Current Psychiatry

The evidence is robust and disheartening: As if the personal suffering and societal stigma of mental illness are not bad enough, psychiatric patients also have a shorter life­span.¹ In the past, most studies have focused on early mortality and loss of potential life-years in schizophrenia,² but many subsequent reports indicate that premature death occurs in all major psychiatric disorders.

Here is a summary of the sobering facts:

• Schizophrenia. In a study of 30,210 patients with schizophrenia, compared with >5 million individuals in the general population in Denmark (where they have an excellent registry), mortality was 16-fold higher among patients with schizophrenia if they had a single somatic illness.³ The illnesses were mostly respiratory, gastrointestinal, or cardiovascular).³ The loss of potential years of life was staggeringly high: 18.7 years for men, 16.3 years for women.⁴ A study conducted in 8 US states reported a loss of 2 to 3 decades of life across each of these states.⁵ The causes of death in patients with schizophrenia were mainly heart disease, cancer, stroke, and pulmonary diseases. A national database in Sweden found that unmedicated patients with schizophrenia had a significantly higher death rate than those receiving antipsychotics.^6,7 Similar findings were reported by researchers in Finland.⁸ The Swedish study by Tiihonen et al⁶ also found that mortality was highest in patients receiving benzodiazepines along with antipsychotics, but there was no increased mortality among patients with schizophrenia receiving antidepressants.
• Bipolar disorder. A shorter life expectancy has also been reported in bipolar disorder,⁹ with a loss of 13.6 years for men and 12.1 years for women. Early death was caused by physical illness (even when suicide deaths were excluded), especially cardio­vascular disease.¹⁰
• Major depressive disorder (MDD). A reduction of life expectancy in persons with MDD (unipolar depression) has been reported, with a loss of 14 years in men and 10 years in women.¹¹ Although suicide contributed to the shorter lifespan, death due to accidents was 500% higher among persons with unipolar depression; the largest causes of death were physical illnesses. Further, Zubenko et al¹² reported alarming findings about excess mortality among first- and second-degree relatives of persons with early-onset depression (some of whom were bipolar). The relatives died an average of 8 years earlier than the local population, and 40% died before reaching age 65. Also, there was a 5-fold increase in infant mortality (in the first year of life) among the relatives. The most common causes of death in adult relatives were heart disease, cancer, and stroke. It is obvious that MDD has a significant negative impact on health and longevity in both patients and their relatives.
• Attention-deficit/hyperactivity disorder (ADHD). A 220% increase in mortality was reported in persons with ADHD at all ages.¹³ Accidents were the most common cause of death. The mortality rate ratio (MRR) was 1.86 for ADHD before age 6, 1.58 for ADHD between age 6 to 17, and 4.25 for those age ≥18. The rate of early mortality was higher in girls and women (MRR = 2.85) than boys and men (MRR = 1.27).
• Obsessive-compulsive disorder (OCD). A study from Denmark of 10,155 persons with OCD followed for 10 years reported a significantly higher risk of death from both natural (MRR = 1.68) and unnatural causes (MRR = 2.61), compared with the general population.¹⁴ Patients with OCD and comorbid depression, anxiety, or substance use had a further increase in mortality risk, but the mortality risk of individuals with OCD without psychiatric comorbidity was still 200% higher than that of the general population.
• Anxiety disorders. One study found no increase in mortality among patients who have generalized anxiety, unless it was associated with depression.¹⁵ Another study reported that the presence of anxiety reduced the risk of cardiovascular mortality in persons with depression.¹⁶ The absence of increased mortality in anxiety disorders was also confirmed in a meta-analysis of 36 studies.¹⁷ However, a study of postmenopausal women with panic attacks found a 3-fold increase in coronary artery disease and stroke in that cohort,¹⁸ which confirmed the findings of an older study¹⁹ that demonstrated a 2-fold increase of mortality among 155 men with panic disorder after a 12-year follow-up. Also, a 25-year follow-up study found that suicide accounted for 20% of deaths in the anxiety group compared with 16.2% in the depression group,²⁰ showing a significant risk of suicide in panic disorder, even exceeding that of depression.
• Oppositional defiant disorder (ODD) and conduct disorder (CD). In a 12-year follow-up study of 9,495 individuals with “disruptive behavioral disorders,” which included ODD and CD, the mortality rate was >400% higher in these patients compared with 1.92 million individuals in the general population (9.66 vs 2.22 per 10,000 person­-years).²¹ Comorbid substance use disorder and ADHD further increased the mortality rate in this cohort.
• Posttraumatic stress disorder (PTSD). Studies show that there is a significantly increased risk of early cardiovascular mortality in PTSD,²² and that the death rate may be associated with accelerated “DNA methylation age” that leads to a 13% increased risk for all-cause mortality.²³
• Borderline personality disorder (BPD). A recent longitudinal study (24 years of follow-up with evaluation every 2 years) reported a significantly higher mortality in patients with BPD compared with those with other personality disorders. The age range when the study started was 18 to 35. The rate of suicide death was Palatino LT Std>400% higher in BPD (5.9% vs 1.4%). Also, non-suicidal death was 250% higher in BPD (14% vs 5.5%). The causes of non-suicidal death included cardiovascular disease, substance-related complications, cancer, and accidents.²⁴
• Other personality disorders. Certain personality traits have been associated with shorter leukocyte telomeres, which signal early death. These traits include neuroticism, conscientiousness, harm avoidance, and reward dependence.²⁵ Another study found shorter telomeres in persons with high neuroticism and low agreeableness²⁶ regardless of age or sex. Short telomeres, which reflect accelerated cellular senescence and aging, have also been reported in several major psychiatric disorders (schizophrenia, bipolar disorder, MDD, and anxiety).^27-29 The cumulative evidence is unassailable; psychiatric brain disorders are not only associated with premature death due to high suicide rates, but also with multiple medical diseases that lead to early mortality and a shorter lifespan. The shortened telomeres reflect high oxidative stress and inflammation, and both those toxic processes are known to be associated with major psychiatric disorders. Compounding the dismal facts about early mortality due to mental illness are the additional grave medical consequences of alcohol and substance use, which are highly comorbid with most psychiatric disorders, further exacerbating the premature death rates among psychiatric patients.

Continue to: There is an important take-home message...

There is an important take-home message in all of this: Our patients are at high risk for potentially fatal medical conditions that require early detection, and intensive ongoing treatment by a primary care clinician (not “provider”; I abhor the widespread use of that term for physicians or nurse practitioners) is an indispensable component of psychiatric care. Thus, collaborative care is vital to protect our psychiatric patients from early mortality and a shortened lifespan. Psychiatrists and psychiatric nurse practitioners must not only win the battle against mental illness, but also diligently avoid losing the war of life and death.

The evidence is robust and disheartening: As if the personal suffering and societal stigma of mental illness are not bad enough, psychiatric patients also have a shorter life­span.¹ In the past, most studies have focused on early mortality and loss of potential life-years in schizophrenia,² but many subsequent reports indicate that premature death occurs in all major psychiatric disorders.

