Risk models that incorporate genetic and circulating biomarker data in addition to established risk factors may improve risk modeling for pancreatic cancer in the general population, according to investigators.

Identifying high-risk individuals could facilitate earlier disease detection, which is essential for curing pancreatic cancer, reported lead author Jihye Kim, PhD, of Harvard School of Public Health, Boston, and colleagues.

“Given the late stage at presentation for most patients with pancreatic cancer, earlier detection approaches are worthy of significant investment as a critical means to reduce mortality from pancreatic cancer, soon to be the second-leading cause of cancer death in the United States,” the investigators wrote in Cancer Epidemiology, Biomarkers & Prevention.

According to the investigators, a variety of risk factors for pancreatic cancer are well established and include clinical, demographic, and lifestyle factors, while recent studies have reported associations with genetic and circulating biomarkers.

“Although risk factors have been investigated individually, their joint contribution to risk discrimination remains largely unknown,” the investigators wrote.

To learn more, Dr. Kim and colleagues performed a nested case-control study in which 500 patients with primary pancreatic adenocarcinoma were matched with 1,091 healthy controls. Data were drawn from four prospective studies: the Nurses’ Health Study, the Health Professionals Follow-up Study, the Women’s Health Initiative Observational Study, and the Physicians’ Health Study I. Via these studies, cases provided blood samples prior to diagnosis with pancreatic cancer.

“Importantly, because all our subjects were enrolled in prospective cohorts, all risk factor data and circulating markers were measured before the cases’ diagnosis of pancreatic cancer,” the investigators wrote. “This design faithfully recapitulates the situation faced by primary care physicians, where decisions related to disease screening are made in the prediagnostic setting using data collected in the several years prior to cancer diagnosis.”

In the present study, the investigators collected patient data for a variety of risk factors, including clinical and lifestyle characteristics, circulating biomarkers such as interleukin-6 and proinsulin, and 22 single-nucleotide polymorphisms. Frequencies and distributions of these factors were used to develop three multivariate risk models: a clinical model, a clinical/genetic model, and a clinical/genetic/biomarker model. To determine absolute risk of pancreatic cancer, these three models were combined with U.S. epidemiologic data, including incidence and mortality rates.

Cross-validation showed that the risk models became increasingly accurate with each added dataset; the area under the curve increased from 0.55 for the clinical model to 0.61 for the clinical/genetic model and ultimately to 0.62 for the clinical/genetic/biomarker model. Consequently, each model identified a greater number of individuals with at least a threefold risk of pancreatic cancer over a 10-year period. For example, the clinical model identified 1.5% of women and 0.2% of men with at least threefold risk, whereas the model that also included genetic and biomarker data identified 2.6% of women and 3.7% of men.

Absolute risk modeling allowed for generation of risk stratification percentiles by age. Women in the 99th risk percentile had a 1.7% risk of developing pancreatic cancer by age 70 years, and a 3.6% risk by age 80. For men, the highest-risk group had a 2.0% risk of pancreatic cancer by age 70 years and a 3.8% risk by age 80. Conversely, both men and women in the 10th risk percentile had a 0.2% risk by age 70 years and a 0.4% risk by age 80.

“[T]he addition of genetic variants and circulating markers added discriminatory ability beyond clinical factors that could be solicited in a physician’s office,” the investigators wrote.

“Further refinement and validation in independent samples will be necessary to make these models clinically actionable and impact survival of patients with pancreatic cancer,” they concluded.

The study was supported by the National Institutes of Health. The investigators reported additional relationships with Bayer, Celgene, Eli Lilly, and others.

SOURCE: Kim J et al. Cancer Epidemiol Biomarkers Prev. 2020 Apr 22. doi: 10.1158/1055-9965.EPI-19-1389.

Risk models that incorporate genetic and circulating biomarker data in addition to established risk factors may improve risk modeling for pancreatic cancer in the general population, according to investigators.

Identifying high-risk individuals could facilitate earlier disease detection, which is essential for curing pancreatic cancer, reported lead author Jihye Kim, PhD, of Harvard School of Public Health, Boston, and colleagues.

“Given the late stage at presentation for most patients with pancreatic cancer, earlier detection approaches are worthy of significant investment as a critical means to reduce mortality from pancreatic cancer, soon to be the second-leading cause of cancer death in the United States,” the investigators wrote in Cancer Epidemiology, Biomarkers & Prevention.

According to the investigators, a variety of risk factors for pancreatic cancer are well established and include clinical, demographic, and lifestyle factors, while recent studies have reported associations with genetic and circulating biomarkers.

“Although risk factors have been investigated individually, their joint contribution to risk discrimination remains largely unknown,” the investigators wrote.

To learn more, Dr. Kim and colleagues performed a nested case-control study in which 500 patients with primary pancreatic adenocarcinoma were matched with 1,091 healthy controls. Data were drawn from four prospective studies: the Nurses’ Health Study, the Health Professionals Follow-up Study, the Women’s Health Initiative Observational Study, and the Physicians’ Health Study I. Via these studies, cases provided blood samples prior to diagnosis with pancreatic cancer.

“Importantly, because all our subjects were enrolled in prospective cohorts, all risk factor data and circulating markers were measured before the cases’ diagnosis of pancreatic cancer,” the investigators wrote. “This design faithfully recapitulates the situation faced by primary care physicians, where decisions related to disease screening are made in the prediagnostic setting using data collected in the several years prior to cancer diagnosis.”

In the present study, the investigators collected patient data for a variety of risk factors, including clinical and lifestyle characteristics, circulating biomarkers such as interleukin-6 and proinsulin, and 22 single-nucleotide polymorphisms. Frequencies and distributions of these factors were used to develop three multivariate risk models: a clinical model, a clinical/genetic model, and a clinical/genetic/biomarker model. To determine absolute risk of pancreatic cancer, these three models were combined with U.S. epidemiologic data, including incidence and mortality rates.

Cross-validation showed that the risk models became increasingly accurate with each added dataset; the area under the curve increased from 0.55 for the clinical model to 0.61 for the clinical/genetic model and ultimately to 0.62 for the clinical/genetic/biomarker model. Consequently, each model identified a greater number of individuals with at least a threefold risk of pancreatic cancer over a 10-year period. For example, the clinical model identified 1.5% of women and 0.2% of men with at least threefold risk, whereas the model that also included genetic and biomarker data identified 2.6% of women and 3.7% of men.

Absolute risk modeling allowed for generation of risk stratification percentiles by age. Women in the 99th risk percentile had a 1.7% risk of developing pancreatic cancer by age 70 years, and a 3.6% risk by age 80. For men, the highest-risk group had a 2.0% risk of pancreatic cancer by age 70 years and a 3.8% risk by age 80. Conversely, both men and women in the 10th risk percentile had a 0.2% risk by age 70 years and a 0.4% risk by age 80.

“[T]he addition of genetic variants and circulating markers added discriminatory ability beyond clinical factors that could be solicited in a physician’s office,” the investigators wrote.

“Further refinement and validation in independent samples will be necessary to make these models clinically actionable and impact survival of patients with pancreatic cancer,” they concluded.

The study was supported by the National Institutes of Health. The investigators reported additional relationships with Bayer, Celgene, Eli Lilly, and others.

SOURCE: Kim J et al. Cancer Epidemiol Biomarkers Prev. 2020 Apr 22. doi: 10.1158/1055-9965.EPI-19-1389.

Risk models that incorporate genetic and circulating biomarker data in addition to established risk factors may improve risk modeling for pancreatic cancer in the general population, according to investigators.

Identifying high-risk individuals could facilitate earlier disease detection, which is essential for curing pancreatic cancer, reported lead author Jihye Kim, PhD, of Harvard School of Public Health, Boston, and colleagues.

“Given the late stage at presentation for most patients with pancreatic cancer, earlier detection approaches are worthy of significant investment as a critical means to reduce mortality from pancreatic cancer, soon to be the second-leading cause of cancer death in the United States,” the investigators wrote in Cancer Epidemiology, Biomarkers & Prevention.

According to the investigators, a variety of risk factors for pancreatic cancer are well established and include clinical, demographic, and lifestyle factors, while recent studies have reported associations with genetic and circulating biomarkers.

“Although risk factors have been investigated individually, their joint contribution to risk discrimination remains largely unknown,” the investigators wrote.

To learn more, Dr. Kim and colleagues performed a nested case-control study in which 500 patients with primary pancreatic adenocarcinoma were matched with 1,091 healthy controls. Data were drawn from four prospective studies: the Nurses’ Health Study, the Health Professionals Follow-up Study, the Women’s Health Initiative Observational Study, and the Physicians’ Health Study I. Via these studies, cases provided blood samples prior to diagnosis with pancreatic cancer.

“Importantly, because all our subjects were enrolled in prospective cohorts, all risk factor data and circulating markers were measured before the cases’ diagnosis of pancreatic cancer,” the investigators wrote. “This design faithfully recapitulates the situation faced by primary care physicians, where decisions related to disease screening are made in the prediagnostic setting using data collected in the several years prior to cancer diagnosis.”

In the present study, the investigators collected patient data for a variety of risk factors, including clinical and lifestyle characteristics, circulating biomarkers such as interleukin-6 and proinsulin, and 22 single-nucleotide polymorphisms. Frequencies and distributions of these factors were used to develop three multivariate risk models: a clinical model, a clinical/genetic model, and a clinical/genetic/biomarker model. To determine absolute risk of pancreatic cancer, these three models were combined with U.S. epidemiologic data, including incidence and mortality rates.

Cross-validation showed that the risk models became increasingly accurate with each added dataset; the area under the curve increased from 0.55 for the clinical model to 0.61 for the clinical/genetic model and ultimately to 0.62 for the clinical/genetic/biomarker model. Consequently, each model identified a greater number of individuals with at least a threefold risk of pancreatic cancer over a 10-year period. For example, the clinical model identified 1.5% of women and 0.2% of men with at least threefold risk, whereas the model that also included genetic and biomarker data identified 2.6% of women and 3.7% of men.

Absolute risk modeling allowed for generation of risk stratification percentiles by age. Women in the 99th risk percentile had a 1.7% risk of developing pancreatic cancer by age 70 years, and a 3.6% risk by age 80. For men, the highest-risk group had a 2.0% risk of pancreatic cancer by age 70 years and a 3.8% risk by age 80. Conversely, both men and women in the 10th risk percentile had a 0.2% risk by age 70 years and a 0.4% risk by age 80.

“[T]he addition of genetic variants and circulating markers added discriminatory ability beyond clinical factors that could be solicited in a physician’s office,” the investigators wrote.

“Further refinement and validation in independent samples will be necessary to make these models clinically actionable and impact survival of patients with pancreatic cancer,” they concluded.

The study was supported by the National Institutes of Health. The investigators reported additional relationships with Bayer, Celgene, Eli Lilly, and others.

SOURCE: Kim J et al. Cancer Epidemiol Biomarkers Prev. 2020 Apr 22. doi: 10.1158/1055-9965.EPI-19-1389.

Patients with eosinophilic esophagitis should receive topical steroids instead of oral steroids or no treatment, according to new recommendations from the American Gastroenterological Association and the Joint Task Force on Allergy-Immunology Practice Parameters.

In a pooled analysis of eight double-blind clinical trials, monotherapy with topical budesonide or topical fluticasone was about 61% more likely than placebo to produce histologic remissions in patients with eosinophilic esophagitis (relative risk of failure to achieve remission, 0.39; 95% confidence interval, 0.26-0.58), wrote Ikuo Hirano, MD, of Northwestern University, Chicago. Although these trials differed methodologically, the results were robust enough to warrant a strong recommendation for topical steroids, wrote Dr. Hirano and coauthors of the guidelines, published in Gastroenterology (doi: 10.1053/j.gastro.2020.02.038). “[T]he same inhaled steroid agents are considered very safe for use in children and adults with asthma and are routinely used in [its] primary management,” they noted.

All other recommendations in the guidelines are graded as conditional, reflecting a lack of high-quality supporting evidence. For example, one only study to date has compared topical and oral steroids for patients with eosinophilic esophagitis. In this pediatric trial, children benefited similarly from fluticasone (two puffs four times daily) and oral prednisone (1 mg/kg twice daily), but prednisone caused side effects (weight gain and cushingoid appearance) in 40% of patients, while topical steroids caused oral candidiasis (thrush) in only 15% of patients. Similarities between pediatric and adult eosinophilic esophagitis support the use of topical versus oral steroids in both groups, the guidelines conclude.

Eosinophilic esophagitis tends to be chronic and can progress to recurrent dysphagia, esophageal impactions, and stricture if left untreated. For this reason, the guidelines call for remitted patients to stay on topical steroids as maintenance therapy despite “very low confidence in the estimated benefits of [any type of] long-term therapy.” In a very small trial, 1 year of low-dose budesonide maintenance therapy (0.25 mg twice daily) outperformed placebo, but only 36% of patients maintained less than 5 eosinophils per high power field. Other studies have produced mixed results. Pending more data, the guidelines call maintenance treatment with topical steroids, proton pump inhibitors, and elimination diets “reasonable options” that comprise “a preference-sensitive area of management.”

Dietary interventions for eosinophilic esophagitis include the elemental diet (amino acid–based formulas), the empiric six-food elimination diet, and eliminating foods based on allergy testing. The guidelines cite moderate-quality evidence for the elemental diet, which induced histologic remissions (less than than 15 eosinophils per high power field) in nearly 94% of patients in six single-arm observational studies (in contrast, the rate of histologic failure with placebo is nearly 87%). However, patients may struggle to adhere to both the elemental diet and the six-food elimination diet, which has less supporting evidence. Hence, patients “may reasonably decline” these treatment options and “may prefer alternative medical or dietary therapies” to a diet exclusively based on food allergens, tests for which are potentially inaccurate, the guidelines state.

Esophageal dilation is recommended for patients with stricture based on a systematic review in which 87% of patients improved with this therapy. However, dilation “does not address the esophageal inflammation associated with eosinophilic esophagitis,” and the “assumption that no clinical improvement would occur if dilation was not performed likely overestimates [its] treatment benefit, given the reported symptom-placebo response noted in controlled trials,” according to the guidelines. Moreover, the evidence for dilation “was considered low quality due to the retrospective, single-arm design of all but one of the reports, and the lack of a standard definition for what constitutes clinical improvement.”

Anti-IgE therapy is not recommended – it failed to improve symptoms or esophageal eosinophilia in the only trial conducted to date. Because of a lack of evidence, the guidelines state that patients should receive only montelukast, cromolyn sodium, immunomodulators, anti–tumor necrosis factor (anti-TNF) therapies, or therapies targeting interleukin (IL)-5, IL-13, or IL-4 in the context of a clinical trial.

Eosinophilic esophagitis is triggered by exposure to food antigens and often overlaps with other atopic conditions, such as asthma, eczema, and allergic rhinitis. It has no approved treatments in the United States, although in 2018, the European Medicines Agency approved a budesonide tablet formulation.

The guideline authors disclosed no conflicts of interest.

SOURCE: Hirano I et al. Gastroenterology. 2020. doi: 10.1053/j.gastro.2020.02.038.

Patients with eosinophilic esophagitis should receive topical steroids instead of oral steroids or no treatment, according to new recommendations from the American Gastroenterological Association and the Joint Task Force on Allergy-Immunology Practice Parameters.

In a pooled analysis of eight double-blind clinical trials, monotherapy with topical budesonide or topical fluticasone was about 61% more likely than placebo to produce histologic remissions in patients with eosinophilic esophagitis (relative risk of failure to achieve remission, 0.39; 95% confidence interval, 0.26-0.58), wrote Ikuo Hirano, MD, of Northwestern University, Chicago. Although these trials differed methodologically, the results were robust enough to warrant a strong recommendation for topical steroids, wrote Dr. Hirano and coauthors of the guidelines, published in Gastroenterology (doi: 10.1053/j.gastro.2020.02.038). “[T]he same inhaled steroid agents are considered very safe for use in children and adults with asthma and are routinely used in [its] primary management,” they noted.

All other recommendations in the guidelines are graded as conditional, reflecting a lack of high-quality supporting evidence. For example, one only study to date has compared topical and oral steroids for patients with eosinophilic esophagitis. In this pediatric trial, children benefited similarly from fluticasone (two puffs four times daily) and oral prednisone (1 mg/kg twice daily), but prednisone caused side effects (weight gain and cushingoid appearance) in 40% of patients, while topical steroids caused oral candidiasis (thrush) in only 15% of patients. Similarities between pediatric and adult eosinophilic esophagitis support the use of topical versus oral steroids in both groups, the guidelines conclude.

Eosinophilic esophagitis tends to be chronic and can progress to recurrent dysphagia, esophageal impactions, and stricture if left untreated. For this reason, the guidelines call for remitted patients to stay on topical steroids as maintenance therapy despite “very low confidence in the estimated benefits of [any type of] long-term therapy.” In a very small trial, 1 year of low-dose budesonide maintenance therapy (0.25 mg twice daily) outperformed placebo, but only 36% of patients maintained less than 5 eosinophils per high power field. Other studies have produced mixed results. Pending more data, the guidelines call maintenance treatment with topical steroids, proton pump inhibitors, and elimination diets “reasonable options” that comprise “a preference-sensitive area of management.”

Dietary interventions for eosinophilic esophagitis include the elemental diet (amino acid–based formulas), the empiric six-food elimination diet, and eliminating foods based on allergy testing. The guidelines cite moderate-quality evidence for the elemental diet, which induced histologic remissions (less than than 15 eosinophils per high power field) in nearly 94% of patients in six single-arm observational studies (in contrast, the rate of histologic failure with placebo is nearly 87%). However, patients may struggle to adhere to both the elemental diet and the six-food elimination diet, which has less supporting evidence. Hence, patients “may reasonably decline” these treatment options and “may prefer alternative medical or dietary therapies” to a diet exclusively based on food allergens, tests for which are potentially inaccurate, the guidelines state.

Esophageal dilation is recommended for patients with stricture based on a systematic review in which 87% of patients improved with this therapy. However, dilation “does not address the esophageal inflammation associated with eosinophilic esophagitis,” and the “assumption that no clinical improvement would occur if dilation was not performed likely overestimates [its] treatment benefit, given the reported symptom-placebo response noted in controlled trials,” according to the guidelines. Moreover, the evidence for dilation “was considered low quality due to the retrospective, single-arm design of all but one of the reports, and the lack of a standard definition for what constitutes clinical improvement.”

Anti-IgE therapy is not recommended – it failed to improve symptoms or esophageal eosinophilia in the only trial conducted to date. Because of a lack of evidence, the guidelines state that patients should receive only montelukast, cromolyn sodium, immunomodulators, anti–tumor necrosis factor (anti-TNF) therapies, or therapies targeting interleukin (IL)-5, IL-13, or IL-4 in the context of a clinical trial.

Eosinophilic esophagitis is triggered by exposure to food antigens and often overlaps with other atopic conditions, such as asthma, eczema, and allergic rhinitis. It has no approved treatments in the United States, although in 2018, the European Medicines Agency approved a budesonide tablet formulation.

The guideline authors disclosed no conflicts of interest.

SOURCE: Hirano I et al. Gastroenterology. 2020. doi: 10.1053/j.gastro.2020.02.038.

Patients with eosinophilic esophagitis should receive topical steroids instead of oral steroids or no treatment, according to new recommendations from the American Gastroenterological Association and the Joint Task Force on Allergy-Immunology Practice Parameters.

In a pooled analysis of eight double-blind clinical trials, monotherapy with topical budesonide or topical fluticasone was about 61% more likely than placebo to produce histologic remissions in patients with eosinophilic esophagitis (relative risk of failure to achieve remission, 0.39; 95% confidence interval, 0.26-0.58), wrote Ikuo Hirano, MD, of Northwestern University, Chicago. Although these trials differed methodologically, the results were robust enough to warrant a strong recommendation for topical steroids, wrote Dr. Hirano and coauthors of the guidelines, published in Gastroenterology (doi: 10.1053/j.gastro.2020.02.038). “[T]he same inhaled steroid agents are considered very safe for use in children and adults with asthma and are routinely used in [its] primary management,” they noted.

All other recommendations in the guidelines are graded as conditional, reflecting a lack of high-quality supporting evidence. For example, one only study to date has compared topical and oral steroids for patients with eosinophilic esophagitis. In this pediatric trial, children benefited similarly from fluticasone (two puffs four times daily) and oral prednisone (1 mg/kg twice daily), but prednisone caused side effects (weight gain and cushingoid appearance) in 40% of patients, while topical steroids caused oral candidiasis (thrush) in only 15% of patients. Similarities between pediatric and adult eosinophilic esophagitis support the use of topical versus oral steroids in both groups, the guidelines conclude.

Eosinophilic esophagitis tends to be chronic and can progress to recurrent dysphagia, esophageal impactions, and stricture if left untreated. For this reason, the guidelines call for remitted patients to stay on topical steroids as maintenance therapy despite “very low confidence in the estimated benefits of [any type of] long-term therapy.” In a very small trial, 1 year of low-dose budesonide maintenance therapy (0.25 mg twice daily) outperformed placebo, but only 36% of patients maintained less than 5 eosinophils per high power field. Other studies have produced mixed results. Pending more data, the guidelines call maintenance treatment with topical steroids, proton pump inhibitors, and elimination diets “reasonable options” that comprise “a preference-sensitive area of management.”

Dietary interventions for eosinophilic esophagitis include the elemental diet (amino acid–based formulas), the empiric six-food elimination diet, and eliminating foods based on allergy testing. The guidelines cite moderate-quality evidence for the elemental diet, which induced histologic remissions (less than than 15 eosinophils per high power field) in nearly 94% of patients in six single-arm observational studies (in contrast, the rate of histologic failure with placebo is nearly 87%). However, patients may struggle to adhere to both the elemental diet and the six-food elimination diet, which has less supporting evidence. Hence, patients “may reasonably decline” these treatment options and “may prefer alternative medical or dietary therapies” to a diet exclusively based on food allergens, tests for which are potentially inaccurate, the guidelines state.

Esophageal dilation is recommended for patients with stricture based on a systematic review in which 87% of patients improved with this therapy. However, dilation “does not address the esophageal inflammation associated with eosinophilic esophagitis,” and the “assumption that no clinical improvement would occur if dilation was not performed likely overestimates [its] treatment benefit, given the reported symptom-placebo response noted in controlled trials,” according to the guidelines. Moreover, the evidence for dilation “was considered low quality due to the retrospective, single-arm design of all but one of the reports, and the lack of a standard definition for what constitutes clinical improvement.”

Anti-IgE therapy is not recommended – it failed to improve symptoms or esophageal eosinophilia in the only trial conducted to date. Because of a lack of evidence, the guidelines state that patients should receive only montelukast, cromolyn sodium, immunomodulators, anti–tumor necrosis factor (anti-TNF) therapies, or therapies targeting interleukin (IL)-5, IL-13, or IL-4 in the context of a clinical trial.

Eosinophilic esophagitis is triggered by exposure to food antigens and often overlaps with other atopic conditions, such as asthma, eczema, and allergic rhinitis. It has no approved treatments in the United States, although in 2018, the European Medicines Agency approved a budesonide tablet formulation.

The guideline authors disclosed no conflicts of interest.

SOURCE: Hirano I et al. Gastroenterology. 2020. doi: 10.1053/j.gastro.2020.02.038.

For more than half a century, haloperidol has been used as a first-line medication for psychiatric agitation constituting a “behavioral emergency” when a patient cannot or will not take oral medication. Today, haloperidol is most commonly administered as an IM injection along with an anticholinergic medication to minimize extrapyramidal symptoms (EPS) and a benzodiazepine for additional sedation. The multiple-medication “cocktail” is often referred to by double-entendre nicknames, such as “B-52” or “5250” (ie, haloperidol, 5 mg; lorazepam, 2 mg; and diphenhydramine, 50 mg). In this article, I discuss whether haloperidol, a first-generation antipsychotic (FGA) medication developed in 1958, still deserves to be the IM “gold standard” for managing emergency psychiatric agitation.

Earlier evidence of haloperidol’s efficacy

The initial “discovery” of antipsychotic medications was made in 1951 based on the inadvertent observation that chlorpromazine had the potential to calm surgical patients with autonomic activation. This calming effect, described as “désintéressment” (meaning a kind of “indifference to the world”),¹ resulted in a new class of medications replacing barbiturates and bromides as go-to options to achieve “rapid tranquilization” of psychiatric agitation.² Although the ability of antipsychotic medications to gradually reduce positive symptoms, such as delusions and hallucinations, has been attributed to dopamine (D2) antagonism, their more immediate sedating and anti-agitation effects are the result of broader effects as histamine (H1) and alpha-1 adrenergic antagonists.

In the 1970s, haloperidol emerged as a first-line option to manage agitation due to its IM and IV availability, as well as its relative lack of sedation and orthostasis compared with low-potency D2 antagonists such as chlorpromazine. However, haloperidol was observed to have a significant risk of acute EPS, including dystonic reactions.² From the 1970s to the 1990s, numerous prospective clinical trials of haloperidol for the treatment of acute psychotic agitation, including several randomized controlled trials (RCTs) comparing haloperidol to lorazepam, were conducted.³ The design and outcomes of the haloperidol vs lorazepam RCTs were fairly consistent^4-7:

• adult participants with acute agitation and a variety of psychiatric diagnoses, for whom informed consent often was waived due to agitation severity
• randomization to either IM haloperidol, 5 mg, or IM lorazepam, 2 mg, administered every 30 minutes until agitation resolved
• behavioral outcomes measured over several hours using various rating scales, without consistent assessment of EPS
• equivalent efficacy of haloperidol and lorazepam, with symptom resolution usually achieved after 1 to 2 doses (in 30 to 60 minutes), but sometimes longer
• anticholinergic “rescue” allowed for EPS, but not administered prophylactically
• EPS, including dystonia and akathisia, were significantly more frequent with haloperidol compared with lorazepam.⁸

In recognition of the greater risk of EPS with haloperidol compared with lorazepam, and the fact that most study participants were already taking standing doses of antipsychotic medications, some researchers have recommended using benzodiazepines alone as the optimal treatment for agitation.^4,9 A 2012 Cochrane review concluded that the involuntary use of haloperidol alone “could be considered unethical.”^10,11 However, other studies that examined the combination of haloperidol and lorazepam compared with either medication alone found that the combination of the 2 medications was associated with a more rapid resolution of symptoms, which suggests a superior synergistic effect.^6,7,12 By the late 1990s, combined haloperidol and lorazepam, often mixed within a single injection, became the most common strategy to achieve rapid tranquilization in the psychiatric emergency setting.¹³ However, while the combination has been justified as a way to reduce the antipsychotic medication dose and EPS risk,² few studies have compared combinations containing <5 mg of haloperidol. As a result, the apparent superiority of combined haloperidol and lorazepam compared with either medication alone may be a simple cumulative dose effect rather than true synergism. It is also important to note that adding lorazepam to haloperidol does not mitigate the risk of EPS such as dystonia in the absence of anticholinergic medication.⁸ To date, however, there have been no clinical trials investigating the efficacy of IM haloperidol, lorazepam, and benztropine or diphenhydramine given together.

Newer RCTs tell a different story

With the availability of second-generation antipsychotics (SGAs) in IM formulations, clinical trials over the past 2 decades have focused on comparing SGAs with haloperidol alone as the “gold standard” control for acute agitation. Compared with previous trials of haloperidol vs lorazepam, these clinical trials of SGAs vs haloperidol included^8,14-22:

• Study participants who signed informed consent (and were likely less agitated)
• IM haloperidol doses typically >5 mg (eg, 6.5 to 10 mg).

As with studies comparing lorazepam with haloperidol, the results of these RCTs revealed that IM aripiprazole, olanzapine, and ziprasidone were at least as effective as IM haloperidol, with haloperidol having a significantly increased risk of akathisia, dystonia, and other EPS.^8,14-22 The greater EPS risk of haloperidol is not surprising given the use of comparison doses up to 10 mg.

An updated 2017 Cochrane review of haloperidol for psychosis-induced aggression or agitation concluded that⁹:

• haloperidol is an effective intervention, although the evidence is “weak”
• significant treatment effects may take as long as 1 to 2 hours following multiple IM injections
• in contrast to SGAs, treatment with haloperidol carries a significant risk of EPS
• adding a benzodiazepine “does not have strong evidence of benefit and carries risk of additional harm.”

Continue to: Haloperidol's well-known toxicity

Haloperidol has been associated with numerous adverse effects:

Akathisia and other acute EPS. Treatment with even a single dose of IM haloperidol can result in acute EPS, including dystonia and akathisia. At best, such adverse effects are subjectively troubling and unpleasant; at worst, akathisia can exacerbate and be mistaken for agitation, leading to administration of more medication²³ and the possible development of suicidal or violent behavior.^24-25 In the studies reviewed above, the overall rate of EPS was as high as 21% after treatment with haloperidol,¹⁶ with parkinsonism occurring in up to 17% of patients,¹⁹ dystonia in up to 11%,⁷ and akathisia in up to 10%.¹⁵ However, because specific EPS were assessed inconsistently, and sometimes not at all, the rate of akathisia—arguably the most relevant and counter-therapeutic adverse effect related to agitation—remains unclear.

In another study that specifically assessed for akathisia in patients treated with haloperidol, up to 40% experienced akathisia 6 hours after a single oral dose of 5 mg.²⁶ Even a single dose of IV prochlorperazine, another dopamine-antagonist routinely used to treat nausea in the emergency department (ED), has been reported to cause akathisia in up to 44% of patients.²⁷ Such results suggest that when akathisia is carefully assessed, the rate with even brief FGA exposure may approach nearly half of treated patients. Because akathisia is typically dose-related, and considering that many patients receiving IM haloperidol may receive multiple injections in addition to standing doses of oral medications, akathisia may be underrecognized in patients who are agitated, with a much greater risk than is generally presumed.

Although anticholinergic medications or benzodiazepinesare often administered as part of a haloperidol “cocktail,” these medications often do not adequately resolve emergent akathisia.^26,28 No clinical trials of IM haloperidol combined with benztropine or diphenhydramine have been published, but several studies suggest that combining haloperidol with promethazine—a phenothiazine with strong antihistaminergic and anticholinergic activity, but only weak antidopaminergic activity—can decrease the risk of dystonia relative to haloperidol alone.^8,22,29,30 However, there have also been reports of promethazine causing dystonia.^31,32 In addition, 1 trial of IM haloperidol, 2.5 mg, combined with promethazine reported that 74% of patients still had at least 1 form of EPS.³⁰ Because the clinical trials of haloperidol with promethazine did not specifically assess for akathisia, promethazine’s ability to decrease the risk of akathisia remains unknown.

Cardiotoxicity. Although low-potency antipsychotic medications such as chlorpromazine are more sedating than haloperidol, the latter is preferred as an IM antipsychotic medication for agitation because of its lower risk of hypotension.² In terms of cardiac effects, all antipsychotic medications carry a risk of QTc prolongation, with possible progression to the potentially lethal arrhythmia torsades de pointes as a result of interference with cardiac potassium channels.³³ In 2007, the FDA added a “black-box” warning about this risk for haloperidol, in the wake of a disproportionately high number of reported cases associated with IV administration, sometimes even after a single dose.³⁴

Continue to: Although there is no direct evidence...

