Evidence-Based Reviews

Obesity and overweight, with or without metabolic dysregulation, pose vexing problems for many patients with mood, anxiety, or psychotic disorders. More than one-half of individuals with severe mental illnesses are obese or overweight,¹ resulting from multiple factors that may include psychiatric symptoms (eg, anergia and hyperphagia), poor dietary choices, sedentary lifestyle, underlying inflammatory processes, medical comorbidities, and iatrogenic consequences of certain medications. Unfortunately, numerous psychotropic medications can increase weight and appetite due to a variety of mechanisms, including antihistaminergic effects, direct appetite-stimulating effects, and proclivities to cause insulin resistance. While individual agents can vary, a recent review identified an overall 2-fold increased risk for rapid, significant weight gain during treatment with antipsychotics as a class.² In addition to lifestyle modifications (diet and exercise), many pharmacologic strategies have been proposed to counter iatrogenic weight gain, including appetite suppressants (eg, pro-dopaminergic agents such as phentermine, stimulants, and amantadine), pro-anorectant anticonvulsants (eg, topiramate or zonisamide), opioid receptor antagonists (eg, olanzapine/samidorphan or naltrexone) and oral hypoglycemics such as metformin. However, the magnitude of impact for most of these agents to reverse iatrogenic weight gain tends to be modest, particularly once significant weight gain (ie, ≥7% of initial body weight) has already occurred.

Pharmacologic strategies to modulate or enhance the effects of insulin hold particular importance for combatting psychotropic-associated weight gain. Insulin transports glucose from the intravascular space to end organs for fuel consumption; to varying degrees, second-generation antipsychotics (SGAs) and some other psychotropic medications can cause insulin resistance. This in turn leads to excessive storage of under­utilized glucose in the liver (glycogenesis), the potential for developing fatty liver (ie, nonalcoholic steatohepatitis), and conversion of excess carbohydrates to fatty acids and triglycerides, with subsequent storage in adipose tissue. Medications that can enhance the activity of insulin (so-called incretin mimetics) can help to overcome insulin resistance caused by SGAs (and potentially by other psychotropic medications) and essentially lead to weight loss through enhanced “fuel efficiency.”

Metformin, typically dosed up to 1,000 mg twice daily with meals, has increasingly become recognized as a first-line strategy to attenuate weight gain and glycemic dysregulation from SGAs via its ability to reduce insulin resistance. Yet meta-analyses have shown that although results are significantly better than placebo, overall long-term weight loss from metformin alone tends to be rather modest (<4 kg) and associated with a reduction in body mass index (BMI) of only approximately 1 point.³ Psychiatrists (and other clinicians who prescribe psychotropic medications that can cause weight gain or metabolic dysregulation) therefore need to become familiar with alternative or adjunctive weight loss options. The use of a relatively new class of incretin mimetics called glucagon-like peptide 1 (GLP-1) agonists (Table) has been associated with profound and often dramatic weight loss and improvement of glycemic parameters in patients with obesity and glycemic dysregulation.

What are GLP-1 agonists?

GLP-1 is a hormone secreted by L cells in the intestinal mucosa in response to food. GLP-1 agonists reduce blood sugar by increasing insulin secretion, decreasing glucagon release (thus downregulating further increases in blood sugar), and reducing insulin resistance. GLP-1 agonists also reduce appetite by directly stimulating the satiety center and slowing gastric emptying and GI motility. In addition to GLP-1 agonism, some medications in this family (notably tirzepatide) also agonize a second hormone, glucose-dependent insulinotropic polypeptide, which can further induce insulin secretion as well as decrease stomach acid secretion, potentially delivering an even more substantial reduction in appetite and weight.

Routes of administration and FDA indications

Due to limited bioavailability, most GLP-1 agonists require subcutaneous (SC) injections (the sole exception is the Rybelsus brand of semaglutide, which comes in a daily pill form). Most are FDA-approved not specifically for weight loss but for patients with type 2 diabetes (defined as a hemoglobin A1C ≥6.5% or a fasting blood glucose level ≥126 mg/dL). Weight loss represents a secondary outcome for GLP-1 agonists FDA-approved for glycemic control in patients with type 2 diabetes. The 2 current exceptions to this classification are the Wegovy brand of semaglutide (ie, dosing of 2.4 mg) and the Saxenda brand of liraglutide, both of which carry FDA indications for chronic weight management alone (when paired with dietary and lifestyle modification) in individuals who are obese (BMI >30 kg/m²) regardless of the presence or absence of diabetes, or for persons who are overweight (BMI >27 kg/m²) and have ≥1 weight-related comorbid condition (eg, hypertension, type 2 diabetes, or dyslipidemia). Although patients at risk for diabetes (ie, prediabetes, defined as a hemoglobin A1C 5.7% to 6.4% or a fasting blood glucose level 100 to 125 mg/dL) were included in FDA registration trials of Saxenda or Wegovy, prediabetes is not an FDA indication for any GLP-1 agonist.

Data in weight loss

Most of the existing empirical data on weight loss with GLP-1 agonists come from studies of individuals who are overweight or obese, with or without type 2 diabetes, rather than from studies using these agents to counteract iatrogenic weight gain. In a retrospective cohort study of patients with type 2 diabetes, coadministration with serotonergic antidepressants (eg, citalopram/escitalopram) was associated with attenuation of the weight loss effects of GLP-1 agonists.⁴

Liraglutide currently is the sole GLP-1 agonist studied for treating SGA-associated weight gain. A 16-week randomized trial compared once-daily SC injected liraglutide vs placebo in patients with schizophrenia who incurred weight gain and prediabetes after taking olanzapine or clozapine.⁵ Significantly more patients taking liraglutide than placebo developed normal glucose tolerance (64% vs 16%), and body weight decreased by a mean of 5.3 kg.

Continue to: In studies of semaglutide...

In studies of semaglutide for overweight/obese patients with type 2 diabetes or prediabetes, clinical trials of oral semaglutide (Rybelsus) found a mean weight loss over 26 weeks of -1.0 kg with dosing at 7 mg/d and -2.6 kg with dosing at 14 mg/d.⁶ A 68-week placebo-controlled trial of semaglutide (dosed at 2.4 mg SC weekly) for overweight/obese adults who did not have diabetes yielded a -15.3 kg weight loss (vs -2.6 kg with placebo); one-half of those who received semaglutide lost 15% of their initial body weight (Figure 1A and Figure 1B).⁷ Similar findings with semaglutide 2.4 mg SC weekly (Wegovy) were observed in overweight/obese adolescents, with 73% of participants losing ≥5% of their baseline weight.⁸ A comparative randomized trial in patients with type 2 diabetes also found modestly but significantly greater weight loss with oral semaglutide than with SC liraglutide.⁹

In a 72-week study of tirzepatide specifically for weight loss in nondiabetic patients who were overweight or obese, findings were especially dramatic (Figure 2A and Figure 2B).¹⁰ An overall 15% decrease in body weight was observed with 5 mg/week dosing alongside a 19.5% decrease in body weight with 10 mg/week dosing and a 20.9% weight reduction with 15 mg/week dosing.¹⁰ As noted in Figure 2B, the observed pattern of weight loss occurred along an exponential decay curve. Notably, a comparative study of tirzepatide vs once-weekly semaglutide (1 mg) in patients with type 2 diabetes¹¹ found significantly greater dose-dependent weight loss with tirzepatide than semaglutide (-1.9 kg at 5 mg, -3.6 kg at 10 mg, and -5.5 kg at 15 mg)—although the somewhat low dosing of semaglutide may have limited its optimal possible weight loss benefit.

Tolerability

Adverse effects with GLP-1 agonists are mainly gastrointestinal (eg, nausea, vomiting, abdominal pain, diarrhea, or constipation)^5-11 and generally transient. SC administration is performed in fatty tissue of the abdomen, thigh, or upper arm; site rotation is recommended to minimize injection site pain. All GLP-1 agonists carry manufacturers’ warning and precaution statements identifying the rare potential for acute pancreatitis, acute gall bladder disease, acute kidney injury, and hypoglycemia. Animal studies also have suggested an increased, dose-dependent risk for thyroid C-cell tumors with GLP-1 agonists; this has not been observed in human trials, although postmarketing pharmacovigilance reports have identified cases of medullary thyroid carcinoma in patients who took liraglutide. A manufacturer’s boxed warning indicates that a personal or family history of medullary carcinoma of the thyroid poses a contraindication for taking semaglutide, liraglutide, or tirzepatide.

Initial evidence prompts additional questions

GLP-1 agonists represent an emerging class of novel agents that can modulate glycemic dysregulation and overweight/obesity, often with dramatic results whose magnitude rivals the efficacy of bariatric surgery. Once-weekly formulations of semaglutide (Wegovy) and daily liraglutide (Saxenda) are FDA-approved for weight loss in patients who are overweight or obese while other existing formulations are approved solely for patients with type 2 diabetes, although it is likely that broader indications for weight loss (regardless of glycemic status) are forthcoming. Targeted use of GLP-1 agonists to counteract SGA-associated weight gain is supported by a handful of preliminary reports, with additional studies likely to come. Unanswered questions include:

• When should GLP-1 agonists be considered within a treatment algorithm for iatrogenic weight gain relative to other antidote strategies such as metformin or appetite-suppressing anticonvulsants?
• How effective might GLP-1 agonists be for iatrogenic weight gain from non-SGA psychotropic medications, such as serotonergic antidepressants?
• When and how can GLP-1 agonists be safely coprescribed with other nonincretin mimetic weight loss medications?
• When should psychiatrists prescribe GLP-1 agonists, or do so collaboratively with primary care physicians or endocrinologists, particularly in patients with metabolic syndrome?

Followers of the rapidly emerging literature in this area will likely find themselves best positioned to address these and other questions about optimal management of psychotropic-induced weight gain for the patients they treat.

Bottom Line

The use of glucagon-like peptide 1 (GLP-1) agonists, a relatively new class of incretin mimetics, has been associated with profound and often dramatic weight loss and improvement of glycemic parameters in patients with obesity and glycemic dysregulation. Preliminary reports support the potential targeted use of GLP-1 agonists to counteract weight gain associated with second-generation antipsychotics.

Related Resources

• Singh F, Allen A, Ianni A. Managing metabolic syndrome in patients with schizophrenia. Current Psychiatry. 2020;19(12):20-24,26. doi:10.12788/cp.0064
• Ard J, Fitch A, Fruh S, et al. Weight loss and maintenance related to the mechanism of action of glucagon-like peptide 1 receptor agonists. Adv Ther. 2021;38(6):2821- 2839. doi:10.1007/s12325-021-01710-0

Drug Brand Names

Amantadine • Gocovri
Citalopram • Celexa
Clozapine • Clozaril
Escitalopram • Lexapro
Liraglutide • Victoza, Saxenda
Metformin • Glucophage
Naltrexone • ReVia
Olanzapine • Zyprexa
Olanzapine/samidorphan • Lybalvi
Phentermine • Ionamin
Semaglutide • Rybelsus, Ozempic, Wegovy
Tirzepatide • Mounjaro
Topiramate • Topamax
Zonisamide • Zonegran

Obesity and overweight, with or without metabolic dysregulation, pose vexing problems for many patients with mood, anxiety, or psychotic disorders. More than one-half of individuals with severe mental illnesses are obese or overweight,¹ resulting from multiple factors that may include psychiatric symptoms (eg, anergia and hyperphagia), poor dietary choices, sedentary lifestyle, underlying inflammatory processes, medical comorbidities, and iatrogenic consequences of certain medications. Unfortunately, numerous psychotropic medications can increase weight and appetite due to a variety of mechanisms, including antihistaminergic effects, direct appetite-stimulating effects, and proclivities to cause insulin resistance. While individual agents can vary, a recent review identified an overall 2-fold increased risk for rapid, significant weight gain during treatment with antipsychotics as a class.² In addition to lifestyle modifications (diet and exercise), many pharmacologic strategies have been proposed to counter iatrogenic weight gain, including appetite suppressants (eg, pro-dopaminergic agents such as phentermine, stimulants, and amantadine), pro-anorectant anticonvulsants (eg, topiramate or zonisamide), opioid receptor antagonists (eg, olanzapine/samidorphan or naltrexone) and oral hypoglycemics such as metformin. However, the magnitude of impact for most of these agents to reverse iatrogenic weight gain tends to be modest, particularly once significant weight gain (ie, ≥7% of initial body weight) has already occurred.

Pharmacologic strategies to modulate or enhance the effects of insulin hold particular importance for combatting psychotropic-associated weight gain. Insulin transports glucose from the intravascular space to end organs for fuel consumption; to varying degrees, second-generation antipsychotics (SGAs) and some other psychotropic medications can cause insulin resistance. This in turn leads to excessive storage of under­utilized glucose in the liver (glycogenesis), the potential for developing fatty liver (ie, nonalcoholic steatohepatitis), and conversion of excess carbohydrates to fatty acids and triglycerides, with subsequent storage in adipose tissue. Medications that can enhance the activity of insulin (so-called incretin mimetics) can help to overcome insulin resistance caused by SGAs (and potentially by other psychotropic medications) and essentially lead to weight loss through enhanced “fuel efficiency.”

Metformin, typically dosed up to 1,000 mg twice daily with meals, has increasingly become recognized as a first-line strategy to attenuate weight gain and glycemic dysregulation from SGAs via its ability to reduce insulin resistance. Yet meta-analyses have shown that although results are significantly better than placebo, overall long-term weight loss from metformin alone tends to be rather modest (<4 kg) and associated with a reduction in body mass index (BMI) of only approximately 1 point.³ Psychiatrists (and other clinicians who prescribe psychotropic medications that can cause weight gain or metabolic dysregulation) therefore need to become familiar with alternative or adjunctive weight loss options. The use of a relatively new class of incretin mimetics called glucagon-like peptide 1 (GLP-1) agonists (Table) has been associated with profound and often dramatic weight loss and improvement of glycemic parameters in patients with obesity and glycemic dysregulation.

What are GLP-1 agonists?

GLP-1 is a hormone secreted by L cells in the intestinal mucosa in response to food. GLP-1 agonists reduce blood sugar by increasing insulin secretion, decreasing glucagon release (thus downregulating further increases in blood sugar), and reducing insulin resistance. GLP-1 agonists also reduce appetite by directly stimulating the satiety center and slowing gastric emptying and GI motility. In addition to GLP-1 agonism, some medications in this family (notably tirzepatide) also agonize a second hormone, glucose-dependent insulinotropic polypeptide, which can further induce insulin secretion as well as decrease stomach acid secretion, potentially delivering an even more substantial reduction in appetite and weight.

Routes of administration and FDA indications

Due to limited bioavailability, most GLP-1 agonists require subcutaneous (SC) injections (the sole exception is the Rybelsus brand of semaglutide, which comes in a daily pill form). Most are FDA-approved not specifically for weight loss but for patients with type 2 diabetes (defined as a hemoglobin A1C ≥6.5% or a fasting blood glucose level ≥126 mg/dL). Weight loss represents a secondary outcome for GLP-1 agonists FDA-approved for glycemic control in patients with type 2 diabetes. The 2 current exceptions to this classification are the Wegovy brand of semaglutide (ie, dosing of 2.4 mg) and the Saxenda brand of liraglutide, both of which carry FDA indications for chronic weight management alone (when paired with dietary and lifestyle modification) in individuals who are obese (BMI >30 kg/m²) regardless of the presence or absence of diabetes, or for persons who are overweight (BMI >27 kg/m²) and have ≥1 weight-related comorbid condition (eg, hypertension, type 2 diabetes, or dyslipidemia). Although patients at risk for diabetes (ie, prediabetes, defined as a hemoglobin A1C 5.7% to 6.4% or a fasting blood glucose level 100 to 125 mg/dL) were included in FDA registration trials of Saxenda or Wegovy, prediabetes is not an FDA indication for any GLP-1 agonist.

Data in weight loss

Most of the existing empirical data on weight loss with GLP-1 agonists come from studies of individuals who are overweight or obese, with or without type 2 diabetes, rather than from studies using these agents to counteract iatrogenic weight gain. In a retrospective cohort study of patients with type 2 diabetes, coadministration with serotonergic antidepressants (eg, citalopram/escitalopram) was associated with attenuation of the weight loss effects of GLP-1 agonists.⁴

Liraglutide currently is the sole GLP-1 agonist studied for treating SGA-associated weight gain. A 16-week randomized trial compared once-daily SC injected liraglutide vs placebo in patients with schizophrenia who incurred weight gain and prediabetes after taking olanzapine or clozapine.⁵ Significantly more patients taking liraglutide than placebo developed normal glucose tolerance (64% vs 16%), and body weight decreased by a mean of 5.3 kg.

Continue to: In studies of semaglutide...

In studies of semaglutide for overweight/obese patients with type 2 diabetes or prediabetes, clinical trials of oral semaglutide (Rybelsus) found a mean weight loss over 26 weeks of -1.0 kg with dosing at 7 mg/d and -2.6 kg with dosing at 14 mg/d.⁶ A 68-week placebo-controlled trial of semaglutide (dosed at 2.4 mg SC weekly) for overweight/obese adults who did not have diabetes yielded a -15.3 kg weight loss (vs -2.6 kg with placebo); one-half of those who received semaglutide lost 15% of their initial body weight (Figure 1A and Figure 1B).⁷ Similar findings with semaglutide 2.4 mg SC weekly (Wegovy) were observed in overweight/obese adolescents, with 73% of participants losing ≥5% of their baseline weight.⁸ A comparative randomized trial in patients with type 2 diabetes also found modestly but significantly greater weight loss with oral semaglutide than with SC liraglutide.⁹

In a 72-week study of tirzepatide specifically for weight loss in nondiabetic patients who were overweight or obese, findings were especially dramatic (Figure 2A and Figure 2B).¹⁰ An overall 15% decrease in body weight was observed with 5 mg/week dosing alongside a 19.5% decrease in body weight with 10 mg/week dosing and a 20.9% weight reduction with 15 mg/week dosing.¹⁰ As noted in Figure 2B, the observed pattern of weight loss occurred along an exponential decay curve. Notably, a comparative study of tirzepatide vs once-weekly semaglutide (1 mg) in patients with type 2 diabetes¹¹ found significantly greater dose-dependent weight loss with tirzepatide than semaglutide (-1.9 kg at 5 mg, -3.6 kg at 10 mg, and -5.5 kg at 15 mg)—although the somewhat low dosing of semaglutide may have limited its optimal possible weight loss benefit.

Tolerability

Adverse effects with GLP-1 agonists are mainly gastrointestinal (eg, nausea, vomiting, abdominal pain, diarrhea, or constipation)^5-11 and generally transient. SC administration is performed in fatty tissue of the abdomen, thigh, or upper arm; site rotation is recommended to minimize injection site pain. All GLP-1 agonists carry manufacturers’ warning and precaution statements identifying the rare potential for acute pancreatitis, acute gall bladder disease, acute kidney injury, and hypoglycemia. Animal studies also have suggested an increased, dose-dependent risk for thyroid C-cell tumors with GLP-1 agonists; this has not been observed in human trials, although postmarketing pharmacovigilance reports have identified cases of medullary thyroid carcinoma in patients who took liraglutide. A manufacturer’s boxed warning indicates that a personal or family history of medullary carcinoma of the thyroid poses a contraindication for taking semaglutide, liraglutide, or tirzepatide.

Initial evidence prompts additional questions

GLP-1 agonists represent an emerging class of novel agents that can modulate glycemic dysregulation and overweight/obesity, often with dramatic results whose magnitude rivals the efficacy of bariatric surgery. Once-weekly formulations of semaglutide (Wegovy) and daily liraglutide (Saxenda) are FDA-approved for weight loss in patients who are overweight or obese while other existing formulations are approved solely for patients with type 2 diabetes, although it is likely that broader indications for weight loss (regardless of glycemic status) are forthcoming. Targeted use of GLP-1 agonists to counteract SGA-associated weight gain is supported by a handful of preliminary reports, with additional studies likely to come. Unanswered questions include:

• When should GLP-1 agonists be considered within a treatment algorithm for iatrogenic weight gain relative to other antidote strategies such as metformin or appetite-suppressing anticonvulsants?
• How effective might GLP-1 agonists be for iatrogenic weight gain from non-SGA psychotropic medications, such as serotonergic antidepressants?
• When and how can GLP-1 agonists be safely coprescribed with other nonincretin mimetic weight loss medications?
• When should psychiatrists prescribe GLP-1 agonists, or do so collaboratively with primary care physicians or endocrinologists, particularly in patients with metabolic syndrome?

Followers of the rapidly emerging literature in this area will likely find themselves best positioned to address these and other questions about optimal management of psychotropic-induced weight gain for the patients they treat.

Bottom Line

The use of glucagon-like peptide 1 (GLP-1) agonists, a relatively new class of incretin mimetics, has been associated with profound and often dramatic weight loss and improvement of glycemic parameters in patients with obesity and glycemic dysregulation. Preliminary reports support the potential targeted use of GLP-1 agonists to counteract weight gain associated with second-generation antipsychotics.

Related Resources

• Singh F, Allen A, Ianni A. Managing metabolic syndrome in patients with schizophrenia. Current Psychiatry. 2020;19(12):20-24,26. doi:10.12788/cp.0064
• Ard J, Fitch A, Fruh S, et al. Weight loss and maintenance related to the mechanism of action of glucagon-like peptide 1 receptor agonists. Adv Ther. 2021;38(6):2821- 2839. doi:10.1007/s12325-021-01710-0

Drug Brand Names

Amantadine • Gocovri
Citalopram • Celexa
Clozapine • Clozaril
Escitalopram • Lexapro
Liraglutide • Victoza, Saxenda
Metformin • Glucophage
Naltrexone • ReVia
Olanzapine • Zyprexa
Olanzapine/samidorphan • Lybalvi
Phentermine • Ionamin
Semaglutide • Rybelsus, Ozempic, Wegovy
Tirzepatide • Mounjaro
Topiramate • Topamax
Zonisamide • Zonegran

Obesity and overweight, with or without metabolic dysregulation, pose vexing problems for many patients with mood, anxiety, or psychotic disorders. More than one-half of individuals with severe mental illnesses are obese or overweight,¹ resulting from multiple factors that may include psychiatric symptoms (eg, anergia and hyperphagia), poor dietary choices, sedentary lifestyle, underlying inflammatory processes, medical comorbidities, and iatrogenic consequences of certain medications. Unfortunately, numerous psychotropic medications can increase weight and appetite due to a variety of mechanisms, including antihistaminergic effects, direct appetite-stimulating effects, and proclivities to cause insulin resistance. While individual agents can vary, a recent review identified an overall 2-fold increased risk for rapid, significant weight gain during treatment with antipsychotics as a class.² In addition to lifestyle modifications (diet and exercise), many pharmacologic strategies have been proposed to counter iatrogenic weight gain, including appetite suppressants (eg, pro-dopaminergic agents such as phentermine, stimulants, and amantadine), pro-anorectant anticonvulsants (eg, topiramate or zonisamide), opioid receptor antagonists (eg, olanzapine/samidorphan or naltrexone) and oral hypoglycemics such as metformin. However, the magnitude of impact for most of these agents to reverse iatrogenic weight gain tends to be modest, particularly once significant weight gain (ie, ≥7% of initial body weight) has already occurred.

Pharmacologic strategies to modulate or enhance the effects of insulin hold particular importance for combatting psychotropic-associated weight gain. Insulin transports glucose from the intravascular space to end organs for fuel consumption; to varying degrees, second-generation antipsychotics (SGAs) and some other psychotropic medications can cause insulin resistance. This in turn leads to excessive storage of under­utilized glucose in the liver (glycogenesis), the potential for developing fatty liver (ie, nonalcoholic steatohepatitis), and conversion of excess carbohydrates to fatty acids and triglycerides, with subsequent storage in adipose tissue. Medications that can enhance the activity of insulin (so-called incretin mimetics) can help to overcome insulin resistance caused by SGAs (and potentially by other psychotropic medications) and essentially lead to weight loss through enhanced “fuel efficiency.”

Metformin, typically dosed up to 1,000 mg twice daily with meals, has increasingly become recognized as a first-line strategy to attenuate weight gain and glycemic dysregulation from SGAs via its ability to reduce insulin resistance. Yet meta-analyses have shown that although results are significantly better than placebo, overall long-term weight loss from metformin alone tends to be rather modest (<4 kg) and associated with a reduction in body mass index (BMI) of only approximately 1 point.³ Psychiatrists (and other clinicians who prescribe psychotropic medications that can cause weight gain or metabolic dysregulation) therefore need to become familiar with alternative or adjunctive weight loss options. The use of a relatively new class of incretin mimetics called glucagon-like peptide 1 (GLP-1) agonists (Table) has been associated with profound and often dramatic weight loss and improvement of glycemic parameters in patients with obesity and glycemic dysregulation.

What are GLP-1 agonists?

GLP-1 is a hormone secreted by L cells in the intestinal mucosa in response to food. GLP-1 agonists reduce blood sugar by increasing insulin secretion, decreasing glucagon release (thus downregulating further increases in blood sugar), and reducing insulin resistance. GLP-1 agonists also reduce appetite by directly stimulating the satiety center and slowing gastric emptying and GI motility. In addition to GLP-1 agonism, some medications in this family (notably tirzepatide) also agonize a second hormone, glucose-dependent insulinotropic polypeptide, which can further induce insulin secretion as well as decrease stomach acid secretion, potentially delivering an even more substantial reduction in appetite and weight.

Routes of administration and FDA indications

Due to limited bioavailability, most GLP-1 agonists require subcutaneous (SC) injections (the sole exception is the Rybelsus brand of semaglutide, which comes in a daily pill form). Most are FDA-approved not specifically for weight loss but for patients with type 2 diabetes (defined as a hemoglobin A1C ≥6.5% or a fasting blood glucose level ≥126 mg/dL). Weight loss represents a secondary outcome for GLP-1 agonists FDA-approved for glycemic control in patients with type 2 diabetes. The 2 current exceptions to this classification are the Wegovy brand of semaglutide (ie, dosing of 2.4 mg) and the Saxenda brand of liraglutide, both of which carry FDA indications for chronic weight management alone (when paired with dietary and lifestyle modification) in individuals who are obese (BMI >30 kg/m²) regardless of the presence or absence of diabetes, or for persons who are overweight (BMI >27 kg/m²) and have ≥1 weight-related comorbid condition (eg, hypertension, type 2 diabetes, or dyslipidemia). Although patients at risk for diabetes (ie, prediabetes, defined as a hemoglobin A1C 5.7% to 6.4% or a fasting blood glucose level 100 to 125 mg/dL) were included in FDA registration trials of Saxenda or Wegovy, prediabetes is not an FDA indication for any GLP-1 agonist.

Data in weight loss

Most of the existing empirical data on weight loss with GLP-1 agonists come from studies of individuals who are overweight or obese, with or without type 2 diabetes, rather than from studies using these agents to counteract iatrogenic weight gain. In a retrospective cohort study of patients with type 2 diabetes, coadministration with serotonergic antidepressants (eg, citalopram/escitalopram) was associated with attenuation of the weight loss effects of GLP-1 agonists.⁴

Liraglutide currently is the sole GLP-1 agonist studied for treating SGA-associated weight gain. A 16-week randomized trial compared once-daily SC injected liraglutide vs placebo in patients with schizophrenia who incurred weight gain and prediabetes after taking olanzapine or clozapine.⁵ Significantly more patients taking liraglutide than placebo developed normal glucose tolerance (64% vs 16%), and body weight decreased by a mean of 5.3 kg.

Continue to: In studies of semaglutide...

In studies of semaglutide for overweight/obese patients with type 2 diabetes or prediabetes, clinical trials of oral semaglutide (Rybelsus) found a mean weight loss over 26 weeks of -1.0 kg with dosing at 7 mg/d and -2.6 kg with dosing at 14 mg/d.⁶ A 68-week placebo-controlled trial of semaglutide (dosed at 2.4 mg SC weekly) for overweight/obese adults who did not have diabetes yielded a -15.3 kg weight loss (vs -2.6 kg with placebo); one-half of those who received semaglutide lost 15% of their initial body weight (Figure 1A and Figure 1B).⁷ Similar findings with semaglutide 2.4 mg SC weekly (Wegovy) were observed in overweight/obese adolescents, with 73% of participants losing ≥5% of their baseline weight.⁸ A comparative randomized trial in patients with type 2 diabetes also found modestly but significantly greater weight loss with oral semaglutide than with SC liraglutide.⁹

In a 72-week study of tirzepatide specifically for weight loss in nondiabetic patients who were overweight or obese, findings were especially dramatic (Figure 2A and Figure 2B).¹⁰ An overall 15% decrease in body weight was observed with 5 mg/week dosing alongside a 19.5% decrease in body weight with 10 mg/week dosing and a 20.9% weight reduction with 15 mg/week dosing.¹⁰ As noted in Figure 2B, the observed pattern of weight loss occurred along an exponential decay curve. Notably, a comparative study of tirzepatide vs once-weekly semaglutide (1 mg) in patients with type 2 diabetes¹¹ found significantly greater dose-dependent weight loss with tirzepatide than semaglutide (-1.9 kg at 5 mg, -3.6 kg at 10 mg, and -5.5 kg at 15 mg)—although the somewhat low dosing of semaglutide may have limited its optimal possible weight loss benefit.

Tolerability

Adverse effects with GLP-1 agonists are mainly gastrointestinal (eg, nausea, vomiting, abdominal pain, diarrhea, or constipation)^5-11 and generally transient. SC administration is performed in fatty tissue of the abdomen, thigh, or upper arm; site rotation is recommended to minimize injection site pain. All GLP-1 agonists carry manufacturers’ warning and precaution statements identifying the rare potential for acute pancreatitis, acute gall bladder disease, acute kidney injury, and hypoglycemia. Animal studies also have suggested an increased, dose-dependent risk for thyroid C-cell tumors with GLP-1 agonists; this has not been observed in human trials, although postmarketing pharmacovigilance reports have identified cases of medullary thyroid carcinoma in patients who took liraglutide. A manufacturer’s boxed warning indicates that a personal or family history of medullary carcinoma of the thyroid poses a contraindication for taking semaglutide, liraglutide, or tirzepatide.

Initial evidence prompts additional questions

GLP-1 agonists represent an emerging class of novel agents that can modulate glycemic dysregulation and overweight/obesity, often with dramatic results whose magnitude rivals the efficacy of bariatric surgery. Once-weekly formulations of semaglutide (Wegovy) and daily liraglutide (Saxenda) are FDA-approved for weight loss in patients who are overweight or obese while other existing formulations are approved solely for patients with type 2 diabetes, although it is likely that broader indications for weight loss (regardless of glycemic status) are forthcoming. Targeted use of GLP-1 agonists to counteract SGA-associated weight gain is supported by a handful of preliminary reports, with additional studies likely to come. Unanswered questions include:

• When should GLP-1 agonists be considered within a treatment algorithm for iatrogenic weight gain relative to other antidote strategies such as metformin or appetite-suppressing anticonvulsants?
• How effective might GLP-1 agonists be for iatrogenic weight gain from non-SGA psychotropic medications, such as serotonergic antidepressants?
• When and how can GLP-1 agonists be safely coprescribed with other nonincretin mimetic weight loss medications?
• When should psychiatrists prescribe GLP-1 agonists, or do so collaboratively with primary care physicians or endocrinologists, particularly in patients with metabolic syndrome?

Followers of the rapidly emerging literature in this area will likely find themselves best positioned to address these and other questions about optimal management of psychotropic-induced weight gain for the patients they treat.

Bottom Line

The use of glucagon-like peptide 1 (GLP-1) agonists, a relatively new class of incretin mimetics, has been associated with profound and often dramatic weight loss and improvement of glycemic parameters in patients with obesity and glycemic dysregulation. Preliminary reports support the potential targeted use of GLP-1 agonists to counteract weight gain associated with second-generation antipsychotics.

Related Resources

• Singh F, Allen A, Ianni A. Managing metabolic syndrome in patients with schizophrenia. Current Psychiatry. 2020;19(12):20-24,26. doi:10.12788/cp.0064
• Ard J, Fitch A, Fruh S, et al. Weight loss and maintenance related to the mechanism of action of glucagon-like peptide 1 receptor agonists. Adv Ther. 2021;38(6):2821- 2839. doi:10.1007/s12325-021-01710-0

Drug Brand Names

Amantadine • Gocovri
Citalopram • Celexa
Clozapine • Clozaril
Escitalopram • Lexapro
Liraglutide • Victoza, Saxenda
Metformin • Glucophage
Naltrexone • ReVia
Olanzapine • Zyprexa
Olanzapine/samidorphan • Lybalvi
Phentermine • Ionamin
Semaglutide • Rybelsus, Ozempic, Wegovy
Tirzepatide • Mounjaro
Topiramate • Topamax
Zonisamide • Zonegran

Catatonia is often difficult to identify and treat. The excited catatonia subtype can be particularly challenging to diagnose because it can present with symptoms similar to those seen in mania or psychosis. In this article, we present 3 cases of excited catatonia that illustrate how to identify it, how to treat the catatonia as well as the underlying pathology, and factors to consider during this process to mitigate the risk of adverse outcomes. We also outline a treatment algorithm we used for the 3 cases. Although we describe using this approach for patients with excited catatonia, it is generalizable to other types of catatonia.

Many causes, varying presentations

Catatonia is a psychomotor syndrome characterized by mutism, negativism, stereotypy, waxy flexibility, and other symptoms.¹ It is defined by the presence of ≥3 of the 12 symptoms listed in the Table.² Causes of catatonia include metabolic abnormalities, endocrine disorders, drug intoxication, neurodevelopmental disorders, medication adverse effects, psychosis, and mood disorders.^1,3

A subtype of this syndrome, excited catatonia, can present with restlessness, agitation, emotional lability, poor sleep, and altered mental status in addition to the more typical symptoms.^1,4 Because excited catatonia can resemble mania or psychosis, it is particularly challenging to identify the underlying disorder causing it and appropriate treatment. Fink et al⁴ discussed how clinicians have interpreted the different presentations of excited catatonia to gain insight into the underlying diagnosis. If the patient’s thought process appears disorganized, psychosis may be suspected.⁴ If the patient is delusional and grandiose, they may be manic, and when altered mental status dominates the presentation, delirium may be the culprit.⁴

Regardless of the underlying cause, the first step is to treat the catatonia. Benzodiazepines and electroconvulsive therapy (ECT) are the most well validated treatments for catatonia and have been used to treat excited catatonia.¹ Excited catatonia is often misdiagnosed and subsequently mistreated. In the following 3 cases, excited catatonia was successfully identified and treated using the same approach (Figure).

Case 1

Mr. A, age 27, has a history of bipolar I disorder. He was brought to the hospital by ambulance after being found to be yelling and acting belligerently, and he was admitted to the inpatient psychiatry unit for manic decompensation due to medication nonadherence. He was started on divalproex sodium 500 mg twice a day for mood stabilization, risperidone 1 mg twice a day for adjunct mood stabilization and psychosis, and lorazepam 1 mg 3 times a day for agitation. Mr. A exhibited odd behavior; he would take off his clothes in the hallway, run around the unit, and randomly yell at staff or to himself. At other times, he would stay silent, repeat the same statements, or oddly posture in the hallway for minutes at a time. These behaviors were seen primarily in the hour or 2 preceding lorazepam administration and improved after he received lorazepam.

Mr. A’s treating team completed the Bush-Francis Catatonia Rating Scale (BFCRS), which yielded a positive catatonia screen of 7/14. As a result, divalproex sodium and risperidone were held, and lorazepam was increased to 2 mg twice a day.

