to work using the same modes of transportation as everyone else. Unfortunately, because the shelter system in New York isn’t nearly large enough to accommodate the vast homeless population, many homeless people sleep in the subway at night. It’s not uncommon to see a still-sleeping homeless person on the subway in the early hours of the morning, and I encountered one on my first official day of work as a doctor.

There I was, dressed for the occasion in a new, freshly ironed white button-down shirt and black slacks. There he was, haggard, disheveled, and smelling of alcohol, lying on a subway bench with an empty bottle of vodka tucked into his pants pocket. Out of both pity and fear of what he might do if someone attempted to wake him, people allowed him to sleep, and politely stood around him as the train proceeded on its route. The homeless man had his legs tucked in the fetal position, and I saw there was enough space on the bench for someone to sit. I wondered why nobody else chose to use that space by his feet, and I saw no harm in sitting there, so I did.

Within seconds of sitting down, the man extended one of his legs and kicked me in the chest while still asleep. Not hard enough to cause pain or injury, but enough to leave a dirty boot print on my shirt. I had to wear that shirt for the rest of the day, and so I spent my first day of residency explaining to hospital staff and patients alike how I was branded by a drunk homeless man on the subway as he slept.

As time wore on in my first year of residency, I learned that encounters with individuals like these were not rare. The majority of the patients I see are people like that man on the subway. “I sleep on the subway” is often the answer when I ask a patient about their living conditions. “I’m on public assistance” is what I hear when questioning what a patient does for money. “I don’t have money to take the bus” is a typical explanation for why they missed their doctor’s appointments and ran out of medicine. And, sadly, “Because I’m lonely” is the main excuse for why patients engage in self-defeating habits such as drug and alcohol abuse.

I didn’t anticipate this part of psychiatry when I applied for residency in this specialty. My notion of this profession was far more romanticized. I was enthralled with the science of neurotransmitters, the parameters of DSM criteria, the interpersonal skills required to elicit information from a patient during an interview, the deliberation in arriving at a diagnosis, and the ever-changing nature of psychopharmacology. That’s the psychiatry I expected to learn when I got on the subway for my first day of residency. It wasn’t until later that I truly considered the human toll that psychiatric illness takes on the individual who suffers from it. To that person, the science behind their illness and the suffering they endure isn’t romantic at all; it’s a burden to be lifted.

Continue to: We use the term...

We use the term “underserved” to identify challenging patient populations, but there are categories of patients that fall below the threshold of merely underserved. I am mortified to know that one-third of homeless people in the United States have a serious and untreated mental illness. Individuals discharged from psychiatric hospitals are 3 times more likely to obtain food from garbage. They are also far more likely to be the victim of a crime than perpetrators of it. As I’ve discovered since starting residency, if a patient doesn’t have a place to live, food to eat, and some semblance of a support system, then it’s often meaningless for them to take pills, regardless of how those pills work in theory.

No definition of sound mental health is complete unless it gives deference to those who lack basic human needs. This is a realization that was literally kicked into me, and one I hope will guide me in the years ahead.

CASE Violent, then catatonic

Mr. T, age 52, has a long history of schizo­affective disorder, depressed type; several suicide attempts; and violent episodes. He is admitted to a mental health rehabilitation center under a forensic commitment.

Several years earlier, Mr. T had been charged with first-degree attempted murder, assault with a deadly weapon, and abuse of a dependent/geriatric adult after allegedly stabbing his mother in the upper chest and neck. At that time, Mr. T was not in psychiatric treatment and was drinking heavily. He had become obsessed with John F. Kennedy’s assassination and believed the Central Intelligence Agency (CIA), not Lee Harvey Oswald, was responsible. He feared the CIA wanted to kill him because of his knowledge, and he heard voices from his television he believed were threatening him. He acquired knives for self-protection. When his mother arrived at his apartment to take him to a psychiatric appointment, he believed she was conspiring with the CIA and attacked her. Mr. T’s mother survived her injuries. He was taken to the county jail, where psychiatric staff noted that Mr. T was psychotic.

The court found Mr. T incompetent to stand trial and sent him to a state hospital for psychiatric treatment and competency restoration. After 3 years, he was declared unable to be restored because of repeated decompensations, placed on a conservatorship, and sent back to county jail.

In the jail, Mr. T began to show signs of catatonia. He refused medications, food, and water, and became mute. He was admitted to a medical center after a 45-minute episode that appeared similar to a seizure; however, all laboratory evaluations were within normal limits, head CT was negative, and an EEG was unremarkable.

Mr. T’s catatonic state gradually resolved with increasing dosages of lorazepam, as well as clozapine. He showed improved mobility and oral intake. A month later, his train of thought was rambling and difficult to follow, circumstantial, and perseverating. However, at times he could be directed and respond to questions in a linear and logical fashion. Lorazepam was tapered, discontinued, and replaced with gabapentin because Mr. T viewed taking lorazepam as a threat to his sobriety.

Recently, Mr. T was transferred to our mental health rehabilitation center, where he expresses that he is grateful to be in a therapeutic environment. Upon admission, his medication regimen consists of clozapine, 300 mg by mouth at bedtime, duloxetine, 60 mg/d by mouth, gabapentin 600 mg by mouth 3 times a day, and docusate sodium, 250 mg/d by mouth. Our team has a discussion about the growing recognition of the pro-inflammatory state present in many patients who experience serious mental illness and the importance of augmenting standard evidence-based psychopharmacotherapy with agents that have neuroprotective properties.^1,2 We offer Mr. T minocycline, 100 mg by mouth twice daily, a potent anti-inflammatory agent that has been shown to improve symptoms of schizophrenia.² Mr. T is reluctant to take minocycline, saying he is happy with his current medication regimen.

[polldaddy:10375843]

The authors’ observations

Several studies have found that acute psychosis is associated with an inflammatory state, and interleukin-6 (IL-6) is a crucial biomarker. A recent meta-analysis of serum cytokines in patients with schizophrenia found that IL-6 levels were significantly increased among acutely ill patients compared with controls.³ IL-6 levels significantly decreased after treating acute episodes of schizophrenia.³ Further, levels of peripheral IL-6 mRNA levels in individuals with schizophrenia are directly correlated with severity of positive symptoms.⁴

Continue to: A meta-analyis reported...

A meta-analysis reported that tumor necrosis factor-alpha and IL-6 are elevated during acute psychosis³; however, IL-6 normalized with treatment, whereas tumor necrosis factor-alpha did not. This means that IL-6 is a more clinically meaningful biomarker to help gauge treatment response.

EVALUATION Elevated markers of inflammation

Laboratory testing reveals that Mr. T’s IL-6 level is 56.64 pg/mL, which is significantly elevated (reference range: 0.31 to 5.00 pg/mL). After reviewing the IL-6 results with Mr. T and explaining that there is “too much inflammation” in his brain, he agrees to take minocycline and complete follow-up IL-6 level tests to monitor his progress during treatment.

HISTORY Alcohol abuse, treatment resistance

According to Mr. T’s mother, he had met all developmental milestones and graduated from high school with plans to enter culinary school. At age 20, Mr. T began to experience psychotic symptoms, telling family members that he was being followed by FBI agents and was receiving messages from televisions. He began drinking heavily and was arrested twice for driving under the influence. In his mid-20s, he attempted suicide by overdose after his father died. Mr. T required inpatient hospitalization nearly every year thereafter. His mother, a registered nurse, was significantly involved in his care and carefully documented his treatment history.

Mr. T has had numerous medication trials, including oral and long-acting injectable risperidone, olanzapine, aripiprazole, ziprasidone, lithium, gabapentin, buspirone, quetiapine, trazodone, bupropion, and paroxetine. None of these medications were effective.

In his mid-40s, Mr. T attempted suicide by wandering into traffic and being struck by a motor vehicle. A year later, he attempted suicide by driving his car at high speed into a concrete highway median. Mr. T told first responders that he was “possessed,” and a demonic entity “forced” him to crash his car. He begged law enforcement officers at the scene to give him a gun so he could shoot himself.

Continue to: Mr. T entered an intensive outpatient treatment program...

Mr. T entered an intensive outpatient treatment program and was switched from long-acting injectable risperidone to oral aripiprazole. After taking aripiprazole for several weeks, he began to gamble compulsively at a nearby casino. Frustrated by the lack of response to psychotropic medications and his idiosyncratic response to aripiprazole, he stopped psychiatric treatment, relapsed to alcohol use, and isolated himself in his apartment shortly before stabbing his mother.

EVALUATION Pharmacogenomics testing

At the mental health rehabilitation center, Mr. T agrees to undergo pharmacogenomics testing, which suggests that he will have a normal response to selective serotonin reuptake inhibitors and is unlikely to experience adverse reactions. He does not carry the 2 alleles that place him at higher risk of serious dermatologic reactions when taking certain mood stabilizers. He is heterozygous for the C677T allele polymorphism in the MTHFR gene that is associated with reduced folic acid metabolism, moderately decreased serum folate levels, and moderately increased homocysteine levels. On the pharmacokinetic genes tested, Mr. T has the normal metabolism genotype on 5 of 6 cytochrome P450 (CYP) enzymes; he has the ultrarapid metabolizer genotype on CYP1A2. He also has normal activity and intermediate metabolizer phenotype on the 2 UGT enzymes tested, which are responsible for the glucuronidation process, a major part of phase II metabolism.

Based on these results, Mr. T’s clozapine dosage is decreased by 50% (from 300 to 150 mg/d) and he is started on fluvoxamine, 50 mg/d, because it is a strong inhibitor of CYP1A2. The reduced conversion of clozapine to norclozapine results in an average serum clozapine level of 527 ng/mL (a level of 350 ng/mL is usually therapeutic in patients with schizophrenia) and norclozapine level of 140 ng/mL (clozapine:norclozapine ratio = 3.8), which is to be expected because fluvoxamine can increase serum clozapine levels.

Due to accumulating evidence in the literature suggesting that latent infections in the CNS play a role in serious mental illnesses such as schizophrenia, Mr. T undergoes further laboratory testing.

[polldaddy:10375845]

The authors’ observations

Mr. T tested positive for TG and CMV and negative for HSV-1. We were aware of accumulating evidence that latent infections in the CNS play a role in serious mental illnesses such as schizophrenia, specifically TG⁵—a parasite transmitted by cats—and CMV and HSV-1,⁶ which are transmitted by humans. The theory that TG infection could be a factor in schizophrenia emerged in the 1990s but only in recent years received mainstream scientific attention. Toxoplasma gondii, the infectious parasite that causes toxoplasmosis, infects more than 30 million people in the United States; however, most individuals are asymptomatic because of the body’s immune response to the parasite.⁷

Continue to: A study of 162 individuals...

A study of 162 individuals with schizophrenia, bipolar disorder, or major depressive disorder found that this immunologic profile is associated with suicide attempts,⁸ which is consistent with Mr. T’s history. Research suggests that individuals with schizophrenia who have latent TG infection have a more severe form of the illness compared with patients without the infection.^9-12 Many of these factors were present in Mr. T’s case (Table 1^8-12).

TREATMENT Improvement, then setback

Mr. T’s medication regimen at the rehabilitation center includes clozapine, 100 mg/d; minocycline, 200 mg/d; fluvoxamine, 200 mg/d; and N-acetylcysteine, 1,200 mg/d. N-acetylcysteine is an antioxidant that could ease negative symptoms of schizophrenia by reducing oxidative stress caused by free radicals.¹³ Mr. T makes slow but steady improvement, and his IL-6 levels drop steadily (Figure 1).

After 6 months in the rehabilitation center, Mr. T no longer experiences catatonic symptoms and is able to participate in the therapeutic program. He is permitted to leave the facility on day passes with family members. However, approximately every 8 weeks, he continues to cycle through periods of intense anxiety, perseverates on topics, and exhibits fragmented thinking and speech. During these episodes, he has difficulty receiving and processing information.

During one of these periods, Mr. T eats 4 oleander leaves he gathered while on day pass outside of the facility. After he experiences stomach pain, nausea, and vomiting, he informs nursing staff that he ate oleander. He is brought to the emergency department, receives activated charcoal and a digoxin antidote, and is placed on continuous electrocardiogram monitoring. When asked why he made the suicide attempt, he said “I realized things will never be the same because of what happened. I felt trapped.” He later expresses regret and wants to return to the mental health rehabilitation center.

At the facility, Mr. T agrees to take 2 more agents—valproic acid and ginger root extract—that specifically target latent toxoplasmosis infection before pursuing electroconvulsive therapy. We offer valproic acid because it inhibits replication of TG in an in vitro model.¹⁴ Mr. T is started on extended-release valproic acid, 1,500 mg/d, which results in a therapeutic serum level of 74.8 µg/mL.

Continue to: Additionally, Mr. T expresses interest...

Additionally, Mr. T expresses interest in taking “natural” agents in addition to psychotropics. After reviewing the quality of available ginger root extract products, Mr. T is started on a supplement that contains 22.4 mg of gingerols and 6.7 mg of shogaols, titrated to 4 capsules twice daily.

The authors’ observations

A retrospective cross-sectional analysis reported that patients with bipolar disorder who received medications with anti-toxoplasmic activity (Table 2¹⁵), specifically valproic acid, had significantly fewer lifetime depressive episodes compared with patients who received medications without anti-toxoplasmic activity.¹⁵

Alternative medicine options

Research has demonstrated the beneficial effects of Chinese herbal plants for toxoplasmosis^16,17 and ginger root extract has potent anti-toxoplasmic activity. A mouse model found that ginger root extract (Zingiber officinale) reduced the number of TG-infected cells by suppressing activation of apoptotic proteins the parasite induces, which prevents programmed cell death.¹⁸

Table 3 presents a stepwise approach to identifying and treating inflammation in patients with treatment-resistant psychosis.

OUTCOME Immune response, improvement

One month after the valproic acid and ginger root extract therapy is initiated, Mr. T’s toxoplasma antibody immunoglobulin G increases by 15.2 IU/mL, indicating that his immune system is mounting an enhanced response against the parasite (Figure 2). Mr. T continues to make progress while receiving the new regimen of clozapine, minocycline, valproic acid, and ginger root extract. He no longer cycles into periods of intense anxiety, perseverative thought, and fragmented thought and speech. He participates meaningfully in weekly psychotherapy and hopes to live independently and obtain gainful employment.

The District Attorney’s office dismisses his criminal charges, and Mr. T is discharged to a less restrictive level of care.

Continue to: Bottom Line

Several studies have shown that neuroinflammation increases the severity of mental illness. Consider adjunct anti-inflammatory agents for patients who have elevated levels of inflammatory biomarkers and for whom standard treatment approaches do not adequately control psychiatric symptoms. Also consider testing for the presence of latent infections in the CNS, which could reveal the underlying cause of treatment resistance or the genesis of disabling psychiatric symptoms.

Related Resources

• Fond G, Macgregor A, Tamouza R, et al. Comparative analysis of anti-toxoplasmic activity of antipsychotic drugs and valproate. Eur Arch Psychiatry Clin Neurosci. 2014;264(2):179-183.
• Hamdani N, Daban-Huard C, Lajnef M, et al. Cognitive deterioration among bipolar disorder patients infected by Toxoplasma gondii is correlated to interleukin 6 levels. J Affect Disord. 2015;179:161-166.
• Monroe JM, Buckley PF, Miller BJ. Meta-analysis of antitoxoplasma gondii IgM antibodies in acute psychosis. Schizophr Bull. 2015;41(4):989-998.

Drug Brand Names

Acyclovir • Zovirax
Aripiprazole • Abilify
Bupropion • Wellbutrin
Buspirone • Buspar
Clozapine • Clozaril
Duloxetine • Cymbalta
Fluphenazine • Prolixin
Fluvoxamine • Luvox
Gabapentin • Neurontin
Haloperidol • Haldol
Lithium • Eskalith, Lithobid
Lorazepam • Ativan
Loxapine • Loxitane
Minocycline • Minocin
Olanzapine • Zyprexa
Paliperidone • Invega
Paroxetine • Paxil
Quetiapine • Seroquel
Risperidone • Risperdal, Risperdal Consta
Thioridazine • Mellaril
Trifluoperazine • Stelazine
Trazodone • Desyrel
Valproic acid • Depakote
Ziprasidone • Geodon

CASE Violent, then catatonic

Mr. T, age 52, has a long history of schizo­affective disorder, depressed type; several suicide attempts; and violent episodes. He is admitted to a mental health rehabilitation center under a forensic commitment.