Here is a summary of the sobering facts:

• Schizophrenia. In a study of 30,210 patients with schizophrenia, compared with >5 million individuals in the general population in Denmark (where they have an excellent registry), mortality was 16-fold higher among patients with schizophrenia if they had a single somatic illness.³ The illnesses were mostly respiratory, gastrointestinal, or cardiovascular).³ The loss of potential years of life was staggeringly high: 18.7 years for men, 16.3 years for women.⁴ A study conducted in 8 US states reported a loss of 2 to 3 decades of life across each of these states.⁵ The causes of death in patients with schizophrenia were mainly heart disease, cancer, stroke, and pulmonary diseases. A national database in Sweden found that unmedicated patients with schizophrenia had a significantly higher death rate than those receiving antipsychotics.^6,7 Similar findings were reported by researchers in Finland.⁸ The Swedish study by Tiihonen et al⁶ also found that mortality was highest in patients receiving benzodiazepines along with antipsychotics, but there was no increased mortality among patients with schizophrenia receiving antidepressants.
• Bipolar disorder. A shorter life expectancy has also been reported in bipolar disorder,⁹ with a loss of 13.6 years for men and 12.1 years for women. Early death was caused by physical illness (even when suicide deaths were excluded), especially cardio­vascular disease.¹⁰
• Major depressive disorder (MDD). A reduction of life expectancy in persons with MDD (unipolar depression) has been reported, with a loss of 14 years in men and 10 years in women.¹¹ Although suicide contributed to the shorter lifespan, death due to accidents was 500% higher among persons with unipolar depression; the largest causes of death were physical illnesses. Further, Zubenko et al¹² reported alarming findings about excess mortality among first- and second-degree relatives of persons with early-onset depression (some of whom were bipolar). The relatives died an average of 8 years earlier than the local population, and 40% died before reaching age 65. Also, there was a 5-fold increase in infant mortality (in the first year of life) among the relatives. The most common causes of death in adult relatives were heart disease, cancer, and stroke. It is obvious that MDD has a significant negative impact on health and longevity in both patients and their relatives.
• Attention-deficit/hyperactivity disorder (ADHD). A 220% increase in mortality was reported in persons with ADHD at all ages.¹³ Accidents were the most common cause of death. The mortality rate ratio (MRR) was 1.86 for ADHD before age 6, 1.58 for ADHD between age 6 to 17, and 4.25 for those age ≥18. The rate of early mortality was higher in girls and women (MRR = 2.85) than boys and men (MRR = 1.27).
• Obsessive-compulsive disorder (OCD). A study from Denmark of 10,155 persons with OCD followed for 10 years reported a significantly higher risk of death from both natural (MRR = 1.68) and unnatural causes (MRR = 2.61), compared with the general population.¹⁴ Patients with OCD and comorbid depression, anxiety, or substance use had a further increase in mortality risk, but the mortality risk of individuals with OCD without psychiatric comorbidity was still 200% higher than that of the general population.
• Anxiety disorders. One study found no increase in mortality among patients who have generalized anxiety, unless it was associated with depression.¹⁵ Another study reported that the presence of anxiety reduced the risk of cardiovascular mortality in persons with depression.¹⁶ The absence of increased mortality in anxiety disorders was also confirmed in a meta-analysis of 36 studies.¹⁷ However, a study of postmenopausal women with panic attacks found a 3-fold increase in coronary artery disease and stroke in that cohort,¹⁸ which confirmed the findings of an older study¹⁹ that demonstrated a 2-fold increase of mortality among 155 men with panic disorder after a 12-year follow-up. Also, a 25-year follow-up study found that suicide accounted for 20% of deaths in the anxiety group compared with 16.2% in the depression group,²⁰ showing a significant risk of suicide in panic disorder, even exceeding that of depression.
• Oppositional defiant disorder (ODD) and conduct disorder (CD). In a 12-year follow-up study of 9,495 individuals with “disruptive behavioral disorders,” which included ODD and CD, the mortality rate was >400% higher in these patients compared with 1.92 million individuals in the general population (9.66 vs 2.22 per 10,000 person­-years).²¹ Comorbid substance use disorder and ADHD further increased the mortality rate in this cohort.
• Posttraumatic stress disorder (PTSD). Studies show that there is a significantly increased risk of early cardiovascular mortality in PTSD,²² and that the death rate may be associated with accelerated “DNA methylation age” that leads to a 13% increased risk for all-cause mortality.²³
• Borderline personality disorder (BPD). A recent longitudinal study (24 years of follow-up with evaluation every 2 years) reported a significantly higher mortality in patients with BPD compared with those with other personality disorders. The age range when the study started was 18 to 35. The rate of suicide death was Palatino LT Std>400% higher in BPD (5.9% vs 1.4%). Also, non-suicidal death was 250% higher in BPD (14% vs 5.5%). The causes of non-suicidal death included cardiovascular disease, substance-related complications, cancer, and accidents.²⁴
• Other personality disorders. Certain personality traits have been associated with shorter leukocyte telomeres, which signal early death. These traits include neuroticism, conscientiousness, harm avoidance, and reward dependence.²⁵ Another study found shorter telomeres in persons with high neuroticism and low agreeableness²⁶ regardless of age or sex. Short telomeres, which reflect accelerated cellular senescence and aging, have also been reported in several major psychiatric disorders (schizophrenia, bipolar disorder, MDD, and anxiety).^27-29 The cumulative evidence is unassailable; psychiatric brain disorders are not only associated with premature death due to high suicide rates, but also with multiple medical diseases that lead to early mortality and a shorter lifespan. The shortened telomeres reflect high oxidative stress and inflammation, and both those toxic processes are known to be associated with major psychiatric disorders. Compounding the dismal facts about early mortality due to mental illness are the additional grave medical consequences of alcohol and substance use, which are highly comorbid with most psychiatric disorders, further exacerbating the premature death rates among psychiatric patients.

Continue to: There is an important take-home message...

There is an important take-home message in all of this: Our patients are at high risk for potentially fatal medical conditions that require early detection, and intensive ongoing treatment by a primary care clinician (not “provider”; I abhor the widespread use of that term for physicians or nurse practitioners) is an indispensable component of psychiatric care. Thus, collaborative care is vital to protect our psychiatric patients from early mortality and a shortened lifespan. Psychiatrists and psychiatric nurse practitioners must not only win the battle against mental illness, but also diligently avoid losing the war of life and death.

The evidence is robust and disheartening: As if the personal suffering and societal stigma of mental illness are not bad enough, psychiatric patients also have a shorter life­span.¹ In the past, most studies have focused on early mortality and loss of potential life-years in schizophrenia,² but many subsequent reports indicate that premature death occurs in all major psychiatric disorders.

Here is a summary of the sobering facts:

• Schizophrenia. In a study of 30,210 patients with schizophrenia, compared with >5 million individuals in the general population in Denmark (where they have an excellent registry), mortality was 16-fold higher among patients with schizophrenia if they had a single somatic illness.³ The illnesses were mostly respiratory, gastrointestinal, or cardiovascular).³ The loss of potential years of life was staggeringly high: 18.7 years for men, 16.3 years for women.⁴ A study conducted in 8 US states reported a loss of 2 to 3 decades of life across each of these states.⁵ The causes of death in patients with schizophrenia were mainly heart disease, cancer, stroke, and pulmonary diseases. A national database in Sweden found that unmedicated patients with schizophrenia had a significantly higher death rate than those receiving antipsychotics.^6,7 Similar findings were reported by researchers in Finland.⁸ The Swedish study by Tiihonen et al⁶ also found that mortality was highest in patients receiving benzodiazepines along with antipsychotics, but there was no increased mortality among patients with schizophrenia receiving antidepressants.
• Bipolar disorder. A shorter life expectancy has also been reported in bipolar disorder,⁹ with a loss of 13.6 years for men and 12.1 years for women. Early death was caused by physical illness (even when suicide deaths were excluded), especially cardio­vascular disease.¹⁰
• Major depressive disorder (MDD). A reduction of life expectancy in persons with MDD (unipolar depression) has been reported, with a loss of 14 years in men and 10 years in women.¹¹ Although suicide contributed to the shorter lifespan, death due to accidents was 500% higher among persons with unipolar depression; the largest causes of death were physical illnesses. Further, Zubenko et al¹² reported alarming findings about excess mortality among first- and second-degree relatives of persons with early-onset depression (some of whom were bipolar). The relatives died an average of 8 years earlier than the local population, and 40% died before reaching age 65. Also, there was a 5-fold increase in infant mortality (in the first year of life) among the relatives. The most common causes of death in adult relatives were heart disease, cancer, and stroke. It is obvious that MDD has a significant negative impact on health and longevity in both patients and their relatives.
• Attention-deficit/hyperactivity disorder (ADHD). A 220% increase in mortality was reported in persons with ADHD at all ages.¹³ Accidents were the most common cause of death. The mortality rate ratio (MRR) was 1.86 for ADHD before age 6, 1.58 for ADHD between age 6 to 17, and 4.25 for those age ≥18. The rate of early mortality was higher in girls and women (MRR = 2.85) than boys and men (MRR = 1.27).
• Obsessive-compulsive disorder (OCD). A study from Denmark of 10,155 persons with OCD followed for 10 years reported a significantly higher risk of death from both natural (MRR = 1.68) and unnatural causes (MRR = 2.61), compared with the general population.¹⁴ Patients with OCD and comorbid depression, anxiety, or substance use had a further increase in mortality risk, but the mortality risk of individuals with OCD without psychiatric comorbidity was still 200% higher than that of the general population.
• Anxiety disorders. One study found no increase in mortality among patients who have generalized anxiety, unless it was associated with depression.¹⁵ Another study reported that the presence of anxiety reduced the risk of cardiovascular mortality in persons with depression.¹⁶ The absence of increased mortality in anxiety disorders was also confirmed in a meta-analysis of 36 studies.¹⁷ However, a study of postmenopausal women with panic attacks found a 3-fold increase in coronary artery disease and stroke in that cohort,¹⁸ which confirmed the findings of an older study¹⁹ that demonstrated a 2-fold increase of mortality among 155 men with panic disorder after a 12-year follow-up. Also, a 25-year follow-up study found that suicide accounted for 20% of deaths in the anxiety group compared with 16.2% in the depression group,²⁰ showing a significant risk of suicide in panic disorder, even exceeding that of depression.
• Oppositional defiant disorder (ODD) and conduct disorder (CD). In a 12-year follow-up study of 9,495 individuals with “disruptive behavioral disorders,” which included ODD and CD, the mortality rate was >400% higher in these patients compared with 1.92 million individuals in the general population (9.66 vs 2.22 per 10,000 person­-years).²¹ Comorbid substance use disorder and ADHD further increased the mortality rate in this cohort.
• Posttraumatic stress disorder (PTSD). Studies show that there is a significantly increased risk of early cardiovascular mortality in PTSD,²² and that the death rate may be associated with accelerated “DNA methylation age” that leads to a 13% increased risk for all-cause mortality.²³
• Borderline personality disorder (BPD). A recent longitudinal study (24 years of follow-up with evaluation every 2 years) reported a significantly higher mortality in patients with BPD compared with those with other personality disorders. The age range when the study started was 18 to 35. The rate of suicide death was Palatino LT Std>400% higher in BPD (5.9% vs 1.4%). Also, non-suicidal death was 250% higher in BPD (14% vs 5.5%). The causes of non-suicidal death included cardiovascular disease, substance-related complications, cancer, and accidents.²⁴
• Other personality disorders. Certain personality traits have been associated with shorter leukocyte telomeres, which signal early death. These traits include neuroticism, conscientiousness, harm avoidance, and reward dependence.²⁵ Another study found shorter telomeres in persons with high neuroticism and low agreeableness²⁶ regardless of age or sex. Short telomeres, which reflect accelerated cellular senescence and aging, have also been reported in several major psychiatric disorders (schizophrenia, bipolar disorder, MDD, and anxiety).^27-29 The cumulative evidence is unassailable; psychiatric brain disorders are not only associated with premature death due to high suicide rates, but also with multiple medical diseases that lead to early mortality and a shorter lifespan. The shortened telomeres reflect high oxidative stress and inflammation, and both those toxic processes are known to be associated with major psychiatric disorders. Compounding the dismal facts about early mortality due to mental illness are the additional grave medical consequences of alcohol and substance use, which are highly comorbid with most psychiatric disorders, further exacerbating the premature death rates among psychiatric patients.

Continue to: There is an important take-home message...

There is an important take-home message in all of this: Our patients are at high risk for potentially fatal medical conditions that require early detection, and intensive ongoing treatment by a primary care clinician (not “provider”; I abhor the widespread use of that term for physicians or nurse practitioners) is an indispensable component of psychiatric care. Thus, collaborative care is vital to protect our psychiatric patients from early mortality and a shortened lifespan. Psychiatrists and psychiatric nurse practitioners must not only win the battle against mental illness, but also diligently avoid losing the war of life and death.

Psychotherapy is among the evidence-based treatment options for treating various psychiatric disorders. How we approach psychiatric disorders via psycho­therapy has been shaped by numerous theories of personality and psychopathology, including psychodynamic, behavioral, cognitive, systems, and existential-humanistic approaches. Whether used as primary treatment or in conjunction with medication, psychotherapy has played a pivotal role in shaping psychiatric disease management and treatment. Several evidence-based therapy modalities have been used throughout the years and continue to significantly improve and impact our patients’ lives. In the armamentarium of treatment modalities, therapy takes the leading role for several conditions. Here we review 4 studies from current psychotherapy literature; these studies are summarized in the Table.^1-4

1. Pompoli A, Furukawa TA, Efthimiou O, et al. Dismantling cognitive-behaviour therapy for panic disorder: a systematic review and component network meta-analysis. Psychol Med. 2018;48(12):1945-1953.

Panic disorder has a lifetime prevalence of 3.7% in the general population. Three treatment modalities recommended for patients with panic disorder are psychological therapy, pharmacologic therapy, and self-help. Among the psychological therapies, cognitive-behavioral therapy (CBT) is one of the most widely used.¹

Cognitive-behavioral therapy for panic disorder has been proven to be an efficacious and impactful treatment. For panic disorder, CBT may consist of different combinations of several therapeutic components, such as relaxation, breathing retraining, cognitive restructuring, interoceptive exposure, and/or in vivo exposure. It is therefore important, both theoretically and clinically, to examine whether specific components of CBT or their combinations are superior to others for treating panic disorder.¹

Pompoli et al¹ conducted a component network meta-analysis (NMA) of 72 studies in order to determine which CBT components were the most efficacious in treating patients with panic disorder. Component NMA is an extension of standard NMA; it is used to disentangle the treatment effects of different components included in composite interventions.¹

The aim of this study was to determine which specific component or combination of components was superior to others when treating panic disorder.¹

Study design

• Researchers reviewed 2,526 references from Medline, EMBASE, PsycINFO, and Cochrane Central and selected 72 studies that included 4,064 patients with panic disorder.¹
• The primary outcome was remission of panic disorder with or without agoraphobia in the short term (3 to 6 months). Remission was defined as achieving a score of ≤7 on the Panic Disorder Severity Scale (PDSS).¹
• Secondary outcomes included response (≥40% reduction in PDSS score from baseline) and dropout for any reason in the short term.¹

Continue to: Outcomes

Outcomes

• Using component NMA, researchers determined that interoceptive exposure and face-to-face setting (administration of therapeutic components in a face-to-face setting rather than through self-help means) led to better efficacy and acceptability. Muscle relaxation and virtual reality exposure corresponded to lower efficacy. Breathing retraining and in vivo exposure improved treatment acceptability, but had small effects on efficacy.¹
• Based on an analysis of remission rates, the most efficacious CBT incorporated cognitive restructuring and interoceptive exposure. The least efficacious CBT incorporated breathing retraining, muscle relaxation, in vivo exposure, and virtual reality exposure.¹
• Application of cognitive and behavioral therapeutic elements was superior to administration of behavioral elements alone. When administering CBT, face-to-face therapy led to better outcomes in response and remission rates. Dropout rates occurred at a lower frequency when CBT was administered face-to-face when compared with self-help groups. The placebo effect was associated with the highest dropout rate.¹

Conclusion

• Findings from this meta-analysis have high practical utility. Which CBT components are used can significantly alter CBT’s efficacy and acceptability in patients with panic disorder.¹
• The “most efficacious CBT” would include cognitive restructuring and interoceptive exposure delivered in a face-to-face setting. Breathing retraining, muscle relaxation, and virtual reality may have a minimal or even negative impact.¹
• Limitations of this meta-analysis include the high number of studies used for the data analysis, complex statistical analysis, inability to include unpublished studies, and limited relevant studies. A future implication of this study is the consideration of formal methodology based on the clinical application of efficacious CBT components when treating patients with panic disorder.¹

2. Sloan DM, Marx BP, Lee DJ, et al. A brief exposure-based treatment vs cognitive processing therapy for posttraumatic stress disorder: a randomized noninferiority clinical trial. JAMA Psychiatry. 2018;75(3):233-239.

Psychotherapy is also a useful modality for treating posttraumatic stress disorder (PTSD). Sloan et al² compared brief exposure-based treatment with cognitive processing therapy (CPT) for PTSD. 

Clinical practice guidelines for the management of PTSD and acute stress disorder recommend the use of individual, trauma-focused therapies that focus on exposure and cognitive restructuring, such as prolonged exposure, CPT, and written narrative exposure.⁵

Continue to: One type of written narrative...