Although there is no direct evidence that the cardiac risks associated with IV haloperidol apply to IM administration, epidemiologic studies indicate that oral haloperidol carries an elevated risk of ventricular arrhythmia and sudden cardiac death,^35,36 with 1 study reporting greater risk compared with other SGAs.³⁷ Haloperidol, whether administered orally or IM, may therefore be an especially poor choice for patients with agitation who are at risk for arrhythmia, including those with relevant medical comorbidities or delirium.³⁴

Neuronal cell death. Several lines of research evidence have demonstrated that haloperidol can cause cellular injury or death in neuronal tissue in a dose-dependent fashion through a variety of mechanisms.³⁸ By contrast, SGAs have been shown to have neuroprotective effects.³⁹ While these findings have mostly come from studies conducted in animals or in vitro human tumor cell lines, some researchers have nonetheless called for haloperidol to be banned, noting that if its neurotoxic effects were more widely known, “we would realize what a travesty it is to use [such] a brain-unfriendly drug.”⁴⁰

Several reasonable alternatives

Echoing the earlier Cochrane review of haloperidol for psychosis-induced aggression or agitation,¹⁰ a 2017 update concluded, “If no other alternative exists, sole use of intramuscular haloperidol could be life-saving. Where additional drugs are available, sole use of haloperidol for extreme emergency could be considered unethical.”⁹

What then are reasonable alternatives to replace IM haloperidol for agitation? Clinicians should consider the following nonpharmacologic and pharmacologic interventions:

Nonpharmacologic interventions. Several behavioral interventions have been demonstrated to be effective for managing acute agitation, including verbal de-escalation, enhanced “programming” on the inpatient units, and the judicious use of seclusion.^41-43 While such interventions may demand additional staff or resources, they have the potential to lower long-term costs, reduce injuries to patients and staff, and improve the quality of care.⁴³ The use of IM haloperidol as a form of “chemical restraint” does not represent standard-of-care treatment,³ and from an ethical perspective, should never be implemented punitively or to compensate for substandard care in the form of inadequate staffing or staff training.

Continue to: Benzodiazepines

Benzodiazepines. Lorazepam offers an attractive alternative to haloperidol without the risk of EPS.^2,4,8 However, lorazepam alone may be perceived as less efficacious than a haloperidol “cocktail” because it represents less overall medication. Some evidence has suggested that lorazepam, 4 mg, might be the most appropriate dose, although it has only rarely been studied in clinical trials of acute agitation.³ Midazolam is another IM benzodiazepine alternative to IM haloperidol that has been shown to achieve more rapid sedation than either haloperidol or lorazepam,^44,45 although it can cause substantial anterograde amnesia and also has an FDA black-box warning for respiratory depression associated with IV administration.

Respiratory depression is frequently cited as an argument against using lorazepam for agitation, as if the therapeutic window is extremely narrow with ineffectiveness at 2 mg, but potential lethality beyond that dose. In fact, serious respiratory depression with lorazepam is unlikely in the absence of chronic obstructive pulmonary disease (COPD), obstructive sleep apnea, or concomitant alcohol or other sedative use.⁴⁶ Case reports have documented therapeutic lorazepam dosing of 2 to 4 mg every 2 hours up to 20 to 30 mg/d in patients with manic agitation.⁴⁷ Even in patients with COPD, significant respiratory depression tends not to occur at doses <8 mg.⁴⁸ A more evidence-based concern about lorazepam dosing is that 2 mg might be ineffective in patients with established tolerance. For example, 1 report described a patient in acute alcohol withdrawal who required dosing lorazepam to 1,600 mg within 24 hours.⁴⁹ Collectively, these reports suggest that lorazepam has a much wider therapeutic window than is typically perceived, and that dosing with 3 to 4 mg IM is a reasonable option for agitation when 2 mg is likely to be inadequate.

Paradoxical disinhibition is another concern that might prevent benzodiazepines from being used alone as a first-line intervention for emergency treatment of agitation. However, similar to respiratory depression, this adverse event is relatively rare and tends to occur in children and geriatric patients, individuals intoxicated with alcohol or other sedatives, and patients with brain injury, developmental delay, or dementia.^23,46 Although exacerbation of aggression has not been demonstrated in the RCTs examining benzodiazepines for agitation reviewed above, based on other research, some clinicians have expressed concerns about the potential for benzodiazepines to exacerbate aggression in patients with impulse control disorders and a history of violent behavior.⁵⁰

The 2005 Expert Consensus Panel for Behavioral Emergencies⁵¹ recommended the use of lorazepam alone over haloperidol for agitation for patients for whom the diagnosis is unknown or includes the following:

• stimulant intoxication
• personality disorder
• comorbid obesity
• comorbid cardiac arrhythmia
• a history of akathisia and other EPS
• a history of amenorrhea/galactorrhea
• a history of seizures.

In surveys, patients have ranked lorazepam as the preferred medication for emergency agitation, whereas haloperidol was ranked as one of the least-preferred options.^51,52

Continue to: Second-generation antipsychotics

Second-generation antipsychotics. The SGAs available in IM formulations, such as aripiprazole, olanzapine, and ziprasidone, have been shown to be at least as effective as haloperidol for the treatment of acute agitation (in 2015, the short-acting injectable formulation of aripiprazole was discontinued in the United States independent of safety or efficacy issues⁵³). A review of RCTs examining IM SGAs for the treatment of agitation concluded that the number needed to treat for response compared with placebo was 5 for aripiprazole, 3 for olanzapine, and 3 for ziprasidone.⁵⁴ In terms of safety, a meta-analysis of studies examining IM medications for agitation confirmed that the risk of acute EPS, including dystonia, akathisia, and parkinsonism, is significantly lower with SGAs compared with haloperidol.⁵⁵ An RCT comparing IM ziprasidone with haloperidol found equivalently modest effects on QTc prolongation.⁵⁶ Therefore, SGAs are an obvious and evidence-based option for replacing haloperidol as a treatment for acute agitation.

Unfortunately, for clinicians hoping to replace haloperidol within a multiple-medication IM “cocktail,” there have been no published controlled trials of SGAs combined with benzodiazepines. Although a short report indicated that aripiprazole and lorazepam are chemically compatible to be combined within a single injection,⁵⁷ the package insert for aripiprazole warns that “If parenteral benzodiazepine therapy is deemed necessary in addition to ABILIFY injection treatment, patients should be monitored for excessive sedation and for orthostatic hypotension.”⁵⁸ The package insert for olanzapine likewise lists the combination of lorazepam and olanzapine as a drug interaction that can potentiate sedation, and the manufacturer issued specific warnings about parenteral combination.^59,60 A single published case of significant hypotension with combined IM olanzapine and lorazepam,⁶⁰ together with the fact that IM olanzapine can cause hypotension by itself,⁶¹ has discouraged the coadministration of these medications. Nonetheless, the combination is used in some emergency settings, with several retro­spective studies failing to provide evidence of hypotension or respiratory depression as adverse effects.^62-64

Droperidol. Droperidol was formerly a popular choice for managing acute agitation, with evidence from RCTs that droperidol, 5 mg, can improve symptoms significantly faster than either haloperidol, 5 mg, or lorazepam, 2 mg, and is absorbed just as rapidly whether administered IV or IM.^65-67 However, a 2001 FDA black-box warning about QTc prolongation included recommendations that a screening electrocardiogram should be obtained before administering droperidol. This action greatly curtailed the use of droperidol, and for some time, it was not marketed or available in the United States.

Over the past decade, however, droperidol has returned to the US market⁶⁸ and its IV and IM usage has been revitalized for managing patients with agitation within or en route to the ED. Studies have demonstrated droperidol efficacy comparable to midazolam, ziprasidone, or olanzapine, as well as effectiveness as an IV adjunct to midazolam.^69-71 In contrast to the FDA black-box warning, retrospective studies and RCTs of both IV and IM droperidol suggest that QTc prolongation and torsades de pointes are rare events that do not occur any more frequently than they do with haloperidol, even at doses >10 mg.^72,73 However, in studies involving patients with drug intoxication and treatment with multiple medications, oversedation to the point of needing rescue intervention was reported. In an emergency setting where these issues are relatively easily managed, such risks may be better tolerated than in psychiatric settings.

With earlier studies examining the use of droperidol in an acute psychiatric setting that reported a more rapid onset of action than haloperidol,^65-67 a 2016 Cochrane review concluded that there was high-quality evidence to support droperidol’s use for psychosis-induced agitation.⁷⁴ However, a 2015 RCT comparing IM droperidol, 10 mg, to haloperidol, 10 mg, found equivalent efficacy and response times (with maximal response occurring within 2 hours) and concluded that droperidol had no advantage over haloperidol.⁷⁵ Because none of the clinical trials that evaluated droperidol have included assessments for EPS, its risk of akathisia remains uncertain.

Continue to: Ketamine

Ketamine. In recent years, ketamine has been used to treat acute agitation within or en route to the ED. Preliminary observational studies support ketamine’s efficacy when administered via IV or IM routes,⁷⁶ with more rapid symptomatic improvement compared with haloperidol, lorazepam, or midazolam alone.⁷⁷ Reported adverse effects of ketamine include dissociation, psychotic exacerbation, and respiratory depression,⁷⁶ although 1 small naturalistic study found no evidence of exacerbation of psychotic or other psychiatric symptoms.⁷⁸ An ongoing RCT is comparing IM ketamine, 5 mg/kg, to combined IM haloperidol, 5 mg, and midazolam, 5 mg.⁷⁹ Although various ketamine formulations are increasingly being used in psychiatry, active psychosis is generally regarded as a contraindication. It is premature to recommend parenteral ketamine administration for agitation within most psychiatric settings until more research on safety has been completed.

Haloperidol, or something else? Practical considerations

Consider the following factors when deciding whether to use haloperidol or one of its alternatives:

Limitations of the evidence. Modern clinical trials requiring informed consent often do not include the kind of severe agitation that clinicians encounter in acute psychiatric, emergency, or forensic settings. In addition, standard interventions, such as 3-medication haloperidol “cocktails,” have not been evaluated in clinical trials. Clinicians are therefore often in the dark about optimal evidence-based practices.

Treatment goals. Psychiatric agitation has many causes, with a range of severity that warrants a commensurate range of responses. Protocols for managing acute agitation should include graded interventions that begin with nonpharmacologic interventions and voluntary oral medications, and move to involuntary IM medications when necessary.

While treatment guidelines clearly recommend against IM medications as “chemical restraint” with a goal of sedating a patient until he/she is unconscious,^3,51 such outcomes are nonetheless often sought by staff who are concerned about the risk of injuries during a behavioral emergency. In such instances, the risks of violence towards patients and staff may outweigh concerns about adverse effects in a risk-benefit analysis. Consequently, clinicians may be prone to “skip over” graded interventions because they assume they “won’t work” in favor of administering involuntary multiple-medication haloperidol “cocktails” despite risks of excess sedation, EPS, and cardiotoxicity. Treatment settings should critically evaluate such biased preferences, with a goal of developing tailored, evidence-based strategies that maximize benefits while minimizing excess sedation and other untoward adverse effects, with an eye towards promoting better overall patient care and reducing length of stay.^42,43,80

Continue to: Limitations of available medications

Limitations of available medications. There is no perfect medication for the management of acute agitation. Evidence indicates that pharmacologic options take 15 minutes to several hours to resolve acute agitation, even potentially more rapid-acting medications such as midazolam and droperidol. This is well beyond most clinicians’ desired window for response time in a behavioral emergency. Multiple-medication “cocktails” may be used with the hope of hastening response time, but may not achieve this goal at the expense of increasing the risk of adverse effects and the likelihood that a patient will remain sedated for a prolonged time. In the real world, this often means that by the time a psychiatrist comes to evaluate a patient who has been given emergency medications, the patient cannot be aroused for an interview. Ideally, medications would calm an agitated patient rapidly, without excess or prolonged sedation.⁸⁰ Less-sedating SGAs, such as ziprasidone, might have this potential, but can sometimes be perceived as ineffective.

Avoiding akathisia. Akathisia’s potential to worsen and be mistaken for agitation makes it an especially concerning, if underappreciated, adverse effect of haloperidol that is often not adequately assessed in clinical trials or practice. In light of evidence that akathisia can occur in nearly half of patients receiving a single 5 mg-dose of haloperidol, it is difficult to justify the use of this medication for agitation when equally effective options exist with a lower risk of EPS.

While haloperidol-induced akathisia could in theory be mitigated by adding anticholinergic medications or benzodiazepines, previous studies have found that such strategies have limited effectiveness compared to “gold standard” treatment with propranolol.^28,81,82 Furthermore, the half-lives of anticholinergic medications, such as benztropine or diphenhydramine, are significantly shorter than that of a single dose of haloperidol, which can be as long as 37 hours.⁸³ Therefore, akathisia and other EPS could emerge or worsen several hours or even days after receiving an IM haloperidol “cocktail” as the shorter-acting medications wear off. Akathisia is best minimized by avoiding FGAs, such as haloperidol, when treating acute agitation.

Promoting adherence. Although haloperidol is often recommended for acute agitation in patients with schizophrenia or bipolar disorder on the basis that it would treat the underlying condition, many patients who receive IM medications for acute agitation are already prescribed standing doses of oral medication, which increases the risk of cumulative toxicity. In addition, receiving a medication likely to cause acute EPS that is ranked near the bottom of patient preferences may erode the potential for a therapeutic alliance and hamper longer-term antipsychotic medication adherence.

Time for a change

For nearly half a century, haloperidol has been a “gold standard” intervention for IM control in patients with agitation. However, given its potential to produce adverse effects, including a significant risk of akathisia that can worsen agitation, along with the availability of newer pharmacologic options that are at least as effective (Table 1, and Table 2), haloperidol should be retired as a first-line medication for the treatment of agitation. Clinicians would benefit from RCTs investigating the safety and efficacy of novel interventions including frequently-used, but untested medication combinations, as well as nonpharmacologic interventions.

Continue to: Bottom Line

Although there is no perfect IM medication to treat acute agitation, haloperidol’s higher risk of adverse effects relative to newer alternatives suggest that it should no longer be considered a first-line intervention.

Related Resources

• Zun LS. Evidence-based review of pharmacotherapy for acute agitation. Part 1: onset of efficacy. J Emerg Med. 2018;54(3):364-374.
• Zun LS. Evidence-based review of pharmacotherapy for acute agitation. Part 2: safety. J Emerg Med. 2018;54(4): 522-532.

Drug Brand Names

Aripiprazole • Abilify
Benztropine • Cogentin
Chlorpromazine • Thorazine
Diphenhydramine • Benadryl
Droperidol • Inapsine
Haloperidol • Haldol
Ketamine • Ketalar
Lorazepam • Ativan
Midazolam • Versed
Olanzapine • Zyprexa
Prochlorperazine • Compazine
Promethazine • Phenergan
Propranolol • Inderal, Pronol
Ziprasidone • Geodon

For more than half a century, haloperidol has been used as a first-line medication for psychiatric agitation constituting a “behavioral emergency” when a patient cannot or will not take oral medication. Today, haloperidol is most commonly administered as an IM injection along with an anticholinergic medication to minimize extrapyramidal symptoms (EPS) and a benzodiazepine for additional sedation. The multiple-medication “cocktail” is often referred to by double-entendre nicknames, such as “B-52” or “5250” (ie, haloperidol, 5 mg; lorazepam, 2 mg; and diphenhydramine, 50 mg). In this article, I discuss whether haloperidol, a first-generation antipsychotic (FGA) medication developed in 1958, still deserves to be the IM “gold standard” for managing emergency psychiatric agitation.

Earlier evidence of haloperidol’s efficacy

The initial “discovery” of antipsychotic medications was made in 1951 based on the inadvertent observation that chlorpromazine had the potential to calm surgical patients with autonomic activation. This calming effect, described as “désintéressment” (meaning a kind of “indifference to the world”),¹ resulted in a new class of medications replacing barbiturates and bromides as go-to options to achieve “rapid tranquilization” of psychiatric agitation.² Although the ability of antipsychotic medications to gradually reduce positive symptoms, such as delusions and hallucinations, has been attributed to dopamine (D2) antagonism, their more immediate sedating and anti-agitation effects are the result of broader effects as histamine (H1) and alpha-1 adrenergic antagonists.

In the 1970s, haloperidol emerged as a first-line option to manage agitation due to its IM and IV availability, as well as its relative lack of sedation and orthostasis compared with low-potency D2 antagonists such as chlorpromazine. However, haloperidol was observed to have a significant risk of acute EPS, including dystonic reactions.² From the 1970s to the 1990s, numerous prospective clinical trials of haloperidol for the treatment of acute psychotic agitation, including several randomized controlled trials (RCTs) comparing haloperidol to lorazepam, were conducted.³ The design and outcomes of the haloperidol vs lorazepam RCTs were fairly consistent^4-7:

• adult participants with acute agitation and a variety of psychiatric diagnoses, for whom informed consent often was waived due to agitation severity
• randomization to either IM haloperidol, 5 mg, or IM lorazepam, 2 mg, administered every 30 minutes until agitation resolved
• behavioral outcomes measured over several hours using various rating scales, without consistent assessment of EPS
• equivalent efficacy of haloperidol and lorazepam, with symptom resolution usually achieved after 1 to 2 doses (in 30 to 60 minutes), but sometimes longer
• anticholinergic “rescue” allowed for EPS, but not administered prophylactically
• EPS, including dystonia and akathisia, were significantly more frequent with haloperidol compared with lorazepam.⁸

In recognition of the greater risk of EPS with haloperidol compared with lorazepam, and the fact that most study participants were already taking standing doses of antipsychotic medications, some researchers have recommended using benzodiazepines alone as the optimal treatment for agitation.^4,9 A 2012 Cochrane review concluded that the involuntary use of haloperidol alone “could be considered unethical.”^10,11 However, other studies that examined the combination of haloperidol and lorazepam compared with either medication alone found that the combination of the 2 medications was associated with a more rapid resolution of symptoms, which suggests a superior synergistic effect.^6,7,12 By the late 1990s, combined haloperidol and lorazepam, often mixed within a single injection, became the most common strategy to achieve rapid tranquilization in the psychiatric emergency setting.¹³ However, while the combination has been justified as a way to reduce the antipsychotic medication dose and EPS risk,² few studies have compared combinations containing <5 mg of haloperidol. As a result, the apparent superiority of combined haloperidol and lorazepam compared with either medication alone may be a simple cumulative dose effect rather than true synergism. It is also important to note that adding lorazepam to haloperidol does not mitigate the risk of EPS such as dystonia in the absence of anticholinergic medication.⁸ To date, however, there have been no clinical trials investigating the efficacy of IM haloperidol, lorazepam, and benztropine or diphenhydramine given together.

Newer RCTs tell a different story

With the availability of second-generation antipsychotics (SGAs) in IM formulations, clinical trials over the past 2 decades have focused on comparing SGAs with haloperidol alone as the “gold standard” control for acute agitation. Compared with previous trials of haloperidol vs lorazepam, these clinical trials of SGAs vs haloperidol included^8,14-22:

• Study participants who signed informed consent (and were likely less agitated)
• IM haloperidol doses typically >5 mg (eg, 6.5 to 10 mg).

As with studies comparing lorazepam with haloperidol, the results of these RCTs revealed that IM aripiprazole, olanzapine, and ziprasidone were at least as effective as IM haloperidol, with haloperidol having a significantly increased risk of akathisia, dystonia, and other EPS.^8,14-22 The greater EPS risk of haloperidol is not surprising given the use of comparison doses up to 10 mg.

An updated 2017 Cochrane review of haloperidol for psychosis-induced aggression or agitation concluded that⁹:

• haloperidol is an effective intervention, although the evidence is “weak”
• significant treatment effects may take as long as 1 to 2 hours following multiple IM injections
• in contrast to SGAs, treatment with haloperidol carries a significant risk of EPS
• adding a benzodiazepine “does not have strong evidence of benefit and carries risk of additional harm.”

Continue to: Haloperidol's well-known toxicity

Haloperidol has been associated with numerous adverse effects:

Akathisia and other acute EPS. Treatment with even a single dose of IM haloperidol can result in acute EPS, including dystonia and akathisia. At best, such adverse effects are subjectively troubling and unpleasant; at worst, akathisia can exacerbate and be mistaken for agitation, leading to administration of more medication²³ and the possible development of suicidal or violent behavior.^24-25 In the studies reviewed above, the overall rate of EPS was as high as 21% after treatment with haloperidol,¹⁶ with parkinsonism occurring in up to 17% of patients,¹⁹ dystonia in up to 11%,⁷ and akathisia in up to 10%.¹⁵ However, because specific EPS were assessed inconsistently, and sometimes not at all, the rate of akathisia—arguably the most relevant and counter-therapeutic adverse effect related to agitation—remains unclear.

In another study that specifically assessed for akathisia in patients treated with haloperidol, up to 40% experienced akathisia 6 hours after a single oral dose of 5 mg.²⁶ Even a single dose of IV prochlorperazine, another dopamine-antagonist routinely used to treat nausea in the emergency department (ED), has been reported to cause akathisia in up to 44% of patients.²⁷ Such results suggest that when akathisia is carefully assessed, the rate with even brief FGA exposure may approach nearly half of treated patients. Because akathisia is typically dose-related, and considering that many patients receiving IM haloperidol may receive multiple injections in addition to standing doses of oral medications, akathisia may be underrecognized in patients who are agitated, with a much greater risk than is generally presumed.

Although anticholinergic medications or benzodiazepinesare often administered as part of a haloperidol “cocktail,” these medications often do not adequately resolve emergent akathisia.^26,28 No clinical trials of IM haloperidol combined with benztropine or diphenhydramine have been published, but several studies suggest that combining haloperidol with promethazine—a phenothiazine with strong antihistaminergic and anticholinergic activity, but only weak antidopaminergic activity—can decrease the risk of dystonia relative to haloperidol alone.^8,22,29,30 However, there have also been reports of promethazine causing dystonia.^31,32 In addition, 1 trial of IM haloperidol, 2.5 mg, combined with promethazine reported that 74% of patients still had at least 1 form of EPS.³⁰ Because the clinical trials of haloperidol with promethazine did not specifically assess for akathisia, promethazine’s ability to decrease the risk of akathisia remains unknown.

Cardiotoxicity. Although low-potency antipsychotic medications such as chlorpromazine are more sedating than haloperidol, the latter is preferred as an IM antipsychotic medication for agitation because of its lower risk of hypotension.² In terms of cardiac effects, all antipsychotic medications carry a risk of QTc prolongation, with possible progression to the potentially lethal arrhythmia torsades de pointes as a result of interference with cardiac potassium channels.³³ In 2007, the FDA added a “black-box” warning about this risk for haloperidol, in the wake of a disproportionately high number of reported cases associated with IV administration, sometimes even after a single dose.³⁴

Continue to: Although there is no direct evidence...

Although there is no direct evidence that the cardiac risks associated with IV haloperidol apply to IM administration, epidemiologic studies indicate that oral haloperidol carries an elevated risk of ventricular arrhythmia and sudden cardiac death,^35,36 with 1 study reporting greater risk compared with other SGAs.³⁷ Haloperidol, whether administered orally or IM, may therefore be an especially poor choice for patients with agitation who are at risk for arrhythmia, including those with relevant medical comorbidities or delirium.³⁴

Neuronal cell death. Several lines of research evidence have demonstrated that haloperidol can cause cellular injury or death in neuronal tissue in a dose-dependent fashion through a variety of mechanisms.³⁸ By contrast, SGAs have been shown to have neuroprotective effects.³⁹ While these findings have mostly come from studies conducted in animals or in vitro human tumor cell lines, some researchers have nonetheless called for haloperidol to be banned, noting that if its neurotoxic effects were more widely known, “we would realize what a travesty it is to use [such] a brain-unfriendly drug.”⁴⁰

Several reasonable alternatives

Echoing the earlier Cochrane review of haloperidol for psychosis-induced aggression or agitation,¹⁰ a 2017 update concluded, “If no other alternative exists, sole use of intramuscular haloperidol could be life-saving. Where additional drugs are available, sole use of haloperidol for extreme emergency could be considered unethical.”⁹

What then are reasonable alternatives to replace IM haloperidol for agitation? Clinicians should consider the following nonpharmacologic and pharmacologic interventions:

Nonpharmacologic interventions. Several behavioral interventions have been demonstrated to be effective for managing acute agitation, including verbal de-escalation, enhanced “programming” on the inpatient units, and the judicious use of seclusion.^41-43 While such interventions may demand additional staff or resources, they have the potential to lower long-term costs, reduce injuries to patients and staff, and improve the quality of care.⁴³ The use of IM haloperidol as a form of “chemical restraint” does not represent standard-of-care treatment,³ and from an ethical perspective, should never be implemented punitively or to compensate for substandard care in the form of inadequate staffing or staff training.

Continue to: Benzodiazepines

Benzodiazepines. Lorazepam offers an attractive alternative to haloperidol without the risk of EPS.^2,4,8 However, lorazepam alone may be perceived as less efficacious than a haloperidol “cocktail” because it represents less overall medication. Some evidence has suggested that lorazepam, 4 mg, might be the most appropriate dose, although it has only rarely been studied in clinical trials of acute agitation.³ Midazolam is another IM benzodiazepine alternative to IM haloperidol that has been shown to achieve more rapid sedation than either haloperidol or lorazepam,^44,45 although it can cause substantial anterograde amnesia and also has an FDA black-box warning for respiratory depression associated with IV administration.

Respiratory depression is frequently cited as an argument against using lorazepam for agitation, as if the therapeutic window is extremely narrow with ineffectiveness at 2 mg, but potential lethality beyond that dose. In fact, serious respiratory depression with lorazepam is unlikely in the absence of chronic obstructive pulmonary disease (COPD), obstructive sleep apnea, or concomitant alcohol or other sedative use.⁴⁶ Case reports have documented therapeutic lorazepam dosing of 2 to 4 mg every 2 hours up to 20 to 30 mg/d in patients with manic agitation.⁴⁷ Even in patients with COPD, significant respiratory depression tends not to occur at doses <8 mg.⁴⁸ A more evidence-based concern about lorazepam dosing is that 2 mg might be ineffective in patients with established tolerance. For example, 1 report described a patient in acute alcohol withdrawal who required dosing lorazepam to 1,600 mg within 24 hours.⁴⁹ Collectively, these reports suggest that lorazepam has a much wider therapeutic window than is typically perceived, and that dosing with 3 to 4 mg IM is a reasonable option for agitation when 2 mg is likely to be inadequate.

Paradoxical disinhibition is another concern that might prevent benzodiazepines from being used alone as a first-line intervention for emergency treatment of agitation. However, similar to respiratory depression, this adverse event is relatively rare and tends to occur in children and geriatric patients, individuals intoxicated with alcohol or other sedatives, and patients with brain injury, developmental delay, or dementia.^23,46 Although exacerbation of aggression has not been demonstrated in the RCTs examining benzodiazepines for agitation reviewed above, based on other research, some clinicians have expressed concerns about the potential for benzodiazepines to exacerbate aggression in patients with impulse control disorders and a history of violent behavior.⁵⁰

The 2005 Expert Consensus Panel for Behavioral Emergencies⁵¹ recommended the use of lorazepam alone over haloperidol for agitation for patients for whom the diagnosis is unknown or includes the following:

• stimulant intoxication
• personality disorder
• comorbid obesity
• comorbid cardiac arrhythmia
• a history of akathisia and other EPS
• a history of amenorrhea/galactorrhea
• a history of seizures.

In surveys, patients have ranked lorazepam as the preferred medication for emergency agitation, whereas haloperidol was ranked as one of the least-preferred options.^51,52

Continue to: Second-generation antipsychotics

Second-generation antipsychotics. The SGAs available in IM formulations, such as aripiprazole, olanzapine, and ziprasidone, have been shown to be at least as effective as haloperidol for the treatment of acute agitation (in 2015, the short-acting injectable formulation of aripiprazole was discontinued in the United States independent of safety or efficacy issues⁵³). A review of RCTs examining IM SGAs for the treatment of agitation concluded that the number needed to treat for response compared with placebo was 5 for aripiprazole, 3 for olanzapine, and 3 for ziprasidone.⁵⁴ In terms of safety, a meta-analysis of studies examining IM medications for agitation confirmed that the risk of acute EPS, including dystonia, akathisia, and parkinsonism, is significantly lower with SGAs compared with haloperidol.⁵⁵ An RCT comparing IM ziprasidone with haloperidol found equivalently modest effects on QTc prolongation.⁵⁶ Therefore, SGAs are an obvious and evidence-based option for replacing haloperidol as a treatment for acute agitation.

Unfortunately, for clinicians hoping to replace haloperidol within a multiple-medication IM “cocktail,” there have been no published controlled trials of SGAs combined with benzodiazepines. Although a short report indicated that aripiprazole and lorazepam are chemically compatible to be combined within a single injection,⁵⁷ the package insert for aripiprazole warns that “If parenteral benzodiazepine therapy is deemed necessary in addition to ABILIFY injection treatment, patients should be monitored for excessive sedation and for orthostatic hypotension.”⁵⁸ The package insert for olanzapine likewise lists the combination of lorazepam and olanzapine as a drug interaction that can potentiate sedation, and the manufacturer issued specific warnings about parenteral combination.^59,60 A single published case of significant hypotension with combined IM olanzapine and lorazepam,⁶⁰ together with the fact that IM olanzapine can cause hypotension by itself,⁶¹ has discouraged the coadministration of these medications. Nonetheless, the combination is used in some emergency settings, with several retro­spective studies failing to provide evidence of hypotension or respiratory depression as adverse effects.^62-64

Droperidol. Droperidol was formerly a popular choice for managing acute agitation, with evidence from RCTs that droperidol, 5 mg, can improve symptoms significantly faster than either haloperidol, 5 mg, or lorazepam, 2 mg, and is absorbed just as rapidly whether administered IV or IM.^65-67 However, a 2001 FDA black-box warning about QTc prolongation included recommendations that a screening electrocardiogram should be obtained before administering droperidol. This action greatly curtailed the use of droperidol, and for some time, it was not marketed or available in the United States.

Over the past decade, however, droperidol has returned to the US market⁶⁸ and its IV and IM usage has been revitalized for managing patients with agitation within or en route to the ED. Studies have demonstrated droperidol efficacy comparable to midazolam, ziprasidone, or olanzapine, as well as effectiveness as an IV adjunct to midazolam.^69-71 In contrast to the FDA black-box warning, retrospective studies and RCTs of both IV and IM droperidol suggest that QTc prolongation and torsades de pointes are rare events that do not occur any more frequently than they do with haloperidol, even at doses >10 mg.^72,73 However, in studies involving patients with drug intoxication and treatment with multiple medications, oversedation to the point of needing rescue intervention was reported. In an emergency setting where these issues are relatively easily managed, such risks may be better tolerated than in psychiatric settings.

With earlier studies examining the use of droperidol in an acute psychiatric setting that reported a more rapid onset of action than haloperidol,^65-67 a 2016 Cochrane review concluded that there was high-quality evidence to support droperidol’s use for psychosis-induced agitation.⁷⁴ However, a 2015 RCT comparing IM droperidol, 10 mg, to haloperidol, 10 mg, found equivalent efficacy and response times (with maximal response occurring within 2 hours) and concluded that droperidol had no advantage over haloperidol.⁷⁵ Because none of the clinical trials that evaluated droperidol have included assessments for EPS, its risk of akathisia remains uncertain.