Several years earlier, Mr. T had been charged with first-degree attempted murder, assault with a deadly weapon, and abuse of a dependent/geriatric adult after allegedly stabbing his mother in the upper chest and neck. At that time, Mr. T was not in psychiatric treatment and was drinking heavily. He had become obsessed with John F. Kennedy’s assassination and believed the Central Intelligence Agency (CIA), not Lee Harvey Oswald, was responsible. He feared the CIA wanted to kill him because of his knowledge, and he heard voices from his television he believed were threatening him. He acquired knives for self-protection. When his mother arrived at his apartment to take him to a psychiatric appointment, he believed she was conspiring with the CIA and attacked her. Mr. T’s mother survived her injuries. He was taken to the county jail, where psychiatric staff noted that Mr. T was psychotic.

The court found Mr. T incompetent to stand trial and sent him to a state hospital for psychiatric treatment and competency restoration. After 3 years, he was declared unable to be restored because of repeated decompensations, placed on a conservatorship, and sent back to county jail.

In the jail, Mr. T began to show signs of catatonia. He refused medications, food, and water, and became mute. He was admitted to a medical center after a 45-minute episode that appeared similar to a seizure; however, all laboratory evaluations were within normal limits, head CT was negative, and an EEG was unremarkable.

Mr. T’s catatonic state gradually resolved with increasing dosages of lorazepam, as well as clozapine. He showed improved mobility and oral intake. A month later, his train of thought was rambling and difficult to follow, circumstantial, and perseverating. However, at times he could be directed and respond to questions in a linear and logical fashion. Lorazepam was tapered, discontinued, and replaced with gabapentin because Mr. T viewed taking lorazepam as a threat to his sobriety.

Recently, Mr. T was transferred to our mental health rehabilitation center, where he expresses that he is grateful to be in a therapeutic environment. Upon admission, his medication regimen consists of clozapine, 300 mg by mouth at bedtime, duloxetine, 60 mg/d by mouth, gabapentin 600 mg by mouth 3 times a day, and docusate sodium, 250 mg/d by mouth. Our team has a discussion about the growing recognition of the pro-inflammatory state present in many patients who experience serious mental illness and the importance of augmenting standard evidence-based psychopharmacotherapy with agents that have neuroprotective properties.^1,2 We offer Mr. T minocycline, 100 mg by mouth twice daily, a potent anti-inflammatory agent that has been shown to improve symptoms of schizophrenia.² Mr. T is reluctant to take minocycline, saying he is happy with his current medication regimen.

[polldaddy:10375843]

The authors’ observations

Several studies have found that acute psychosis is associated with an inflammatory state, and interleukin-6 (IL-6) is a crucial biomarker. A recent meta-analysis of serum cytokines in patients with schizophrenia found that IL-6 levels were significantly increased among acutely ill patients compared with controls.³ IL-6 levels significantly decreased after treating acute episodes of schizophrenia.³ Further, levels of peripheral IL-6 mRNA levels in individuals with schizophrenia are directly correlated with severity of positive symptoms.⁴

Continue to: A meta-analyis reported...

A meta-analysis reported that tumor necrosis factor-alpha and IL-6 are elevated during acute psychosis³; however, IL-6 normalized with treatment, whereas tumor necrosis factor-alpha did not. This means that IL-6 is a more clinically meaningful biomarker to help gauge treatment response.

EVALUATION Elevated markers of inflammation

Laboratory testing reveals that Mr. T’s IL-6 level is 56.64 pg/mL, which is significantly elevated (reference range: 0.31 to 5.00 pg/mL). After reviewing the IL-6 results with Mr. T and explaining that there is “too much inflammation” in his brain, he agrees to take minocycline and complete follow-up IL-6 level tests to monitor his progress during treatment.

HISTORY Alcohol abuse, treatment resistance

According to Mr. T’s mother, he had met all developmental milestones and graduated from high school with plans to enter culinary school. At age 20, Mr. T began to experience psychotic symptoms, telling family members that he was being followed by FBI agents and was receiving messages from televisions. He began drinking heavily and was arrested twice for driving under the influence. In his mid-20s, he attempted suicide by overdose after his father died. Mr. T required inpatient hospitalization nearly every year thereafter. His mother, a registered nurse, was significantly involved in his care and carefully documented his treatment history.

Mr. T has had numerous medication trials, including oral and long-acting injectable risperidone, olanzapine, aripiprazole, ziprasidone, lithium, gabapentin, buspirone, quetiapine, trazodone, bupropion, and paroxetine. None of these medications were effective.

In his mid-40s, Mr. T attempted suicide by wandering into traffic and being struck by a motor vehicle. A year later, he attempted suicide by driving his car at high speed into a concrete highway median. Mr. T told first responders that he was “possessed,” and a demonic entity “forced” him to crash his car. He begged law enforcement officers at the scene to give him a gun so he could shoot himself.

Continue to: Mr. T entered an intensive outpatient treatment program...

Mr. T entered an intensive outpatient treatment program and was switched from long-acting injectable risperidone to oral aripiprazole. After taking aripiprazole for several weeks, he began to gamble compulsively at a nearby casino. Frustrated by the lack of response to psychotropic medications and his idiosyncratic response to aripiprazole, he stopped psychiatric treatment, relapsed to alcohol use, and isolated himself in his apartment shortly before stabbing his mother.

EVALUATION Pharmacogenomics testing

At the mental health rehabilitation center, Mr. T agrees to undergo pharmacogenomics testing, which suggests that he will have a normal response to selective serotonin reuptake inhibitors and is unlikely to experience adverse reactions. He does not carry the 2 alleles that place him at higher risk of serious dermatologic reactions when taking certain mood stabilizers. He is heterozygous for the C677T allele polymorphism in the MTHFR gene that is associated with reduced folic acid metabolism, moderately decreased serum folate levels, and moderately increased homocysteine levels. On the pharmacokinetic genes tested, Mr. T has the normal metabolism genotype on 5 of 6 cytochrome P450 (CYP) enzymes; he has the ultrarapid metabolizer genotype on CYP1A2. He also has normal activity and intermediate metabolizer phenotype on the 2 UGT enzymes tested, which are responsible for the glucuronidation process, a major part of phase II metabolism.

Based on these results, Mr. T’s clozapine dosage is decreased by 50% (from 300 to 150 mg/d) and he is started on fluvoxamine, 50 mg/d, because it is a strong inhibitor of CYP1A2. The reduced conversion of clozapine to norclozapine results in an average serum clozapine level of 527 ng/mL (a level of 350 ng/mL is usually therapeutic in patients with schizophrenia) and norclozapine level of 140 ng/mL (clozapine:norclozapine ratio = 3.8), which is to be expected because fluvoxamine can increase serum clozapine levels.

Due to accumulating evidence in the literature suggesting that latent infections in the CNS play a role in serious mental illnesses such as schizophrenia, Mr. T undergoes further laboratory testing.

[polldaddy:10375845]

The authors’ observations

Mr. T tested positive for TG and CMV and negative for HSV-1. We were aware of accumulating evidence that latent infections in the CNS play a role in serious mental illnesses such as schizophrenia, specifically TG⁵—a parasite transmitted by cats—and CMV and HSV-1,⁶ which are transmitted by humans. The theory that TG infection could be a factor in schizophrenia emerged in the 1990s but only in recent years received mainstream scientific attention. Toxoplasma gondii, the infectious parasite that causes toxoplasmosis, infects more than 30 million people in the United States; however, most individuals are asymptomatic because of the body’s immune response to the parasite.⁷

Continue to: A study of 162 individuals...

A study of 162 individuals with schizophrenia, bipolar disorder, or major depressive disorder found that this immunologic profile is associated with suicide attempts,⁸ which is consistent with Mr. T’s history. Research suggests that individuals with schizophrenia who have latent TG infection have a more severe form of the illness compared with patients without the infection.^9-12 Many of these factors were present in Mr. T’s case (Table 1^8-12).

TREATMENT Improvement, then setback

Mr. T’s medication regimen at the rehabilitation center includes clozapine, 100 mg/d; minocycline, 200 mg/d; fluvoxamine, 200 mg/d; and N-acetylcysteine, 1,200 mg/d. N-acetylcysteine is an antioxidant that could ease negative symptoms of schizophrenia by reducing oxidative stress caused by free radicals.¹³ Mr. T makes slow but steady improvement, and his IL-6 levels drop steadily (Figure 1).

After 6 months in the rehabilitation center, Mr. T no longer experiences catatonic symptoms and is able to participate in the therapeutic program. He is permitted to leave the facility on day passes with family members. However, approximately every 8 weeks, he continues to cycle through periods of intense anxiety, perseverates on topics, and exhibits fragmented thinking and speech. During these episodes, he has difficulty receiving and processing information.

During one of these periods, Mr. T eats 4 oleander leaves he gathered while on day pass outside of the facility. After he experiences stomach pain, nausea, and vomiting, he informs nursing staff that he ate oleander. He is brought to the emergency department, receives activated charcoal and a digoxin antidote, and is placed on continuous electrocardiogram monitoring. When asked why he made the suicide attempt, he said “I realized things will never be the same because of what happened. I felt trapped.” He later expresses regret and wants to return to the mental health rehabilitation center.

At the facility, Mr. T agrees to take 2 more agents—valproic acid and ginger root extract—that specifically target latent toxoplasmosis infection before pursuing electroconvulsive therapy. We offer valproic acid because it inhibits replication of TG in an in vitro model.¹⁴ Mr. T is started on extended-release valproic acid, 1,500 mg/d, which results in a therapeutic serum level of 74.8 µg/mL.

Continue to: Additionally, Mr. T expresses interest...

Additionally, Mr. T expresses interest in taking “natural” agents in addition to psychotropics. After reviewing the quality of available ginger root extract products, Mr. T is started on a supplement that contains 22.4 mg of gingerols and 6.7 mg of shogaols, titrated to 4 capsules twice daily.

The authors’ observations

A retrospective cross-sectional analysis reported that patients with bipolar disorder who received medications with anti-toxoplasmic activity (Table 2¹⁵), specifically valproic acid, had significantly fewer lifetime depressive episodes compared with patients who received medications without anti-toxoplasmic activity.¹⁵

Alternative medicine options

Research has demonstrated the beneficial effects of Chinese herbal plants for toxoplasmosis^16,17 and ginger root extract has potent anti-toxoplasmic activity. A mouse model found that ginger root extract (Zingiber officinale) reduced the number of TG-infected cells by suppressing activation of apoptotic proteins the parasite induces, which prevents programmed cell death.¹⁸

Table 3 presents a stepwise approach to identifying and treating inflammation in patients with treatment-resistant psychosis.

OUTCOME Immune response, improvement

One month after the valproic acid and ginger root extract therapy is initiated, Mr. T’s toxoplasma antibody immunoglobulin G increases by 15.2 IU/mL, indicating that his immune system is mounting an enhanced response against the parasite (Figure 2). Mr. T continues to make progress while receiving the new regimen of clozapine, minocycline, valproic acid, and ginger root extract. He no longer cycles into periods of intense anxiety, perseverative thought, and fragmented thought and speech. He participates meaningfully in weekly psychotherapy and hopes to live independently and obtain gainful employment.

The District Attorney’s office dismisses his criminal charges, and Mr. T is discharged to a less restrictive level of care.

Continue to: Bottom Line

Several studies have shown that neuroinflammation increases the severity of mental illness. Consider adjunct anti-inflammatory agents for patients who have elevated levels of inflammatory biomarkers and for whom standard treatment approaches do not adequately control psychiatric symptoms. Also consider testing for the presence of latent infections in the CNS, which could reveal the underlying cause of treatment resistance or the genesis of disabling psychiatric symptoms.

Related Resources

• Fond G, Macgregor A, Tamouza R, et al. Comparative analysis of anti-toxoplasmic activity of antipsychotic drugs and valproate. Eur Arch Psychiatry Clin Neurosci. 2014;264(2):179-183.
• Hamdani N, Daban-Huard C, Lajnef M, et al. Cognitive deterioration among bipolar disorder patients infected by Toxoplasma gondii is correlated to interleukin 6 levels. J Affect Disord. 2015;179:161-166.
• Monroe JM, Buckley PF, Miller BJ. Meta-analysis of antitoxoplasma gondii IgM antibodies in acute psychosis. Schizophr Bull. 2015;41(4):989-998.

Drug Brand Names

Acyclovir • Zovirax
Aripiprazole • Abilify
Bupropion • Wellbutrin
Buspirone • Buspar
Clozapine • Clozaril
Duloxetine • Cymbalta
Fluphenazine • Prolixin
Fluvoxamine • Luvox
Gabapentin • Neurontin
Haloperidol • Haldol
Lithium • Eskalith, Lithobid
Lorazepam • Ativan
Loxapine • Loxitane
Minocycline • Minocin
Olanzapine • Zyprexa
Paliperidone • Invega
Paroxetine • Paxil
Quetiapine • Seroquel
Risperidone • Risperdal, Risperdal Consta
Thioridazine • Mellaril
Trifluoperazine • Stelazine
Trazodone • Desyrel
Valproic acid • Depakote
Ziprasidone • Geodon

CASE Violent, then catatonic

Mr. T, age 52, has a long history of schizo­affective disorder, depressed type; several suicide attempts; and violent episodes. He is admitted to a mental health rehabilitation center under a forensic commitment.

Several years earlier, Mr. T had been charged with first-degree attempted murder, assault with a deadly weapon, and abuse of a dependent/geriatric adult after allegedly stabbing his mother in the upper chest and neck. At that time, Mr. T was not in psychiatric treatment and was drinking heavily. He had become obsessed with John F. Kennedy’s assassination and believed the Central Intelligence Agency (CIA), not Lee Harvey Oswald, was responsible. He feared the CIA wanted to kill him because of his knowledge, and he heard voices from his television he believed were threatening him. He acquired knives for self-protection. When his mother arrived at his apartment to take him to a psychiatric appointment, he believed she was conspiring with the CIA and attacked her. Mr. T’s mother survived her injuries. He was taken to the county jail, where psychiatric staff noted that Mr. T was psychotic.

The court found Mr. T incompetent to stand trial and sent him to a state hospital for psychiatric treatment and competency restoration. After 3 years, he was declared unable to be restored because of repeated decompensations, placed on a conservatorship, and sent back to county jail.

In the jail, Mr. T began to show signs of catatonia. He refused medications, food, and water, and became mute. He was admitted to a medical center after a 45-minute episode that appeared similar to a seizure; however, all laboratory evaluations were within normal limits, head CT was negative, and an EEG was unremarkable.

Mr. T’s catatonic state gradually resolved with increasing dosages of lorazepam, as well as clozapine. He showed improved mobility and oral intake. A month later, his train of thought was rambling and difficult to follow, circumstantial, and perseverating. However, at times he could be directed and respond to questions in a linear and logical fashion. Lorazepam was tapered, discontinued, and replaced with gabapentin because Mr. T viewed taking lorazepam as a threat to his sobriety.

Recently, Mr. T was transferred to our mental health rehabilitation center, where he expresses that he is grateful to be in a therapeutic environment. Upon admission, his medication regimen consists of clozapine, 300 mg by mouth at bedtime, duloxetine, 60 mg/d by mouth, gabapentin 600 mg by mouth 3 times a day, and docusate sodium, 250 mg/d by mouth. Our team has a discussion about the growing recognition of the pro-inflammatory state present in many patients who experience serious mental illness and the importance of augmenting standard evidence-based psychopharmacotherapy with agents that have neuroprotective properties.^1,2 We offer Mr. T minocycline, 100 mg by mouth twice daily, a potent anti-inflammatory agent that has been shown to improve symptoms of schizophrenia.² Mr. T is reluctant to take minocycline, saying he is happy with his current medication regimen.