One type of written narrative exposure treatment is written exposure therapy (WET), which consists of 5 sessions during which patients write about their trauma. The first session is comprised of psychoeducation about PTSD and a review of treatment reasoning, followed by 30 minutes of writing. The therapist provides feedback and instructions. Written exposure therapy requires less therapist training and less supervision than prolonged exposure or CPT. Prior studies have suggested that WET can significantly reduce PTSD symptoms in various trauma survivors.²

Although efficacious for PTSD, WET had not been compared with CPT, which is the most commonly used first-line treatment of PTSD. The aim of this study was to determine whether WET is noninferior to CPT.²

Study design

• In this randomized noninferiority clinical trial conducted in Boston, Massachusetts from February 28, 2013 to November 6, 2016, 126 veterans and non-veteran adults were randomized to WET or CPT. Participants met DSM-5 criteria for PTSD and were taking stable doses of their medications for at least 4 weeks.² 
• Participants assigned to CPT (n = 63) underwent 12 sessions, and participants assigned to WET (n = 63) received 5 sessions. Cognitive processing therapy was conducted over 60-minute weekly sessions. Written exposure therapy consisted of an initial session that was 60 minutes long and four 40-minute follow-up sessions.²
• Interviews were conducted by 4 independent evaluators at baseline and 6, 12, 24, and 36 weeks. During the WET sessions, participants wrote about a traumatic event while focusing on details, thoughts, and feelings associated with the event.²
• Cognitive processing therapy involved 12 trauma-focused therapy sessions during which participants learn how to become aware of and address problematic cognitions about the trauma as well as thoughts about themselves and others. Between sessions, participants were required to write 2 trauma accounts and complete other assignments.²

Outcomes

• The primary outcome was change in total score on the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5). The CAPS-5 scores for participants in the WET group were noninferior to those for participants in the CPT group at all assessment points.²
• Participants did not significantly differ in age, education, income, or PTSD severity. Participants in the 2 groups did not differ in treatment expectations or level of satisfaction with treatment. Individuals assigned to CPT were more likely to drop out of the study: 20 participants in the CPT group dropped out in the first 5 sessions, whereas only 4 dropped out of the WET group. The dropout rate in the CPT group was 39.7%. Improvements in PTSD symptoms in the WET group were noninferior to improvements in the CPT group.²
• Written exposure therapy showed no difference compared with CPT in decreasing PTSD symptoms. Furthermore, this study demonstrated that PTSD symptoms can decrease with a smaller number of shorter therapeutic sessions.²

Conclusion

• This study demonstrated noninferiority between an established, commonly used PTSD therapy (CPT) and a version of exposure therapy that is briefer, simpler, and requires less homework and less therapist training and expertise. This “lower-dose” approach may improve access for the expanding number of patients who require treatment for PTSD, especially in the Veterans Affairs system.²
• In summary, WET is well tolerated and time-efficient. Although it requires fewer sessions, WET was noninferior to CPT.²

Continue to: Multisystemic therapy versus management as usual...

3. Fonagy P, Butler S, Cottrell D, et al. Multisystemic therapy versus management as usual in the treatment of adolescent antisocial behaviour (START): a pragmatic, randomised controlled, superiority trial. Lancet Psychiatry. 2018;5(2):119-133.

Multisystemic therapy (MST) is an intensive, family-based, home-based intervention for young people with serious antisocial behavior. It has been found effective for childhood conduct disorders in the United States. However, previous studies that supported its efficacy were conducted by the therapy’s developers and used noncomprehensive comparators, such as individual therapy. Fonagy et al³ assessed the effectiveness and cost-effectiveness of MST vs management as usual for treating adolescent antisocial behavior. This is the first study that was performed by independent investigators and used a comprehensive control.³

Study design

• This 18-month, multisite, pragmatic, randomized controlled superiority trial was conducted in England.³
• Participants were age 11 to 17, with moderate to severe antisocial behavior. They had at least 3 severity criteria indicating difficulties across several settings and at least one of the 5 inclusion criteria for antisocial behavior. Six hundred eighty-four families were randomly assigned to MST or management as usual, and 491 families completed the study.³
• For the MST intervention, therapists worked with the adolescent’s caregiver 3 times a week for 3 to 5 months to improve parenting skills, enhance family relationships, increase support from social networks, develop skills and resources, address communication problems, increase school attendance and achievement, and reduce the adolescent’s association with delinquent peers.³
• For the management as usual intervention, management was based on local services for young people and was designed to be in line with current community practice.³

Outcomes

• The primary outcome was the proportion of participants in out-of-home placements at 18 months. The secondary outcomes were time to first criminal offense and the total number of offenses.³
• In terms of the risk of out-of-home placement, MST had no effect: 13% of participants in the MST group had out-of-home placement at 18 months, compared with 11% in the management-as-usual group.³
• Multisystemic therapy also did not significantly delay the time to first offense (hazard ratio, 1.06; 95% confidence interval, 0.84 to 1.33). Also, at 18-month follow-up, participants in the MST group had committed more offenses than those in the management-as-usual group, although the difference was not statistically significant.³
• Parents in the MST group reported increased parental support and involvement and reduced problems at 6 months, but the adolescents’ reports of parenting behavior indicated no significant effect for MST vs management as usual at any time point.³

Conclusion

• Multisystemic therapy was not superior to management as usual in reducing out-of-home placements. Although the parents believed that MST brought about a rapid and effective change, this was not reflected in objective indicators of antisocial behavior. These results are contrary to previous studies in the United States. The substantial improvements observed in both groups reflected the effectiveness of routinely offered interventions for this group of young people, at least when observed in clinical trials.³

Continue to: Mindfulness-based cognitive therapy...

4. Janssen L, Kan CC, Carpentier PJ, et al. Mindfulness-based cognitive therapy v. treatment as usual in adults with ADHD: a multicentre, single-blind, randomised controlled trial. Psychol Med. 2019;49(1):55-65.

There is empirical support for using psychotherapy to treat attention-deficit/hyperactivity disorder (ADHD). Although medication management plays a leading role in treating ADHD, Janssen et al⁴ conducted a multicenter, single-blind trial comparing mindfulness-based cognitive therapy (MBCT) vs treatment as usual (TAU) for ADHD.

The aim of this study was to determine the efficacy of MBCT plus TAU vs TAU only in decreasing symptoms of adults with ADHD.⁴

Study design

• This multicenter, single-blind randomized controlled trial was conducted in the Netherlands. Participants (N = 120) met criteria for ADHD and were age ≥18. Patients were randomly assigned to MBCT plus TAU (n = 60) or TAU only (n = 60). Patients in the MBCT plus TAU group received weekly group therapy sessions, meditation exercises, psychoeducation, and group discussions. Patients in the TAU-only group received pharmacotherapy and psychoeducation.⁴ 
• Blinded clinicians used the Connors’ Adult ADHD Rating Scale to assess ADHD symptoms.⁴
• Secondary outcomes were determined by self-reported questionnaires that patients completed online.⁴
• All statistical analyses were performed on an intention-to-treat sample as well as the per protocol sample.⁴

Outcomes

• The primary outcome was ADHD symptoms rated by clinicians. Secondary outcomes included self-reported ADHD symptoms, executive functioning, mindfulness skills, positive mental health, and general functioning. Outcomes were examined at baseline and then at post treatment and 3- and 6-month follow-up.⁴
• Patients in the MBCT plus TAU group had a significant decrease in clinician-rated ADHD symptoms that was maintained at 6-month follow-up. More patients in the MBCT plus TAU group (27%) vs patients in the TAU group (4%) showed a ≥30% reduction in ADHD symptoms. Compared with patients in the TAU group, patients in the MBCT plus TAU group had significant improvements in ADHD symptoms, mindfulness skills, and positive mental health at post treatment and at 6-month follow-up. Compared with those receiving TAU only, patients treated with MBCT plus TAU reported no improvement in executive functioning at post treatment, but did improve at 6-month follow-up.⁴

Continue to: Conclusion

Conclusion

• Compared with TAU only, MBCT plus TAU is more effective in reducing ADHD symptoms, with a lasting effect at 6-month follow-up. In terms of secondary outcomes, MBCT plus TAU proved to be effective in improving mindfulness, self-compassion, positive mental health, and executive functioning. The results of this trial demonstrate that psychosocial treatments can be effective in addition to TAU in patients with ADHD, and MBCT holds promise for adult ADHD.⁴

Psychotherapy is among the evidence-based treatment options for treating various psychiatric disorders. How we approach psychiatric disorders via psycho­therapy has been shaped by numerous theories of personality and psychopathology, including psychodynamic, behavioral, cognitive, systems, and existential-humanistic approaches. Whether used as primary treatment or in conjunction with medication, psychotherapy has played a pivotal role in shaping psychiatric disease management and treatment. Several evidence-based therapy modalities have been used throughout the years and continue to significantly improve and impact our patients’ lives. In the armamentarium of treatment modalities, therapy takes the leading role for several conditions. Here we review 4 studies from current psychotherapy literature; these studies are summarized in the Table.^1-4

1. Pompoli A, Furukawa TA, Efthimiou O, et al. Dismantling cognitive-behaviour therapy for panic disorder: a systematic review and component network meta-analysis. Psychol Med. 2018;48(12):1945-1953.