Continue to: Ketamine

Ketamine. In recent years, ketamine has been used to treat acute agitation within or en route to the ED. Preliminary observational studies support ketamine’s efficacy when administered via IV or IM routes,⁷⁶ with more rapid symptomatic improvement compared with haloperidol, lorazepam, or midazolam alone.⁷⁷ Reported adverse effects of ketamine include dissociation, psychotic exacerbation, and respiratory depression,⁷⁶ although 1 small naturalistic study found no evidence of exacerbation of psychotic or other psychiatric symptoms.⁷⁸ An ongoing RCT is comparing IM ketamine, 5 mg/kg, to combined IM haloperidol, 5 mg, and midazolam, 5 mg.⁷⁹ Although various ketamine formulations are increasingly being used in psychiatry, active psychosis is generally regarded as a contraindication. It is premature to recommend parenteral ketamine administration for agitation within most psychiatric settings until more research on safety has been completed.

Haloperidol, or something else? Practical considerations

Consider the following factors when deciding whether to use haloperidol or one of its alternatives:

Limitations of the evidence. Modern clinical trials requiring informed consent often do not include the kind of severe agitation that clinicians encounter in acute psychiatric, emergency, or forensic settings. In addition, standard interventions, such as 3-medication haloperidol “cocktails,” have not been evaluated in clinical trials. Clinicians are therefore often in the dark about optimal evidence-based practices.

Treatment goals. Psychiatric agitation has many causes, with a range of severity that warrants a commensurate range of responses. Protocols for managing acute agitation should include graded interventions that begin with nonpharmacologic interventions and voluntary oral medications, and move to involuntary IM medications when necessary.

While treatment guidelines clearly recommend against IM medications as “chemical restraint” with a goal of sedating a patient until he/she is unconscious,^3,51 such outcomes are nonetheless often sought by staff who are concerned about the risk of injuries during a behavioral emergency. In such instances, the risks of violence towards patients and staff may outweigh concerns about adverse effects in a risk-benefit analysis. Consequently, clinicians may be prone to “skip over” graded interventions because they assume they “won’t work” in favor of administering involuntary multiple-medication haloperidol “cocktails” despite risks of excess sedation, EPS, and cardiotoxicity. Treatment settings should critically evaluate such biased preferences, with a goal of developing tailored, evidence-based strategies that maximize benefits while minimizing excess sedation and other untoward adverse effects, with an eye towards promoting better overall patient care and reducing length of stay.^42,43,80

Continue to: Limitations of available medications

Limitations of available medications. There is no perfect medication for the management of acute agitation. Evidence indicates that pharmacologic options take 15 minutes to several hours to resolve acute agitation, even potentially more rapid-acting medications such as midazolam and droperidol. This is well beyond most clinicians’ desired window for response time in a behavioral emergency. Multiple-medication “cocktails” may be used with the hope of hastening response time, but may not achieve this goal at the expense of increasing the risk of adverse effects and the likelihood that a patient will remain sedated for a prolonged time. In the real world, this often means that by the time a psychiatrist comes to evaluate a patient who has been given emergency medications, the patient cannot be aroused for an interview. Ideally, medications would calm an agitated patient rapidly, without excess or prolonged sedation.⁸⁰ Less-sedating SGAs, such as ziprasidone, might have this potential, but can sometimes be perceived as ineffective.

Avoiding akathisia. Akathisia’s potential to worsen and be mistaken for agitation makes it an especially concerning, if underappreciated, adverse effect of haloperidol that is often not adequately assessed in clinical trials or practice. In light of evidence that akathisia can occur in nearly half of patients receiving a single 5 mg-dose of haloperidol, it is difficult to justify the use of this medication for agitation when equally effective options exist with a lower risk of EPS.

While haloperidol-induced akathisia could in theory be mitigated by adding anticholinergic medications or benzodiazepines, previous studies have found that such strategies have limited effectiveness compared to “gold standard” treatment with propranolol.^28,81,82 Furthermore, the half-lives of anticholinergic medications, such as benztropine or diphenhydramine, are significantly shorter than that of a single dose of haloperidol, which can be as long as 37 hours.⁸³ Therefore, akathisia and other EPS could emerge or worsen several hours or even days after receiving an IM haloperidol “cocktail” as the shorter-acting medications wear off. Akathisia is best minimized by avoiding FGAs, such as haloperidol, when treating acute agitation.

Promoting adherence. Although haloperidol is often recommended for acute agitation in patients with schizophrenia or bipolar disorder on the basis that it would treat the underlying condition, many patients who receive IM medications for acute agitation are already prescribed standing doses of oral medication, which increases the risk of cumulative toxicity. In addition, receiving a medication likely to cause acute EPS that is ranked near the bottom of patient preferences may erode the potential for a therapeutic alliance and hamper longer-term antipsychotic medication adherence.

Time for a change

For nearly half a century, haloperidol has been a “gold standard” intervention for IM control in patients with agitation. However, given its potential to produce adverse effects, including a significant risk of akathisia that can worsen agitation, along with the availability of newer pharmacologic options that are at least as effective (Table 1, and Table 2), haloperidol should be retired as a first-line medication for the treatment of agitation. Clinicians would benefit from RCTs investigating the safety and efficacy of novel interventions including frequently-used, but untested medication combinations, as well as nonpharmacologic interventions.

Continue to: Bottom Line

Although there is no perfect IM medication to treat acute agitation, haloperidol’s higher risk of adverse effects relative to newer alternatives suggest that it should no longer be considered a first-line intervention.

Related Resources

• Zun LS. Evidence-based review of pharmacotherapy for acute agitation. Part 1: onset of efficacy. J Emerg Med. 2018;54(3):364-374.
• Zun LS. Evidence-based review of pharmacotherapy for acute agitation. Part 2: safety. J Emerg Med. 2018;54(4): 522-532.

Drug Brand Names

Aripiprazole • Abilify
Benztropine • Cogentin
Chlorpromazine • Thorazine
Diphenhydramine • Benadryl
Droperidol • Inapsine
Haloperidol • Haldol
Ketamine • Ketalar
Lorazepam • Ativan
Midazolam • Versed
Olanzapine • Zyprexa
Prochlorperazine • Compazine
Promethazine • Phenergan
Propranolol • Inderal, Pronol
Ziprasidone • Geodon

For more than half a century, haloperidol has been used as a first-line medication for psychiatric agitation constituting a “behavioral emergency” when a patient cannot or will not take oral medication. Today, haloperidol is most commonly administered as an IM injection along with an anticholinergic medication to minimize extrapyramidal symptoms (EPS) and a benzodiazepine for additional sedation. The multiple-medication “cocktail” is often referred to by double-entendre nicknames, such as “B-52” or “5250” (ie, haloperidol, 5 mg; lorazepam, 2 mg; and diphenhydramine, 50 mg). In this article, I discuss whether haloperidol, a first-generation antipsychotic (FGA) medication developed in 1958, still deserves to be the IM “gold standard” for managing emergency psychiatric agitation.

Earlier evidence of haloperidol’s efficacy

The initial “discovery” of antipsychotic medications was made in 1951 based on the inadvertent observation that chlorpromazine had the potential to calm surgical patients with autonomic activation. This calming effect, described as “désintéressment” (meaning a kind of “indifference to the world”),¹ resulted in a new class of medications replacing barbiturates and bromides as go-to options to achieve “rapid tranquilization” of psychiatric agitation.² Although the ability of antipsychotic medications to gradually reduce positive symptoms, such as delusions and hallucinations, has been attributed to dopamine (D2) antagonism, their more immediate sedating and anti-agitation effects are the result of broader effects as histamine (H1) and alpha-1 adrenergic antagonists.

In the 1970s, haloperidol emerged as a first-line option to manage agitation due to its IM and IV availability, as well as its relative lack of sedation and orthostasis compared with low-potency D2 antagonists such as chlorpromazine. However, haloperidol was observed to have a significant risk of acute EPS, including dystonic reactions.² From the 1970s to the 1990s, numerous prospective clinical trials of haloperidol for the treatment of acute psychotic agitation, including several randomized controlled trials (RCTs) comparing haloperidol to lorazepam, were conducted.³ The design and outcomes of the haloperidol vs lorazepam RCTs were fairly consistent^4-7:

• adult participants with acute agitation and a variety of psychiatric diagnoses, for whom informed consent often was waived due to agitation severity
• randomization to either IM haloperidol, 5 mg, or IM lorazepam, 2 mg, administered every 30 minutes until agitation resolved
• behavioral outcomes measured over several hours using various rating scales, without consistent assessment of EPS
• equivalent efficacy of haloperidol and lorazepam, with symptom resolution usually achieved after 1 to 2 doses (in 30 to 60 minutes), but sometimes longer
• anticholinergic “rescue” allowed for EPS, but not administered prophylactically
• EPS, including dystonia and akathisia, were significantly more frequent with haloperidol compared with lorazepam.⁸

In recognition of the greater risk of EPS with haloperidol compared with lorazepam, and the fact that most study participants were already taking standing doses of antipsychotic medications, some researchers have recommended using benzodiazepines alone as the optimal treatment for agitation.^4,9 A 2012 Cochrane review concluded that the involuntary use of haloperidol alone “could be considered unethical.”^10,11 However, other studies that examined the combination of haloperidol and lorazepam compared with either medication alone found that the combination of the 2 medications was associated with a more rapid resolution of symptoms, which suggests a superior synergistic effect.^6,7,12 By the late 1990s, combined haloperidol and lorazepam, often mixed within a single injection, became the most common strategy to achieve rapid tranquilization in the psychiatric emergency setting.¹³ However, while the combination has been justified as a way to reduce the antipsychotic medication dose and EPS risk,² few studies have compared combinations containing <5 mg of haloperidol. As a result, the apparent superiority of combined haloperidol and lorazepam compared with either medication alone may be a simple cumulative dose effect rather than true synergism. It is also important to note that adding lorazepam to haloperidol does not mitigate the risk of EPS such as dystonia in the absence of anticholinergic medication.⁸ To date, however, there have been no clinical trials investigating the efficacy of IM haloperidol, lorazepam, and benztropine or diphenhydramine given together.

Newer RCTs tell a different story

With the availability of second-generation antipsychotics (SGAs) in IM formulations, clinical trials over the past 2 decades have focused on comparing SGAs with haloperidol alone as the “gold standard” control for acute agitation. Compared with previous trials of haloperidol vs lorazepam, these clinical trials of SGAs vs haloperidol included^8,14-22:

• Study participants who signed informed consent (and were likely less agitated)
• IM haloperidol doses typically >5 mg (eg, 6.5 to 10 mg).

As with studies comparing lorazepam with haloperidol, the results of these RCTs revealed that IM aripiprazole, olanzapine, and ziprasidone were at least as effective as IM haloperidol, with haloperidol having a significantly increased risk of akathisia, dystonia, and other EPS.^8,14-22 The greater EPS risk of haloperidol is not surprising given the use of comparison doses up to 10 mg.

An updated 2017 Cochrane review of haloperidol for psychosis-induced aggression or agitation concluded that⁹:

• haloperidol is an effective intervention, although the evidence is “weak”
• significant treatment effects may take as long as 1 to 2 hours following multiple IM injections
• in contrast to SGAs, treatment with haloperidol carries a significant risk of EPS
• adding a benzodiazepine “does not have strong evidence of benefit and carries risk of additional harm.”

Continue to: Haloperidol's well-known toxicity

Haloperidol has been associated with numerous adverse effects:

Akathisia and other acute EPS. Treatment with even a single dose of IM haloperidol can result in acute EPS, including dystonia and akathisia. At best, such adverse effects are subjectively troubling and unpleasant; at worst, akathisia can exacerbate and be mistaken for agitation, leading to administration of more medication²³ and the possible development of suicidal or violent behavior.^24-25 In the studies reviewed above, the overall rate of EPS was as high as 21% after treatment with haloperidol,¹⁶ with parkinsonism occurring in up to 17% of patients,¹⁹ dystonia in up to 11%,⁷ and akathisia in up to 10%.¹⁵ However, because specific EPS were assessed inconsistently, and sometimes not at all, the rate of akathisia—arguably the most relevant and counter-therapeutic adverse effect related to agitation—remains unclear.

In another study that specifically assessed for akathisia in patients treated with haloperidol, up to 40% experienced akathisia 6 hours after a single oral dose of 5 mg.²⁶ Even a single dose of IV prochlorperazine, another dopamine-antagonist routinely used to treat nausea in the emergency department (ED), has been reported to cause akathisia in up to 44% of patients.²⁷ Such results suggest that when akathisia is carefully assessed, the rate with even brief FGA exposure may approach nearly half of treated patients. Because akathisia is typically dose-related, and considering that many patients receiving IM haloperidol may receive multiple injections in addition to standing doses of oral medications, akathisia may be underrecognized in patients who are agitated, with a much greater risk than is generally presumed.

Although anticholinergic medications or benzodiazepinesare often administered as part of a haloperidol “cocktail,” these medications often do not adequately resolve emergent akathisia.^26,28 No clinical trials of IM haloperidol combined with benztropine or diphenhydramine have been published, but several studies suggest that combining haloperidol with promethazine—a phenothiazine with strong antihistaminergic and anticholinergic activity, but only weak antidopaminergic activity—can decrease the risk of dystonia relative to haloperidol alone.^8,22,29,30 However, there have also been reports of promethazine causing dystonia.^31,32 In addition, 1 trial of IM haloperidol, 2.5 mg, combined with promethazine reported that 74% of patients still had at least 1 form of EPS.³⁰ Because the clinical trials of haloperidol with promethazine did not specifically assess for akathisia, promethazine’s ability to decrease the risk of akathisia remains unknown.

Cardiotoxicity. Although low-potency antipsychotic medications such as chlorpromazine are more sedating than haloperidol, the latter is preferred as an IM antipsychotic medication for agitation because of its lower risk of hypotension.² In terms of cardiac effects, all antipsychotic medications carry a risk of QTc prolongation, with possible progression to the potentially lethal arrhythmia torsades de pointes as a result of interference with cardiac potassium channels.³³ In 2007, the FDA added a “black-box” warning about this risk for haloperidol, in the wake of a disproportionately high number of reported cases associated with IV administration, sometimes even after a single dose.³⁴

Continue to: Although there is no direct evidence...

Although there is no direct evidence that the cardiac risks associated with IV haloperidol apply to IM administration, epidemiologic studies indicate that oral haloperidol carries an elevated risk of ventricular arrhythmia and sudden cardiac death,^35,36 with 1 study reporting greater risk compared with other SGAs.³⁷ Haloperidol, whether administered orally or IM, may therefore be an especially poor choice for patients with agitation who are at risk for arrhythmia, including those with relevant medical comorbidities or delirium.³⁴

Neuronal cell death. Several lines of research evidence have demonstrated that haloperidol can cause cellular injury or death in neuronal tissue in a dose-dependent fashion through a variety of mechanisms.³⁸ By contrast, SGAs have been shown to have neuroprotective effects.³⁹ While these findings have mostly come from studies conducted in animals or in vitro human tumor cell lines, some researchers have nonetheless called for haloperidol to be banned, noting that if its neurotoxic effects were more widely known, “we would realize what a travesty it is to use [such] a brain-unfriendly drug.”⁴⁰

Several reasonable alternatives

Echoing the earlier Cochrane review of haloperidol for psychosis-induced aggression or agitation,¹⁰ a 2017 update concluded, “If no other alternative exists, sole use of intramuscular haloperidol could be life-saving. Where additional drugs are available, sole use of haloperidol for extreme emergency could be considered unethical.”⁹

What then are reasonable alternatives to replace IM haloperidol for agitation? Clinicians should consider the following nonpharmacologic and pharmacologic interventions:

Nonpharmacologic interventions. Several behavioral interventions have been demonstrated to be effective for managing acute agitation, including verbal de-escalation, enhanced “programming” on the inpatient units, and the judicious use of seclusion.^41-43 While such interventions may demand additional staff or resources, they have the potential to lower long-term costs, reduce injuries to patients and staff, and improve the quality of care.⁴³ The use of IM haloperidol as a form of “chemical restraint” does not represent standard-of-care treatment,³ and from an ethical perspective, should never be implemented punitively or to compensate for substandard care in the form of inadequate staffing or staff training.

Continue to: Benzodiazepines

Benzodiazepines. Lorazepam offers an attractive alternative to haloperidol without the risk of EPS.^2,4,8 However, lorazepam alone may be perceived as less efficacious than a haloperidol “cocktail” because it represents less overall medication. Some evidence has suggested that lorazepam, 4 mg, might be the most appropriate dose, although it has only rarely been studied in clinical trials of acute agitation.³ Midazolam is another IM benzodiazepine alternative to IM haloperidol that has been shown to achieve more rapid sedation than either haloperidol or lorazepam,^44,45 although it can cause substantial anterograde amnesia and also has an FDA black-box warning for respiratory depression associated with IV administration.

Respiratory depression is frequently cited as an argument against using lorazepam for agitation, as if the therapeutic window is extremely narrow with ineffectiveness at 2 mg, but potential lethality beyond that dose. In fact, serious respiratory depression with lorazepam is unlikely in the absence of chronic obstructive pulmonary disease (COPD), obstructive sleep apnea, or concomitant alcohol or other sedative use.⁴⁶ Case reports have documented therapeutic lorazepam dosing of 2 to 4 mg every 2 hours up to 20 to 30 mg/d in patients with manic agitation.⁴⁷ Even in patients with COPD, significant respiratory depression tends not to occur at doses <8 mg.⁴⁸ A more evidence-based concern about lorazepam dosing is that 2 mg might be ineffective in patients with established tolerance. For example, 1 report described a patient in acute alcohol withdrawal who required dosing lorazepam to 1,600 mg within 24 hours.⁴⁹ Collectively, these reports suggest that lorazepam has a much wider therapeutic window than is typically perceived, and that dosing with 3 to 4 mg IM is a reasonable option for agitation when 2 mg is likely to be inadequate.

Paradoxical disinhibition is another concern that might prevent benzodiazepines from being used alone as a first-line intervention for emergency treatment of agitation. However, similar to respiratory depression, this adverse event is relatively rare and tends to occur in children and geriatric patients, individuals intoxicated with alcohol or other sedatives, and patients with brain injury, developmental delay, or dementia.^23,46 Although exacerbation of aggression has not been demonstrated in the RCTs examining benzodiazepines for agitation reviewed above, based on other research, some clinicians have expressed concerns about the potential for benzodiazepines to exacerbate aggression in patients with impulse control disorders and a history of violent behavior.⁵⁰

The 2005 Expert Consensus Panel for Behavioral Emergencies⁵¹ recommended the use of lorazepam alone over haloperidol for agitation for patients for whom the diagnosis is unknown or includes the following:

• stimulant intoxication
• personality disorder
• comorbid obesity
• comorbid cardiac arrhythmia
• a history of akathisia and other EPS
• a history of amenorrhea/galactorrhea
• a history of seizures.

In surveys, patients have ranked lorazepam as the preferred medication for emergency agitation, whereas haloperidol was ranked as one of the least-preferred options.^51,52

Continue to: Second-generation antipsychotics

Second-generation antipsychotics. The SGAs available in IM formulations, such as aripiprazole, olanzapine, and ziprasidone, have been shown to be at least as effective as haloperidol for the treatment of acute agitation (in 2015, the short-acting injectable formulation of aripiprazole was discontinued in the United States independent of safety or efficacy issues⁵³). A review of RCTs examining IM SGAs for the treatment of agitation concluded that the number needed to treat for response compared with placebo was 5 for aripiprazole, 3 for olanzapine, and 3 for ziprasidone.⁵⁴ In terms of safety, a meta-analysis of studies examining IM medications for agitation confirmed that the risk of acute EPS, including dystonia, akathisia, and parkinsonism, is significantly lower with SGAs compared with haloperidol.⁵⁵ An RCT comparing IM ziprasidone with haloperidol found equivalently modest effects on QTc prolongation.⁵⁶ Therefore, SGAs are an obvious and evidence-based option for replacing haloperidol as a treatment for acute agitation.

Unfortunately, for clinicians hoping to replace haloperidol within a multiple-medication IM “cocktail,” there have been no published controlled trials of SGAs combined with benzodiazepines. Although a short report indicated that aripiprazole and lorazepam are chemically compatible to be combined within a single injection,⁵⁷ the package insert for aripiprazole warns that “If parenteral benzodiazepine therapy is deemed necessary in addition to ABILIFY injection treatment, patients should be monitored for excessive sedation and for orthostatic hypotension.”⁵⁸ The package insert for olanzapine likewise lists the combination of lorazepam and olanzapine as a drug interaction that can potentiate sedation, and the manufacturer issued specific warnings about parenteral combination.^59,60 A single published case of significant hypotension with combined IM olanzapine and lorazepam,⁶⁰ together with the fact that IM olanzapine can cause hypotension by itself,⁶¹ has discouraged the coadministration of these medications. Nonetheless, the combination is used in some emergency settings, with several retro­spective studies failing to provide evidence of hypotension or respiratory depression as adverse effects.^62-64

Droperidol. Droperidol was formerly a popular choice for managing acute agitation, with evidence from RCTs that droperidol, 5 mg, can improve symptoms significantly faster than either haloperidol, 5 mg, or lorazepam, 2 mg, and is absorbed just as rapidly whether administered IV or IM.^65-67 However, a 2001 FDA black-box warning about QTc prolongation included recommendations that a screening electrocardiogram should be obtained before administering droperidol. This action greatly curtailed the use of droperidol, and for some time, it was not marketed or available in the United States.

Over the past decade, however, droperidol has returned to the US market⁶⁸ and its IV and IM usage has been revitalized for managing patients with agitation within or en route to the ED. Studies have demonstrated droperidol efficacy comparable to midazolam, ziprasidone, or olanzapine, as well as effectiveness as an IV adjunct to midazolam.^69-71 In contrast to the FDA black-box warning, retrospective studies and RCTs of both IV and IM droperidol suggest that QTc prolongation and torsades de pointes are rare events that do not occur any more frequently than they do with haloperidol, even at doses >10 mg.^72,73 However, in studies involving patients with drug intoxication and treatment with multiple medications, oversedation to the point of needing rescue intervention was reported. In an emergency setting where these issues are relatively easily managed, such risks may be better tolerated than in psychiatric settings.

With earlier studies examining the use of droperidol in an acute psychiatric setting that reported a more rapid onset of action than haloperidol,^65-67 a 2016 Cochrane review concluded that there was high-quality evidence to support droperidol’s use for psychosis-induced agitation.⁷⁴ However, a 2015 RCT comparing IM droperidol, 10 mg, to haloperidol, 10 mg, found equivalent efficacy and response times (with maximal response occurring within 2 hours) and concluded that droperidol had no advantage over haloperidol.⁷⁵ Because none of the clinical trials that evaluated droperidol have included assessments for EPS, its risk of akathisia remains uncertain.

Continue to: Ketamine

Ketamine. In recent years, ketamine has been used to treat acute agitation within or en route to the ED. Preliminary observational studies support ketamine’s efficacy when administered via IV or IM routes,⁷⁶ with more rapid symptomatic improvement compared with haloperidol, lorazepam, or midazolam alone.⁷⁷ Reported adverse effects of ketamine include dissociation, psychotic exacerbation, and respiratory depression,⁷⁶ although 1 small naturalistic study found no evidence of exacerbation of psychotic or other psychiatric symptoms.⁷⁸ An ongoing RCT is comparing IM ketamine, 5 mg/kg, to combined IM haloperidol, 5 mg, and midazolam, 5 mg.⁷⁹ Although various ketamine formulations are increasingly being used in psychiatry, active psychosis is generally regarded as a contraindication. It is premature to recommend parenteral ketamine administration for agitation within most psychiatric settings until more research on safety has been completed.

Haloperidol, or something else? Practical considerations

Consider the following factors when deciding whether to use haloperidol or one of its alternatives:

Limitations of the evidence. Modern clinical trials requiring informed consent often do not include the kind of severe agitation that clinicians encounter in acute psychiatric, emergency, or forensic settings. In addition, standard interventions, such as 3-medication haloperidol “cocktails,” have not been evaluated in clinical trials. Clinicians are therefore often in the dark about optimal evidence-based practices.

Treatment goals. Psychiatric agitation has many causes, with a range of severity that warrants a commensurate range of responses. Protocols for managing acute agitation should include graded interventions that begin with nonpharmacologic interventions and voluntary oral medications, and move to involuntary IM medications when necessary.

While treatment guidelines clearly recommend against IM medications as “chemical restraint” with a goal of sedating a patient until he/she is unconscious,^3,51 such outcomes are nonetheless often sought by staff who are concerned about the risk of injuries during a behavioral emergency. In such instances, the risks of violence towards patients and staff may outweigh concerns about adverse effects in a risk-benefit analysis. Consequently, clinicians may be prone to “skip over” graded interventions because they assume they “won’t work” in favor of administering involuntary multiple-medication haloperidol “cocktails” despite risks of excess sedation, EPS, and cardiotoxicity. Treatment settings should critically evaluate such biased preferences, with a goal of developing tailored, evidence-based strategies that maximize benefits while minimizing excess sedation and other untoward adverse effects, with an eye towards promoting better overall patient care and reducing length of stay.^42,43,80

Continue to: Limitations of available medications

Limitations of available medications. There is no perfect medication for the management of acute agitation. Evidence indicates that pharmacologic options take 15 minutes to several hours to resolve acute agitation, even potentially more rapid-acting medications such as midazolam and droperidol. This is well beyond most clinicians’ desired window for response time in a behavioral emergency. Multiple-medication “cocktails” may be used with the hope of hastening response time, but may not achieve this goal at the expense of increasing the risk of adverse effects and the likelihood that a patient will remain sedated for a prolonged time. In the real world, this often means that by the time a psychiatrist comes to evaluate a patient who has been given emergency medications, the patient cannot be aroused for an interview. Ideally, medications would calm an agitated patient rapidly, without excess or prolonged sedation.⁸⁰ Less-sedating SGAs, such as ziprasidone, might have this potential, but can sometimes be perceived as ineffective.

Avoiding akathisia. Akathisia’s potential to worsen and be mistaken for agitation makes it an especially concerning, if underappreciated, adverse effect of haloperidol that is often not adequately assessed in clinical trials or practice. In light of evidence that akathisia can occur in nearly half of patients receiving a single 5 mg-dose of haloperidol, it is difficult to justify the use of this medication for agitation when equally effective options exist with a lower risk of EPS.

While haloperidol-induced akathisia could in theory be mitigated by adding anticholinergic medications or benzodiazepines, previous studies have found that such strategies have limited effectiveness compared to “gold standard” treatment with propranolol.^28,81,82 Furthermore, the half-lives of anticholinergic medications, such as benztropine or diphenhydramine, are significantly shorter than that of a single dose of haloperidol, which can be as long as 37 hours.⁸³ Therefore, akathisia and other EPS could emerge or worsen several hours or even days after receiving an IM haloperidol “cocktail” as the shorter-acting medications wear off. Akathisia is best minimized by avoiding FGAs, such as haloperidol, when treating acute agitation.

Promoting adherence. Although haloperidol is often recommended for acute agitation in patients with schizophrenia or bipolar disorder on the basis that it would treat the underlying condition, many patients who receive IM medications for acute agitation are already prescribed standing doses of oral medication, which increases the risk of cumulative toxicity. In addition, receiving a medication likely to cause acute EPS that is ranked near the bottom of patient preferences may erode the potential for a therapeutic alliance and hamper longer-term antipsychotic medication adherence.

Time for a change

For nearly half a century, haloperidol has been a “gold standard” intervention for IM control in patients with agitation. However, given its potential to produce adverse effects, including a significant risk of akathisia that can worsen agitation, along with the availability of newer pharmacologic options that are at least as effective (Table 1, and Table 2), haloperidol should be retired as a first-line medication for the treatment of agitation. Clinicians would benefit from RCTs investigating the safety and efficacy of novel interventions including frequently-used, but untested medication combinations, as well as nonpharmacologic interventions.

Continue to: Bottom Line

Although there is no perfect IM medication to treat acute agitation, haloperidol’s higher risk of adverse effects relative to newer alternatives suggest that it should no longer be considered a first-line intervention.

Related Resources

• Zun LS. Evidence-based review of pharmacotherapy for acute agitation. Part 1: onset of efficacy. J Emerg Med. 2018;54(3):364-374.
• Zun LS. Evidence-based review of pharmacotherapy for acute agitation. Part 2: safety. J Emerg Med. 2018;54(4): 522-532.

Drug Brand Names

Aripiprazole • Abilify
Benztropine • Cogentin
Chlorpromazine • Thorazine
Diphenhydramine • Benadryl
Droperidol • Inapsine
Haloperidol • Haldol
Ketamine • Ketalar
Lorazepam • Ativan
Midazolam • Versed
Olanzapine • Zyprexa
Prochlorperazine • Compazine
Promethazine • Phenergan
Propranolol • Inderal, Pronol
Ziprasidone • Geodon

The natural state of human beings is to live together and function as organized groups. The beginnings of communities have primeval origins; evolutionarily, societies that worked together were more productive, efficient and—probably most important—safer. Thousands of years of evolution have ingrained these behaviors as part of our genetic constitution and developmental process. Social integration and acceptance thus are an integral part of basic human behavior and provide a sense of protection, pleasure, and purpose in life.

Unfortunately, the social isolation necessary to address the coronavirus disease 2019 (COVID-19) pandemic is preventing this integration, and is likely to worsen what some have called an epidemic of loneliness. As mental health clinicians, we need to use technology to strengthen our patients’ social support systems.

Loneliness: A growing problem

Changes in society over the last few decades have led to increased isolation. In the last 50 years, there has been a rise in single-person households in the United States. This is most common in large cities, where the prevalence is approximately 40%.¹ The average number of confidants or the size of an American’s social network reduced by more than one-third from 1985 to 2009.² In a study published in 2018, the health service company Cigna used the UCLA Loneliness Scale to survey >20,000 American adults.³ Nearly half of respondents reported always feeling alone (46%) or left out (47%), and individuals age 18 to 22 were the loneliest age group and claimed to be in worse health than older age groups. Furthermore, the results suggested that people who felt lonelier were more likely to have poor sleep and be less physically active. Americans who lived with others were less likely to report feeling lonely, except for single parents living only with their children. The results also showed that people who engage in meaningful interactions with others had lower loneliness scores and perceived that they were in better overall health.³

Studies have consistently demonstrated a link between loneliness and health problems such as cardiovascular disease, substance use disorders (SUDs), and mood disorders. A 2010 meta-analysis of 148 prospective studies with 308,849 participants found that the influence of social relationships on the risk of mortality is comparable to well-established risk factors for mortality such as smoking and alcohol consumption.⁴ These findings were confirmed in a 2015 meta-analysis that included 70 studies with 3.4 million participants followed for an average of 7 years. ⁵

Loneliness has been identified as a social determinant of health and is considered by many to be epidemic in proportion in developed countries. According to a 2019 Business Insider survey, almost 20% of US health care leaders planned to address social isolation in the next 12 months.⁶

Increased vulnerability during COVID-19 isolation

The forced quarantines and social distancing imposed by the COVID-19 crisis are likely to further exacerbate the loneliness epidemic. Hopefully, this increased isolation will not last more than several months, and its effect on chronic medical illnesses will be minor. However, for patients with mental illness, this further isolation, in conjunction with rising societal anxiety and fear of the potentially devastating financial consequences, could worsen their illness, and might even lead to suicidal ideation or behavior.