[polldaddy:10375843]

The authors’ observations

Several studies have found that acute psychosis is associated with an inflammatory state, and interleukin-6 (IL-6) is a crucial biomarker. A recent meta-analysis of serum cytokines in patients with schizophrenia found that IL-6 levels were significantly increased among acutely ill patients compared with controls.³ IL-6 levels significantly decreased after treating acute episodes of schizophrenia.³ Further, levels of peripheral IL-6 mRNA levels in individuals with schizophrenia are directly correlated with severity of positive symptoms.⁴

Continue to: A meta-analyis reported...

A meta-analysis reported that tumor necrosis factor-alpha and IL-6 are elevated during acute psychosis³; however, IL-6 normalized with treatment, whereas tumor necrosis factor-alpha did not. This means that IL-6 is a more clinically meaningful biomarker to help gauge treatment response.

EVALUATION Elevated markers of inflammation

Laboratory testing reveals that Mr. T’s IL-6 level is 56.64 pg/mL, which is significantly elevated (reference range: 0.31 to 5.00 pg/mL). After reviewing the IL-6 results with Mr. T and explaining that there is “too much inflammation” in his brain, he agrees to take minocycline and complete follow-up IL-6 level tests to monitor his progress during treatment.

HISTORY Alcohol abuse, treatment resistance

According to Mr. T’s mother, he had met all developmental milestones and graduated from high school with plans to enter culinary school. At age 20, Mr. T began to experience psychotic symptoms, telling family members that he was being followed by FBI agents and was receiving messages from televisions. He began drinking heavily and was arrested twice for driving under the influence. In his mid-20s, he attempted suicide by overdose after his father died. Mr. T required inpatient hospitalization nearly every year thereafter. His mother, a registered nurse, was significantly involved in his care and carefully documented his treatment history.

Mr. T has had numerous medication trials, including oral and long-acting injectable risperidone, olanzapine, aripiprazole, ziprasidone, lithium, gabapentin, buspirone, quetiapine, trazodone, bupropion, and paroxetine. None of these medications were effective.

In his mid-40s, Mr. T attempted suicide by wandering into traffic and being struck by a motor vehicle. A year later, he attempted suicide by driving his car at high speed into a concrete highway median. Mr. T told first responders that he was “possessed,” and a demonic entity “forced” him to crash his car. He begged law enforcement officers at the scene to give him a gun so he could shoot himself.

Continue to: Mr. T entered an intensive outpatient treatment program...

Mr. T entered an intensive outpatient treatment program and was switched from long-acting injectable risperidone to oral aripiprazole. After taking aripiprazole for several weeks, he began to gamble compulsively at a nearby casino. Frustrated by the lack of response to psychotropic medications and his idiosyncratic response to aripiprazole, he stopped psychiatric treatment, relapsed to alcohol use, and isolated himself in his apartment shortly before stabbing his mother.

EVALUATION Pharmacogenomics testing

At the mental health rehabilitation center, Mr. T agrees to undergo pharmacogenomics testing, which suggests that he will have a normal response to selective serotonin reuptake inhibitors and is unlikely to experience adverse reactions. He does not carry the 2 alleles that place him at higher risk of serious dermatologic reactions when taking certain mood stabilizers. He is heterozygous for the C677T allele polymorphism in the MTHFR gene that is associated with reduced folic acid metabolism, moderately decreased serum folate levels, and moderately increased homocysteine levels. On the pharmacokinetic genes tested, Mr. T has the normal metabolism genotype on 5 of 6 cytochrome P450 (CYP) enzymes; he has the ultrarapid metabolizer genotype on CYP1A2. He also has normal activity and intermediate metabolizer phenotype on the 2 UGT enzymes tested, which are responsible for the glucuronidation process, a major part of phase II metabolism.

Based on these results, Mr. T’s clozapine dosage is decreased by 50% (from 300 to 150 mg/d) and he is started on fluvoxamine, 50 mg/d, because it is a strong inhibitor of CYP1A2. The reduced conversion of clozapine to norclozapine results in an average serum clozapine level of 527 ng/mL (a level of 350 ng/mL is usually therapeutic in patients with schizophrenia) and norclozapine level of 140 ng/mL (clozapine:norclozapine ratio = 3.8), which is to be expected because fluvoxamine can increase serum clozapine levels.

Due to accumulating evidence in the literature suggesting that latent infections in the CNS play a role in serious mental illnesses such as schizophrenia, Mr. T undergoes further laboratory testing.

[polldaddy:10375845]

The authors’ observations

Mr. T tested positive for TG and CMV and negative for HSV-1. We were aware of accumulating evidence that latent infections in the CNS play a role in serious mental illnesses such as schizophrenia, specifically TG⁵—a parasite transmitted by cats—and CMV and HSV-1,⁶ which are transmitted by humans. The theory that TG infection could be a factor in schizophrenia emerged in the 1990s but only in recent years received mainstream scientific attention. Toxoplasma gondii, the infectious parasite that causes toxoplasmosis, infects more than 30 million people in the United States; however, most individuals are asymptomatic because of the body’s immune response to the parasite.⁷

Continue to: A study of 162 individuals...

A study of 162 individuals with schizophrenia, bipolar disorder, or major depressive disorder found that this immunologic profile is associated with suicide attempts,⁸ which is consistent with Mr. T’s history. Research suggests that individuals with schizophrenia who have latent TG infection have a more severe form of the illness compared with patients without the infection.^9-12 Many of these factors were present in Mr. T’s case (Table 1^8-12).

TREATMENT Improvement, then setback

Mr. T’s medication regimen at the rehabilitation center includes clozapine, 100 mg/d; minocycline, 200 mg/d; fluvoxamine, 200 mg/d; and N-acetylcysteine, 1,200 mg/d. N-acetylcysteine is an antioxidant that could ease negative symptoms of schizophrenia by reducing oxidative stress caused by free radicals.¹³ Mr. T makes slow but steady improvement, and his IL-6 levels drop steadily (Figure 1).

After 6 months in the rehabilitation center, Mr. T no longer experiences catatonic symptoms and is able to participate in the therapeutic program. He is permitted to leave the facility on day passes with family members. However, approximately every 8 weeks, he continues to cycle through periods of intense anxiety, perseverates on topics, and exhibits fragmented thinking and speech. During these episodes, he has difficulty receiving and processing information.

During one of these periods, Mr. T eats 4 oleander leaves he gathered while on day pass outside of the facility. After he experiences stomach pain, nausea, and vomiting, he informs nursing staff that he ate oleander. He is brought to the emergency department, receives activated charcoal and a digoxin antidote, and is placed on continuous electrocardiogram monitoring. When asked why he made the suicide attempt, he said “I realized things will never be the same because of what happened. I felt trapped.” He later expresses regret and wants to return to the mental health rehabilitation center.

At the facility, Mr. T agrees to take 2 more agents—valproic acid and ginger root extract—that specifically target latent toxoplasmosis infection before pursuing electroconvulsive therapy. We offer valproic acid because it inhibits replication of TG in an in vitro model.¹⁴ Mr. T is started on extended-release valproic acid, 1,500 mg/d, which results in a therapeutic serum level of 74.8 µg/mL.

Continue to: Additionally, Mr. T expresses interest...

Additionally, Mr. T expresses interest in taking “natural” agents in addition to psychotropics. After reviewing the quality of available ginger root extract products, Mr. T is started on a supplement that contains 22.4 mg of gingerols and 6.7 mg of shogaols, titrated to 4 capsules twice daily.

The authors’ observations

A retrospective cross-sectional analysis reported that patients with bipolar disorder who received medications with anti-toxoplasmic activity (Table 2¹⁵), specifically valproic acid, had significantly fewer lifetime depressive episodes compared with patients who received medications without anti-toxoplasmic activity.¹⁵

Alternative medicine options

Research has demonstrated the beneficial effects of Chinese herbal plants for toxoplasmosis^16,17 and ginger root extract has potent anti-toxoplasmic activity. A mouse model found that ginger root extract (Zingiber officinale) reduced the number of TG-infected cells by suppressing activation of apoptotic proteins the parasite induces, which prevents programmed cell death.¹⁸

Table 3 presents a stepwise approach to identifying and treating inflammation in patients with treatment-resistant psychosis.

OUTCOME Immune response, improvement

One month after the valproic acid and ginger root extract therapy is initiated, Mr. T’s toxoplasma antibody immunoglobulin G increases by 15.2 IU/mL, indicating that his immune system is mounting an enhanced response against the parasite (Figure 2). Mr. T continues to make progress while receiving the new regimen of clozapine, minocycline, valproic acid, and ginger root extract. He no longer cycles into periods of intense anxiety, perseverative thought, and fragmented thought and speech. He participates meaningfully in weekly psychotherapy and hopes to live independently and obtain gainful employment.

The District Attorney’s office dismisses his criminal charges, and Mr. T is discharged to a less restrictive level of care.

Continue to: Bottom Line

Several studies have shown that neuroinflammation increases the severity of mental illness. Consider adjunct anti-inflammatory agents for patients who have elevated levels of inflammatory biomarkers and for whom standard treatment approaches do not adequately control psychiatric symptoms. Also consider testing for the presence of latent infections in the CNS, which could reveal the underlying cause of treatment resistance or the genesis of disabling psychiatric symptoms.

Related Resources

• Fond G, Macgregor A, Tamouza R, et al. Comparative analysis of anti-toxoplasmic activity of antipsychotic drugs and valproate. Eur Arch Psychiatry Clin Neurosci. 2014;264(2):179-183.
• Hamdani N, Daban-Huard C, Lajnef M, et al. Cognitive deterioration among bipolar disorder patients infected by Toxoplasma gondii is correlated to interleukin 6 levels. J Affect Disord. 2015;179:161-166.
• Monroe JM, Buckley PF, Miller BJ. Meta-analysis of antitoxoplasma gondii IgM antibodies in acute psychosis. Schizophr Bull. 2015;41(4):989-998.

Drug Brand Names

Acyclovir • Zovirax
Aripiprazole • Abilify
Bupropion • Wellbutrin
Buspirone • Buspar
Clozapine • Clozaril
Duloxetine • Cymbalta
Fluphenazine • Prolixin
Fluvoxamine • Luvox
Gabapentin • Neurontin
Haloperidol • Haldol
Lithium • Eskalith, Lithobid
Lorazepam • Ativan
Loxapine • Loxitane
Minocycline • Minocin
Olanzapine • Zyprexa
Paliperidone • Invega
Paroxetine • Paxil
Quetiapine • Seroquel
Risperidone • Risperdal, Risperdal Consta
Thioridazine • Mellaril
Trifluoperazine • Stelazine
Trazodone • Desyrel
Valproic acid • Depakote
Ziprasidone • Geodon

Narcissism has an evil reputation. But is it justified? A modicum of narcissism is actually healthy. It can bolster self-confidence, assertiveness, and success in business and in the sociobiology of mating. Perhaps that’s why narcissism as a trait has a survival value from an evolutionary perspective.

Taking an excessive number of “selfies” with a smartphone is probably the most common and relatively benign form of mild narcissism (and not in DSM-5, yet). Narcissistic personality disorder (NPD), with a prevalence of 1%, is on the extreme end of the narcissism continuum. It has become tainted with such an intensely negative halo that it has become a despised trait, an insult, and even a vile epithet, like a 4-letter word. But as psychiatrists and other mental health professionals, we clinically relate to patients with NPD as being afflicted with a serious neuropsychiatric disorder, not as despicable individuals. Many people outside the mental health profession abhor persons with NPD because of their gargantuan hubris, insufferable selfishness, self-aggrandizement, emotional abuse of others, and irremediable vanity. Narcissistic personality disorder deprives its sufferers of the prosocial capacity for empathy, which leads them to belittle others or treat competent individuals with disdain, never as equals. They also seem to be incapable of experiencing shame as they inflate their self-importance and megalomania at the expense of those they degrade. They cannot tolerate any success by others because it threatens to overshadow their own exaggerated achievements. They can be mercilessly harsh towards their underlings. They are incapable of fostering warm, long-term loving relationships, where bidirectional respect is essential. Their lives often are replete with brief, broken-up relationships because they emotionally, physically, or sexually abuse their intimate partners.

Primary NPD has been shown in twin studies to be highly genetic, and more strongly heritable than 17 other personality dimensions.¹ It is also resistant to any effective psychotherapeutic, pharmacologic, or somatic treatments. This is particularly relevant given the proclivity of individuals with NPD to experience a crushing disappointment, commonly known as “narcissistic injury,” following a real or imagined failure. This could lead to a painful depression or an outburst of “narcissistic rage” directed at anyone perceived as undermining them, and may even lead to violent behavior.²

Apart from heritable narcissism, there is also another form of narcissism that can develop in some individuals following life events. That hazardous condition, known as “acquired narcissism,” is most often associated with achieving the coveted status of an exalted celebrity. At risk for this acquired personality affliction are famous actors, singers, movie directors, TV anchors, or politicians (although some politicians are natural-born narcissists, driven to seek the powers of public office), and less frequently physicians (perhaps because the practice of medicine is not done in front of spectators) or scientists (because research, no matter how momentous, rarely procures the glamour or public adulation of the entertainment industry). The ardent fans of those “celebs” shower them with such intense attention and adulation that it malignantly transforms previously “normal” individuals into narcissists who start believing they are indeed “very special” and superior to the rest of us mortals (especially as their earning power balloons into the millions after growing up with humble social or economic roots).

Social media has become a catalyst for acquired narcissism, with millions of followers on Twitter, Facebook, or YouTube. Cable TV also caters to politicians, some of whom morph into narcissists, intoxicated with their newfound eminence and stature among their partisan followers, and become genuinely convinced that they have supreme power or influence over the masses. They get carried away with their own exaggerated self-importance as oracles of the “truth,” regardless of how extreme their views may be. Celebrity, politics, social media, and cable TV have converged into a combustible mix, a crucible for acquired narcissism.

An interesting feature of acquired narcissism is “collective narcissism,” in which celebrities coalesce to consolidate their imagined superhuman attributes that go beyond the technical skills of their professions such as acting, singing, sports, or politics. Thus, entertainers or star athletes believe they can enunciate radical statements about contemporary social, political, or environmental issues (at both ends of the debate) as though their artistic success renders them wise arbiters of the truth. What complicates matters is their delirious fans, who revere and mimic whatever their idols say (and their fashion or their tattoos), which further intensifies the grandiosity and megalomania of acquired narcissism. Celebrity triggers mindless idolatry, fueling the narcissism of individuals who are blessed (or cursed?) with runaway personal success. Neuroscientists should conduct research into how the brain is neurobiologically altered by fame, but there are many more urgent questions that demand their attention. It would be important to know if it is reversible or enduring, even as fame inevitably dims.

Continue to: The pursuit of wealth and fame...

The pursuit of wealth and fame is widely prevalent and can be healthy if it is not all-consuming. But if achieved beyond the aspirer’s wildest dreams, he/she may reach an inflection point conducive to a pathologic degree of acquired narcissism. That’s what the French refer to as “les risques du métier” (ie, occupational hazard). I recall reading about celebrities who became enraged when a policeman “dared” to stop their car for some driving violation, confronting the officer with “Do you know who I am?” That question may be a clinical biomarker of acquired narcissism.

Interestingly, several years ago, when the American Psychiatry Association last revised the DSM—sometimes referred to as the “bible” of psychiatric nosology—it came close to dropping NPD from its listed disorders, but then reverted and kept it as one of the 275 diagnostic categories included in DSM-5.³ Had the NPD diagnosis been discarded, one wonders if the mythical god of narcissism would have suffered a transcendental “narcissistic injury”…

Narcissism has an evil reputation. But is it justified? A modicum of narcissism is actually healthy. It can bolster self-confidence, assertiveness, and success in business and in the sociobiology of mating. Perhaps that’s why narcissism as a trait has a survival value from an evolutionary perspective.