Panic disorder has a lifetime prevalence of 3.7% in the general population. Three treatment modalities recommended for patients with panic disorder are psychological therapy, pharmacologic therapy, and self-help. Among the psychological therapies, cognitive-behavioral therapy (CBT) is one of the most widely used.¹

Cognitive-behavioral therapy for panic disorder has been proven to be an efficacious and impactful treatment. For panic disorder, CBT may consist of different combinations of several therapeutic components, such as relaxation, breathing retraining, cognitive restructuring, interoceptive exposure, and/or in vivo exposure. It is therefore important, both theoretically and clinically, to examine whether specific components of CBT or their combinations are superior to others for treating panic disorder.¹

Pompoli et al¹ conducted a component network meta-analysis (NMA) of 72 studies in order to determine which CBT components were the most efficacious in treating patients with panic disorder. Component NMA is an extension of standard NMA; it is used to disentangle the treatment effects of different components included in composite interventions.¹

The aim of this study was to determine which specific component or combination of components was superior to others when treating panic disorder.¹

Study design

• Researchers reviewed 2,526 references from Medline, EMBASE, PsycINFO, and Cochrane Central and selected 72 studies that included 4,064 patients with panic disorder.¹
• The primary outcome was remission of panic disorder with or without agoraphobia in the short term (3 to 6 months). Remission was defined as achieving a score of ≤7 on the Panic Disorder Severity Scale (PDSS).¹
• Secondary outcomes included response (≥40% reduction in PDSS score from baseline) and dropout for any reason in the short term.¹

Continue to: Outcomes

Outcomes

• Using component NMA, researchers determined that interoceptive exposure and face-to-face setting (administration of therapeutic components in a face-to-face setting rather than through self-help means) led to better efficacy and acceptability. Muscle relaxation and virtual reality exposure corresponded to lower efficacy. Breathing retraining and in vivo exposure improved treatment acceptability, but had small effects on efficacy.¹
• Based on an analysis of remission rates, the most efficacious CBT incorporated cognitive restructuring and interoceptive exposure. The least efficacious CBT incorporated breathing retraining, muscle relaxation, in vivo exposure, and virtual reality exposure.¹
• Application of cognitive and behavioral therapeutic elements was superior to administration of behavioral elements alone. When administering CBT, face-to-face therapy led to better outcomes in response and remission rates. Dropout rates occurred at a lower frequency when CBT was administered face-to-face when compared with self-help groups. The placebo effect was associated with the highest dropout rate.¹

Conclusion

• Findings from this meta-analysis have high practical utility. Which CBT components are used can significantly alter CBT’s efficacy and acceptability in patients with panic disorder.¹
• The “most efficacious CBT” would include cognitive restructuring and interoceptive exposure delivered in a face-to-face setting. Breathing retraining, muscle relaxation, and virtual reality may have a minimal or even negative impact.¹
• Limitations of this meta-analysis include the high number of studies used for the data analysis, complex statistical analysis, inability to include unpublished studies, and limited relevant studies. A future implication of this study is the consideration of formal methodology based on the clinical application of efficacious CBT components when treating patients with panic disorder.¹

2. Sloan DM, Marx BP, Lee DJ, et al. A brief exposure-based treatment vs cognitive processing therapy for posttraumatic stress disorder: a randomized noninferiority clinical trial. JAMA Psychiatry. 2018;75(3):233-239.

Psychotherapy is also a useful modality for treating posttraumatic stress disorder (PTSD). Sloan et al² compared brief exposure-based treatment with cognitive processing therapy (CPT) for PTSD. 

Clinical practice guidelines for the management of PTSD and acute stress disorder recommend the use of individual, trauma-focused therapies that focus on exposure and cognitive restructuring, such as prolonged exposure, CPT, and written narrative exposure.⁵

Continue to: One type of written narrative...

One type of written narrative exposure treatment is written exposure therapy (WET), which consists of 5 sessions during which patients write about their trauma. The first session is comprised of psychoeducation about PTSD and a review of treatment reasoning, followed by 30 minutes of writing. The therapist provides feedback and instructions. Written exposure therapy requires less therapist training and less supervision than prolonged exposure or CPT. Prior studies have suggested that WET can significantly reduce PTSD symptoms in various trauma survivors.²

Although efficacious for PTSD, WET had not been compared with CPT, which is the most commonly used first-line treatment of PTSD. The aim of this study was to determine whether WET is noninferior to CPT.²

Study design

• In this randomized noninferiority clinical trial conducted in Boston, Massachusetts from February 28, 2013 to November 6, 2016, 126 veterans and non-veteran adults were randomized to WET or CPT. Participants met DSM-5 criteria for PTSD and were taking stable doses of their medications for at least 4 weeks.² 
• Participants assigned to CPT (n = 63) underwent 12 sessions, and participants assigned to WET (n = 63) received 5 sessions. Cognitive processing therapy was conducted over 60-minute weekly sessions. Written exposure therapy consisted of an initial session that was 60 minutes long and four 40-minute follow-up sessions.²
• Interviews were conducted by 4 independent evaluators at baseline and 6, 12, 24, and 36 weeks. During the WET sessions, participants wrote about a traumatic event while focusing on details, thoughts, and feelings associated with the event.²
• Cognitive processing therapy involved 12 trauma-focused therapy sessions during which participants learn how to become aware of and address problematic cognitions about the trauma as well as thoughts about themselves and others. Between sessions, participants were required to write 2 trauma accounts and complete other assignments.²

Outcomes

• The primary outcome was change in total score on the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5). The CAPS-5 scores for participants in the WET group were noninferior to those for participants in the CPT group at all assessment points.²
• Participants did not significantly differ in age, education, income, or PTSD severity. Participants in the 2 groups did not differ in treatment expectations or level of satisfaction with treatment. Individuals assigned to CPT were more likely to drop out of the study: 20 participants in the CPT group dropped out in the first 5 sessions, whereas only 4 dropped out of the WET group. The dropout rate in the CPT group was 39.7%. Improvements in PTSD symptoms in the WET group were noninferior to improvements in the CPT group.²
• Written exposure therapy showed no difference compared with CPT in decreasing PTSD symptoms. Furthermore, this study demonstrated that PTSD symptoms can decrease with a smaller number of shorter therapeutic sessions.²

Conclusion

• This study demonstrated noninferiority between an established, commonly used PTSD therapy (CPT) and a version of exposure therapy that is briefer, simpler, and requires less homework and less therapist training and expertise. This “lower-dose” approach may improve access for the expanding number of patients who require treatment for PTSD, especially in the Veterans Affairs system.²
• In summary, WET is well tolerated and time-efficient. Although it requires fewer sessions, WET was noninferior to CPT.²

Continue to: Multisystemic therapy versus management as usual...

3. Fonagy P, Butler S, Cottrell D, et al. Multisystemic therapy versus management as usual in the treatment of adolescent antisocial behaviour (START): a pragmatic, randomised controlled, superiority trial. Lancet Psychiatry. 2018;5(2):119-133.