Individuals with SUDs are particularly vulnerable to the social limitations required by COVID-19. While social isolation is essential to limit the spread of COVID-19, this restriction poses unique challenges for these patients because connection and social support are important aspects of achieving and maintaining sobriety.⁷

Continue to: A call to action

As mental health clinicians, we need to proactively engage with our patients to develop a plan to strengthen their social support systems. This may mean suggesting that they stay in contact with their network of people via video conferencing or by using the phone. We need to identify high-risk patients and continue to provide treatment via telepsychiatry. This is especially necessary to prevent relapse among patients with SUDs or mood disorders, and to minimize the risk of suicide.

We are ethically required to provide an atmosphere of trust, safety, and social inclusion by using resources, such as telehealth, video conferencing, and other online tools, to ameliorate the short- and long-term impact of COVID-19 isolation. Providing avenues that are easily accessible, are supportive, and maintain standards of care are essential. These resources should be implemented as early as possible to avoid negative outcomes regarding both COVID-19 and mental health.

There is also a significant risk that once circumstances improve, there will be a surge in the number of patients seeking a higher level of mental health care. Our actions and preparedness today will define the trajectory of our patients’ mental health in the future, potentially for years to come. While presently we are forced to be reactive, hopefully what is borne out of this crisis will translate into proactive measures for future crises.

Let this brief commentary serve as a call to action. As society finds ways to work from home, mental health clinicians need to lead the charge to use these same technologies to increase our patients’ social interactions. If we do not find ways to address the mental health burden of the COVID-19 pandemic, who will? We are all part of the mental health community, and we need to continue to function as an organized group, as has been the natural state of human beings for thousands of years.

Bottom Line

The social isolation required to limit the spread of the coronavirus disease 2019 pandemic is likely to increase loneliness, particularly among vulnerable patients with mood disorders and/or substance use disorders. As mental health clinicians, we need to work to strengthen our patients’ social support systems using resources such as video conferencing and other technologies.

Related Resources

• Cacioppo S, Grippo AJ, London S, et al. Loneliness: clinical import and interventions. Perspect Psychol Sci. 2015;10(2):238-249.
• Geriatric loneliness with Dr. Steven Wengel. Psychcast (podcast). https://www.mdedge.com/podcasts/psychcast/geriatricloneliness-dr-steven-wengel. Published April 1, 2020.

The natural state of human beings is to live together and function as organized groups. The beginnings of communities have primeval origins; evolutionarily, societies that worked together were more productive, efficient and—probably most important—safer. Thousands of years of evolution have ingrained these behaviors as part of our genetic constitution and developmental process. Social integration and acceptance thus are an integral part of basic human behavior and provide a sense of protection, pleasure, and purpose in life.

Unfortunately, the social isolation necessary to address the coronavirus disease 2019 (COVID-19) pandemic is preventing this integration, and is likely to worsen what some have called an epidemic of loneliness. As mental health clinicians, we need to use technology to strengthen our patients’ social support systems.

Loneliness: A growing problem

Changes in society over the last few decades have led to increased isolation. In the last 50 years, there has been a rise in single-person households in the United States. This is most common in large cities, where the prevalence is approximately 40%.¹ The average number of confidants or the size of an American’s social network reduced by more than one-third from 1985 to 2009.² In a study published in 2018, the health service company Cigna used the UCLA Loneliness Scale to survey >20,000 American adults.³ Nearly half of respondents reported always feeling alone (46%) or left out (47%), and individuals age 18 to 22 were the loneliest age group and claimed to be in worse health than older age groups. Furthermore, the results suggested that people who felt lonelier were more likely to have poor sleep and be less physically active. Americans who lived with others were less likely to report feeling lonely, except for single parents living only with their children. The results also showed that people who engage in meaningful interactions with others had lower loneliness scores and perceived that they were in better overall health.³

Studies have consistently demonstrated a link between loneliness and health problems such as cardiovascular disease, substance use disorders (SUDs), and mood disorders. A 2010 meta-analysis of 148 prospective studies with 308,849 participants found that the influence of social relationships on the risk of mortality is comparable to well-established risk factors for mortality such as smoking and alcohol consumption.⁴ These findings were confirmed in a 2015 meta-analysis that included 70 studies with 3.4 million participants followed for an average of 7 years. ⁵

Loneliness has been identified as a social determinant of health and is considered by many to be epidemic in proportion in developed countries. According to a 2019 Business Insider survey, almost 20% of US health care leaders planned to address social isolation in the next 12 months.⁶

Increased vulnerability during COVID-19 isolation

The forced quarantines and social distancing imposed by the COVID-19 crisis are likely to further exacerbate the loneliness epidemic. Hopefully, this increased isolation will not last more than several months, and its effect on chronic medical illnesses will be minor. However, for patients with mental illness, this further isolation, in conjunction with rising societal anxiety and fear of the potentially devastating financial consequences, could worsen their illness, and might even lead to suicidal ideation or behavior.

Individuals with SUDs are particularly vulnerable to the social limitations required by COVID-19. While social isolation is essential to limit the spread of COVID-19, this restriction poses unique challenges for these patients because connection and social support are important aspects of achieving and maintaining sobriety.⁷

Continue to: A call to action

As mental health clinicians, we need to proactively engage with our patients to develop a plan to strengthen their social support systems. This may mean suggesting that they stay in contact with their network of people via video conferencing or by using the phone. We need to identify high-risk patients and continue to provide treatment via telepsychiatry. This is especially necessary to prevent relapse among patients with SUDs or mood disorders, and to minimize the risk of suicide.

We are ethically required to provide an atmosphere of trust, safety, and social inclusion by using resources, such as telehealth, video conferencing, and other online tools, to ameliorate the short- and long-term impact of COVID-19 isolation. Providing avenues that are easily accessible, are supportive, and maintain standards of care are essential. These resources should be implemented as early as possible to avoid negative outcomes regarding both COVID-19 and mental health.

There is also a significant risk that once circumstances improve, there will be a surge in the number of patients seeking a higher level of mental health care. Our actions and preparedness today will define the trajectory of our patients’ mental health in the future, potentially for years to come. While presently we are forced to be reactive, hopefully what is borne out of this crisis will translate into proactive measures for future crises.

Let this brief commentary serve as a call to action. As society finds ways to work from home, mental health clinicians need to lead the charge to use these same technologies to increase our patients’ social interactions. If we do not find ways to address the mental health burden of the COVID-19 pandemic, who will? We are all part of the mental health community, and we need to continue to function as an organized group, as has been the natural state of human beings for thousands of years.

Bottom Line

The social isolation required to limit the spread of the coronavirus disease 2019 pandemic is likely to increase loneliness, particularly among vulnerable patients with mood disorders and/or substance use disorders. As mental health clinicians, we need to work to strengthen our patients’ social support systems using resources such as video conferencing and other technologies.

Related Resources

• Cacioppo S, Grippo AJ, London S, et al. Loneliness: clinical import and interventions. Perspect Psychol Sci. 2015;10(2):238-249.
• Geriatric loneliness with Dr. Steven Wengel. Psychcast (podcast). https://www.mdedge.com/podcasts/psychcast/geriatricloneliness-dr-steven-wengel. Published April 1, 2020.

The natural state of human beings is to live together and function as organized groups. The beginnings of communities have primeval origins; evolutionarily, societies that worked together were more productive, efficient and—probably most important—safer. Thousands of years of evolution have ingrained these behaviors as part of our genetic constitution and developmental process. Social integration and acceptance thus are an integral part of basic human behavior and provide a sense of protection, pleasure, and purpose in life.

Unfortunately, the social isolation necessary to address the coronavirus disease 2019 (COVID-19) pandemic is preventing this integration, and is likely to worsen what some have called an epidemic of loneliness. As mental health clinicians, we need to use technology to strengthen our patients’ social support systems.

Loneliness: A growing problem

Changes in society over the last few decades have led to increased isolation. In the last 50 years, there has been a rise in single-person households in the United States. This is most common in large cities, where the prevalence is approximately 40%.¹ The average number of confidants or the size of an American’s social network reduced by more than one-third from 1985 to 2009.² In a study published in 2018, the health service company Cigna used the UCLA Loneliness Scale to survey >20,000 American adults.³ Nearly half of respondents reported always feeling alone (46%) or left out (47%), and individuals age 18 to 22 were the loneliest age group and claimed to be in worse health than older age groups. Furthermore, the results suggested that people who felt lonelier were more likely to have poor sleep and be less physically active. Americans who lived with others were less likely to report feeling lonely, except for single parents living only with their children. The results also showed that people who engage in meaningful interactions with others had lower loneliness scores and perceived that they were in better overall health.³

Studies have consistently demonstrated a link between loneliness and health problems such as cardiovascular disease, substance use disorders (SUDs), and mood disorders. A 2010 meta-analysis of 148 prospective studies with 308,849 participants found that the influence of social relationships on the risk of mortality is comparable to well-established risk factors for mortality such as smoking and alcohol consumption.⁴ These findings were confirmed in a 2015 meta-analysis that included 70 studies with 3.4 million participants followed for an average of 7 years. ⁵

Loneliness has been identified as a social determinant of health and is considered by many to be epidemic in proportion in developed countries. According to a 2019 Business Insider survey, almost 20% of US health care leaders planned to address social isolation in the next 12 months.⁶

Increased vulnerability during COVID-19 isolation

The forced quarantines and social distancing imposed by the COVID-19 crisis are likely to further exacerbate the loneliness epidemic. Hopefully, this increased isolation will not last more than several months, and its effect on chronic medical illnesses will be minor. However, for patients with mental illness, this further isolation, in conjunction with rising societal anxiety and fear of the potentially devastating financial consequences, could worsen their illness, and might even lead to suicidal ideation or behavior.

Individuals with SUDs are particularly vulnerable to the social limitations required by COVID-19. While social isolation is essential to limit the spread of COVID-19, this restriction poses unique challenges for these patients because connection and social support are important aspects of achieving and maintaining sobriety.⁷

Continue to: A call to action

As mental health clinicians, we need to proactively engage with our patients to develop a plan to strengthen their social support systems. This may mean suggesting that they stay in contact with their network of people via video conferencing or by using the phone. We need to identify high-risk patients and continue to provide treatment via telepsychiatry. This is especially necessary to prevent relapse among patients with SUDs or mood disorders, and to minimize the risk of suicide.

We are ethically required to provide an atmosphere of trust, safety, and social inclusion by using resources, such as telehealth, video conferencing, and other online tools, to ameliorate the short- and long-term impact of COVID-19 isolation. Providing avenues that are easily accessible, are supportive, and maintain standards of care are essential. These resources should be implemented as early as possible to avoid negative outcomes regarding both COVID-19 and mental health.

There is also a significant risk that once circumstances improve, there will be a surge in the number of patients seeking a higher level of mental health care. Our actions and preparedness today will define the trajectory of our patients’ mental health in the future, potentially for years to come. While presently we are forced to be reactive, hopefully what is borne out of this crisis will translate into proactive measures for future crises.

Let this brief commentary serve as a call to action. As society finds ways to work from home, mental health clinicians need to lead the charge to use these same technologies to increase our patients’ social interactions. If we do not find ways to address the mental health burden of the COVID-19 pandemic, who will? We are all part of the mental health community, and we need to continue to function as an organized group, as has been the natural state of human beings for thousands of years.

Bottom Line

The social isolation required to limit the spread of the coronavirus disease 2019 pandemic is likely to increase loneliness, particularly among vulnerable patients with mood disorders and/or substance use disorders. As mental health clinicians, we need to work to strengthen our patients’ social support systems using resources such as video conferencing and other technologies.

Related Resources

• Cacioppo S, Grippo AJ, London S, et al. Loneliness: clinical import and interventions. Perspect Psychol Sci. 2015;10(2):238-249.
• Geriatric loneliness with Dr. Steven Wengel. Psychcast (podcast). https://www.mdedge.com/podcasts/psychcast/geriatricloneliness-dr-steven-wengel. Published April 1, 2020.

During these unprecedented times, venturing into the unknown of the coronavirus disease 2019 (COVID-19) pandemic, a feeling of impending doom prevails. Almost all of us have been restricted to our homes. Although the physical dimensions of what we call home may vary, the meaning of this restriction is fairly universal. No matter how our sociodemographics differ, with no guidance for this situation from anything even remotely comparable in the past, our lives have been transformed into a work in progress.

During this pandemic, I have observed a wide range of human emotions and behavior—many of them familiar and predictable, some abysmal, and some inspiring.

’Why should I care?’

On December 31, 2019, health officials in China informed the World Health Organization about a pneumonia-like presentation in a group of people in Wuhan. On January 7, 2020, a novel coronavirus was identified as the cause, and the first death was reported a few days later. In the following days and weeks the disease rapidly spread, as did the growing sense that this was not a typical virus.

While these events occurred, the rest of the world was in what I call a ”Why should I care?” mode. Most humans tend to suffer from this indifference. This has been observed repeatedly through the years, such as when the Ebola outbreak occurred in Africa in 2014-2016. It was only when cases started to develop in Europe and the United States that other countries started to pay attention. A similar phenomenon has been observed every time we’ve faced a global outbreak (avian influenza, Middle East respiratory syndrome, etc.).

When are we going to learn? It is time to realize that global borders are more porous than we think, and human interactions cannot be blocked by any wall. When a catastrophic event, outbreak, or disaster starts in any part of the world, it is naive to assume that we will not be affected. We will eventually be affected—the only question is how, when, and to what extent? We are always all in this together.

An abundance of ignorance and stupidity

Within a few weeks of the first reports from China, cases of COVID-19 were reported in South Korea, Italy, Spain, Germany, and many other countries. Slowly, COVID-19 reached the United States, which as of mid-April had the highest number of cases worldwide. When COVID-19 hit the United States, the response was that of shock and anger. How could this happen to us? Why is the government not doing anything?

Amidst this pandemonium, ignorance and stupidity of the highest degree were commonplace. This was not restricted to any particular country or region. Almost 2 months into the pandemic, the Ministry of Tourism in my home country of Nepal declared Nepal a ”coronavirus-free zone” and took measures to bring in tourists, focusing specifically on China, where COVID-19 had already killed hundreds. In India, some people were drinking cow urine in hopes of warding off the virus. In the United Sates, thousands of young people flocked to beaches for Spring Break, disregarding measures for social distancing. ”If I get corona, I get corona,” one young man said in an interview that went viral. Personally, I have encountered people who responded to this pandemic by saying the disease was ”cooties” or ”just a flu,” and dismissing it with ”If I die from this, I die.”

Continue to: Rising panic and fear

Rising panic and fear

For most people, seeing COVID-19 at their doorstep triggered a panic, and sent many into a frenzy of buying and hoarding. Once again, we proved that people everywhere are equally stupid, as toilet paper began to vanish from stores across the globe. And yet, this again was a moment when some people began to experience a false sense of immunity: ”I have enough food, money, and toilet paper to last me for 2 years. Why should I be worried?”

When the numbers of COVID-19 deaths in Europe were first reported, the fear became palpable. In Italy and Spain, towns were locked down, and tens of thousands of people (mostly older adults) have died. It was truly heartbreaking to see people alone and at their weakest with no family members allowed to be by their side.

A glimmer of hope

Despite all of this, there were superheroes—the nurses, physicians, allied health professionals, first responders, store workers, restaurant workers, delivery personnel, and others who didn’t have the option of staying home, or who volunteered to help people in need. In moments like this, the actions of these individuals give us hope, reminding us that the human spirit is resilient, and that we will get through this.

A rotation in the emergency department during COVID-19

As a psychiatry resident, it is unlikely that my peers and I face the same risks as our colleagues in other medical specialities. But those of us who happened to be in medical rotations during this time have had the chance to experience this very closely. My personal experience, albeit a brief one, of working in an emergency department with suspected COVID-19 patients has been sobering. Watching nurses and physicians walk into a room wearing personal protective equipment, fearful inside but with a reassuring smile for a scared patient, definitely was one of the most compelling moments of my life. Living in a distant land, with my daughter, wife, parents, and extended family back home in Nepal, has made this even more challenging.

We will overcome this as we have overcome previous challenges in the past. There will be death and chaos, but we will prevail. The only thing is to ask ourselves: How do we want to continue living when this is over?

During these unprecedented times, venturing into the unknown of the coronavirus disease 2019 (COVID-19) pandemic, a feeling of impending doom prevails. Almost all of us have been restricted to our homes. Although the physical dimensions of what we call home may vary, the meaning of this restriction is fairly universal. No matter how our sociodemographics differ, with no guidance for this situation from anything even remotely comparable in the past, our lives have been transformed into a work in progress.

During this pandemic, I have observed a wide range of human emotions and behavior—many of them familiar and predictable, some abysmal, and some inspiring.

’Why should I care?’

On December 31, 2019, health officials in China informed the World Health Organization about a pneumonia-like presentation in a group of people in Wuhan. On January 7, 2020, a novel coronavirus was identified as the cause, and the first death was reported a few days later. In the following days and weeks the disease rapidly spread, as did the growing sense that this was not a typical virus.

While these events occurred, the rest of the world was in what I call a ”Why should I care?” mode. Most humans tend to suffer from this indifference. This has been observed repeatedly through the years, such as when the Ebola outbreak occurred in Africa in 2014-2016. It was only when cases started to develop in Europe and the United States that other countries started to pay attention. A similar phenomenon has been observed every time we’ve faced a global outbreak (avian influenza, Middle East respiratory syndrome, etc.).

When are we going to learn? It is time to realize that global borders are more porous than we think, and human interactions cannot be blocked by any wall. When a catastrophic event, outbreak, or disaster starts in any part of the world, it is naive to assume that we will not be affected. We will eventually be affected—the only question is how, when, and to what extent? We are always all in this together.

An abundance of ignorance and stupidity

Within a few weeks of the first reports from China, cases of COVID-19 were reported in South Korea, Italy, Spain, Germany, and many other countries. Slowly, COVID-19 reached the United States, which as of mid-April had the highest number of cases worldwide. When COVID-19 hit the United States, the response was that of shock and anger. How could this happen to us? Why is the government not doing anything?

Amidst this pandemonium, ignorance and stupidity of the highest degree were commonplace. This was not restricted to any particular country or region. Almost 2 months into the pandemic, the Ministry of Tourism in my home country of Nepal declared Nepal a ”coronavirus-free zone” and took measures to bring in tourists, focusing specifically on China, where COVID-19 had already killed hundreds. In India, some people were drinking cow urine in hopes of warding off the virus. In the United Sates, thousands of young people flocked to beaches for Spring Break, disregarding measures for social distancing. ”If I get corona, I get corona,” one young man said in an interview that went viral. Personally, I have encountered people who responded to this pandemic by saying the disease was ”cooties” or ”just a flu,” and dismissing it with ”If I die from this, I die.”

Continue to: Rising panic and fear

Rising panic and fear

For most people, seeing COVID-19 at their doorstep triggered a panic, and sent many into a frenzy of buying and hoarding. Once again, we proved that people everywhere are equally stupid, as toilet paper began to vanish from stores across the globe. And yet, this again was a moment when some people began to experience a false sense of immunity: ”I have enough food, money, and toilet paper to last me for 2 years. Why should I be worried?”

When the numbers of COVID-19 deaths in Europe were first reported, the fear became palpable. In Italy and Spain, towns were locked down, and tens of thousands of people (mostly older adults) have died. It was truly heartbreaking to see people alone and at their weakest with no family members allowed to be by their side.

A glimmer of hope

Despite all of this, there were superheroes—the nurses, physicians, allied health professionals, first responders, store workers, restaurant workers, delivery personnel, and others who didn’t have the option of staying home, or who volunteered to help people in need. In moments like this, the actions of these individuals give us hope, reminding us that the human spirit is resilient, and that we will get through this.

A rotation in the emergency department during COVID-19

As a psychiatry resident, it is unlikely that my peers and I face the same risks as our colleagues in other medical specialities. But those of us who happened to be in medical rotations during this time have had the chance to experience this very closely. My personal experience, albeit a brief one, of working in an emergency department with suspected COVID-19 patients has been sobering. Watching nurses and physicians walk into a room wearing personal protective equipment, fearful inside but with a reassuring smile for a scared patient, definitely was one of the most compelling moments of my life. Living in a distant land, with my daughter, wife, parents, and extended family back home in Nepal, has made this even more challenging.

We will overcome this as we have overcome previous challenges in the past. There will be death and chaos, but we will prevail. The only thing is to ask ourselves: How do we want to continue living when this is over?

During these unprecedented times, venturing into the unknown of the coronavirus disease 2019 (COVID-19) pandemic, a feeling of impending doom prevails. Almost all of us have been restricted to our homes. Although the physical dimensions of what we call home may vary, the meaning of this restriction is fairly universal. No matter how our sociodemographics differ, with no guidance for this situation from anything even remotely comparable in the past, our lives have been transformed into a work in progress.

During this pandemic, I have observed a wide range of human emotions and behavior—many of them familiar and predictable, some abysmal, and some inspiring.

’Why should I care?’

On December 31, 2019, health officials in China informed the World Health Organization about a pneumonia-like presentation in a group of people in Wuhan. On January 7, 2020, a novel coronavirus was identified as the cause, and the first death was reported a few days later. In the following days and weeks the disease rapidly spread, as did the growing sense that this was not a typical virus.

While these events occurred, the rest of the world was in what I call a ”Why should I care?” mode. Most humans tend to suffer from this indifference. This has been observed repeatedly through the years, such as when the Ebola outbreak occurred in Africa in 2014-2016. It was only when cases started to develop in Europe and the United States that other countries started to pay attention. A similar phenomenon has been observed every time we’ve faced a global outbreak (avian influenza, Middle East respiratory syndrome, etc.).

When are we going to learn? It is time to realize that global borders are more porous than we think, and human interactions cannot be blocked by any wall. When a catastrophic event, outbreak, or disaster starts in any part of the world, it is naive to assume that we will not be affected. We will eventually be affected—the only question is how, when, and to what extent? We are always all in this together.

An abundance of ignorance and stupidity

Within a few weeks of the first reports from China, cases of COVID-19 were reported in South Korea, Italy, Spain, Germany, and many other countries. Slowly, COVID-19 reached the United States, which as of mid-April had the highest number of cases worldwide. When COVID-19 hit the United States, the response was that of shock and anger. How could this happen to us? Why is the government not doing anything?

Amidst this pandemonium, ignorance and stupidity of the highest degree were commonplace. This was not restricted to any particular country or region. Almost 2 months into the pandemic, the Ministry of Tourism in my home country of Nepal declared Nepal a ”coronavirus-free zone” and took measures to bring in tourists, focusing specifically on China, where COVID-19 had already killed hundreds. In India, some people were drinking cow urine in hopes of warding off the virus. In the United Sates, thousands of young people flocked to beaches for Spring Break, disregarding measures for social distancing. ”If I get corona, I get corona,” one young man said in an interview that went viral. Personally, I have encountered people who responded to this pandemic by saying the disease was ”cooties” or ”just a flu,” and dismissing it with ”If I die from this, I die.”

Continue to: Rising panic and fear

Rising panic and fear

For most people, seeing COVID-19 at their doorstep triggered a panic, and sent many into a frenzy of buying and hoarding. Once again, we proved that people everywhere are equally stupid, as toilet paper began to vanish from stores across the globe. And yet, this again was a moment when some people began to experience a false sense of immunity: ”I have enough food, money, and toilet paper to last me for 2 years. Why should I be worried?”

When the numbers of COVID-19 deaths in Europe were first reported, the fear became palpable. In Italy and Spain, towns were locked down, and tens of thousands of people (mostly older adults) have died. It was truly heartbreaking to see people alone and at their weakest with no family members allowed to be by their side.

A glimmer of hope

Despite all of this, there were superheroes—the nurses, physicians, allied health professionals, first responders, store workers, restaurant workers, delivery personnel, and others who didn’t have the option of staying home, or who volunteered to help people in need. In moments like this, the actions of these individuals give us hope, reminding us that the human spirit is resilient, and that we will get through this.

A rotation in the emergency department during COVID-19

As a psychiatry resident, it is unlikely that my peers and I face the same risks as our colleagues in other medical specialities. But those of us who happened to be in medical rotations during this time have had the chance to experience this very closely. My personal experience, albeit a brief one, of working in an emergency department with suspected COVID-19 patients has been sobering. Watching nurses and physicians walk into a room wearing personal protective equipment, fearful inside but with a reassuring smile for a scared patient, definitely was one of the most compelling moments of my life. Living in a distant land, with my daughter, wife, parents, and extended family back home in Nepal, has made this even more challenging.

We will overcome this as we have overcome previous challenges in the past. There will be death and chaos, but we will prevail. The only thing is to ask ourselves: How do we want to continue living when this is over?

Screening for adolescent substance use

I want to congratulate Dr. Verma on her article “Opioid use disorder in adolescents: An overview” (Evidence-Based Reviews, Current Psychiatry. February 2020, p. 12-14,16-21) and would like to make some contributions. Her article describes several screening tools that are available to assess adolescent substance use disorder (SUD), including the CRAFFT Interview, National Institute on Drug Abuse–modified ASSIST, Drug Use Screening Inventory (DUSI), Problem-Oriented Screening Instrument for Teenagers (POSIT), and Personal Experience Screening Questionnaire (PESQ). The ideal screening tool should be brief, easy to use, sensitive, specific to substance use and related problems, and able to guide subsequent assessment and intervention when appropriate.

Because evidence suggests there are continued barriers, such as time constraints, in evaluating for adolescent SUD,^1,2 I believe the Screen to Brief Intervention (S2BI) and Brief Screener for Tobacco, Alcohol and Drug (BSTAD) should be included.^3,4 The S2BI and BSTAD are brief screeners that assess substance use, are validated for adolescent patients, can be completed online, and can assist in identifying DSM-5 criteria for SUD.

The S2BI has demonstrated high sensitivity and specificity for identifying SUD.³ The single screening assessment for “past-year use” is quick and can be administered in a variety of clinical settings. The S2BI begins by asking a patient about his/her frequency of tobacco, alcohol, and/or marijuana use in the past year. If the patient endorses past-year use of any of these substances, the S2BI prompts follow-up questions about the use of prescription medications, illicit drugs, inhalants, and herbal products. A patient’s frequency of use is strongly correlated with the likelihood of having a SUD. Adolescents who report using a substance “once or twice” in the past year are very unlikely to have a SUD. Patients who endorse “monthly” use are more likely to meet the criteria for a mild or moderate SUD, and those reporting “weekly or more” use are more likely to have a severe SUD.

The BSTAD is an electronic, validated, high-sensitivity, high-specificity instrument for identifying SUD.¹ It asks a single frequency question about past-year use of tobacco, alcohol, and marijuana, which are the most commonly used substances among adolescents. Patients who report using any of these substances are then asked about additional substance use. Based on the patient’s self-report of past year use, the screen places him/her into 1 of 3 risk categories for SUD: no reported use, lower risk, and higher risk. Each risk level maps to suggested clinical actions that are summarized in the results section.

Kevin M. Simon, MD
Child & Adolescent Psychiatry Fellow
Boston Children’s Hospital
Clinical Fellow in Psychiatry
Harvard Medical School
Boston, Massachusetts

Disclosure: The author reports no financial relationships with any companies whose products are mentioned in this article, or with manufacturers of competing products.

References

1. Palmer A, Karakus M, Mark T. Barriers faced by physicians in screening for substance use disorders among adolescents. Psychiatr Serv. 2019;70(5):409-412.
2. D’Souza-Li L, Harris SK. The future of screening, brief intervention and referral to treatment in adolescent primary care: research directions and dissemination challenges. Curr Opin Pediatr. 2016;28(4):434-440. 
3. Levy S, Weiss R, Sherritt L, et al. An electronic screen for triaging adolescent substance use by risk levels. JAMA Pediatr. 2014;168(9):822-828.
4. Kelly SM, Gryczynski J, Mitchell SG, et al. Validity of brief screening instrument for adolescent tobacco, alcohol, and drug use. Pediatrics. 2014;133(5):819-826.

Continue to: The author responds

The author responds

I thank Dr. Simon for his words of encouragement. I agree that both the S2BI and BSTAD have high sensitivity and specificity and are easy to use for screening for the use of multiple substances. Once substance use is established, both tools recommend administering high-risk assessment with additional scales such as the CRAFFT. During the initial evaluation, many psychiatrists take their patient’s history of substance use in detail, including age of onset, frequency, amount used, severity, and the time of his/her last use, without using a screening instrument. My article focused on instruments that can determine whether there is need for a further detailed evaluation. I agree that the S2BI and BSTAD would assist psychiatrists or physicians in other specialties (eg, pediatrics, family medicine) who might not take a complete substance use history during their initial evaluations.

Shikha Verma, MD
Rogers Behavioral Health
Kenosha, Wisconsin
Assistant Professor
Department of Psychiatry and Behavioral Health
Rosalind Franklin University of Medicine and Science
North Chicago, Illinois

Continue to: Changes as a result of COVID-19

I thank Dr. Nasrallah for his editorial “During a viral pandemic, anxiety is endemic: The psychiatric aspects of COVID-19” (From the Editor, Current Psychiatry. April 2020, p. e3-e5).

I appreciated the editorial because it got me thinking about how the pandemic has changed me and my family:

1. We are engaging more in social media.

2. I feel uncomfortable when I go to the grocery store.

3. I feel better when I don’t access the news about COVID-19.

4. My children need physical socialization with their friends (sports, games, other activities, etc.).

5. My children function better with a schedule, but we find it difficult to keep them on a good schedule. Our teenagers stay up late at night (because all of their friends do), and they sleep in late the next morning.

Here are some positive changes:

1. Creating a weekly family calendar on a dry-erase board, so the family can see what is going on during the week.

2. Creating responsibility for our older children (eg, washing their own clothes, cleaning their bathroom).

3. Eating most meals as a family and organizing meals better, too.

4. Playing games together.

5. Cleaning the house together.

6. Getting outside to walk the dog and appreciate nature more.

7. Exercising.

8. Utilizing positive social media.

9. Getting caught up on life.

Again, I thank Dr. Nasrallah for writing this editorial because it led me to self-reflect on this situation, and helped me feel normal.

Doug Dolenc
Westfield, Indiana

Disclosure: The author reports no financial relationships with any companies whose products are mentioned in this article, or with manufacturers of competing products.

Screening for adolescent substance use

I want to congratulate Dr. Verma on her article “Opioid use disorder in adolescents: An overview” (Evidence-Based Reviews, Current Psychiatry. February 2020, p. 12-14,16-21) and would like to make some contributions. Her article describes several screening tools that are available to assess adolescent substance use disorder (SUD), including the CRAFFT Interview, National Institute on Drug Abuse–modified ASSIST, Drug Use Screening Inventory (DUSI), Problem-Oriented Screening Instrument for Teenagers (POSIT), and Personal Experience Screening Questionnaire (PESQ). The ideal screening tool should be brief, easy to use, sensitive, specific to substance use and related problems, and able to guide subsequent assessment and intervention when appropriate.

Because evidence suggests there are continued barriers, such as time constraints, in evaluating for adolescent SUD,^1,2 I believe the Screen to Brief Intervention (S2BI) and Brief Screener for Tobacco, Alcohol and Drug (BSTAD) should be included.^3,4 The S2BI and BSTAD are brief screeners that assess substance use, are validated for adolescent patients, can be completed online, and can assist in identifying DSM-5 criteria for SUD.

The S2BI has demonstrated high sensitivity and specificity for identifying SUD.³ The single screening assessment for “past-year use” is quick and can be administered in a variety of clinical settings. The S2BI begins by asking a patient about his/her frequency of tobacco, alcohol, and/or marijuana use in the past year. If the patient endorses past-year use of any of these substances, the S2BI prompts follow-up questions about the use of prescription medications, illicit drugs, inhalants, and herbal products. A patient’s frequency of use is strongly correlated with the likelihood of having a SUD. Adolescents who report using a substance “once or twice” in the past year are very unlikely to have a SUD. Patients who endorse “monthly” use are more likely to meet the criteria for a mild or moderate SUD, and those reporting “weekly or more” use are more likely to have a severe SUD.