Taking an excessive number of “selfies” with a smartphone is probably the most common and relatively benign form of mild narcissism (and not in DSM-5, yet). Narcissistic personality disorder (NPD), with a prevalence of 1%, is on the extreme end of the narcissism continuum. It has become tainted with such an intensely negative halo that it has become a despised trait, an insult, and even a vile epithet, like a 4-letter word. But as psychiatrists and other mental health professionals, we clinically relate to patients with NPD as being afflicted with a serious neuropsychiatric disorder, not as despicable individuals. Many people outside the mental health profession abhor persons with NPD because of their gargantuan hubris, insufferable selfishness, self-aggrandizement, emotional abuse of others, and irremediable vanity. Narcissistic personality disorder deprives its sufferers of the prosocial capacity for empathy, which leads them to belittle others or treat competent individuals with disdain, never as equals. They also seem to be incapable of experiencing shame as they inflate their self-importance and megalomania at the expense of those they degrade. They cannot tolerate any success by others because it threatens to overshadow their own exaggerated achievements. They can be mercilessly harsh towards their underlings. They are incapable of fostering warm, long-term loving relationships, where bidirectional respect is essential. Their lives often are replete with brief, broken-up relationships because they emotionally, physically, or sexually abuse their intimate partners.

Primary NPD has been shown in twin studies to be highly genetic, and more strongly heritable than 17 other personality dimensions.¹ It is also resistant to any effective psychotherapeutic, pharmacologic, or somatic treatments. This is particularly relevant given the proclivity of individuals with NPD to experience a crushing disappointment, commonly known as “narcissistic injury,” following a real or imagined failure. This could lead to a painful depression or an outburst of “narcissistic rage” directed at anyone perceived as undermining them, and may even lead to violent behavior.²

Apart from heritable narcissism, there is also another form of narcissism that can develop in some individuals following life events. That hazardous condition, known as “acquired narcissism,” is most often associated with achieving the coveted status of an exalted celebrity. At risk for this acquired personality affliction are famous actors, singers, movie directors, TV anchors, or politicians (although some politicians are natural-born narcissists, driven to seek the powers of public office), and less frequently physicians (perhaps because the practice of medicine is not done in front of spectators) or scientists (because research, no matter how momentous, rarely procures the glamour or public adulation of the entertainment industry). The ardent fans of those “celebs” shower them with such intense attention and adulation that it malignantly transforms previously “normal” individuals into narcissists who start believing they are indeed “very special” and superior to the rest of us mortals (especially as their earning power balloons into the millions after growing up with humble social or economic roots).

Social media has become a catalyst for acquired narcissism, with millions of followers on Twitter, Facebook, or YouTube. Cable TV also caters to politicians, some of whom morph into narcissists, intoxicated with their newfound eminence and stature among their partisan followers, and become genuinely convinced that they have supreme power or influence over the masses. They get carried away with their own exaggerated self-importance as oracles of the “truth,” regardless of how extreme their views may be. Celebrity, politics, social media, and cable TV have converged into a combustible mix, a crucible for acquired narcissism.

An interesting feature of acquired narcissism is “collective narcissism,” in which celebrities coalesce to consolidate their imagined superhuman attributes that go beyond the technical skills of their professions such as acting, singing, sports, or politics. Thus, entertainers or star athletes believe they can enunciate radical statements about contemporary social, political, or environmental issues (at both ends of the debate) as though their artistic success renders them wise arbiters of the truth. What complicates matters is their delirious fans, who revere and mimic whatever their idols say (and their fashion or their tattoos), which further intensifies the grandiosity and megalomania of acquired narcissism. Celebrity triggers mindless idolatry, fueling the narcissism of individuals who are blessed (or cursed?) with runaway personal success. Neuroscientists should conduct research into how the brain is neurobiologically altered by fame, but there are many more urgent questions that demand their attention. It would be important to know if it is reversible or enduring, even as fame inevitably dims.

Continue to: The pursuit of wealth and fame...

The pursuit of wealth and fame is widely prevalent and can be healthy if it is not all-consuming. But if achieved beyond the aspirer’s wildest dreams, he/she may reach an inflection point conducive to a pathologic degree of acquired narcissism. That’s what the French refer to as “les risques du métier” (ie, occupational hazard). I recall reading about celebrities who became enraged when a policeman “dared” to stop their car for some driving violation, confronting the officer with “Do you know who I am?” That question may be a clinical biomarker of acquired narcissism.

Interestingly, several years ago, when the American Psychiatry Association last revised the DSM—sometimes referred to as the “bible” of psychiatric nosology—it came close to dropping NPD from its listed disorders, but then reverted and kept it as one of the 275 diagnostic categories included in DSM-5.³ Had the NPD diagnosis been discarded, one wonders if the mythical god of narcissism would have suffered a transcendental “narcissistic injury”…

Narcissism has an evil reputation. But is it justified? A modicum of narcissism is actually healthy. It can bolster self-confidence, assertiveness, and success in business and in the sociobiology of mating. Perhaps that’s why narcissism as a trait has a survival value from an evolutionary perspective.

Taking an excessive number of “selfies” with a smartphone is probably the most common and relatively benign form of mild narcissism (and not in DSM-5, yet). Narcissistic personality disorder (NPD), with a prevalence of 1%, is on the extreme end of the narcissism continuum. It has become tainted with such an intensely negative halo that it has become a despised trait, an insult, and even a vile epithet, like a 4-letter word. But as psychiatrists and other mental health professionals, we clinically relate to patients with NPD as being afflicted with a serious neuropsychiatric disorder, not as despicable individuals. Many people outside the mental health profession abhor persons with NPD because of their gargantuan hubris, insufferable selfishness, self-aggrandizement, emotional abuse of others, and irremediable vanity. Narcissistic personality disorder deprives its sufferers of the prosocial capacity for empathy, which leads them to belittle others or treat competent individuals with disdain, never as equals. They also seem to be incapable of experiencing shame as they inflate their self-importance and megalomania at the expense of those they degrade. They cannot tolerate any success by others because it threatens to overshadow their own exaggerated achievements. They can be mercilessly harsh towards their underlings. They are incapable of fostering warm, long-term loving relationships, where bidirectional respect is essential. Their lives often are replete with brief, broken-up relationships because they emotionally, physically, or sexually abuse their intimate partners.

Primary NPD has been shown in twin studies to be highly genetic, and more strongly heritable than 17 other personality dimensions.¹ It is also resistant to any effective psychotherapeutic, pharmacologic, or somatic treatments. This is particularly relevant given the proclivity of individuals with NPD to experience a crushing disappointment, commonly known as “narcissistic injury,” following a real or imagined failure. This could lead to a painful depression or an outburst of “narcissistic rage” directed at anyone perceived as undermining them, and may even lead to violent behavior.²

Apart from heritable narcissism, there is also another form of narcissism that can develop in some individuals following life events. That hazardous condition, known as “acquired narcissism,” is most often associated with achieving the coveted status of an exalted celebrity. At risk for this acquired personality affliction are famous actors, singers, movie directors, TV anchors, or politicians (although some politicians are natural-born narcissists, driven to seek the powers of public office), and less frequently physicians (perhaps because the practice of medicine is not done in front of spectators) or scientists (because research, no matter how momentous, rarely procures the glamour or public adulation of the entertainment industry). The ardent fans of those “celebs” shower them with such intense attention and adulation that it malignantly transforms previously “normal” individuals into narcissists who start believing they are indeed “very special” and superior to the rest of us mortals (especially as their earning power balloons into the millions after growing up with humble social or economic roots).

Social media has become a catalyst for acquired narcissism, with millions of followers on Twitter, Facebook, or YouTube. Cable TV also caters to politicians, some of whom morph into narcissists, intoxicated with their newfound eminence and stature among their partisan followers, and become genuinely convinced that they have supreme power or influence over the masses. They get carried away with their own exaggerated self-importance as oracles of the “truth,” regardless of how extreme their views may be. Celebrity, politics, social media, and cable TV have converged into a combustible mix, a crucible for acquired narcissism.

An interesting feature of acquired narcissism is “collective narcissism,” in which celebrities coalesce to consolidate their imagined superhuman attributes that go beyond the technical skills of their professions such as acting, singing, sports, or politics. Thus, entertainers or star athletes believe they can enunciate radical statements about contemporary social, political, or environmental issues (at both ends of the debate) as though their artistic success renders them wise arbiters of the truth. What complicates matters is their delirious fans, who revere and mimic whatever their idols say (and their fashion or their tattoos), which further intensifies the grandiosity and megalomania of acquired narcissism. Celebrity triggers mindless idolatry, fueling the narcissism of individuals who are blessed (or cursed?) with runaway personal success. Neuroscientists should conduct research into how the brain is neurobiologically altered by fame, but there are many more urgent questions that demand their attention. It would be important to know if it is reversible or enduring, even as fame inevitably dims.

Continue to: The pursuit of wealth and fame...

The pursuit of wealth and fame is widely prevalent and can be healthy if it is not all-consuming. But if achieved beyond the aspirer’s wildest dreams, he/she may reach an inflection point conducive to a pathologic degree of acquired narcissism. That’s what the French refer to as “les risques du métier” (ie, occupational hazard). I recall reading about celebrities who became enraged when a policeman “dared” to stop their car for some driving violation, confronting the officer with “Do you know who I am?” That question may be a clinical biomarker of acquired narcissism.

Interestingly, several years ago, when the American Psychiatry Association last revised the DSM—sometimes referred to as the “bible” of psychiatric nosology—it came close to dropping NPD from its listed disorders, but then reverted and kept it as one of the 275 diagnostic categories included in DSM-5.³ Had the NPD diagnosis been discarded, one wonders if the mythical god of narcissism would have suffered a transcendental “narcissistic injury”…

I strongly disagree with the editorial by Ahmed A. Aboraya, MD, DrPH, and Henry A. Nasrallah, MD, (“It’s time to implement measurement-based care in psychiatric practice,” From the Editor, Current Psychiatry. June 2019, p. 6-8). I am 76 years old and recently retired. I have seen many attempts to “objectify” medicine. These have all failed, but each has taken a piece of medicine with it to the grave.

We do not have much more to lose before it’s a checklist, vital signs, and a script. I now refer to our profession as “McMedicine.” If you don’t have what is on the menu, you cannot get served. Diseases are rarely treated, symptoms are treated. This is not the profession of medicine. We are not fixing much; we are mostly providing consumers for pharmaceutical companies.

Few psychiatric disorders have been subjected to more measurement than depression. Quite a while ago, someone tried to compare depression scales. They correlated scale scores with the results of evaluations by board-certified psychiatrists. The best scale was a single question: “Are you depressed?” This had been included as a control. Can you do better?

Furthermore, the “paper and numbers” people can’t wait to get an “objective” wrench to tighten the screws and apply the principles of the industrial revolution to squeeze more money out of the system. They will find some way to turn patients into standardized products.

John L. Schenkel, MD
Retired psychiatrist
Peru, NY

I disagree with Drs. Aboraya and Nasrallah regarding implementing rating scales in psychiatry. Frankly, medicine has become awash in details—mounds and mounds of details.

With the use of an electronic medical record, what should be a simple 1-page note is transformed into a 5-page note of details. Doctors no longer attend to their patients but rather to their computers. Has this raised consciousness—the most important metric, according to Dr. David Hawkins? I doubt it.

In the words of my great professor, Dr. James Gustafson, I will continue to start my interview with what concerns the patient. Most of the time, they implicitly know.

Our focus should instead be on bringing down the cost of health care. This is what angers our patients most, and yet we do not make it a priority.

Mike Primc, MD
Psychiatrist
Glenbeigh Hospital
Rock Creek, Ohio
Signature Health
Ashtabula, Ohio
Behavioral Wellness Group
Mentor, Ohio

Continue to: The authors respond

We appreciate Drs. Schenkel’s and Primc’s comments on our editorial regarding measurement-based care (MBC). However, MBC will not increase the workload of psychiatrists; rather, it will streamline the evaluation of patients and measure the severity of their symptoms or adverse effects as well as the degree of their improvement. The proper use of scales with the appropriate patient populations may actually help clinicians to reduce the extensive amount of details that go into medical records.

The following quote, an excerpt from another article we wrote on MBC,¹ speaks to Dr. Primc’s concerns:

“…measures in psychiatry could be considered the equivalent of a thermometer and a stethoscope to a physician. No measure, scale, or diagnostic interview will ever replace a seasoned, experienced clinician who has been evaluating and treating real patients for years. MBC is not intended to replace clinical judgment and cannot substitute for an observant and caring clinician. Just as thermometers, stethoscopes, and lab tests help other types of physicians reach accurate diagnoses and provide appropriate management, the use of MBC by psychiatrists has the potential to improve the accuracy of diagnoses and improve the outcomes of care.”

Ahmed A. Aboraya, MD, DrPH
Assistant Professor
Department of Behavioral Medicine and Psychiatry
Chief of Psychiatry
Sharpe Hospital West Virginia University
Weston, West Virginia

Henry A. Nasrallah, MD
Professor of Psychiatry, Neurology, and Neuroscience
Medical Director: Neuropsychiatry
Director, Schizophrenia and Neuropsychiatry Programs
University of Cincinnati College of Medicine
Cincinnati, Ohio
Professor Emeritus, Saint Louis University
St. Louis, Missouri

Reference
1. Aboraya A, Nasrallah HA, Elswick DE, et al. Measurement-based care in psychiatry-past, present, and future. Innov Clin Neurosci. 2018;15(11-12):13-26.

I strongly disagree with the editorial by Ahmed A. Aboraya, MD, DrPH, and Henry A. Nasrallah, MD, (“It’s time to implement measurement-based care in psychiatric practice,” From the Editor, Current Psychiatry. June 2019, p. 6-8). I am 76 years old and recently retired. I have seen many attempts to “objectify” medicine. These have all failed, but each has taken a piece of medicine with it to the grave.

We do not have much more to lose before it’s a checklist, vital signs, and a script. I now refer to our profession as “McMedicine.” If you don’t have what is on the menu, you cannot get served. Diseases are rarely treated, symptoms are treated. This is not the profession of medicine. We are not fixing much; we are mostly providing consumers for pharmaceutical companies.

Few psychiatric disorders have been subjected to more measurement than depression. Quite a while ago, someone tried to compare depression scales. They correlated scale scores with the results of evaluations by board-certified psychiatrists. The best scale was a single question: “Are you depressed?” This had been included as a control. Can you do better?

Furthermore, the “paper and numbers” people can’t wait to get an “objective” wrench to tighten the screws and apply the principles of the industrial revolution to squeeze more money out of the system. They will find some way to turn patients into standardized products.

John L. Schenkel, MD
Retired psychiatrist
Peru, NY

I disagree with Drs. Aboraya and Nasrallah regarding implementing rating scales in psychiatry. Frankly, medicine has become awash in details—mounds and mounds of details.

With the use of an electronic medical record, what should be a simple 1-page note is transformed into a 5-page note of details. Doctors no longer attend to their patients but rather to their computers. Has this raised consciousness—the most important metric, according to Dr. David Hawkins? I doubt it.

In the words of my great professor, Dr. James Gustafson, I will continue to start my interview with what concerns the patient. Most of the time, they implicitly know.

Our focus should instead be on bringing down the cost of health care. This is what angers our patients most, and yet we do not make it a priority.

Mike Primc, MD
Psychiatrist
Glenbeigh Hospital
Rock Creek, Ohio
Signature Health
Ashtabula, Ohio
Behavioral Wellness Group
Mentor, Ohio

Continue to: The authors respond

We appreciate Drs. Schenkel’s and Primc’s comments on our editorial regarding measurement-based care (MBC). However, MBC will not increase the workload of psychiatrists; rather, it will streamline the evaluation of patients and measure the severity of their symptoms or adverse effects as well as the degree of their improvement. The proper use of scales with the appropriate patient populations may actually help clinicians to reduce the extensive amount of details that go into medical records.

The following quote, an excerpt from another article we wrote on MBC,¹ speaks to Dr. Primc’s concerns:

“…measures in psychiatry could be considered the equivalent of a thermometer and a stethoscope to a physician. No measure, scale, or diagnostic interview will ever replace a seasoned, experienced clinician who has been evaluating and treating real patients for years. MBC is not intended to replace clinical judgment and cannot substitute for an observant and caring clinician. Just as thermometers, stethoscopes, and lab tests help other types of physicians reach accurate diagnoses and provide appropriate management, the use of MBC by psychiatrists has the potential to improve the accuracy of diagnoses and improve the outcomes of care.”