Multisystemic therapy (MST) is an intensive, family-based, home-based intervention for young people with serious antisocial behavior. It has been found effective for childhood conduct disorders in the United States. However, previous studies that supported its efficacy were conducted by the therapy’s developers and used noncomprehensive comparators, such as individual therapy. Fonagy et al³ assessed the effectiveness and cost-effectiveness of MST vs management as usual for treating adolescent antisocial behavior. This is the first study that was performed by independent investigators and used a comprehensive control.³

Study design

• This 18-month, multisite, pragmatic, randomized controlled superiority trial was conducted in England.³
• Participants were age 11 to 17, with moderate to severe antisocial behavior. They had at least 3 severity criteria indicating difficulties across several settings and at least one of the 5 inclusion criteria for antisocial behavior. Six hundred eighty-four families were randomly assigned to MST or management as usual, and 491 families completed the study.³
• For the MST intervention, therapists worked with the adolescent’s caregiver 3 times a week for 3 to 5 months to improve parenting skills, enhance family relationships, increase support from social networks, develop skills and resources, address communication problems, increase school attendance and achievement, and reduce the adolescent’s association with delinquent peers.³
• For the management as usual intervention, management was based on local services for young people and was designed to be in line with current community practice.³

Outcomes

• The primary outcome was the proportion of participants in out-of-home placements at 18 months. The secondary outcomes were time to first criminal offense and the total number of offenses.³
• In terms of the risk of out-of-home placement, MST had no effect: 13% of participants in the MST group had out-of-home placement at 18 months, compared with 11% in the management-as-usual group.³
• Multisystemic therapy also did not significantly delay the time to first offense (hazard ratio, 1.06; 95% confidence interval, 0.84 to 1.33). Also, at 18-month follow-up, participants in the MST group had committed more offenses than those in the management-as-usual group, although the difference was not statistically significant.³
• Parents in the MST group reported increased parental support and involvement and reduced problems at 6 months, but the adolescents’ reports of parenting behavior indicated no significant effect for MST vs management as usual at any time point.³

Conclusion

• Multisystemic therapy was not superior to management as usual in reducing out-of-home placements. Although the parents believed that MST brought about a rapid and effective change, this was not reflected in objective indicators of antisocial behavior. These results are contrary to previous studies in the United States. The substantial improvements observed in both groups reflected the effectiveness of routinely offered interventions for this group of young people, at least when observed in clinical trials.³

Continue to: Mindfulness-based cognitive therapy...

4. Janssen L, Kan CC, Carpentier PJ, et al. Mindfulness-based cognitive therapy v. treatment as usual in adults with ADHD: a multicentre, single-blind, randomised controlled trial. Psychol Med. 2019;49(1):55-65.

There is empirical support for using psychotherapy to treat attention-deficit/hyperactivity disorder (ADHD). Although medication management plays a leading role in treating ADHD, Janssen et al⁴ conducted a multicenter, single-blind trial comparing mindfulness-based cognitive therapy (MBCT) vs treatment as usual (TAU) for ADHD.

The aim of this study was to determine the efficacy of MBCT plus TAU vs TAU only in decreasing symptoms of adults with ADHD.⁴

Study design

• This multicenter, single-blind randomized controlled trial was conducted in the Netherlands. Participants (N = 120) met criteria for ADHD and were age ≥18. Patients were randomly assigned to MBCT plus TAU (n = 60) or TAU only (n = 60). Patients in the MBCT plus TAU group received weekly group therapy sessions, meditation exercises, psychoeducation, and group discussions. Patients in the TAU-only group received pharmacotherapy and psychoeducation.⁴ 
• Blinded clinicians used the Connors’ Adult ADHD Rating Scale to assess ADHD symptoms.⁴
• Secondary outcomes were determined by self-reported questionnaires that patients completed online.⁴
• All statistical analyses were performed on an intention-to-treat sample as well as the per protocol sample.⁴

Outcomes

• The primary outcome was ADHD symptoms rated by clinicians. Secondary outcomes included self-reported ADHD symptoms, executive functioning, mindfulness skills, positive mental health, and general functioning. Outcomes were examined at baseline and then at post treatment and 3- and 6-month follow-up.⁴
• Patients in the MBCT plus TAU group had a significant decrease in clinician-rated ADHD symptoms that was maintained at 6-month follow-up. More patients in the MBCT plus TAU group (27%) vs patients in the TAU group (4%) showed a ≥30% reduction in ADHD symptoms. Compared with patients in the TAU group, patients in the MBCT plus TAU group had significant improvements in ADHD symptoms, mindfulness skills, and positive mental health at post treatment and at 6-month follow-up. Compared with those receiving TAU only, patients treated with MBCT plus TAU reported no improvement in executive functioning at post treatment, but did improve at 6-month follow-up.⁴

Continue to: Conclusion

Conclusion

• Compared with TAU only, MBCT plus TAU is more effective in reducing ADHD symptoms, with a lasting effect at 6-month follow-up. In terms of secondary outcomes, MBCT plus TAU proved to be effective in improving mindfulness, self-compassion, positive mental health, and executive functioning. The results of this trial demonstrate that psychosocial treatments can be effective in addition to TAU in patients with ADHD, and MBCT holds promise for adult ADHD.⁴

Psychotherapy is among the evidence-based treatment options for treating various psychiatric disorders. How we approach psychiatric disorders via psycho­therapy has been shaped by numerous theories of personality and psychopathology, including psychodynamic, behavioral, cognitive, systems, and existential-humanistic approaches. Whether used as primary treatment or in conjunction with medication, psychotherapy has played a pivotal role in shaping psychiatric disease management and treatment. Several evidence-based therapy modalities have been used throughout the years and continue to significantly improve and impact our patients’ lives. In the armamentarium of treatment modalities, therapy takes the leading role for several conditions. Here we review 4 studies from current psychotherapy literature; these studies are summarized in the Table.^1-4

1. Pompoli A, Furukawa TA, Efthimiou O, et al. Dismantling cognitive-behaviour therapy for panic disorder: a systematic review and component network meta-analysis. Psychol Med. 2018;48(12):1945-1953.

Panic disorder has a lifetime prevalence of 3.7% in the general population. Three treatment modalities recommended for patients with panic disorder are psychological therapy, pharmacologic therapy, and self-help. Among the psychological therapies, cognitive-behavioral therapy (CBT) is one of the most widely used.¹

Cognitive-behavioral therapy for panic disorder has been proven to be an efficacious and impactful treatment. For panic disorder, CBT may consist of different combinations of several therapeutic components, such as relaxation, breathing retraining, cognitive restructuring, interoceptive exposure, and/or in vivo exposure. It is therefore important, both theoretically and clinically, to examine whether specific components of CBT or their combinations are superior to others for treating panic disorder.¹

Pompoli et al¹ conducted a component network meta-analysis (NMA) of 72 studies in order to determine which CBT components were the most efficacious in treating patients with panic disorder. Component NMA is an extension of standard NMA; it is used to disentangle the treatment effects of different components included in composite interventions.¹

The aim of this study was to determine which specific component or combination of components was superior to others when treating panic disorder.¹

Study design

• Researchers reviewed 2,526 references from Medline, EMBASE, PsycINFO, and Cochrane Central and selected 72 studies that included 4,064 patients with panic disorder.¹
• The primary outcome was remission of panic disorder with or without agoraphobia in the short term (3 to 6 months). Remission was defined as achieving a score of ≤7 on the Panic Disorder Severity Scale (PDSS).¹
• Secondary outcomes included response (≥40% reduction in PDSS score from baseline) and dropout for any reason in the short term.¹

Continue to: Outcomes

Outcomes

• Using component NMA, researchers determined that interoceptive exposure and face-to-face setting (administration of therapeutic components in a face-to-face setting rather than through self-help means) led to better efficacy and acceptability. Muscle relaxation and virtual reality exposure corresponded to lower efficacy. Breathing retraining and in vivo exposure improved treatment acceptability, but had small effects on efficacy.¹
• Based on an analysis of remission rates, the most efficacious CBT incorporated cognitive restructuring and interoceptive exposure. The least efficacious CBT incorporated breathing retraining, muscle relaxation, in vivo exposure, and virtual reality exposure.¹
• Application of cognitive and behavioral therapeutic elements was superior to administration of behavioral elements alone. When administering CBT, face-to-face therapy led to better outcomes in response and remission rates. Dropout rates occurred at a lower frequency when CBT was administered face-to-face when compared with self-help groups. The placebo effect was associated with the highest dropout rate.¹

Conclusion

• Findings from this meta-analysis have high practical utility. Which CBT components are used can significantly alter CBT’s efficacy and acceptability in patients with panic disorder.¹
• The “most efficacious CBT” would include cognitive restructuring and interoceptive exposure delivered in a face-to-face setting. Breathing retraining, muscle relaxation, and virtual reality may have a minimal or even negative impact.¹
• Limitations of this meta-analysis include the high number of studies used for the data analysis, complex statistical analysis, inability to include unpublished studies, and limited relevant studies. A future implication of this study is the consideration of formal methodology based on the clinical application of efficacious CBT components when treating patients with panic disorder.¹

2. Sloan DM, Marx BP, Lee DJ, et al. A brief exposure-based treatment vs cognitive processing therapy for posttraumatic stress disorder: a randomized noninferiority clinical trial. JAMA Psychiatry. 2018;75(3):233-239.