After several days, Mr. A was no longer acting oddly and was able to speak more spontaneously; however, he began to exhibit overt signs of mania. He would speak rapidly and make grandiose claims about managing millions of dollars as the CEO of a famous company. Divalproex sodium was restarted at 500 mg twice a day and increased to 500 mg 3 times a day for mood stabilization. Mr. A continued to receive lorazepam 2 mg 3 times a day for catatonia, and risperidone was restarted at 1 mg twice a day to more effectively target his manic symptoms. Risperidone was increased to 2 mg twice a day. After this change, Mr. A’s grandiosity dissipated, his speech normalized, and his thought process became organized. He was discharged on lorazepam 2 mg 3 times a day, divalproex sodium 500 mg 3 times a day, and risperidone 2 mg twice a day. Mr. A’s length of stay (LOS) for this admission was 11 days.

Continue to: Case 2

Case 2

Mr. B, age 49, presented with irritability and odd posturing. He has a history of schizoaffective disorder, bipolar type for which he was receiving a maintenance regimen of lithium 600 mg/d at bedtime and risperidone 2 mg/d at bedtime. He had multiple previous psychiatric admissions for catatonia. On this admission, Mr. B was irritable and difficult to redirect. He yelled at staff members and had a stiff gait. The BFCRS yielded a positive screening score of 3/14 and a severity score of 8/23. As a result, the treatment team conducted a lorazepam challenge.

After Mr. B received lorazepam 1 mg IM, his thought organization and irritability improved, which allowed him to have a coherent conversation with the interviewer. His gait stiffness also improved. His risperidone and lithium were held, and oral lorazepam 1 mg 3 times a day was started for catatonia. Lorazepam was gradually increased to 4 mg 3 times a day. Mr. B became euthymic and redirectable, and had an improved gait. However, he was also tangential and hyperverbal; these symptoms were indicative of the underlying mania that precipitated his catatonia.

Divalproex sodium extended release (ER) was started and increased to 1,500 mg/d at bedtime for mood stabilization. Lithium was restarted and increased to 300 mg twice a day for adjunct mood stabilization. Risperidone was not restarted. Toward the end of his admission, Mr. B was noted to be overly sedated, so the lorazepam dosage was decreased. He was discharged on lorazepam 2 mg 3 times a day, divalproex sodium ER 1,500 mg/d at bedtime, and lithium 300 mg twice a day. At discharge, Mr. B was calm and euthymic, with a linear thought process. His LOS was 25 days.

Case 3

Mr. C, age 62, presented to the emergency department (ED) because he had exhibited erratic behavior and had not slept for the past week. He has a history of bipolar I disorder, hypothyroidism, diabetes, and hypertension. For many years, he had been stable on divalproex sodium ER 2,500 mg/d at bedtime for mood stabilization and clozapine 100 mg/d at bedtime for adjunct mood stabilization and psychosis. In the ED, Mr. C was irritable, distractible, and tangential. On admission, he was speaking slowly with increased speech latency in response to questions, exhibiting stereotypy, repeating statements over and over, and walking very slowly.

The BFCRS yielded a positive screening score of 5/14 and a severity score of 10/23. Lorazepam 1 mg IM was administered. After 15 minutes, Mr. C’s speech, gait, and distractibility improved. As a result, clozapine and divalproex sodium were held, and he was started on oral lorazepam 1 mg 3 times a day. After several days, Mr. C was speaking fluently and no longer exhibiting stereotypy or having outbursts where he would make repetitive statements. However, he was tangential and irritable at times, which were signs of his underlying mania. Divalproex sodium ER was restarted at 250 mg/d at bedtime for mood stabilization and gradually increased to 2,500 mg/d at bedtime. Clozapine was also restarted at 25 mg/d at bedtime and gradually increased to 200 mg/d at bedtime. The lorazepam was gradually tapered and discontinued over the course of 3 weeks due to oversedation.

Continue to: At discharge...

At discharge, Mr. C was euthymic, calm, linear, and goal-directed. He was discharged on divalproex sodium ER 2,500 mg/d at bedtime and clozapine 200 mg/d at bedtime. His LOS for this admission was 22 days.

A stepwise approach can improve outcomes

The Figure outlines the method we used to manage excited catatonia in these 3 cases. Each of these patients exhibited signs of excited catatonia, but because those symptoms were nearly identical to those of mania, it was initially difficult to identify catatonia. Excited catatonia was suspected after more typical catatonic symptoms—such as a stiff gait, slowed speech, and stereotypy—were observed. The BFCRS was completed to get an objective measure of the likelihood that the patient was catatonic. In all 3 cases, the BFCRS resulted in a positive screen for catatonia. Following this, the patients described in Case 2 and Case 3 received a lorazepam challenge, which confirmed their catatonia. No lorazepam challenge was performed in Case 1 because the patient was already receiving lorazepam when the BFCRS was completed. Although most catatonic patients will respond to a lorazepam challenge, not all will. Therefore, clinicians should maintain some degree of suspicion for catatonia if a patient has a positive screen on the BFCRS but a negative lorazepam challenge.

In all 3 cases, after catatonia was confirmed, the patient’s psychotropic medications were discontinued. In all 3 cases, the antipsychotic was held to prevent progression to neuroleptic malignant syndrome (NMS) or malignant catatonia. Rasmussen et al³ found that 3.6% of the catatonic patients in their sample who were treated with antipsychotics developed NMS. A review of prospective studies looking at patients treated with antipsychotics found the incidence of NMS was .07% to 1.8%.⁵ Because NMS is often clinically indistinguishable from malignant catatonia,^4,6 this incidence of NMS may have represented an increased incidence in malignant catatonia.

In all 3 cases, the mood stabilizer was held to prevent it from complicating the clinical picture. Discontinuing the mood stabilizer and focusing on treating the catatonia before targeting the underlying mania increased the likelihood of differentiating the patient’s catatonic symptoms from manic symptoms. This resulted in more precise medication selection and titration by allowing us to identify the specific symptoms that were being targeted by each medication.

Oral lorazepam was prescribed to target catatonia in all 3 cases, and the dosage was gradually increased until symptoms began to resolve. As the catatonia resolved, the manic symptoms became more easily identifiable, and at this point a mood stabilizer was started and titrated to a therapeutic dose to target the mania. In Case 1 and Case 3, the antipsychotic was restarted to treat the mania more effectively. It was not restarted in Case 2 because the patient’s mania was effectively being managed by 2 mood stabilizers. The risks and benefits of starting an antipsychotic in a catatonic or recently catatonic patient should be carefully considered. In the 2 cases where the antipsychotic was restarted, the patients were closely monitored, and there were no signs of NMS or malignant catatonia.

Continue to: As discharge approached...

As discharge approached, the dosages of oral lorazepam were reevaluated. Catatonic patients can typically tolerate high doses of benzodiazepines without becoming overly sedated, but each patient has a different threshold at which the dosage causes oversedation. In all 3 patients, lorazepam was initially titrated to a dose that treated their catatonic symptoms without causing intolerable sedation. In Case 2 and Case 3, as the catatonia began to resolve, the patients became increasingly sedated on their existing lorazepam dosage, so it was decreased. Because the patient in Case 1 did not become overly sedated, his lorazepam dosage did not need to be reduced.

For 2 of these patients, our approach resulted in a shorter LOS compared to their previous hospitalizations. The LOS in Case 2 was 25 days; 5 years earlier, he had a 49-day LOS for mania and catatonia. During the past admission, the identification and treatment of the catatonia was delayed, which resulted in the patient requiring multiple transfers to the medical unit for unstable vital signs. The LOS in Case 3 was 22 days; 6 months prior to this admission, the patient had 2 psychiatric admissions that totaled 37 days. Although the patient’s presentation in the 2 previous admissions was similar to his presentation as described in Case 3, catatonia had not been identified or treated in either admission. Since his catatonia and mania were treated in Case 3, he has not required a readmission. The patient in Case 1 was previously hospitalized, but information about the LOS of these admissions was not available. These results suggest that early identification and treatment of catatonia via the approach we used can improve patient outcomes.

Bottom Line

Excited catatonia can be challenging to diagnose and treat because it can present with symptoms similar to those seen in mania or psychosis. We describe 3 cases in which we used a stepwise approach to optimize treatment and improve outcomes for patients with excited catatonia. This approach may work equally well for other catatonia subtypes.

Related Resources

• Dubovsky SL, Dubovsky AN. Catatonia: how to identify and treat it. Current Psychiatry. 2018;17(8):16-26.
• Crouse EL, Joel B. Moran JB. Catatonia: recognition, management, and prevention of complications. Current Psychiatry. 2018;17(12):45-49.

Drug Brand Names

Clozapine • Clozaril
Lithium • Eskalith, Lithobid
Lorazepam • Ativan
Risperidone • Risperdal
Divalproex sodium • Depakote

Catatonia is often difficult to identify and treat. The excited catatonia subtype can be particularly challenging to diagnose because it can present with symptoms similar to those seen in mania or psychosis. In this article, we present 3 cases of excited catatonia that illustrate how to identify it, how to treat the catatonia as well as the underlying pathology, and factors to consider during this process to mitigate the risk of adverse outcomes. We also outline a treatment algorithm we used for the 3 cases. Although we describe using this approach for patients with excited catatonia, it is generalizable to other types of catatonia.

Many causes, varying presentations

Catatonia is a psychomotor syndrome characterized by mutism, negativism, stereotypy, waxy flexibility, and other symptoms.¹ It is defined by the presence of ≥3 of the 12 symptoms listed in the Table.² Causes of catatonia include metabolic abnormalities, endocrine disorders, drug intoxication, neurodevelopmental disorders, medication adverse effects, psychosis, and mood disorders.^1,3

A subtype of this syndrome, excited catatonia, can present with restlessness, agitation, emotional lability, poor sleep, and altered mental status in addition to the more typical symptoms.^1,4 Because excited catatonia can resemble mania or psychosis, it is particularly challenging to identify the underlying disorder causing it and appropriate treatment. Fink et al⁴ discussed how clinicians have interpreted the different presentations of excited catatonia to gain insight into the underlying diagnosis. If the patient’s thought process appears disorganized, psychosis may be suspected.⁴ If the patient is delusional and grandiose, they may be manic, and when altered mental status dominates the presentation, delirium may be the culprit.⁴

Regardless of the underlying cause, the first step is to treat the catatonia. Benzodiazepines and electroconvulsive therapy (ECT) are the most well validated treatments for catatonia and have been used to treat excited catatonia.¹ Excited catatonia is often misdiagnosed and subsequently mistreated. In the following 3 cases, excited catatonia was successfully identified and treated using the same approach (Figure).

Case 1

Mr. A, age 27, has a history of bipolar I disorder. He was brought to the hospital by ambulance after being found to be yelling and acting belligerently, and he was admitted to the inpatient psychiatry unit for manic decompensation due to medication nonadherence. He was started on divalproex sodium 500 mg twice a day for mood stabilization, risperidone 1 mg twice a day for adjunct mood stabilization and psychosis, and lorazepam 1 mg 3 times a day for agitation. Mr. A exhibited odd behavior; he would take off his clothes in the hallway, run around the unit, and randomly yell at staff or to himself. At other times, he would stay silent, repeat the same statements, or oddly posture in the hallway for minutes at a time. These behaviors were seen primarily in the hour or 2 preceding lorazepam administration and improved after he received lorazepam.

Mr. A’s treating team completed the Bush-Francis Catatonia Rating Scale (BFCRS), which yielded a positive catatonia screen of 7/14. As a result, divalproex sodium and risperidone were held, and lorazepam was increased to 2 mg twice a day.

After several days, Mr. A was no longer acting oddly and was able to speak more spontaneously; however, he began to exhibit overt signs of mania. He would speak rapidly and make grandiose claims about managing millions of dollars as the CEO of a famous company. Divalproex sodium was restarted at 500 mg twice a day and increased to 500 mg 3 times a day for mood stabilization. Mr. A continued to receive lorazepam 2 mg 3 times a day for catatonia, and risperidone was restarted at 1 mg twice a day to more effectively target his manic symptoms. Risperidone was increased to 2 mg twice a day. After this change, Mr. A’s grandiosity dissipated, his speech normalized, and his thought process became organized. He was discharged on lorazepam 2 mg 3 times a day, divalproex sodium 500 mg 3 times a day, and risperidone 2 mg twice a day. Mr. A’s length of stay (LOS) for this admission was 11 days.

Continue to: Case 2

Case 2

Mr. B, age 49, presented with irritability and odd posturing. He has a history of schizoaffective disorder, bipolar type for which he was receiving a maintenance regimen of lithium 600 mg/d at bedtime and risperidone 2 mg/d at bedtime. He had multiple previous psychiatric admissions for catatonia. On this admission, Mr. B was irritable and difficult to redirect. He yelled at staff members and had a stiff gait. The BFCRS yielded a positive screening score of 3/14 and a severity score of 8/23. As a result, the treatment team conducted a lorazepam challenge.

After Mr. B received lorazepam 1 mg IM, his thought organization and irritability improved, which allowed him to have a coherent conversation with the interviewer. His gait stiffness also improved. His risperidone and lithium were held, and oral lorazepam 1 mg 3 times a day was started for catatonia. Lorazepam was gradually increased to 4 mg 3 times a day. Mr. B became euthymic and redirectable, and had an improved gait. However, he was also tangential and hyperverbal; these symptoms were indicative of the underlying mania that precipitated his catatonia.

Divalproex sodium extended release (ER) was started and increased to 1,500 mg/d at bedtime for mood stabilization. Lithium was restarted and increased to 300 mg twice a day for adjunct mood stabilization. Risperidone was not restarted. Toward the end of his admission, Mr. B was noted to be overly sedated, so the lorazepam dosage was decreased. He was discharged on lorazepam 2 mg 3 times a day, divalproex sodium ER 1,500 mg/d at bedtime, and lithium 300 mg twice a day. At discharge, Mr. B was calm and euthymic, with a linear thought process. His LOS was 25 days.

Case 3

Mr. C, age 62, presented to the emergency department (ED) because he had exhibited erratic behavior and had not slept for the past week. He has a history of bipolar I disorder, hypothyroidism, diabetes, and hypertension. For many years, he had been stable on divalproex sodium ER 2,500 mg/d at bedtime for mood stabilization and clozapine 100 mg/d at bedtime for adjunct mood stabilization and psychosis. In the ED, Mr. C was irritable, distractible, and tangential. On admission, he was speaking slowly with increased speech latency in response to questions, exhibiting stereotypy, repeating statements over and over, and walking very slowly.

The BFCRS yielded a positive screening score of 5/14 and a severity score of 10/23. Lorazepam 1 mg IM was administered. After 15 minutes, Mr. C’s speech, gait, and distractibility improved. As a result, clozapine and divalproex sodium were held, and he was started on oral lorazepam 1 mg 3 times a day. After several days, Mr. C was speaking fluently and no longer exhibiting stereotypy or having outbursts where he would make repetitive statements. However, he was tangential and irritable at times, which were signs of his underlying mania. Divalproex sodium ER was restarted at 250 mg/d at bedtime for mood stabilization and gradually increased to 2,500 mg/d at bedtime. Clozapine was also restarted at 25 mg/d at bedtime and gradually increased to 200 mg/d at bedtime. The lorazepam was gradually tapered and discontinued over the course of 3 weeks due to oversedation.

Continue to: At discharge...

At discharge, Mr. C was euthymic, calm, linear, and goal-directed. He was discharged on divalproex sodium ER 2,500 mg/d at bedtime and clozapine 200 mg/d at bedtime. His LOS for this admission was 22 days.

A stepwise approach can improve outcomes

The Figure outlines the method we used to manage excited catatonia in these 3 cases. Each of these patients exhibited signs of excited catatonia, but because those symptoms were nearly identical to those of mania, it was initially difficult to identify catatonia. Excited catatonia was suspected after more typical catatonic symptoms—such as a stiff gait, slowed speech, and stereotypy—were observed. The BFCRS was completed to get an objective measure of the likelihood that the patient was catatonic. In all 3 cases, the BFCRS resulted in a positive screen for catatonia. Following this, the patients described in Case 2 and Case 3 received a lorazepam challenge, which confirmed their catatonia. No lorazepam challenge was performed in Case 1 because the patient was already receiving lorazepam when the BFCRS was completed. Although most catatonic patients will respond to a lorazepam challenge, not all will. Therefore, clinicians should maintain some degree of suspicion for catatonia if a patient has a positive screen on the BFCRS but a negative lorazepam challenge.

In all 3 cases, after catatonia was confirmed, the patient’s psychotropic medications were discontinued. In all 3 cases, the antipsychotic was held to prevent progression to neuroleptic malignant syndrome (NMS) or malignant catatonia. Rasmussen et al³ found that 3.6% of the catatonic patients in their sample who were treated with antipsychotics developed NMS. A review of prospective studies looking at patients treated with antipsychotics found the incidence of NMS was .07% to 1.8%.⁵ Because NMS is often clinically indistinguishable from malignant catatonia,^4,6 this incidence of NMS may have represented an increased incidence in malignant catatonia.

In all 3 cases, the mood stabilizer was held to prevent it from complicating the clinical picture. Discontinuing the mood stabilizer and focusing on treating the catatonia before targeting the underlying mania increased the likelihood of differentiating the patient’s catatonic symptoms from manic symptoms. This resulted in more precise medication selection and titration by allowing us to identify the specific symptoms that were being targeted by each medication.

Oral lorazepam was prescribed to target catatonia in all 3 cases, and the dosage was gradually increased until symptoms began to resolve. As the catatonia resolved, the manic symptoms became more easily identifiable, and at this point a mood stabilizer was started and titrated to a therapeutic dose to target the mania. In Case 1 and Case 3, the antipsychotic was restarted to treat the mania more effectively. It was not restarted in Case 2 because the patient’s mania was effectively being managed by 2 mood stabilizers. The risks and benefits of starting an antipsychotic in a catatonic or recently catatonic patient should be carefully considered. In the 2 cases where the antipsychotic was restarted, the patients were closely monitored, and there were no signs of NMS or malignant catatonia.

Continue to: As discharge approached...

As discharge approached, the dosages of oral lorazepam were reevaluated. Catatonic patients can typically tolerate high doses of benzodiazepines without becoming overly sedated, but each patient has a different threshold at which the dosage causes oversedation. In all 3 patients, lorazepam was initially titrated to a dose that treated their catatonic symptoms without causing intolerable sedation. In Case 2 and Case 3, as the catatonia began to resolve, the patients became increasingly sedated on their existing lorazepam dosage, so it was decreased. Because the patient in Case 1 did not become overly sedated, his lorazepam dosage did not need to be reduced.

For 2 of these patients, our approach resulted in a shorter LOS compared to their previous hospitalizations. The LOS in Case 2 was 25 days; 5 years earlier, he had a 49-day LOS for mania and catatonia. During the past admission, the identification and treatment of the catatonia was delayed, which resulted in the patient requiring multiple transfers to the medical unit for unstable vital signs. The LOS in Case 3 was 22 days; 6 months prior to this admission, the patient had 2 psychiatric admissions that totaled 37 days. Although the patient’s presentation in the 2 previous admissions was similar to his presentation as described in Case 3, catatonia had not been identified or treated in either admission. Since his catatonia and mania were treated in Case 3, he has not required a readmission. The patient in Case 1 was previously hospitalized, but information about the LOS of these admissions was not available. These results suggest that early identification and treatment of catatonia via the approach we used can improve patient outcomes.

Bottom Line

Excited catatonia can be challenging to diagnose and treat because it can present with symptoms similar to those seen in mania or psychosis. We describe 3 cases in which we used a stepwise approach to optimize treatment and improve outcomes for patients with excited catatonia. This approach may work equally well for other catatonia subtypes.

Related Resources

• Dubovsky SL, Dubovsky AN. Catatonia: how to identify and treat it. Current Psychiatry. 2018;17(8):16-26.
• Crouse EL, Joel B. Moran JB. Catatonia: recognition, management, and prevention of complications. Current Psychiatry. 2018;17(12):45-49.

Drug Brand Names

Clozapine • Clozaril
Lithium • Eskalith, Lithobid
Lorazepam • Ativan
Risperidone • Risperdal
Divalproex sodium • Depakote

Catatonia is often difficult to identify and treat. The excited catatonia subtype can be particularly challenging to diagnose because it can present with symptoms similar to those seen in mania or psychosis. In this article, we present 3 cases of excited catatonia that illustrate how to identify it, how to treat the catatonia as well as the underlying pathology, and factors to consider during this process to mitigate the risk of adverse outcomes. We also outline a treatment algorithm we used for the 3 cases. Although we describe using this approach for patients with excited catatonia, it is generalizable to other types of catatonia.

Many causes, varying presentations

Catatonia is a psychomotor syndrome characterized by mutism, negativism, stereotypy, waxy flexibility, and other symptoms.¹ It is defined by the presence of ≥3 of the 12 symptoms listed in the Table.² Causes of catatonia include metabolic abnormalities, endocrine disorders, drug intoxication, neurodevelopmental disorders, medication adverse effects, psychosis, and mood disorders.^1,3

A subtype of this syndrome, excited catatonia, can present with restlessness, agitation, emotional lability, poor sleep, and altered mental status in addition to the more typical symptoms.^1,4 Because excited catatonia can resemble mania or psychosis, it is particularly challenging to identify the underlying disorder causing it and appropriate treatment. Fink et al⁴ discussed how clinicians have interpreted the different presentations of excited catatonia to gain insight into the underlying diagnosis. If the patient’s thought process appears disorganized, psychosis may be suspected.⁴ If the patient is delusional and grandiose, they may be manic, and when altered mental status dominates the presentation, delirium may be the culprit.⁴

Regardless of the underlying cause, the first step is to treat the catatonia. Benzodiazepines and electroconvulsive therapy (ECT) are the most well validated treatments for catatonia and have been used to treat excited catatonia.¹ Excited catatonia is often misdiagnosed and subsequently mistreated. In the following 3 cases, excited catatonia was successfully identified and treated using the same approach (Figure).

Case 1

Mr. A, age 27, has a history of bipolar I disorder. He was brought to the hospital by ambulance after being found to be yelling and acting belligerently, and he was admitted to the inpatient psychiatry unit for manic decompensation due to medication nonadherence. He was started on divalproex sodium 500 mg twice a day for mood stabilization, risperidone 1 mg twice a day for adjunct mood stabilization and psychosis, and lorazepam 1 mg 3 times a day for agitation. Mr. A exhibited odd behavior; he would take off his clothes in the hallway, run around the unit, and randomly yell at staff or to himself. At other times, he would stay silent, repeat the same statements, or oddly posture in the hallway for minutes at a time. These behaviors were seen primarily in the hour or 2 preceding lorazepam administration and improved after he received lorazepam.

Mr. A’s treating team completed the Bush-Francis Catatonia Rating Scale (BFCRS), which yielded a positive catatonia screen of 7/14. As a result, divalproex sodium and risperidone were held, and lorazepam was increased to 2 mg twice a day.

After several days, Mr. A was no longer acting oddly and was able to speak more spontaneously; however, he began to exhibit overt signs of mania. He would speak rapidly and make grandiose claims about managing millions of dollars as the CEO of a famous company. Divalproex sodium was restarted at 500 mg twice a day and increased to 500 mg 3 times a day for mood stabilization. Mr. A continued to receive lorazepam 2 mg 3 times a day for catatonia, and risperidone was restarted at 1 mg twice a day to more effectively target his manic symptoms. Risperidone was increased to 2 mg twice a day. After this change, Mr. A’s grandiosity dissipated, his speech normalized, and his thought process became organized. He was discharged on lorazepam 2 mg 3 times a day, divalproex sodium 500 mg 3 times a day, and risperidone 2 mg twice a day. Mr. A’s length of stay (LOS) for this admission was 11 days.

Continue to: Case 2

Case 2

Mr. B, age 49, presented with irritability and odd posturing. He has a history of schizoaffective disorder, bipolar type for which he was receiving a maintenance regimen of lithium 600 mg/d at bedtime and risperidone 2 mg/d at bedtime. He had multiple previous psychiatric admissions for catatonia. On this admission, Mr. B was irritable and difficult to redirect. He yelled at staff members and had a stiff gait. The BFCRS yielded a positive screening score of 3/14 and a severity score of 8/23. As a result, the treatment team conducted a lorazepam challenge.

After Mr. B received lorazepam 1 mg IM, his thought organization and irritability improved, which allowed him to have a coherent conversation with the interviewer. His gait stiffness also improved. His risperidone and lithium were held, and oral lorazepam 1 mg 3 times a day was started for catatonia. Lorazepam was gradually increased to 4 mg 3 times a day. Mr. B became euthymic and redirectable, and had an improved gait. However, he was also tangential and hyperverbal; these symptoms were indicative of the underlying mania that precipitated his catatonia.

Divalproex sodium extended release (ER) was started and increased to 1,500 mg/d at bedtime for mood stabilization. Lithium was restarted and increased to 300 mg twice a day for adjunct mood stabilization. Risperidone was not restarted. Toward the end of his admission, Mr. B was noted to be overly sedated, so the lorazepam dosage was decreased. He was discharged on lorazepam 2 mg 3 times a day, divalproex sodium ER 1,500 mg/d at bedtime, and lithium 300 mg twice a day. At discharge, Mr. B was calm and euthymic, with a linear thought process. His LOS was 25 days.

Case 3

Mr. C, age 62, presented to the emergency department (ED) because he had exhibited erratic behavior and had not slept for the past week. He has a history of bipolar I disorder, hypothyroidism, diabetes, and hypertension. For many years, he had been stable on divalproex sodium ER 2,500 mg/d at bedtime for mood stabilization and clozapine 100 mg/d at bedtime for adjunct mood stabilization and psychosis. In the ED, Mr. C was irritable, distractible, and tangential. On admission, he was speaking slowly with increased speech latency in response to questions, exhibiting stereotypy, repeating statements over and over, and walking very slowly.

The BFCRS yielded a positive screening score of 5/14 and a severity score of 10/23. Lorazepam 1 mg IM was administered. After 15 minutes, Mr. C’s speech, gait, and distractibility improved. As a result, clozapine and divalproex sodium were held, and he was started on oral lorazepam 1 mg 3 times a day. After several days, Mr. C was speaking fluently and no longer exhibiting stereotypy or having outbursts where he would make repetitive statements. However, he was tangential and irritable at times, which were signs of his underlying mania. Divalproex sodium ER was restarted at 250 mg/d at bedtime for mood stabilization and gradually increased to 2,500 mg/d at bedtime. Clozapine was also restarted at 25 mg/d at bedtime and gradually increased to 200 mg/d at bedtime. The lorazepam was gradually tapered and discontinued over the course of 3 weeks due to oversedation.

Continue to: At discharge...

At discharge, Mr. C was euthymic, calm, linear, and goal-directed. He was discharged on divalproex sodium ER 2,500 mg/d at bedtime and clozapine 200 mg/d at bedtime. His LOS for this admission was 22 days.

A stepwise approach can improve outcomes

The Figure outlines the method we used to manage excited catatonia in these 3 cases. Each of these patients exhibited signs of excited catatonia, but because those symptoms were nearly identical to those of mania, it was initially difficult to identify catatonia. Excited catatonia was suspected after more typical catatonic symptoms—such as a stiff gait, slowed speech, and stereotypy—were observed. The BFCRS was completed to get an objective measure of the likelihood that the patient was catatonic. In all 3 cases, the BFCRS resulted in a positive screen for catatonia. Following this, the patients described in Case 2 and Case 3 received a lorazepam challenge, which confirmed their catatonia. No lorazepam challenge was performed in Case 1 because the patient was already receiving lorazepam when the BFCRS was completed. Although most catatonic patients will respond to a lorazepam challenge, not all will. Therefore, clinicians should maintain some degree of suspicion for catatonia if a patient has a positive screen on the BFCRS but a negative lorazepam challenge.

In all 3 cases, after catatonia was confirmed, the patient’s psychotropic medications were discontinued. In all 3 cases, the antipsychotic was held to prevent progression to neuroleptic malignant syndrome (NMS) or malignant catatonia. Rasmussen et al³ found that 3.6% of the catatonic patients in their sample who were treated with antipsychotics developed NMS. A review of prospective studies looking at patients treated with antipsychotics found the incidence of NMS was .07% to 1.8%.⁵ Because NMS is often clinically indistinguishable from malignant catatonia,^4,6 this incidence of NMS may have represented an increased incidence in malignant catatonia.

In all 3 cases, the mood stabilizer was held to prevent it from complicating the clinical picture. Discontinuing the mood stabilizer and focusing on treating the catatonia before targeting the underlying mania increased the likelihood of differentiating the patient’s catatonic symptoms from manic symptoms. This resulted in more precise medication selection and titration by allowing us to identify the specific symptoms that were being targeted by each medication.

Oral lorazepam was prescribed to target catatonia in all 3 cases, and the dosage was gradually increased until symptoms began to resolve. As the catatonia resolved, the manic symptoms became more easily identifiable, and at this point a mood stabilizer was started and titrated to a therapeutic dose to target the mania. In Case 1 and Case 3, the antipsychotic was restarted to treat the mania more effectively. It was not restarted in Case 2 because the patient’s mania was effectively being managed by 2 mood stabilizers. The risks and benefits of starting an antipsychotic in a catatonic or recently catatonic patient should be carefully considered. In the 2 cases where the antipsychotic was restarted, the patients were closely monitored, and there were no signs of NMS or malignant catatonia.

Continue to: As discharge approached...

As discharge approached, the dosages of oral lorazepam were reevaluated. Catatonic patients can typically tolerate high doses of benzodiazepines without becoming overly sedated, but each patient has a different threshold at which the dosage causes oversedation. In all 3 patients, lorazepam was initially titrated to a dose that treated their catatonic symptoms without causing intolerable sedation. In Case 2 and Case 3, as the catatonia began to resolve, the patients became increasingly sedated on their existing lorazepam dosage, so it was decreased. Because the patient in Case 1 did not become overly sedated, his lorazepam dosage did not need to be reduced.

For 2 of these patients, our approach resulted in a shorter LOS compared to their previous hospitalizations. The LOS in Case 2 was 25 days; 5 years earlier, he had a 49-day LOS for mania and catatonia. During the past admission, the identification and treatment of the catatonia was delayed, which resulted in the patient requiring multiple transfers to the medical unit for unstable vital signs. The LOS in Case 3 was 22 days; 6 months prior to this admission, the patient had 2 psychiatric admissions that totaled 37 days. Although the patient’s presentation in the 2 previous admissions was similar to his presentation as described in Case 3, catatonia had not been identified or treated in either admission. Since his catatonia and mania were treated in Case 3, he has not required a readmission. The patient in Case 1 was previously hospitalized, but information about the LOS of these admissions was not available. These results suggest that early identification and treatment of catatonia via the approach we used can improve patient outcomes.

Bottom Line

Excited catatonia can be challenging to diagnose and treat because it can present with symptoms similar to those seen in mania or psychosis. We describe 3 cases in which we used a stepwise approach to optimize treatment and improve outcomes for patients with excited catatonia. This approach may work equally well for other catatonia subtypes.

Related Resources

• Dubovsky SL, Dubovsky AN. Catatonia: how to identify and treat it. Current Psychiatry. 2018;17(8):16-26.
• Crouse EL, Joel B. Moran JB. Catatonia: recognition, management, and prevention of complications. Current Psychiatry. 2018;17(12):45-49.

Drug Brand Names

Clozapine • Clozaril
Lithium • Eskalith, Lithobid
Lorazepam • Ativan
Risperidone • Risperdal
Divalproex sodium • Depakote

Psychedelics are a class of substances known to produce alterations in consciousness and perception. In the last 2 decades, psychedelic research has garnered increasing attention from scientists, therapists, entrepreneurs, and the public. While many of these compounds remain illegal in the United States and in many parts of the world (Box¹), a recent resurrection of psychedelic research has motivated the FDA to designate multiple psychedelic compounds as “breakthrough therapies,” thereby expediting the investigation, development, and review of psychedelic treatments.

Box

There is growing evidence that psychedelics may be efficacious for treating a range of psychiatric disorders. Potential clinical indications for psychedelics include some forms of depression, posttraumatic stress disorder (PTSD), and substance use disorders (Table 1^2,3). In most instances, the clinical use of psychedelics is being investigated and offered in the context of psychedelic-assisted psychotherapy, though ketamine is a prominent exception. Ketamine and esketamine are already being used to treat depression, and FDA approval is anticipated for other psychedelics. An examination of the safety considerations of psychedelics for the treatment of psychiatric disorders is therefore highly relevant and timely.

This article examines the adverse effect profile of classical (psilocybin [“mushrooms”], lysergic acid diethylamide [LSD], and N,N-dimethyltryptamine [DMT]/ayahuasca) and nonclassical (the entactogen 3,4-methylenedioxymethamphetamine [MDMA, known as “ecstasy”] and the dissociative anesthetic ketamine) psychedelics.

Psilocybin

Psilocybin is typically administered as a single dose of 10 to 30 mg and used in conjunction with preintegration and postintegration psychotherapy. Administration of psilocybin typically produces perceptual distortions and mind-altering effects, which are mediated through 5-HT2A brain receptor agonistic action.⁴ The acute effects last approximately 6 hours.⁵ While psilocybin has generated promising results in early clinical trials,³ the adverse effects of these agents have received less attention.

The adverse effect profile of psilocybin in adults appears promising but its powerful psychoactive effects necessitate cautious use.⁶ It has a very wide therapeutic index, and in a recent meta-analysis of psilocybin for depression, no serious adverse effects were reported in any of the 7 included studies.⁷ Common adverse effects in the context of clinical use include anxiety, dysphoria, confusion, and an increase in blood pressure and heart rate.⁶ Due to potential cardiac effects, psilocybin is contraindicated in individuals with cardiovascular and cerebrovascular disease.⁸ In recreational/nonclinical use, reactions such as suicidality, violence, convulsions, panic attacks, paranoia, confusion, prolonged dissociation, and mania have been reported.^9,10 Animal and human studies indicate the risk of abuse and physical dependence is low. Major national surveys indicate low rates of abuse, treatment-seeking, and harm.¹¹ In a recent 6-week randomized controlled trial (RCT) of psilocybin vs escitalopram for depression,¹² no serious adverse events were reported. Adverse events reported in the psilocybin group in this trial are listed in Table 2.¹²

A recent phase 2 double-blind trial of single-dose psilocybin (1 mg, 10 mg, and 25 mg) for treatment-resistant depression (N = 233) sheds more light on the risk of adverse effects.¹³ The percentage of individuals experiencing adverse effects on Day 1 of administration was high: 61% in the 25 mg psilocybin group. Headache, nausea, fatigue, and dizziness were the most common effects. The incidence of any adverse event in the 25 mg group was 56% from Day 2 to Week 3, and 29% from Week 3 to Week 12. Suicidal ideation, suicidal behavior, or self-injury occurred in all 3 dose groups. Overall, 14% in the 25 mg group, 17% in the 10 mg group, and 9% in the 1 mg group showed worsening of suicidality from baseline to Week 3. Suicidal behavior was reported by 3 individuals in the 25 mg group after Week 3. The new-onset or worsening of preexisting suicidality with psilocybin reported in this study requires further investigation.

Lysergic acid diethylamide

LSD is similar to psilocybin in its agonistic action at the 5-HT2A brain receptors.⁴ It is typically administered as a single 100 to 200 μg dose and is used in conjunction with preintegration and postintegration psychotherapy.¹⁴ Its acute effects last approximately 12 hours.¹⁵

Continue to: Like psilocybin...

Like psilocybin, LSD has a wide therapeutic index. Commonly reported adverse effects of LSD are increased anxiety, dysphoria, and confusion. LSD can also lead to physiological adverse effects, such as increased blood pressure and heart rate, and thus is contraindicated in patients with severe heart disease.⁶ In a systematic review of the therapeutic use of LSD that included 567 participants,¹⁶ 2 cases of serious adverse events were reported: a tonic-clonic seizure in a patient with a prior history of seizures, and a case of prolonged psychosis in a 21-year-old with a history of psychotic disorder.