Ahmed A. Aboraya, MD, DrPH
Assistant Professor
Department of Behavioral Medicine and Psychiatry
Chief of Psychiatry
Sharpe Hospital West Virginia University
Weston, West Virginia

Henry A. Nasrallah, MD
Professor of Psychiatry, Neurology, and Neuroscience
Medical Director: Neuropsychiatry
Director, Schizophrenia and Neuropsychiatry Programs
University of Cincinnati College of Medicine
Cincinnati, Ohio
Professor Emeritus, Saint Louis University
St. Louis, Missouri

Reference
1. Aboraya A, Nasrallah HA, Elswick DE, et al. Measurement-based care in psychiatry-past, present, and future. Innov Clin Neurosci. 2018;15(11-12):13-26.

I strongly disagree with the editorial by Ahmed A. Aboraya, MD, DrPH, and Henry A. Nasrallah, MD, (“It’s time to implement measurement-based care in psychiatric practice,” From the Editor, Current Psychiatry. June 2019, p. 6-8). I am 76 years old and recently retired. I have seen many attempts to “objectify” medicine. These have all failed, but each has taken a piece of medicine with it to the grave.

We do not have much more to lose before it’s a checklist, vital signs, and a script. I now refer to our profession as “McMedicine.” If you don’t have what is on the menu, you cannot get served. Diseases are rarely treated, symptoms are treated. This is not the profession of medicine. We are not fixing much; we are mostly providing consumers for pharmaceutical companies.

Few psychiatric disorders have been subjected to more measurement than depression. Quite a while ago, someone tried to compare depression scales. They correlated scale scores with the results of evaluations by board-certified psychiatrists. The best scale was a single question: “Are you depressed?” This had been included as a control. Can you do better?

Furthermore, the “paper and numbers” people can’t wait to get an “objective” wrench to tighten the screws and apply the principles of the industrial revolution to squeeze more money out of the system. They will find some way to turn patients into standardized products.

John L. Schenkel, MD
Retired psychiatrist
Peru, NY

I disagree with Drs. Aboraya and Nasrallah regarding implementing rating scales in psychiatry. Frankly, medicine has become awash in details—mounds and mounds of details.

With the use of an electronic medical record, what should be a simple 1-page note is transformed into a 5-page note of details. Doctors no longer attend to their patients but rather to their computers. Has this raised consciousness—the most important metric, according to Dr. David Hawkins? I doubt it.

In the words of my great professor, Dr. James Gustafson, I will continue to start my interview with what concerns the patient. Most of the time, they implicitly know.

Our focus should instead be on bringing down the cost of health care. This is what angers our patients most, and yet we do not make it a priority.

Mike Primc, MD
Psychiatrist
Glenbeigh Hospital
Rock Creek, Ohio
Signature Health
Ashtabula, Ohio
Behavioral Wellness Group
Mentor, Ohio

Continue to: The authors respond

We appreciate Drs. Schenkel’s and Primc’s comments on our editorial regarding measurement-based care (MBC). However, MBC will not increase the workload of psychiatrists; rather, it will streamline the evaluation of patients and measure the severity of their symptoms or adverse effects as well as the degree of their improvement. The proper use of scales with the appropriate patient populations may actually help clinicians to reduce the extensive amount of details that go into medical records.

The following quote, an excerpt from another article we wrote on MBC,¹ speaks to Dr. Primc’s concerns:

“…measures in psychiatry could be considered the equivalent of a thermometer and a stethoscope to a physician. No measure, scale, or diagnostic interview will ever replace a seasoned, experienced clinician who has been evaluating and treating real patients for years. MBC is not intended to replace clinical judgment and cannot substitute for an observant and caring clinician. Just as thermometers, stethoscopes, and lab tests help other types of physicians reach accurate diagnoses and provide appropriate management, the use of MBC by psychiatrists has the potential to improve the accuracy of diagnoses and improve the outcomes of care.”

Ahmed A. Aboraya, MD, DrPH
Assistant Professor
Department of Behavioral Medicine and Psychiatry
Chief of Psychiatry
Sharpe Hospital West Virginia University
Weston, West Virginia

Henry A. Nasrallah, MD
Professor of Psychiatry, Neurology, and Neuroscience
Medical Director: Neuropsychiatry
Director, Schizophrenia and Neuropsychiatry Programs
University of Cincinnati College of Medicine
Cincinnati, Ohio
Professor Emeritus, Saint Louis University
St. Louis, Missouri

Reference
1. Aboraya A, Nasrallah HA, Elswick DE, et al. Measurement-based care in psychiatry-past, present, and future. Innov Clin Neurosci. 2018;15(11-12):13-26.

CASE Increasingly frequent paroxysmal episodes

Ms. N, age 12, comes to the hospital for evaluation of paroxysmal episodes of pain, weakness, and muscle spasms. A neurologist who evaluated her as an outpatient had recommended a routine electroencephalogram (EEG); after those results were inconclusive, Ms. N’s mother brought her to the hospital for a 24-hour video EEG.

Ms. N has a history of asthma. She has no history of seizures or headache, but her mother has an unspecified seizure disorder that has been stable with antiepileptic medication for many years. Ms. N has no other family history of autoimmune or neurologic disorders.

Ms. N’s episodes began 6 months ago and have progressively increased in frequency from 5 to 12 episodes a day. She says that before she has an episode, she “ feels tingling in her fingers and mouth, and butterflies in her belly,” and then her “whole body clenches up.” She denies experiencing tongue biting, facial or extremity weakness, incontinence, or loss of consciousness during these episodes.

Shortly before her hospitalization, Ms. N had won a scholarship to attend an overnight art camp. Because her episodes were becoming more frequent and their etiology remained unclear, Ms. N and her mother decided it would be unsafe for her to attend, and that she should go to the hospital for evaluation instead.

EVALUATION Tough questions reveal answers

The pediatric team evaluates Ms. N. Her physical exam, laboratory values, and imaging are all within normal limits. Her neurologic exam demonstrates full strength, tone, and sensation in all extremities. All cranial nerves and reflexes are intact. No dysmorphic features or gait abnormalities are noted. All laboratory and imaging tests are normal, including complete blood cell count, electrolytes, calcium, magnesium, phosphorus, glucose, creatine kinase, liver enzymes, urine drug screen, human chorionic gonadotropin (hCG) urine test, and head CT.

After the initial workup, the pediatric team consults the child and adolescent psychiatry team for a complete assessment of Ms. N due to concerns that a psychological component is contributing to her episodes. According to the psychosocial history obtained from Ms. N and her mother, Ms. N had experienced disrupted attachment, trauma, and loss. At age 5, Ms. N was temporarily removed from her mother’s custody after a fight between her mother and brother. At age 9, Ms. N’s stepfather, her primary father figure, died of a brain tumor.

Ms. N also has significant trauma stemming from her relationship with her biological father. Ms. N’s mother reports that her daughter was conceived during nonconsensual sexual intercourse. Ms. N did not have much contact with her biological father until 6 months ago, when he started picking her up at school and taking her to his home for several hours without permission or supervision. Afterwards, Ms. N confided to her mother and a teacher that her father sexually assaulted her during those visits.

Continue to: Ms. N and her mother...

Ms. N and her mother reported the assault to the police and were awaiting legal action.

During the interview with the psychiatry team, Ms. N denies that any thoughts or actions trigger the episodes and reports that she cannot control when they happen. Because she cannot anticipate the episodes, she says she is afraid to leave her house. She does not know why the episodes are happening and feels frustrated that they are getting worse. Ms. N says, “I have been feeling down lately,” but she denies hopelessness, worthlessness, suicidal ideation, homicidal ideation, delusions, or hallucinations.

In the hospital, when the psychiatry team asks Ms. N about her visits with her father, she says that they are “too painful to talk about,” and fears that discussing them will trigger an episode. However, her mother suggests that her daughter’s sexual trauma, as well as ongoing frustrations with the legal system, are influencing her mood; she has had low energy, poor appetite, and is spending more time in bed. Her mother also reports that Ms. N “avoids going out in the sun and spending time with her friends outside. She doesn’t seem to enjoy shopping and art like she used to.” Ms. N told her mother that she was having nightmares about the trauma and “could not stop thinking about some of the bad stuff that happened during the day.”

Ten minutes into the interview, while being questioned about her father, Ms. N experiences a spastic episode. She curls up in bed on her left side, clenches her entire body, and shuts her eyes. Her mother quickly runs to her bedside and counts the seconds until the end of the episode. After 25 seconds, Ms. N awakes with full recollection of the episode. On review of the video EEG during the episode, no ictal patterns are seen.

[polldaddy:10375873]

The authors’ observations

Paroxysmal episodes of weakness, numbness, and muscle spasms in a young female are suggestive of either epilepsy or nonepileptic seizure (NES).^1,2 The negative EEG and physical features are inconsistent with epileptiform seizure, and Ms. N’s history and evaluation are suggestive of NES. Nonepileptic seizures are a type of a conversion disorder, or functional neurologic symptom disorder, in which a patient experiences weakness, abnormal movements, or seizure-like episodes that are inconsistent with organic neurologic disease.³ When a diagnosis of conversion disorder is suspected, a clinician must always consider other pathology that can explain the symptoms, such as migraine, vasovagal syncope, or intracranial mass. If a patient has focal neurologic deficits, head imaging should be pursued. Additionally, the clinician must screen for malingering and factitious disorder before establishing a definitive diagnosis. However, conversion disorder is not a diagnosis of exclusion. For example, a negative EEG does not rule out epilepsy, and patients can have both epilepsy and concomitant NES.

Continue to: Although NES is a common...

Although NES is a common type of conversion disorder, it is often difficult to diagnose, manage, and treat. Patients often receive antiepileptic medications but continue to have worsening events that are refractory to treatment. Various clinical features can suggest NES instead of epilepsy. Forced eye closure on video recording is a specific finding suggestive of NES, yet this feature is not sufficient to make the diagnosis.⁴ A video EEG must be performed to assess for epilepsy. The diagnosis of NES does not exclude the possibility that a patient has epilepsy, as NES can occur in up to 40% of patients with epilepsy.⁵ A video EEG without ictal patterns before, during, and after an observed episode is diagnostic of NES.⁶

[polldaddy:10375874]

The authors’ observations

Conversion disorders such as NES are a presentation of neurologic symptoms that cannot be readily accounted for by other conditions and are often associated with antecedent trauma. Multiple factors in Ms. N’s history increase her risk of NES, including loss of multiple loved ones, ongoing legal involvement, and alleged sexual abuse by her father.

Victims of sexual abuse are more likely than the general population to demonstrate symptoms of conversion disorder, especially NES.^7,8 The onset of paroxysmal episodes after incestuous abuse in a teenage girl is characteristic of NES. Compared with patients with complex partial epilepsy (CPE), patients with NES are 3 times more likely to report sexual trauma.^9,10 Children who report sexual abuse that precedes NES are more likely to have been victimized by a first-degree relative than patients with CPE who report sexual abuse.¹¹ Risk factors for victims developing NES may be related to the severity of adversity, stress sensitivity, and decreased hippocampal volume.^12,13

Ms. N endorsed many psychiatric symptoms that accompany her paroxysmal episodes; this is similar to findings in other patients with NES._¹⁴ One study found that depression is 3 times more prevalent and PTSD is 8 times more prevalent in patients with NES.¹² During the evaluation, Ms. N’s mother said her daughter had low energy, poor appetite, lethargy, and anhedonia for the preceding 5 months, which is consistent with adjustment disorder._³ Her flashbacks, nightmares, difficulty sleeping, and agoraphobia, along with her trouble engaging with the people and activities that used to bring her joy, are symptoms of PTSD. Nonepileptic seizure is often associated with PTSD and can be viewed as an expression of a dissociated subtype.¹⁵

In a literature review, Durrant et al¹⁶ isolated prognostic indicators for NES (Table¹⁶). This study found that 70% of children and 40% of adults achieve remission from NES. Ms. N’s case has multiple concerning features, such as her comorbid psychiatric conditions, ongoing involvement in a legal case, and sexual trauma; this last factor is associated with the most severe symptoms and worse outcomes.^16,17 Despite this somber reality, Ms. N has the support of her mother and is relatively young, which play a vital role in recovery.

Continue to: TREATMENT A strategy for minimizing the episodes

Ms. N’s medical workup remains unremarkable throughout the rest of her hospital stay. The psychiatry and pediatric teams discuss their assessments and agree that NES is the most likely diagnosis. The psychiatry team counsels Ms. N and her mother on the diagnosis and etiology of NES.

[polldaddy:10375876]

The authors’ observations

Cognitive-behavioral therapy is currently the treatment of choice for reducing seizure frequency in patients with NES.^18,19 The use of CBT was suggested due to the theory that NES represents a dissociative response to trauma. Therapy focuses on changing a patient’s beliefs and perceptions associated with attacks.⁵ A randomized study of 66 patients with NES compared the use of CBT plus standard medical care with standard medical care alone.¹⁸ The standard medical care consisted of supportive treatment, an explanation of NES from a neuropsychiatrist, and supervised withdrawal of antiepileptic drugs. The CBT treatment group was offered weekly hour-long sessions for 12 weeks, accompanied by CBT homework and journaling the frequency and nature of seizure episodes (the CBT techniques are outlined in the Figure¹⁸). After 4 months, the CBT treatment group had fewer seizures, and after a 6-month follow-up, they were more likely to be seizure-free. However, in this study, CBT treatment did not improve mood or employment status.

A later investigation looked at using selective serotonin reuptake inhibitors to treat NES in adults.¹⁹ This study divided participants into 4 treatment groups: CBT with informed psychotherapy (CBT-ip), CBT-ip plus sertraline, sertraline alone, and treatment as usual. Sertraline was titrated up to a dose of 200 mg/d as tolerated. After 16 weeks of sertraline alone, seizure frequency did not decrease. Although both CBT groups showed a reduction in symptoms of up to 60%, the CBT-ip group reported fewer psychiatric symptoms with better social interactions, quality of life, and global functioning compared with patients treated with CBT-ip plus sertraline. The authors suggested that this may be due to the somatic adverse effects associated with sertraline. This study suggests that CBT without medication is the treatment of choice.

In addition to CBT, studies of psychodynamic psychotherapy for NES have had promising findings.²⁰ Psychodynamic psychotherapy focuses on addressing conscious and unconscious anger, loss, feelings of isolation, and trauma. Through improving emotional processing, insight, coping skills and self-regulation, patients often benefit from an improvement in seizures, psychosocial functioning and health care utilization.

Metin et al²¹ found that group therapy alongside a family-centered approach elicited a strong and durable reduction in seizures in patients with NES. At enrollment, investigators distributed information on NES to patients and families. Psychoeducation and psychoanalysis with behavior modification techniques were provided in 90-minute weekly group sessions over 3 months. Participants also underwent monthly individualized sessions for standard psychiatric care for 9 months. During the group sessions, operant conditioning techniques were used to prevent secondary gain from seizure-like activity. Families met 4 times for 1 hour each to discuss seizures, receive psychoeducation on a subconscious etiology of NES, and learn behavior modification techniques. All 9 participants who completed group and individual therapy reported a significant and sustained reduction in seizure frequency by at least 50% at 12-month follow-up. Patients also demonstrated improvements in mood, anxiety, and quality of life.

Continue to: A meta-analysis...

A meta-analysis by Carlson and Perry²² that included 13 studies and 228 participants, examined different treatment modalities and their effectiveness for NES. They found that patients who received psychological intervention had a 47% remission rate and 82% improvement in seizure frequency compared with only 14% to 23% of those who did not receive therapy. They postulated that therapy for this illness must be flexible to properly address the socially, psychologically, and functionally heterogenous patient population. Although there are few randomized controlled trials for NES to determine the best evidence-based intervention, there is now consensus that NES has a favorable prognosis when barriers to psychological care are eliminated.