Psychotherapy is also a useful modality for treating posttraumatic stress disorder (PTSD). Sloan et al² compared brief exposure-based treatment with cognitive processing therapy (CPT) for PTSD. 

Clinical practice guidelines for the management of PTSD and acute stress disorder recommend the use of individual, trauma-focused therapies that focus on exposure and cognitive restructuring, such as prolonged exposure, CPT, and written narrative exposure.⁵

Continue to: One type of written narrative...

One type of written narrative exposure treatment is written exposure therapy (WET), which consists of 5 sessions during which patients write about their trauma. The first session is comprised of psychoeducation about PTSD and a review of treatment reasoning, followed by 30 minutes of writing. The therapist provides feedback and instructions. Written exposure therapy requires less therapist training and less supervision than prolonged exposure or CPT. Prior studies have suggested that WET can significantly reduce PTSD symptoms in various trauma survivors.²

Although efficacious for PTSD, WET had not been compared with CPT, which is the most commonly used first-line treatment of PTSD. The aim of this study was to determine whether WET is noninferior to CPT.²

Study design

• In this randomized noninferiority clinical trial conducted in Boston, Massachusetts from February 28, 2013 to November 6, 2016, 126 veterans and non-veteran adults were randomized to WET or CPT. Participants met DSM-5 criteria for PTSD and were taking stable doses of their medications for at least 4 weeks.² 
• Participants assigned to CPT (n = 63) underwent 12 sessions, and participants assigned to WET (n = 63) received 5 sessions. Cognitive processing therapy was conducted over 60-minute weekly sessions. Written exposure therapy consisted of an initial session that was 60 minutes long and four 40-minute follow-up sessions.²
• Interviews were conducted by 4 independent evaluators at baseline and 6, 12, 24, and 36 weeks. During the WET sessions, participants wrote about a traumatic event while focusing on details, thoughts, and feelings associated with the event.²
• Cognitive processing therapy involved 12 trauma-focused therapy sessions during which participants learn how to become aware of and address problematic cognitions about the trauma as well as thoughts about themselves and others. Between sessions, participants were required to write 2 trauma accounts and complete other assignments.²

Outcomes

• The primary outcome was change in total score on the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5). The CAPS-5 scores for participants in the WET group were noninferior to those for participants in the CPT group at all assessment points.²
• Participants did not significantly differ in age, education, income, or PTSD severity. Participants in the 2 groups did not differ in treatment expectations or level of satisfaction with treatment. Individuals assigned to CPT were more likely to drop out of the study: 20 participants in the CPT group dropped out in the first 5 sessions, whereas only 4 dropped out of the WET group. The dropout rate in the CPT group was 39.7%. Improvements in PTSD symptoms in the WET group were noninferior to improvements in the CPT group.²
• Written exposure therapy showed no difference compared with CPT in decreasing PTSD symptoms. Furthermore, this study demonstrated that PTSD symptoms can decrease with a smaller number of shorter therapeutic sessions.²

Conclusion

• This study demonstrated noninferiority between an established, commonly used PTSD therapy (CPT) and a version of exposure therapy that is briefer, simpler, and requires less homework and less therapist training and expertise. This “lower-dose” approach may improve access for the expanding number of patients who require treatment for PTSD, especially in the Veterans Affairs system.²
• In summary, WET is well tolerated and time-efficient. Although it requires fewer sessions, WET was noninferior to CPT.²

Continue to: Multisystemic therapy versus management as usual...

3. Fonagy P, Butler S, Cottrell D, et al. Multisystemic therapy versus management as usual in the treatment of adolescent antisocial behaviour (START): a pragmatic, randomised controlled, superiority trial. Lancet Psychiatry. 2018;5(2):119-133.

Multisystemic therapy (MST) is an intensive, family-based, home-based intervention for young people with serious antisocial behavior. It has been found effective for childhood conduct disorders in the United States. However, previous studies that supported its efficacy were conducted by the therapy’s developers and used noncomprehensive comparators, such as individual therapy. Fonagy et al³ assessed the effectiveness and cost-effectiveness of MST vs management as usual for treating adolescent antisocial behavior. This is the first study that was performed by independent investigators and used a comprehensive control.³

Study design

• This 18-month, multisite, pragmatic, randomized controlled superiority trial was conducted in England.³
• Participants were age 11 to 17, with moderate to severe antisocial behavior. They had at least 3 severity criteria indicating difficulties across several settings and at least one of the 5 inclusion criteria for antisocial behavior. Six hundred eighty-four families were randomly assigned to MST or management as usual, and 491 families completed the study.³
• For the MST intervention, therapists worked with the adolescent’s caregiver 3 times a week for 3 to 5 months to improve parenting skills, enhance family relationships, increase support from social networks, develop skills and resources, address communication problems, increase school attendance and achievement, and reduce the adolescent’s association with delinquent peers.³
• For the management as usual intervention, management was based on local services for young people and was designed to be in line with current community practice.³

Outcomes

• The primary outcome was the proportion of participants in out-of-home placements at 18 months. The secondary outcomes were time to first criminal offense and the total number of offenses.³
• In terms of the risk of out-of-home placement, MST had no effect: 13% of participants in the MST group had out-of-home placement at 18 months, compared with 11% in the management-as-usual group.³
• Multisystemic therapy also did not significantly delay the time to first offense (hazard ratio, 1.06; 95% confidence interval, 0.84 to 1.33). Also, at 18-month follow-up, participants in the MST group had committed more offenses than those in the management-as-usual group, although the difference was not statistically significant.³
• Parents in the MST group reported increased parental support and involvement and reduced problems at 6 months, but the adolescents’ reports of parenting behavior indicated no significant effect for MST vs management as usual at any time point.³

Conclusion

• Multisystemic therapy was not superior to management as usual in reducing out-of-home placements. Although the parents believed that MST brought about a rapid and effective change, this was not reflected in objective indicators of antisocial behavior. These results are contrary to previous studies in the United States. The substantial improvements observed in both groups reflected the effectiveness of routinely offered interventions for this group of young people, at least when observed in clinical trials.³

Continue to: Mindfulness-based cognitive therapy...

4. Janssen L, Kan CC, Carpentier PJ, et al. Mindfulness-based cognitive therapy v. treatment as usual in adults with ADHD: a multicentre, single-blind, randomised controlled trial. Psychol Med. 2019;49(1):55-65.

There is empirical support for using psychotherapy to treat attention-deficit/hyperactivity disorder (ADHD). Although medication management plays a leading role in treating ADHD, Janssen et al⁴ conducted a multicenter, single-blind trial comparing mindfulness-based cognitive therapy (MBCT) vs treatment as usual (TAU) for ADHD.