The BSTAD is an electronic, validated, high-sensitivity, high-specificity instrument for identifying SUD.¹ It asks a single frequency question about past-year use of tobacco, alcohol, and marijuana, which are the most commonly used substances among adolescents. Patients who report using any of these substances are then asked about additional substance use. Based on the patient’s self-report of past year use, the screen places him/her into 1 of 3 risk categories for SUD: no reported use, lower risk, and higher risk. Each risk level maps to suggested clinical actions that are summarized in the results section.

Kevin M. Simon, MD
Child & Adolescent Psychiatry Fellow
Boston Children’s Hospital
Clinical Fellow in Psychiatry
Harvard Medical School
Boston, Massachusetts

Disclosure: The author reports no financial relationships with any companies whose products are mentioned in this article, or with manufacturers of competing products.

References

1. Palmer A, Karakus M, Mark T. Barriers faced by physicians in screening for substance use disorders among adolescents. Psychiatr Serv. 2019;70(5):409-412.
2. D’Souza-Li L, Harris SK. The future of screening, brief intervention and referral to treatment in adolescent primary care: research directions and dissemination challenges. Curr Opin Pediatr. 2016;28(4):434-440. 
3. Levy S, Weiss R, Sherritt L, et al. An electronic screen for triaging adolescent substance use by risk levels. JAMA Pediatr. 2014;168(9):822-828.
4. Kelly SM, Gryczynski J, Mitchell SG, et al. Validity of brief screening instrument for adolescent tobacco, alcohol, and drug use. Pediatrics. 2014;133(5):819-826.

Continue to: The author responds

The author responds

I thank Dr. Simon for his words of encouragement. I agree that both the S2BI and BSTAD have high sensitivity and specificity and are easy to use for screening for the use of multiple substances. Once substance use is established, both tools recommend administering high-risk assessment with additional scales such as the CRAFFT. During the initial evaluation, many psychiatrists take their patient’s history of substance use in detail, including age of onset, frequency, amount used, severity, and the time of his/her last use, without using a screening instrument. My article focused on instruments that can determine whether there is need for a further detailed evaluation. I agree that the S2BI and BSTAD would assist psychiatrists or physicians in other specialties (eg, pediatrics, family medicine) who might not take a complete substance use history during their initial evaluations.

Shikha Verma, MD
Rogers Behavioral Health
Kenosha, Wisconsin
Assistant Professor
Department of Psychiatry and Behavioral Health
Rosalind Franklin University of Medicine and Science
North Chicago, Illinois

Continue to: Changes as a result of COVID-19

I thank Dr. Nasrallah for his editorial “During a viral pandemic, anxiety is endemic: The psychiatric aspects of COVID-19” (From the Editor, Current Psychiatry. April 2020, p. e3-e5).

I appreciated the editorial because it got me thinking about how the pandemic has changed me and my family:

1. We are engaging more in social media.

2. I feel uncomfortable when I go to the grocery store.

3. I feel better when I don’t access the news about COVID-19.

4. My children need physical socialization with their friends (sports, games, other activities, etc.).

5. My children function better with a schedule, but we find it difficult to keep them on a good schedule. Our teenagers stay up late at night (because all of their friends do), and they sleep in late the next morning.

Here are some positive changes:

1. Creating a weekly family calendar on a dry-erase board, so the family can see what is going on during the week.

2. Creating responsibility for our older children (eg, washing their own clothes, cleaning their bathroom).

3. Eating most meals as a family and organizing meals better, too.

4. Playing games together.

5. Cleaning the house together.

6. Getting outside to walk the dog and appreciate nature more.

7. Exercising.

8. Utilizing positive social media.

9. Getting caught up on life.

Again, I thank Dr. Nasrallah for writing this editorial because it led me to self-reflect on this situation, and helped me feel normal.

Doug Dolenc
Westfield, Indiana

Disclosure: The author reports no financial relationships with any companies whose products are mentioned in this article, or with manufacturers of competing products.

Screening for adolescent substance use

I want to congratulate Dr. Verma on her article “Opioid use disorder in adolescents: An overview” (Evidence-Based Reviews, Current Psychiatry. February 2020, p. 12-14,16-21) and would like to make some contributions. Her article describes several screening tools that are available to assess adolescent substance use disorder (SUD), including the CRAFFT Interview, National Institute on Drug Abuse–modified ASSIST, Drug Use Screening Inventory (DUSI), Problem-Oriented Screening Instrument for Teenagers (POSIT), and Personal Experience Screening Questionnaire (PESQ). The ideal screening tool should be brief, easy to use, sensitive, specific to substance use and related problems, and able to guide subsequent assessment and intervention when appropriate.

Because evidence suggests there are continued barriers, such as time constraints, in evaluating for adolescent SUD,^1,2 I believe the Screen to Brief Intervention (S2BI) and Brief Screener for Tobacco, Alcohol and Drug (BSTAD) should be included.^3,4 The S2BI and BSTAD are brief screeners that assess substance use, are validated for adolescent patients, can be completed online, and can assist in identifying DSM-5 criteria for SUD.

The S2BI has demonstrated high sensitivity and specificity for identifying SUD.³ The single screening assessment for “past-year use” is quick and can be administered in a variety of clinical settings. The S2BI begins by asking a patient about his/her frequency of tobacco, alcohol, and/or marijuana use in the past year. If the patient endorses past-year use of any of these substances, the S2BI prompts follow-up questions about the use of prescription medications, illicit drugs, inhalants, and herbal products. A patient’s frequency of use is strongly correlated with the likelihood of having a SUD. Adolescents who report using a substance “once or twice” in the past year are very unlikely to have a SUD. Patients who endorse “monthly” use are more likely to meet the criteria for a mild or moderate SUD, and those reporting “weekly or more” use are more likely to have a severe SUD.

The BSTAD is an electronic, validated, high-sensitivity, high-specificity instrument for identifying SUD.¹ It asks a single frequency question about past-year use of tobacco, alcohol, and marijuana, which are the most commonly used substances among adolescents. Patients who report using any of these substances are then asked about additional substance use. Based on the patient’s self-report of past year use, the screen places him/her into 1 of 3 risk categories for SUD: no reported use, lower risk, and higher risk. Each risk level maps to suggested clinical actions that are summarized in the results section.

Kevin M. Simon, MD
Child & Adolescent Psychiatry Fellow
Boston Children’s Hospital
Clinical Fellow in Psychiatry
Harvard Medical School
Boston, Massachusetts

Disclosure: The author reports no financial relationships with any companies whose products are mentioned in this article, or with manufacturers of competing products.

References

1. Palmer A, Karakus M, Mark T. Barriers faced by physicians in screening for substance use disorders among adolescents. Psychiatr Serv. 2019;70(5):409-412.
2. D’Souza-Li L, Harris SK. The future of screening, brief intervention and referral to treatment in adolescent primary care: research directions and dissemination challenges. Curr Opin Pediatr. 2016;28(4):434-440. 
3. Levy S, Weiss R, Sherritt L, et al. An electronic screen for triaging adolescent substance use by risk levels. JAMA Pediatr. 2014;168(9):822-828.
4. Kelly SM, Gryczynski J, Mitchell SG, et al. Validity of brief screening instrument for adolescent tobacco, alcohol, and drug use. Pediatrics. 2014;133(5):819-826.

Continue to: The author responds

The author responds

I thank Dr. Simon for his words of encouragement. I agree that both the S2BI and BSTAD have high sensitivity and specificity and are easy to use for screening for the use of multiple substances. Once substance use is established, both tools recommend administering high-risk assessment with additional scales such as the CRAFFT. During the initial evaluation, many psychiatrists take their patient’s history of substance use in detail, including age of onset, frequency, amount used, severity, and the time of his/her last use, without using a screening instrument. My article focused on instruments that can determine whether there is need for a further detailed evaluation. I agree that the S2BI and BSTAD would assist psychiatrists or physicians in other specialties (eg, pediatrics, family medicine) who might not take a complete substance use history during their initial evaluations.

Shikha Verma, MD
Rogers Behavioral Health
Kenosha, Wisconsin
Assistant Professor
Department of Psychiatry and Behavioral Health
Rosalind Franklin University of Medicine and Science
North Chicago, Illinois

Continue to: Changes as a result of COVID-19

I thank Dr. Nasrallah for his editorial “During a viral pandemic, anxiety is endemic: The psychiatric aspects of COVID-19” (From the Editor, Current Psychiatry. April 2020, p. e3-e5).

I appreciated the editorial because it got me thinking about how the pandemic has changed me and my family:

1. We are engaging more in social media.

2. I feel uncomfortable when I go to the grocery store.

3. I feel better when I don’t access the news about COVID-19.

4. My children need physical socialization with their friends (sports, games, other activities, etc.).

5. My children function better with a schedule, but we find it difficult to keep them on a good schedule. Our teenagers stay up late at night (because all of their friends do), and they sleep in late the next morning.

Here are some positive changes:

1. Creating a weekly family calendar on a dry-erase board, so the family can see what is going on during the week.

2. Creating responsibility for our older children (eg, washing their own clothes, cleaning their bathroom).

3. Eating most meals as a family and organizing meals better, too.

4. Playing games together.

5. Cleaning the house together.

6. Getting outside to walk the dog and appreciate nature more.

7. Exercising.

8. Utilizing positive social media.

9. Getting caught up on life.

Again, I thank Dr. Nasrallah for writing this editorial because it led me to self-reflect on this situation, and helped me feel normal.

Doug Dolenc
Westfield, Indiana

Disclosure: The author reports no financial relationships with any companies whose products are mentioned in this article, or with manufacturers of competing products.

Several months ago, I sat with a woman just a few days after the emergent Cesarean section delivery of her first child. She cried as she told me about her entire life—childhood trauma, a pattern of difficult relationships, several miscarriages, and now, finally, a baby—delivered under circumstances so scary, all she remembered was overwhelming fear. Now, she had returned to the hospital with severe postpartum depression, layered with struggles that are common during the first days with a newborn—little sleep, loss of autonomy, guilt, and loneliness. It was hard to listen to it all, but I encouraged her to express her pain, believing that burdens are lighter when shared.

Words often fail us in times of desperation. Much of my education has involved borrowing words, phrases, or ideas from my experienced attendings and mentors, applying them like a salve when I don’t know what else to say. Sitting with another person in silence is often powerful enough, but when something needs to be said, I fall back on these inherited ideas. One of the mantras I often use, and what I said to my patient that day, is about hope: “When you’re down in this depression, you feel hopeless, and you can’t see the hope. It doesn’t mean there isn’t hope; just that you can’t see it.” I’ve watched that idea take root in patients who—despite their own beliefs in the moment—do get better, thus proving the point. Another favorite phrase: “With any luck at all, tomorrow will be better than today.” When you talk to someone on the worst day of their life, what else is there to say?

Today, my conversation with that woman seems like an eternity ago. Public discourse has been overtaken by coronavirus disease 2019 (COVID-19)—the journalism, reflections on the journalism, medical advice, debate about the medical advice, and the innumerable ways in which this worldwide strife has created pain: celebrations and long-awaited plans cancelled, weddings and funerals put on hold, isolation, loneliness, death, and, of course, the fear of death. Those feelings and any other permutations are valid; another phrase, “It’s OK to feel what you are feeling,” carries weight for me these days. I work in a hospital, so I add to the list the breathless fears about what’s going to happen in our local environment. The chronic uncertainty was wearing us thin even before we had begun to do here in Ohio what was already being done elsewhere: working extra shifts, intubating new patients, praying we don’t get sick ourselves.

Our work during COVID-19

Amidst this, my colleagues and I continue our work as psychiatrists, sitting with humans experiencing complex grief (a man whose wife died alone in a nursing home, because of visitor restrictions), confusion (delirium resulting from respiratory failure), and even psychosis (inability to access stabilizing medications coupled with crippling paranoia). These remain just as real and debilitating in a pandemic as they do in other times. In addition to pre-existing mental illnesses, for some individuals, the shared anxiety will progress to clinically significant disorders that may last even longer than the effects of the virus. The resulting complex symptoms could affect everything from home lives to interpersonal relationships to our local and global economies. These are not minor issues. Although often triaged aside in a disaster, our collective mental health remains in some ways more central than ever.

Modern psychiatry would not often use the word “love,” but that’s what I am trying to do—show love to the people who need it the most right now (which is all of us, really). This love takes strange shapes, and sometimes new forms, but it’s just about all I have to give. Like everyone else, I don’t have concrete answers for the grief and fear and panic. But I’m content to share the burden of pain, believing that burdens are lighter when shared. And I have a few words that, however little comfort they offer in the moment, are eventually proven true: Just because you can’t see the hope doesn’t mean it isn’t there. It’s OK to feel what you are feeling. With any luck at all, tomorrow will be better than today.

Several months ago, I sat with a woman just a few days after the emergent Cesarean section delivery of her first child. She cried as she told me about her entire life—childhood trauma, a pattern of difficult relationships, several miscarriages, and now, finally, a baby—delivered under circumstances so scary, all she remembered was overwhelming fear. Now, she had returned to the hospital with severe postpartum depression, layered with struggles that are common during the first days with a newborn—little sleep, loss of autonomy, guilt, and loneliness. It was hard to listen to it all, but I encouraged her to express her pain, believing that burdens are lighter when shared.

Words often fail us in times of desperation. Much of my education has involved borrowing words, phrases, or ideas from my experienced attendings and mentors, applying them like a salve when I don’t know what else to say. Sitting with another person in silence is often powerful enough, but when something needs to be said, I fall back on these inherited ideas. One of the mantras I often use, and what I said to my patient that day, is about hope: “When you’re down in this depression, you feel hopeless, and you can’t see the hope. It doesn’t mean there isn’t hope; just that you can’t see it.” I’ve watched that idea take root in patients who—despite their own beliefs in the moment—do get better, thus proving the point. Another favorite phrase: “With any luck at all, tomorrow will be better than today.” When you talk to someone on the worst day of their life, what else is there to say?

Today, my conversation with that woman seems like an eternity ago. Public discourse has been overtaken by coronavirus disease 2019 (COVID-19)—the journalism, reflections on the journalism, medical advice, debate about the medical advice, and the innumerable ways in which this worldwide strife has created pain: celebrations and long-awaited plans cancelled, weddings and funerals put on hold, isolation, loneliness, death, and, of course, the fear of death. Those feelings and any other permutations are valid; another phrase, “It’s OK to feel what you are feeling,” carries weight for me these days. I work in a hospital, so I add to the list the breathless fears about what’s going to happen in our local environment. The chronic uncertainty was wearing us thin even before we had begun to do here in Ohio what was already being done elsewhere: working extra shifts, intubating new patients, praying we don’t get sick ourselves.

Our work during COVID-19

Amidst this, my colleagues and I continue our work as psychiatrists, sitting with humans experiencing complex grief (a man whose wife died alone in a nursing home, because of visitor restrictions), confusion (delirium resulting from respiratory failure), and even psychosis (inability to access stabilizing medications coupled with crippling paranoia). These remain just as real and debilitating in a pandemic as they do in other times. In addition to pre-existing mental illnesses, for some individuals, the shared anxiety will progress to clinically significant disorders that may last even longer than the effects of the virus. The resulting complex symptoms could affect everything from home lives to interpersonal relationships to our local and global economies. These are not minor issues. Although often triaged aside in a disaster, our collective mental health remains in some ways more central than ever.

Modern psychiatry would not often use the word “love,” but that’s what I am trying to do—show love to the people who need it the most right now (which is all of us, really). This love takes strange shapes, and sometimes new forms, but it’s just about all I have to give. Like everyone else, I don’t have concrete answers for the grief and fear and panic. But I’m content to share the burden of pain, believing that burdens are lighter when shared. And I have a few words that, however little comfort they offer in the moment, are eventually proven true: Just because you can’t see the hope doesn’t mean it isn’t there. It’s OK to feel what you are feeling. With any luck at all, tomorrow will be better than today.

Several months ago, I sat with a woman just a few days after the emergent Cesarean section delivery of her first child. She cried as she told me about her entire life—childhood trauma, a pattern of difficult relationships, several miscarriages, and now, finally, a baby—delivered under circumstances so scary, all she remembered was overwhelming fear. Now, she had returned to the hospital with severe postpartum depression, layered with struggles that are common during the first days with a newborn—little sleep, loss of autonomy, guilt, and loneliness. It was hard to listen to it all, but I encouraged her to express her pain, believing that burdens are lighter when shared.

Words often fail us in times of desperation. Much of my education has involved borrowing words, phrases, or ideas from my experienced attendings and mentors, applying them like a salve when I don’t know what else to say. Sitting with another person in silence is often powerful enough, but when something needs to be said, I fall back on these inherited ideas. One of the mantras I often use, and what I said to my patient that day, is about hope: “When you’re down in this depression, you feel hopeless, and you can’t see the hope. It doesn’t mean there isn’t hope; just that you can’t see it.” I’ve watched that idea take root in patients who—despite their own beliefs in the moment—do get better, thus proving the point. Another favorite phrase: “With any luck at all, tomorrow will be better than today.” When you talk to someone on the worst day of their life, what else is there to say?

Today, my conversation with that woman seems like an eternity ago. Public discourse has been overtaken by coronavirus disease 2019 (COVID-19)—the journalism, reflections on the journalism, medical advice, debate about the medical advice, and the innumerable ways in which this worldwide strife has created pain: celebrations and long-awaited plans cancelled, weddings and funerals put on hold, isolation, loneliness, death, and, of course, the fear of death. Those feelings and any other permutations are valid; another phrase, “It’s OK to feel what you are feeling,” carries weight for me these days. I work in a hospital, so I add to the list the breathless fears about what’s going to happen in our local environment. The chronic uncertainty was wearing us thin even before we had begun to do here in Ohio what was already being done elsewhere: working extra shifts, intubating new patients, praying we don’t get sick ourselves.

Our work during COVID-19

Amidst this, my colleagues and I continue our work as psychiatrists, sitting with humans experiencing complex grief (a man whose wife died alone in a nursing home, because of visitor restrictions), confusion (delirium resulting from respiratory failure), and even psychosis (inability to access stabilizing medications coupled with crippling paranoia). These remain just as real and debilitating in a pandemic as they do in other times. In addition to pre-existing mental illnesses, for some individuals, the shared anxiety will progress to clinically significant disorders that may last even longer than the effects of the virus. The resulting complex symptoms could affect everything from home lives to interpersonal relationships to our local and global economies. These are not minor issues. Although often triaged aside in a disaster, our collective mental health remains in some ways more central than ever.

Modern psychiatry would not often use the word “love,” but that’s what I am trying to do—show love to the people who need it the most right now (which is all of us, really). This love takes strange shapes, and sometimes new forms, but it’s just about all I have to give. Like everyone else, I don’t have concrete answers for the grief and fear and panic. But I’m content to share the burden of pain, believing that burdens are lighter when shared. And I have a few words that, however little comfort they offer in the moment, are eventually proven true: Just because you can’t see the hope doesn’t mean it isn’t there. It’s OK to feel what you are feeling. With any luck at all, tomorrow will be better than today.

Posttraumatic stress disorder (PTSD) occurs acutely and chronically in the aftermath of severe and potentially life-threatening trauma.¹ The prevalence of PTSD varies significantly across countries and by type of trauma (Box^1-7).

Box

Individuals who develop PTSD experience a wide range of symptoms.⁸ These can be categorized as PTSD-specific symptoms, or nonspecific symptoms. PTSD-specific symptoms include nightmares, flashbacks, dissociative reactions, hyperreactivity or hyperarousal, distress with reminders of trauma, and avoidance of trauma-related physical reminders and thoughts/feelings (Table⁸). Nonspecific symptoms include depressive and anxiety symptoms and significant problems in social, relationship, or work situations.⁸

While successful treatment necessitates taking all of these symptoms into account, understanding the pathophysiology of PTSD can inform a more focused and ration­al treatment approach. In this article, we describe some key pathophysiologic PTSD studies, and focus on PTSD-specific psychopathology to inform treatment.

Brain systems implicated in PTSD

Neuropeptide Y (NPY) is an anxiolytic endogenous peptide that has connections to the hypothalamic-pituitary-adrenal (HPA) axis. Its levels can be modulated by stress.⁹ Preclinical and clinical studies strongly support a potential role of NPY dysfunction in the pathophysiology of PTSD. Lower concentrations of NPY increase susceptibility to PTSD in combat veterans¹⁰ and in animal models.¹¹ Three single-nucleotide polymorphisms (SNPs) appear to mediate this effect.¹² These findings strongly support pharmaceutical targeting this system as a useful therapeutic approach.^13,14 Indeed, intranasal NPY administered as a single dose reduces anxiety in animal models¹⁵ and in humans,¹⁶ but this work has not yet translated into clinical tools.

Corticotropin-releasing hormone receptor (CRHR1) gene. Corticotropin-releasing hormone has been implicated in PTSD.¹⁷ Corticotropin-releasing hormone receptors (CRHR) are important mediators in response to stress.^18,19 They bind corticotropin-releasing hormone and contribute to the integration of autonomic, behavioral, and immune responses to stress.²⁰ Single-nucleotide polymorphisms in the regulatory portion of the CRHR1 gene are associated with an increased risk for depression in adults who have a history of child abuse.²¹

The CRHR1 receptor antagonist GSK561679 is an investigational agent for the treatment of mood and anxiety disorders.²² In exploratory studies,^23,24 GSK561679 was found to inhibit fear-potentiated startle in patients with PTSD, but not overall PTSD symptoms, although a subset of women with a specific genetic variant of the CRHR1 gene (rs110402) experienced significant benefit.^25,26 This suggests that we must learn more about this system before we proceed.²⁷

Brain-derived neurotrophic factor (BDNF). The synthesis of BDNF is influenced by neuronal activity in the brain and plays a role in synaptic transmission and plasticity.²⁸ Brain-derived neuro­trophic factor is encoded by the BDNF gene, which has been implicated in stress vulnerability.²⁹ A common SNP in the pro-region of the human BDNF gene results in a valine-to-methionine substitution at the 66th amino acid (Val66Met). The functional Val66Met polymorphism may have a role in the risk of developing PTSD. However, not all studies support this finding. One study found that an SNP with a resulting Val66Met polymorphism is associated with adult PTSD symptoms after childhood abuse, while a meta-analysis of 7 studies did not confirm this.^30,31 We need to learn more about BDNF before we proceed.³²

Continue to: Serotonin transporter (5-HTT) gene

Serotonin transporter (5-HTT) gene. Serotonin transporter is a monoamine transporter protein that terminates the neurotransmitter signal by transporting serotonin from the synaptic cleft back into the presynaptic neuron. It is encoded by the SLC6A4 gene, which resides on the long arm of chromosome 17(17q11.1-q12). It is a large gene with 31 kilo bases and 14 separate exons (transcribed regions).^33,34

This gene has several variants. The best-studied is a variation in the promoter region. A 44-bp insertion or deletion yields the “long” and “short” alleles, respectively. The proteins produced by the 2 alleles are identical, but the amount of expressed protein is different. The short allele (“S”) is associated with a nearly 50% reduction in 5-HTT expression in both homozygotes and heterozygotes.³⁵ A greater incidence of serotonin transporter promoter region (5-HTTLPR) S has been found in individuals with PTSD compared with those without PTSD,^36-38 and 5-HTTLPR S increases the risk of PTSD in individuals with low social support³⁹ or after very few traumatic events.⁴⁰ The short allele variant is also associated with depression in individuals who face adversity.^35,41

The overrepresentation of the short form of 5-HTTLPR in individuals who develop PTSD may represent a potential problem with current treatment paradigms, in which an antidepressant is the first-line treatment, because this allele is associated with reduced response to antidepressants.^42,43 More distressing is the possible association of this allele with increased suicide risk, particularly violent suicide⁴⁴ or repeated suicide attempts.⁴⁵

Furthermore, a functional MRI study of patients who were anxious revealed that in individuals with the short allele, administration of citalopram was associated with increased amygdala activity in response to negative stimuli, and reduced activity in response to positive stimuli.⁴⁶ This suggests that antidepressant treatment may actually worsen fear response in patients with PTSD. Clearly, additional research is needed to determine if having the SLC6A4 gene alters clinical outcomes in response to an antidepressant in a patient with PTSD. In the meantime, clinicians should use vigilance and a critical mindset when they administer antidepressants to a patient who has PTSD.

Catechol-o-methyltransferase (COMT) is one of the enzymes that degrades catecholamines such as dopamine, epinephrine, and norepinephrine (NE).⁴⁷ In humans, COMT protein is encoded by the COMT gene. This gene is associated with allelic variants; the best-studied of these is Val158Met. COMT Val158Met polymorphism (rs4860) has been linked to deficits in stress response and emotional resilience.^48,49 Val158Met is associated with a 40% reduction in enzyme activity and slower catalysis of catecholamines, resulting in increases in catecholamines levels in the brain, which may increase the risk of developing PTSD.⁵⁰ Individuals homozygous for this SNP (Met/Met) are highly susceptible to develop PTSD independently of the severity of the trauma they experienced.⁵¹ The Val158Met polymorphism may be associated with other abnormalities, such as cognitive problems with specific frontal cortical activity, and also with improved antidepressant response (valine homozygotes less responsive than methionine homozygotes).⁵² This gene is available on gene testing profiles.

Continue to: The role of norepinephrine in PTSD

The role of norepinephrine in PTSD

Perhaps the greatest advance in the understanding of the pathophysiology of PTSD relates to changes in brain NE. The HPA axis is responsible for coordinating the hormonal response to stress. Dysregulation of this axis and increased activity of the central and peripheral noradrenergic systems are usually observed in patients with PTSD.⁵³ Several monoamine neurotransmitters are important in the regulation and function of the HPA axis. Norepinephrine plays a major role in stress.

The clinical PTSD-specific criteria are all descriptions of excessive noradrenergic tone.⁵⁴ For example, hypervigilance and hyperstartle are clearly anticipated as evidence of NE stimulation. Flashbacks, particularly those that might be precipitated by environmental cues, also can be a manifestation of the vigilance induced by NE. Sleep disturbances (insomnia and nightmares) are present; insomnia is reported more often than nightmares.⁵⁵ Increased catecholamine levels, particularly NE, are a feature of sleep disturbances associated with middle insomnia. Dreams can be remembered only if you wake up during dreaming. Catecholamines do not change the content of dreams, just recall.⁵⁶

In a study of central noradrenergic tone in patients with PTSD, 6 hourly CSF samples were collected from 11 male combat veterans with PTSD and 8 healthy controls.⁵⁷ Participants with PTSD had significantly higher CSF NE concentrations (0.55 ± 0.17 pmol/ml vs 0.39 ± 0.16 pmol/mL in the PTSD and control groups, respectively; F = 4.49, P < .05).⁵⁷ Overall PTSD symptoms correlated significantly with CSF NE levels (r = 0.82, P <.005), and PTSD-specific symptoms such as avoidance (r = 0.79, P = .004). Intrusive thoughts (r = 0.57, P = .07) and hyperarousal (r = 0.54, P = .09) were also related.⁵⁷ This relationship is unique; patients with PTSD with predominant depressive symptoms do not have elevated plasma NE levels.⁵⁸

In the human brain, there are 3 main groups of NE receptors: alpha-1 receptors, alpha-2 receptors, and beta receptors.⁵⁹ Alpha-1 receptors (alpha-1A, alpha-1B, and alpha-1D) are postsynaptic and mediate increase in inositol trisphosphate (IP₃) and intracellular calcium (Ca²⁺). Alpha-2 receptors (alpha-2A, alpha-2B, alpha-2C) in the CNS are presynaptic autoreceptors and serve to reduce NE release. Beta receptors (beta-1, beta-2, beta-3) inhibit cyclic adenosine monophosphate (cAMP) production.⁵⁹ The effects of inhibition of alpha or beta receptors are different. Inhibition of beta receptors is associated with depressive symptoms and depressive syndrome, inhibition of peripheral beta receptors is associated with reductions in anxiety (generally reduction of pulse, sweating, tremor),⁶⁰ and inhibition of central alpha-1 receptors is associated with reduced PTSD symptoms.⁶¹

Choice of agents for PTSD-specific symptoms

As outlined in the Table,⁸ PTSD is characterized by 3 types of symptoms that are specific for PTSD. Trauma-focused psychotherapy^62,63 and selective serotonin reuptake inhibitors (SSRIs)⁶⁴ are considered first-line therapy for PTSD. Only sertraline and paroxetine are FDA-approved for treating PTSD. However, the effect size for SSRIs is quite small; improvement is only 23% to 30% greater than placebo.^64,65 Furthermore, studies have shown that these medications have little effect on insomnia, hyperarousal, or other PTSD-specific symptoms.^66,67 Studies examining military veterans with PTSD have found that these patients tend to have little or no response to antidepressants.^68,69

Continue to: Serotonin transporter promoter...

Serotonin transporter promoter region gene short-type variants, which possibly increase an individual’s predisposition to developing PTSD, may explain the abundance of depressive symptoms in this condition and the subdued response to antidepressants. Specifically, an anticipated preponderance of these alleles may be associated with poorer outcomes. Non-SSRI treatments, such as low-dose aripiprazole, may be alternatives,⁷⁰ but these approaches have not been adequately developed.

On the other hand, animal models support antagonism of the postsynaptic alpha-1 adrenergic receptor of the CNS as a target for PTSD treatment.⁷¹ Although prazosin is not currently FDA-approved for treating PTSD, in placebo-controlled studies, nightmares and PTSD total symptoms improved with prazosin, and evidence suggests that it should be used 2 or 3 times a day for all PTSD symptoms.⁶¹ Prazosin may be helpful for treating sleep problems commonly experienced by people with PTSD. Blockade of histamine will also improve sleep disturbance and reduce nightmares, but it may not be as effective as prazosin.⁷²

Quetiapine might be another non-SSRI option for treating patients with PTSD. It is an antagonist with high affinity tothehistamine-1 receptor at low doses. Norquetiapine is an alpha-2 antagonist that increases brain NE levels. Both quetiapine and norquetiapine are alpha-1 antagonists. There is no beta blockade and no SSRI effect, but some 5HT2A blockade, which may be anxiolytic. Compared with placebo, an average quetiapine dose of 258 mg/d resulted in significantly greater reductions in Clinician-Administered PTSD Scale total score, re-experiencing score, and hyperarousal score.⁷³

Unfortunately, none of the non-SSRI options have been adequately evaluated. For now, clinicians need to continue to use SSRIs, and researchers need to continue to explore mechanism-guided alternatives.

Bottom Line

Understanding the mechanisms of the pathophysiology of posttraumatic stress disorder (PTSD) may allow clinicians to “jump ahead” of clinical studies and FDA indications. Clinicians may reasonably use alpha-1 antagonists (eg, prazosin, quetiapine) for general clinical improvement of patients with PTSD, particularly for PTSD-specific symptoms. Using antihistamines to reduce anxiety (especially in patients who have the COMT Val158Met polymorphism) may also be reasonable.

Related Resources

• North CS, Hong BA, Downs DL. PTSD: a systematic approach to diagnosis and treatment. Current Psychiatry. 2018;17(4):35-43.
• Zhang Y, Ren R, Sanford LD, et al. The effects of prazosin on sleep disturbances in post-traumatic stress disorder: a systematic review and meta-analysis. Sleep Med. 2019; 67:225-231.