OUTCOME Referral for CBT

The treatment team advises Ms. N to engage in outpatient therapy after discharge from the hospital. Ms. N and her mother agree to the treatment plan, and leave the hospital with a referral for CBT the next day.

Bottom Line

Nonepileptic seizure (NES) is a type of conversion disorder characterized by seizure-like episodes without ictal qualities. Risk factors for NES include concomitant epilepsy, psychiatric disorders, unstable psychosocial situations, and antecedent trauma. Patients with a history of incestuous sexual abuse are most at risk for developing NES. A normal EEG that fully captures a seizure-like episode is diagnostic of NES. Cognitive-behavioral therapy can minimize seizure frequency and intensity.

Related Resources

• Marsh P, Benbadis S, Fernandez F. Psychogenic nonepileptic seizures: ways to win over skeptical patients. Current Psychiatry. 2008;7(1):21-24, 32-35.
• LaFrance WC Jr. Eye-opening behaviors help diagnose nonepileptic seizures. Current Psychiatry. 2006;5(11):121-122, 124, 130.
• LaFrance WC Jr, Kanner AM, Barry JJ. Treating patients with psychological nonepileptic seizures. In: Ettinger AB, Kanner AM, eds. Psychiatric issues in epilepsy: a practical guide to diagnosis and treatment. 2nd ed. Philadelphia, PA: Wolters Kluwer Health/ Lippincott Williams & Wilkins; 2007:461-488.

Drug Brand Name

Sertraline • Zoloft

CASE Increasingly frequent paroxysmal episodes

Ms. N, age 12, comes to the hospital for evaluation of paroxysmal episodes of pain, weakness, and muscle spasms. A neurologist who evaluated her as an outpatient had recommended a routine electroencephalogram (EEG); after those results were inconclusive, Ms. N’s mother brought her to the hospital for a 24-hour video EEG.

Ms. N has a history of asthma. She has no history of seizures or headache, but her mother has an unspecified seizure disorder that has been stable with antiepileptic medication for many years. Ms. N has no other family history of autoimmune or neurologic disorders.

Ms. N’s episodes began 6 months ago and have progressively increased in frequency from 5 to 12 episodes a day. She says that before she has an episode, she “ feels tingling in her fingers and mouth, and butterflies in her belly,” and then her “whole body clenches up.” She denies experiencing tongue biting, facial or extremity weakness, incontinence, or loss of consciousness during these episodes.

Shortly before her hospitalization, Ms. N had won a scholarship to attend an overnight art camp. Because her episodes were becoming more frequent and their etiology remained unclear, Ms. N and her mother decided it would be unsafe for her to attend, and that she should go to the hospital for evaluation instead.

EVALUATION Tough questions reveal answers

The pediatric team evaluates Ms. N. Her physical exam, laboratory values, and imaging are all within normal limits. Her neurologic exam demonstrates full strength, tone, and sensation in all extremities. All cranial nerves and reflexes are intact. No dysmorphic features or gait abnormalities are noted. All laboratory and imaging tests are normal, including complete blood cell count, electrolytes, calcium, magnesium, phosphorus, glucose, creatine kinase, liver enzymes, urine drug screen, human chorionic gonadotropin (hCG) urine test, and head CT.

After the initial workup, the pediatric team consults the child and adolescent psychiatry team for a complete assessment of Ms. N due to concerns that a psychological component is contributing to her episodes. According to the psychosocial history obtained from Ms. N and her mother, Ms. N had experienced disrupted attachment, trauma, and loss. At age 5, Ms. N was temporarily removed from her mother’s custody after a fight between her mother and brother. At age 9, Ms. N’s stepfather, her primary father figure, died of a brain tumor.

Ms. N also has significant trauma stemming from her relationship with her biological father. Ms. N’s mother reports that her daughter was conceived during nonconsensual sexual intercourse. Ms. N did not have much contact with her biological father until 6 months ago, when he started picking her up at school and taking her to his home for several hours without permission or supervision. Afterwards, Ms. N confided to her mother and a teacher that her father sexually assaulted her during those visits.

Continue to: Ms. N and her mother...

Ms. N and her mother reported the assault to the police and were awaiting legal action.

During the interview with the psychiatry team, Ms. N denies that any thoughts or actions trigger the episodes and reports that she cannot control when they happen. Because she cannot anticipate the episodes, she says she is afraid to leave her house. She does not know why the episodes are happening and feels frustrated that they are getting worse. Ms. N says, “I have been feeling down lately,” but she denies hopelessness, worthlessness, suicidal ideation, homicidal ideation, delusions, or hallucinations.

In the hospital, when the psychiatry team asks Ms. N about her visits with her father, she says that they are “too painful to talk about,” and fears that discussing them will trigger an episode. However, her mother suggests that her daughter’s sexual trauma, as well as ongoing frustrations with the legal system, are influencing her mood; she has had low energy, poor appetite, and is spending more time in bed. Her mother also reports that Ms. N “avoids going out in the sun and spending time with her friends outside. She doesn’t seem to enjoy shopping and art like she used to.” Ms. N told her mother that she was having nightmares about the trauma and “could not stop thinking about some of the bad stuff that happened during the day.”

Ten minutes into the interview, while being questioned about her father, Ms. N experiences a spastic episode. She curls up in bed on her left side, clenches her entire body, and shuts her eyes. Her mother quickly runs to her bedside and counts the seconds until the end of the episode. After 25 seconds, Ms. N awakes with full recollection of the episode. On review of the video EEG during the episode, no ictal patterns are seen.

[polldaddy:10375873]

The authors’ observations

Paroxysmal episodes of weakness, numbness, and muscle spasms in a young female are suggestive of either epilepsy or nonepileptic seizure (NES).^1,2 The negative EEG and physical features are inconsistent with epileptiform seizure, and Ms. N’s history and evaluation are suggestive of NES. Nonepileptic seizures are a type of a conversion disorder, or functional neurologic symptom disorder, in which a patient experiences weakness, abnormal movements, or seizure-like episodes that are inconsistent with organic neurologic disease.³ When a diagnosis of conversion disorder is suspected, a clinician must always consider other pathology that can explain the symptoms, such as migraine, vasovagal syncope, or intracranial mass. If a patient has focal neurologic deficits, head imaging should be pursued. Additionally, the clinician must screen for malingering and factitious disorder before establishing a definitive diagnosis. However, conversion disorder is not a diagnosis of exclusion. For example, a negative EEG does not rule out epilepsy, and patients can have both epilepsy and concomitant NES.

Continue to: Although NES is a common...

Although NES is a common type of conversion disorder, it is often difficult to diagnose, manage, and treat. Patients often receive antiepileptic medications but continue to have worsening events that are refractory to treatment. Various clinical features can suggest NES instead of epilepsy. Forced eye closure on video recording is a specific finding suggestive of NES, yet this feature is not sufficient to make the diagnosis.⁴ A video EEG must be performed to assess for epilepsy. The diagnosis of NES does not exclude the possibility that a patient has epilepsy, as NES can occur in up to 40% of patients with epilepsy.⁵ A video EEG without ictal patterns before, during, and after an observed episode is diagnostic of NES.⁶

[polldaddy:10375874]

The authors’ observations

Conversion disorders such as NES are a presentation of neurologic symptoms that cannot be readily accounted for by other conditions and are often associated with antecedent trauma. Multiple factors in Ms. N’s history increase her risk of NES, including loss of multiple loved ones, ongoing legal involvement, and alleged sexual abuse by her father.

Victims of sexual abuse are more likely than the general population to demonstrate symptoms of conversion disorder, especially NES.^7,8 The onset of paroxysmal episodes after incestuous abuse in a teenage girl is characteristic of NES. Compared with patients with complex partial epilepsy (CPE), patients with NES are 3 times more likely to report sexual trauma.^9,10 Children who report sexual abuse that precedes NES are more likely to have been victimized by a first-degree relative than patients with CPE who report sexual abuse.¹¹ Risk factors for victims developing NES may be related to the severity of adversity, stress sensitivity, and decreased hippocampal volume.^12,13

Ms. N endorsed many psychiatric symptoms that accompany her paroxysmal episodes; this is similar to findings in other patients with NES._¹⁴ One study found that depression is 3 times more prevalent and PTSD is 8 times more prevalent in patients with NES.¹² During the evaluation, Ms. N’s mother said her daughter had low energy, poor appetite, lethargy, and anhedonia for the preceding 5 months, which is consistent with adjustment disorder._³ Her flashbacks, nightmares, difficulty sleeping, and agoraphobia, along with her trouble engaging with the people and activities that used to bring her joy, are symptoms of PTSD. Nonepileptic seizure is often associated with PTSD and can be viewed as an expression of a dissociated subtype.¹⁵

In a literature review, Durrant et al¹⁶ isolated prognostic indicators for NES (Table¹⁶). This study found that 70% of children and 40% of adults achieve remission from NES. Ms. N’s case has multiple concerning features, such as her comorbid psychiatric conditions, ongoing involvement in a legal case, and sexual trauma; this last factor is associated with the most severe symptoms and worse outcomes.^16,17 Despite this somber reality, Ms. N has the support of her mother and is relatively young, which play a vital role in recovery.

Continue to: TREATMENT A strategy for minimizing the episodes

Ms. N’s medical workup remains unremarkable throughout the rest of her hospital stay. The psychiatry and pediatric teams discuss their assessments and agree that NES is the most likely diagnosis. The psychiatry team counsels Ms. N and her mother on the diagnosis and etiology of NES.

[polldaddy:10375876]

The authors’ observations

Cognitive-behavioral therapy is currently the treatment of choice for reducing seizure frequency in patients with NES.^18,19 The use of CBT was suggested due to the theory that NES represents a dissociative response to trauma. Therapy focuses on changing a patient’s beliefs and perceptions associated with attacks.⁵ A randomized study of 66 patients with NES compared the use of CBT plus standard medical care with standard medical care alone.¹⁸ The standard medical care consisted of supportive treatment, an explanation of NES from a neuropsychiatrist, and supervised withdrawal of antiepileptic drugs. The CBT treatment group was offered weekly hour-long sessions for 12 weeks, accompanied by CBT homework and journaling the frequency and nature of seizure episodes (the CBT techniques are outlined in the Figure¹⁸). After 4 months, the CBT treatment group had fewer seizures, and after a 6-month follow-up, they were more likely to be seizure-free. However, in this study, CBT treatment did not improve mood or employment status.

A later investigation looked at using selective serotonin reuptake inhibitors to treat NES in adults.¹⁹ This study divided participants into 4 treatment groups: CBT with informed psychotherapy (CBT-ip), CBT-ip plus sertraline, sertraline alone, and treatment as usual. Sertraline was titrated up to a dose of 200 mg/d as tolerated. After 16 weeks of sertraline alone, seizure frequency did not decrease. Although both CBT groups showed a reduction in symptoms of up to 60%, the CBT-ip group reported fewer psychiatric symptoms with better social interactions, quality of life, and global functioning compared with patients treated with CBT-ip plus sertraline. The authors suggested that this may be due to the somatic adverse effects associated with sertraline. This study suggests that CBT without medication is the treatment of choice.

In addition to CBT, studies of psychodynamic psychotherapy for NES have had promising findings.²⁰ Psychodynamic psychotherapy focuses on addressing conscious and unconscious anger, loss, feelings of isolation, and trauma. Through improving emotional processing, insight, coping skills and self-regulation, patients often benefit from an improvement in seizures, psychosocial functioning and health care utilization.

Metin et al²¹ found that group therapy alongside a family-centered approach elicited a strong and durable reduction in seizures in patients with NES. At enrollment, investigators distributed information on NES to patients and families. Psychoeducation and psychoanalysis with behavior modification techniques were provided in 90-minute weekly group sessions over 3 months. Participants also underwent monthly individualized sessions for standard psychiatric care for 9 months. During the group sessions, operant conditioning techniques were used to prevent secondary gain from seizure-like activity. Families met 4 times for 1 hour each to discuss seizures, receive psychoeducation on a subconscious etiology of NES, and learn behavior modification techniques. All 9 participants who completed group and individual therapy reported a significant and sustained reduction in seizure frequency by at least 50% at 12-month follow-up. Patients also demonstrated improvements in mood, anxiety, and quality of life.

Continue to: A meta-analysis...

A meta-analysis by Carlson and Perry²² that included 13 studies and 228 participants, examined different treatment modalities and their effectiveness for NES. They found that patients who received psychological intervention had a 47% remission rate and 82% improvement in seizure frequency compared with only 14% to 23% of those who did not receive therapy. They postulated that therapy for this illness must be flexible to properly address the socially, psychologically, and functionally heterogenous patient population. Although there are few randomized controlled trials for NES to determine the best evidence-based intervention, there is now consensus that NES has a favorable prognosis when barriers to psychological care are eliminated.

OUTCOME Referral for CBT

The treatment team advises Ms. N to engage in outpatient therapy after discharge from the hospital. Ms. N and her mother agree to the treatment plan, and leave the hospital with a referral for CBT the next day.

Bottom Line

Nonepileptic seizure (NES) is a type of conversion disorder characterized by seizure-like episodes without ictal qualities. Risk factors for NES include concomitant epilepsy, psychiatric disorders, unstable psychosocial situations, and antecedent trauma. Patients with a history of incestuous sexual abuse are most at risk for developing NES. A normal EEG that fully captures a seizure-like episode is diagnostic of NES. Cognitive-behavioral therapy can minimize seizure frequency and intensity.

Related Resources

• Marsh P, Benbadis S, Fernandez F. Psychogenic nonepileptic seizures: ways to win over skeptical patients. Current Psychiatry. 2008;7(1):21-24, 32-35.
• LaFrance WC Jr. Eye-opening behaviors help diagnose nonepileptic seizures. Current Psychiatry. 2006;5(11):121-122, 124, 130.
• LaFrance WC Jr, Kanner AM, Barry JJ. Treating patients with psychological nonepileptic seizures. In: Ettinger AB, Kanner AM, eds. Psychiatric issues in epilepsy: a practical guide to diagnosis and treatment. 2nd ed. Philadelphia, PA: Wolters Kluwer Health/ Lippincott Williams & Wilkins; 2007:461-488.

Drug Brand Name

Sertraline • Zoloft

CASE Increasingly frequent paroxysmal episodes

Ms. N, age 12, comes to the hospital for evaluation of paroxysmal episodes of pain, weakness, and muscle spasms. A neurologist who evaluated her as an outpatient had recommended a routine electroencephalogram (EEG); after those results were inconclusive, Ms. N’s mother brought her to the hospital for a 24-hour video EEG.

Ms. N has a history of asthma. She has no history of seizures or headache, but her mother has an unspecified seizure disorder that has been stable with antiepileptic medication for many years. Ms. N has no other family history of autoimmune or neurologic disorders.

Ms. N’s episodes began 6 months ago and have progressively increased in frequency from 5 to 12 episodes a day. She says that before she has an episode, she “ feels tingling in her fingers and mouth, and butterflies in her belly,” and then her “whole body clenches up.” She denies experiencing tongue biting, facial or extremity weakness, incontinence, or loss of consciousness during these episodes.

Shortly before her hospitalization, Ms. N had won a scholarship to attend an overnight art camp. Because her episodes were becoming more frequent and their etiology remained unclear, Ms. N and her mother decided it would be unsafe for her to attend, and that she should go to the hospital for evaluation instead.

EVALUATION Tough questions reveal answers

The pediatric team evaluates Ms. N. Her physical exam, laboratory values, and imaging are all within normal limits. Her neurologic exam demonstrates full strength, tone, and sensation in all extremities. All cranial nerves and reflexes are intact. No dysmorphic features or gait abnormalities are noted. All laboratory and imaging tests are normal, including complete blood cell count, electrolytes, calcium, magnesium, phosphorus, glucose, creatine kinase, liver enzymes, urine drug screen, human chorionic gonadotropin (hCG) urine test, and head CT.

After the initial workup, the pediatric team consults the child and adolescent psychiatry team for a complete assessment of Ms. N due to concerns that a psychological component is contributing to her episodes. According to the psychosocial history obtained from Ms. N and her mother, Ms. N had experienced disrupted attachment, trauma, and loss. At age 5, Ms. N was temporarily removed from her mother’s custody after a fight between her mother and brother. At age 9, Ms. N’s stepfather, her primary father figure, died of a brain tumor.