Though few psychedelic studies have examined the adverse effects of these agents in older adults, a recent phase 1 study that recruited 48 healthy older adults (age 55 to 75) found that, compared to placebo, low doses (5 to 20 μg) of LSD 2 times a week for 3 weeks had similar adverse effects, cognitive impairment, or balance impairment.¹⁷ The only adverse effect noted to be different between the placebo group and active treatment groups was headache (50% for LSD 10 μg, 25% for LSD 20 μg, and 8% for placebo). Because the dose range (5 to 20 μg) used in this study was substantially lower than the typical therapeutic dose range of 100 to 200 μg, these results should not be interpreted as supporting the safety of LSD at higher doses in older adults.

DMT/ayahuasca

Ayahuasca is a plant-based psychedelic that contains an admixture of substances, including DMT, which acts as a 5-HT2A receptor agonist. In addition to DMT, ayahuasca also contains the alkaloid harmaline, which acts as a monoamine inhibitor. Use of ayahuasca can therefore pose a particular risk for individuals taking other serotonergic or noradrenergic medications or substances. The acute effects of DMT last approximately 4 hours,¹⁸ and acute administration of ayahuasca leads to a transient modified state of consciousness that is characterized by introspection, visions, enhanced emotions, and recall of personal memories.¹⁹ Research shows ayahuasca has been dosed at approximately 0.36 mg/kg of DMT for 1 dosing session alongside 6 2-hour therapy sessions.²⁰

A recent review by Orsolini et al²¹ consolidated 40 preclinical, observational, and experimental studies of ayahuasca, and this compound appeared to be safe and well-tolerated; the most common adverse effects were transient emesis and nausea. In an RCT by Palhano-Fontes et al,²⁰ nausea was observed in 71% of participants in the ayahuasca group (vs 26% placebo), vomiting in 57% of participants (vs 0% placebo), and restlessness in 50% of participants (vs 20% placebo). The authors noted that for some participants the ayahuasca session “was not necessarily a pleasant experience,” and was accompanied by psychological distress.²⁰ Vomiting is traditionally viewed as an expected part of the purging process of ayahuasca religious ceremonies. Another review found that there appears to be good long-term tolerability of ayahuasca consumption among individuals who use this compound in religious ceremonies.²²

MDMA

Entactogens (or empathogens) are a class of psychoactive substances that produce experiences of emotional openness and connection. MDMA is an entactogen known to release serotonin, norepinephrine, and dopamine by inhibiting reuptake.²³ This process leads to the stimulation of neurohormonal signaling of oxytocin, cortisol, and other signaling molecules such as brain-derived neurotrophic factor.²⁴ Memory reconsolidation and fear extinction may also play a therapeutic role, enabled by reduced activity in the amygdala and insula, and increased connectivity between the amygdala and hippocampus.²⁴ MDMA has been reported to enhance feelings of well-being and increase prosocial behavior.²⁵ In the therapeutic setting, MDMA has been generally dosed at 75 to 125 mg in 2 to 3 sessions alongside 10 therapy sessions. Administration of MDMA gives the user a subjective experience of energy and distortions in time and perception.²⁶ These acute effects last approximately 2 to 4 hours.²⁷

Continue to: A meta-analysis...

A meta-analysis of 5 RCTs of MDMA-assisted therapy for PTSD in adults demonstrated that MDMA was well-tolerated, and few serious adverse events were reported.²⁸ Two trials from 2018 that were included in this meta-analysis—Mithoefer et al²⁹ and Ot’alora et al³⁰—illustrate the incidence of specific adverse effects. In a randomized, double-blind trial of 26 veterans and first responders with chronic PTSD, Mithoefer et al²⁹ found the most commonly reported reactions during experimental sessions with MDMA were anxiety (81%), headache (69%), fatigue (62%), muscle tension (62%), and jaw clenching or tight jaw (50%). The most commonly reported reactions during 7 days of contact were fatigue (88%), anxiety (73%), insomnia (69%), headache (46%), muscle tension (46%), and increased irritability (46%). One instance of suicidal ideation was severe enough to require psychiatric hospitalization (this was the only instance of suicidal ideation among the 106 patients in the meta-analysis by Bahji et al²⁸); the patient subsequently completed the trial. Transient elevation in pulse, blood pressure, and body temperature were noted during sessions that did not require medical intervention.²⁹ Ot’alora et al³⁰ found similar common adverse reactions: anxiety, dizziness, fatigue, headache, jaw clenching, muscle tension, and irritability. There were no serious adverse effects.

While the use of MDMA in controlled interventional settings has resulted in relatively few adverse events, robust literature describes the risks associated with the nonclinical/recreational use of MDMA. In cases of MDMA toxicity, death has been reported.³¹ Acutely, MDMA may lead to sympathomimetic effects, including serotonin syndrome.³¹ Longer-term studies of MDMA users have found chronic recreational use to be associated with worse sleep, poor mood, anxiety disturbances, memory deficits, and attention problems.³² MDMA has also been found to have moderate potential for abuse.³³

Ketamine/esketamine

Ketamine is a dissociative anesthetic with some hallucinogenic effects. It is an N-methyl-d-aspartate (NMDA) antagonist frequently used in anesthesia, and it can induce a state of sedation, immobility, pain relief, and amnesia. In low doses, ketamine is used off-label to treat major depressive disorder and treatment-resistant depression. Most clinical trials of ketamine for depression have dosed IV ketamine from 0.5 to 1 mg/kg 1 to 3 times a week. It can also be administered as an IM, intranasal, oral, subcutaneous, or sublingual formulation.³⁴

Esketamine, the S(+)-enantiomer of ketamine, is also an NDMA antagonist. It has been developed as an intranasal formulation, typically dosed between 56 and 84 mg 2 times a week for 1 month, once a week for the following month, and once every 1 to 2 weeks thereafter.³⁵ In most ketamine and esketamine trials, these compounds have been used without psychotherapy, although some interventions have integrated psychotherapy with ketamine treatment.³⁶

Bennett et al³⁷ elaborated on 3 paradigms for ketamine treatment: biochemical, psychotherapeutic, and psychedelic. The biochemical model examines the neuro­biological effects of the medication. The psychotherapeutic model views ketamine as a way of assisting the psychotherapy process. The psychedelic model utilizes ketamine’s dissociative and psychedelic properties to induce an altered state of consciousness for therapeutic purposes and psychospiritual exploration.

Continue to: A systematic review...

A systematic review of the common adverse effects associated with ketamine use in clinical trials for depression reported dissociation, sedation, perceptual disturbances, anxiety, agitation, euphoria, hypertension, tachycardia, headache, and dizziness.³⁸ Adverse effects experienced with esketamine in clinical trials include dissociation, dizziness, sedation, hypertension, hypoesthesia, gastrointestinal symptoms, and euphoric mood (Table 3³⁹). A recent systemic review found both ketamine and esketamine demonstrated higher adverse events than control conditions. IV ketamine also demonstrated lower dropouts and adverse events when compared to intranasal esketamine.⁴⁰

Nonclinical/recreational use of ketamine is notable for urinary toxicity; 20% to 30% of frequent users of ketamine experience urinary problems that can range from ketamine-induced cystitis to hydronephrosis and kidney failure.⁴¹ Liver toxicity has also been reported with chronic use of high-dose ketamine. Ketamine is liable to abuse, dependence, and tolerance. There is evidence that nonclinical use of ketamine may lead to morbidity; impairment of memory, cognition, and attention; and urinary, gastric, and hepatic pathology.⁴²

The FDA prescribing information for esketamine lists aneurysmal vascular disease, arteriovenous malformation, and intracerebral hemorrhage as contraindications.³⁹ Patients with cardiovascular and cerebrovascular conditions and risk factors may be at increased risk of adverse effects due to an increase in blood pressure. Esketamine can impair attention, judgment, thinking, reaction speed, and motor skills. Other adverse effects of esketamine noted in the prescribing information include dissociation, dizziness, nausea, sedation, vertigo, hypoesthesia, anxiety, lethargy, vomiting, feeling drunk, and euphoric mood.³⁹A study of postmarketing safety concerns with esketamine using reports submitted to the FDA Adverse Event Reporting System (FAERS) revealed signals for suicidal ideation (reporting odds ratio [ROR] 24.03; 95% CI, 18.72 to 30.84), and completed suicide (ROR 5.75; 95% CI, 3.18 to 10.41).⁴³ The signals for suicidal and self-injurious ideation remained significant when compared to venlafaxine in the FAERS database, while suicide attempts and fatal suicide attempts were no longer significant.⁴³ Concerns regarding acute ketamine withdrawal have also been described in case reports.⁴⁴

Other safety considerations of psychedelics

Hallucinogen persisting perception disorder

Hallucinogen persisting perception disorder (HPPD) is a rare condition associated with hallucinogen use. It is characterized by the recurrence of perceptual disturbances that an individual experienced while using hallucinogenic substances that creates significant distress or impairment.⁴⁵ Because HPPD is a rare disorder, the exact prevalence is not well characterized, but DSM-5 suggests it is approximately 4.2%.⁴⁶ HPPD is associated with numerous psychoactive substances, including psilocybin, ayahuasca, MDMA, and ketamine, but is most associated with LSD.⁴⁵ HPPD is more likely to arise in individuals with histories of psychiatric illness or substance use disorders.⁴⁷

Serotonin toxicity and other serotonergic interactions

Serotonin toxicity is a risk of serotonergic psychedelics, particularly when such agents are used in combination with serotonergic psychotropic medications. The most severe manifestation of serotonin toxicity is serotonin syndrome, which manifests as a life-threatening condition characterized by myoclonus, rigidity, agitation, delirium, and unstable cardiovascular functioning. Many psychedelic compounds have transient serotonin-related adverse effects, but serotonin toxicity due to psychedelic use is rare.⁴⁸ Due to their mechanism of action, classical psychedelics are relatively safe in combination with monoamine oxidase inhibitors (MAOIs) and selective serotonin reuptake inhibitors. MDMA is a serotonin-releasing agent that has a higher risk of serotonin syndrome or hypertensive crisis when used in combination with MAOIs.⁴⁸

Boundary violations in psychedelic-assisted psychotherapy

A key task facing psychedelic research is to establish parameters for the safe and ethical use of these agents. This is particularly relevant given the hype that surrounds the psychedelic resurgence and what we know about the controversial history of these substances. Anderson et al⁴⁹ argued that “psychedelics can have lingering effects that include increased suggestibility and affective instability, as well as altered ego structure, social behaviour, and philosophical worldview. Stated simply, psychedelics can induce a vulnerable state both during and after treatment sessions.”

Continue to: Psychedelic treatment...

Psychedelic treatments such as psilocybin and MDMA are typically offered within the context of psychedelic-assisted psychotherapy, and some researchers have raised concerns regarding boundary violations,⁵⁰ given the patients’ particularly vulnerable states. In addition to concerns about sexual harassment, the financial exploitation of older adults is also a possible risk.⁵¹

Caveats to consider

Novel psychedelics therapies have demonstrated promising preliminary results for a broad range of psychiatric indications, including depression, end-of-life distress, substance use disorders, PTSD, and improving well-being. To date, psychedelics are generally well-tolerated in adults in clinical trials.

However, when it comes to adverse effects, there are challenges in regards to interpreting the psychedelic state.⁵² Some consider any unpleasant or unsettling psychedelic experience as an adverse reaction, while others consider it part of the therapeutic process. This is exemplified by the case of vomiting during ayahuasca ceremonies, which is generally considered part of the ritual. In such instances, it is essential to obtain informed consent and ensure participants are aware of these aspects of the experience. Compared to substances such as alcohol, opioids, and cocaine, psychedelics are remarkably safe from a physiological perspective, especially with regards to the risks of toxicity, mortality, and dependence.⁵³ Their psychological safety is less established, and more caution and research is needed. The high incidence of adverse effects and suicidality noted in the recent phase 2 trial of psilocybin in treatment resistant depression are a reminder of this.¹³

There is uncertainty regarding the magnitude of risk in real-world clinical practice, particularly regarding addiction, suicidality, and precipitation or worsening of psychotic disorders. For example, note the extensive exclusion criteria used in the psilocybin vs escitalopram RCT by Carhart-Harris et al¹²: currently or previously diagnosed psychotic disorder, immediate family member with a diagnosed psychotic disorder, significant medical comorbidity (eg, diabetes, epilepsy, severe cardiovascular disease, hepatic or renal failure), history of suicide attempts requiring hospitalization, history of mania, pregnancy, and abnormal QT interval prolongation, among others. It would be prudent to keep these contraindications in mind regarding the clinical use of psychedelics in the future. This is particularly important in older adults because such patients often have substantial medical comorbidities and are at greater risk for adverse effects. For ketamine, research has implicated the role of mu opioid agonism in mediating ketamine’s antidepressant effects.⁵⁴ This raises concerns about abuse, dependence, and addiction, especially with long-term use. There are also concerns regarding protracted withdrawal symptoms and associated suicidality.⁵⁵

The therapeutic use of psychedelics is an exciting and promising avenue, with ongoing research and a rapidly evolving literature. An attitude of cautious optimism is warranted, but efficacy and safety should be demonstrated in well-designed and rigorous trials with adequate long-term follow-up before routine clinical use is recommended.

Bottom Line

In clinical trials for psychiatric disorders, psychedelics have been associated with a range of cognitive, psychiatric, and psychoactive adverse effects but generally have been well-tolerated, with a low incidence of serious adverse effects.

Related Resources

• American Psychiatric Association. Position Statement on the Use of Psychedelic and Empathogenic Agents for Mental Health Conditions. Updated July 2022. Accessed October 24, 2022. https://www.psychiatry.org/getattachment/d5c13619-ca1f-491f-a7a8-b7141c800904/Position-Use-of-Psychedelic-Empathogenic-Agents.pdf
• Johns Hopkins Center for Psychedelic & Consciousness Research. https://hopkinspsychedelic.org/
• Multidisciplinary Association for Psychedelic Studies (MAPS). https://maps.org/

Drug Brand Names

Esketamine • Spravato
Ketamine • Ketalar
Venlafaxine • Effexor

Psychedelics are a class of substances known to produce alterations in consciousness and perception. In the last 2 decades, psychedelic research has garnered increasing attention from scientists, therapists, entrepreneurs, and the public. While many of these compounds remain illegal in the United States and in many parts of the world (Box¹), a recent resurrection of psychedelic research has motivated the FDA to designate multiple psychedelic compounds as “breakthrough therapies,” thereby expediting the investigation, development, and review of psychedelic treatments.

Box

There is growing evidence that psychedelics may be efficacious for treating a range of psychiatric disorders. Potential clinical indications for psychedelics include some forms of depression, posttraumatic stress disorder (PTSD), and substance use disorders (Table 1^2,3). In most instances, the clinical use of psychedelics is being investigated and offered in the context of psychedelic-assisted psychotherapy, though ketamine is a prominent exception. Ketamine and esketamine are already being used to treat depression, and FDA approval is anticipated for other psychedelics. An examination of the safety considerations of psychedelics for the treatment of psychiatric disorders is therefore highly relevant and timely.

This article examines the adverse effect profile of classical (psilocybin [“mushrooms”], lysergic acid diethylamide [LSD], and N,N-dimethyltryptamine [DMT]/ayahuasca) and nonclassical (the entactogen 3,4-methylenedioxymethamphetamine [MDMA, known as “ecstasy”] and the dissociative anesthetic ketamine) psychedelics.

Psilocybin

Psilocybin is typically administered as a single dose of 10 to 30 mg and used in conjunction with preintegration and postintegration psychotherapy. Administration of psilocybin typically produces perceptual distortions and mind-altering effects, which are mediated through 5-HT2A brain receptor agonistic action.⁴ The acute effects last approximately 6 hours.⁵ While psilocybin has generated promising results in early clinical trials,³ the adverse effects of these agents have received less attention.

The adverse effect profile of psilocybin in adults appears promising but its powerful psychoactive effects necessitate cautious use.⁶ It has a very wide therapeutic index, and in a recent meta-analysis of psilocybin for depression, no serious adverse effects were reported in any of the 7 included studies.⁷ Common adverse effects in the context of clinical use include anxiety, dysphoria, confusion, and an increase in blood pressure and heart rate.⁶ Due to potential cardiac effects, psilocybin is contraindicated in individuals with cardiovascular and cerebrovascular disease.⁸ In recreational/nonclinical use, reactions such as suicidality, violence, convulsions, panic attacks, paranoia, confusion, prolonged dissociation, and mania have been reported.^9,10 Animal and human studies indicate the risk of abuse and physical dependence is low. Major national surveys indicate low rates of abuse, treatment-seeking, and harm.¹¹ In a recent 6-week randomized controlled trial (RCT) of psilocybin vs escitalopram for depression,¹² no serious adverse events were reported. Adverse events reported in the psilocybin group in this trial are listed in Table 2.¹²

A recent phase 2 double-blind trial of single-dose psilocybin (1 mg, 10 mg, and 25 mg) for treatment-resistant depression (N = 233) sheds more light on the risk of adverse effects.¹³ The percentage of individuals experiencing adverse effects on Day 1 of administration was high: 61% in the 25 mg psilocybin group. Headache, nausea, fatigue, and dizziness were the most common effects. The incidence of any adverse event in the 25 mg group was 56% from Day 2 to Week 3, and 29% from Week 3 to Week 12. Suicidal ideation, suicidal behavior, or self-injury occurred in all 3 dose groups. Overall, 14% in the 25 mg group, 17% in the 10 mg group, and 9% in the 1 mg group showed worsening of suicidality from baseline to Week 3. Suicidal behavior was reported by 3 individuals in the 25 mg group after Week 3. The new-onset or worsening of preexisting suicidality with psilocybin reported in this study requires further investigation.

Lysergic acid diethylamide

LSD is similar to psilocybin in its agonistic action at the 5-HT2A brain receptors.⁴ It is typically administered as a single 100 to 200 μg dose and is used in conjunction with preintegration and postintegration psychotherapy.¹⁴ Its acute effects last approximately 12 hours.¹⁵

Continue to: Like psilocybin...

Like psilocybin, LSD has a wide therapeutic index. Commonly reported adverse effects of LSD are increased anxiety, dysphoria, and confusion. LSD can also lead to physiological adverse effects, such as increased blood pressure and heart rate, and thus is contraindicated in patients with severe heart disease.⁶ In a systematic review of the therapeutic use of LSD that included 567 participants,¹⁶ 2 cases of serious adverse events were reported: a tonic-clonic seizure in a patient with a prior history of seizures, and a case of prolonged psychosis in a 21-year-old with a history of psychotic disorder.

Though few psychedelic studies have examined the adverse effects of these agents in older adults, a recent phase 1 study that recruited 48 healthy older adults (age 55 to 75) found that, compared to placebo, low doses (5 to 20 μg) of LSD 2 times a week for 3 weeks had similar adverse effects, cognitive impairment, or balance impairment.¹⁷ The only adverse effect noted to be different between the placebo group and active treatment groups was headache (50% for LSD 10 μg, 25% for LSD 20 μg, and 8% for placebo). Because the dose range (5 to 20 μg) used in this study was substantially lower than the typical therapeutic dose range of 100 to 200 μg, these results should not be interpreted as supporting the safety of LSD at higher doses in older adults.

DMT/ayahuasca

Ayahuasca is a plant-based psychedelic that contains an admixture of substances, including DMT, which acts as a 5-HT2A receptor agonist. In addition to DMT, ayahuasca also contains the alkaloid harmaline, which acts as a monoamine inhibitor. Use of ayahuasca can therefore pose a particular risk for individuals taking other serotonergic or noradrenergic medications or substances. The acute effects of DMT last approximately 4 hours,¹⁸ and acute administration of ayahuasca leads to a transient modified state of consciousness that is characterized by introspection, visions, enhanced emotions, and recall of personal memories.¹⁹ Research shows ayahuasca has been dosed at approximately 0.36 mg/kg of DMT for 1 dosing session alongside 6 2-hour therapy sessions.²⁰

A recent review by Orsolini et al²¹ consolidated 40 preclinical, observational, and experimental studies of ayahuasca, and this compound appeared to be safe and well-tolerated; the most common adverse effects were transient emesis and nausea. In an RCT by Palhano-Fontes et al,²⁰ nausea was observed in 71% of participants in the ayahuasca group (vs 26% placebo), vomiting in 57% of participants (vs 0% placebo), and restlessness in 50% of participants (vs 20% placebo). The authors noted that for some participants the ayahuasca session “was not necessarily a pleasant experience,” and was accompanied by psychological distress.²⁰ Vomiting is traditionally viewed as an expected part of the purging process of ayahuasca religious ceremonies. Another review found that there appears to be good long-term tolerability of ayahuasca consumption among individuals who use this compound in religious ceremonies.²²

MDMA

Entactogens (or empathogens) are a class of psychoactive substances that produce experiences of emotional openness and connection. MDMA is an entactogen known to release serotonin, norepinephrine, and dopamine by inhibiting reuptake.²³ This process leads to the stimulation of neurohormonal signaling of oxytocin, cortisol, and other signaling molecules such as brain-derived neurotrophic factor.²⁴ Memory reconsolidation and fear extinction may also play a therapeutic role, enabled by reduced activity in the amygdala and insula, and increased connectivity between the amygdala and hippocampus.²⁴ MDMA has been reported to enhance feelings of well-being and increase prosocial behavior.²⁵ In the therapeutic setting, MDMA has been generally dosed at 75 to 125 mg in 2 to 3 sessions alongside 10 therapy sessions. Administration of MDMA gives the user a subjective experience of energy and distortions in time and perception.²⁶ These acute effects last approximately 2 to 4 hours.²⁷

Continue to: A meta-analysis...

A meta-analysis of 5 RCTs of MDMA-assisted therapy for PTSD in adults demonstrated that MDMA was well-tolerated, and few serious adverse events were reported.²⁸ Two trials from 2018 that were included in this meta-analysis—Mithoefer et al²⁹ and Ot’alora et al³⁰—illustrate the incidence of specific adverse effects. In a randomized, double-blind trial of 26 veterans and first responders with chronic PTSD, Mithoefer et al²⁹ found the most commonly reported reactions during experimental sessions with MDMA were anxiety (81%), headache (69%), fatigue (62%), muscle tension (62%), and jaw clenching or tight jaw (50%). The most commonly reported reactions during 7 days of contact were fatigue (88%), anxiety (73%), insomnia (69%), headache (46%), muscle tension (46%), and increased irritability (46%). One instance of suicidal ideation was severe enough to require psychiatric hospitalization (this was the only instance of suicidal ideation among the 106 patients in the meta-analysis by Bahji et al²⁸); the patient subsequently completed the trial. Transient elevation in pulse, blood pressure, and body temperature were noted during sessions that did not require medical intervention.²⁹ Ot’alora et al³⁰ found similar common adverse reactions: anxiety, dizziness, fatigue, headache, jaw clenching, muscle tension, and irritability. There were no serious adverse effects.

While the use of MDMA in controlled interventional settings has resulted in relatively few adverse events, robust literature describes the risks associated with the nonclinical/recreational use of MDMA. In cases of MDMA toxicity, death has been reported.³¹ Acutely, MDMA may lead to sympathomimetic effects, including serotonin syndrome.³¹ Longer-term studies of MDMA users have found chronic recreational use to be associated with worse sleep, poor mood, anxiety disturbances, memory deficits, and attention problems.³² MDMA has also been found to have moderate potential for abuse.³³

Ketamine/esketamine

Ketamine is a dissociative anesthetic with some hallucinogenic effects. It is an N-methyl-d-aspartate (NMDA) antagonist frequently used in anesthesia, and it can induce a state of sedation, immobility, pain relief, and amnesia. In low doses, ketamine is used off-label to treat major depressive disorder and treatment-resistant depression. Most clinical trials of ketamine for depression have dosed IV ketamine from 0.5 to 1 mg/kg 1 to 3 times a week. It can also be administered as an IM, intranasal, oral, subcutaneous, or sublingual formulation.³⁴

Esketamine, the S(+)-enantiomer of ketamine, is also an NDMA antagonist. It has been developed as an intranasal formulation, typically dosed between 56 and 84 mg 2 times a week for 1 month, once a week for the following month, and once every 1 to 2 weeks thereafter.³⁵ In most ketamine and esketamine trials, these compounds have been used without psychotherapy, although some interventions have integrated psychotherapy with ketamine treatment.³⁶

Bennett et al³⁷ elaborated on 3 paradigms for ketamine treatment: biochemical, psychotherapeutic, and psychedelic. The biochemical model examines the neuro­biological effects of the medication. The psychotherapeutic model views ketamine as a way of assisting the psychotherapy process. The psychedelic model utilizes ketamine’s dissociative and psychedelic properties to induce an altered state of consciousness for therapeutic purposes and psychospiritual exploration.

Continue to: A systematic review...

A systematic review of the common adverse effects associated with ketamine use in clinical trials for depression reported dissociation, sedation, perceptual disturbances, anxiety, agitation, euphoria, hypertension, tachycardia, headache, and dizziness.³⁸ Adverse effects experienced with esketamine in clinical trials include dissociation, dizziness, sedation, hypertension, hypoesthesia, gastrointestinal symptoms, and euphoric mood (Table 3³⁹). A recent systemic review found both ketamine and esketamine demonstrated higher adverse events than control conditions. IV ketamine also demonstrated lower dropouts and adverse events when compared to intranasal esketamine.⁴⁰

Nonclinical/recreational use of ketamine is notable for urinary toxicity; 20% to 30% of frequent users of ketamine experience urinary problems that can range from ketamine-induced cystitis to hydronephrosis and kidney failure.⁴¹ Liver toxicity has also been reported with chronic use of high-dose ketamine. Ketamine is liable to abuse, dependence, and tolerance. There is evidence that nonclinical use of ketamine may lead to morbidity; impairment of memory, cognition, and attention; and urinary, gastric, and hepatic pathology.⁴²

The FDA prescribing information for esketamine lists aneurysmal vascular disease, arteriovenous malformation, and intracerebral hemorrhage as contraindications.³⁹ Patients with cardiovascular and cerebrovascular conditions and risk factors may be at increased risk of adverse effects due to an increase in blood pressure. Esketamine can impair attention, judgment, thinking, reaction speed, and motor skills. Other adverse effects of esketamine noted in the prescribing information include dissociation, dizziness, nausea, sedation, vertigo, hypoesthesia, anxiety, lethargy, vomiting, feeling drunk, and euphoric mood.³⁹A study of postmarketing safety concerns with esketamine using reports submitted to the FDA Adverse Event Reporting System (FAERS) revealed signals for suicidal ideation (reporting odds ratio [ROR] 24.03; 95% CI, 18.72 to 30.84), and completed suicide (ROR 5.75; 95% CI, 3.18 to 10.41).⁴³ The signals for suicidal and self-injurious ideation remained significant when compared to venlafaxine in the FAERS database, while suicide attempts and fatal suicide attempts were no longer significant.⁴³ Concerns regarding acute ketamine withdrawal have also been described in case reports.⁴⁴

Other safety considerations of psychedelics

Hallucinogen persisting perception disorder

Hallucinogen persisting perception disorder (HPPD) is a rare condition associated with hallucinogen use. It is characterized by the recurrence of perceptual disturbances that an individual experienced while using hallucinogenic substances that creates significant distress or impairment.⁴⁵ Because HPPD is a rare disorder, the exact prevalence is not well characterized, but DSM-5 suggests it is approximately 4.2%.⁴⁶ HPPD is associated with numerous psychoactive substances, including psilocybin, ayahuasca, MDMA, and ketamine, but is most associated with LSD.⁴⁵ HPPD is more likely to arise in individuals with histories of psychiatric illness or substance use disorders.⁴⁷

Serotonin toxicity and other serotonergic interactions

Serotonin toxicity is a risk of serotonergic psychedelics, particularly when such agents are used in combination with serotonergic psychotropic medications. The most severe manifestation of serotonin toxicity is serotonin syndrome, which manifests as a life-threatening condition characterized by myoclonus, rigidity, agitation, delirium, and unstable cardiovascular functioning. Many psychedelic compounds have transient serotonin-related adverse effects, but serotonin toxicity due to psychedelic use is rare.⁴⁸ Due to their mechanism of action, classical psychedelics are relatively safe in combination with monoamine oxidase inhibitors (MAOIs) and selective serotonin reuptake inhibitors. MDMA is a serotonin-releasing agent that has a higher risk of serotonin syndrome or hypertensive crisis when used in combination with MAOIs.⁴⁸

Boundary violations in psychedelic-assisted psychotherapy

A key task facing psychedelic research is to establish parameters for the safe and ethical use of these agents. This is particularly relevant given the hype that surrounds the psychedelic resurgence and what we know about the controversial history of these substances. Anderson et al⁴⁹ argued that “psychedelics can have lingering effects that include increased suggestibility and affective instability, as well as altered ego structure, social behaviour, and philosophical worldview. Stated simply, psychedelics can induce a vulnerable state both during and after treatment sessions.”

Continue to: Psychedelic treatment...

Psychedelic treatments such as psilocybin and MDMA are typically offered within the context of psychedelic-assisted psychotherapy, and some researchers have raised concerns regarding boundary violations,⁵⁰ given the patients’ particularly vulnerable states. In addition to concerns about sexual harassment, the financial exploitation of older adults is also a possible risk.⁵¹

Caveats to consider

Novel psychedelics therapies have demonstrated promising preliminary results for a broad range of psychiatric indications, including depression, end-of-life distress, substance use disorders, PTSD, and improving well-being. To date, psychedelics are generally well-tolerated in adults in clinical trials.

However, when it comes to adverse effects, there are challenges in regards to interpreting the psychedelic state.⁵² Some consider any unpleasant or unsettling psychedelic experience as an adverse reaction, while others consider it part of the therapeutic process. This is exemplified by the case of vomiting during ayahuasca ceremonies, which is generally considered part of the ritual. In such instances, it is essential to obtain informed consent and ensure participants are aware of these aspects of the experience. Compared to substances such as alcohol, opioids, and cocaine, psychedelics are remarkably safe from a physiological perspective, especially with regards to the risks of toxicity, mortality, and dependence.⁵³ Their psychological safety is less established, and more caution and research is needed. The high incidence of adverse effects and suicidality noted in the recent phase 2 trial of psilocybin in treatment resistant depression are a reminder of this.¹³

There is uncertainty regarding the magnitude of risk in real-world clinical practice, particularly regarding addiction, suicidality, and precipitation or worsening of psychotic disorders. For example, note the extensive exclusion criteria used in the psilocybin vs escitalopram RCT by Carhart-Harris et al¹²: currently or previously diagnosed psychotic disorder, immediate family member with a diagnosed psychotic disorder, significant medical comorbidity (eg, diabetes, epilepsy, severe cardiovascular disease, hepatic or renal failure), history of suicide attempts requiring hospitalization, history of mania, pregnancy, and abnormal QT interval prolongation, among others. It would be prudent to keep these contraindications in mind regarding the clinical use of psychedelics in the future. This is particularly important in older adults because such patients often have substantial medical comorbidities and are at greater risk for adverse effects. For ketamine, research has implicated the role of mu opioid agonism in mediating ketamine’s antidepressant effects.⁵⁴ This raises concerns about abuse, dependence, and addiction, especially with long-term use. There are also concerns regarding protracted withdrawal symptoms and associated suicidality.⁵⁵

The therapeutic use of psychedelics is an exciting and promising avenue, with ongoing research and a rapidly evolving literature. An attitude of cautious optimism is warranted, but efficacy and safety should be demonstrated in well-designed and rigorous trials with adequate long-term follow-up before routine clinical use is recommended.

Bottom Line

In clinical trials for psychiatric disorders, psychedelics have been associated with a range of cognitive, psychiatric, and psychoactive adverse effects but generally have been well-tolerated, with a low incidence of serious adverse effects.

Related Resources

• American Psychiatric Association. Position Statement on the Use of Psychedelic and Empathogenic Agents for Mental Health Conditions. Updated July 2022. Accessed October 24, 2022. https://www.psychiatry.org/getattachment/d5c13619-ca1f-491f-a7a8-b7141c800904/Position-Use-of-Psychedelic-Empathogenic-Agents.pdf
• Johns Hopkins Center for Psychedelic & Consciousness Research. https://hopkinspsychedelic.org/
• Multidisciplinary Association for Psychedelic Studies (MAPS). https://maps.org/

Drug Brand Names

Esketamine • Spravato
Ketamine • Ketalar
Venlafaxine • Effexor

Psychedelics are a class of substances known to produce alterations in consciousness and perception. In the last 2 decades, psychedelic research has garnered increasing attention from scientists, therapists, entrepreneurs, and the public. While many of these compounds remain illegal in the United States and in many parts of the world (Box¹), a recent resurrection of psychedelic research has motivated the FDA to designate multiple psychedelic compounds as “breakthrough therapies,” thereby expediting the investigation, development, and review of psychedelic treatments.

Box

There is growing evidence that psychedelics may be efficacious for treating a range of psychiatric disorders. Potential clinical indications for psychedelics include some forms of depression, posttraumatic stress disorder (PTSD), and substance use disorders (Table 1^2,3). In most instances, the clinical use of psychedelics is being investigated and offered in the context of psychedelic-assisted psychotherapy, though ketamine is a prominent exception. Ketamine and esketamine are already being used to treat depression, and FDA approval is anticipated for other psychedelics. An examination of the safety considerations of psychedelics for the treatment of psychiatric disorders is therefore highly relevant and timely.

This article examines the adverse effect profile of classical (psilocybin [“mushrooms”], lysergic acid diethylamide [LSD], and N,N-dimethyltryptamine [DMT]/ayahuasca) and nonclassical (the entactogen 3,4-methylenedioxymethamphetamine [MDMA, known as “ecstasy”] and the dissociative anesthetic ketamine) psychedelics.

Psilocybin

Psilocybin is typically administered as a single dose of 10 to 30 mg and used in conjunction with preintegration and postintegration psychotherapy. Administration of psilocybin typically produces perceptual distortions and mind-altering effects, which are mediated through 5-HT2A brain receptor agonistic action.⁴ The acute effects last approximately 6 hours.⁵ While psilocybin has generated promising results in early clinical trials,³ the adverse effects of these agents have received less attention.

The adverse effect profile of psilocybin in adults appears promising but its powerful psychoactive effects necessitate cautious use.⁶ It has a very wide therapeutic index, and in a recent meta-analysis of psilocybin for depression, no serious adverse effects were reported in any of the 7 included studies.⁷ Common adverse effects in the context of clinical use include anxiety, dysphoria, confusion, and an increase in blood pressure and heart rate.⁶ Due to potential cardiac effects, psilocybin is contraindicated in individuals with cardiovascular and cerebrovascular disease.⁸ In recreational/nonclinical use, reactions such as suicidality, violence, convulsions, panic attacks, paranoia, confusion, prolonged dissociation, and mania have been reported.^9,10 Animal and human studies indicate the risk of abuse and physical dependence is low. Major national surveys indicate low rates of abuse, treatment-seeking, and harm.¹¹ In a recent 6-week randomized controlled trial (RCT) of psilocybin vs escitalopram for depression,¹² no serious adverse events were reported. Adverse events reported in the psilocybin group in this trial are listed in Table 2.¹²

A recent phase 2 double-blind trial of single-dose psilocybin (1 mg, 10 mg, and 25 mg) for treatment-resistant depression (N = 233) sheds more light on the risk of adverse effects.¹³ The percentage of individuals experiencing adverse effects on Day 1 of administration was high: 61% in the 25 mg psilocybin group. Headache, nausea, fatigue, and dizziness were the most common effects. The incidence of any adverse event in the 25 mg group was 56% from Day 2 to Week 3, and 29% from Week 3 to Week 12. Suicidal ideation, suicidal behavior, or self-injury occurred in all 3 dose groups. Overall, 14% in the 25 mg group, 17% in the 10 mg group, and 9% in the 1 mg group showed worsening of suicidality from baseline to Week 3. Suicidal behavior was reported by 3 individuals in the 25 mg group after Week 3. The new-onset or worsening of preexisting suicidality with psilocybin reported in this study requires further investigation.