Drug Brand Names

Aripiprazole • Abilify
Citalopram • Celexa
Paroxetine • Paxil
Prazosin • Minipress
Quetiapine • Seroquel
Sertraline • Zoloft

Posttraumatic stress disorder (PTSD) occurs acutely and chronically in the aftermath of severe and potentially life-threatening trauma.¹ The prevalence of PTSD varies significantly across countries and by type of trauma (Box^1-7).

Box

Individuals who develop PTSD experience a wide range of symptoms.⁸ These can be categorized as PTSD-specific symptoms, or nonspecific symptoms. PTSD-specific symptoms include nightmares, flashbacks, dissociative reactions, hyperreactivity or hyperarousal, distress with reminders of trauma, and avoidance of trauma-related physical reminders and thoughts/feelings (Table⁸). Nonspecific symptoms include depressive and anxiety symptoms and significant problems in social, relationship, or work situations.⁸

While successful treatment necessitates taking all of these symptoms into account, understanding the pathophysiology of PTSD can inform a more focused and ration­al treatment approach. In this article, we describe some key pathophysiologic PTSD studies, and focus on PTSD-specific psychopathology to inform treatment.

Brain systems implicated in PTSD

Neuropeptide Y (NPY) is an anxiolytic endogenous peptide that has connections to the hypothalamic-pituitary-adrenal (HPA) axis. Its levels can be modulated by stress.⁹ Preclinical and clinical studies strongly support a potential role of NPY dysfunction in the pathophysiology of PTSD. Lower concentrations of NPY increase susceptibility to PTSD in combat veterans¹⁰ and in animal models.¹¹ Three single-nucleotide polymorphisms (SNPs) appear to mediate this effect.¹² These findings strongly support pharmaceutical targeting this system as a useful therapeutic approach.^13,14 Indeed, intranasal NPY administered as a single dose reduces anxiety in animal models¹⁵ and in humans,¹⁶ but this work has not yet translated into clinical tools.

Corticotropin-releasing hormone receptor (CRHR1) gene. Corticotropin-releasing hormone has been implicated in PTSD.¹⁷ Corticotropin-releasing hormone receptors (CRHR) are important mediators in response to stress.^18,19 They bind corticotropin-releasing hormone and contribute to the integration of autonomic, behavioral, and immune responses to stress.²⁰ Single-nucleotide polymorphisms in the regulatory portion of the CRHR1 gene are associated with an increased risk for depression in adults who have a history of child abuse.²¹

The CRHR1 receptor antagonist GSK561679 is an investigational agent for the treatment of mood and anxiety disorders.²² In exploratory studies,^23,24 GSK561679 was found to inhibit fear-potentiated startle in patients with PTSD, but not overall PTSD symptoms, although a subset of women with a specific genetic variant of the CRHR1 gene (rs110402) experienced significant benefit.^25,26 This suggests that we must learn more about this system before we proceed.²⁷

Brain-derived neurotrophic factor (BDNF). The synthesis of BDNF is influenced by neuronal activity in the brain and plays a role in synaptic transmission and plasticity.²⁸ Brain-derived neuro­trophic factor is encoded by the BDNF gene, which has been implicated in stress vulnerability.²⁹ A common SNP in the pro-region of the human BDNF gene results in a valine-to-methionine substitution at the 66th amino acid (Val66Met). The functional Val66Met polymorphism may have a role in the risk of developing PTSD. However, not all studies support this finding. One study found that an SNP with a resulting Val66Met polymorphism is associated with adult PTSD symptoms after childhood abuse, while a meta-analysis of 7 studies did not confirm this.^30,31 We need to learn more about BDNF before we proceed.³²

Continue to: Serotonin transporter (5-HTT) gene

Serotonin transporter (5-HTT) gene. Serotonin transporter is a monoamine transporter protein that terminates the neurotransmitter signal by transporting serotonin from the synaptic cleft back into the presynaptic neuron. It is encoded by the SLC6A4 gene, which resides on the long arm of chromosome 17(17q11.1-q12). It is a large gene with 31 kilo bases and 14 separate exons (transcribed regions).^33,34

This gene has several variants. The best-studied is a variation in the promoter region. A 44-bp insertion or deletion yields the “long” and “short” alleles, respectively. The proteins produced by the 2 alleles are identical, but the amount of expressed protein is different. The short allele (“S”) is associated with a nearly 50% reduction in 5-HTT expression in both homozygotes and heterozygotes.³⁵ A greater incidence of serotonin transporter promoter region (5-HTTLPR) S has been found in individuals with PTSD compared with those without PTSD,^36-38 and 5-HTTLPR S increases the risk of PTSD in individuals with low social support³⁹ or after very few traumatic events.⁴⁰ The short allele variant is also associated with depression in individuals who face adversity.^35,41

The overrepresentation of the short form of 5-HTTLPR in individuals who develop PTSD may represent a potential problem with current treatment paradigms, in which an antidepressant is the first-line treatment, because this allele is associated with reduced response to antidepressants.^42,43 More distressing is the possible association of this allele with increased suicide risk, particularly violent suicide⁴⁴ or repeated suicide attempts.⁴⁵

Furthermore, a functional MRI study of patients who were anxious revealed that in individuals with the short allele, administration of citalopram was associated with increased amygdala activity in response to negative stimuli, and reduced activity in response to positive stimuli.⁴⁶ This suggests that antidepressant treatment may actually worsen fear response in patients with PTSD. Clearly, additional research is needed to determine if having the SLC6A4 gene alters clinical outcomes in response to an antidepressant in a patient with PTSD. In the meantime, clinicians should use vigilance and a critical mindset when they administer antidepressants to a patient who has PTSD.

Catechol-o-methyltransferase (COMT) is one of the enzymes that degrades catecholamines such as dopamine, epinephrine, and norepinephrine (NE).⁴⁷ In humans, COMT protein is encoded by the COMT gene. This gene is associated with allelic variants; the best-studied of these is Val158Met. COMT Val158Met polymorphism (rs4860) has been linked to deficits in stress response and emotional resilience.^48,49 Val158Met is associated with a 40% reduction in enzyme activity and slower catalysis of catecholamines, resulting in increases in catecholamines levels in the brain, which may increase the risk of developing PTSD.⁵⁰ Individuals homozygous for this SNP (Met/Met) are highly susceptible to develop PTSD independently of the severity of the trauma they experienced.⁵¹ The Val158Met polymorphism may be associated with other abnormalities, such as cognitive problems with specific frontal cortical activity, and also with improved antidepressant response (valine homozygotes less responsive than methionine homozygotes).⁵² This gene is available on gene testing profiles.

Continue to: The role of norepinephrine in PTSD

The role of norepinephrine in PTSD

Perhaps the greatest advance in the understanding of the pathophysiology of PTSD relates to changes in brain NE. The HPA axis is responsible for coordinating the hormonal response to stress. Dysregulation of this axis and increased activity of the central and peripheral noradrenergic systems are usually observed in patients with PTSD.⁵³ Several monoamine neurotransmitters are important in the regulation and function of the HPA axis. Norepinephrine plays a major role in stress.

The clinical PTSD-specific criteria are all descriptions of excessive noradrenergic tone.⁵⁴ For example, hypervigilance and hyperstartle are clearly anticipated as evidence of NE stimulation. Flashbacks, particularly those that might be precipitated by environmental cues, also can be a manifestation of the vigilance induced by NE. Sleep disturbances (insomnia and nightmares) are present; insomnia is reported more often than nightmares.⁵⁵ Increased catecholamine levels, particularly NE, are a feature of sleep disturbances associated with middle insomnia. Dreams can be remembered only if you wake up during dreaming. Catecholamines do not change the content of dreams, just recall.⁵⁶

In a study of central noradrenergic tone in patients with PTSD, 6 hourly CSF samples were collected from 11 male combat veterans with PTSD and 8 healthy controls.⁵⁷ Participants with PTSD had significantly higher CSF NE concentrations (0.55 ± 0.17 pmol/ml vs 0.39 ± 0.16 pmol/mL in the PTSD and control groups, respectively; F = 4.49, P < .05).⁵⁷ Overall PTSD symptoms correlated significantly with CSF NE levels (r = 0.82, P <.005), and PTSD-specific symptoms such as avoidance (r = 0.79, P = .004). Intrusive thoughts (r = 0.57, P = .07) and hyperarousal (r = 0.54, P = .09) were also related.⁵⁷ This relationship is unique; patients with PTSD with predominant depressive symptoms do not have elevated plasma NE levels.⁵⁸

In the human brain, there are 3 main groups of NE receptors: alpha-1 receptors, alpha-2 receptors, and beta receptors.⁵⁹ Alpha-1 receptors (alpha-1A, alpha-1B, and alpha-1D) are postsynaptic and mediate increase in inositol trisphosphate (IP₃) and intracellular calcium (Ca²⁺). Alpha-2 receptors (alpha-2A, alpha-2B, alpha-2C) in the CNS are presynaptic autoreceptors and serve to reduce NE release. Beta receptors (beta-1, beta-2, beta-3) inhibit cyclic adenosine monophosphate (cAMP) production.⁵⁹ The effects of inhibition of alpha or beta receptors are different. Inhibition of beta receptors is associated with depressive symptoms and depressive syndrome, inhibition of peripheral beta receptors is associated with reductions in anxiety (generally reduction of pulse, sweating, tremor),⁶⁰ and inhibition of central alpha-1 receptors is associated with reduced PTSD symptoms.⁶¹

Choice of agents for PTSD-specific symptoms

As outlined in the Table,⁸ PTSD is characterized by 3 types of symptoms that are specific for PTSD. Trauma-focused psychotherapy^62,63 and selective serotonin reuptake inhibitors (SSRIs)⁶⁴ are considered first-line therapy for PTSD. Only sertraline and paroxetine are FDA-approved for treating PTSD. However, the effect size for SSRIs is quite small; improvement is only 23% to 30% greater than placebo.^64,65 Furthermore, studies have shown that these medications have little effect on insomnia, hyperarousal, or other PTSD-specific symptoms.^66,67 Studies examining military veterans with PTSD have found that these patients tend to have little or no response to antidepressants.^68,69

Continue to: Serotonin transporter promoter...

Serotonin transporter promoter region gene short-type variants, which possibly increase an individual’s predisposition to developing PTSD, may explain the abundance of depressive symptoms in this condition and the subdued response to antidepressants. Specifically, an anticipated preponderance of these alleles may be associated with poorer outcomes. Non-SSRI treatments, such as low-dose aripiprazole, may be alternatives,⁷⁰ but these approaches have not been adequately developed.

On the other hand, animal models support antagonism of the postsynaptic alpha-1 adrenergic receptor of the CNS as a target for PTSD treatment.⁷¹ Although prazosin is not currently FDA-approved for treating PTSD, in placebo-controlled studies, nightmares and PTSD total symptoms improved with prazosin, and evidence suggests that it should be used 2 or 3 times a day for all PTSD symptoms.⁶¹ Prazosin may be helpful for treating sleep problems commonly experienced by people with PTSD. Blockade of histamine will also improve sleep disturbance and reduce nightmares, but it may not be as effective as prazosin.⁷²

Quetiapine might be another non-SSRI option for treating patients with PTSD. It is an antagonist with high affinity tothehistamine-1 receptor at low doses. Norquetiapine is an alpha-2 antagonist that increases brain NE levels. Both quetiapine and norquetiapine are alpha-1 antagonists. There is no beta blockade and no SSRI effect, but some 5HT2A blockade, which may be anxiolytic. Compared with placebo, an average quetiapine dose of 258 mg/d resulted in significantly greater reductions in Clinician-Administered PTSD Scale total score, re-experiencing score, and hyperarousal score.⁷³

Unfortunately, none of the non-SSRI options have been adequately evaluated. For now, clinicians need to continue to use SSRIs, and researchers need to continue to explore mechanism-guided alternatives.

Bottom Line

Understanding the mechanisms of the pathophysiology of posttraumatic stress disorder (PTSD) may allow clinicians to “jump ahead” of clinical studies and FDA indications. Clinicians may reasonably use alpha-1 antagonists (eg, prazosin, quetiapine) for general clinical improvement of patients with PTSD, particularly for PTSD-specific symptoms. Using antihistamines to reduce anxiety (especially in patients who have the COMT Val158Met polymorphism) may also be reasonable.

Related Resources

• North CS, Hong BA, Downs DL. PTSD: a systematic approach to diagnosis and treatment. Current Psychiatry. 2018;17(4):35-43.
• Zhang Y, Ren R, Sanford LD, et al. The effects of prazosin on sleep disturbances in post-traumatic stress disorder: a systematic review and meta-analysis. Sleep Med. 2019; 67:225-231.

Drug Brand Names

Aripiprazole • Abilify
Citalopram • Celexa
Paroxetine • Paxil
Prazosin • Minipress
Quetiapine • Seroquel
Sertraline • Zoloft

Posttraumatic stress disorder (PTSD) occurs acutely and chronically in the aftermath of severe and potentially life-threatening trauma.¹ The prevalence of PTSD varies significantly across countries and by type of trauma (Box^1-7).

Box

Individuals who develop PTSD experience a wide range of symptoms.⁸ These can be categorized as PTSD-specific symptoms, or nonspecific symptoms. PTSD-specific symptoms include nightmares, flashbacks, dissociative reactions, hyperreactivity or hyperarousal, distress with reminders of trauma, and avoidance of trauma-related physical reminders and thoughts/feelings (Table⁸). Nonspecific symptoms include depressive and anxiety symptoms and significant problems in social, relationship, or work situations.⁸

While successful treatment necessitates taking all of these symptoms into account, understanding the pathophysiology of PTSD can inform a more focused and ration­al treatment approach. In this article, we describe some key pathophysiologic PTSD studies, and focus on PTSD-specific psychopathology to inform treatment.

Brain systems implicated in PTSD

Neuropeptide Y (NPY) is an anxiolytic endogenous peptide that has connections to the hypothalamic-pituitary-adrenal (HPA) axis. Its levels can be modulated by stress.⁹ Preclinical and clinical studies strongly support a potential role of NPY dysfunction in the pathophysiology of PTSD. Lower concentrations of NPY increase susceptibility to PTSD in combat veterans¹⁰ and in animal models.¹¹ Three single-nucleotide polymorphisms (SNPs) appear to mediate this effect.¹² These findings strongly support pharmaceutical targeting this system as a useful therapeutic approach.^13,14 Indeed, intranasal NPY administered as a single dose reduces anxiety in animal models¹⁵ and in humans,¹⁶ but this work has not yet translated into clinical tools.

Corticotropin-releasing hormone receptor (CRHR1) gene. Corticotropin-releasing hormone has been implicated in PTSD.¹⁷ Corticotropin-releasing hormone receptors (CRHR) are important mediators in response to stress.^18,19 They bind corticotropin-releasing hormone and contribute to the integration of autonomic, behavioral, and immune responses to stress.²⁰ Single-nucleotide polymorphisms in the regulatory portion of the CRHR1 gene are associated with an increased risk for depression in adults who have a history of child abuse.²¹

The CRHR1 receptor antagonist GSK561679 is an investigational agent for the treatment of mood and anxiety disorders.²² In exploratory studies,^23,24 GSK561679 was found to inhibit fear-potentiated startle in patients with PTSD, but not overall PTSD symptoms, although a subset of women with a specific genetic variant of the CRHR1 gene (rs110402) experienced significant benefit.^25,26 This suggests that we must learn more about this system before we proceed.²⁷

Brain-derived neurotrophic factor (BDNF). The synthesis of BDNF is influenced by neuronal activity in the brain and plays a role in synaptic transmission and plasticity.²⁸ Brain-derived neuro­trophic factor is encoded by the BDNF gene, which has been implicated in stress vulnerability.²⁹ A common SNP in the pro-region of the human BDNF gene results in a valine-to-methionine substitution at the 66th amino acid (Val66Met). The functional Val66Met polymorphism may have a role in the risk of developing PTSD. However, not all studies support this finding. One study found that an SNP with a resulting Val66Met polymorphism is associated with adult PTSD symptoms after childhood abuse, while a meta-analysis of 7 studies did not confirm this.^30,31 We need to learn more about BDNF before we proceed.³²

Continue to: Serotonin transporter (5-HTT) gene

Serotonin transporter (5-HTT) gene. Serotonin transporter is a monoamine transporter protein that terminates the neurotransmitter signal by transporting serotonin from the synaptic cleft back into the presynaptic neuron. It is encoded by the SLC6A4 gene, which resides on the long arm of chromosome 17(17q11.1-q12). It is a large gene with 31 kilo bases and 14 separate exons (transcribed regions).^33,34

This gene has several variants. The best-studied is a variation in the promoter region. A 44-bp insertion or deletion yields the “long” and “short” alleles, respectively. The proteins produced by the 2 alleles are identical, but the amount of expressed protein is different. The short allele (“S”) is associated with a nearly 50% reduction in 5-HTT expression in both homozygotes and heterozygotes.³⁵ A greater incidence of serotonin transporter promoter region (5-HTTLPR) S has been found in individuals with PTSD compared with those without PTSD,^36-38 and 5-HTTLPR S increases the risk of PTSD in individuals with low social support³⁹ or after very few traumatic events.⁴⁰ The short allele variant is also associated with depression in individuals who face adversity.^35,41

The overrepresentation of the short form of 5-HTTLPR in individuals who develop PTSD may represent a potential problem with current treatment paradigms, in which an antidepressant is the first-line treatment, because this allele is associated with reduced response to antidepressants.^42,43 More distressing is the possible association of this allele with increased suicide risk, particularly violent suicide⁴⁴ or repeated suicide attempts.⁴⁵

Furthermore, a functional MRI study of patients who were anxious revealed that in individuals with the short allele, administration of citalopram was associated with increased amygdala activity in response to negative stimuli, and reduced activity in response to positive stimuli.⁴⁶ This suggests that antidepressant treatment may actually worsen fear response in patients with PTSD. Clearly, additional research is needed to determine if having the SLC6A4 gene alters clinical outcomes in response to an antidepressant in a patient with PTSD. In the meantime, clinicians should use vigilance and a critical mindset when they administer antidepressants to a patient who has PTSD.

Catechol-o-methyltransferase (COMT) is one of the enzymes that degrades catecholamines such as dopamine, epinephrine, and norepinephrine (NE).⁴⁷ In humans, COMT protein is encoded by the COMT gene. This gene is associated with allelic variants; the best-studied of these is Val158Met. COMT Val158Met polymorphism (rs4860) has been linked to deficits in stress response and emotional resilience.^48,49 Val158Met is associated with a 40% reduction in enzyme activity and slower catalysis of catecholamines, resulting in increases in catecholamines levels in the brain, which may increase the risk of developing PTSD.⁵⁰ Individuals homozygous for this SNP (Met/Met) are highly susceptible to develop PTSD independently of the severity of the trauma they experienced.⁵¹ The Val158Met polymorphism may be associated with other abnormalities, such as cognitive problems with specific frontal cortical activity, and also with improved antidepressant response (valine homozygotes less responsive than methionine homozygotes).⁵² This gene is available on gene testing profiles.

Continue to: The role of norepinephrine in PTSD

The role of norepinephrine in PTSD

Perhaps the greatest advance in the understanding of the pathophysiology of PTSD relates to changes in brain NE. The HPA axis is responsible for coordinating the hormonal response to stress. Dysregulation of this axis and increased activity of the central and peripheral noradrenergic systems are usually observed in patients with PTSD.⁵³ Several monoamine neurotransmitters are important in the regulation and function of the HPA axis. Norepinephrine plays a major role in stress.

The clinical PTSD-specific criteria are all descriptions of excessive noradrenergic tone.⁵⁴ For example, hypervigilance and hyperstartle are clearly anticipated as evidence of NE stimulation. Flashbacks, particularly those that might be precipitated by environmental cues, also can be a manifestation of the vigilance induced by NE. Sleep disturbances (insomnia and nightmares) are present; insomnia is reported more often than nightmares.⁵⁵ Increased catecholamine levels, particularly NE, are a feature of sleep disturbances associated with middle insomnia. Dreams can be remembered only if you wake up during dreaming. Catecholamines do not change the content of dreams, just recall.⁵⁶

In a study of central noradrenergic tone in patients with PTSD, 6 hourly CSF samples were collected from 11 male combat veterans with PTSD and 8 healthy controls.⁵⁷ Participants with PTSD had significantly higher CSF NE concentrations (0.55 ± 0.17 pmol/ml vs 0.39 ± 0.16 pmol/mL in the PTSD and control groups, respectively; F = 4.49, P < .05).⁵⁷ Overall PTSD symptoms correlated significantly with CSF NE levels (r = 0.82, P <.005), and PTSD-specific symptoms such as avoidance (r = 0.79, P = .004). Intrusive thoughts (r = 0.57, P = .07) and hyperarousal (r = 0.54, P = .09) were also related.⁵⁷ This relationship is unique; patients with PTSD with predominant depressive symptoms do not have elevated plasma NE levels.⁵⁸

In the human brain, there are 3 main groups of NE receptors: alpha-1 receptors, alpha-2 receptors, and beta receptors.⁵⁹ Alpha-1 receptors (alpha-1A, alpha-1B, and alpha-1D) are postsynaptic and mediate increase in inositol trisphosphate (IP₃) and intracellular calcium (Ca²⁺). Alpha-2 receptors (alpha-2A, alpha-2B, alpha-2C) in the CNS are presynaptic autoreceptors and serve to reduce NE release. Beta receptors (beta-1, beta-2, beta-3) inhibit cyclic adenosine monophosphate (cAMP) production.⁵⁹ The effects of inhibition of alpha or beta receptors are different. Inhibition of beta receptors is associated with depressive symptoms and depressive syndrome, inhibition of peripheral beta receptors is associated with reductions in anxiety (generally reduction of pulse, sweating, tremor),⁶⁰ and inhibition of central alpha-1 receptors is associated with reduced PTSD symptoms.⁶¹

Choice of agents for PTSD-specific symptoms

As outlined in the Table,⁸ PTSD is characterized by 3 types of symptoms that are specific for PTSD. Trauma-focused psychotherapy^62,63 and selective serotonin reuptake inhibitors (SSRIs)⁶⁴ are considered first-line therapy for PTSD. Only sertraline and paroxetine are FDA-approved for treating PTSD. However, the effect size for SSRIs is quite small; improvement is only 23% to 30% greater than placebo.^64,65 Furthermore, studies have shown that these medications have little effect on insomnia, hyperarousal, or other PTSD-specific symptoms.^66,67 Studies examining military veterans with PTSD have found that these patients tend to have little or no response to antidepressants.^68,69

Continue to: Serotonin transporter promoter...

Serotonin transporter promoter region gene short-type variants, which possibly increase an individual’s predisposition to developing PTSD, may explain the abundance of depressive symptoms in this condition and the subdued response to antidepressants. Specifically, an anticipated preponderance of these alleles may be associated with poorer outcomes. Non-SSRI treatments, such as low-dose aripiprazole, may be alternatives,⁷⁰ but these approaches have not been adequately developed.

On the other hand, animal models support antagonism of the postsynaptic alpha-1 adrenergic receptor of the CNS as a target for PTSD treatment.⁷¹ Although prazosin is not currently FDA-approved for treating PTSD, in placebo-controlled studies, nightmares and PTSD total symptoms improved with prazosin, and evidence suggests that it should be used 2 or 3 times a day for all PTSD symptoms.⁶¹ Prazosin may be helpful for treating sleep problems commonly experienced by people with PTSD. Blockade of histamine will also improve sleep disturbance and reduce nightmares, but it may not be as effective as prazosin.⁷²

Quetiapine might be another non-SSRI option for treating patients with PTSD. It is an antagonist with high affinity tothehistamine-1 receptor at low doses. Norquetiapine is an alpha-2 antagonist that increases brain NE levels. Both quetiapine and norquetiapine are alpha-1 antagonists. There is no beta blockade and no SSRI effect, but some 5HT2A blockade, which may be anxiolytic. Compared with placebo, an average quetiapine dose of 258 mg/d resulted in significantly greater reductions in Clinician-Administered PTSD Scale total score, re-experiencing score, and hyperarousal score.⁷³

Unfortunately, none of the non-SSRI options have been adequately evaluated. For now, clinicians need to continue to use SSRIs, and researchers need to continue to explore mechanism-guided alternatives.

Bottom Line

Understanding the mechanisms of the pathophysiology of posttraumatic stress disorder (PTSD) may allow clinicians to “jump ahead” of clinical studies and FDA indications. Clinicians may reasonably use alpha-1 antagonists (eg, prazosin, quetiapine) for general clinical improvement of patients with PTSD, particularly for PTSD-specific symptoms. Using antihistamines to reduce anxiety (especially in patients who have the COMT Val158Met polymorphism) may also be reasonable.

Related Resources

• North CS, Hong BA, Downs DL. PTSD: a systematic approach to diagnosis and treatment. Current Psychiatry. 2018;17(4):35-43.
• Zhang Y, Ren R, Sanford LD, et al. The effects of prazosin on sleep disturbances in post-traumatic stress disorder: a systematic review and meta-analysis. Sleep Med. 2019; 67:225-231.

Drug Brand Names

Aripiprazole • Abilify
Citalopram • Celexa
Paroxetine • Paxil
Prazosin • Minipress
Quetiapine • Seroquel
Sertraline • Zoloft

CASE Aggressive, impulsive, and not sleeping

Mr. S, age 22, is brought by his family to his outpatient psychiatrist because he has begun to exhibit motor and verbal tics, excessive adherence to rules and routines, and increased impulsivity and agitation.

Mr. S has significant language impairment and is unreliable as a narrator. His family reports that Mr. S’s behavior has resulted in declining academic performance, and they have curtailed his social activities due to behavioral issues. Both his family and teachers report that it is increasingly difficult to redirect Mr. S’s behavior. Although not physically aggressive, Mr. S becomes verbally agitated when rituals are incomplete. He has gone from sleeping 8 hours each night to only 3 to 4 hours, but he does not appear tired during the day.

HISTORY Multiple hospitalizations

As a child, Mr. S had been diagnosed with autism and intellectual disability. When he was 13, he began exhibiting marked stereotypy, restlessness, impulsivity, frenzy, agitation, combativeness, and purposeless motor activity. At that time, he was not receiving any medications. Mr. S had not slept for 2 days and had been walking in circles nonstop. He became aggressive whenever anyone attempted to redirect his behavior. The family took Mr. S to the emergency department (ED), where clinicians ruled out organic causes for his behavioral disturbances, including infections, drug intoxication, and use of illicit substances. Mr. S was transferred from the ED to a child and adolescent psychiatry ward at a nearby university hospital for inpatient treatment.

On the inpatient unit, the treatment team diagnosed Mr. S with bipolar disorder and believed that he was experiencing a manic episode. He was prescribed quetiapine, 25 mg by mouth during the day and 75 mg by mouth at night, to stabilize his agitation, and was discharged with a plan to follow up with his outpatient psychiatrist. However, within 1 week, his symptoms returned, with markedly increased aggression and agitation, so he was readmitted, tapered off quetiapine, and prescribed valproic acid, 125 mg by mouth during the day and 375 mg by mouth at bedtime. With this regimen, Mr. S became calmer, but when he was discharged home, he was subdued and withdrawn, overly adherent to rules and routines, constantly irritable, and often unable to focus.

Two years later, Mr. S developed hyperammonemia. Valproic acid was discontinued, and many of his behavioral issues resolved. He flourished both academically and socially. He experienced no exacerbation of symptoms until his current presentation.

[polldaddy:10544547]

EVALUATION Pinpointing the cause

Mr. S’s physical examination reveals that his vital signs are within normal limits. Mr. S is mildly tachycardic (heart rate, 105 bpm), with regular rate and rhythm. No murmurs, gallops, or rubs are auscultated. The remainder of the physical exam, including a detailed neurologic exam, is normal.

On mental status examination, Mr. S makes limited eye contact. He has difficulty sitting in the chair, with increased rocking, finger flicking, and hand flapping from baseline. Some compulsive behaviors are noted, such as tapping his neck. He has increased tics (eye blinking and mouth opening) and increased verbigeration and repetitive verbal statements. He loudly and repeatedly demands to go home, and uses short sentences with incorrect pronouns. His affect is difficult to assess, but he is agitated. His thought process is concrete. There is no evidence of suicidal ideation, homicidal ideation, or psychosis. Mr. S denies auditory hallucinations. His insight and judgment are limited.

Continue to: The psychiatrist rules out...

The psychiatrist rules out a behavioral exacerbation of autism based on an interview with Mr. S’s family and established rapport from treating him for several years. Mr. S’s family reports that many of his behaviors are not new but that the increased drive and intensity is worrisome. Further, his family cannot identify any stressors or precipitants for the behaviors and reports that offering preferred reinforcers did not help. An anxiety disorder is ruled out because according to the family, Mr. S’s drive to constantly move and complete rituals is fueling his anxiety. Schizoaffective disorder is ruled out because Mr. S denies auditory hallucinations and has not been observed responding to internal stimuli.

His Bush-Francis Catatonia Rating Scale (BFCRS) score is 26, which suggests a high likelihood of catatonia. Based on the BFCRS score, Mr. S’s psychiatrist makes the diagnosis of hyperkinetic catatonia.

The authors’ observations

The psychiatrist determined that Mr. S had been misdiagnosed with bipolar disorder at age 13. At that time, he had experienced his first episode of hyperkinetic catatonia and his symptoms decreased after he received lorazepam in the ED. However, the treatment team did not correctly identify this, most likely due to limited knowledge of catatonia among emergency medicine clinicians.

This case exemplifies a cognitive error of premature closure. Rather than considering catatonia as a complication of autism when Mr. S was 13, the clinicians added a second psychiatric diagnosis of bipolar disorder.Although premature closure errors generally occur when the physician assumes the patient is having a common complication of a known illness,¹ in Mr. S’s case, the opposite occurred.

Conceptualizing catatonia

One helpful model for conceptualizing catatonia is to think of it as a basal ganglia disorder, with lesions in the basal ganglia thalamocortical tracts and the anterior cingulate/medial orbitofrontal circuit. Disrupting these pathways can result in symptoms such as mutism or repetitive and imitative behaviors. This is likely due to decreased disinhibition by gamma-aminobutyric acid (GABA), resulting in a hypodopaminergic state. This explains why benzodiazepines, which act to increase GABA, are effective for treating catatonia, and antipsychotics that act to decrease dopamine can exacerbate symptoms. Fricchione et al² developed a model to visually represent the neurobiologic pathophysiology of catatonia (Figure²).

Continue to: Underlying causes of catatonia

Catatonia is most often seen in individuals with an underlying psychiatric condition such as schizophrenia, mood disorders, or autism. However, catatonia also occurs in the context of general neurologic and medical disorders, including (but not limited to) infections, metabolic disorders, endocrinopathies, epilepsy, neurodegenerative diseases, delirium, hypertensive encephalopathy, autoimmune encephalitis, and liver and kidney transplantation.³

Subtypes of catatonia include⁴:

• hypokinetic catatonia, which presents as stupor, mutism, and negativism
• hyperkinetic catatonia, which presents as hyperactivity, agitation, and stereotypy (as observed in Mr. S)
• malignant catatonia, which is a potentially lethal form of catatonia that occurs when hypo- or hyperkinetic catatonia is accompanied by autonomic instability such as tachycardia, tachypnea, hypertension, fever, and muscle rigidity
• periodic catatonia, which is characterized by brief episodes of stupor or excitatory catatonia lasting 4 to 10 days. These episodes recur over weeks to years, with patients remaining asymptomatic between episodes, or showing mild symptoms, such as facial grimacing or negativisms. Periodic catatonia often is autosomal dominant, involves linkage for the long arm of chromosome 15, and has a better prognosis than the other forms.