Ms. N also has significant trauma stemming from her relationship with her biological father. Ms. N’s mother reports that her daughter was conceived during nonconsensual sexual intercourse. Ms. N did not have much contact with her biological father until 6 months ago, when he started picking her up at school and taking her to his home for several hours without permission or supervision. Afterwards, Ms. N confided to her mother and a teacher that her father sexually assaulted her during those visits.

Continue to: Ms. N and her mother...

Ms. N and her mother reported the assault to the police and were awaiting legal action.

During the interview with the psychiatry team, Ms. N denies that any thoughts or actions trigger the episodes and reports that she cannot control when they happen. Because she cannot anticipate the episodes, she says she is afraid to leave her house. She does not know why the episodes are happening and feels frustrated that they are getting worse. Ms. N says, “I have been feeling down lately,” but she denies hopelessness, worthlessness, suicidal ideation, homicidal ideation, delusions, or hallucinations.

In the hospital, when the psychiatry team asks Ms. N about her visits with her father, she says that they are “too painful to talk about,” and fears that discussing them will trigger an episode. However, her mother suggests that her daughter’s sexual trauma, as well as ongoing frustrations with the legal system, are influencing her mood; she has had low energy, poor appetite, and is spending more time in bed. Her mother also reports that Ms. N “avoids going out in the sun and spending time with her friends outside. She doesn’t seem to enjoy shopping and art like she used to.” Ms. N told her mother that she was having nightmares about the trauma and “could not stop thinking about some of the bad stuff that happened during the day.”

Ten minutes into the interview, while being questioned about her father, Ms. N experiences a spastic episode. She curls up in bed on her left side, clenches her entire body, and shuts her eyes. Her mother quickly runs to her bedside and counts the seconds until the end of the episode. After 25 seconds, Ms. N awakes with full recollection of the episode. On review of the video EEG during the episode, no ictal patterns are seen.

[polldaddy:10375873]

The authors’ observations

Paroxysmal episodes of weakness, numbness, and muscle spasms in a young female are suggestive of either epilepsy or nonepileptic seizure (NES).^1,2 The negative EEG and physical features are inconsistent with epileptiform seizure, and Ms. N’s history and evaluation are suggestive of NES. Nonepileptic seizures are a type of a conversion disorder, or functional neurologic symptom disorder, in which a patient experiences weakness, abnormal movements, or seizure-like episodes that are inconsistent with organic neurologic disease.³ When a diagnosis of conversion disorder is suspected, a clinician must always consider other pathology that can explain the symptoms, such as migraine, vasovagal syncope, or intracranial mass. If a patient has focal neurologic deficits, head imaging should be pursued. Additionally, the clinician must screen for malingering and factitious disorder before establishing a definitive diagnosis. However, conversion disorder is not a diagnosis of exclusion. For example, a negative EEG does not rule out epilepsy, and patients can have both epilepsy and concomitant NES.

Continue to: Although NES is a common...

Although NES is a common type of conversion disorder, it is often difficult to diagnose, manage, and treat. Patients often receive antiepileptic medications but continue to have worsening events that are refractory to treatment. Various clinical features can suggest NES instead of epilepsy. Forced eye closure on video recording is a specific finding suggestive of NES, yet this feature is not sufficient to make the diagnosis.⁴ A video EEG must be performed to assess for epilepsy. The diagnosis of NES does not exclude the possibility that a patient has epilepsy, as NES can occur in up to 40% of patients with epilepsy.⁵ A video EEG without ictal patterns before, during, and after an observed episode is diagnostic of NES.⁶

[polldaddy:10375874]

The authors’ observations

Conversion disorders such as NES are a presentation of neurologic symptoms that cannot be readily accounted for by other conditions and are often associated with antecedent trauma. Multiple factors in Ms. N’s history increase her risk of NES, including loss of multiple loved ones, ongoing legal involvement, and alleged sexual abuse by her father.

Victims of sexual abuse are more likely than the general population to demonstrate symptoms of conversion disorder, especially NES.^7,8 The onset of paroxysmal episodes after incestuous abuse in a teenage girl is characteristic of NES. Compared with patients with complex partial epilepsy (CPE), patients with NES are 3 times more likely to report sexual trauma.^9,10 Children who report sexual abuse that precedes NES are more likely to have been victimized by a first-degree relative than patients with CPE who report sexual abuse.¹¹ Risk factors for victims developing NES may be related to the severity of adversity, stress sensitivity, and decreased hippocampal volume.^12,13

Ms. N endorsed many psychiatric symptoms that accompany her paroxysmal episodes; this is similar to findings in other patients with NES._¹⁴ One study found that depression is 3 times more prevalent and PTSD is 8 times more prevalent in patients with NES.¹² During the evaluation, Ms. N’s mother said her daughter had low energy, poor appetite, lethargy, and anhedonia for the preceding 5 months, which is consistent with adjustment disorder._³ Her flashbacks, nightmares, difficulty sleeping, and agoraphobia, along with her trouble engaging with the people and activities that used to bring her joy, are symptoms of PTSD. Nonepileptic seizure is often associated with PTSD and can be viewed as an expression of a dissociated subtype.¹⁵

In a literature review, Durrant et al¹⁶ isolated prognostic indicators for NES (Table¹⁶). This study found that 70% of children and 40% of adults achieve remission from NES. Ms. N’s case has multiple concerning features, such as her comorbid psychiatric conditions, ongoing involvement in a legal case, and sexual trauma; this last factor is associated with the most severe symptoms and worse outcomes.^16,17 Despite this somber reality, Ms. N has the support of her mother and is relatively young, which play a vital role in recovery.

Continue to: TREATMENT A strategy for minimizing the episodes

Ms. N’s medical workup remains unremarkable throughout the rest of her hospital stay. The psychiatry and pediatric teams discuss their assessments and agree that NES is the most likely diagnosis. The psychiatry team counsels Ms. N and her mother on the diagnosis and etiology of NES.

[polldaddy:10375876]

The authors’ observations

Cognitive-behavioral therapy is currently the treatment of choice for reducing seizure frequency in patients with NES.^18,19 The use of CBT was suggested due to the theory that NES represents a dissociative response to trauma. Therapy focuses on changing a patient’s beliefs and perceptions associated with attacks.⁵ A randomized study of 66 patients with NES compared the use of CBT plus standard medical care with standard medical care alone.¹⁸ The standard medical care consisted of supportive treatment, an explanation of NES from a neuropsychiatrist, and supervised withdrawal of antiepileptic drugs. The CBT treatment group was offered weekly hour-long sessions for 12 weeks, accompanied by CBT homework and journaling the frequency and nature of seizure episodes (the CBT techniques are outlined in the Figure¹⁸). After 4 months, the CBT treatment group had fewer seizures, and after a 6-month follow-up, they were more likely to be seizure-free. However, in this study, CBT treatment did not improve mood or employment status.

A later investigation looked at using selective serotonin reuptake inhibitors to treat NES in adults.¹⁹ This study divided participants into 4 treatment groups: CBT with informed psychotherapy (CBT-ip), CBT-ip plus sertraline, sertraline alone, and treatment as usual. Sertraline was titrated up to a dose of 200 mg/d as tolerated. After 16 weeks of sertraline alone, seizure frequency did not decrease. Although both CBT groups showed a reduction in symptoms of up to 60%, the CBT-ip group reported fewer psychiatric symptoms with better social interactions, quality of life, and global functioning compared with patients treated with CBT-ip plus sertraline. The authors suggested that this may be due to the somatic adverse effects associated with sertraline. This study suggests that CBT without medication is the treatment of choice.

In addition to CBT, studies of psychodynamic psychotherapy for NES have had promising findings.²⁰ Psychodynamic psychotherapy focuses on addressing conscious and unconscious anger, loss, feelings of isolation, and trauma. Through improving emotional processing, insight, coping skills and self-regulation, patients often benefit from an improvement in seizures, psychosocial functioning and health care utilization.

Metin et al²¹ found that group therapy alongside a family-centered approach elicited a strong and durable reduction in seizures in patients with NES. At enrollment, investigators distributed information on NES to patients and families. Psychoeducation and psychoanalysis with behavior modification techniques were provided in 90-minute weekly group sessions over 3 months. Participants also underwent monthly individualized sessions for standard psychiatric care for 9 months. During the group sessions, operant conditioning techniques were used to prevent secondary gain from seizure-like activity. Families met 4 times for 1 hour each to discuss seizures, receive psychoeducation on a subconscious etiology of NES, and learn behavior modification techniques. All 9 participants who completed group and individual therapy reported a significant and sustained reduction in seizure frequency by at least 50% at 12-month follow-up. Patients also demonstrated improvements in mood, anxiety, and quality of life.

Continue to: A meta-analysis...

A meta-analysis by Carlson and Perry²² that included 13 studies and 228 participants, examined different treatment modalities and their effectiveness for NES. They found that patients who received psychological intervention had a 47% remission rate and 82% improvement in seizure frequency compared with only 14% to 23% of those who did not receive therapy. They postulated that therapy for this illness must be flexible to properly address the socially, psychologically, and functionally heterogenous patient population. Although there are few randomized controlled trials for NES to determine the best evidence-based intervention, there is now consensus that NES has a favorable prognosis when barriers to psychological care are eliminated.

OUTCOME Referral for CBT

The treatment team advises Ms. N to engage in outpatient therapy after discharge from the hospital. Ms. N and her mother agree to the treatment plan, and leave the hospital with a referral for CBT the next day.

Bottom Line

Nonepileptic seizure (NES) is a type of conversion disorder characterized by seizure-like episodes without ictal qualities. Risk factors for NES include concomitant epilepsy, psychiatric disorders, unstable psychosocial situations, and antecedent trauma. Patients with a history of incestuous sexual abuse are most at risk for developing NES. A normal EEG that fully captures a seizure-like episode is diagnostic of NES. Cognitive-behavioral therapy can minimize seizure frequency and intensity.

Related Resources

• Marsh P, Benbadis S, Fernandez F. Psychogenic nonepileptic seizures: ways to win over skeptical patients. Current Psychiatry. 2008;7(1):21-24, 32-35.
• LaFrance WC Jr. Eye-opening behaviors help diagnose nonepileptic seizures. Current Psychiatry. 2006;5(11):121-122, 124, 130.
• LaFrance WC Jr, Kanner AM, Barry JJ. Treating patients with psychological nonepileptic seizures. In: Ettinger AB, Kanner AM, eds. Psychiatric issues in epilepsy: a practical guide to diagnosis and treatment. 2nd ed. Philadelphia, PA: Wolters Kluwer Health/ Lippincott Williams & Wilkins; 2007:461-488.

Drug Brand Name

Sertraline • Zoloft

To determine whether a patient meets the criteria for a DSM-5 diagnosis, we rely on objective data, direct observations, and individual biopsychosocial factors as well as our patient’s subjective report of symptoms. However, because the line differentiating normal from abnormal emotional responses can sometimes be blurred, we should be prudent when establishing a diagnosis. Specifically, we need to avoid falling into the trap of “checklist” psychiatry—relegating diagnostic assessments to robotic statements about whether patients meet DSM criteria—because this can lead to making diagnoses too quickly or inaccurately.¹ Potential consequences of checklist psychiatry include^1,2:

• becoming so “married” to a particular diagnosis that you don’t consider alternative diagnoses
• labeling patients with a diagnosis that many clinicians may view as pejorative (eg, antisocial personality disorder), which might affect their ability to receive future treatment
• developing ineffective treatment plans based on an incorrect diagnosis, including exposing patients to medications that could have serious adverse effects
• performing suicide or violence risk assessments based on inaccurate diagnoses, thereby over- or underestimating the possible risk for an adverse outcome
• leading patients to assume the identity of the inaccurate diagnosis and possibly viewing themselves as dysfunctional or impaired.

When you are uncertain whether your patient has a diagnosable condition, it can be useful to use the terms “no diagnosis” or “diagnosis deferred.” However, many insurance companies will not reimburse without an actual diagnosis. Therefore, the following tips may be helpful in establishing an accurate diagnosis while avoiding checklist psychiatry.^1,2

Ask patients about the degree and duration of impairment in functioning. Although impairment in functioning is a criterion of almost all DSM-5 diagnoses, not all endorsed symptoms warrant a diagnosis. Mild symptoms often resolve spontaneously over time without the need for diagnostic labels or interventions.

Make longitudinal observations. Inter­viewing patients over a long period of time and on multiple occasions can provide data on the consistency of reported symptoms, the presence or absence of behavioral correlates to reported symptomatology, the degree of impairment from the reported symptoms, and the evolution of symptoms.

Collect collateral information. Although we often rely on our patients’ reports of symptoms to establish a diagnosis, this information should not be the sole source. We can obtain a more complete picture if we approach a patient’s family members for their input, including asking about a family history of mental illness or substance use disorders. We can also review prior treatment records and gather observations from clinic or inpatient staff for additional information.

Order laboratory studies. Serum studies and urine toxicology screens provide information that can help form an accurate diagnosis. This information is helpful because certain medical conditions, substance intoxication, and substance withdrawal can mimic psychiatric symptoms.

Continuously re-evaluate your diagnoses. As clinicians, we’d like to provide an accurate diagnosis at the onset of treatment; however, this may not be realistic because the patient’s presentation might change over time. It is paramount that we view diagnoses as evolving, so that we can more readily adjust our approach to treatment, especially when the patient is not benefitting from a well-formulated and comprehensive treatment plan.

Our patients are best served when we take the necessary time to use all resources to conceptualize them as more than a checklist of symptoms.

To determine whether a patient meets the criteria for a DSM-5 diagnosis, we rely on objective data, direct observations, and individual biopsychosocial factors as well as our patient’s subjective report of symptoms. However, because the line differentiating normal from abnormal emotional responses can sometimes be blurred, we should be prudent when establishing a diagnosis. Specifically, we need to avoid falling into the trap of “checklist” psychiatry—relegating diagnostic assessments to robotic statements about whether patients meet DSM criteria—because this can lead to making diagnoses too quickly or inaccurately.¹ Potential consequences of checklist psychiatry include^1,2:

• becoming so “married” to a particular diagnosis that you don’t consider alternative diagnoses
• labeling patients with a diagnosis that many clinicians may view as pejorative (eg, antisocial personality disorder), which might affect their ability to receive future treatment
• developing ineffective treatment plans based on an incorrect diagnosis, including exposing patients to medications that could have serious adverse effects
• performing suicide or violence risk assessments based on inaccurate diagnoses, thereby over- or underestimating the possible risk for an adverse outcome
• leading patients to assume the identity of the inaccurate diagnosis and possibly viewing themselves as dysfunctional or impaired.

When you are uncertain whether your patient has a diagnosable condition, it can be useful to use the terms “no diagnosis” or “diagnosis deferred.” However, many insurance companies will not reimburse without an actual diagnosis. Therefore, the following tips may be helpful in establishing an accurate diagnosis while avoiding checklist psychiatry.^1,2

Ask patients about the degree and duration of impairment in functioning. Although impairment in functioning is a criterion of almost all DSM-5 diagnoses, not all endorsed symptoms warrant a diagnosis. Mild symptoms often resolve spontaneously over time without the need for diagnostic labels or interventions.

Make longitudinal observations. Inter­viewing patients over a long period of time and on multiple occasions can provide data on the consistency of reported symptoms, the presence or absence of behavioral correlates to reported symptomatology, the degree of impairment from the reported symptoms, and the evolution of symptoms.

Collect collateral information. Although we often rely on our patients’ reports of symptoms to establish a diagnosis, this information should not be the sole source. We can obtain a more complete picture if we approach a patient’s family members for their input, including asking about a family history of mental illness or substance use disorders. We can also review prior treatment records and gather observations from clinic or inpatient staff for additional information.

Order laboratory studies. Serum studies and urine toxicology screens provide information that can help form an accurate diagnosis. This information is helpful because certain medical conditions, substance intoxication, and substance withdrawal can mimic psychiatric symptoms.