Lysergic acid diethylamide

LSD is similar to psilocybin in its agonistic action at the 5-HT2A brain receptors.⁴ It is typically administered as a single 100 to 200 μg dose and is used in conjunction with preintegration and postintegration psychotherapy.¹⁴ Its acute effects last approximately 12 hours.¹⁵

Continue to: Like psilocybin...

Like psilocybin, LSD has a wide therapeutic index. Commonly reported adverse effects of LSD are increased anxiety, dysphoria, and confusion. LSD can also lead to physiological adverse effects, such as increased blood pressure and heart rate, and thus is contraindicated in patients with severe heart disease.⁶ In a systematic review of the therapeutic use of LSD that included 567 participants,¹⁶ 2 cases of serious adverse events were reported: a tonic-clonic seizure in a patient with a prior history of seizures, and a case of prolonged psychosis in a 21-year-old with a history of psychotic disorder.

Though few psychedelic studies have examined the adverse effects of these agents in older adults, a recent phase 1 study that recruited 48 healthy older adults (age 55 to 75) found that, compared to placebo, low doses (5 to 20 μg) of LSD 2 times a week for 3 weeks had similar adverse effects, cognitive impairment, or balance impairment.¹⁷ The only adverse effect noted to be different between the placebo group and active treatment groups was headache (50% for LSD 10 μg, 25% for LSD 20 μg, and 8% for placebo). Because the dose range (5 to 20 μg) used in this study was substantially lower than the typical therapeutic dose range of 100 to 200 μg, these results should not be interpreted as supporting the safety of LSD at higher doses in older adults.

DMT/ayahuasca

Ayahuasca is a plant-based psychedelic that contains an admixture of substances, including DMT, which acts as a 5-HT2A receptor agonist. In addition to DMT, ayahuasca also contains the alkaloid harmaline, which acts as a monoamine inhibitor. Use of ayahuasca can therefore pose a particular risk for individuals taking other serotonergic or noradrenergic medications or substances. The acute effects of DMT last approximately 4 hours,¹⁸ and acute administration of ayahuasca leads to a transient modified state of consciousness that is characterized by introspection, visions, enhanced emotions, and recall of personal memories.¹⁹ Research shows ayahuasca has been dosed at approximately 0.36 mg/kg of DMT for 1 dosing session alongside 6 2-hour therapy sessions.²⁰

A recent review by Orsolini et al²¹ consolidated 40 preclinical, observational, and experimental studies of ayahuasca, and this compound appeared to be safe and well-tolerated; the most common adverse effects were transient emesis and nausea. In an RCT by Palhano-Fontes et al,²⁰ nausea was observed in 71% of participants in the ayahuasca group (vs 26% placebo), vomiting in 57% of participants (vs 0% placebo), and restlessness in 50% of participants (vs 20% placebo). The authors noted that for some participants the ayahuasca session “was not necessarily a pleasant experience,” and was accompanied by psychological distress.²⁰ Vomiting is traditionally viewed as an expected part of the purging process of ayahuasca religious ceremonies. Another review found that there appears to be good long-term tolerability of ayahuasca consumption among individuals who use this compound in religious ceremonies.²²

MDMA

Entactogens (or empathogens) are a class of psychoactive substances that produce experiences of emotional openness and connection. MDMA is an entactogen known to release serotonin, norepinephrine, and dopamine by inhibiting reuptake.²³ This process leads to the stimulation of neurohormonal signaling of oxytocin, cortisol, and other signaling molecules such as brain-derived neurotrophic factor.²⁴ Memory reconsolidation and fear extinction may also play a therapeutic role, enabled by reduced activity in the amygdala and insula, and increased connectivity between the amygdala and hippocampus.²⁴ MDMA has been reported to enhance feelings of well-being and increase prosocial behavior.²⁵ In the therapeutic setting, MDMA has been generally dosed at 75 to 125 mg in 2 to 3 sessions alongside 10 therapy sessions. Administration of MDMA gives the user a subjective experience of energy and distortions in time and perception.²⁶ These acute effects last approximately 2 to 4 hours.²⁷

Continue to: A meta-analysis...

A meta-analysis of 5 RCTs of MDMA-assisted therapy for PTSD in adults demonstrated that MDMA was well-tolerated, and few serious adverse events were reported.²⁸ Two trials from 2018 that were included in this meta-analysis—Mithoefer et al²⁹ and Ot’alora et al³⁰—illustrate the incidence of specific adverse effects. In a randomized, double-blind trial of 26 veterans and first responders with chronic PTSD, Mithoefer et al²⁹ found the most commonly reported reactions during experimental sessions with MDMA were anxiety (81%), headache (69%), fatigue (62%), muscle tension (62%), and jaw clenching or tight jaw (50%). The most commonly reported reactions during 7 days of contact were fatigue (88%), anxiety (73%), insomnia (69%), headache (46%), muscle tension (46%), and increased irritability (46%). One instance of suicidal ideation was severe enough to require psychiatric hospitalization (this was the only instance of suicidal ideation among the 106 patients in the meta-analysis by Bahji et al²⁸); the patient subsequently completed the trial. Transient elevation in pulse, blood pressure, and body temperature were noted during sessions that did not require medical intervention.²⁹ Ot’alora et al³⁰ found similar common adverse reactions: anxiety, dizziness, fatigue, headache, jaw clenching, muscle tension, and irritability. There were no serious adverse effects.

While the use of MDMA in controlled interventional settings has resulted in relatively few adverse events, robust literature describes the risks associated with the nonclinical/recreational use of MDMA. In cases of MDMA toxicity, death has been reported.³¹ Acutely, MDMA may lead to sympathomimetic effects, including serotonin syndrome.³¹ Longer-term studies of MDMA users have found chronic recreational use to be associated with worse sleep, poor mood, anxiety disturbances, memory deficits, and attention problems.³² MDMA has also been found to have moderate potential for abuse.³³

Ketamine/esketamine

Ketamine is a dissociative anesthetic with some hallucinogenic effects. It is an N-methyl-d-aspartate (NMDA) antagonist frequently used in anesthesia, and it can induce a state of sedation, immobility, pain relief, and amnesia. In low doses, ketamine is used off-label to treat major depressive disorder and treatment-resistant depression. Most clinical trials of ketamine for depression have dosed IV ketamine from 0.5 to 1 mg/kg 1 to 3 times a week. It can also be administered as an IM, intranasal, oral, subcutaneous, or sublingual formulation.³⁴

Esketamine, the S(+)-enantiomer of ketamine, is also an NDMA antagonist. It has been developed as an intranasal formulation, typically dosed between 56 and 84 mg 2 times a week for 1 month, once a week for the following month, and once every 1 to 2 weeks thereafter.³⁵ In most ketamine and esketamine trials, these compounds have been used without psychotherapy, although some interventions have integrated psychotherapy with ketamine treatment.³⁶

Bennett et al³⁷ elaborated on 3 paradigms for ketamine treatment: biochemical, psychotherapeutic, and psychedelic. The biochemical model examines the neuro­biological effects of the medication. The psychotherapeutic model views ketamine as a way of assisting the psychotherapy process. The psychedelic model utilizes ketamine’s dissociative and psychedelic properties to induce an altered state of consciousness for therapeutic purposes and psychospiritual exploration.

Continue to: A systematic review...

A systematic review of the common adverse effects associated with ketamine use in clinical trials for depression reported dissociation, sedation, perceptual disturbances, anxiety, agitation, euphoria, hypertension, tachycardia, headache, and dizziness.³⁸ Adverse effects experienced with esketamine in clinical trials include dissociation, dizziness, sedation, hypertension, hypoesthesia, gastrointestinal symptoms, and euphoric mood (Table 3³⁹). A recent systemic review found both ketamine and esketamine demonstrated higher adverse events than control conditions. IV ketamine also demonstrated lower dropouts and adverse events when compared to intranasal esketamine.⁴⁰

Nonclinical/recreational use of ketamine is notable for urinary toxicity; 20% to 30% of frequent users of ketamine experience urinary problems that can range from ketamine-induced cystitis to hydronephrosis and kidney failure.⁴¹ Liver toxicity has also been reported with chronic use of high-dose ketamine. Ketamine is liable to abuse, dependence, and tolerance. There is evidence that nonclinical use of ketamine may lead to morbidity; impairment of memory, cognition, and attention; and urinary, gastric, and hepatic pathology.⁴²

The FDA prescribing information for esketamine lists aneurysmal vascular disease, arteriovenous malformation, and intracerebral hemorrhage as contraindications.³⁹ Patients with cardiovascular and cerebrovascular conditions and risk factors may be at increased risk of adverse effects due to an increase in blood pressure. Esketamine can impair attention, judgment, thinking, reaction speed, and motor skills. Other adverse effects of esketamine noted in the prescribing information include dissociation, dizziness, nausea, sedation, vertigo, hypoesthesia, anxiety, lethargy, vomiting, feeling drunk, and euphoric mood.³⁹A study of postmarketing safety concerns with esketamine using reports submitted to the FDA Adverse Event Reporting System (FAERS) revealed signals for suicidal ideation (reporting odds ratio [ROR] 24.03; 95% CI, 18.72 to 30.84), and completed suicide (ROR 5.75; 95% CI, 3.18 to 10.41).⁴³ The signals for suicidal and self-injurious ideation remained significant when compared to venlafaxine in the FAERS database, while suicide attempts and fatal suicide attempts were no longer significant.⁴³ Concerns regarding acute ketamine withdrawal have also been described in case reports.⁴⁴

Other safety considerations of psychedelics

Hallucinogen persisting perception disorder

Hallucinogen persisting perception disorder (HPPD) is a rare condition associated with hallucinogen use. It is characterized by the recurrence of perceptual disturbances that an individual experienced while using hallucinogenic substances that creates significant distress or impairment.⁴⁵ Because HPPD is a rare disorder, the exact prevalence is not well characterized, but DSM-5 suggests it is approximately 4.2%.⁴⁶ HPPD is associated with numerous psychoactive substances, including psilocybin, ayahuasca, MDMA, and ketamine, but is most associated with LSD.⁴⁵ HPPD is more likely to arise in individuals with histories of psychiatric illness or substance use disorders.⁴⁷

Serotonin toxicity and other serotonergic interactions

Serotonin toxicity is a risk of serotonergic psychedelics, particularly when such agents are used in combination with serotonergic psychotropic medications. The most severe manifestation of serotonin toxicity is serotonin syndrome, which manifests as a life-threatening condition characterized by myoclonus, rigidity, agitation, delirium, and unstable cardiovascular functioning. Many psychedelic compounds have transient serotonin-related adverse effects, but serotonin toxicity due to psychedelic use is rare.⁴⁸ Due to their mechanism of action, classical psychedelics are relatively safe in combination with monoamine oxidase inhibitors (MAOIs) and selective serotonin reuptake inhibitors. MDMA is a serotonin-releasing agent that has a higher risk of serotonin syndrome or hypertensive crisis when used in combination with MAOIs.⁴⁸

Boundary violations in psychedelic-assisted psychotherapy

A key task facing psychedelic research is to establish parameters for the safe and ethical use of these agents. This is particularly relevant given the hype that surrounds the psychedelic resurgence and what we know about the controversial history of these substances. Anderson et al⁴⁹ argued that “psychedelics can have lingering effects that include increased suggestibility and affective instability, as well as altered ego structure, social behaviour, and philosophical worldview. Stated simply, psychedelics can induce a vulnerable state both during and after treatment sessions.”

Continue to: Psychedelic treatment...

Psychedelic treatments such as psilocybin and MDMA are typically offered within the context of psychedelic-assisted psychotherapy, and some researchers have raised concerns regarding boundary violations,⁵⁰ given the patients’ particularly vulnerable states. In addition to concerns about sexual harassment, the financial exploitation of older adults is also a possible risk.⁵¹

Caveats to consider

Novel psychedelics therapies have demonstrated promising preliminary results for a broad range of psychiatric indications, including depression, end-of-life distress, substance use disorders, PTSD, and improving well-being. To date, psychedelics are generally well-tolerated in adults in clinical trials.

However, when it comes to adverse effects, there are challenges in regards to interpreting the psychedelic state.⁵² Some consider any unpleasant or unsettling psychedelic experience as an adverse reaction, while others consider it part of the therapeutic process. This is exemplified by the case of vomiting during ayahuasca ceremonies, which is generally considered part of the ritual. In such instances, it is essential to obtain informed consent and ensure participants are aware of these aspects of the experience. Compared to substances such as alcohol, opioids, and cocaine, psychedelics are remarkably safe from a physiological perspective, especially with regards to the risks of toxicity, mortality, and dependence.⁵³ Their psychological safety is less established, and more caution and research is needed. The high incidence of adverse effects and suicidality noted in the recent phase 2 trial of psilocybin in treatment resistant depression are a reminder of this.¹³

There is uncertainty regarding the magnitude of risk in real-world clinical practice, particularly regarding addiction, suicidality, and precipitation or worsening of psychotic disorders. For example, note the extensive exclusion criteria used in the psilocybin vs escitalopram RCT by Carhart-Harris et al¹²: currently or previously diagnosed psychotic disorder, immediate family member with a diagnosed psychotic disorder, significant medical comorbidity (eg, diabetes, epilepsy, severe cardiovascular disease, hepatic or renal failure), history of suicide attempts requiring hospitalization, history of mania, pregnancy, and abnormal QT interval prolongation, among others. It would be prudent to keep these contraindications in mind regarding the clinical use of psychedelics in the future. This is particularly important in older adults because such patients often have substantial medical comorbidities and are at greater risk for adverse effects. For ketamine, research has implicated the role of mu opioid agonism in mediating ketamine’s antidepressant effects.⁵⁴ This raises concerns about abuse, dependence, and addiction, especially with long-term use. There are also concerns regarding protracted withdrawal symptoms and associated suicidality.⁵⁵

The therapeutic use of psychedelics is an exciting and promising avenue, with ongoing research and a rapidly evolving literature. An attitude of cautious optimism is warranted, but efficacy and safety should be demonstrated in well-designed and rigorous trials with adequate long-term follow-up before routine clinical use is recommended.

Bottom Line

In clinical trials for psychiatric disorders, psychedelics have been associated with a range of cognitive, psychiatric, and psychoactive adverse effects but generally have been well-tolerated, with a low incidence of serious adverse effects.

Related Resources

• American Psychiatric Association. Position Statement on the Use of Psychedelic and Empathogenic Agents for Mental Health Conditions. Updated July 2022. Accessed October 24, 2022. https://www.psychiatry.org/getattachment/d5c13619-ca1f-491f-a7a8-b7141c800904/Position-Use-of-Psychedelic-Empathogenic-Agents.pdf
• Johns Hopkins Center for Psychedelic & Consciousness Research. https://hopkinspsychedelic.org/
• Multidisciplinary Association for Psychedelic Studies (MAPS). https://maps.org/

Drug Brand Names

Esketamine • Spravato
Ketamine • Ketalar
Venlafaxine • Effexor

Resilience has been defined as the ability to adapt and thrive in the face of adversity, acute stress, or trauma.¹ Originally conceived as an inborn trait characteristic, resilience is now conceptualized as a dynamic, multidimensional capacity influenced by the interactions between internal factors (eg, personality, cognitive capacity, physical health) and environmental resources (eg, social status, financial stability).^2,3 Resilience in older adults (typically defined as age ≥65) can improve the prognosis and outcomes for physical and mental conditions.⁴ The construct is closely aligned with “successful aging” and can be fostered in older adults, leading to improved physical and mental health and well-being.⁵

While initially resilience was conceptualized as the opposite of depressive states, recent research has identified resilience in the context of major depressive disorder (MDD) as the net effects of various psychosocial and biological variables that decrease the risk of onset, relapse, or depressive illness severity and increase the probability or speed of recovery.⁶ Late-life depression (LLD) in adults age >65 is a common and debilitating disease, often leading to decreased psychological well-being, increased cognitive decline, and excess mortality.^7,8 LLD is associated with several factors, such as cerebrovascular disease, neurodegenerative disease, and inflammation, all of which could contribute to brain vulnerability and an increased risk of depression.⁹ Physical and cognitive engagement, physical activity, and high brain reserve have been shown to confer resilience to affective and cognitive changes in older adults, despite brain vulnerability.⁹

The greatest levels of resilience have been observed in individuals in their fifth decade of life and later,^4,10 with high levels of resilience significantly contributing to longevity⁵; however, little is known about which factors contribute to heterogeneity in resilience characteristics and outcomes.⁴ Furthermore, the concept of resilience continues to raise numerous questions, including:

• how resilience should be measured or defined
• what factors promote or deter the development of resilience
• the effects of resilience on various health and psychological outcomes
• which interventions are effective in enhancing resilience in older adults.⁴

In this article, we describe resilience in older adults with LLD, its clinical and neurocognitive correlates, and underlying neurobiological and immunological biomarkers. We also examine resilience-building interventions, such as mind-body therapies (MBTs), that have been shown to enhance resilience by promoting positive perceptions of difficult experiences and challenges.

Clinical and neurocognitive correlates of resilience

Resilience varies substantially among older adults with LLD as well as across the lifespan of an individual.¹¹ Identifying clinical components and predictors of resilience may usefully inform the development and testing of interventions to prevent and treat LLD.¹¹ One tool widely used to measure resilience—the self-report Connor-Davidson Resilience Scale (CD-RISC)¹²— has been found to have clinically relevant characteristics.^1,11 Using data from 337 older adults with LLD, Laird et al¹¹ performed an exploratory factor analysis of the CD-RISC and found a 4-factor model:

• grit
• adaptive coping self-efficacy
• accommodative coping self-efficacy
• spirituality.^1,11

Having a strong sense of purpose and not being easily discouraged by failure were items characteristic of grit.^1,11 The preference to take the lead in problem-solving was typical of items loading on adaptive coping self-efficacy, while accommodative coping self-efficacy measured flexibility, cognitive reframing, a sense of humor, and acceptance in the face of uncontrollable stress.^1,11 Finally, the belief that “things happen for a reason” and that “sometimes fate or God can help me” are characteristics of spirituality. ^1,11 Using a multivariate model, the greatest variance in total resilience scores was explained by less depression, less apathy, higher quality of life, non-White race, and, somewhat counterintuitively, greater medical comorbidity.^1,11 Thus, interventions designed to help older adults cultivate grit, active coping, accommodative coping, and spirituality may enhance resilience in LLD.^1,11

Resilience may also be positively associated with cognitive functioning and could be neuroprotective in LLD.¹³ Laird et al¹³ investigated associations between baseline resilience and several domains of neurocognitive functioning in 288 older adults with LLD. Several positive associations were found between measured language performance and total resilience, active coping, and accommodative coping.¹³ Additionally, total resilience and accommodative coping were significantly associated with a lower self-reported frequency of forgetfulness, a subjective measure of memory used in this study.¹³ Together, these results suggest that interventions targeting language might be useful to improve coping in LLD.¹³ Another interesting finding was that the resilience subdomain of spirituality was negatively associated with memory, language, and executive functioning performance.¹³ A distinction must be made between religious attendance (eg, regular attendance at religious institutions) vs religious beliefs, which may account for the previously reported associations between spirituality and improved cognition.¹³

Continue to: Self-reported resilience...

Self-reported resilience may also predict greater responsivity to antidepressant medication in patients with LLD.¹⁴ Older adults with LLD and greater self-reported baseline resilience were more likely to experience improvement or remission from depression with antidepressant treatment.¹⁴ This is congruent with conceptualizations of resilience as “the ability to adapt to and recover from stress.”^14,15 Of the 4 identified resilience factors (grit, adaptive coping, accommodative coping, and spirituality), it appears that accommodative coping predicts LLD treatment response and remission.¹⁴ The unique ability to accommodate is associated with better mental health outcomes in the face of uncontrollable stress.^14,16-18 Older adults appear to engage in more accommodative coping due to frequent uncontrollable stress and aging-related physiological changes (eg, sleep changes, chronic pain, declining cognition). This could make accommodative coping especially important in this population.^14,19

The Figure, adapted from Weisenbach et al,⁹ exhibits factors that contribute to LLD, including cerebrovascular disease, neurodegeneration, and chronic inflammation, all of which can lead to a vulnerable aging brain that is at higher risk for depression, particularly within the context of stress. Clinical and neurocognitive factors associated with resilience can help buffer vulnerable brains from developing depression.

Neurobiological biomarkers of resilience in LLD

Psychobiological consequences can add to existing risk factors and bidirectionally interact to increase health risks, including LLD.⁶ Stress is the primary factor in examining resilience, whether through protective measures or its adverse effects on biological and psychological systems. Resilience is often seen as adaptive maintenance of homeostasis in the face of stress.⁶ Stress and resilience were examined over multiple studies through the lens of several biomarkers, including gross anatomical features, stress response (endocrine, immune, and inflammatory), and cardiovascular indicators.

Gross anatomical indicators: Findings from neuroimaging

The neurobiology underlying psychological resilience involves brain networks associated with stress response, negative affect, and emotional control.¹⁹ Increased amygdala reactivity and amygdala frontal connectivity are often implicated in neurobiological models of resilience.²⁰ Leaver et al²⁰ correlated psychological resilience measures with amygdala function in 48 depressed vs nondepressed individuals using functional magnetic resonance imaging. Specifically, they targeted the basolateral, centromedial, and superficial nuclei groups of the amygdala while comparing the 2 groups based on resilience scores (CD-RISC), depressive symptom severity, and depression status.²⁰ A significant correlation was identified between resilience and connectivity between the superficial group of amygdala nuclei and the ventral default mode network (VDMN).²⁰ High levels of psychological resilience were associated with lower basal amygdala activity and decreased connectivity between amygdala nuclei and the VDMN.²⁰ Additionally, lower depressive symptoms were associated with higher connectivity between the amygdalae and the dorsal frontal networks.²⁰ These results suggest a complex relationship between amygdala activity, dorsal frontal regions, resilience, and LLD.²⁰

Vlasova et al²¹ further addressed the multi­factorial character of psychological resilience. The associations between the 4 factors of resilience and the regional integrity of white matter in older adults with LLD were examined using diffusion-weighted MRI.²¹ Grit was found to be associated with greater white matter integrity in the genu of the corpus callosum and cingulum bundle in LLD.²¹ There was also a positive association between grit and fractional anisotropy (FA) in the callosal region connecting the prefrontal cortex and FA in the cingulum fibers.²¹ However, results regarding the FA in the cingulum fibers did not survive correction for multiple comparisons and should be considered with caution, pending further research.²¹

Continue to: Stress response biomarkers of resilience

Stress response biomarkers include endocrine, immune, and inflammatory indices. Stress has been identified as a factor in inflammatory responses. Stress-related overstimulation of the HPA axis may increase the risk of LLD.²² Numerous studies have demonstrated an association between increased levels of peripheral proinflammatory cytokines and depressive symptoms in older adults.²³ Interleukin-6 (IL-6) has been increasingly linked with depressive symptoms and poor memory performance in older adults.⁹ There also appears to be an interaction of inflammatory and vascular processes predisposing to LLD, as increased levels of IL-6 and C-reactive protein have been associated with higher white matter pathology.⁹ Additionally, proinflammatory cytokines impact monoamine neurotransmitter pathways, leading to a reduction in tryptophan and serotonin synthesis, disruption of glucocorticoid receptors, and a decrease in hippocampal neurotrophic support.⁹ Alexopoulos et al²⁴ further explain that a prolonged CNS immune response can affect emotional and cognitive network functions related to LLD and has a role in the etiology of depressive symptoms in older adults.

Cardiovascular comorbidity and autonomic nervous system dysfunction

Many studies have revealed evidence of a bidirectional association between cardio­vascular disease and depression.²⁵ Dysregulation of the autonomic nervous system (ANS) is an underlying mechanism that could explain the link between cardiovascular risk and MDD via heart rate variability (HRV), though research examining age-related capacities provide conflicting data.^25,26 HRV is a surrogate index of resting cardiac vagal outflow that represents the ability of the ANS to adapt to psychological, social, and physical environmental changes.²⁷ Higher overall HRV is associated with greater self-regulating capacity, including behavioral, cognitive, and emotional control.²⁸ Additionally, higher HRV may serve as a biomarker of resilience to the development of stress-related disorders such as MDD. Recent studies have shown an overall reduction in HRV in older adults with LLD.²⁹ When high- and low-frequency HRV were investigated separately, only low-frequency HRV was significantly reduced in patients with depression.²⁹ One explanation is that older adults with depression have impaired or reduced baroreflex sensitivity and gain, which is often associated with an increased risk of mortality following cardiac events.³⁰ More research is needed to examine the complex processes required to better characterize the correlation between resilience in cardiovascular disease and autonomic dysfunction.

The Box^6,31,32 describes the relationship between markers of cellular health and resilience.

Box

Mind-body therapies

There is increasing interest in improving older adults’ physical and emotional well-being while promoting resilience through stress-reducing lifestyle interventions such as MBTs.³³ Because MBTs are often considered a natural and safer option compared to conventional medicine, these interventions are rapidly gaining popularity in the United States.^33,34 According to a 2017 National Health Survey, there were 5% to 10% increases in the use of yoga, meditation, and chiropractic care from 2012 to 2017, with growing evidence supporting MBTs as minimally invasive, cost-effective approaches for managing stress and neurocognitive disorders.³⁵ In contrast to pharmacologic approaches, MBTs can be used to train individuals to self-regulate in the face of adversity and stress, thus increasing their resilience.

MBTs can be divided into mindful movement exercises and meditative practices. Mindful movement exercises include yoga, tai chi, and qigong. Meditative practices that do not include movement include progressive relaxation, mindfulness, meditation, and acceptance therapies. On average, both mindful movement exercise (eg, yoga) and multicomponent mindfulness-based interventions (eg, mindfulness-based cognitive therapy, mindfulness-based stress reduction [MBSR], and mindfulness-based relapse prevention) can be as effective as other active treatments for psychiatric disorders such as MDD, anxiety, and substance use disorders.^36,37 MBSR specifically has been shown to increase empathy, self-control, self-compassion, relationship quality, mindfulness, and spirituality as well as decrease rumination in healthy older adults.³⁸ This suggests that MBSR can help strengthen the 4 factors of resilience.

Continue to: Research has also begun...

Research has also begun to evaluate the neurobiological mechanisms by which meditative therapies enhance resilience in mental health disorders, and several promising mechanistic domains (neural, hormonal, immune, cellular, and cardiovascular) have been identified.³⁹ The physical yoga discipline includes asanas (postures), pranayama (breathing techniques), and dhyana (meditation). With the inclusion of mindfulness training, yoga involves the practice of meditation as well as the dynamic combination of proprioceptive and interoceptive awareness, resulting in both attention and profound focus.⁴⁰ Dedicated yoga practice allows an individual to develop skills to withdraw the senses (pratyahara), concentrate the mind (dharana), and establish unwavering awareness (dhyana).⁴¹ The physical and cognitive benefits associated with yoga and mindfulness may be due to mechanisms including pranayama and activation of the parasympathetic nervous system; meditative or contemplative practices; increased body perception; stronger functional connectivity within the basal ganglia; or neuroplastic effects of increased grey matter volume and amygdala with regional enlargement.⁴¹ The new learning aspect of yoga practice may contribute to enhancing or improving various aspects of cognition, although the mechanisms are yet to be clarified.

Continued research in this area will promote the integration of MBTs into mainstream clinical practice and help alleviate the increased chronic health burden of an aging population. In the face of the COVID-19 pandemic, public interest in improving resilience and mental health⁴² can be supported by MBTs that can improve coping with the stress of the pandemic and enhance critical organ function (eg, lungs, heart, brain).^43,44 As a result of these limitations, many resources and health care services have used telehealth and virtual platforms to adapt to these challenges and continue offering MBTs.⁴⁵

Enhancing resilience to improve clinical outcomes

Increasing our understanding of clinical, neurocognitive, and neurobiological markers of resilience in older adults with and without depression could inform the development of interventions that treat and prevent mood and cognitive disorders of aging. Furthermore, stress reduction, decreased inflammation, and improved emotional regulation may have direct neuroplastic effects on the brain, leading to greater resilience. Complementary use of MBTs combined with standard antidepressant treatment may allow for additional improvement in clinical outcomes of LLD, including resilience, quality of life, general health, and cognitive function. Additional research testing the efficacy of those interventions designed to improve resilience in older adults with mood and mental disorders is needed.

Bottom Line

Identifying the clinical, neurocognitive, and neurobiological biomarkers of resilience in late-life depression could aid in the development of targeted interventions that treat and prevent mood and cognitive disorders of aging. Mind-body interventions can help boost resilience and improve outcomes in geriatric patients with mood and cognitive disorders.

Related Resources

• Lavretsky H. Resilience and Aging: Research and Practice. Johns Hopkins University Press; 2014.
• Lavretsky H, Sajatovic M, Reynolds CF, eds. Complementary and Integrative Therapies for Mental Health and Aging. Oxford University Press; 2016.
• Eyre HA, Berk M, Lavretsky H, et al, eds. Convergence Mental Health: A Transdisciplinary Approach to Innovation. Oxford University Press; 2021.
• UCLA Jane & Terry Semel Institute for Neuroscience & Human Behavior. Late-life Depression, Stress, and Wellness Research Program. https://www.semel.ucla.edu/latelife

Resilience has been defined as the ability to adapt and thrive in the face of adversity, acute stress, or trauma.¹ Originally conceived as an inborn trait characteristic, resilience is now conceptualized as a dynamic, multidimensional capacity influenced by the interactions between internal factors (eg, personality, cognitive capacity, physical health) and environmental resources (eg, social status, financial stability).^2,3 Resilience in older adults (typically defined as age ≥65) can improve the prognosis and outcomes for physical and mental conditions.⁴ The construct is closely aligned with “successful aging” and can be fostered in older adults, leading to improved physical and mental health and well-being.⁵

While initially resilience was conceptualized as the opposite of depressive states, recent research has identified resilience in the context of major depressive disorder (MDD) as the net effects of various psychosocial and biological variables that decrease the risk of onset, relapse, or depressive illness severity and increase the probability or speed of recovery.⁶ Late-life depression (LLD) in adults age >65 is a common and debilitating disease, often leading to decreased psychological well-being, increased cognitive decline, and excess mortality.^7,8 LLD is associated with several factors, such as cerebrovascular disease, neurodegenerative disease, and inflammation, all of which could contribute to brain vulnerability and an increased risk of depression.⁹ Physical and cognitive engagement, physical activity, and high brain reserve have been shown to confer resilience to affective and cognitive changes in older adults, despite brain vulnerability.⁹

The greatest levels of resilience have been observed in individuals in their fifth decade of life and later,^4,10 with high levels of resilience significantly contributing to longevity⁵; however, little is known about which factors contribute to heterogeneity in resilience characteristics and outcomes.⁴ Furthermore, the concept of resilience continues to raise numerous questions, including:

• how resilience should be measured or defined
• what factors promote or deter the development of resilience
• the effects of resilience on various health and psychological outcomes
• which interventions are effective in enhancing resilience in older adults.⁴

In this article, we describe resilience in older adults with LLD, its clinical and neurocognitive correlates, and underlying neurobiological and immunological biomarkers. We also examine resilience-building interventions, such as mind-body therapies (MBTs), that have been shown to enhance resilience by promoting positive perceptions of difficult experiences and challenges.

Clinical and neurocognitive correlates of resilience

Resilience varies substantially among older adults with LLD as well as across the lifespan of an individual.¹¹ Identifying clinical components and predictors of resilience may usefully inform the development and testing of interventions to prevent and treat LLD.¹¹ One tool widely used to measure resilience—the self-report Connor-Davidson Resilience Scale (CD-RISC)¹²— has been found to have clinically relevant characteristics.^1,11 Using data from 337 older adults with LLD, Laird et al¹¹ performed an exploratory factor analysis of the CD-RISC and found a 4-factor model:

• grit
• adaptive coping self-efficacy
• accommodative coping self-efficacy
• spirituality.^1,11

Having a strong sense of purpose and not being easily discouraged by failure were items characteristic of grit.^1,11 The preference to take the lead in problem-solving was typical of items loading on adaptive coping self-efficacy, while accommodative coping self-efficacy measured flexibility, cognitive reframing, a sense of humor, and acceptance in the face of uncontrollable stress.^1,11 Finally, the belief that “things happen for a reason” and that “sometimes fate or God can help me” are characteristics of spirituality. ^1,11 Using a multivariate model, the greatest variance in total resilience scores was explained by less depression, less apathy, higher quality of life, non-White race, and, somewhat counterintuitively, greater medical comorbidity.^1,11 Thus, interventions designed to help older adults cultivate grit, active coping, accommodative coping, and spirituality may enhance resilience in LLD.^1,11

Resilience may also be positively associated with cognitive functioning and could be neuroprotective in LLD.¹³ Laird et al¹³ investigated associations between baseline resilience and several domains of neurocognitive functioning in 288 older adults with LLD. Several positive associations were found between measured language performance and total resilience, active coping, and accommodative coping.¹³ Additionally, total resilience and accommodative coping were significantly associated with a lower self-reported frequency of forgetfulness, a subjective measure of memory used in this study.¹³ Together, these results suggest that interventions targeting language might be useful to improve coping in LLD.¹³ Another interesting finding was that the resilience subdomain of spirituality was negatively associated with memory, language, and executive functioning performance.¹³ A distinction must be made between religious attendance (eg, regular attendance at religious institutions) vs religious beliefs, which may account for the previously reported associations between spirituality and improved cognition.¹³

Continue to: Self-reported resilience...

Self-reported resilience may also predict greater responsivity to antidepressant medication in patients with LLD.¹⁴ Older adults with LLD and greater self-reported baseline resilience were more likely to experience improvement or remission from depression with antidepressant treatment.¹⁴ This is congruent with conceptualizations of resilience as “the ability to adapt to and recover from stress.”^14,15 Of the 4 identified resilience factors (grit, adaptive coping, accommodative coping, and spirituality), it appears that accommodative coping predicts LLD treatment response and remission.¹⁴ The unique ability to accommodate is associated with better mental health outcomes in the face of uncontrollable stress.^14,16-18 Older adults appear to engage in more accommodative coping due to frequent uncontrollable stress and aging-related physiological changes (eg, sleep changes, chronic pain, declining cognition). This could make accommodative coping especially important in this population.^14,19

The Figure, adapted from Weisenbach et al,⁹ exhibits factors that contribute to LLD, including cerebrovascular disease, neurodegeneration, and chronic inflammation, all of which can lead to a vulnerable aging brain that is at higher risk for depression, particularly within the context of stress. Clinical and neurocognitive factors associated with resilience can help buffer vulnerable brains from developing depression.

Neurobiological biomarkers of resilience in LLD

Psychobiological consequences can add to existing risk factors and bidirectionally interact to increase health risks, including LLD.⁶ Stress is the primary factor in examining resilience, whether through protective measures or its adverse effects on biological and psychological systems. Resilience is often seen as adaptive maintenance of homeostasis in the face of stress.⁶ Stress and resilience were examined over multiple studies through the lens of several biomarkers, including gross anatomical features, stress response (endocrine, immune, and inflammatory), and cardiovascular indicators.