Autism and catatonia

Most individuals with autism who experience a catatonic episode first do so between age 10 and 19, and many episodes are precipitated by sudden changes in routine resulting in stress.⁵ An estimated 12% to 18% of patients with autism are diagnosed with catatonia in their lifetime, but the actual prevalence is likely higher.⁴

One of the reasons for this might be that although catatonia is well known in the psychiatric community, it is relatively unknown in the general medical community. Children and adolescents with psychiatric illness are likely to have symptoms of catatonia overlooked because catatonia often is not included in the differential diagnosis.⁶

In Mr. S’s case, it became clear that he did not have a mood disorder, but was prone to episodes of hyperkinetic catatonia due to his autism.

Continue to: Better recognition of catatonia

As catatonia becomes better elucidated and more clearly described in the literature, there is increasing awareness that symptoms do not always involve stupor, mutism, and slowed motor activity, but can include increased motor activity, agitation, and stereotypies. The BFCRS is extremely useful for quantifying symptoms of catatonia. The best way to confirm the diagnosis is to use a lorazepam challenge in an inpatient setting, or a trial of lorazepam in an outpatient setting.⁵

[polldaddy:10544548]

The authors’ observations

Lorazepam is often considered the first-line treatment for catatonia because it is one of the most widely studied medications. Other benzodiazepines, such as oxazepam and clonazepam, and the sedative/hypnotic zolpidem have also been shown to be effective. Antipsychotics with dopamine-blocking mechanisms can exacerbate symptoms of catatonia and should be avoided in these patients. Furthermore, in cases of refractory catatonia, bilateral electroconvulsive therapy is an important and necessary treatment.⁷

TREATMENT Pharmacologic agents decrease BFCRS score

Mr. S is prescribed a regimen of lorazepam, 2 mg by mouth daily, and the supplement N-acetylcysteine, 600 mg by mouth daily. Within 2 weeks of starting this regimen, Mr. S’s BFCRS score decreases from 26 to 14. After 6 months of treatment with lorazepam, Mr. S shows considerable improvement. The stereotypic behaviors and impulsivity decrease significantly, leading to improved sleep and performance in school. After 6 months Mr. S is successfully tapered off the lorazepam, with a complete return to baseline.

Bottom Line

Hyperkinetic catatonia is easily overlooked, especially in the emergency setting. Catatonia should always be ruled out, particularly in patients with underlying conditions associated with it. Hyperkinetic catatonia is an underrecognized comorbidity in patients with autism.

Related Resources

• Dhossche DM, Wing L, Ohta M, et al. International Review of Neurobiology: Catatonia in autism spectrum disorders, vol 72. New York, NY: Academic Press/Elsevier; 2006.
• Taylor MA, Fink M. Catatonia in psychiatric classification: a home of its own. Am J Psychiatry. 2003;160(7):1233-1241.

Drug Brand Names

Amantadine • Symmetrel
Bromocriptine • Parlodel
Clonazepam • Klonopin
Lorazepam • Ativan
Memantine • Namenda
Oxazepam • Serax
Quetiapine • Seroquel
Valproic acid • Depakene, Depakote
Zolpidem • Ambien

CASE Aggressive, impulsive, and not sleeping

Mr. S, age 22, is brought by his family to his outpatient psychiatrist because he has begun to exhibit motor and verbal tics, excessive adherence to rules and routines, and increased impulsivity and agitation.

Mr. S has significant language impairment and is unreliable as a narrator. His family reports that Mr. S’s behavior has resulted in declining academic performance, and they have curtailed his social activities due to behavioral issues. Both his family and teachers report that it is increasingly difficult to redirect Mr. S’s behavior. Although not physically aggressive, Mr. S becomes verbally agitated when rituals are incomplete. He has gone from sleeping 8 hours each night to only 3 to 4 hours, but he does not appear tired during the day.

HISTORY Multiple hospitalizations

As a child, Mr. S had been diagnosed with autism and intellectual disability. When he was 13, he began exhibiting marked stereotypy, restlessness, impulsivity, frenzy, agitation, combativeness, and purposeless motor activity. At that time, he was not receiving any medications. Mr. S had not slept for 2 days and had been walking in circles nonstop. He became aggressive whenever anyone attempted to redirect his behavior. The family took Mr. S to the emergency department (ED), where clinicians ruled out organic causes for his behavioral disturbances, including infections, drug intoxication, and use of illicit substances. Mr. S was transferred from the ED to a child and adolescent psychiatry ward at a nearby university hospital for inpatient treatment.

On the inpatient unit, the treatment team diagnosed Mr. S with bipolar disorder and believed that he was experiencing a manic episode. He was prescribed quetiapine, 25 mg by mouth during the day and 75 mg by mouth at night, to stabilize his agitation, and was discharged with a plan to follow up with his outpatient psychiatrist. However, within 1 week, his symptoms returned, with markedly increased aggression and agitation, so he was readmitted, tapered off quetiapine, and prescribed valproic acid, 125 mg by mouth during the day and 375 mg by mouth at bedtime. With this regimen, Mr. S became calmer, but when he was discharged home, he was subdued and withdrawn, overly adherent to rules and routines, constantly irritable, and often unable to focus.

Two years later, Mr. S developed hyperammonemia. Valproic acid was discontinued, and many of his behavioral issues resolved. He flourished both academically and socially. He experienced no exacerbation of symptoms until his current presentation.

[polldaddy:10544547]

EVALUATION Pinpointing the cause

Mr. S’s physical examination reveals that his vital signs are within normal limits. Mr. S is mildly tachycardic (heart rate, 105 bpm), with regular rate and rhythm. No murmurs, gallops, or rubs are auscultated. The remainder of the physical exam, including a detailed neurologic exam, is normal.

On mental status examination, Mr. S makes limited eye contact. He has difficulty sitting in the chair, with increased rocking, finger flicking, and hand flapping from baseline. Some compulsive behaviors are noted, such as tapping his neck. He has increased tics (eye blinking and mouth opening) and increased verbigeration and repetitive verbal statements. He loudly and repeatedly demands to go home, and uses short sentences with incorrect pronouns. His affect is difficult to assess, but he is agitated. His thought process is concrete. There is no evidence of suicidal ideation, homicidal ideation, or psychosis. Mr. S denies auditory hallucinations. His insight and judgment are limited.

Continue to: The psychiatrist rules out...

The psychiatrist rules out a behavioral exacerbation of autism based on an interview with Mr. S’s family and established rapport from treating him for several years. Mr. S’s family reports that many of his behaviors are not new but that the increased drive and intensity is worrisome. Further, his family cannot identify any stressors or precipitants for the behaviors and reports that offering preferred reinforcers did not help. An anxiety disorder is ruled out because according to the family, Mr. S’s drive to constantly move and complete rituals is fueling his anxiety. Schizoaffective disorder is ruled out because Mr. S denies auditory hallucinations and has not been observed responding to internal stimuli.

His Bush-Francis Catatonia Rating Scale (BFCRS) score is 26, which suggests a high likelihood of catatonia. Based on the BFCRS score, Mr. S’s psychiatrist makes the diagnosis of hyperkinetic catatonia.

The authors’ observations

The psychiatrist determined that Mr. S had been misdiagnosed with bipolar disorder at age 13. At that time, he had experienced his first episode of hyperkinetic catatonia and his symptoms decreased after he received lorazepam in the ED. However, the treatment team did not correctly identify this, most likely due to limited knowledge of catatonia among emergency medicine clinicians.

This case exemplifies a cognitive error of premature closure. Rather than considering catatonia as a complication of autism when Mr. S was 13, the clinicians added a second psychiatric diagnosis of bipolar disorder.Although premature closure errors generally occur when the physician assumes the patient is having a common complication of a known illness,¹ in Mr. S’s case, the opposite occurred.

Conceptualizing catatonia

One helpful model for conceptualizing catatonia is to think of it as a basal ganglia disorder, with lesions in the basal ganglia thalamocortical tracts and the anterior cingulate/medial orbitofrontal circuit. Disrupting these pathways can result in symptoms such as mutism or repetitive and imitative behaviors. This is likely due to decreased disinhibition by gamma-aminobutyric acid (GABA), resulting in a hypodopaminergic state. This explains why benzodiazepines, which act to increase GABA, are effective for treating catatonia, and antipsychotics that act to decrease dopamine can exacerbate symptoms. Fricchione et al² developed a model to visually represent the neurobiologic pathophysiology of catatonia (Figure²).

Continue to: Underlying causes of catatonia

Catatonia is most often seen in individuals with an underlying psychiatric condition such as schizophrenia, mood disorders, or autism. However, catatonia also occurs in the context of general neurologic and medical disorders, including (but not limited to) infections, metabolic disorders, endocrinopathies, epilepsy, neurodegenerative diseases, delirium, hypertensive encephalopathy, autoimmune encephalitis, and liver and kidney transplantation.³

Subtypes of catatonia include⁴:

• hypokinetic catatonia, which presents as stupor, mutism, and negativism
• hyperkinetic catatonia, which presents as hyperactivity, agitation, and stereotypy (as observed in Mr. S)
• malignant catatonia, which is a potentially lethal form of catatonia that occurs when hypo- or hyperkinetic catatonia is accompanied by autonomic instability such as tachycardia, tachypnea, hypertension, fever, and muscle rigidity
• periodic catatonia, which is characterized by brief episodes of stupor or excitatory catatonia lasting 4 to 10 days. These episodes recur over weeks to years, with patients remaining asymptomatic between episodes, or showing mild symptoms, such as facial grimacing or negativisms. Periodic catatonia often is autosomal dominant, involves linkage for the long arm of chromosome 15, and has a better prognosis than the other forms.

Autism and catatonia

Most individuals with autism who experience a catatonic episode first do so between age 10 and 19, and many episodes are precipitated by sudden changes in routine resulting in stress.⁵ An estimated 12% to 18% of patients with autism are diagnosed with catatonia in their lifetime, but the actual prevalence is likely higher.⁴

One of the reasons for this might be that although catatonia is well known in the psychiatric community, it is relatively unknown in the general medical community. Children and adolescents with psychiatric illness are likely to have symptoms of catatonia overlooked because catatonia often is not included in the differential diagnosis.⁶

In Mr. S’s case, it became clear that he did not have a mood disorder, but was prone to episodes of hyperkinetic catatonia due to his autism.

Continue to: Better recognition of catatonia

As catatonia becomes better elucidated and more clearly described in the literature, there is increasing awareness that symptoms do not always involve stupor, mutism, and slowed motor activity, but can include increased motor activity, agitation, and stereotypies. The BFCRS is extremely useful for quantifying symptoms of catatonia. The best way to confirm the diagnosis is to use a lorazepam challenge in an inpatient setting, or a trial of lorazepam in an outpatient setting.⁵

[polldaddy:10544548]

The authors’ observations

Lorazepam is often considered the first-line treatment for catatonia because it is one of the most widely studied medications. Other benzodiazepines, such as oxazepam and clonazepam, and the sedative/hypnotic zolpidem have also been shown to be effective. Antipsychotics with dopamine-blocking mechanisms can exacerbate symptoms of catatonia and should be avoided in these patients. Furthermore, in cases of refractory catatonia, bilateral electroconvulsive therapy is an important and necessary treatment.⁷

TREATMENT Pharmacologic agents decrease BFCRS score

Mr. S is prescribed a regimen of lorazepam, 2 mg by mouth daily, and the supplement N-acetylcysteine, 600 mg by mouth daily. Within 2 weeks of starting this regimen, Mr. S’s BFCRS score decreases from 26 to 14. After 6 months of treatment with lorazepam, Mr. S shows considerable improvement. The stereotypic behaviors and impulsivity decrease significantly, leading to improved sleep and performance in school. After 6 months Mr. S is successfully tapered off the lorazepam, with a complete return to baseline.

Bottom Line

Hyperkinetic catatonia is easily overlooked, especially in the emergency setting. Catatonia should always be ruled out, particularly in patients with underlying conditions associated with it. Hyperkinetic catatonia is an underrecognized comorbidity in patients with autism.

Related Resources

• Dhossche DM, Wing L, Ohta M, et al. International Review of Neurobiology: Catatonia in autism spectrum disorders, vol 72. New York, NY: Academic Press/Elsevier; 2006.
• Taylor MA, Fink M. Catatonia in psychiatric classification: a home of its own. Am J Psychiatry. 2003;160(7):1233-1241.

Drug Brand Names

Amantadine • Symmetrel
Bromocriptine • Parlodel
Clonazepam • Klonopin
Lorazepam • Ativan
Memantine • Namenda
Oxazepam • Serax
Quetiapine • Seroquel
Valproic acid • Depakene, Depakote
Zolpidem • Ambien

CASE Aggressive, impulsive, and not sleeping

Mr. S, age 22, is brought by his family to his outpatient psychiatrist because he has begun to exhibit motor and verbal tics, excessive adherence to rules and routines, and increased impulsivity and agitation.

Mr. S has significant language impairment and is unreliable as a narrator. His family reports that Mr. S’s behavior has resulted in declining academic performance, and they have curtailed his social activities due to behavioral issues. Both his family and teachers report that it is increasingly difficult to redirect Mr. S’s behavior. Although not physically aggressive, Mr. S becomes verbally agitated when rituals are incomplete. He has gone from sleeping 8 hours each night to only 3 to 4 hours, but he does not appear tired during the day.

HISTORY Multiple hospitalizations

As a child, Mr. S had been diagnosed with autism and intellectual disability. When he was 13, he began exhibiting marked stereotypy, restlessness, impulsivity, frenzy, agitation, combativeness, and purposeless motor activity. At that time, he was not receiving any medications. Mr. S had not slept for 2 days and had been walking in circles nonstop. He became aggressive whenever anyone attempted to redirect his behavior. The family took Mr. S to the emergency department (ED), where clinicians ruled out organic causes for his behavioral disturbances, including infections, drug intoxication, and use of illicit substances. Mr. S was transferred from the ED to a child and adolescent psychiatry ward at a nearby university hospital for inpatient treatment.

On the inpatient unit, the treatment team diagnosed Mr. S with bipolar disorder and believed that he was experiencing a manic episode. He was prescribed quetiapine, 25 mg by mouth during the day and 75 mg by mouth at night, to stabilize his agitation, and was discharged with a plan to follow up with his outpatient psychiatrist. However, within 1 week, his symptoms returned, with markedly increased aggression and agitation, so he was readmitted, tapered off quetiapine, and prescribed valproic acid, 125 mg by mouth during the day and 375 mg by mouth at bedtime. With this regimen, Mr. S became calmer, but when he was discharged home, he was subdued and withdrawn, overly adherent to rules and routines, constantly irritable, and often unable to focus.

Two years later, Mr. S developed hyperammonemia. Valproic acid was discontinued, and many of his behavioral issues resolved. He flourished both academically and socially. He experienced no exacerbation of symptoms until his current presentation.

[polldaddy:10544547]

EVALUATION Pinpointing the cause

Mr. S’s physical examination reveals that his vital signs are within normal limits. Mr. S is mildly tachycardic (heart rate, 105 bpm), with regular rate and rhythm. No murmurs, gallops, or rubs are auscultated. The remainder of the physical exam, including a detailed neurologic exam, is normal.

On mental status examination, Mr. S makes limited eye contact. He has difficulty sitting in the chair, with increased rocking, finger flicking, and hand flapping from baseline. Some compulsive behaviors are noted, such as tapping his neck. He has increased tics (eye blinking and mouth opening) and increased verbigeration and repetitive verbal statements. He loudly and repeatedly demands to go home, and uses short sentences with incorrect pronouns. His affect is difficult to assess, but he is agitated. His thought process is concrete. There is no evidence of suicidal ideation, homicidal ideation, or psychosis. Mr. S denies auditory hallucinations. His insight and judgment are limited.

Continue to: The psychiatrist rules out...

The psychiatrist rules out a behavioral exacerbation of autism based on an interview with Mr. S’s family and established rapport from treating him for several years. Mr. S’s family reports that many of his behaviors are not new but that the increased drive and intensity is worrisome. Further, his family cannot identify any stressors or precipitants for the behaviors and reports that offering preferred reinforcers did not help. An anxiety disorder is ruled out because according to the family, Mr. S’s drive to constantly move and complete rituals is fueling his anxiety. Schizoaffective disorder is ruled out because Mr. S denies auditory hallucinations and has not been observed responding to internal stimuli.

His Bush-Francis Catatonia Rating Scale (BFCRS) score is 26, which suggests a high likelihood of catatonia. Based on the BFCRS score, Mr. S’s psychiatrist makes the diagnosis of hyperkinetic catatonia.

The authors’ observations

The psychiatrist determined that Mr. S had been misdiagnosed with bipolar disorder at age 13. At that time, he had experienced his first episode of hyperkinetic catatonia and his symptoms decreased after he received lorazepam in the ED. However, the treatment team did not correctly identify this, most likely due to limited knowledge of catatonia among emergency medicine clinicians.

This case exemplifies a cognitive error of premature closure. Rather than considering catatonia as a complication of autism when Mr. S was 13, the clinicians added a second psychiatric diagnosis of bipolar disorder.Although premature closure errors generally occur when the physician assumes the patient is having a common complication of a known illness,¹ in Mr. S’s case, the opposite occurred.

Conceptualizing catatonia

One helpful model for conceptualizing catatonia is to think of it as a basal ganglia disorder, with lesions in the basal ganglia thalamocortical tracts and the anterior cingulate/medial orbitofrontal circuit. Disrupting these pathways can result in symptoms such as mutism or repetitive and imitative behaviors. This is likely due to decreased disinhibition by gamma-aminobutyric acid (GABA), resulting in a hypodopaminergic state. This explains why benzodiazepines, which act to increase GABA, are effective for treating catatonia, and antipsychotics that act to decrease dopamine can exacerbate symptoms. Fricchione et al² developed a model to visually represent the neurobiologic pathophysiology of catatonia (Figure²).

Continue to: Underlying causes of catatonia

Catatonia is most often seen in individuals with an underlying psychiatric condition such as schizophrenia, mood disorders, or autism. However, catatonia also occurs in the context of general neurologic and medical disorders, including (but not limited to) infections, metabolic disorders, endocrinopathies, epilepsy, neurodegenerative diseases, delirium, hypertensive encephalopathy, autoimmune encephalitis, and liver and kidney transplantation.³

Subtypes of catatonia include⁴:

• hypokinetic catatonia, which presents as stupor, mutism, and negativism
• hyperkinetic catatonia, which presents as hyperactivity, agitation, and stereotypy (as observed in Mr. S)
• malignant catatonia, which is a potentially lethal form of catatonia that occurs when hypo- or hyperkinetic catatonia is accompanied by autonomic instability such as tachycardia, tachypnea, hypertension, fever, and muscle rigidity
• periodic catatonia, which is characterized by brief episodes of stupor or excitatory catatonia lasting 4 to 10 days. These episodes recur over weeks to years, with patients remaining asymptomatic between episodes, or showing mild symptoms, such as facial grimacing or negativisms. Periodic catatonia often is autosomal dominant, involves linkage for the long arm of chromosome 15, and has a better prognosis than the other forms.

Autism and catatonia

Most individuals with autism who experience a catatonic episode first do so between age 10 and 19, and many episodes are precipitated by sudden changes in routine resulting in stress.⁵ An estimated 12% to 18% of patients with autism are diagnosed with catatonia in their lifetime, but the actual prevalence is likely higher.⁴

One of the reasons for this might be that although catatonia is well known in the psychiatric community, it is relatively unknown in the general medical community. Children and adolescents with psychiatric illness are likely to have symptoms of catatonia overlooked because catatonia often is not included in the differential diagnosis.⁶

In Mr. S’s case, it became clear that he did not have a mood disorder, but was prone to episodes of hyperkinetic catatonia due to his autism.

Continue to: Better recognition of catatonia

As catatonia becomes better elucidated and more clearly described in the literature, there is increasing awareness that symptoms do not always involve stupor, mutism, and slowed motor activity, but can include increased motor activity, agitation, and stereotypies. The BFCRS is extremely useful for quantifying symptoms of catatonia. The best way to confirm the diagnosis is to use a lorazepam challenge in an inpatient setting, or a trial of lorazepam in an outpatient setting.⁵

[polldaddy:10544548]

The authors’ observations

Lorazepam is often considered the first-line treatment for catatonia because it is one of the most widely studied medications. Other benzodiazepines, such as oxazepam and clonazepam, and the sedative/hypnotic zolpidem have also been shown to be effective. Antipsychotics with dopamine-blocking mechanisms can exacerbate symptoms of catatonia and should be avoided in these patients. Furthermore, in cases of refractory catatonia, bilateral electroconvulsive therapy is an important and necessary treatment.⁷

TREATMENT Pharmacologic agents decrease BFCRS score

Mr. S is prescribed a regimen of lorazepam, 2 mg by mouth daily, and the supplement N-acetylcysteine, 600 mg by mouth daily. Within 2 weeks of starting this regimen, Mr. S’s BFCRS score decreases from 26 to 14. After 6 months of treatment with lorazepam, Mr. S shows considerable improvement. The stereotypic behaviors and impulsivity decrease significantly, leading to improved sleep and performance in school. After 6 months Mr. S is successfully tapered off the lorazepam, with a complete return to baseline.

Bottom Line

Hyperkinetic catatonia is easily overlooked, especially in the emergency setting. Catatonia should always be ruled out, particularly in patients with underlying conditions associated with it. Hyperkinetic catatonia is an underrecognized comorbidity in patients with autism.

Related Resources

• Dhossche DM, Wing L, Ohta M, et al. International Review of Neurobiology: Catatonia in autism spectrum disorders, vol 72. New York, NY: Academic Press/Elsevier; 2006.
• Taylor MA, Fink M. Catatonia in psychiatric classification: a home of its own. Am J Psychiatry. 2003;160(7):1233-1241.

Drug Brand Names

Amantadine • Symmetrel
Bromocriptine • Parlodel
Clonazepam • Klonopin
Lorazepam • Ativan
Memantine • Namenda
Oxazepam • Serax
Quetiapine • Seroquel
Valproic acid • Depakene, Depakote
Zolpidem • Ambien

Dear colleagues and friends,

I write to introduce to you the new Perspectives section of GI & Hepatology News.

A more appropriate description is perhaps old-new, because Perspectives is the continuation and legacy of AGA Perspectives, the content of which has been consolidated into GI & Hepatology News. Perspectives will continue to feature the point/counterpoint expert debates about an important GI topic, which has historically been immensely popular with readers. In this edition, experts from Mayo Clinic and Cleveland Clinic discuss the pros and cons of universal multigene panel testing for colorectal cancer. These debates never end with the publication itself, and I hope they will continue to stimulate further thought and discussion. As always, I welcome your comments and suggestions for future topics.

–Charles I. Kahi, MD, MS, AGAF, is professor of medicine at Indiana University School of Medicine, Indianapolis. He is also an Associate Editor for GI & Hepatology News.

For everyone

By N. Jewel Samadder, MD, MSC

Traditionally, health care structure has been directed predominantly toward treatment rather than prevention. Advances in genomic medicine offer the opportunity to deliver a more personalized, predictive, and preventive strategy toward colorectal cancer. Approximately 150,000 men and women are diagnosed with colorectal cancer (CRC) every year in the United States.¹ An estimated 10%-15% of these cancers are likely attributable to hereditary (germline) causes.² Several genes are associated with an increased risk of developing CRC, and those of key interest include those for Lynch syndrome, MLH1, MSH2, MSH6, PMS2, EPCAM; adenomatous polyposis conditions (APC), MUTYH, POLE, POLD1, NTHL1; hamartomatous polyposis syndromes PTEN, SMAD4, STK11, and other rare cancer predisposition states where colorectal cancer is part of the phenotype, CHEK2 and TP532.

A universal strategy for multigene panel testing in all patients with CRC is an option versus the current strategy of guideline-based testing using family history and tumor features. In addition, the identification of germline alterations has substantial clinical implications including targeted therapies and future cancer prevention in the patient and relatives. This article will focus on the benefits of universal strategy for germline genetic evaluation in all patients with colorectal cancer.
 

The role and utility of current guideline-based testing
Given the therapeutic and prevention implications, the National Comprehensive Cancer Network (along with other professional organizations) has guidance on when patients with CRC should undergo genetic evaluation.³ Currently, these guidelines advocate an approach based heavily on family cancer history or utilizing colorectal phenotype based on the number and histology of polyps or tumor-based molecular features. Although family history is important for the diagnosis of hereditary CRC, the ability to accurately capture extended family cancer history in routine practice, from multiple generations and for different cancer types can be a challenge. The largest drawback of all such approaches is the focus on Lynch syndrome or only a few of the cancer predisposition syndromes. Recent studies have reported a substantial number (7%-10%) of CRC patients will have mutations in non–Lynch syndrome–associated genes and over half of these would be missed by using standard criteria for genetic evaluation.

Role of tumor-based screening approaches
More recently, health care institutions have begun to widely adopt “universal” tumor screening using microsatellite instability and/or immunohistochemistry (IHC) showing deficient expression of the mismatch repair proteins (MLH1, MSH2, MSH6, PMS2) to identify patients with colorectal or endometrial cancers that are likely to have Lynch syndrome. However, the sensitivity and specificity of IHC for Lynch syndrome ranges between 60% and 75% and there is considerable interobserver variation by pathologists in their interpretation.

Thus, both clinical guidelines (largely focused around family history and patient phenotype) and tumor molecular features will fail to identify a significant number of patients with inherited cancer predisposition.
 

Cost and availability of genetic testing
In the past, cost and availability of genetic testing were an impediment to such care. This has rapidly changed in the last few years. With modern next-generation sequencing technology and an ever increasing number of testing laboratories, the cost of genetic testing has dropped to below $500 and multigene panels can now test for dozens of genes in parallel offering comprehensive testing of genetic predisposition across multiple cancer types. The popularity of direct-to-consumer health-related genetic testing (with the inclusion of certain BRCA variants on these panels) has also fueled the public interest in cancer genetic testing.

Cancer prevention for family members
In individuals with CRC and hereditary cancer predisposition, implications for family members are clinically meaningful and include increased colorectal and extracolonic surveillance, consideration of risk-reducing hysterectomy, salpingo-oophorectomy, and bilateral mastectomy for colorectal, uterine, ovarian, breast, and other cancer prevention depending on the germline mutation.² The goal of these intensive surveillance strategies is to either prevent the occurrence of cancer altogether or detect cancer at an earlier stage when cure is likely. Identifying these high-risk groups can thus play a significant role in our goal to reduce the burden of cancer in society.

Precision targeted treatment and chemoprevention
The treatment implications for patients with CRC and pathogenic mutations in the Lynch syndrome MMR genes are the best characterized and include response to immune checkpoint inhibitor therapy.⁴ Mismatch repair deficiency is highly predictive of response to immunotherapy in metastatic CRCs and led to expedited approval of both pembrolizumab and nivolumab monotherapies with disease control rates of 69%-77% with durable response and combination therapy with nivolumab and ipilimumab with likely even greater benefit. Multiple clinical trials are examining the role of immune checkpoint inhibitor therapy for first-line palliative treatment of MSI-high CRC (ClinicalTrials.gov ID NCT02563002; NCT02997228), adjuvant therapy (ClinicalTrials.gov ID NCT02912559), and even as potential chemoprevention in those with Lynch syndrome (ClinicalTrials.gov ID NCT03631641).

Long-term cancer prevention using a chemopreventive approach has long been a desire in the hereditary cancer community.⁵ The most well-studied group to date has been Lynch syndrome, where a large randomized clinical trial showed the effect of high-dose aspirin in decreasing the incidence of colorectal and other Lynch-associated cancers by nearly 60%.⁶ Similar smaller (earlier-phase) studies in familial adenomatous polyposis have suggested targeted chemoprevention options for the regression of colorectal or duodenal polyposis with COX inhibitors, EGFR inhibitors, DFMO (NCT01483144), and IL-23 blockade (ClinicalTrials.gov ID NCT03649971) may all be possible.

Cancer programs have already started to introduce genomic profiling (germline and tumor somatic) into the frontline care of their patients to help guide precision therapy approaches that optimize disease control, minimize side effects, and reduce risk of long-term recurrence.
 

The future
The approach to genomic profiling of cancer patients is rapidly changing because of the lack of sensitivity for the identification of these hereditary cancer predisposition syndromes utilizing current approaches focused on family history, clinical phenotype, and tumor features. The wide availability of low-cost/affordable multigene panel testing has implications for cancer therapy selection and cancer prevention. This supports establishing a universal approach to multigene panel testing of all patients with CRC.

It will be important for physicians of many different specialties – including gastroenterology and oncology – to become more adept in this changing landscape of genomic medicine and to work closely with the genetic counseling resources available in their communities to provide the best care for these high-risk cancer patients.
 

References

1. Siegel RL et al. CA Cancer J Clin. 2017;67:177-93.

2. Kanth P et al. Am J Gastroenterol. 2017;112:1509-25.

3. Gupta S et al. J Natl Compr Canc Netw. 2019;17:1032-41.

4. Ribas A, Wolchok JD. Science. 2018;359:1350-5.

5. Ramamurthy C et al. Surg Oncol Clin N Am. 2017;26:729-50.

6. Burn J et al. Lancet 2011;378:2081-7.

Dr. Samadder is a gastroenterologist in the division of gastroenterology and hepatology, Mayo Clinic, Phoenix. He is a consultant for Janssen Research & Development and Cancer Prevention Pharmaceuticals.

Not for everyone

By Carol A. Burke, MD, AGAF, and Brandie Heald Leach, MS

Multigene panel testing (MGPT) takes advantage of next-generation sequencing (NGS) a non-Sanger-based DNA sequencing technology which has revolutionized genomic research and clinical care because it can be run quickly, is lower cost than Sanger sequencing, can sequence an entire genome or exome, or specific genes of interest. Currently, cancer gene panels (disease specific or pan-cancer) are commonly utilized.

Approximately 10% of colorectal cancers (CRCs) are heritable because of a germline pathogenic variant (PV), most commonly in Lynch syndrome genes. Identification of patients with hereditary CRC is important because they are at greatest CRC and extracolonic cancer risk, benefit from aggressive cancer surveillance. and when indicated may need prophylactic surgery of at-risk organs, require multidisciplinary care, and may have at-risk family members who need testing.

Red flags regarding family cancer history may allow clinical inference as to the cause of CRC and direct who is offered germline testing. These include young age of cancer (age less than 50), synchronous or metachronous cancers, multiple relatives with CRC or extracolonic cancers, and cumulative lifetime numbers of adenomas or hamartomas. While overt clinical manifestations can be specific for predicting the causative gene defect, such as Amsterdam criteria for Lynch syndrome or numerous adenomas at a young age in familial adenomatous polyposis, overlap can occur between syndromes and single gene testing has its limitations. While family pedigrees with a phenotype that meets clinical criteria, such as Amsterdam II, can be very specific (although less sensitive) for predicting Lynch syndrome, or overt clinical manifestations such as 100 adenomatous polyps in an individual by the age of 40 is highly suggestive of familial adenomatous polyposis, overlap can occur between syndromes and single gene testing has its limitations.