Continuously re-evaluate your diagnoses. As clinicians, we’d like to provide an accurate diagnosis at the onset of treatment; however, this may not be realistic because the patient’s presentation might change over time. It is paramount that we view diagnoses as evolving, so that we can more readily adjust our approach to treatment, especially when the patient is not benefitting from a well-formulated and comprehensive treatment plan.

Our patients are best served when we take the necessary time to use all resources to conceptualize them as more than a checklist of symptoms.

To determine whether a patient meets the criteria for a DSM-5 diagnosis, we rely on objective data, direct observations, and individual biopsychosocial factors as well as our patient’s subjective report of symptoms. However, because the line differentiating normal from abnormal emotional responses can sometimes be blurred, we should be prudent when establishing a diagnosis. Specifically, we need to avoid falling into the trap of “checklist” psychiatry—relegating diagnostic assessments to robotic statements about whether patients meet DSM criteria—because this can lead to making diagnoses too quickly or inaccurately.¹ Potential consequences of checklist psychiatry include^1,2:

• becoming so “married” to a particular diagnosis that you don’t consider alternative diagnoses
• labeling patients with a diagnosis that many clinicians may view as pejorative (eg, antisocial personality disorder), which might affect their ability to receive future treatment
• developing ineffective treatment plans based on an incorrect diagnosis, including exposing patients to medications that could have serious adverse effects
• performing suicide or violence risk assessments based on inaccurate diagnoses, thereby over- or underestimating the possible risk for an adverse outcome
• leading patients to assume the identity of the inaccurate diagnosis and possibly viewing themselves as dysfunctional or impaired.

When you are uncertain whether your patient has a diagnosable condition, it can be useful to use the terms “no diagnosis” or “diagnosis deferred.” However, many insurance companies will not reimburse without an actual diagnosis. Therefore, the following tips may be helpful in establishing an accurate diagnosis while avoiding checklist psychiatry.^1,2

Ask patients about the degree and duration of impairment in functioning. Although impairment in functioning is a criterion of almost all DSM-5 diagnoses, not all endorsed symptoms warrant a diagnosis. Mild symptoms often resolve spontaneously over time without the need for diagnostic labels or interventions.

Make longitudinal observations. Inter­viewing patients over a long period of time and on multiple occasions can provide data on the consistency of reported symptoms, the presence or absence of behavioral correlates to reported symptomatology, the degree of impairment from the reported symptoms, and the evolution of symptoms.

Collect collateral information. Although we often rely on our patients’ reports of symptoms to establish a diagnosis, this information should not be the sole source. We can obtain a more complete picture if we approach a patient’s family members for their input, including asking about a family history of mental illness or substance use disorders. We can also review prior treatment records and gather observations from clinic or inpatient staff for additional information.

Order laboratory studies. Serum studies and urine toxicology screens provide information that can help form an accurate diagnosis. This information is helpful because certain medical conditions, substance intoxication, and substance withdrawal can mimic psychiatric symptoms.

Continuously re-evaluate your diagnoses. As clinicians, we’d like to provide an accurate diagnosis at the onset of treatment; however, this may not be realistic because the patient’s presentation might change over time. It is paramount that we view diagnoses as evolving, so that we can more readily adjust our approach to treatment, especially when the patient is not benefitting from a well-formulated and comprehensive treatment plan.

Our patients are best served when we take the necessary time to use all resources to conceptualize them as more than a checklist of symptoms.

Child trafficking—a modern-day form of slavery that continues to destroy many lives—often is hidden, even from the clinicians who see its victims. Traffickers typically exploit children for labor or commercial sexual work. The signs and symptoms that suggest a child is being trafficked may be less clear than those of the psychiatric illnesses we usually diagnose and treat. In this article, I summarize characteristics that could be helpful to note when you suspect a child is being trafficked, and offer some resources for helping victims.

How to identify possible victims

Children can be trafficked anywhere. The concept of a child being picked up off a street corner is outdated. Trafficking occurs in cities, suburbs, and rural areas. It happens in hotel rooms, at truck stops, on quiet residential streets, and in expensive homes. The internet has made it easier for traffickers to find victims.

Traffickers typically target youth who are emotionally and physically vulnerable. They often seek out teenagers who are undergoing financial hardships, experiencing family conflict, or have survived natural disasters. Many victims are runaways. In 2016, 1 in 6 child runaways reported to the National Center for Missing and Exploited Children were likely victims of trafficking.¹ Of those children, 86% were receiving social services support or living in foster homes.

Traffickers are adept at emotional manipulation, which may explain why a child or adolescent might minimize the abuse during a clinical visit. Traffickers shroud the realities of trafficking with notions of love and inclusion. They use several physical and mental schemes to keep children and adolescents in their grip, such as withholding food, sleep, or medical care. Therefore, we should check for signs and symptoms of chronic medical conditions that have gone untreated, malnutrition, or bruises in various stages of healing.

Connecting risk factors for trafficking to dramatic changes in a young patient’s behavior is challenging. These youth often have dropped out of school, lack consistent family support, and spend their nights in search of a warm place to sleep. Their lives are upended. A child who once was more social may be forced into isolation and make excuses for why she no longer spends time with her friends.

In a study of 106 survivors of domestic sex trafficking, approximately 89% of respondents reported depression during depression. Many respondents reported experiencing anxiety (76.4%), nightmares (73.6%), flashbacks (68%), low self-esteem (81.1%), or feelings of shame or guilt (82.1%).² Almost 88% of respondents said that they saw a doctor or other clinician while being trafficked, but their clinicians were unable to recognize the signs of trafficking. Part of the challenge is that many children and adolescents are not comfortable discussing their situations with clinicians because they may struggle with shame and guilt. Their traffickers also might have convinced them that they are criminals, not victims. These patients also may have an overwhelming fear of their trafficker, being reported to child welfare authorities, being arrested, being deported, or having their traffickers retaliate against their families. Gaining the trust of a patient who is being trafficked is critical, but not easy, because children may be skeptical of a clinician’s promise of confidentiality.

Some signs of trafficking overlap with the psychiatric presentations with which we are more familiar. These patients may abuse drugs or alcohol as means of escape or because their traffickers force them to use substances.² They may show symptoms of depression or posttraumatic stress disorder (PTSD) and may be disoriented. Other indicators may be more telling, such as if a child or adolescent describes:

• having no control of their schedules or forms of identification
• having to work excessively long hours, often to pay off an overwhelming debt
• having high security measures installed in their place of residence (such as cameras or barred windows).

Continue to: Also, they may be...

Also, they may be dressed inappropriately for the weather.

We should be concerned when patients’ responses seem coached, if they say they are isolated from their family and community, or if they are submissive or overly timid. In addition, our suspicions should be raised if an accompanying adult guardian insists on sitting in on the appointment or translating for the child. In such instances, we may request that the guardian remain in the waiting area during the appointment so the child will have the opportunity to speak freely.²

How to help a suspected victim

Several local and national organizations help trafficking victims. These organizations provide educational materials and training opportunities for clinicians, as well as direct support for victims. The Homeland Security Blue Campaign advises against confronting a suspected trafficker directly and encourages clinicians to instead report suspected cases to 1-866-347-2423.³

Clinicians can better help children who are trafficked by taking the following 5 steps:

1. Learn about the risk factors and signs of child trafficking.
2. Post the National Human Trafficking Hotline (1-888-373-7888) in your waiting room.
3. Determine if your patient is in danger and needs to be moved to a safe place.
4. Connect the patient to social service agencies that can provide financial support and housing assistance so he/she doesn’t feel trapped by financial burdens.
5. Work to rebuild their emotional and physical well-being while treating depression, PTSD, substance abuse, or any other mental illness.

Child trafficking—a modern-day form of slavery that continues to destroy many lives—often is hidden, even from the clinicians who see its victims. Traffickers typically exploit children for labor or commercial sexual work. The signs and symptoms that suggest a child is being trafficked may be less clear than those of the psychiatric illnesses we usually diagnose and treat. In this article, I summarize characteristics that could be helpful to note when you suspect a child is being trafficked, and offer some resources for helping victims.

How to identify possible victims

Children can be trafficked anywhere. The concept of a child being picked up off a street corner is outdated. Trafficking occurs in cities, suburbs, and rural areas. It happens in hotel rooms, at truck stops, on quiet residential streets, and in expensive homes. The internet has made it easier for traffickers to find victims.

Traffickers typically target youth who are emotionally and physically vulnerable. They often seek out teenagers who are undergoing financial hardships, experiencing family conflict, or have survived natural disasters. Many victims are runaways. In 2016, 1 in 6 child runaways reported to the National Center for Missing and Exploited Children were likely victims of trafficking.¹ Of those children, 86% were receiving social services support or living in foster homes.

Traffickers are adept at emotional manipulation, which may explain why a child or adolescent might minimize the abuse during a clinical visit. Traffickers shroud the realities of trafficking with notions of love and inclusion. They use several physical and mental schemes to keep children and adolescents in their grip, such as withholding food, sleep, or medical care. Therefore, we should check for signs and symptoms of chronic medical conditions that have gone untreated, malnutrition, or bruises in various stages of healing.

Connecting risk factors for trafficking to dramatic changes in a young patient’s behavior is challenging. These youth often have dropped out of school, lack consistent family support, and spend their nights in search of a warm place to sleep. Their lives are upended. A child who once was more social may be forced into isolation and make excuses for why she no longer spends time with her friends.

In a study of 106 survivors of domestic sex trafficking, approximately 89% of respondents reported depression during depression. Many respondents reported experiencing anxiety (76.4%), nightmares (73.6%), flashbacks (68%), low self-esteem (81.1%), or feelings of shame or guilt (82.1%).² Almost 88% of respondents said that they saw a doctor or other clinician while being trafficked, but their clinicians were unable to recognize the signs of trafficking. Part of the challenge is that many children and adolescents are not comfortable discussing their situations with clinicians because they may struggle with shame and guilt. Their traffickers also might have convinced them that they are criminals, not victims. These patients also may have an overwhelming fear of their trafficker, being reported to child welfare authorities, being arrested, being deported, or having their traffickers retaliate against their families. Gaining the trust of a patient who is being trafficked is critical, but not easy, because children may be skeptical of a clinician’s promise of confidentiality.

Some signs of trafficking overlap with the psychiatric presentations with which we are more familiar. These patients may abuse drugs or alcohol as means of escape or because their traffickers force them to use substances.² They may show symptoms of depression or posttraumatic stress disorder (PTSD) and may be disoriented. Other indicators may be more telling, such as if a child or adolescent describes:

• having no control of their schedules or forms of identification
• having to work excessively long hours, often to pay off an overwhelming debt
• having high security measures installed in their place of residence (such as cameras or barred windows).

Continue to: Also, they may be...

Also, they may be dressed inappropriately for the weather.

We should be concerned when patients’ responses seem coached, if they say they are isolated from their family and community, or if they are submissive or overly timid. In addition, our suspicions should be raised if an accompanying adult guardian insists on sitting in on the appointment or translating for the child. In such instances, we may request that the guardian remain in the waiting area during the appointment so the child will have the opportunity to speak freely.²

How to help a suspected victim

Several local and national organizations help trafficking victims. These organizations provide educational materials and training opportunities for clinicians, as well as direct support for victims. The Homeland Security Blue Campaign advises against confronting a suspected trafficker directly and encourages clinicians to instead report suspected cases to 1-866-347-2423.³

Clinicians can better help children who are trafficked by taking the following 5 steps:

1. Learn about the risk factors and signs of child trafficking.
2. Post the National Human Trafficking Hotline (1-888-373-7888) in your waiting room.
3. Determine if your patient is in danger and needs to be moved to a safe place.
4. Connect the patient to social service agencies that can provide financial support and housing assistance so he/she doesn’t feel trapped by financial burdens.
5. Work to rebuild their emotional and physical well-being while treating depression, PTSD, substance abuse, or any other mental illness.

Child trafficking—a modern-day form of slavery that continues to destroy many lives—often is hidden, even from the clinicians who see its victims. Traffickers typically exploit children for labor or commercial sexual work. The signs and symptoms that suggest a child is being trafficked may be less clear than those of the psychiatric illnesses we usually diagnose and treat. In this article, I summarize characteristics that could be helpful to note when you suspect a child is being trafficked, and offer some resources for helping victims.

How to identify possible victims

Children can be trafficked anywhere. The concept of a child being picked up off a street corner is outdated. Trafficking occurs in cities, suburbs, and rural areas. It happens in hotel rooms, at truck stops, on quiet residential streets, and in expensive homes. The internet has made it easier for traffickers to find victims.

Traffickers typically target youth who are emotionally and physically vulnerable. They often seek out teenagers who are undergoing financial hardships, experiencing family conflict, or have survived natural disasters. Many victims are runaways. In 2016, 1 in 6 child runaways reported to the National Center for Missing and Exploited Children were likely victims of trafficking.¹ Of those children, 86% were receiving social services support or living in foster homes.

Traffickers are adept at emotional manipulation, which may explain why a child or adolescent might minimize the abuse during a clinical visit. Traffickers shroud the realities of trafficking with notions of love and inclusion. They use several physical and mental schemes to keep children and adolescents in their grip, such as withholding food, sleep, or medical care. Therefore, we should check for signs and symptoms of chronic medical conditions that have gone untreated, malnutrition, or bruises in various stages of healing.

Connecting risk factors for trafficking to dramatic changes in a young patient’s behavior is challenging. These youth often have dropped out of school, lack consistent family support, and spend their nights in search of a warm place to sleep. Their lives are upended. A child who once was more social may be forced into isolation and make excuses for why she no longer spends time with her friends.

In a study of 106 survivors of domestic sex trafficking, approximately 89% of respondents reported depression during depression. Many respondents reported experiencing anxiety (76.4%), nightmares (73.6%), flashbacks (68%), low self-esteem (81.1%), or feelings of shame or guilt (82.1%).² Almost 88% of respondents said that they saw a doctor or other clinician while being trafficked, but their clinicians were unable to recognize the signs of trafficking. Part of the challenge is that many children and adolescents are not comfortable discussing their situations with clinicians because they may struggle with shame and guilt. Their traffickers also might have convinced them that they are criminals, not victims. These patients also may have an overwhelming fear of their trafficker, being reported to child welfare authorities, being arrested, being deported, or having their traffickers retaliate against their families. Gaining the trust of a patient who is being trafficked is critical, but not easy, because children may be skeptical of a clinician’s promise of confidentiality.

Some signs of trafficking overlap with the psychiatric presentations with which we are more familiar. These patients may abuse drugs or alcohol as means of escape or because their traffickers force them to use substances.² They may show symptoms of depression or posttraumatic stress disorder (PTSD) and may be disoriented. Other indicators may be more telling, such as if a child or adolescent describes:

• having no control of their schedules or forms of identification
• having to work excessively long hours, often to pay off an overwhelming debt
• having high security measures installed in their place of residence (such as cameras or barred windows).

Continue to: Also, they may be...

Also, they may be dressed inappropriately for the weather.

We should be concerned when patients’ responses seem coached, if they say they are isolated from their family and community, or if they are submissive or overly timid. In addition, our suspicions should be raised if an accompanying adult guardian insists on sitting in on the appointment or translating for the child. In such instances, we may request that the guardian remain in the waiting area during the appointment so the child will have the opportunity to speak freely.²

How to help a suspected victim

Several local and national organizations help trafficking victims. These organizations provide educational materials and training opportunities for clinicians, as well as direct support for victims. The Homeland Security Blue Campaign advises against confronting a suspected trafficker directly and encourages clinicians to instead report suspected cases to 1-866-347-2423.³

Clinicians can better help children who are trafficked by taking the following 5 steps:

1. Learn about the risk factors and signs of child trafficking.
2. Post the National Human Trafficking Hotline (1-888-373-7888) in your waiting room.
3. Determine if your patient is in danger and needs to be moved to a safe place.
4. Connect the patient to social service agencies that can provide financial support and housing assistance so he/she doesn’t feel trapped by financial burdens.
5. Work to rebuild their emotional and physical well-being while treating depression, PTSD, substance abuse, or any other mental illness.