Gross anatomical indicators: Findings from neuroimaging

The neurobiology underlying psychological resilience involves brain networks associated with stress response, negative affect, and emotional control.¹⁹ Increased amygdala reactivity and amygdala frontal connectivity are often implicated in neurobiological models of resilience.²⁰ Leaver et al²⁰ correlated psychological resilience measures with amygdala function in 48 depressed vs nondepressed individuals using functional magnetic resonance imaging. Specifically, they targeted the basolateral, centromedial, and superficial nuclei groups of the amygdala while comparing the 2 groups based on resilience scores (CD-RISC), depressive symptom severity, and depression status.²⁰ A significant correlation was identified between resilience and connectivity between the superficial group of amygdala nuclei and the ventral default mode network (VDMN).²⁰ High levels of psychological resilience were associated with lower basal amygdala activity and decreased connectivity between amygdala nuclei and the VDMN.²⁰ Additionally, lower depressive symptoms were associated with higher connectivity between the amygdalae and the dorsal frontal networks.²⁰ These results suggest a complex relationship between amygdala activity, dorsal frontal regions, resilience, and LLD.²⁰

Vlasova et al²¹ further addressed the multi­factorial character of psychological resilience. The associations between the 4 factors of resilience and the regional integrity of white matter in older adults with LLD were examined using diffusion-weighted MRI.²¹ Grit was found to be associated with greater white matter integrity in the genu of the corpus callosum and cingulum bundle in LLD.²¹ There was also a positive association between grit and fractional anisotropy (FA) in the callosal region connecting the prefrontal cortex and FA in the cingulum fibers.²¹ However, results regarding the FA in the cingulum fibers did not survive correction for multiple comparisons and should be considered with caution, pending further research.²¹

Continue to: Stress response biomarkers of resilience

Stress response biomarkers include endocrine, immune, and inflammatory indices. Stress has been identified as a factor in inflammatory responses. Stress-related overstimulation of the HPA axis may increase the risk of LLD.²² Numerous studies have demonstrated an association between increased levels of peripheral proinflammatory cytokines and depressive symptoms in older adults.²³ Interleukin-6 (IL-6) has been increasingly linked with depressive symptoms and poor memory performance in older adults.⁹ There also appears to be an interaction of inflammatory and vascular processes predisposing to LLD, as increased levels of IL-6 and C-reactive protein have been associated with higher white matter pathology.⁹ Additionally, proinflammatory cytokines impact monoamine neurotransmitter pathways, leading to a reduction in tryptophan and serotonin synthesis, disruption of glucocorticoid receptors, and a decrease in hippocampal neurotrophic support.⁹ Alexopoulos et al²⁴ further explain that a prolonged CNS immune response can affect emotional and cognitive network functions related to LLD and has a role in the etiology of depressive symptoms in older adults.

Cardiovascular comorbidity and autonomic nervous system dysfunction

Many studies have revealed evidence of a bidirectional association between cardio­vascular disease and depression.²⁵ Dysregulation of the autonomic nervous system (ANS) is an underlying mechanism that could explain the link between cardiovascular risk and MDD via heart rate variability (HRV), though research examining age-related capacities provide conflicting data.^25,26 HRV is a surrogate index of resting cardiac vagal outflow that represents the ability of the ANS to adapt to psychological, social, and physical environmental changes.²⁷ Higher overall HRV is associated with greater self-regulating capacity, including behavioral, cognitive, and emotional control.²⁸ Additionally, higher HRV may serve as a biomarker of resilience to the development of stress-related disorders such as MDD. Recent studies have shown an overall reduction in HRV in older adults with LLD.²⁹ When high- and low-frequency HRV were investigated separately, only low-frequency HRV was significantly reduced in patients with depression.²⁹ One explanation is that older adults with depression have impaired or reduced baroreflex sensitivity and gain, which is often associated with an increased risk of mortality following cardiac events.³⁰ More research is needed to examine the complex processes required to better characterize the correlation between resilience in cardiovascular disease and autonomic dysfunction.

The Box^6,31,32 describes the relationship between markers of cellular health and resilience.

Box

Mind-body therapies

There is increasing interest in improving older adults’ physical and emotional well-being while promoting resilience through stress-reducing lifestyle interventions such as MBTs.³³ Because MBTs are often considered a natural and safer option compared to conventional medicine, these interventions are rapidly gaining popularity in the United States.^33,34 According to a 2017 National Health Survey, there were 5% to 10% increases in the use of yoga, meditation, and chiropractic care from 2012 to 2017, with growing evidence supporting MBTs as minimally invasive, cost-effective approaches for managing stress and neurocognitive disorders.³⁵ In contrast to pharmacologic approaches, MBTs can be used to train individuals to self-regulate in the face of adversity and stress, thus increasing their resilience.

MBTs can be divided into mindful movement exercises and meditative practices. Mindful movement exercises include yoga, tai chi, and qigong. Meditative practices that do not include movement include progressive relaxation, mindfulness, meditation, and acceptance therapies. On average, both mindful movement exercise (eg, yoga) and multicomponent mindfulness-based interventions (eg, mindfulness-based cognitive therapy, mindfulness-based stress reduction [MBSR], and mindfulness-based relapse prevention) can be as effective as other active treatments for psychiatric disorders such as MDD, anxiety, and substance use disorders.^36,37 MBSR specifically has been shown to increase empathy, self-control, self-compassion, relationship quality, mindfulness, and spirituality as well as decrease rumination in healthy older adults.³⁸ This suggests that MBSR can help strengthen the 4 factors of resilience.

Continue to: Research has also begun...

Research has also begun to evaluate the neurobiological mechanisms by which meditative therapies enhance resilience in mental health disorders, and several promising mechanistic domains (neural, hormonal, immune, cellular, and cardiovascular) have been identified.³⁹ The physical yoga discipline includes asanas (postures), pranayama (breathing techniques), and dhyana (meditation). With the inclusion of mindfulness training, yoga involves the practice of meditation as well as the dynamic combination of proprioceptive and interoceptive awareness, resulting in both attention and profound focus.⁴⁰ Dedicated yoga practice allows an individual to develop skills to withdraw the senses (pratyahara), concentrate the mind (dharana), and establish unwavering awareness (dhyana).⁴¹ The physical and cognitive benefits associated with yoga and mindfulness may be due to mechanisms including pranayama and activation of the parasympathetic nervous system; meditative or contemplative practices; increased body perception; stronger functional connectivity within the basal ganglia; or neuroplastic effects of increased grey matter volume and amygdala with regional enlargement.⁴¹ The new learning aspect of yoga practice may contribute to enhancing or improving various aspects of cognition, although the mechanisms are yet to be clarified.

Continued research in this area will promote the integration of MBTs into mainstream clinical practice and help alleviate the increased chronic health burden of an aging population. In the face of the COVID-19 pandemic, public interest in improving resilience and mental health⁴² can be supported by MBTs that can improve coping with the stress of the pandemic and enhance critical organ function (eg, lungs, heart, brain).^43,44 As a result of these limitations, many resources and health care services have used telehealth and virtual platforms to adapt to these challenges and continue offering MBTs.⁴⁵

Enhancing resilience to improve clinical outcomes

Increasing our understanding of clinical, neurocognitive, and neurobiological markers of resilience in older adults with and without depression could inform the development of interventions that treat and prevent mood and cognitive disorders of aging. Furthermore, stress reduction, decreased inflammation, and improved emotional regulation may have direct neuroplastic effects on the brain, leading to greater resilience. Complementary use of MBTs combined with standard antidepressant treatment may allow for additional improvement in clinical outcomes of LLD, including resilience, quality of life, general health, and cognitive function. Additional research testing the efficacy of those interventions designed to improve resilience in older adults with mood and mental disorders is needed.

Bottom Line

Identifying the clinical, neurocognitive, and neurobiological biomarkers of resilience in late-life depression could aid in the development of targeted interventions that treat and prevent mood and cognitive disorders of aging. Mind-body interventions can help boost resilience and improve outcomes in geriatric patients with mood and cognitive disorders.

Related Resources

• Lavretsky H. Resilience and Aging: Research and Practice. Johns Hopkins University Press; 2014.
• Lavretsky H, Sajatovic M, Reynolds CF, eds. Complementary and Integrative Therapies for Mental Health and Aging. Oxford University Press; 2016.
• Eyre HA, Berk M, Lavretsky H, et al, eds. Convergence Mental Health: A Transdisciplinary Approach to Innovation. Oxford University Press; 2021.
• UCLA Jane & Terry Semel Institute for Neuroscience & Human Behavior. Late-life Depression, Stress, and Wellness Research Program. https://www.semel.ucla.edu/latelife

Resilience has been defined as the ability to adapt and thrive in the face of adversity, acute stress, or trauma.¹ Originally conceived as an inborn trait characteristic, resilience is now conceptualized as a dynamic, multidimensional capacity influenced by the interactions between internal factors (eg, personality, cognitive capacity, physical health) and environmental resources (eg, social status, financial stability).^2,3 Resilience in older adults (typically defined as age ≥65) can improve the prognosis and outcomes for physical and mental conditions.⁴ The construct is closely aligned with “successful aging” and can be fostered in older adults, leading to improved physical and mental health and well-being.⁵

While initially resilience was conceptualized as the opposite of depressive states, recent research has identified resilience in the context of major depressive disorder (MDD) as the net effects of various psychosocial and biological variables that decrease the risk of onset, relapse, or depressive illness severity and increase the probability or speed of recovery.⁶ Late-life depression (LLD) in adults age >65 is a common and debilitating disease, often leading to decreased psychological well-being, increased cognitive decline, and excess mortality.^7,8 LLD is associated with several factors, such as cerebrovascular disease, neurodegenerative disease, and inflammation, all of which could contribute to brain vulnerability and an increased risk of depression.⁹ Physical and cognitive engagement, physical activity, and high brain reserve have been shown to confer resilience to affective and cognitive changes in older adults, despite brain vulnerability.⁹

The greatest levels of resilience have been observed in individuals in their fifth decade of life and later,^4,10 with high levels of resilience significantly contributing to longevity⁵; however, little is known about which factors contribute to heterogeneity in resilience characteristics and outcomes.⁴ Furthermore, the concept of resilience continues to raise numerous questions, including:

• how resilience should be measured or defined
• what factors promote or deter the development of resilience
• the effects of resilience on various health and psychological outcomes
• which interventions are effective in enhancing resilience in older adults.⁴

In this article, we describe resilience in older adults with LLD, its clinical and neurocognitive correlates, and underlying neurobiological and immunological biomarkers. We also examine resilience-building interventions, such as mind-body therapies (MBTs), that have been shown to enhance resilience by promoting positive perceptions of difficult experiences and challenges.

Clinical and neurocognitive correlates of resilience

Resilience varies substantially among older adults with LLD as well as across the lifespan of an individual.¹¹ Identifying clinical components and predictors of resilience may usefully inform the development and testing of interventions to prevent and treat LLD.¹¹ One tool widely used to measure resilience—the self-report Connor-Davidson Resilience Scale (CD-RISC)¹²— has been found to have clinically relevant characteristics.^1,11 Using data from 337 older adults with LLD, Laird et al¹¹ performed an exploratory factor analysis of the CD-RISC and found a 4-factor model:

• grit
• adaptive coping self-efficacy
• accommodative coping self-efficacy
• spirituality.^1,11

Having a strong sense of purpose and not being easily discouraged by failure were items characteristic of grit.^1,11 The preference to take the lead in problem-solving was typical of items loading on adaptive coping self-efficacy, while accommodative coping self-efficacy measured flexibility, cognitive reframing, a sense of humor, and acceptance in the face of uncontrollable stress.^1,11 Finally, the belief that “things happen for a reason” and that “sometimes fate or God can help me” are characteristics of spirituality. ^1,11 Using a multivariate model, the greatest variance in total resilience scores was explained by less depression, less apathy, higher quality of life, non-White race, and, somewhat counterintuitively, greater medical comorbidity.^1,11 Thus, interventions designed to help older adults cultivate grit, active coping, accommodative coping, and spirituality may enhance resilience in LLD.^1,11

Resilience may also be positively associated with cognitive functioning and could be neuroprotective in LLD.¹³ Laird et al¹³ investigated associations between baseline resilience and several domains of neurocognitive functioning in 288 older adults with LLD. Several positive associations were found between measured language performance and total resilience, active coping, and accommodative coping.¹³ Additionally, total resilience and accommodative coping were significantly associated with a lower self-reported frequency of forgetfulness, a subjective measure of memory used in this study.¹³ Together, these results suggest that interventions targeting language might be useful to improve coping in LLD.¹³ Another interesting finding was that the resilience subdomain of spirituality was negatively associated with memory, language, and executive functioning performance.¹³ A distinction must be made between religious attendance (eg, regular attendance at religious institutions) vs religious beliefs, which may account for the previously reported associations between spirituality and improved cognition.¹³

Continue to: Self-reported resilience...

Self-reported resilience may also predict greater responsivity to antidepressant medication in patients with LLD.¹⁴ Older adults with LLD and greater self-reported baseline resilience were more likely to experience improvement or remission from depression with antidepressant treatment.¹⁴ This is congruent with conceptualizations of resilience as “the ability to adapt to and recover from stress.”^14,15 Of the 4 identified resilience factors (grit, adaptive coping, accommodative coping, and spirituality), it appears that accommodative coping predicts LLD treatment response and remission.¹⁴ The unique ability to accommodate is associated with better mental health outcomes in the face of uncontrollable stress.^14,16-18 Older adults appear to engage in more accommodative coping due to frequent uncontrollable stress and aging-related physiological changes (eg, sleep changes, chronic pain, declining cognition). This could make accommodative coping especially important in this population.^14,19

The Figure, adapted from Weisenbach et al,⁹ exhibits factors that contribute to LLD, including cerebrovascular disease, neurodegeneration, and chronic inflammation, all of which can lead to a vulnerable aging brain that is at higher risk for depression, particularly within the context of stress. Clinical and neurocognitive factors associated with resilience can help buffer vulnerable brains from developing depression.

Neurobiological biomarkers of resilience in LLD

Psychobiological consequences can add to existing risk factors and bidirectionally interact to increase health risks, including LLD.⁶ Stress is the primary factor in examining resilience, whether through protective measures or its adverse effects on biological and psychological systems. Resilience is often seen as adaptive maintenance of homeostasis in the face of stress.⁶ Stress and resilience were examined over multiple studies through the lens of several biomarkers, including gross anatomical features, stress response (endocrine, immune, and inflammatory), and cardiovascular indicators.

Gross anatomical indicators: Findings from neuroimaging

The neurobiology underlying psychological resilience involves brain networks associated with stress response, negative affect, and emotional control.¹⁹ Increased amygdala reactivity and amygdala frontal connectivity are often implicated in neurobiological models of resilience.²⁰ Leaver et al²⁰ correlated psychological resilience measures with amygdala function in 48 depressed vs nondepressed individuals using functional magnetic resonance imaging. Specifically, they targeted the basolateral, centromedial, and superficial nuclei groups of the amygdala while comparing the 2 groups based on resilience scores (CD-RISC), depressive symptom severity, and depression status.²⁰ A significant correlation was identified between resilience and connectivity between the superficial group of amygdala nuclei and the ventral default mode network (VDMN).²⁰ High levels of psychological resilience were associated with lower basal amygdala activity and decreased connectivity between amygdala nuclei and the VDMN.²⁰ Additionally, lower depressive symptoms were associated with higher connectivity between the amygdalae and the dorsal frontal networks.²⁰ These results suggest a complex relationship between amygdala activity, dorsal frontal regions, resilience, and LLD.²⁰

Vlasova et al²¹ further addressed the multi­factorial character of psychological resilience. The associations between the 4 factors of resilience and the regional integrity of white matter in older adults with LLD were examined using diffusion-weighted MRI.²¹ Grit was found to be associated with greater white matter integrity in the genu of the corpus callosum and cingulum bundle in LLD.²¹ There was also a positive association between grit and fractional anisotropy (FA) in the callosal region connecting the prefrontal cortex and FA in the cingulum fibers.²¹ However, results regarding the FA in the cingulum fibers did not survive correction for multiple comparisons and should be considered with caution, pending further research.²¹

Continue to: Stress response biomarkers of resilience

Stress response biomarkers include endocrine, immune, and inflammatory indices. Stress has been identified as a factor in inflammatory responses. Stress-related overstimulation of the HPA axis may increase the risk of LLD.²² Numerous studies have demonstrated an association between increased levels of peripheral proinflammatory cytokines and depressive symptoms in older adults.²³ Interleukin-6 (IL-6) has been increasingly linked with depressive symptoms and poor memory performance in older adults.⁹ There also appears to be an interaction of inflammatory and vascular processes predisposing to LLD, as increased levels of IL-6 and C-reactive protein have been associated with higher white matter pathology.⁹ Additionally, proinflammatory cytokines impact monoamine neurotransmitter pathways, leading to a reduction in tryptophan and serotonin synthesis, disruption of glucocorticoid receptors, and a decrease in hippocampal neurotrophic support.⁹ Alexopoulos et al²⁴ further explain that a prolonged CNS immune response can affect emotional and cognitive network functions related to LLD and has a role in the etiology of depressive symptoms in older adults.

Cardiovascular comorbidity and autonomic nervous system dysfunction

Many studies have revealed evidence of a bidirectional association between cardio­vascular disease and depression.²⁵ Dysregulation of the autonomic nervous system (ANS) is an underlying mechanism that could explain the link between cardiovascular risk and MDD via heart rate variability (HRV), though research examining age-related capacities provide conflicting data.^25,26 HRV is a surrogate index of resting cardiac vagal outflow that represents the ability of the ANS to adapt to psychological, social, and physical environmental changes.²⁷ Higher overall HRV is associated with greater self-regulating capacity, including behavioral, cognitive, and emotional control.²⁸ Additionally, higher HRV may serve as a biomarker of resilience to the development of stress-related disorders such as MDD. Recent studies have shown an overall reduction in HRV in older adults with LLD.²⁹ When high- and low-frequency HRV were investigated separately, only low-frequency HRV was significantly reduced in patients with depression.²⁹ One explanation is that older adults with depression have impaired or reduced baroreflex sensitivity and gain, which is often associated with an increased risk of mortality following cardiac events.³⁰ More research is needed to examine the complex processes required to better characterize the correlation between resilience in cardiovascular disease and autonomic dysfunction.

The Box^6,31,32 describes the relationship between markers of cellular health and resilience.

Box

Mind-body therapies

There is increasing interest in improving older adults’ physical and emotional well-being while promoting resilience through stress-reducing lifestyle interventions such as MBTs.³³ Because MBTs are often considered a natural and safer option compared to conventional medicine, these interventions are rapidly gaining popularity in the United States.^33,34 According to a 2017 National Health Survey, there were 5% to 10% increases in the use of yoga, meditation, and chiropractic care from 2012 to 2017, with growing evidence supporting MBTs as minimally invasive, cost-effective approaches for managing stress and neurocognitive disorders.³⁵ In contrast to pharmacologic approaches, MBTs can be used to train individuals to self-regulate in the face of adversity and stress, thus increasing their resilience.

MBTs can be divided into mindful movement exercises and meditative practices. Mindful movement exercises include yoga, tai chi, and qigong. Meditative practices that do not include movement include progressive relaxation, mindfulness, meditation, and acceptance therapies. On average, both mindful movement exercise (eg, yoga) and multicomponent mindfulness-based interventions (eg, mindfulness-based cognitive therapy, mindfulness-based stress reduction [MBSR], and mindfulness-based relapse prevention) can be as effective as other active treatments for psychiatric disorders such as MDD, anxiety, and substance use disorders.^36,37 MBSR specifically has been shown to increase empathy, self-control, self-compassion, relationship quality, mindfulness, and spirituality as well as decrease rumination in healthy older adults.³⁸ This suggests that MBSR can help strengthen the 4 factors of resilience.

Continue to: Research has also begun...

Research has also begun to evaluate the neurobiological mechanisms by which meditative therapies enhance resilience in mental health disorders, and several promising mechanistic domains (neural, hormonal, immune, cellular, and cardiovascular) have been identified.³⁹ The physical yoga discipline includes asanas (postures), pranayama (breathing techniques), and dhyana (meditation). With the inclusion of mindfulness training, yoga involves the practice of meditation as well as the dynamic combination of proprioceptive and interoceptive awareness, resulting in both attention and profound focus.⁴⁰ Dedicated yoga practice allows an individual to develop skills to withdraw the senses (pratyahara), concentrate the mind (dharana), and establish unwavering awareness (dhyana).⁴¹ The physical and cognitive benefits associated with yoga and mindfulness may be due to mechanisms including pranayama and activation of the parasympathetic nervous system; meditative or contemplative practices; increased body perception; stronger functional connectivity within the basal ganglia; or neuroplastic effects of increased grey matter volume and amygdala with regional enlargement.⁴¹ The new learning aspect of yoga practice may contribute to enhancing or improving various aspects of cognition, although the mechanisms are yet to be clarified.

Continued research in this area will promote the integration of MBTs into mainstream clinical practice and help alleviate the increased chronic health burden of an aging population. In the face of the COVID-19 pandemic, public interest in improving resilience and mental health⁴² can be supported by MBTs that can improve coping with the stress of the pandemic and enhance critical organ function (eg, lungs, heart, brain).^43,44 As a result of these limitations, many resources and health care services have used telehealth and virtual platforms to adapt to these challenges and continue offering MBTs.⁴⁵

Enhancing resilience to improve clinical outcomes

Increasing our understanding of clinical, neurocognitive, and neurobiological markers of resilience in older adults with and without depression could inform the development of interventions that treat and prevent mood and cognitive disorders of aging. Furthermore, stress reduction, decreased inflammation, and improved emotional regulation may have direct neuroplastic effects on the brain, leading to greater resilience. Complementary use of MBTs combined with standard antidepressant treatment may allow for additional improvement in clinical outcomes of LLD, including resilience, quality of life, general health, and cognitive function. Additional research testing the efficacy of those interventions designed to improve resilience in older adults with mood and mental disorders is needed.

Bottom Line

Identifying the clinical, neurocognitive, and neurobiological biomarkers of resilience in late-life depression could aid in the development of targeted interventions that treat and prevent mood and cognitive disorders of aging. Mind-body interventions can help boost resilience and improve outcomes in geriatric patients with mood and cognitive disorders.

Related Resources

• Lavretsky H. Resilience and Aging: Research and Practice. Johns Hopkins University Press; 2014.
• Lavretsky H, Sajatovic M, Reynolds CF, eds. Complementary and Integrative Therapies for Mental Health and Aging. Oxford University Press; 2016.
• Eyre HA, Berk M, Lavretsky H, et al, eds. Convergence Mental Health: A Transdisciplinary Approach to Innovation. Oxford University Press; 2021.
• UCLA Jane & Terry Semel Institute for Neuroscience & Human Behavior. Late-life Depression, Stress, and Wellness Research Program. https://www.semel.ucla.edu/latelife

Ms. A, age 22, is a college student who presents for an initial psychiatric evaluation. Her body mass index (BMI) is 20 (normal range: 18.5 to 24.9), and her medical history is positive only for childhood asthma. She has been treated for major depressive disorder with venlafaxine by her previous psychiatrist. While this antidepressant has been effective for some symptoms, she has experienced adverse effects and is interested in a different medication. During the evaluation, Ms. A remarks that she had a “scare” last night when the condom broke while having sex with her boyfriend. She says that she is interested in having children at some point, but not at present; she is concerned that getting pregnant now would cause her depression to “spiral out of control.”

Unwanted or mistimed pregnancies account for 45% of all pregnancies.¹ While there are ramifications for any unintended pregnancy, the risks for patients with mental illness are greater and include potential adverse effects on the neonate from both psychiatric disease and psychiatric medication use, worse obstetrical outcomes for patients with untreated mental illness, and worsening of psychiatric symptoms and suicide risk in the peripartum period.² These risks become even more pronounced when psychiatric medications are reflexively discontinued or reduced in pregnancy, which is commonly done contrary to best practice recommendations. In the United States, the recent Supreme Court decision in Dobbs v Jackson Women’s Health Organization has erased federal protections for abortion previously conferred by Roe v Wade. As a result, as of early October 2022, abortion had been made illegal in 11 states, and was likely to be banned in many others, most commonly in states where there is limited support for either parents or children. Thus, preventing unplanned pregnancies should be a treatment consideration for all medical disciplines.³

Psychiatrists may hesitate to prescribe emergency contraception (EC) due to fears it falls outside the scope of their practice. However, psychiatry has already moved towards prescribing nonpsychiatric medications when doing so clearly benefits the patient. One example is prescribing metformin to address metabolic syndrome related to the use of second-generation antipsychotics. Emergency contraceptives have strong safety profiles and are easy to prescribe. Unfortunately, there are many barriers to increasing access to emergency contraceptives for psychiatric patients.⁴ These include the erroneous belief that laboratory and physical exams are needed before starting EC, cost and/or limited stock of emergency contraceptives at pharmacies, and general confusion regarding what constitutes EC vs an oral abortive (Table 1^5-10). Psychiatrists are particularly well-positioned to support the reproductive autonomy and well-being of patients who struggle to engage with other clinicians. This article aims to help psychiatrists better understand EC so they can comfortably prescribe it before their patients need it.

What is emergency contraception?

EC is medications or devices that patients can use after sexual intercourse to prevent pregnancy. They do not impede the development of an established pregnancy and thus are not abortifacients. EC is not recommended as a primary means of contraception,⁹ but it can be extremely valuable to reduce pregnancy risk after unprotected intercourse or contraceptive failures such as broken condoms or missed doses of birth control pills. EC can prevent ≥95% of pregnancies when taken within 5 days of at-risk intercourse.¹¹

Methods of EC fall into 2 categories: oral medications (sometimes referred to as “morning after pills”) and intrauterine devices (IUDs). IUDs are the most effective means of EC, especially for patients with higher BMIs or who may be taking medications such as cytochrome P450 (CYP)3A4 inducers that could interfere with the effectiveness of oral methods. IUDs also have the advantage of providing highly effective ongoing contraception.⁶ However, IUDs require in-office placement by a trained clinician, and patients may experience difficulty obtaining placement within 5 days of unprotected sex. Therefore, oral medication is the most common form of EC.

Oral EC is safe and effective, and professional societies (including the American College of Obstetricians and Gynecologists⁶ and the American Academy of Pediatrics⁷) recommend routinely prescribing oral EC for patients in advance of need. Advance prescribing eliminates barriers to accessing EC, increases the use of EC, and does not encourage risky sexual behaviors.¹⁰

Overview of oral emergency contraception

Two medications are FDA-approved for use as oral EC: ulipristal acetate and levonorgestrel. Both are available in generic and branded versions. While many common birth control pills can also be safely used off-label as emergency contraception (an approach known as the Yuzpe method), they are less effective, not as well-tolerated, and require knowledge of the specific type of pill the patient has available.⁹ Oral EC appears to work primarily through delay or inhibition of ovulation, and is unlikely to prevent implantation of a fertilized egg.⁹

Continue to: Ulipristal acetate

Ulipristal acetate (UPA) is an oral progesterone receptor agonist-antagonist taken as a single 30 mg dose up to 5 days after unprotected sex. Pregnancy rates from a single act of unprotected sex followed by UPA use range from 0% to 1.8%.⁴ Many pharmacies stock UPA, and others (especially chain pharmacies) report being able to order and fill it within 24 hours.¹²

Levonorgestrel (LNG) is an oral progestin that is available by prescription and has also been approved for over-the-counter sale to patients of all ages and sexes (without the need to show identification) since 2013.⁸ It is administered as a single 1.5 mg dose taken as soon as possible up to 3 days after unprotected sex, although it may continue to provide benefits when taken within 5 days. Pregnancy rates from a single act of unprotected sex followed by LNG use range from 0.3% to 2.6%, with much higher odds among women who are obese.⁴ LNG is available both by prescription or over-the-counter,¹³ although it is often kept in a locked cabinet or behind the counter, and staff are often misinformed regarding the lack of age restrictions for sale without a prescription.¹⁴

Safety and adverse effects. According to the CDC, there are no conditions for which the risks outweigh the advantages of use of either UPA or LNG,⁵ and patients for whom hormonal birth control is otherwise contraindicated can still use them safely. If a pregnancy has already occurred, taking EC will not harm the developing fetus; it is also safe to use when breastfeeding.⁵ Both medications are generally well-tolerated—neither has been causally linked to deaths or serious complications,⁵ and the most common adverse effects are headache (approximately 19%) and nausea (approximately 12%), in addition to irregular bleeding, fatigue, dizziness, and abdominal pain.¹⁵ Oral EC may be used more than once, even within the same menstrual cycle. Patients who use EC repeatedly should be encouraged to discuss more efficacious contraceptive options with their primary physician or gynecologist.

Will oral EC affect psychiatric treatment?

Oral EC is unlikely to have a meaningful effect on psychiatric symptoms or management, particularly when compared to the significant impacts of unintended pregnancies. Neither medication is known to have any clinically significant impacts on the pharmacokinetics or pharmacodynamics of psychotropic medications, although the effectiveness of both medications can be impaired by CYP3A4 inducers such as carbamazepine.⁵ In addition, while research has not specifically examined the impact of EC on psychiatric symptoms, the broader literature on hormonal contraception indicates that most patients with psychiatric disorders generally report similar or lower rates of mood symptoms associated with their use.¹⁶ Some women treated with hormonal contraceptives do develop dysphoric mood,¹⁶ but any such effects resulting from LNG would likely be transient. Mood disruptions or other psychiatric symptoms have not been associated with UPA use.

How to prescribe oral emergency contraception

Who and when. Women of reproductive age should be counseled about EC as part of anticipatory guidance, regardless of their current intentions for sexual behaviors. Patients do not need a physical examination or pregnancy test before being prescribed or using oral EC.⁹ Much like how intranasal naloxone is prescribed, prescriptions should be provided in advance of need, with multiple refills to facilitate ready access when needed.

Continue to: Which to prescribe

Which to prescribe. UPA is more effective in preventing pregnancy than LNG at all time points up to 120 hours after sex, including for women who are overweight or obese.¹⁵ As such, it is recommended as the first-line choice. However, because LNG is available without prescription and is more readily available (including via online order), it may be a good choice for patients who need rapid EC or who prefer a medication that does not require a prescription (Table 2^4,5,8,9,15).

What to tell patients. Patients should be instructed to fill their prescription before they expect to use it, to ensure ready availability when desired (Table 3^5,9). Oral EC is shelf stable for at least 3 years when stored in a cool, dry environment. Patients should take the medication as soon as possible following at-risk sexual intercourse (Table 4). Tell them that if they vomit within 3 hours of taking the medication, they should take a second dose. Remind patients that EC does not protect against sexually transmitted infections, or from sex that occurs after the medication is taken (in fact, they can increase the possibility of pregnancy later in that menstrual cycle due to delayed ovulation).⁹ Counsel patients to abstain from sex or to use barrier contraception for 7 days after use. Those who take birth control pills can resume use immediately after using LNG; they should wait 5 days after taking UPA.

No routine follow-up is needed after taking UPA or LNG. However, patients should get a pregnancy test if their period does not start within 3 weeks, and should seek medical evaluation if they experience significant lower abdominal pain or persistent irregular bleeding in order to rule out pregnancy-related complications. Patients who use EC repeatedly should be recommended to pursue routine contraceptive care.

Billing. Counseling your patients about contraception can increase the reimbursement you receive by adding to the complexity of the encounter (regardless of whether you prescribe a medication) through use of the ICD-10 code Z30.0.

Emergency contraception for special populations

Some patients face additional challenges to effective EC that should be considered when counseling and prescribing. Table 5^{4,5,7,15,17-21} discusses the use of EC in these special populations. Of particular importance for psychiatrists, LNG is less effective at preventing undesired pregnancy among patients who are overweight or obese,^15,17,18 and strong CYP3A4-inducing agents may decrease the effectiveness of both LNG and UPA.⁵ Keep in mind, however, that the advantages of using either UPA or LNG outweigh the risks for all populations.⁵ Patients must be aware of appropriate information in order to make informed decisions, but should not be discouraged from using EC.

Continue to: Other groups of patients...

Other groups of patients may face barriers due to some clinicians’ hesitancy regarding their ability to consent to reproductive care. Most patients with psychiatric illnesses have decision-making capacity regarding reproductive issues.²² Although EC is supported by the American Academy of Pediatrics,⁷ patients age <18 have varying rights to consent across states,²¹ and merit special consideration.

CASE CONTINUED

Ms. A does not wish to get pregnant at this time, and expresses fears that her recent contraceptive failure could lead to an unintended pregnancy. In addition to her psychiatric treatment, her psychiatrist should discuss EC options with her. She has a healthy BMI and had inadequately protected sex <1 day ago, so her clinician may prescribe LNG (to ensure rapid access for immediate use) in addition to UPA for her to have available in case of future “scares.” The psychiatrist should consider pharmacologic treatment with an antidepressant with a relatively safe reproductive record (eg, sertraline).²³ This is considered preventive ethics, since Ms. A is of reproductive age, even if she is not presently planning to get pregnant, due to the aforementioned high rate of unplanned pregnancy.^23,24 It is also important for the psychiatrist to continue the dialogue in future sessions about preventing unintended pregnancy. Since Ms. A has benefited from a psychotropic medication when not pregnant, it will be important to discuss with her the risks and benefits of medication should she plan a pregnancy.

Bottom Line

Patients with mental illnesses are at increased risk of adverse outcomes resulting from unintended pregnancies. Clinicians should counsel patients about emergency contraception (EC) as a part of routine psychiatric care, and should prescribe oral EC in advance of patient need to facilitate effective use.

Related Resources

• American College of Obstetricians and Gynecologists Practice Bulletin on Emergency Contraception. https://www.acog.org/clinical/clinical-guidance/practice-bulletin/ articles/2015/09/emergency-contraception
• State policies on emergency contraception. https://www.guttmacher.org/state-policy/explore/emergency-contraception
• State policies on minors’ access to contraceptive services. https://www.guttmacher.org/state-policy/explore/minors-access-contraceptive-services
• Patient-oriented contraceptive education materials (in English and Spanish). https://shop.powertodecide.org/ptd-category/educational-materials

Drug Brand Names

Carbamazepine • Tegretol
Levonorgestrel • Plan B One-Step, Fallback
Metformin • Glucophage
Naloxone • Narcan
Norethindrone • Aygestin
Sertraline • Zoloft
Topiramate • Topamax
Ulipristal acetate • Ella
Venlafaxine • Effexor

Ms. A, age 22, is a college student who presents for an initial psychiatric evaluation. Her body mass index (BMI) is 20 (normal range: 18.5 to 24.9), and her medical history is positive only for childhood asthma. She has been treated for major depressive disorder with venlafaxine by her previous psychiatrist. While this antidepressant has been effective for some symptoms, she has experienced adverse effects and is interested in a different medication. During the evaluation, Ms. A remarks that she had a “scare” last night when the condom broke while having sex with her boyfriend. She says that she is interested in having children at some point, but not at present; she is concerned that getting pregnant now would cause her depression to “spiral out of control.”

Unwanted or mistimed pregnancies account for 45% of all pregnancies.¹ While there are ramifications for any unintended pregnancy, the risks for patients with mental illness are greater and include potential adverse effects on the neonate from both psychiatric disease and psychiatric medication use, worse obstetrical outcomes for patients with untreated mental illness, and worsening of psychiatric symptoms and suicide risk in the peripartum period.² These risks become even more pronounced when psychiatric medications are reflexively discontinued or reduced in pregnancy, which is commonly done contrary to best practice recommendations. In the United States, the recent Supreme Court decision in Dobbs v Jackson Women’s Health Organization has erased federal protections for abortion previously conferred by Roe v Wade. As a result, as of early October 2022, abortion had been made illegal in 11 states, and was likely to be banned in many others, most commonly in states where there is limited support for either parents or children. Thus, preventing unplanned pregnancies should be a treatment consideration for all medical disciplines.³

Psychiatrists may hesitate to prescribe emergency contraception (EC) due to fears it falls outside the scope of their practice. However, psychiatry has already moved towards prescribing nonpsychiatric medications when doing so clearly benefits the patient. One example is prescribing metformin to address metabolic syndrome related to the use of second-generation antipsychotics. Emergency contraceptives have strong safety profiles and are easy to prescribe. Unfortunately, there are many barriers to increasing access to emergency contraceptives for psychiatric patients.⁴ These include the erroneous belief that laboratory and physical exams are needed before starting EC, cost and/or limited stock of emergency contraceptives at pharmacies, and general confusion regarding what constitutes EC vs an oral abortive (Table 1^5-10). Psychiatrists are particularly well-positioned to support the reproductive autonomy and well-being of patients who struggle to engage with other clinicians. This article aims to help psychiatrists better understand EC so they can comfortably prescribe it before their patients need it.

What is emergency contraception?