The current standard of care for patients with CRC is germline testing after assessment of tumor mismatch repair (MMR) proficiency by microsatellite instability (MSI) testing and/or immunohistochemistry (IHC). Broadly, tumors that show high levels of MSI and or loss of expression of MMR proteins (not attributed to MLH1 promoter hypermethylation or double somatic mutations/loss of heterozygosity) are considered MMR deficient (MMRd) and suggestive of Lynch syndrome. MMRd directs treatment (immune check point inhibitors) and is a hallmark of Lynch syndrome as 95% of Lynch syndrome–related CRCs are MMRd.

The utility of MGPT in individuals with CRC can be inferred from two studies. In both, a 25-gene pan-cancer panel test was performed. In the first, 1,058 unselected individuals with CRC at a mean age of 56 were assessed regardless of MMR status; 9.9% were diagnosed with moderately (4.7%) or highly penetrant (5.2%) PV.^{1 In these individuals with CRC, 31}% were diagnosed with Lynch syndrome and nearly all Lynch syndrome patients had MMRd tumors and met criteria for germline testing for Lynch syndrome; 22% of patients had other high-penetrance PV found, the majority lacking clinical features consistent with the PV. The second study,² tested 450 patients with CRC diagnosed under the age of 50. Germline PV were detected in 16%. The majority of patients with an MMRd tumor were diagnosed with Lynch syndrome. Eight percent of patients with an MMR-proficient tumor had a PV detected. Nearly one-third did not meet clinical criteria for testing. Germline variants of uncertain significance (VUS) were noted in approximately 32% of patients in both studies. These data support the current standard of tumor assessment for MMRd, followed by Lynch syndrome germline testing as directed by IHC.

While MGPT for patients with CRC is feasible, the high rates of VUS, detection of moderate and low penetrance PV for which no clinical guidance exists, and dearth of evidence on penetrance and cancer risk attributable to incidentally found PV, need consideration. Prior to germline testing, patients and providers must understand potential testing outcomes, possible detection of incidental findings and VUS, and how each influence patient cancer risks and management. The commercial genetic testing companies accumulate information on VUS over time and reclassify the significance of the finding, but this process could take months to years. Providers ordering genetic testing must have a system to inform the patient when a VUS is reclassified.

Pre- and post-test genetic counseling, ideally by an individual with understanding of medical genetics, should be offered, including caveats, risks, benefits, and alternatives to germline testing, a plan for results disclosure, including to family members, and a plan for follow-up care. Patients with uninformative findings and VUS need to be followed as technology and research evolve. Patient preferences regarding genetic testing need to be considered. There still remains stigma and fear associated with genetic testing. Despite protections from the Genetic Information Non-Discrimination Act, many patients remain fearful of genetic discrimination. A genetic diagnosis comes with the burden that it reveals not only information about the patient’s risks, but potentially also his/her family members’ risks. These are valid patient concerns that need to be vetted and addressed.

Selection of correct testing strategy is important. A patient with a known PV in the family might benefit most from single-site analysis for the family mutation. For a patient with an affected relative who had negative genetic testing, additional genetic testing for that patients is unlikely to be beneficial. For a patient with no known PV in the family who meet genetic testing criteria, a cancer gene panel should be considered. However, guidance on which MGPT to order is lacking in professional guidelines and often left to the discretion of the provider and patient. Utilization of a “disease specific panel” (i.e., a panel of genes related to CRC risk) is useful for understanding the cause of the patient’s disease and guiding treatment, screening, and cascade testing while minimizing the number of VUS identified. Pan-cancer gene panels increase diagnostic yield, but include identification of PV in genes unrelated to phenotype or more poorly described risk and management recommendations and have a higher rate of VUS.

Finally, the cost of MGPT to the health care system needs to be considered. Despite dropping costs, the process of genetic counseling and testing remains expensive and will rise if and when testing is expanded to all patients with CRC.

MGPT is not for everyone.
 

References

1. Yurgelun MB et al. J Clin Oncol. 2017;35:1086-95.

2. Pearlman R et al. JAMA Oncol. 2017 Apr 01;3(4):464-71.
 

Dr. Burke is with the department of gastroenterology, hepatology, and nutrition, Sanford R. Weiss Center for Hereditary Colorectal Neoplasia, Digestive Disease and Surgical Institute, Cleveland Clinic; Ms. Leach is with the Center for Personalized Genetic Healthcare, Sanford R. Weiss Center for Hereditary Colorectal Neoplasia, Digestive Disease and Surgical Institute, Cleveland Clinic. Dr. Burke has no conflicts of interest, Ms. Leach serves on the advisory board of Invitae.

Dear colleagues and friends,

I write to introduce to you the new Perspectives section of GI & Hepatology News.

A more appropriate description is perhaps old-new, because Perspectives is the continuation and legacy of AGA Perspectives, the content of which has been consolidated into GI & Hepatology News. Perspectives will continue to feature the point/counterpoint expert debates about an important GI topic, which has historically been immensely popular with readers. In this edition, experts from Mayo Clinic and Cleveland Clinic discuss the pros and cons of universal multigene panel testing for colorectal cancer. These debates never end with the publication itself, and I hope they will continue to stimulate further thought and discussion. As always, I welcome your comments and suggestions for future topics.

–Charles I. Kahi, MD, MS, AGAF, is professor of medicine at Indiana University School of Medicine, Indianapolis. He is also an Associate Editor for GI & Hepatology News.

For everyone

By N. Jewel Samadder, MD, MSC

Traditionally, health care structure has been directed predominantly toward treatment rather than prevention. Advances in genomic medicine offer the opportunity to deliver a more personalized, predictive, and preventive strategy toward colorectal cancer. Approximately 150,000 men and women are diagnosed with colorectal cancer (CRC) every year in the United States.¹ An estimated 10%-15% of these cancers are likely attributable to hereditary (germline) causes.² Several genes are associated with an increased risk of developing CRC, and those of key interest include those for Lynch syndrome, MLH1, MSH2, MSH6, PMS2, EPCAM; adenomatous polyposis conditions (APC), MUTYH, POLE, POLD1, NTHL1; hamartomatous polyposis syndromes PTEN, SMAD4, STK11, and other rare cancer predisposition states where colorectal cancer is part of the phenotype, CHEK2 and TP532.

A universal strategy for multigene panel testing in all patients with CRC is an option versus the current strategy of guideline-based testing using family history and tumor features. In addition, the identification of germline alterations has substantial clinical implications including targeted therapies and future cancer prevention in the patient and relatives. This article will focus on the benefits of universal strategy for germline genetic evaluation in all patients with colorectal cancer.
 

The role and utility of current guideline-based testing
Given the therapeutic and prevention implications, the National Comprehensive Cancer Network (along with other professional organizations) has guidance on when patients with CRC should undergo genetic evaluation.³ Currently, these guidelines advocate an approach based heavily on family cancer history or utilizing colorectal phenotype based on the number and histology of polyps or tumor-based molecular features. Although family history is important for the diagnosis of hereditary CRC, the ability to accurately capture extended family cancer history in routine practice, from multiple generations and for different cancer types can be a challenge. The largest drawback of all such approaches is the focus on Lynch syndrome or only a few of the cancer predisposition syndromes. Recent studies have reported a substantial number (7%-10%) of CRC patients will have mutations in non–Lynch syndrome–associated genes and over half of these would be missed by using standard criteria for genetic evaluation.

Role of tumor-based screening approaches
More recently, health care institutions have begun to widely adopt “universal” tumor screening using microsatellite instability and/or immunohistochemistry (IHC) showing deficient expression of the mismatch repair proteins (MLH1, MSH2, MSH6, PMS2) to identify patients with colorectal or endometrial cancers that are likely to have Lynch syndrome. However, the sensitivity and specificity of IHC for Lynch syndrome ranges between 60% and 75% and there is considerable interobserver variation by pathologists in their interpretation.

Thus, both clinical guidelines (largely focused around family history and patient phenotype) and tumor molecular features will fail to identify a significant number of patients with inherited cancer predisposition.
 

Cost and availability of genetic testing
In the past, cost and availability of genetic testing were an impediment to such care. This has rapidly changed in the last few years. With modern next-generation sequencing technology and an ever increasing number of testing laboratories, the cost of genetic testing has dropped to below $500 and multigene panels can now test for dozens of genes in parallel offering comprehensive testing of genetic predisposition across multiple cancer types. The popularity of direct-to-consumer health-related genetic testing (with the inclusion of certain BRCA variants on these panels) has also fueled the public interest in cancer genetic testing.

Cancer prevention for family members
In individuals with CRC and hereditary cancer predisposition, implications for family members are clinically meaningful and include increased colorectal and extracolonic surveillance, consideration of risk-reducing hysterectomy, salpingo-oophorectomy, and bilateral mastectomy for colorectal, uterine, ovarian, breast, and other cancer prevention depending on the germline mutation.² The goal of these intensive surveillance strategies is to either prevent the occurrence of cancer altogether or detect cancer at an earlier stage when cure is likely. Identifying these high-risk groups can thus play a significant role in our goal to reduce the burden of cancer in society.

Precision targeted treatment and chemoprevention
The treatment implications for patients with CRC and pathogenic mutations in the Lynch syndrome MMR genes are the best characterized and include response to immune checkpoint inhibitor therapy.⁴ Mismatch repair deficiency is highly predictive of response to immunotherapy in metastatic CRCs and led to expedited approval of both pembrolizumab and nivolumab monotherapies with disease control rates of 69%-77% with durable response and combination therapy with nivolumab and ipilimumab with likely even greater benefit. Multiple clinical trials are examining the role of immune checkpoint inhibitor therapy for first-line palliative treatment of MSI-high CRC (ClinicalTrials.gov ID NCT02563002; NCT02997228), adjuvant therapy (ClinicalTrials.gov ID NCT02912559), and even as potential chemoprevention in those with Lynch syndrome (ClinicalTrials.gov ID NCT03631641).

Long-term cancer prevention using a chemopreventive approach has long been a desire in the hereditary cancer community.⁵ The most well-studied group to date has been Lynch syndrome, where a large randomized clinical trial showed the effect of high-dose aspirin in decreasing the incidence of colorectal and other Lynch-associated cancers by nearly 60%.⁶ Similar smaller (earlier-phase) studies in familial adenomatous polyposis have suggested targeted chemoprevention options for the regression of colorectal or duodenal polyposis with COX inhibitors, EGFR inhibitors, DFMO (NCT01483144), and IL-23 blockade (ClinicalTrials.gov ID NCT03649971) may all be possible.

Cancer programs have already started to introduce genomic profiling (germline and tumor somatic) into the frontline care of their patients to help guide precision therapy approaches that optimize disease control, minimize side effects, and reduce risk of long-term recurrence.
 

The future
The approach to genomic profiling of cancer patients is rapidly changing because of the lack of sensitivity for the identification of these hereditary cancer predisposition syndromes utilizing current approaches focused on family history, clinical phenotype, and tumor features. The wide availability of low-cost/affordable multigene panel testing has implications for cancer therapy selection and cancer prevention. This supports establishing a universal approach to multigene panel testing of all patients with CRC.

It will be important for physicians of many different specialties – including gastroenterology and oncology – to become more adept in this changing landscape of genomic medicine and to work closely with the genetic counseling resources available in their communities to provide the best care for these high-risk cancer patients.
 

References

1. Siegel RL et al. CA Cancer J Clin. 2017;67:177-93.

2. Kanth P et al. Am J Gastroenterol. 2017;112:1509-25.

3. Gupta S et al. J Natl Compr Canc Netw. 2019;17:1032-41.

4. Ribas A, Wolchok JD. Science. 2018;359:1350-5.

5. Ramamurthy C et al. Surg Oncol Clin N Am. 2017;26:729-50.

6. Burn J et al. Lancet 2011;378:2081-7.

Dr. Samadder is a gastroenterologist in the division of gastroenterology and hepatology, Mayo Clinic, Phoenix. He is a consultant for Janssen Research & Development and Cancer Prevention Pharmaceuticals.

Not for everyone

By Carol A. Burke, MD, AGAF, and Brandie Heald Leach, MS

Multigene panel testing (MGPT) takes advantage of next-generation sequencing (NGS) a non-Sanger-based DNA sequencing technology which has revolutionized genomic research and clinical care because it can be run quickly, is lower cost than Sanger sequencing, can sequence an entire genome or exome, or specific genes of interest. Currently, cancer gene panels (disease specific or pan-cancer) are commonly utilized.

Approximately 10% of colorectal cancers (CRCs) are heritable because of a germline pathogenic variant (PV), most commonly in Lynch syndrome genes. Identification of patients with hereditary CRC is important because they are at greatest CRC and extracolonic cancer risk, benefit from aggressive cancer surveillance. and when indicated may need prophylactic surgery of at-risk organs, require multidisciplinary care, and may have at-risk family members who need testing.

Red flags regarding family cancer history may allow clinical inference as to the cause of CRC and direct who is offered germline testing. These include young age of cancer (age less than 50), synchronous or metachronous cancers, multiple relatives with CRC or extracolonic cancers, and cumulative lifetime numbers of adenomas or hamartomas. While overt clinical manifestations can be specific for predicting the causative gene defect, such as Amsterdam criteria for Lynch syndrome or numerous adenomas at a young age in familial adenomatous polyposis, overlap can occur between syndromes and single gene testing has its limitations. While family pedigrees with a phenotype that meets clinical criteria, such as Amsterdam II, can be very specific (although less sensitive) for predicting Lynch syndrome, or overt clinical manifestations such as 100 adenomatous polyps in an individual by the age of 40 is highly suggestive of familial adenomatous polyposis, overlap can occur between syndromes and single gene testing has its limitations.

The current standard of care for patients with CRC is germline testing after assessment of tumor mismatch repair (MMR) proficiency by microsatellite instability (MSI) testing and/or immunohistochemistry (IHC). Broadly, tumors that show high levels of MSI and or loss of expression of MMR proteins (not attributed to MLH1 promoter hypermethylation or double somatic mutations/loss of heterozygosity) are considered MMR deficient (MMRd) and suggestive of Lynch syndrome. MMRd directs treatment (immune check point inhibitors) and is a hallmark of Lynch syndrome as 95% of Lynch syndrome–related CRCs are MMRd.

The utility of MGPT in individuals with CRC can be inferred from two studies. In both, a 25-gene pan-cancer panel test was performed. In the first, 1,058 unselected individuals with CRC at a mean age of 56 were assessed regardless of MMR status; 9.9% were diagnosed with moderately (4.7%) or highly penetrant (5.2%) PV.^{1 In these individuals with CRC, 31}% were diagnosed with Lynch syndrome and nearly all Lynch syndrome patients had MMRd tumors and met criteria for germline testing for Lynch syndrome; 22% of patients had other high-penetrance PV found, the majority lacking clinical features consistent with the PV. The second study,² tested 450 patients with CRC diagnosed under the age of 50. Germline PV were detected in 16%. The majority of patients with an MMRd tumor were diagnosed with Lynch syndrome. Eight percent of patients with an MMR-proficient tumor had a PV detected. Nearly one-third did not meet clinical criteria for testing. Germline variants of uncertain significance (VUS) were noted in approximately 32% of patients in both studies. These data support the current standard of tumor assessment for MMRd, followed by Lynch syndrome germline testing as directed by IHC.

While MGPT for patients with CRC is feasible, the high rates of VUS, detection of moderate and low penetrance PV for which no clinical guidance exists, and dearth of evidence on penetrance and cancer risk attributable to incidentally found PV, need consideration. Prior to germline testing, patients and providers must understand potential testing outcomes, possible detection of incidental findings and VUS, and how each influence patient cancer risks and management. The commercial genetic testing companies accumulate information on VUS over time and reclassify the significance of the finding, but this process could take months to years. Providers ordering genetic testing must have a system to inform the patient when a VUS is reclassified.

Pre- and post-test genetic counseling, ideally by an individual with understanding of medical genetics, should be offered, including caveats, risks, benefits, and alternatives to germline testing, a plan for results disclosure, including to family members, and a plan for follow-up care. Patients with uninformative findings and VUS need to be followed as technology and research evolve. Patient preferences regarding genetic testing need to be considered. There still remains stigma and fear associated with genetic testing. Despite protections from the Genetic Information Non-Discrimination Act, many patients remain fearful of genetic discrimination. A genetic diagnosis comes with the burden that it reveals not only information about the patient’s risks, but potentially also his/her family members’ risks. These are valid patient concerns that need to be vetted and addressed.

Selection of correct testing strategy is important. A patient with a known PV in the family might benefit most from single-site analysis for the family mutation. For a patient with an affected relative who had negative genetic testing, additional genetic testing for that patients is unlikely to be beneficial. For a patient with no known PV in the family who meet genetic testing criteria, a cancer gene panel should be considered. However, guidance on which MGPT to order is lacking in professional guidelines and often left to the discretion of the provider and patient. Utilization of a “disease specific panel” (i.e., a panel of genes related to CRC risk) is useful for understanding the cause of the patient’s disease and guiding treatment, screening, and cascade testing while minimizing the number of VUS identified. Pan-cancer gene panels increase diagnostic yield, but include identification of PV in genes unrelated to phenotype or more poorly described risk and management recommendations and have a higher rate of VUS.

Finally, the cost of MGPT to the health care system needs to be considered. Despite dropping costs, the process of genetic counseling and testing remains expensive and will rise if and when testing is expanded to all patients with CRC.

MGPT is not for everyone.
 

References

1. Yurgelun MB et al. J Clin Oncol. 2017;35:1086-95.

2. Pearlman R et al. JAMA Oncol. 2017 Apr 01;3(4):464-71.
 

Dr. Burke is with the department of gastroenterology, hepatology, and nutrition, Sanford R. Weiss Center for Hereditary Colorectal Neoplasia, Digestive Disease and Surgical Institute, Cleveland Clinic; Ms. Leach is with the Center for Personalized Genetic Healthcare, Sanford R. Weiss Center for Hereditary Colorectal Neoplasia, Digestive Disease and Surgical Institute, Cleveland Clinic. Dr. Burke has no conflicts of interest, Ms. Leach serves on the advisory board of Invitae.

Dear colleagues and friends,

I write to introduce to you the new Perspectives section of GI & Hepatology News.

A more appropriate description is perhaps old-new, because Perspectives is the continuation and legacy of AGA Perspectives, the content of which has been consolidated into GI & Hepatology News. Perspectives will continue to feature the point/counterpoint expert debates about an important GI topic, which has historically been immensely popular with readers. In this edition, experts from Mayo Clinic and Cleveland Clinic discuss the pros and cons of universal multigene panel testing for colorectal cancer. These debates never end with the publication itself, and I hope they will continue to stimulate further thought and discussion. As always, I welcome your comments and suggestions for future topics.

–Charles I. Kahi, MD, MS, AGAF, is professor of medicine at Indiana University School of Medicine, Indianapolis. He is also an Associate Editor for GI & Hepatology News.

For everyone

By N. Jewel Samadder, MD, MSC

Traditionally, health care structure has been directed predominantly toward treatment rather than prevention. Advances in genomic medicine offer the opportunity to deliver a more personalized, predictive, and preventive strategy toward colorectal cancer. Approximately 150,000 men and women are diagnosed with colorectal cancer (CRC) every year in the United States.¹ An estimated 10%-15% of these cancers are likely attributable to hereditary (germline) causes.² Several genes are associated with an increased risk of developing CRC, and those of key interest include those for Lynch syndrome, MLH1, MSH2, MSH6, PMS2, EPCAM; adenomatous polyposis conditions (APC), MUTYH, POLE, POLD1, NTHL1; hamartomatous polyposis syndromes PTEN, SMAD4, STK11, and other rare cancer predisposition states where colorectal cancer is part of the phenotype, CHEK2 and TP532.

A universal strategy for multigene panel testing in all patients with CRC is an option versus the current strategy of guideline-based testing using family history and tumor features. In addition, the identification of germline alterations has substantial clinical implications including targeted therapies and future cancer prevention in the patient and relatives. This article will focus on the benefits of universal strategy for germline genetic evaluation in all patients with colorectal cancer.
 

The role and utility of current guideline-based testing
Given the therapeutic and prevention implications, the National Comprehensive Cancer Network (along with other professional organizations) has guidance on when patients with CRC should undergo genetic evaluation.³ Currently, these guidelines advocate an approach based heavily on family cancer history or utilizing colorectal phenotype based on the number and histology of polyps or tumor-based molecular features. Although family history is important for the diagnosis of hereditary CRC, the ability to accurately capture extended family cancer history in routine practice, from multiple generations and for different cancer types can be a challenge. The largest drawback of all such approaches is the focus on Lynch syndrome or only a few of the cancer predisposition syndromes. Recent studies have reported a substantial number (7%-10%) of CRC patients will have mutations in non–Lynch syndrome–associated genes and over half of these would be missed by using standard criteria for genetic evaluation.

Role of tumor-based screening approaches
More recently, health care institutions have begun to widely adopt “universal” tumor screening using microsatellite instability and/or immunohistochemistry (IHC) showing deficient expression of the mismatch repair proteins (MLH1, MSH2, MSH6, PMS2) to identify patients with colorectal or endometrial cancers that are likely to have Lynch syndrome. However, the sensitivity and specificity of IHC for Lynch syndrome ranges between 60% and 75% and there is considerable interobserver variation by pathologists in their interpretation.

Thus, both clinical guidelines (largely focused around family history and patient phenotype) and tumor molecular features will fail to identify a significant number of patients with inherited cancer predisposition.
 

Cost and availability of genetic testing
In the past, cost and availability of genetic testing were an impediment to such care. This has rapidly changed in the last few years. With modern next-generation sequencing technology and an ever increasing number of testing laboratories, the cost of genetic testing has dropped to below $500 and multigene panels can now test for dozens of genes in parallel offering comprehensive testing of genetic predisposition across multiple cancer types. The popularity of direct-to-consumer health-related genetic testing (with the inclusion of certain BRCA variants on these panels) has also fueled the public interest in cancer genetic testing.

Cancer prevention for family members
In individuals with CRC and hereditary cancer predisposition, implications for family members are clinically meaningful and include increased colorectal and extracolonic surveillance, consideration of risk-reducing hysterectomy, salpingo-oophorectomy, and bilateral mastectomy for colorectal, uterine, ovarian, breast, and other cancer prevention depending on the germline mutation.² The goal of these intensive surveillance strategies is to either prevent the occurrence of cancer altogether or detect cancer at an earlier stage when cure is likely. Identifying these high-risk groups can thus play a significant role in our goal to reduce the burden of cancer in society.

Precision targeted treatment and chemoprevention
The treatment implications for patients with CRC and pathogenic mutations in the Lynch syndrome MMR genes are the best characterized and include response to immune checkpoint inhibitor therapy.⁴ Mismatch repair deficiency is highly predictive of response to immunotherapy in metastatic CRCs and led to expedited approval of both pembrolizumab and nivolumab monotherapies with disease control rates of 69%-77% with durable response and combination therapy with nivolumab and ipilimumab with likely even greater benefit. Multiple clinical trials are examining the role of immune checkpoint inhibitor therapy for first-line palliative treatment of MSI-high CRC (ClinicalTrials.gov ID NCT02563002; NCT02997228), adjuvant therapy (ClinicalTrials.gov ID NCT02912559), and even as potential chemoprevention in those with Lynch syndrome (ClinicalTrials.gov ID NCT03631641).

Long-term cancer prevention using a chemopreventive approach has long been a desire in the hereditary cancer community.⁵ The most well-studied group to date has been Lynch syndrome, where a large randomized clinical trial showed the effect of high-dose aspirin in decreasing the incidence of colorectal and other Lynch-associated cancers by nearly 60%.⁶ Similar smaller (earlier-phase) studies in familial adenomatous polyposis have suggested targeted chemoprevention options for the regression of colorectal or duodenal polyposis with COX inhibitors, EGFR inhibitors, DFMO (NCT01483144), and IL-23 blockade (ClinicalTrials.gov ID NCT03649971) may all be possible.

Cancer programs have already started to introduce genomic profiling (germline and tumor somatic) into the frontline care of their patients to help guide precision therapy approaches that optimize disease control, minimize side effects, and reduce risk of long-term recurrence.
 

The future
The approach to genomic profiling of cancer patients is rapidly changing because of the lack of sensitivity for the identification of these hereditary cancer predisposition syndromes utilizing current approaches focused on family history, clinical phenotype, and tumor features. The wide availability of low-cost/affordable multigene panel testing has implications for cancer therapy selection and cancer prevention. This supports establishing a universal approach to multigene panel testing of all patients with CRC.

It will be important for physicians of many different specialties – including gastroenterology and oncology – to become more adept in this changing landscape of genomic medicine and to work closely with the genetic counseling resources available in their communities to provide the best care for these high-risk cancer patients.
 

References

1. Siegel RL et al. CA Cancer J Clin. 2017;67:177-93.

2. Kanth P et al. Am J Gastroenterol. 2017;112:1509-25.

3. Gupta S et al. J Natl Compr Canc Netw. 2019;17:1032-41.

4. Ribas A, Wolchok JD. Science. 2018;359:1350-5.

5. Ramamurthy C et al. Surg Oncol Clin N Am. 2017;26:729-50.

6. Burn J et al. Lancet 2011;378:2081-7.

Dr. Samadder is a gastroenterologist in the division of gastroenterology and hepatology, Mayo Clinic, Phoenix. He is a consultant for Janssen Research & Development and Cancer Prevention Pharmaceuticals.

Not for everyone

By Carol A. Burke, MD, AGAF, and Brandie Heald Leach, MS

Multigene panel testing (MGPT) takes advantage of next-generation sequencing (NGS) a non-Sanger-based DNA sequencing technology which has revolutionized genomic research and clinical care because it can be run quickly, is lower cost than Sanger sequencing, can sequence an entire genome or exome, or specific genes of interest. Currently, cancer gene panels (disease specific or pan-cancer) are commonly utilized.

Approximately 10% of colorectal cancers (CRCs) are heritable because of a germline pathogenic variant (PV), most commonly in Lynch syndrome genes. Identification of patients with hereditary CRC is important because they are at greatest CRC and extracolonic cancer risk, benefit from aggressive cancer surveillance. and when indicated may need prophylactic surgery of at-risk organs, require multidisciplinary care, and may have at-risk family members who need testing.

Red flags regarding family cancer history may allow clinical inference as to the cause of CRC and direct who is offered germline testing. These include young age of cancer (age less than 50), synchronous or metachronous cancers, multiple relatives with CRC or extracolonic cancers, and cumulative lifetime numbers of adenomas or hamartomas. While overt clinical manifestations can be specific for predicting the causative gene defect, such as Amsterdam criteria for Lynch syndrome or numerous adenomas at a young age in familial adenomatous polyposis, overlap can occur between syndromes and single gene testing has its limitations. While family pedigrees with a phenotype that meets clinical criteria, such as Amsterdam II, can be very specific (although less sensitive) for predicting Lynch syndrome, or overt clinical manifestations such as 100 adenomatous polyps in an individual by the age of 40 is highly suggestive of familial adenomatous polyposis, overlap can occur between syndromes and single gene testing has its limitations.

The current standard of care for patients with CRC is germline testing after assessment of tumor mismatch repair (MMR) proficiency by microsatellite instability (MSI) testing and/or immunohistochemistry (IHC). Broadly, tumors that show high levels of MSI and or loss of expression of MMR proteins (not attributed to MLH1 promoter hypermethylation or double somatic mutations/loss of heterozygosity) are considered MMR deficient (MMRd) and suggestive of Lynch syndrome. MMRd directs treatment (immune check point inhibitors) and is a hallmark of Lynch syndrome as 95% of Lynch syndrome–related CRCs are MMRd.

The utility of MGPT in individuals with CRC can be inferred from two studies. In both, a 25-gene pan-cancer panel test was performed. In the first, 1,058 unselected individuals with CRC at a mean age of 56 were assessed regardless of MMR status; 9.9% were diagnosed with moderately (4.7%) or highly penetrant (5.2%) PV.^{1 In these individuals with CRC, 31}% were diagnosed with Lynch syndrome and nearly all Lynch syndrome patients had MMRd tumors and met criteria for germline testing for Lynch syndrome; 22% of patients had other high-penetrance PV found, the majority lacking clinical features consistent with the PV. The second study,² tested 450 patients with CRC diagnosed under the age of 50. Germline PV were detected in 16%. The majority of patients with an MMRd tumor were diagnosed with Lynch syndrome. Eight percent of patients with an MMR-proficient tumor had a PV detected. Nearly one-third did not meet clinical criteria for testing. Germline variants of uncertain significance (VUS) were noted in approximately 32% of patients in both studies. These data support the current standard of tumor assessment for MMRd, followed by Lynch syndrome germline testing as directed by IHC.

While MGPT for patients with CRC is feasible, the high rates of VUS, detection of moderate and low penetrance PV for which no clinical guidance exists, and dearth of evidence on penetrance and cancer risk attributable to incidentally found PV, need consideration. Prior to germline testing, patients and providers must understand potential testing outcomes, possible detection of incidental findings and VUS, and how each influence patient cancer risks and management. The commercial genetic testing companies accumulate information on VUS over time and reclassify the significance of the finding, but this process could take months to years. Providers ordering genetic testing must have a system to inform the patient when a VUS is reclassified.

Pre- and post-test genetic counseling, ideally by an individual with understanding of medical genetics, should be offered, including caveats, risks, benefits, and alternatives to germline testing, a plan for results disclosure, including to family members, and a plan for follow-up care. Patients with uninformative findings and VUS need to be followed as technology and research evolve. Patient preferences regarding genetic testing need to be considered. There still remains stigma and fear associated with genetic testing. Despite protections from the Genetic Information Non-Discrimination Act, many patients remain fearful of genetic discrimination. A genetic diagnosis comes with the burden that it reveals not only information about the patient’s risks, but potentially also his/her family members’ risks. These are valid patient concerns that need to be vetted and addressed.

Selection of correct testing strategy is important. A patient with a known PV in the family might benefit most from single-site analysis for the family mutation. For a patient with an affected relative who had negative genetic testing, additional genetic testing for that patients is unlikely to be beneficial. For a patient with no known PV in the family who meet genetic testing criteria, a cancer gene panel should be considered. However, guidance on which MGPT to order is lacking in professional guidelines and often left to the discretion of the provider and patient. Utilization of a “disease specific panel” (i.e., a panel of genes related to CRC risk) is useful for understanding the cause of the patient’s disease and guiding treatment, screening, and cascade testing while minimizing the number of VUS identified. Pan-cancer gene panels increase diagnostic yield, but include identification of PV in genes unrelated to phenotype or more poorly described risk and management recommendations and have a higher rate of VUS.

Finally, the cost of MGPT to the health care system needs to be considered. Despite dropping costs, the process of genetic counseling and testing remains expensive and will rise if and when testing is expanded to all patients with CRC.

MGPT is not for everyone.
 

References

1. Yurgelun MB et al. J Clin Oncol. 2017;35:1086-95.

2. Pearlman R et al. JAMA Oncol. 2017 Apr 01;3(4):464-71.
 

Dr. Burke is with the department of gastroenterology, hepatology, and nutrition, Sanford R. Weiss Center for Hereditary Colorectal Neoplasia, Digestive Disease and Surgical Institute, Cleveland Clinic; Ms. Leach is with the Center for Personalized Genetic Healthcare, Sanford R. Weiss Center for Hereditary Colorectal Neoplasia, Digestive Disease and Surgical Institute, Cleveland Clinic. Dr. Burke has no conflicts of interest, Ms. Leach serves on the advisory board of Invitae.