EC is medications or devices that patients can use after sexual intercourse to prevent pregnancy. They do not impede the development of an established pregnancy and thus are not abortifacients. EC is not recommended as a primary means of contraception,⁹ but it can be extremely valuable to reduce pregnancy risk after unprotected intercourse or contraceptive failures such as broken condoms or missed doses of birth control pills. EC can prevent ≥95% of pregnancies when taken within 5 days of at-risk intercourse.¹¹

Methods of EC fall into 2 categories: oral medications (sometimes referred to as “morning after pills”) and intrauterine devices (IUDs). IUDs are the most effective means of EC, especially for patients with higher BMIs or who may be taking medications such as cytochrome P450 (CYP)3A4 inducers that could interfere with the effectiveness of oral methods. IUDs also have the advantage of providing highly effective ongoing contraception.⁶ However, IUDs require in-office placement by a trained clinician, and patients may experience difficulty obtaining placement within 5 days of unprotected sex. Therefore, oral medication is the most common form of EC.

Oral EC is safe and effective, and professional societies (including the American College of Obstetricians and Gynecologists⁶ and the American Academy of Pediatrics⁷) recommend routinely prescribing oral EC for patients in advance of need. Advance prescribing eliminates barriers to accessing EC, increases the use of EC, and does not encourage risky sexual behaviors.¹⁰

Overview of oral emergency contraception

Two medications are FDA-approved for use as oral EC: ulipristal acetate and levonorgestrel. Both are available in generic and branded versions. While many common birth control pills can also be safely used off-label as emergency contraception (an approach known as the Yuzpe method), they are less effective, not as well-tolerated, and require knowledge of the specific type of pill the patient has available.⁹ Oral EC appears to work primarily through delay or inhibition of ovulation, and is unlikely to prevent implantation of a fertilized egg.⁹

Continue to: Ulipristal acetate

Ulipristal acetate (UPA) is an oral progesterone receptor agonist-antagonist taken as a single 30 mg dose up to 5 days after unprotected sex. Pregnancy rates from a single act of unprotected sex followed by UPA use range from 0% to 1.8%.⁴ Many pharmacies stock UPA, and others (especially chain pharmacies) report being able to order and fill it within 24 hours.¹²

Levonorgestrel (LNG) is an oral progestin that is available by prescription and has also been approved for over-the-counter sale to patients of all ages and sexes (without the need to show identification) since 2013.⁸ It is administered as a single 1.5 mg dose taken as soon as possible up to 3 days after unprotected sex, although it may continue to provide benefits when taken within 5 days. Pregnancy rates from a single act of unprotected sex followed by LNG use range from 0.3% to 2.6%, with much higher odds among women who are obese.⁴ LNG is available both by prescription or over-the-counter,¹³ although it is often kept in a locked cabinet or behind the counter, and staff are often misinformed regarding the lack of age restrictions for sale without a prescription.¹⁴

Safety and adverse effects. According to the CDC, there are no conditions for which the risks outweigh the advantages of use of either UPA or LNG,⁵ and patients for whom hormonal birth control is otherwise contraindicated can still use them safely. If a pregnancy has already occurred, taking EC will not harm the developing fetus; it is also safe to use when breastfeeding.⁵ Both medications are generally well-tolerated—neither has been causally linked to deaths or serious complications,⁵ and the most common adverse effects are headache (approximately 19%) and nausea (approximately 12%), in addition to irregular bleeding, fatigue, dizziness, and abdominal pain.¹⁵ Oral EC may be used more than once, even within the same menstrual cycle. Patients who use EC repeatedly should be encouraged to discuss more efficacious contraceptive options with their primary physician or gynecologist.

Will oral EC affect psychiatric treatment?

Oral EC is unlikely to have a meaningful effect on psychiatric symptoms or management, particularly when compared to the significant impacts of unintended pregnancies. Neither medication is known to have any clinically significant impacts on the pharmacokinetics or pharmacodynamics of psychotropic medications, although the effectiveness of both medications can be impaired by CYP3A4 inducers such as carbamazepine.⁵ In addition, while research has not specifically examined the impact of EC on psychiatric symptoms, the broader literature on hormonal contraception indicates that most patients with psychiatric disorders generally report similar or lower rates of mood symptoms associated with their use.¹⁶ Some women treated with hormonal contraceptives do develop dysphoric mood,¹⁶ but any such effects resulting from LNG would likely be transient. Mood disruptions or other psychiatric symptoms have not been associated with UPA use.

How to prescribe oral emergency contraception

Who and when. Women of reproductive age should be counseled about EC as part of anticipatory guidance, regardless of their current intentions for sexual behaviors. Patients do not need a physical examination or pregnancy test before being prescribed or using oral EC.⁹ Much like how intranasal naloxone is prescribed, prescriptions should be provided in advance of need, with multiple refills to facilitate ready access when needed.

Continue to: Which to prescribe

Which to prescribe. UPA is more effective in preventing pregnancy than LNG at all time points up to 120 hours after sex, including for women who are overweight or obese.¹⁵ As such, it is recommended as the first-line choice. However, because LNG is available without prescription and is more readily available (including via online order), it may be a good choice for patients who need rapid EC or who prefer a medication that does not require a prescription (Table 2^4,5,8,9,15).

What to tell patients. Patients should be instructed to fill their prescription before they expect to use it, to ensure ready availability when desired (Table 3^5,9). Oral EC is shelf stable for at least 3 years when stored in a cool, dry environment. Patients should take the medication as soon as possible following at-risk sexual intercourse (Table 4). Tell them that if they vomit within 3 hours of taking the medication, they should take a second dose. Remind patients that EC does not protect against sexually transmitted infections, or from sex that occurs after the medication is taken (in fact, they can increase the possibility of pregnancy later in that menstrual cycle due to delayed ovulation).⁹ Counsel patients to abstain from sex or to use barrier contraception for 7 days after use. Those who take birth control pills can resume use immediately after using LNG; they should wait 5 days after taking UPA.

No routine follow-up is needed after taking UPA or LNG. However, patients should get a pregnancy test if their period does not start within 3 weeks, and should seek medical evaluation if they experience significant lower abdominal pain or persistent irregular bleeding in order to rule out pregnancy-related complications. Patients who use EC repeatedly should be recommended to pursue routine contraceptive care.

Billing. Counseling your patients about contraception can increase the reimbursement you receive by adding to the complexity of the encounter (regardless of whether you prescribe a medication) through use of the ICD-10 code Z30.0.

Emergency contraception for special populations

Some patients face additional challenges to effective EC that should be considered when counseling and prescribing. Table 5^{4,5,7,15,17-21} discusses the use of EC in these special populations. Of particular importance for psychiatrists, LNG is less effective at preventing undesired pregnancy among patients who are overweight or obese,^15,17,18 and strong CYP3A4-inducing agents may decrease the effectiveness of both LNG and UPA.⁵ Keep in mind, however, that the advantages of using either UPA or LNG outweigh the risks for all populations.⁵ Patients must be aware of appropriate information in order to make informed decisions, but should not be discouraged from using EC.

Continue to: Other groups of patients...

Other groups of patients may face barriers due to some clinicians’ hesitancy regarding their ability to consent to reproductive care. Most patients with psychiatric illnesses have decision-making capacity regarding reproductive issues.²² Although EC is supported by the American Academy of Pediatrics,⁷ patients age <18 have varying rights to consent across states,²¹ and merit special consideration.

CASE CONTINUED

Ms. A does not wish to get pregnant at this time, and expresses fears that her recent contraceptive failure could lead to an unintended pregnancy. In addition to her psychiatric treatment, her psychiatrist should discuss EC options with her. She has a healthy BMI and had inadequately protected sex <1 day ago, so her clinician may prescribe LNG (to ensure rapid access for immediate use) in addition to UPA for her to have available in case of future “scares.” The psychiatrist should consider pharmacologic treatment with an antidepressant with a relatively safe reproductive record (eg, sertraline).²³ This is considered preventive ethics, since Ms. A is of reproductive age, even if she is not presently planning to get pregnant, due to the aforementioned high rate of unplanned pregnancy.^23,24 It is also important for the psychiatrist to continue the dialogue in future sessions about preventing unintended pregnancy. Since Ms. A has benefited from a psychotropic medication when not pregnant, it will be important to discuss with her the risks and benefits of medication should she plan a pregnancy.

Bottom Line

Patients with mental illnesses are at increased risk of adverse outcomes resulting from unintended pregnancies. Clinicians should counsel patients about emergency contraception (EC) as a part of routine psychiatric care, and should prescribe oral EC in advance of patient need to facilitate effective use.

Related Resources

• American College of Obstetricians and Gynecologists Practice Bulletin on Emergency Contraception. https://www.acog.org/clinical/clinical-guidance/practice-bulletin/ articles/2015/09/emergency-contraception
• State policies on emergency contraception. https://www.guttmacher.org/state-policy/explore/emergency-contraception
• State policies on minors’ access to contraceptive services. https://www.guttmacher.org/state-policy/explore/minors-access-contraceptive-services
• Patient-oriented contraceptive education materials (in English and Spanish). https://shop.powertodecide.org/ptd-category/educational-materials

Drug Brand Names

Carbamazepine • Tegretol
Levonorgestrel • Plan B One-Step, Fallback
Metformin • Glucophage
Naloxone • Narcan
Norethindrone • Aygestin
Sertraline • Zoloft
Topiramate • Topamax
Ulipristal acetate • Ella
Venlafaxine • Effexor

Ms. A, age 22, is a college student who presents for an initial psychiatric evaluation. Her body mass index (BMI) is 20 (normal range: 18.5 to 24.9), and her medical history is positive only for childhood asthma. She has been treated for major depressive disorder with venlafaxine by her previous psychiatrist. While this antidepressant has been effective for some symptoms, she has experienced adverse effects and is interested in a different medication. During the evaluation, Ms. A remarks that she had a “scare” last night when the condom broke while having sex with her boyfriend. She says that she is interested in having children at some point, but not at present; she is concerned that getting pregnant now would cause her depression to “spiral out of control.”

Unwanted or mistimed pregnancies account for 45% of all pregnancies.¹ While there are ramifications for any unintended pregnancy, the risks for patients with mental illness are greater and include potential adverse effects on the neonate from both psychiatric disease and psychiatric medication use, worse obstetrical outcomes for patients with untreated mental illness, and worsening of psychiatric symptoms and suicide risk in the peripartum period.² These risks become even more pronounced when psychiatric medications are reflexively discontinued or reduced in pregnancy, which is commonly done contrary to best practice recommendations. In the United States, the recent Supreme Court decision in Dobbs v Jackson Women’s Health Organization has erased federal protections for abortion previously conferred by Roe v Wade. As a result, as of early October 2022, abortion had been made illegal in 11 states, and was likely to be banned in many others, most commonly in states where there is limited support for either parents or children. Thus, preventing unplanned pregnancies should be a treatment consideration for all medical disciplines.³

Psychiatrists may hesitate to prescribe emergency contraception (EC) due to fears it falls outside the scope of their practice. However, psychiatry has already moved towards prescribing nonpsychiatric medications when doing so clearly benefits the patient. One example is prescribing metformin to address metabolic syndrome related to the use of second-generation antipsychotics. Emergency contraceptives have strong safety profiles and are easy to prescribe. Unfortunately, there are many barriers to increasing access to emergency contraceptives for psychiatric patients.⁴ These include the erroneous belief that laboratory and physical exams are needed before starting EC, cost and/or limited stock of emergency contraceptives at pharmacies, and general confusion regarding what constitutes EC vs an oral abortive (Table 1^5-10). Psychiatrists are particularly well-positioned to support the reproductive autonomy and well-being of patients who struggle to engage with other clinicians. This article aims to help psychiatrists better understand EC so they can comfortably prescribe it before their patients need it.

What is emergency contraception?

EC is medications or devices that patients can use after sexual intercourse to prevent pregnancy. They do not impede the development of an established pregnancy and thus are not abortifacients. EC is not recommended as a primary means of contraception,⁹ but it can be extremely valuable to reduce pregnancy risk after unprotected intercourse or contraceptive failures such as broken condoms or missed doses of birth control pills. EC can prevent ≥95% of pregnancies when taken within 5 days of at-risk intercourse.¹¹

Methods of EC fall into 2 categories: oral medications (sometimes referred to as “morning after pills”) and intrauterine devices (IUDs). IUDs are the most effective means of EC, especially for patients with higher BMIs or who may be taking medications such as cytochrome P450 (CYP)3A4 inducers that could interfere with the effectiveness of oral methods. IUDs also have the advantage of providing highly effective ongoing contraception.⁶ However, IUDs require in-office placement by a trained clinician, and patients may experience difficulty obtaining placement within 5 days of unprotected sex. Therefore, oral medication is the most common form of EC.

Oral EC is safe and effective, and professional societies (including the American College of Obstetricians and Gynecologists⁶ and the American Academy of Pediatrics⁷) recommend routinely prescribing oral EC for patients in advance of need. Advance prescribing eliminates barriers to accessing EC, increases the use of EC, and does not encourage risky sexual behaviors.¹⁰

Overview of oral emergency contraception

Two medications are FDA-approved for use as oral EC: ulipristal acetate and levonorgestrel. Both are available in generic and branded versions. While many common birth control pills can also be safely used off-label as emergency contraception (an approach known as the Yuzpe method), they are less effective, not as well-tolerated, and require knowledge of the specific type of pill the patient has available.⁹ Oral EC appears to work primarily through delay or inhibition of ovulation, and is unlikely to prevent implantation of a fertilized egg.⁹

Continue to: Ulipristal acetate

Ulipristal acetate (UPA) is an oral progesterone receptor agonist-antagonist taken as a single 30 mg dose up to 5 days after unprotected sex. Pregnancy rates from a single act of unprotected sex followed by UPA use range from 0% to 1.8%.⁴ Many pharmacies stock UPA, and others (especially chain pharmacies) report being able to order and fill it within 24 hours.¹²

Levonorgestrel (LNG) is an oral progestin that is available by prescription and has also been approved for over-the-counter sale to patients of all ages and sexes (without the need to show identification) since 2013.⁸ It is administered as a single 1.5 mg dose taken as soon as possible up to 3 days after unprotected sex, although it may continue to provide benefits when taken within 5 days. Pregnancy rates from a single act of unprotected sex followed by LNG use range from 0.3% to 2.6%, with much higher odds among women who are obese.⁴ LNG is available both by prescription or over-the-counter,¹³ although it is often kept in a locked cabinet or behind the counter, and staff are often misinformed regarding the lack of age restrictions for sale without a prescription.¹⁴

Safety and adverse effects. According to the CDC, there are no conditions for which the risks outweigh the advantages of use of either UPA or LNG,⁵ and patients for whom hormonal birth control is otherwise contraindicated can still use them safely. If a pregnancy has already occurred, taking EC will not harm the developing fetus; it is also safe to use when breastfeeding.⁵ Both medications are generally well-tolerated—neither has been causally linked to deaths or serious complications,⁵ and the most common adverse effects are headache (approximately 19%) and nausea (approximately 12%), in addition to irregular bleeding, fatigue, dizziness, and abdominal pain.¹⁵ Oral EC may be used more than once, even within the same menstrual cycle. Patients who use EC repeatedly should be encouraged to discuss more efficacious contraceptive options with their primary physician or gynecologist.

Will oral EC affect psychiatric treatment?

Oral EC is unlikely to have a meaningful effect on psychiatric symptoms or management, particularly when compared to the significant impacts of unintended pregnancies. Neither medication is known to have any clinically significant impacts on the pharmacokinetics or pharmacodynamics of psychotropic medications, although the effectiveness of both medications can be impaired by CYP3A4 inducers such as carbamazepine.⁵ In addition, while research has not specifically examined the impact of EC on psychiatric symptoms, the broader literature on hormonal contraception indicates that most patients with psychiatric disorders generally report similar or lower rates of mood symptoms associated with their use.¹⁶ Some women treated with hormonal contraceptives do develop dysphoric mood,¹⁶ but any such effects resulting from LNG would likely be transient. Mood disruptions or other psychiatric symptoms have not been associated with UPA use.

How to prescribe oral emergency contraception

Who and when. Women of reproductive age should be counseled about EC as part of anticipatory guidance, regardless of their current intentions for sexual behaviors. Patients do not need a physical examination or pregnancy test before being prescribed or using oral EC.⁹ Much like how intranasal naloxone is prescribed, prescriptions should be provided in advance of need, with multiple refills to facilitate ready access when needed.

Continue to: Which to prescribe

Which to prescribe. UPA is more effective in preventing pregnancy than LNG at all time points up to 120 hours after sex, including for women who are overweight or obese.¹⁵ As such, it is recommended as the first-line choice. However, because LNG is available without prescription and is more readily available (including via online order), it may be a good choice for patients who need rapid EC or who prefer a medication that does not require a prescription (Table 2^4,5,8,9,15).

What to tell patients. Patients should be instructed to fill their prescription before they expect to use it, to ensure ready availability when desired (Table 3^5,9). Oral EC is shelf stable for at least 3 years when stored in a cool, dry environment. Patients should take the medication as soon as possible following at-risk sexual intercourse (Table 4). Tell them that if they vomit within 3 hours of taking the medication, they should take a second dose. Remind patients that EC does not protect against sexually transmitted infections, or from sex that occurs after the medication is taken (in fact, they can increase the possibility of pregnancy later in that menstrual cycle due to delayed ovulation).⁹ Counsel patients to abstain from sex or to use barrier contraception for 7 days after use. Those who take birth control pills can resume use immediately after using LNG; they should wait 5 days after taking UPA.

No routine follow-up is needed after taking UPA or LNG. However, patients should get a pregnancy test if their period does not start within 3 weeks, and should seek medical evaluation if they experience significant lower abdominal pain or persistent irregular bleeding in order to rule out pregnancy-related complications. Patients who use EC repeatedly should be recommended to pursue routine contraceptive care.

Billing. Counseling your patients about contraception can increase the reimbursement you receive by adding to the complexity of the encounter (regardless of whether you prescribe a medication) through use of the ICD-10 code Z30.0.

Emergency contraception for special populations

Some patients face additional challenges to effective EC that should be considered when counseling and prescribing. Table 5^{4,5,7,15,17-21} discusses the use of EC in these special populations. Of particular importance for psychiatrists, LNG is less effective at preventing undesired pregnancy among patients who are overweight or obese,^15,17,18 and strong CYP3A4-inducing agents may decrease the effectiveness of both LNG and UPA.⁵ Keep in mind, however, that the advantages of using either UPA or LNG outweigh the risks for all populations.⁵ Patients must be aware of appropriate information in order to make informed decisions, but should not be discouraged from using EC.

Continue to: Other groups of patients...

Other groups of patients may face barriers due to some clinicians’ hesitancy regarding their ability to consent to reproductive care. Most patients with psychiatric illnesses have decision-making capacity regarding reproductive issues.²² Although EC is supported by the American Academy of Pediatrics,⁷ patients age <18 have varying rights to consent across states,²¹ and merit special consideration.

CASE CONTINUED

Ms. A does not wish to get pregnant at this time, and expresses fears that her recent contraceptive failure could lead to an unintended pregnancy. In addition to her psychiatric treatment, her psychiatrist should discuss EC options with her. She has a healthy BMI and had inadequately protected sex <1 day ago, so her clinician may prescribe LNG (to ensure rapid access for immediate use) in addition to UPA for her to have available in case of future “scares.” The psychiatrist should consider pharmacologic treatment with an antidepressant with a relatively safe reproductive record (eg, sertraline).²³ This is considered preventive ethics, since Ms. A is of reproductive age, even if she is not presently planning to get pregnant, due to the aforementioned high rate of unplanned pregnancy.^23,24 It is also important for the psychiatrist to continue the dialogue in future sessions about preventing unintended pregnancy. Since Ms. A has benefited from a psychotropic medication when not pregnant, it will be important to discuss with her the risks and benefits of medication should she plan a pregnancy.

Bottom Line

Patients with mental illnesses are at increased risk of adverse outcomes resulting from unintended pregnancies. Clinicians should counsel patients about emergency contraception (EC) as a part of routine psychiatric care, and should prescribe oral EC in advance of patient need to facilitate effective use.

Related Resources

• American College of Obstetricians and Gynecologists Practice Bulletin on Emergency Contraception. https://www.acog.org/clinical/clinical-guidance/practice-bulletin/ articles/2015/09/emergency-contraception
• State policies on emergency contraception. https://www.guttmacher.org/state-policy/explore/emergency-contraception
• State policies on minors’ access to contraceptive services. https://www.guttmacher.org/state-policy/explore/minors-access-contraceptive-services
• Patient-oriented contraceptive education materials (in English and Spanish). https://shop.powertodecide.org/ptd-category/educational-materials

Drug Brand Names

Carbamazepine • Tegretol
Levonorgestrel • Plan B One-Step, Fallback
Metformin • Glucophage
Naloxone • Narcan
Norethindrone • Aygestin
Sertraline • Zoloft
Topiramate • Topamax
Ulipristal acetate • Ella
Venlafaxine • Effexor

The principles and practices of positive psychiatry are especially well-suited for work with children, adolescents, and families. Positive psychiatry is “the science and practice of psychiatry that seeks to understand and promote well-being through assessments and interventions aimed at enhancing positive psychosocial factors among people who have or are at risk for developing mental or physical illnesses.”¹ The concept sprung from the momentum of positive psychology, which originated from Seligman et al.² Importantly, the standards and techniques of positive psychiatry are designed as an enhancement, perhaps even as a completion, of more traditional psychiatry, rather than an alternative.³ They come from an acknowledgment that to be most effective as a mental health professional, it is important for clinicians to be experts in the full range of mental functioning.^4,5

For most clinicians currently practicing “traditional” child and adolescent psychiatry, adapting at least some of the principles of positive psychiatry within one’s routine practice will not necessarily involve a radical transformation of thought or effort. Indeed, upon hearing about positive psychiatry principles, many non­professionals express surprise that this is not already considered routine practice. This article briefly outlines some of the basic tenets of positive child psychiatry and describes practical initial steps that can be readily incorporated into one’s day-to-day approach.

Defining pediatric positive psychiatry

There remains a fair amount of discussion and debate regarding what positive psychiatry is and isn’t, and how it fits into routine practice. While there is no official doctrine as to what “counts” as the practice of positive psychiatry, one can arguably divide most of its interventions into 2 main areas. The first is paying additional clinical attention to behaviors commonly associated with wellness or health promotion in youth. These include domains such as exercise, sleep habits, an authoritative parenting style, screen limits, and nutrition. The second area relates to specific techniques or procedures designed to cultivate positive emotions and mindsets; these often are referred to as positive psychology interventions (PPIs).⁶ Examples include gratitude exercises, practicing forgiveness, and activities that build optimism and hope. Many of the latter procedures share poorly defined boundaries with “tried and true” cognitive-behavioral therapy techniques, while others are more distinct to positive psychology and psychiatry. For both health promotion and PPIs, the goal of these interventions is to go beyond response and even remission for a patient to actual mental well-being, which is a construct that has also proven to be somewhat elusive and difficult to define. One well-described model by Seligman⁷ that has been gaining traction is the PERMA model, which breaks down well-being into 5 main components: positive emotions, engagement, relationships, meaning, and accomplishment.

Positive psychiatry: The evidence base

One myth about positive psychiatry is that it involves the pursuit of fringe and scientifically suspect techniques that have fallen under the expanding umbrella of “wellness.” Sadly, numerous unscientific and ineffective remedies have been widely promoted under the guise of wellness, leaving many families and clinicians uncertain about which areas have a solid evidence base and which are scientifically on shakier ground. While the lines delineating what are often referred to as PPI and more traditional psychotherapeutic techniques are blurry, there is increasing evidence supporting the use of PPI.⁸ A recent meta-analysis indicated that these techniques have larger effect sizes for children and young adults compared to older adults.⁹ More research, however, is needed, particularly for youth with diagnosable mental health conditions and for younger children.¹⁰

The evidence supporting the role of wellness and health promotion in preventing and treating pediatric mental health conditions has a quite robust research base. For example, a recent randomized controlled trial found greater reductions in multiple areas of emotional-behavior problems in children treated in a primary care setting with a wellness and health promotion model (the Vermont Family Based Approach) compared to those in a control condition.¹¹ Another study examining the course of attention-deficit/hyperactivity disorder (ADHD) showed a 62% reduction of diagnosis among children who met 7 of 9 health promotion recommendations in areas such as nutrition, physical activity, and screen time, compared to those who met just 1 to 3 of these recommendations.¹² Techniques such as mindfulness also have been found to be useful for adolescents with anxiety disorders.¹³ While a full review of the evidence is beyond the scope of this article, it is fair to say that many health promotion areas (such as exercise, nutrition, sleep habits, positive parenting skills, and some types of mindfulness) have strong scientific support—arguably at a level that is comparable to or even exceeds that of the off-label use of many psychiatric medications. The American Academy of Child and Adolescent Psychiatry has published a brief document that summarizes many age-related health promotion recommendations.¹⁴ The studies that underlie many of these recommendations contradict the misperception that wellness activities are only for already healthy individuals who want to become healthier, and show their utility for patients with more significant and chronic mental health conditions.

Incorporating core principles of positive psychiatry

Table 1 summarizes the core principles of positive child and adolescent psychiatry. There is no official procedure or certification one must complete to be considered a “positive psychiatrist,” and the term itself is somewhat debatable. Incorporating many of the principles of positive psychiatry into one’s daily routine does not necessitate a practice overhaul, and clinicians can integrate as many of these ideas as they deem clinically appropriate. That said, some adjustments to one’s perspective, approach, and workflow are likely needed, and the practice of positive psychiatry is arguably difficult to accomplish within the common “med check” model that emphasizes high volumes of short appointments that focus primarily on symptoms and adverse effects of medications.

Contrary to another misconception about positive psychiatry, working within a positive psychiatry framework does not involve encouraging patients to “put on a happy face” and ignore the very real suffering and trauma that many of them have experienced. Further, adhering to positive psychiatry does not entail abandoning the use of psychopharmacology (although careful prescribing is generally recommended) or applying gimmicks to superficially cover a person’s emotional pain.

Continue to: Rather, incorporating positive psychiatry...

Rather, incorporating positive psychiatry is best viewed as the creation of a supplementary toolbox that allows clinicians an expanded set of focus areas that can be used along with traditional psychotherapy and pharmacotherapy to help patients achieve a more robust and sustained response to treatment.^4,5,15 The positive psychiatrist looks beyond the individual to examine a youth’s entire environment, and beyond areas of challenge to assess strengths, hopes, and aspirations.¹⁶ While many of these values are already in the formal description of a child psychiatrist, these priorities can take a back seat when trying to get through a busy day. For some, being a positive child psychiatrist means prescribing exercise rather than a sleep medication, assessing a child’s character strengths in addition to their behavioral challenges, or discussing the concept of parental warmth and how a struggling mother or father can replenish their tank when it feels like there is little left to give. It can mean reading literature on subjects such as happiness and optimal parenting practices in addition to depression and child maltreatment, and seeing oneself as an expert in mental health rather than just mental illness.

I have published a previous case example of positive psychiatry.¹⁷ Here I provide a brief vignette to further illustrate these concepts, and to compare traditional vs positive child psychiatry (Table 2).

CASE REPORT

Tyler, age 7, presents to a child and adolescent psychiatrist for refractory ADHD problems, continued defiance, and aggressive outbursts. Approximately 1 year ago, Tyler’s pediatrician had diagnosed him with fairly classic ADHD symptoms and prescribed long-acting methylphenidate. Tyler’s attention has improved somewhat at school, but there remains a significant degree of conflict and dysregulation at home. Tyler remains easily frustrated and is often very negative. The pediatrician is looking for additional treatment recommendations.

Traditional approach

The child psychiatrist assesses Tyler and gathers data from the patient, his parents, and his school. She confirms the diagnosis of ADHD, but in reviewing other potential conditions also discovers that Tyler meets DSM-5 criteria for oppositional defiant disorder. The clinician suspects there may also be a co-occurring learning disability and notices that Tyler has chronic difficulties getting to sleep. She also hypothesizes the stimulant medication is wearing off at about the time Tyler gets home from school. The psychiatrist recommends adding an immediate-release formulation of methylphenidate upon return from school, melatonin at night, a school psychoeducational assessment, and behavioral therapy for Tyler and his parents to focus on his disrespectful and oppositional behavior.

Three months later, there has been incremental improvement with the additional medication and a school individualized education plan. Tyler is also working with a therapist, who does some play therapy with Tyler and works on helping his parents create incentives for prosocial behavior, but progress has been slow and the amount of improvement in this area is minimal. Further, the initial positive effect of the melatonin on sleep has waned lately, and the parents now ask about “something stronger.”

Continue to: Positive psychiatry approach

In addition to assessing problem areas and DSM-5 criteria, the psychiatrist assesses a number of other domains. She finds that most of the interaction between Tyler and his parents are negative to the point that his parents often just stay out of his way. She also discovers that Tyler does little in the way of structured activities and spends most of his time at home playing video games, sometimes well into the evening. He gets little to no physical activity outside of school. He also is a very selective eater and often skips breakfast entirely due to the usually chaotic home scene in the morning. A brief mental health screen of the parents further reveals that the mother would also likely meet criteria for ADHD, and the father may be experiencing depression.

The psychiatrist prescribes an additional immediate-release formulation stimulant for the afternoon but holds off on prescribing sleep medication. Instead, she discusses a plan in which Tyler can earn his screen time by reading or exercising, and urges the parents to do some regular physical activity together. She discusses the findings of her screenings of the parents and helps them get a more thorough assessment. She also encourages more family time and introduces them to the “rose, thorn, bud” exercise where each family member discusses a success, challenge, and opportunity of the day.

Three months later, Tyler’s attention and negativity have decreased. His increased physical activity has helped his sleep, and ADHD treatment for the mother has made the mornings much smoother, allowing Tyler to eat a regular breakfast. Both improvements contribute further to Tyler’s improved attention during the day. Challenges remain, but the increased positive family experiences are helping the parents feel less depleted. As a result, they engage with Tyler more productively, and he has responded with more confidence and enthusiasm.

A natural extension of traditional work

The principles and practices associated with positive psychiatry represent a natural and highly needed extension of traditional work within child and adolescent psychiatry. Its emphasis on health promotion activities, family functioning, parental mental health, and utilization of strengths align closely with the growing scientific knowledge base that supports the complex interplay between the many genetic and environmental factors that underlie mental and physical health across the lifespan. For most psychiatrists, incorporating these important concepts and approaches will not require a radical transformation of one’s outlook or methodology, although some adjustments to practice and knowledge base augmentations are often needed. Clinicians interested in supplementing their skill set and working toward becoming an expert in the full range of mental functioning are encouraged to begin taking some of the steps outlined in this article to further their proficiency in the emerging discipline of positive psychiatry.

Bottom Line

Positive psychiatry is an important development that complements traditional approaches to child and adolescent mental health treatment through health promotion and cultivation of positive emotions and qualities. Incorporating it into routine practice is well within reach.

Related Resources

• Jeste DV, Palmer BW, eds. Positive Psychiatry: A Clinical Handbook. American Psychiatric Publishing; 2015.
• Positive Psychology Center. University of Pennsylvania School of Arts and Sciences. https://ppc.sas.upenn.edu/
• Rettew DC. Building healthy brains: a brief tip sheet for parents and schools. American Academy of Child & Adolescent Psychiatry. https://www.aacap.org/App_Themes/AACAP/Docs/resource_centers/schools/Wellness_Dev_Tips.pdf

Drug Brand Names

Methylphenidate extended-release • Concerta, Ritalin LA

The principles and practices of positive psychiatry are especially well-suited for work with children, adolescents, and families. Positive psychiatry is “the science and practice of psychiatry that seeks to understand and promote well-being through assessments and interventions aimed at enhancing positive psychosocial factors among people who have or are at risk for developing mental or physical illnesses.”¹ The concept sprung from the momentum of positive psychology, which originated from Seligman et al.² Importantly, the standards and techniques of positive psychiatry are designed as an enhancement, perhaps even as a completion, of more traditional psychiatry, rather than an alternative.³ They come from an acknowledgment that to be most effective as a mental health professional, it is important for clinicians to be experts in the full range of mental functioning.^4,5

For most clinicians currently practicing “traditional” child and adolescent psychiatry, adapting at least some of the principles of positive psychiatry within one’s routine practice will not necessarily involve a radical transformation of thought or effort. Indeed, upon hearing about positive psychiatry principles, many non­professionals express surprise that this is not already considered routine practice. This article briefly outlines some of the basic tenets of positive child psychiatry and describes practical initial steps that can be readily incorporated into one’s day-to-day approach.

Defining pediatric positive psychiatry

There remains a fair amount of discussion and debate regarding what positive psychiatry is and isn’t, and how it fits into routine practice. While there is no official doctrine as to what “counts” as the practice of positive psychiatry, one can arguably divide most of its interventions into 2 main areas. The first is paying additional clinical attention to behaviors commonly associated with wellness or health promotion in youth. These include domains such as exercise, sleep habits, an authoritative parenting style, screen limits, and nutrition. The second area relates to specific techniques or procedures designed to cultivate positive emotions and mindsets; these often are referred to as positive psychology interventions (PPIs).⁶ Examples include gratitude exercises, practicing forgiveness, and activities that build optimism and hope. Many of the latter procedures share poorly defined boundaries with “tried and true” cognitive-behavioral therapy techniques, while others are more distinct to positive psychology and psychiatry. For both health promotion and PPIs, the goal of these interventions is to go beyond response and even remission for a patient to actual mental well-being, which is a construct that has also proven to be somewhat elusive and difficult to define. One well-described model by Seligman⁷ that has been gaining traction is the PERMA model, which breaks down well-being into 5 main components: positive emotions, engagement, relationships, meaning, and accomplishment.

Positive psychiatry: The evidence base

One myth about positive psychiatry is that it involves the pursuit of fringe and scientifically suspect techniques that have fallen under the expanding umbrella of “wellness.” Sadly, numerous unscientific and ineffective remedies have been widely promoted under the guise of wellness, leaving many families and clinicians uncertain about which areas have a solid evidence base and which are scientifically on shakier ground. While the lines delineating what are often referred to as PPI and more traditional psychotherapeutic techniques are blurry, there is increasing evidence supporting the use of PPI.⁸ A recent meta-analysis indicated that these techniques have larger effect sizes for children and young adults compared to older adults.⁹ More research, however, is needed, particularly for youth with diagnosable mental health conditions and for younger children.¹⁰

The evidence supporting the role of wellness and health promotion in preventing and treating pediatric mental health conditions has a quite robust research base. For example, a recent randomized controlled trial found greater reductions in multiple areas of emotional-behavior problems in children treated in a primary care setting with a wellness and health promotion model (the Vermont Family Based Approach) compared to those in a control condition.¹¹ Another study examining the course of attention-deficit/hyperactivity disorder (ADHD) showed a 62% reduction of diagnosis among children who met 7 of 9 health promotion recommendations in areas such as nutrition, physical activity, and screen time, compared to those who met just 1 to 3 of these recommendations.¹² Techniques such as mindfulness also have been found to be useful for adolescents with anxiety disorders.¹³ While a full review of the evidence is beyond the scope of this article, it is fair to say that many health promotion areas (such as exercise, nutrition, sleep habits, positive parenting skills, and some types of mindfulness) have strong scientific support—arguably at a level that is comparable to or even exceeds that of the off-label use of many psychiatric medications. The American Academy of Child and Adolescent Psychiatry has published a brief document that summarizes many age-related health promotion recommendations.¹⁴ The studies that underlie many of these recommendations contradict the misperception that wellness activities are only for already healthy individuals who want to become healthier, and show their utility for patients with more significant and chronic mental health conditions.

Incorporating core principles of positive psychiatry

Table 1 summarizes the core principles of positive child and adolescent psychiatry. There is no official procedure or certification one must complete to be considered a “positive psychiatrist,” and the term itself is somewhat debatable. Incorporating many of the principles of positive psychiatry into one’s daily routine does not necessitate a practice overhaul, and clinicians can integrate as many of these ideas as they deem clinically appropriate. That said, some adjustments to one’s perspective, approach, and workflow are likely needed, and the practice of positive psychiatry is arguably difficult to accomplish within the common “med check” model that emphasizes high volumes of short appointments that focus primarily on symptoms and adverse effects of medications.

Contrary to another misconception about positive psychiatry, working within a positive psychiatry framework does not involve encouraging patients to “put on a happy face” and ignore the very real suffering and trauma that many of them have experienced. Further, adhering to positive psychiatry does not entail abandoning the use of psychopharmacology (although careful prescribing is generally recommended) or applying gimmicks to superficially cover a person’s emotional pain.

Continue to: Rather, incorporating positive psychiatry...

Rather, incorporating positive psychiatry is best viewed as the creation of a supplementary toolbox that allows clinicians an expanded set of focus areas that can be used along with traditional psychotherapy and pharmacotherapy to help patients achieve a more robust and sustained response to treatment.^4,5,15 The positive psychiatrist looks beyond the individual to examine a youth’s entire environment, and beyond areas of challenge to assess strengths, hopes, and aspirations.¹⁶ While many of these values are already in the formal description of a child psychiatrist, these priorities can take a back seat when trying to get through a busy day. For some, being a positive child psychiatrist means prescribing exercise rather than a sleep medication, assessing a child’s character strengths in addition to their behavioral challenges, or discussing the concept of parental warmth and how a struggling mother or father can replenish their tank when it feels like there is little left to give. It can mean reading literature on subjects such as happiness and optimal parenting practices in addition to depression and child maltreatment, and seeing oneself as an expert in mental health rather than just mental illness.

I have published a previous case example of positive psychiatry.¹⁷ Here I provide a brief vignette to further illustrate these concepts, and to compare traditional vs positive child psychiatry (Table 2).

CASE REPORT

Tyler, age 7, presents to a child and adolescent psychiatrist for refractory ADHD problems, continued defiance, and aggressive outbursts. Approximately 1 year ago, Tyler’s pediatrician had diagnosed him with fairly classic ADHD symptoms and prescribed long-acting methylphenidate. Tyler’s attention has improved somewhat at school, but there remains a significant degree of conflict and dysregulation at home. Tyler remains easily frustrated and is often very negative. The pediatrician is looking for additional treatment recommendations.

Traditional approach

The child psychiatrist assesses Tyler and gathers data from the patient, his parents, and his school. She confirms the diagnosis of ADHD, but in reviewing other potential conditions also discovers that Tyler meets DSM-5 criteria for oppositional defiant disorder. The clinician suspects there may also be a co-occurring learning disability and notices that Tyler has chronic difficulties getting to sleep. She also hypothesizes the stimulant medication is wearing off at about the time Tyler gets home from school. The psychiatrist recommends adding an immediate-release formulation of methylphenidate upon return from school, melatonin at night, a school psychoeducational assessment, and behavioral therapy for Tyler and his parents to focus on his disrespectful and oppositional behavior.

Three months later, there has been incremental improvement with the additional medication and a school individualized education plan. Tyler is also working with a therapist, who does some play therapy with Tyler and works on helping his parents create incentives for prosocial behavior, but progress has been slow and the amount of improvement in this area is minimal. Further, the initial positive effect of the melatonin on sleep has waned lately, and the parents now ask about “something stronger.”

Continue to: Positive psychiatry approach

In addition to assessing problem areas and DSM-5 criteria, the psychiatrist assesses a number of other domains. She finds that most of the interaction between Tyler and his parents are negative to the point that his parents often just stay out of his way. She also discovers that Tyler does little in the way of structured activities and spends most of his time at home playing video games, sometimes well into the evening. He gets little to no physical activity outside of school. He also is a very selective eater and often skips breakfast entirely due to the usually chaotic home scene in the morning. A brief mental health screen of the parents further reveals that the mother would also likely meet criteria for ADHD, and the father may be experiencing depression.

The psychiatrist prescribes an additional immediate-release formulation stimulant for the afternoon but holds off on prescribing sleep medication. Instead, she discusses a plan in which Tyler can earn his screen time by reading or exercising, and urges the parents to do some regular physical activity together. She discusses the findings of her screenings of the parents and helps them get a more thorough assessment. She also encourages more family time and introduces them to the “rose, thorn, bud” exercise where each family member discusses a success, challenge, and opportunity of the day.

Three months later, Tyler’s attention and negativity have decreased. His increased physical activity has helped his sleep, and ADHD treatment for the mother has made the mornings much smoother, allowing Tyler to eat a regular breakfast. Both improvements contribute further to Tyler’s improved attention during the day. Challenges remain, but the increased positive family experiences are helping the parents feel less depleted. As a result, they engage with Tyler more productively, and he has responded with more confidence and enthusiasm.

A natural extension of traditional work

The principles and practices associated with positive psychiatry represent a natural and highly needed extension of traditional work within child and adolescent psychiatry. Its emphasis on health promotion activities, family functioning, parental mental health, and utilization of strengths align closely with the growing scientific knowledge base that supports the complex interplay between the many genetic and environmental factors that underlie mental and physical health across the lifespan. For most psychiatrists, incorporating these important concepts and approaches will not require a radical transformation of one’s outlook or methodology, although some adjustments to practice and knowledge base augmentations are often needed. Clinicians interested in supplementing their skill set and working toward becoming an expert in the full range of mental functioning are encouraged to begin taking some of the steps outlined in this article to further their proficiency in the emerging discipline of positive psychiatry.

Bottom Line

Positive psychiatry is an important development that complements traditional approaches to child and adolescent mental health treatment through health promotion and cultivation of positive emotions and qualities. Incorporating it into routine practice is well within reach.

Related Resources

• Jeste DV, Palmer BW, eds. Positive Psychiatry: A Clinical Handbook. American Psychiatric Publishing; 2015.
• Positive Psychology Center. University of Pennsylvania School of Arts and Sciences. https://ppc.sas.upenn.edu/
• Rettew DC. Building healthy brains: a brief tip sheet for parents and schools. American Academy of Child & Adolescent Psychiatry. https://www.aacap.org/App_Themes/AACAP/Docs/resource_centers/schools/Wellness_Dev_Tips.pdf

Drug Brand Names

Methylphenidate extended-release • Concerta, Ritalin LA

The principles and practices of positive psychiatry are especially well-suited for work with children, adolescents, and families. Positive psychiatry is “the science and practice of psychiatry that seeks to understand and promote well-being through assessments and interventions aimed at enhancing positive psychosocial factors among people who have or are at risk for developing mental or physical illnesses.”¹ The concept sprung from the momentum of positive psychology, which originated from Seligman et al.² Importantly, the standards and techniques of positive psychiatry are designed as an enhancement, perhaps even as a completion, of more traditional psychiatry, rather than an alternative.³ They come from an acknowledgment that to be most effective as a mental health professional, it is important for clinicians to be experts in the full range of mental functioning.^4,5

For most clinicians currently practicing “traditional” child and adolescent psychiatry, adapting at least some of the principles of positive psychiatry within one’s routine practice will not necessarily involve a radical transformation of thought or effort. Indeed, upon hearing about positive psychiatry principles, many non­professionals express surprise that this is not already considered routine practice. This article briefly outlines some of the basic tenets of positive child psychiatry and describes practical initial steps that can be readily incorporated into one’s day-to-day approach.

Defining pediatric positive psychiatry

There remains a fair amount of discussion and debate regarding what positive psychiatry is and isn’t, and how it fits into routine practice. While there is no official doctrine as to what “counts” as the practice of positive psychiatry, one can arguably divide most of its interventions into 2 main areas. The first is paying additional clinical attention to behaviors commonly associated with wellness or health promotion in youth. These include domains such as exercise, sleep habits, an authoritative parenting style, screen limits, and nutrition. The second area relates to specific techniques or procedures designed to cultivate positive emotions and mindsets; these often are referred to as positive psychology interventions (PPIs).⁶ Examples include gratitude exercises, practicing forgiveness, and activities that build optimism and hope. Many of the latter procedures share poorly defined boundaries with “tried and true” cognitive-behavioral therapy techniques, while others are more distinct to positive psychology and psychiatry. For both health promotion and PPIs, the goal of these interventions is to go beyond response and even remission for a patient to actual mental well-being, which is a construct that has also proven to be somewhat elusive and difficult to define. One well-described model by Seligman⁷ that has been gaining traction is the PERMA model, which breaks down well-being into 5 main components: positive emotions, engagement, relationships, meaning, and accomplishment.

Positive psychiatry: The evidence base

One myth about positive psychiatry is that it involves the pursuit of fringe and scientifically suspect techniques that have fallen under the expanding umbrella of “wellness.” Sadly, numerous unscientific and ineffective remedies have been widely promoted under the guise of wellness, leaving many families and clinicians uncertain about which areas have a solid evidence base and which are scientifically on shakier ground. While the lines delineating what are often referred to as PPI and more traditional psychotherapeutic techniques are blurry, there is increasing evidence supporting the use of PPI.⁸ A recent meta-analysis indicated that these techniques have larger effect sizes for children and young adults compared to older adults.⁹ More research, however, is needed, particularly for youth with diagnosable mental health conditions and for younger children.¹⁰

The evidence supporting the role of wellness and health promotion in preventing and treating pediatric mental health conditions has a quite robust research base. For example, a recent randomized controlled trial found greater reductions in multiple areas of emotional-behavior problems in children treated in a primary care setting with a wellness and health promotion model (the Vermont Family Based Approach) compared to those in a control condition.¹¹ Another study examining the course of attention-deficit/hyperactivity disorder (ADHD) showed a 62% reduction of diagnosis among children who met 7 of 9 health promotion recommendations in areas such as nutrition, physical activity, and screen time, compared to those who met just 1 to 3 of these recommendations.¹² Techniques such as mindfulness also have been found to be useful for adolescents with anxiety disorders.¹³ While a full review of the evidence is beyond the scope of this article, it is fair to say that many health promotion areas (such as exercise, nutrition, sleep habits, positive parenting skills, and some types of mindfulness) have strong scientific support—arguably at a level that is comparable to or even exceeds that of the off-label use of many psychiatric medications. The American Academy of Child and Adolescent Psychiatry has published a brief document that summarizes many age-related health promotion recommendations.¹⁴ The studies that underlie many of these recommendations contradict the misperception that wellness activities are only for already healthy individuals who want to become healthier, and show their utility for patients with more significant and chronic mental health conditions.

Incorporating core principles of positive psychiatry

Table 1 summarizes the core principles of positive child and adolescent psychiatry. There is no official procedure or certification one must complete to be considered a “positive psychiatrist,” and the term itself is somewhat debatable. Incorporating many of the principles of positive psychiatry into one’s daily routine does not necessitate a practice overhaul, and clinicians can integrate as many of these ideas as they deem clinically appropriate. That said, some adjustments to one’s perspective, approach, and workflow are likely needed, and the practice of positive psychiatry is arguably difficult to accomplish within the common “med check” model that emphasizes high volumes of short appointments that focus primarily on symptoms and adverse effects of medications.

Contrary to another misconception about positive psychiatry, working within a positive psychiatry framework does not involve encouraging patients to “put on a happy face” and ignore the very real suffering and trauma that many of them have experienced. Further, adhering to positive psychiatry does not entail abandoning the use of psychopharmacology (although careful prescribing is generally recommended) or applying gimmicks to superficially cover a person’s emotional pain.

Continue to: Rather, incorporating positive psychiatry...

Rather, incorporating positive psychiatry is best viewed as the creation of a supplementary toolbox that allows clinicians an expanded set of focus areas that can be used along with traditional psychotherapy and pharmacotherapy to help patients achieve a more robust and sustained response to treatment.^4,5,15 The positive psychiatrist looks beyond the individual to examine a youth’s entire environment, and beyond areas of challenge to assess strengths, hopes, and aspirations.¹⁶ While many of these values are already in the formal description of a child psychiatrist, these priorities can take a back seat when trying to get through a busy day. For some, being a positive child psychiatrist means prescribing exercise rather than a sleep medication, assessing a child’s character strengths in addition to their behavioral challenges, or discussing the concept of parental warmth and how a struggling mother or father can replenish their tank when it feels like there is little left to give. It can mean reading literature on subjects such as happiness and optimal parenting practices in addition to depression and child maltreatment, and seeing oneself as an expert in mental health rather than just mental illness.

I have published a previous case example of positive psychiatry.¹⁷ Here I provide a brief vignette to further illustrate these concepts, and to compare traditional vs positive child psychiatry (Table 2).

CASE REPORT

Tyler, age 7, presents to a child and adolescent psychiatrist for refractory ADHD problems, continued defiance, and aggressive outbursts. Approximately 1 year ago, Tyler’s pediatrician had diagnosed him with fairly classic ADHD symptoms and prescribed long-acting methylphenidate. Tyler’s attention has improved somewhat at school, but there remains a significant degree of conflict and dysregulation at home. Tyler remains easily frustrated and is often very negative. The pediatrician is looking for additional treatment recommendations.

Traditional approach

The child psychiatrist assesses Tyler and gathers data from the patient, his parents, and his school. She confirms the diagnosis of ADHD, but in reviewing other potential conditions also discovers that Tyler meets DSM-5 criteria for oppositional defiant disorder. The clinician suspects there may also be a co-occurring learning disability and notices that Tyler has chronic difficulties getting to sleep. She also hypothesizes the stimulant medication is wearing off at about the time Tyler gets home from school. The psychiatrist recommends adding an immediate-release formulation of methylphenidate upon return from school, melatonin at night, a school psychoeducational assessment, and behavioral therapy for Tyler and his parents to focus on his disrespectful and oppositional behavior.

Three months later, there has been incremental improvement with the additional medication and a school individualized education plan. Tyler is also working with a therapist, who does some play therapy with Tyler and works on helping his parents create incentives for prosocial behavior, but progress has been slow and the amount of improvement in this area is minimal. Further, the initial positive effect of the melatonin on sleep has waned lately, and the parents now ask about “something stronger.”

Continue to: Positive psychiatry approach

In addition to assessing problem areas and DSM-5 criteria, the psychiatrist assesses a number of other domains. She finds that most of the interaction between Tyler and his parents are negative to the point that his parents often just stay out of his way. She also discovers that Tyler does little in the way of structured activities and spends most of his time at home playing video games, sometimes well into the evening. He gets little to no physical activity outside of school. He also is a very selective eater and often skips breakfast entirely due to the usually chaotic home scene in the morning. A brief mental health screen of the parents further reveals that the mother would also likely meet criteria for ADHD, and the father may be experiencing depression.

The psychiatrist prescribes an additional immediate-release formulation stimulant for the afternoon but holds off on prescribing sleep medication. Instead, she discusses a plan in which Tyler can earn his screen time by reading or exercising, and urges the parents to do some regular physical activity together. She discusses the findings of her screenings of the parents and helps them get a more thorough assessment. She also encourages more family time and introduces them to the “rose, thorn, bud” exercise where each family member discusses a success, challenge, and opportunity of the day.

Three months later, Tyler’s attention and negativity have decreased. His increased physical activity has helped his sleep, and ADHD treatment for the mother has made the mornings much smoother, allowing Tyler to eat a regular breakfast. Both improvements contribute further to Tyler’s improved attention during the day. Challenges remain, but the increased positive family experiences are helping the parents feel less depleted. As a result, they engage with Tyler more productively, and he has responded with more confidence and enthusiasm.

A natural extension of traditional work

The principles and practices associated with positive psychiatry represent a natural and highly needed extension of traditional work within child and adolescent psychiatry. Its emphasis on health promotion activities, family functioning, parental mental health, and utilization of strengths align closely with the growing scientific knowledge base that supports the complex interplay between the many genetic and environmental factors that underlie mental and physical health across the lifespan. For most psychiatrists, incorporating these important concepts and approaches will not require a radical transformation of one’s outlook or methodology, although some adjustments to practice and knowledge base augmentations are often needed. Clinicians interested in supplementing their skill set and working toward becoming an expert in the full range of mental functioning are encouraged to begin taking some of the steps outlined in this article to further their proficiency in the emerging discipline of positive psychiatry.

Bottom Line

Positive psychiatry is an important development that complements traditional approaches to child and adolescent mental health treatment through health promotion and cultivation of positive emotions and qualities. Incorporating it into routine practice is well within reach.

Related Resources

• Jeste DV, Palmer BW, eds. Positive Psychiatry: A Clinical Handbook. American Psychiatric Publishing; 2015.
• Positive Psychology Center. University of Pennsylvania School of Arts and Sciences. https://ppc.sas.upenn.edu/
• Rettew DC. Building healthy brains: a brief tip sheet for parents and schools. American Academy of Child & Adolescent Psychiatry. https://www.aacap.org/App_Themes/AACAP/Docs/resource_centers/schools/Wellness_Dev_Tips.pdf

Drug Brand Names

Methylphenidate extended-release • Concerta, Ritalin LA

Complex posttraumatic stress disorder (CPTSD) is a condition characterized by classic trauma-related symptoms in addition to disturbances in self organization (DSO).^1-3 DSO symptoms include negative self-concept, emotional dysregulation, and interpersonal problems. CPTSD differs from PTSD in that it includes symptoms of DSO, and differs from borderline personality disorder (BPD) in that it does not include extreme self-injurious behavior, a complete lack of sense of self, and avoidance of rejection or abandonment (Table^1,2). The maladaptive traits of CPTSD are often the result of a chronic lack of safety in early childhood, particularly childhood sexual abuse (CSA). CSA may affect up to 20% of women and is defined by the CDC as “any completed or attempted sexual act, sexual contact with, or exploitation of a child by a caregiver.”^4,5

Maternal lifetime trauma is more common among women who are in low-income minority groups and can lead to adverse birth outcomes in this vulnerable patient population.⁶ Recent research has found that trauma can increase cortisol levels during pregnancy, leading to increased placental permeability, inflammatory response, and longstanding alterations in the fetal hypothalamic-pituitary adrenal axis.⁶ A CPTSD diagnosis is of particular interest during the perinatal period because CPTSD is often a response to interpersonal trauma and attachment adversity, which can be reactivated during the perinatal period.⁷ CPTSD in survivors of CSA can be exacerbated due to feelings of disempowerment secondary to loss of bodily control throughout pregnancy, childbirth, breastfeeding, and obstetrical exams.^5,8 Little is known about perinatal CPTSD, but we can extrapolate from trauma research that it is likely associated with the worsening of other maternal mental health conditions, suicidality, physical complaints, quality of life, maternal-child bonding outcomes, and low birth weight in offspring.^5,9,10

Although there are no consensus guidelines on how to diagnose and treat CPTSD during the perinatal period, or how to promote family functioning thereafter, there are many opportunities for intervention. Mental health clinicians are in a particularly important position to care for women in the perinatal period, as collaborative work with obstetricians, pediatricians, and social services can have long-lasting effects.

In this article, we present cases of 3 CSA survivors who experienced worsening of CPTSD symptoms during the perinatal period and received psychiatric care via telehealth during the COVID-19 pandemic. We also identify best practice approaches and highlight areas for future research.

Case descriptions

Case 1

Ms. A, age 33, is married, has 3 children, has asthma, and is vaccinated against COVID-19. Her psychiatric history includes self-reported dissociative identity disorder and bulimia nervosa. At 2 months postpartum following an unplanned yet desired pregnancy, Ms. A presents to the outpatient clinic after a violent episode toward her husband during sexual intercourse. Since the first trimester of her pregnancy, she has expressed increased anxiety and difficulty sleeping, hypervigilance, intimacy avoidance, and negative views of herself and the world, yet she denies persistent depressive, manic, or psychotic symptoms, other maladaptive personality traits, or substance use. She recalls experiencing similar symptoms during her 2 previous peripartum periods, and attributes it to worsening memories of sexual abuse during childhood. Ms. A has a history of psychiatric hospitalizations during adolescence and young adulthood for suicidal ideation. She had been treated with various medications, including chlorpromazine, lamotrigine, carbamazepine, and clonazepam, but self-discontinued these medications in 2016 because she felt they were ineffective. Since becoming a mother, she has consistently denied depressive symptoms or suicidal ideation, and intermittently engaged in interpersonal psychotherapy targeting her conflictual relationship with her husband and parenting struggles.

Ms. A underwent an induced vaginal delivery at 36 weeks gestation due to preeclampsia and had success with breastfeeding. While engaging in sexual activity for the first time postpartum, she dissociated and later learned she had forcefully grabbed her husband’s neck for several seconds but did not cause any longstanding physical damage. Upon learning of this episode, Ms. A’s psychiatrist asks her to complete the International Trauma Questionnaire (ITQ), a brief self-report measure developed for the assessment of the ICD-11 diagnosis of CPTSD (Figure¹¹). Ms. A also completes the PTSD Checklist for DSM-5 (PCL-5), the Dissociative Experiences Scale, and the Edinburgh Postnatal Depression Scale (EPDS) to assist with assessing her symptoms.^12-15 The psychiatrist uses ICD-11 criteria to diagnose Ms. A with CPTSD, given her functional impairment associated with both PTSD and DSO symptoms, which have acutely worsened during the perinatal period.

Ms. A initially engages in extensive trauma psychoeducation and supportive psychotherapy for 3 months. She later pursues prolonged exposure psychotherapy targeting intimacy, and after 6 months of treatment, improves her avoidance behaviors and marriage.

Continue to: Case 2

Ms. R, age 35, is a partnered mother expecting her third child. She has no relevant medical history and is not vaccinated against COVID-19. Her psychiatric history includes self-reported panic attacks and bipolar affective disorder (BPAD). During the second trimester of a desired, unplanned pregnancy, Ms. R presents to an outpatient psychiatry clinic with symptoms of worsening dysphoria and insomnia. She endorses frequent nightmares and flashbacks of CSA as well as remote intimate partner violence. These symptoms, along with hypervigilance, insomnia, anxiety, dysphoria, negative views of herself and her surroundings, and hallucinations of a shadow that whispers “come” when she is alone, worsened during the first trimester of her pregnancy. She recalls experiencing similar trauma-related symptoms during a previous pregnancy but denies a history of pervasive depressive, manic, or psychotic symptoms. She has no other maladaptive personality traits, denies prior substance use or suicidal behavior, and has never been psychiatrically hospitalized or taken psychotropic medications.

Ms. R completes the PCL-5, ITQ, EPDS, and Mood Disorder Questionnaire (MDQ). The results are notable for significant functional impairment related to PTSD and DSO symptoms with minimal concern for BPAD symptoms. The psychiatrist uses ICD-11 criteria to diagnose Ms. R with CPTSD and discusses treatment options with her and her obstetrician. Ms. R is reluctant to take medication until she delivers her baby. She intermittently attends supportive therapy while pregnant. Her pregnancy is complicated by gestational diabetes, and she often misses appointments with her obstetrician and nutritionist.

Ms. R has an uncomplicated vaginal delivery at 38 weeks gestation and success with breastfeeding, but continues to have CPTSD symptoms. She is prescribed quetiapine 25 mg/d for anxiety, insomnia, mood, and psychotic symptoms, but stops taking the medication after 3 days due to excessive sedation. Ms. R is then prescribed sertraline 50 mg/d, which she finds helpful, but has intermittent adherence. She misses multiple virtual appointments with the psychiatrist and does not want to attend in-person sessions due to fear of contracting COVID-19. The psychiatrist encourages Ms. R to get vaccinated, focuses on organizational skills during sessions to promote attendance, and recommends in-person appointments to increase her motivation for treatment and alliance building. Despite numerous outreach attempts, Ms. R is lost to follow-up at 10 months postpartum.

Case 3

Ms. S, age 29, is a partnered mother expecting her fourth child. Her medical history includes chronic back pain. She is not vaccinated against COVID-19, and her psychiatric history includes BPAD. During the first trimester of an undesired, unplanned pregnancy, Ms. S presents to an outpatient psychiatric clinic following an episode where she held a knife over her gravid abdomen during a fight with her partner. She recounts that she became dysregulated and held a knife to her body to communicate her distress, but she did not cut herself, and adamantly denies wanting to hurt herself or the fetus. Ms. S struggles with affective instability, poor frustration tolerance, and irritability. After 1 month of treatment, she discloses surviving prolonged CSA that led to her current nightmares and flashbacks. She also endorses impaired sleep, intimacy avoidance, hypervigilance, impulsive reckless behaviors (including excessive gambling), and negative views about herself and the world that worsened since she learned she was pregnant. Ms. S reports that these same symptoms were aggravated during prior perinatal periods and recalls 2 episodes of severe dysregulation that led to an interrupted suicide attempt and a violent episode toward a loved one. She denies other self-harm behaviors, substance use, or psychotic symptoms, and denies having a history of psychiatric hospitalizations. Ms. S recalls receiving a brief trial of topiramate for BPAD and migraine when she was last in outpatient psychiatric care 8 years ago.

Her psychiatrist administers the PCL-5, ITQ, MDQ, EPDS, and Borderline Symptoms List 23 (BLS-23). The results are notable for significant PTSD and DSO symptoms.¹⁶ The psychiatrist diagnoses Ms. S with CPTSD and bipolar II disorder, exacerbated during the peripartum period. Throughout the remainder of her pregnancy, she endorses mood instability with significant irritability but declines pharmacotherapy. Ms. S intermittently engages in psychotherapy using dialectical behavioral therapy (DBT) focusing on distress tolerance because she is unable to tolerate trauma-focused psychotherapy.

Continue to: Ms. S maintains the pregnancy...

Ms. S maintains the pregnancy without any additional complications and has a vaginal delivery at 39 weeks gestation. She initiates breastfeeding but chooses not to continue after 1 month due to fatigue, insomnia, and worsening mood. Her psychiatrist wants to contact Ms. S’s partner to discuss childcare support at night to promote better sleep conditions for Ms. S, but Ms. S declines. Ms. S intermittently attends virtual appointments, adamantly refuses the COVID-19 vaccine, and is fearful of starting a mood stabilizer despite extensive psychoeducation. At 5 months postpartum, Ms. S reports that she is in a worse mood and does not want to continue the appointment or further treatment, and abruptly ends the telepsychiatry session. Her psychiatrist reaches out the following week to schedule an in-person session if Ms. S agrees to wear personal protective equipment, which she is amenable to. During that appointment, the psychiatrist discusses the risks of bipolar depression and CPTSD on both her and her childrens’ development, against the risk of lamotrigine. Ms. S begins taking lamotrigine, which she tolerates without adverse effects, and quickly notices improvement in her mood as the medication is titrated up slowly to 200 mg/d. Ms. S then engages more consistently in psychotherapy and her CPTSD and bipolar II disorder symptoms much improve at 9 months postpartum.

Ensuring an accurate CPTSD diagnosis

These 3 cases illustrate the diversity and complexity of presentations for perinatal CPTSD following CSA. A CPTSD diagnosis is complicated because the differential is broad for those reporting PTSD and DSO symptoms, and CPTSD is commonly comorbid with other disorders such as anxiety and depression.¹⁷ While various scales can facilitate PTSD screening, the ITQ is helpful because it catalogs the symptoms of disturbances in self organization and functional impairment inherent in CPTSD. The ITQ can help clinicians and patients conceptualize symptoms and track progress (Figure¹¹).

Once a patient screens positive, a CPTSD diagnosis is best made by the clinician after a full psychiatric interview, similar to other diagnoses. Psychiatrists must use ICD-11 criteria,¹ as currently there are no formal DSM-5 criteria for CPTSD.² Additional scales facilitate CPTSD symptom inventory, such as the PCL-5 to screen and monitor for PTSD symptoms and the BLS-23 to delineate between BPD or DSO symptoms.¹⁸ Furthermore, clinicians should screen for other comorbid conditions using additional scales such as the MDQ for BPAD and the EPDS for perinatal mood and anxiety disorders. Sharing a CPTSD diagnosis with a patient is an essential step when initiating treatment. Sensitive psychoeducation on the condition and its application to the perinatal period is key to establishing safety and trust, while also empowering survivors to make their own choices regarding treatment, all essential elements to trauma-informed care.¹⁹

A range of treatment options

Once CPTSD is appropriately diagnosed, clinicians must determine whether to use pharmacotherapy, psychotherapy, or both. A meta-analysis by Coventry et al²⁰ sought to determine the best treatment strategies for complex traumatic events such as CSA, Multicomponent interventions were most promising, and psychological interventions were associated with larger effect sizes than pharmacologic interventions for managing PTSD, mood, and sleep. Therapeutic targets include trauma memory processing, self-perception, and dissociation, along with emotion, interpersonal, and somatic regulation.²¹

Psychotherapy. While there are no standardized guidelines for treating CPTSD, PTSD guidelines suggest using trauma-focused cognitive-behavioral therapy (TF-CBT) as a first-line therapy, though a longer course may be needed to resolve CPTSD symptoms compared to PTSD symptoms.³ DBT for PTSD can be particularly helpful in targeting DSO symptoms.²² Narrative therapy focused on identity, embodiment, and parenting has also shown to be effective for survivors of CSA in the perinatal period, specifically with the goal of meaning-making.⁵ Therapy can also be effective in a group setting (ie, a “Victim to Survivor” TF-CBT group).²³ Sex and couples therapy may be indicated to reestablish trust, especially when it is evident there is sexual inhibition from trauma that influences the relationship, as seen in Case 1.²⁴

Continue to: Pharmacotherapy

Pharmacotherapy. Case 2 and Case 3 both demonstrate that while the peripartum period presents an increased risk for exacerbation of psychiatric symptoms, patients and clinicians may be reluctant to start medications due to concerns for safety during pregnancy or lactation.²⁵ Clinicians must weigh the risks of medication exposure against the risks of exposing the fetus or newborn to untreated psychiatric disease and consult an expert in reproductive psychiatry if questions or concerns arise.²⁶

Adverse effects of psychotropic medications must be considered, especially sedation. Medications that lead to sedation may not be safe or feasible for a mother following delivery, especially if she is breastfeeding. This was exemplified in Case 2, when Ms. R was having troubling hallucinations for which the clinician prescribed quetiapine. The medication resulted in excessive sedation and Ms. R did not feel comfortable performing childcare duties while taking the medication, which greatly influenced future therapy decisions.

Making the decision to prescribe a certain medication for CPTSD is highly influenced by the patient’s most troubling symptoms and their comorbid diagnoses. Selective serotonin reuptake inhibitors (SSRIs) generally are considered safe during pregnancy and breastfeeding, and should be considered as a first-line intervention for PTSD, mood disorders, and anxiety disorders during the perinatal period.²⁷ While prazosin is effective for PTSD symptoms outside of pregnancy, there is limited data regarding its safety during pregnancy and lactation, and it may lead to maternal hypotension and subsequent fetal adverse effects.²⁸

Many patients with a history of CSA experience hallucinations and dissociative symptoms, as demonstrated by Case 1 and Case 2.²⁹ In Case 3, Ms. S displayed features of BPAD with significant hypomanic symptoms and worsening suicidality during prior postpartum periods. The clinician felt comfortable prescribing lamotrigine, a relatively safe medication during the perinatal period compared to other mood stabilizers. Ms. S was amenable to taking lamotrigine, and her clinician avoided the use of an SSRI due to a concern of worsening a bipolar diathesis in this high-risk case.³⁰ Case 2 and Case 3 both highlight the need to closely screen for comorbid conditions such as BPAD and using caution when considering an SSRI in light of the risk of precipitating mania, especially as the patient popu­lation is younger and at higher risk for antidepressant-associated mania.^31,32

Help patients tap into their sources for strength

Other therapeutic strategies when treating patients with perinatal CPTSD include encouraging survivors to mobilize their support network and sources for strength. Chamberlain et al⁸ suggest incorporating socioecological and cultural contexts when considering outlets for social support systems and encourage collaborating with families, especially partners, along with community and spiritual networks. As seen in Case 3, clinicians should attempt to speak to family members on behalf of their patients to promote better sleeping conditions, which can greatly alleviate CPTSD and comorbid mood symptoms, and thus reduce suicide risk.³³ Sources for strength should be accentuated and clinicians may need to advocate with child protective services to support parenting rights. As demonstrated in Case 1, motherhood can greatly reduce suicide risk, and should be promoted if a child’s safety is not in danger.³⁴

Continue to: Clinicians must recognize...

Clinicians must recognize that patients in the perinatal period face barriers to obtaining health care, especially those with CPTSD, as these patients can be difficult to engage and retain. Each case described in this article challenged the psychiatrist with engagement and alliance-building, stemming from the patient’s CPTSD symptoms of interpersonal difficulties and negative views of surroundings. Case 2 demonstrates how the diagnosis can prevent patients from receiving appropriate prenatal care, while Case 3 shows how clinicians may need more flexible attendance policies and assertive outreach attempts to deliver the mental health care these patients deserve.

These vignettes highlight the psychosocial barriers women face during the perinatal period, such as caring for their child, financial stressors, and COVID-19 pandemic–related factors that can hinder treatment, which can be compounded by trauma. The uncertainty, unpredictability, loss of control, and loss of support structures collectively experienced during the pandemic can be triggering and precipitate worsening CPTSD symptoms.³⁵ Women who experience trauma are less likely to obtain the COVID-19 vaccine for themselves or their children, and this hesitancy is often driven by institutional distrust.³⁶ Policy leaders and clinicians should consider these factors to promote trauma-informed COVID-19 vaccine initiatives and expand mental health access using less orthodox treatment settings, such as telepsychiatry. Telepsychiatry can serve as a bridge to in-person care as patients may feel a higher sense of control when in a familiar home environment. Case 2 and Case 3 exemplify the difficulties of delivering mental health care to perinatal women with CPTSD during the pandemic, especially those who are vaccine-hesitant, and illustrate the importance of adapting a patient’s treatment plan in a personalized and trauma-informed way.

Psychiatrists can help obstetricians and pediatricians by explaining that avoidance patterns and distrust in the clinical setting may be related to trauma and are not grounds for conscious or subconscious punishment or abandonment. Educating other clinicians about trauma-informed care, precautions to use for perinatal patients, and ways to effectively support survivors of CSA can greatly improve health outcomes for perinatal women and their offspring.³⁷

Bottom Line

Complex posttraumatic stress disorder (CPTSD) is characterized by classic PTSD symptoms as well as disturbances in self organization, which can include mood symptoms, psychotic symptoms, and maladaptive personality traits. CPTSD resulting from childhood sexual abuse is of particular concern for women, especially during the perinatal period. Clinicians must know how to recognize the signs and symptoms of CPTSD so they can tailor a trauma-informed treatment plan and promote treatment access in this highly vulnerable patient population.

Related Resources

• Tillman B, Sloan N, Westmoreland P. How COVID-19 affects peripartum women’s mental health. Current Psychiatry. 2021;20(6):18-22. doi:10.12788/cp.0129
• Keswani M, Nemcek S, Rashid N. Is it bipolar disorder, or a complex form of PTSD? Current Psychiatry. 2021;20(12):42-49. doi:10.12788/cp.0188

Drug Brand Names

Carbamazepine • Carbatrol
Clonazepam • Klonopin
Lamotrigine • Lamictal
Prazosin • Minipress
Quetiapine • Seroquel
Sertraline • Zoloft
Topiramate • Topamax

Complex posttraumatic stress disorder (CPTSD) is a condition characterized by classic trauma-related symptoms in addition to disturbances in self organization (DSO).^1-3 DSO symptoms include negative self-concept, emotional dysregulation, and interpersonal problems. CPTSD differs from PTSD in that it includes symptoms of DSO, and differs from borderline personality disorder (BPD) in that it does not include extreme self-injurious behavior, a complete lack of sense of self, and avoidance of rejection or abandonment (Table^1,2). The maladaptive traits of CPTSD are often the result of a chronic lack of safety in early childhood, particularly childhood sexual abuse (CSA). CSA may affect up to 20% of women and is defined by the CDC as “any completed or attempted sexual act, sexual contact with, or exploitation of a child by a caregiver.”^4,5

Maternal lifetime trauma is more common among women who are in low-income minority groups and can lead to adverse birth outcomes in this vulnerable patient population.⁶ Recent research has found that trauma can increase cortisol levels during pregnancy, leading to increased placental permeability, inflammatory response, and longstanding alterations in the fetal hypothalamic-pituitary adrenal axis.⁶ A CPTSD diagnosis is of particular interest during the perinatal period because CPTSD is often a response to interpersonal trauma and attachment adversity, which can be reactivated during the perinatal period.⁷ CPTSD in survivors of CSA can be exacerbated due to feelings of disempowerment secondary to loss of bodily control throughout pregnancy, childbirth, breastfeeding, and obstetrical exams.^5,8 Little is known about perinatal CPTSD, but we can extrapolate from trauma research that it is likely associated with the worsening of other maternal mental health conditions, suicidality, physical complaints, quality of life, maternal-child bonding outcomes, and low birth weight in offspring.^5,9,10

Although there are no consensus guidelines on how to diagnose and treat CPTSD during the perinatal period, or how to promote family functioning thereafter, there are many opportunities for intervention. Mental health clinicians are in a particularly important position to care for women in the perinatal period, as collaborative work with obstetricians, pediatricians, and social services can have long-lasting effects.

In this article, we present cases of 3 CSA survivors who experienced worsening of CPTSD symptoms during the perinatal period and received psychiatric care via telehealth during the COVID-19 pandemic. We also identify best practice approaches and highlight areas for future research.

Case descriptions

Case 1

Ms. A, age 33, is married, has 3 children, has asthma, and is vaccinated against COVID-19. Her psychiatric history includes self-reported dissociative identity disorder and bulimia nervosa. At 2 months postpartum following an unplanned yet desired pregnancy, Ms. A presents to the outpatient clinic after a violent episode toward her husband during sexual intercourse. Since the first trimester of her pregnancy, she has expressed increased anxiety and difficulty sleeping, hypervigilance, intimacy avoidance, and negative views of herself and the world, yet she denies persistent depressive, manic, or psychotic symptoms, other maladaptive personality traits, or substance use. She recalls experiencing similar symptoms during her 2 previous peripartum periods, and attributes it to worsening memories of sexual abuse during childhood. Ms. A has a history of psychiatric hospitalizations during adolescence and young adulthood for suicidal ideation. She had been treated with various medications, including chlorpromazine, lamotrigine, carbamazepine, and clonazepam, but self-discontinued these medications in 2016 because she felt they were ineffective. Since becoming a mother, she has consistently denied depressive symptoms or suicidal ideation, and intermittently engaged in interpersonal psychotherapy targeting her conflictual relationship with her husband and parenting struggles.

Ms. A underwent an induced vaginal delivery at 36 weeks gestation due to preeclampsia and had success with breastfeeding. While engaging in sexual activity for the first time postpartum, she dissociated and later learned she had forcefully grabbed her husband’s neck for several seconds but did not cause any longstanding physical damage. Upon learning of this episode, Ms. A’s psychiatrist asks her to complete the International Trauma Questionnaire (ITQ), a brief self-report measure developed for the assessment of the ICD-11 diagnosis of CPTSD (Figure¹¹). Ms. A also completes the PTSD Checklist for DSM-5 (PCL-5), the Dissociative Experiences Scale, and the Edinburgh Postnatal Depression Scale (EPDS) to assist with assessing her symptoms.^12-15 The psychiatrist uses ICD-11 criteria to diagnose Ms. A with CPTSD, given her functional impairment associated with both PTSD and DSO symptoms, which have acutely worsened during the perinatal period.

Ms. A initially engages in extensive trauma psychoeducation and supportive psychotherapy for 3 months. She later pursues prolonged exposure psychotherapy targeting intimacy, and after 6 months of treatment, improves her avoidance behaviors and marriage.

Continue to: Case 2

Ms. R, age 35, is a partnered mother expecting her third child. She has no relevant medical history and is not vaccinated against COVID-19. Her psychiatric history includes self-reported panic attacks and bipolar affective disorder (BPAD). During the second trimester of a desired, unplanned pregnancy, Ms. R presents to an outpatient psychiatry clinic with symptoms of worsening dysphoria and insomnia. She endorses frequent nightmares and flashbacks of CSA as well as remote intimate partner violence. These symptoms, along with hypervigilance, insomnia, anxiety, dysphoria, negative views of herself and her surroundings, and hallucinations of a shadow that whispers “come” when she is alone, worsened during the first trimester of her pregnancy. She recalls experiencing similar trauma-related symptoms during a previous pregnancy but denies a history of pervasive depressive, manic, or psychotic symptoms. She has no other maladaptive personality traits, denies prior substance use or suicidal behavior, and has never been psychiatrically hospitalized or taken psychotropic medications.

Ms. R completes the PCL-5, ITQ, EPDS, and Mood Disorder Questionnaire (MDQ). The results are notable for significant functional impairment related to PTSD and DSO symptoms with minimal concern for BPAD symptoms. The psychiatrist uses ICD-11 criteria to diagnose Ms. R with CPTSD and discusses treatment options with her and her obstetrician. Ms. R is reluctant to take medication until she delivers her baby. She intermittently attends supportive therapy while pregnant. Her pregnancy is complicated by gestational diabetes, and she often misses appointments with her obstetrician and nutritionist.

Ms. R has an uncomplicated vaginal delivery at 38 weeks gestation and success with breastfeeding, but continues to have CPTSD symptoms. She is prescribed quetiapine 25 mg/d for anxiety, insomnia, mood, and psychotic symptoms, but stops taking the medication after 3 days due to excessive sedation. Ms. R is then prescribed sertraline 50 mg/d, which she finds helpful, but has intermittent adherence. She misses multiple virtual appointments with the psychiatrist and does not want to attend in-person sessions due to fear of contracting COVID-19. The psychiatrist encourages Ms. R to get vaccinated, focuses on organizational skills during sessions to promote attendance, and recommends in-person appointments to increase her motivation for treatment and alliance building. Despite numerous outreach attempts, Ms. R is lost to follow-up at 10 months postpartum.

Case 3

Ms. S, age 29, is a partnered mother expecting her fourth child. Her medical history includes chronic back pain. She is not vaccinated against COVID-19, and her psychiatric history includes BPAD. During the first trimester of an undesired, unplanned pregnancy, Ms. S presents to an outpatient psychiatric clinic following an episode where she held a knife over her gravid abdomen during a fight with her partner. She recounts that she became dysregulated and held a knife to her body to communicate her distress, but she did not cut herself, and adamantly denies wanting to hurt herself or the fetus. Ms. S struggles with affective instability, poor frustration tolerance, and irritability. After 1 month of treatment, she discloses surviving prolonged CSA that led to her current nightmares and flashbacks. She also endorses impaired sleep, intimacy avoidance, hypervigilance, impulsive reckless behaviors (including excessive gambling), and negative views about herself and the world that worsened since she learned she was pregnant. Ms. S reports that these same symptoms were aggravated during prior perinatal periods and recalls 2 episodes of severe dysregulation that led to an interrupted suicide attempt and a violent episode toward a loved one. She denies other self-harm behaviors, substance use, or psychotic symptoms, and denies having a history of psychiatric hospitalizations. Ms. S recalls receiving a brief trial of topiramate for BPAD and migraine when she was last in outpatient psychiatric care 8 years ago.

Her psychiatrist administers the PCL-5, ITQ, MDQ, EPDS, and Borderline Symptoms List 23 (BLS-23). The results are notable for significant PTSD and DSO symptoms.¹⁶ The psychiatrist diagnoses Ms. S with CPTSD and bipolar II disorder, exacerbated during the peripartum period. Throughout the remainder of her pregnancy, she endorses mood instability with significant irritability but declines pharmacotherapy. Ms. S intermittently engages in psychotherapy using dialectical behavioral therapy (DBT) focusing on distress tolerance because she is unable to tolerate trauma-focused psychotherapy.

Continue to: Ms. S maintains the pregnancy...

Ms. S maintains the pregnancy without any additional complications and has a vaginal delivery at 39 weeks gestation. She initiates breastfeeding but chooses not to continue after 1 month due to fatigue, insomnia, and worsening mood. Her psychiatrist wants to contact Ms. S’s partner to discuss childcare support at night to promote better sleep conditions for Ms. S, but Ms. S declines. Ms. S intermittently attends virtual appointments, adamantly refuses the COVID-19 vaccine, and is fearful of starting a mood stabilizer despite extensive psychoeducation. At 5 months postpartum, Ms. S reports that she is in a worse mood and does not want to continue the appointment or further treatment, and abruptly ends the telepsychiatry session. Her psychiatrist reaches out the following week to schedule an in-person session if Ms. S agrees to wear personal protective equipment, which she is amenable to. During that appointment, the psychiatrist discusses the risks of bipolar depression and CPTSD on both her and her childrens’ development, against the risk of lamotrigine. Ms. S begins taking lamotrigine, which she tolerates without adverse effects, and quickly notices improvement in her mood as the medication is titrated up slowly to 200 mg/d. Ms. S then engages more consistently in psychotherapy and her CPTSD and bipolar II disorder symptoms much improve at 9 months postpartum.

Ensuring an accurate CPTSD diagnosis

These 3 cases illustrate the diversity and complexity of presentations for perinatal CPTSD following CSA. A CPTSD diagnosis is complicated because the differential is broad for those reporting PTSD and DSO symptoms, and CPTSD is commonly comorbid with other disorders such as anxiety and depression.¹⁷ While various scales can facilitate PTSD screening, the ITQ is helpful because it catalogs the symptoms of disturbances in self organization and functional impairment inherent in CPTSD. The ITQ can help clinicians and patients conceptualize symptoms and track progress (Figure¹¹).

Once a patient screens positive, a CPTSD diagnosis is best made by the clinician after a full psychiatric interview, similar to other diagnoses. Psychiatrists must use ICD-11 criteria,¹ as currently there are no formal DSM-5 criteria for CPTSD.² Additional scales facilitate CPTSD symptom inventory, such as the PCL-5 to screen and monitor for PTSD symptoms and the BLS-23 to delineate between BPD or DSO symptoms.¹⁸ Furthermore, clinicians should screen for other comorbid conditions using additional scales such as the MDQ for BPAD and the EPDS for perinatal mood and anxiety disorders. Sharing a CPTSD diagnosis with a patient is an essential step when initiating treatment. Sensitive psychoeducation on the condition and its application to the perinatal period is key to establishing safety and trust, while also empowering survivors to make their own choices regarding treatment, all essential elements to trauma-informed care.¹⁹

A range of treatment options

Once CPTSD is appropriately diagnosed, clinicians must determine whether to use pharmacotherapy, psychotherapy, or both. A meta-analysis by Coventry et al²⁰ sought to determine the best treatment strategies for complex traumatic events such as CSA, Multicomponent interventions were most promising, and psychological interventions were associated with larger effect sizes than pharmacologic interventions for managing PTSD, mood, and sleep. Therapeutic targets include trauma memory processing, self-perception, and dissociation, along with emotion, interpersonal, and somatic regulation.²¹

Psychotherapy. While there are no standardized guidelines for treating CPTSD, PTSD guidelines suggest using trauma-focused cognitive-behavioral therapy (TF-CBT) as a first-line therapy, though a longer course may be needed to resolve CPTSD symptoms compared to PTSD symptoms.³ DBT for PTSD can be particularly helpful in targeting DSO symptoms.²² Narrative therapy focused on identity, embodiment, and parenting has also shown to be effective for survivors of CSA in the perinatal period, specifically with the goal of meaning-making.⁵ Therapy can also be effective in a group setting (ie, a “Victim to Survivor” TF-CBT group).²³ Sex and couples therapy may be indicated to reestablish trust, especially when it is evident there is sexual inhibition from trauma that influences the relationship, as seen in Case 1.²⁴

Continue to: Pharmacotherapy

Pharmacotherapy. Case 2 and Case 3 both demonstrate that while the peripartum period presents an increased risk for exacerbation of psychiatric symptoms, patients and clinicians may be reluctant to start medications due to concerns for safety during pregnancy or lactation.²⁵ Clinicians must weigh the risks of medication exposure against the risks of exposing the fetus or newborn to untreated psychiatric disease and consult an expert in reproductive psychiatry if questions or concerns arise.²⁶

Adverse effects of psychotropic medications must be considered, especially sedation. Medications that lead to sedation may not be safe or feasible for a mother following delivery, especially if she is breastfeeding. This was exemplified in Case 2, when Ms. R was having troubling hallucinations for which the clinician prescribed quetiapine. The medication resulted in excessive sedation and Ms. R did not feel comfortable performing childcare duties while taking the medication, which greatly influenced future therapy decisions.

Making the decision to prescribe a certain medication for CPTSD is highly influenced by the patient’s most troubling symptoms and their comorbid diagnoses. Selective serotonin reuptake inhibitors (SSRIs) generally are considered safe during pregnancy and breastfeeding, and should be considered as a first-line intervention for PTSD, mood disorders, and anxiety disorders during the perinatal period.²⁷ While prazosin is effective for PTSD symptoms outside of pregnancy, there is limited data regarding its safety during pregnancy and lactation, and it may lead to maternal hypotension and subsequent fetal adverse effects.²⁸

Many patients with a history of CSA experience hallucinations and dissociative symptoms, as demonstrated by Case 1 and Case 2.²⁹ In Case 3, Ms. S displayed features of BPAD with significant hypomanic symptoms and worsening suicidality during prior postpartum periods. The clinician felt comfortable prescribing lamotrigine, a relatively safe medication during the perinatal period compared to other mood stabilizers. Ms. S was amenable to taking lamotrigine, and her clinician avoided the use of an SSRI due to a concern of worsening a bipolar diathesis in this high-risk case.³⁰ Case 2 and Case 3 both highlight the need to closely screen for comorbid conditions such as BPAD and using caution when considering an SSRI in light of the risk of precipitating mania, especially as the patient popu­lation is younger and at higher risk for antidepressant-associated mania.^31,32

Help patients tap into their sources for strength

Other therapeutic strategies when treating patients with perinatal CPTSD include encouraging survivors to mobilize their support network and sources for strength. Chamberlain et al⁸ suggest incorporating socioecological and cultural contexts when considering outlets for social support systems and encourage collaborating with families, especially partners, along with community and spiritual networks. As seen in Case 3, clinicians should attempt to speak to family members on behalf of their patients to promote better sleeping conditions, which can greatly alleviate CPTSD and comorbid mood symptoms, and thus reduce suicide risk.³³ Sources for strength should be accentuated and clinicians may need to advocate with child protective services to support parenting rights. As demonstrated in Case 1, motherhood can greatly reduce suicide risk, and should be promoted if a child’s safety is not in danger.³⁴

Continue to: Clinicians must recognize...

Clinicians must recognize that patients in the perinatal period face barriers to obtaining health care, especially those with CPTSD, as these patients can be difficult to engage and retain. Each case described in this article challenged the psychiatrist with engagement and alliance-building, stemming from the patient’s CPTSD symptoms of interpersonal difficulties and negative views of surroundings. Case 2 demonstrates how the diagnosis can prevent patients from receiving appropriate prenatal care, while Case 3 shows how clinicians may need more flexible attendance policies and assertive outreach attempts to deliver the mental health care these patients deserve.

These vignettes highlight the psychosocial barriers women face during the perinatal period, such as caring for their child, financial stressors, and COVID-19 pandemic–related factors that can hinder treatment, which can be compounded by trauma. The uncertainty, unpredictability, loss of control, and loss of support structures collectively experienced during the pandemic can be triggering and precipitate worsening CPTSD symptoms.³⁵ Women who experience trauma are less likely to obtain the COVID-19 vaccine for themselves or their children, and this hesitancy is often driven by institutional distrust.³⁶ Policy leaders and clinicians should consider these factors to promote trauma-informed COVID-19 vaccine initiatives and expand mental health access using less orthodox treatment settings, such as telepsychiatry. Telepsychiatry can serve as a bridge to in-person care as patients may feel a higher sense of control when in a familiar home environment. Case 2 and Case 3 exemplify the difficulties of delivering mental health care to perinatal women with CPTSD during the pandemic, especially those who are vaccine-hesitant, and illustrate the importance of adapting a patient’s treatment plan in a personalized and trauma-informed way.

Psychiatrists can help obstetricians and pediatricians by explaining that avoidance patterns and distrust in the clinical setting may be related to trauma and are not grounds for conscious or subconscious punishment or abandonment. Educating other clinicians about trauma-informed care, precautions to use for perinatal patients, and ways to effectively support survivors of CSA can greatly improve health outcomes for perinatal women and their offspring.³⁷

Bottom Line

Complex posttraumatic stress disorder (CPTSD) is characterized by classic PTSD symptoms as well as disturbances in self organization, which can include mood symptoms, psychotic symptoms, and maladaptive personality traits. CPTSD resulting from childhood sexual abuse is of particular concern for women, especially during the perinatal period. Clinicians must know how to recognize the signs and symptoms of CPTSD so they can tailor a trauma-informed treatment plan and promote treatment access in this highly vulnerable patient population.

Related Resources

• Tillman B, Sloan N, Westmoreland P. How COVID-19 affects peripartum women’s mental health. Current Psychiatry. 2021;20(6):18-22. doi:10.12788/cp.0129
• Keswani M, Nemcek S, Rashid N. Is it bipolar disorder, or a complex form of PTSD? Current Psychiatry. 2021;20(12):42-49. doi:10.12788/cp.0188

Drug Brand Names

Carbamazepine • Carbatrol
Clonazepam • Klonopin
Lamotrigine • Lamictal
Prazosin • Minipress
Quetiapine • Seroquel
Sertraline • Zoloft
Topiramate • Topamax

Complex posttraumatic stress disorder (CPTSD) is a condition characterized by classic trauma-related symptoms in addition to disturbances in self organization (DSO).^1-3 DSO symptoms include negative self-concept, emotional dysregulation, and interpersonal problems. CPTSD differs from PTSD in that it includes symptoms of DSO, and differs from borderline personality disorder (BPD) in that it does not include extreme self-injurious behavior, a complete lack of sense of self, and avoidance of rejection or abandonment (Table^1,2). The maladaptive traits of CPTSD are often the result of a chronic lack of safety in early childhood, particularly childhood sexual abuse (CSA). CSA may affect up to 20% of women and is defined by the CDC as “any completed or attempted sexual act, sexual contact with, or exploitation of a child by a caregiver.”^4,5

Maternal lifetime trauma is more common among women who are in low-income minority groups and can lead to adverse birth outcomes in this vulnerable patient population.⁶ Recent research has found that trauma can increase cortisol levels during pregnancy, leading to increased placental permeability, inflammatory response, and longstanding alterations in the fetal hypothalamic-pituitary adrenal axis.⁶ A CPTSD diagnosis is of particular interest during the perinatal period because CPTSD is often a response to interpersonal trauma and attachment adversity, which can be reactivated during the perinatal period.⁷ CPTSD in survivors of CSA can be exacerbated due to feelings of disempowerment secondary to loss of bodily control throughout pregnancy, childbirth, breastfeeding, and obstetrical exams.^5,8 Little is known about perinatal CPTSD, but we can extrapolate from trauma research that it is likely associated with the worsening of other maternal mental health conditions, suicidality, physical complaints, quality of life, maternal-child bonding outcomes, and low birth weight in offspring.^5,9,10

Although there are no consensus guidelines on how to diagnose and treat CPTSD during the perinatal period, or how to promote family functioning thereafter, there are many opportunities for intervention. Mental health clinicians are in a particularly important position to care for women in the perinatal period, as collaborative work with obstetricians, pediatricians, and social services can have long-lasting effects.

In this article, we present cases of 3 CSA survivors who experienced worsening of CPTSD symptoms during the perinatal period and received psychiatric care via telehealth during the COVID-19 pandemic. We also identify best practice approaches and highlight areas for future research.

Case descriptions

Case 1

Ms. A, age 33, is married, has 3 children, has asthma, and is vaccinated against COVID-19. Her psychiatric history includes self-reported dissociative identity disorder and bulimia nervosa. At 2 months postpartum following an unplanned yet desired pregnancy, Ms. A presents to the outpatient clinic after a violent episode toward her husband during sexual intercourse. Since the first trimester of her pregnancy, she has expressed increased anxiety and difficulty sleeping, hypervigilance, intimacy avoidance, and negative views of herself and the world, yet she denies persistent depressive, manic, or psychotic symptoms, other maladaptive personality traits, or substance use. She recalls experiencing similar symptoms during her 2 previous peripartum periods, and attributes it to worsening memories of sexual abuse during childhood. Ms. A has a history of psychiatric hospitalizations during adolescence and young adulthood for suicidal ideation. She had been treated with various medications, including chlorpromazine, lamotrigine, carbamazepine, and clonazepam, but self-discontinued these medications in 2016 because she felt they were ineffective. Since becoming a mother, she has consistently denied depressive symptoms or suicidal ideation, and intermittently engaged in interpersonal psychotherapy targeting her conflictual relationship with her husband and parenting struggles.

Ms. A underwent an induced vaginal delivery at 36 weeks gestation due to preeclampsia and had success with breastfeeding. While engaging in sexual activity for the first time postpartum, she dissociated and later learned she had forcefully grabbed her husband’s neck for several seconds but did not cause any longstanding physical damage. Upon learning of this episode, Ms. A’s psychiatrist asks her to complete the International Trauma Questionnaire (ITQ), a brief self-report measure developed for the assessment of the ICD-11 diagnosis of CPTSD (Figure¹¹). Ms. A also completes the PTSD Checklist for DSM-5 (PCL-5), the Dissociative Experiences Scale, and the Edinburgh Postnatal Depression Scale (EPDS) to assist with assessing her symptoms.^12-15 The psychiatrist uses ICD-11 criteria to diagnose Ms. A with CPTSD, given her functional impairment associated with both PTSD and DSO symptoms, which have acutely worsened during the perinatal period.

Ms. A initially engages in extensive trauma psychoeducation and supportive psychotherapy for 3 months. She later pursues prolonged exposure psychotherapy targeting intimacy, and after 6 months of treatment, improves her avoidance behaviors and marriage.

Continue to: Case 2

Ms. R, age 35, is a partnered mother expecting her third child. She has no relevant medical history and is not vaccinated against COVID-19. Her psychiatric history includes self-reported panic attacks and bipolar affective disorder (BPAD). During the second trimester of a desired, unplanned pregnancy, Ms. R presents to an outpatient psychiatry clinic with symptoms of worsening dysphoria and insomnia. She endorses frequent nightmares and flashbacks of CSA as well as remote intimate partner violence. These symptoms, along with hypervigilance, insomnia, anxiety, dysphoria, negative views of herself and her surroundings, and hallucinations of a shadow that whispers “come” when she is alone, worsened during the first trimester of her pregnancy. She recalls experiencing similar trauma-related symptoms during a previous pregnancy but denies a history of pervasive depressive, manic, or psychotic symptoms. She has no other maladaptive personality traits, denies prior substance use or suicidal behavior, and has never been psychiatrically hospitalized or taken psychotropic medications.

Ms. R completes the PCL-5, ITQ, EPDS, and Mood Disorder Questionnaire (MDQ). The results are notable for significant functional impairment related to PTSD and DSO symptoms with minimal concern for BPAD symptoms. The psychiatrist uses ICD-11 criteria to diagnose Ms. R with CPTSD and discusses treatment options with her and her obstetrician. Ms. R is reluctant to take medication until she delivers her baby. She intermittently attends supportive therapy while pregnant. Her pregnancy is complicated by gestational diabetes, and she often misses appointments with her obstetrician and nutritionist.

Ms. R has an uncomplicated vaginal delivery at 38 weeks gestation and success with breastfeeding, but continues to have CPTSD symptoms. She is prescribed quetiapine 25 mg/d for anxiety, insomnia, mood, and psychotic symptoms, but stops taking the medication after 3 days due to excessive sedation. Ms. R is then prescribed sertraline 50 mg/d, which she finds helpful, but has intermittent adherence. She misses multiple virtual appointments with the psychiatrist and does not want to attend in-person sessions due to fear of contracting COVID-19. The psychiatrist encourages Ms. R to get vaccinated, focuses on organizational skills during sessions to promote attendance, and recommends in-person appointments to increase her motivation for treatment and alliance building. Despite numerous outreach attempts, Ms. R is lost to follow-up at 10 months postpartum.

Case 3

Ms. S, age 29, is a partnered mother expecting her fourth child. Her medical history includes chronic back pain. She is not vaccinated against COVID-19, and her psychiatric history includes BPAD. During the first trimester of an undesired, unplanned pregnancy, Ms. S presents to an outpatient psychiatric clinic following an episode where she held a knife over her gravid abdomen during a fight with her partner. She recounts that she became dysregulated and held a knife to her body to communicate her distress, but she did not cut herself, and adamantly denies wanting to hurt herself or the fetus. Ms. S struggles with affective instability, poor frustration tolerance, and irritability. After 1 month of treatment, she discloses surviving prolonged CSA that led to her current nightmares and flashbacks. She also endorses impaired sleep, intimacy avoidance, hypervigilance, impulsive reckless behaviors (including excessive gambling), and negative views about herself and the world that worsened since she learned she was pregnant. Ms. S reports that these same symptoms were aggravated during prior perinatal periods and recalls 2 episodes of severe dysregulation that led to an interrupted suicide attempt and a violent episode toward a loved one. She denies other self-harm behaviors, substance use, or psychotic symptoms, and denies having a history of psychiatric hospitalizations. Ms. S recalls receiving a brief trial of topiramate for BPAD and migraine when she was last in outpatient psychiatric care 8 years ago.

Her psychiatrist administers the PCL-5, ITQ, MDQ, EPDS, and Borderline Symptoms List 23 (BLS-23). The results are notable for significant PTSD and DSO symptoms.¹⁶ The psychiatrist diagnoses Ms. S with CPTSD and bipolar II disorder, exacerbated during the peripartum period. Throughout the remainder of her pregnancy, she endorses mood instability with significant irritability but declines pharmacotherapy. Ms. S intermittently engages in psychotherapy using dialectical behavioral therapy (DBT) focusing on distress tolerance because she is unable to tolerate trauma-focused psychotherapy.

Continue to: Ms. S maintains the pregnancy...

Ms. S maintains the pregnancy without any additional complications and has a vaginal delivery at 39 weeks gestation. She initiates breastfeeding but chooses not to continue after 1 month due to fatigue, insomnia, and worsening mood. Her psychiatrist wants to contact Ms. S’s partner to discuss childcare support at night to promote better sleep conditions for Ms. S, but Ms. S declines. Ms. S intermittently attends virtual appointments, adamantly refuses the COVID-19 vaccine, and is fearful of starting a mood stabilizer despite extensive psychoeducation. At 5 months postpartum, Ms. S reports that she is in a worse mood and does not want to continue the appointment or further treatment, and abruptly ends the telepsychiatry session. Her psychiatrist reaches out the following week to schedule an in-person session if Ms. S agrees to wear personal protective equipment, which she is amenable to. During that appointment, the psychiatrist discusses the risks of bipolar depression and CPTSD on both her and her childrens’ development, against the risk of lamotrigine. Ms. S begins taking lamotrigine, which she tolerates without adverse effects, and quickly notices improvement in her mood as the medication is titrated up slowly to 200 mg/d. Ms. S then engages more consistently in psychotherapy and her CPTSD and bipolar II disorder symptoms much improve at 9 months postpartum.

Ensuring an accurate CPTSD diagnosis

These 3 cases illustrate the diversity and complexity of presentations for perinatal CPTSD following CSA. A CPTSD diagnosis is complicated because the differential is broad for those reporting PTSD and DSO symptoms, and CPTSD is commonly comorbid with other disorders such as anxiety and depression.¹⁷ While various scales can facilitate PTSD screening, the ITQ is helpful because it catalogs the symptoms of disturbances in self organization and functional impairment inherent in CPTSD. The ITQ can help clinicians and patients conceptualize symptoms and track progress (Figure¹¹).

Once a patient screens positive, a CPTSD diagnosis is best made by the clinician after a full psychiatric interview, similar to other diagnoses. Psychiatrists must use ICD-11 criteria,¹ as currently there are no formal DSM-5 criteria for CPTSD.² Additional scales facilitate CPTSD symptom inventory, such as the PCL-5 to screen and monitor for PTSD symptoms and the BLS-23 to delineate between BPD or DSO symptoms.¹⁸ Furthermore, clinicians should screen for other comorbid conditions using additional scales such as the MDQ for BPAD and the EPDS for perinatal mood and anxiety disorders. Sharing a CPTSD diagnosis with a patient is an essential step when initiating treatment. Sensitive psychoeducation on the condition and its application to the perinatal period is key to establishing safety and trust, while also empowering survivors to make their own choices regarding treatment, all essential elements to trauma-informed care.¹⁹

A range of treatment options

Once CPTSD is appropriately diagnosed, clinicians must determine whether to use pharmacotherapy, psychotherapy, or both. A meta-analysis by Coventry et al²⁰ sought to determine the best treatment strategies for complex traumatic events such as CSA, Multicomponent interventions were most promising, and psychological interventions were associated with larger effect sizes than pharmacologic interventions for managing PTSD, mood, and sleep. Therapeutic targets include trauma memory processing, self-perception, and dissociation, along with emotion, interpersonal, and somatic regulation.²¹

Psychotherapy. While there are no standardized guidelines for treating CPTSD, PTSD guidelines suggest using trauma-focused cognitive-behavioral therapy (TF-CBT) as a first-line therapy, though a longer course may be needed to resolve CPTSD symptoms compared to PTSD symptoms.³ DBT for PTSD can be particularly helpful in targeting DSO symptoms.²² Narrative therapy focused on identity, embodiment, and parenting has also shown to be effective for survivors of CSA in the perinatal period, specifically with the goal of meaning-making.⁵ Therapy can also be effective in a group setting (ie, a “Victim to Survivor” TF-CBT group).²³ Sex and couples therapy may be indicated to reestablish trust, especially when it is evident there is sexual inhibition from trauma that influences the relationship, as seen in Case 1.²⁴

Continue to: Pharmacotherapy

Pharmacotherapy. Case 2 and Case 3 both demonstrate that while the peripartum period presents an increased risk for exacerbation of psychiatric symptoms, patients and clinicians may be reluctant to start medications due to concerns for safety during pregnancy or lactation.²⁵ Clinicians must weigh the risks of medication exposure against the risks of exposing the fetus or newborn to untreated psychiatric disease and consult an expert in reproductive psychiatry if questions or concerns arise.²⁶

Adverse effects of psychotropic medications must be considered, especially sedation. Medications that lead to sedation may not be safe or feasible for a mother following delivery, especially if she is breastfeeding. This was exemplified in Case 2, when Ms. R was having troubling hallucinations for which the clinician prescribed quetiapine. The medication resulted in excessive sedation and Ms. R did not feel comfortable performing childcare duties while taking the medication, which greatly influenced future therapy decisions.

Making the decision to prescribe a certain medication for CPTSD is highly influenced by the patient’s most troubling symptoms and their comorbid diagnoses. Selective serotonin reuptake inhibitors (SSRIs) generally are considered safe during pregnancy and breastfeeding, and should be considered as a first-line intervention for PTSD, mood disorders, and anxiety disorders during the perinatal period.²⁷ While prazosin is effective for PTSD symptoms outside of pregnancy, there is limited data regarding its safety during pregnancy and lactation, and it may lead to maternal hypotension and subsequent fetal adverse effects.²⁸

Many patients with a history of CSA experience hallucinations and dissociative symptoms, as demonstrated by Case 1 and Case 2.²⁹ In Case 3, Ms. S displayed features of BPAD with significant hypomanic symptoms and worsening suicidality during prior postpartum periods. The clinician felt comfortable prescribing lamotrigine, a relatively safe medication during the perinatal period compared to other mood stabilizers. Ms. S was amenable to taking lamotrigine, and her clinician avoided the use of an SSRI due to a concern of worsening a bipolar diathesis in this high-risk case.³⁰ Case 2 and Case 3 both highlight the need to closely screen for comorbid conditions such as BPAD and using caution when considering an SSRI in light of the risk of precipitating mania, especially as the patient popu­lation is younger and at higher risk for antidepressant-associated mania.^31,32

Help patients tap into their sources for strength

Other therapeutic strategies when treating patients with perinatal CPTSD include encouraging survivors to mobilize their support network and sources for strength. Chamberlain et al⁸ suggest incorporating socioecological and cultural contexts when considering outlets for social support systems and encourage collaborating with families, especially partners, along with community and spiritual networks. As seen in Case 3, clinicians should attempt to speak to family members on behalf of their patients to promote better sleeping conditions, which can greatly alleviate CPTSD and comorbid mood symptoms, and thus reduce suicide risk.³³ Sources for strength should be accentuated and clinicians may need to advocate with child protective services to support parenting rights. As demonstrated in Case 1, motherhood can greatly reduce suicide risk, and should be promoted if a child’s safety is not in danger.³⁴

Continue to: Clinicians must recognize...

Clinicians must recognize that patients in the perinatal period face barriers to obtaining health care, especially those with CPTSD, as these patients can be difficult to engage and retain. Each case described in this article challenged the psychiatrist with engagement and alliance-building, stemming from the patient’s CPTSD symptoms of interpersonal difficulties and negative views of surroundings. Case 2 demonstrates how the diagnosis can prevent patients from receiving appropriate prenatal care, while Case 3 shows how clinicians may need more flexible attendance policies and assertive outreach attempts to deliver the mental health care these patients deserve.

These vignettes highlight the psychosocial barriers women face during the perinatal period, such as caring for their child, financial stressors, and COVID-19 pandemic–related factors that can hinder treatment, which can be compounded by trauma. The uncertainty, unpredictability, loss of control, and loss of support structures collectively experienced during the pandemic can be triggering and precipitate worsening CPTSD symptoms.³⁵ Women who experience trauma are less likely to obtain the COVID-19 vaccine for themselves or their children, and this hesitancy is often driven by institutional distrust.³⁶ Policy leaders and clinicians should consider these factors to promote trauma-informed COVID-19 vaccine initiatives and expand mental health access using less orthodox treatment settings, such as telepsychiatry. Telepsychiatry can serve as a bridge to in-person care as patients may feel a higher sense of control when in a familiar home environment. Case 2 and Case 3 exemplify the difficulties of delivering mental health care to perinatal women with CPTSD during the pandemic, especially those who are vaccine-hesitant, and illustrate the importance of adapting a patient’s treatment plan in a personalized and trauma-informed way.

Psychiatrists can help obstetricians and pediatricians by explaining that avoidance patterns and distrust in the clinical setting may be related to trauma and are not grounds for conscious or subconscious punishment or abandonment. Educating other clinicians about trauma-informed care, precautions to use for perinatal patients, and ways to effectively support survivors of CSA can greatly improve health outcomes for perinatal women and their offspring.³⁷

Bottom Line

Complex posttraumatic stress disorder (CPTSD) is characterized by classic PTSD symptoms as well as disturbances in self organization, which can include mood symptoms, psychotic symptoms, and maladaptive personality traits. CPTSD resulting from childhood sexual abuse is of particular concern for women, especially during the perinatal period. Clinicians must know how to recognize the signs and symptoms of CPTSD so they can tailor a trauma-informed treatment plan and promote treatment access in this highly vulnerable patient population.

Related Resources

• Tillman B, Sloan N, Westmoreland P. How COVID-19 affects peripartum women’s mental health. Current Psychiatry. 2021;20(6):18-22. doi:10.12788/cp.0129
• Keswani M, Nemcek S, Rashid N. Is it bipolar disorder, or a complex form of PTSD? Current Psychiatry. 2021;20(12):42-49. doi:10.12788/cp.0188

Drug Brand Names

Carbamazepine • Carbatrol
Clonazepam • Klonopin
Lamotrigine • Lamictal
Prazosin • Minipress
Quetiapine • Seroquel
Sertraline • Zoloft
Topiramate • Topamax