The aim of this study was to determine the efficacy of MBCT plus TAU vs TAU only in decreasing symptoms of adults with ADHD.⁴

Study design

• This multicenter, single-blind randomized controlled trial was conducted in the Netherlands. Participants (N = 120) met criteria for ADHD and were age ≥18. Patients were randomly assigned to MBCT plus TAU (n = 60) or TAU only (n = 60). Patients in the MBCT plus TAU group received weekly group therapy sessions, meditation exercises, psychoeducation, and group discussions. Patients in the TAU-only group received pharmacotherapy and psychoeducation.⁴ 
• Blinded clinicians used the Connors’ Adult ADHD Rating Scale to assess ADHD symptoms.⁴
• Secondary outcomes were determined by self-reported questionnaires that patients completed online.⁴
• All statistical analyses were performed on an intention-to-treat sample as well as the per protocol sample.⁴

Outcomes

• The primary outcome was ADHD symptoms rated by clinicians. Secondary outcomes included self-reported ADHD symptoms, executive functioning, mindfulness skills, positive mental health, and general functioning. Outcomes were examined at baseline and then at post treatment and 3- and 6-month follow-up.⁴
• Patients in the MBCT plus TAU group had a significant decrease in clinician-rated ADHD symptoms that was maintained at 6-month follow-up. More patients in the MBCT plus TAU group (27%) vs patients in the TAU group (4%) showed a ≥30% reduction in ADHD symptoms. Compared with patients in the TAU group, patients in the MBCT plus TAU group had significant improvements in ADHD symptoms, mindfulness skills, and positive mental health at post treatment and at 6-month follow-up. Compared with those receiving TAU only, patients treated with MBCT plus TAU reported no improvement in executive functioning at post treatment, but did improve at 6-month follow-up.⁴

Continue to: Conclusion

Conclusion

• Compared with TAU only, MBCT plus TAU is more effective in reducing ADHD symptoms, with a lasting effect at 6-month follow-up. In terms of secondary outcomes, MBCT plus TAU proved to be effective in improving mindfulness, self-compassion, positive mental health, and executive functioning. The results of this trial demonstrate that psychosocial treatments can be effective in addition to TAU in patients with ADHD, and MBCT holds promise for adult ADHD.⁴

CASE Agitated, uncooperative, and irritable

Mr. X, age 84, presents to the emergency department with agitation, mania-like symptoms, and mood-congruent psychotic symptoms that started 2 weeks ago. Mr. X, who is accompanied by his wife, has no psychiatric history.

On examination, Mr. X is easily agitated and uncooperative. His speech is fast, but not pressured, with increased volume and tone. He states, “My mood is fantastic” with mood-congruent affect. His thought process reveals circumstantiality and loose association. Mr. X’s thought content includes flight of ideas and delusions of grandeur; he claims to be a state boxing champion and a psychologist. He also claims that he will run for Congress in the near future. He reports that he’s started knocking on his neighbors’ doors, pitched the idea to buy their house, and convinced them to vote for him as their congressman. He denies any suicidal or homicidal ideations. There is no evidence of perceptual disturbance. Mr. X undergoes a Mini-Mental State Examination (MMSE) and scores 26/30, which suggests no cognitive impairment. However, his insight and judgment are poor.

Mr. X’s physical examination is unremarkable. His laboratory workup includes a complete blood count, comprehensive metabolic panel, urinalysis, thyroid function test, vitamin B12 and folate levels, urine drug screen, and blood alcohol level. All results are within normal limits. He has no history of alcohol or recreational drug use as evident by the laboratory results and collateral information from his wife. Further, a non-contrast CT scan of his head shows no abnormality.

Approximately 1 month ago, Mr. X was diagnosed with restless leg syndrome (RLS). Mr. X’s medication regimen consists of gabapentin, 300 mg 3 times daily, prescribed years ago by his neurologist for neuropathic pain; and ropinirole, 3 mg/d, for RLS. His neurologist had prescribed him ropinirole, which was started at 1 mg/d and titrated to 3 mg/d within a 1-week span. Two weeks after Mr. X started this medication regimen, his wife reports that she noticed changes in his behavior, including severe agitation, irritability, delusions of grandeur, decreased need for sleep, and racing of thoughts.

[polldaddy:10417490]

The authors’ observations

Mr. X was diagnosed with medication (ropinirole)-induced bipolar and related disorder with mood-congruent psychotic features.

To determine this diagnosis, we initially considered Mr. X’s age and medical conditions, including stroke and space-occupying lesions of the brain. However, the laboratory and neuroimaging studies, which included a CT scan of the head and MRI of the brain, were negative. Next, because Mr. X had sudden onset manic symptoms after ropinirole was initiated, we considered the possibility of a substance/medication-induced bipolar and related disorder. Further, ropinirole is capable of producing the symptoms in criterion A of DSM-5 criteria for substance/medication-induced bipolar and related disorder. Mr. X met all DSM-5 criteria for substance/medication-induced bipolar and related disorder (Table¹).

[polldaddy:10417494]

TREATMENT Medication adjustments and improvement

The admitting clinician discontinues ropinirole and initiates divalproex sodium, 500 mg twice a day. By Day 4, Mr. X shows significant improvement, including no irritable mood and regression of delusions of grandeur, and his sleep cycle returns to normal. At this time, the divalproex sodium is also discontinued.

Continue to: The authors' observations

Dopamine agonist agents are a standard treatment in the management of Parkinson’s disease and RLS.^2-5 Ropinirole, a dopamine receptor agonist, has a high affinity for dopamine D2 and D3 receptor subtypes.⁴ Published reports have linked dopamine agonists to mania with psychotic features.^6,7 In a study by Stoner et al,⁸ of 95 patients treated with ropinirole, 13 patients developed psychotic features that necessitated the use of antipsychotic medications or a lower dose of ropinirole.

The recommended starting dose for ropinirole is 0.25 mg/d. The dose can be increased to 0.5 mg in the next 2 days, and to 1 mg/d at the end of the first week.⁹ The mean effective daily dose is 2 mg/d, and maximum recommended dose is 4 mg/d.⁹ For Mr. X, ropinirole was quickly titrated to 3 mg/d over 1 week, which resulted in mania and psychosis. We suggest that when treating geriatric patients, clinicians should consider prescribing the lowest effective dose of psychotropic medications, such as ropinirole, to prevent adverse effects. Higher doses of dopamine agonists, especially in geriatric patients, increase the risk of common adverse effects, such as nausea (25% to 50%), headache (7% to 22%), fatigue (1% to 19%), dizziness (6% to 18%), and vomiting (5% to 11%).¹⁰ When prescribing dopamine agonists, clinicians should educate patients and their caregivers about the rare but potential risk of medication-induced mania and psychosis.

Mr. X’s case emphasizes the importance of a comprehensive psychiatric evaluation and medical workup to rule out a wide differential diagnosis when approaching new-onset mania and psychosis in geriatric patients.¹¹ Our case contributes to the evidence that dopamine agonist medications are associated with mania and psychotic symptoms.

OUTCOME A return to baseline

On Day 12, Mr. X is discharged home in a stable condition. Two weeks later, at an outpatient follow-up visit, Mr. X is asymptomatic and has returned to his baseline functioning.

Bottom Line

When approaching new-onset mania and psychosis in geriatric patients, a comprehensive psychiatric evaluation and medical workup are necessary to rule out a wide differential diagnosis. Ropinirole use can lead to mania and psychotic symptoms, especially in geriatric patients. As should be done with all other dopaminergic agents, increase the dose of ropinirole with caution, and be vigilant for the emergence of signs of mania and/or psychosis.

Continue to: Related Resources

• Adabie A, Jackson JC, Torrence CL. Older-age bipolar disorder: A case series. Current Psychiatry. 2019;18(2):24-29.
• Chen P, Dols A, Rej S, et al. Update on the epidemiology, diagnosis, and treatment of mania in older-age bipolar disorder. Curr Psychiatry Rep. 2017;19(8):46.

Drug Brand Names

Divalproex sodium • Depakote
Gabapentin • Neurontin
Ropinirole • Requip

CASE Agitated, uncooperative, and irritable

Mr. X, age 84, presents to the emergency department with agitation, mania-like symptoms, and mood-congruent psychotic symptoms that started 2 weeks ago. Mr. X, who is accompanied by his wife, has no psychiatric history.

On examination, Mr. X is easily agitated and uncooperative. His speech is fast, but not pressured, with increased volume and tone. He states, “My mood is fantastic” with mood-congruent affect. His thought process reveals circumstantiality and loose association. Mr. X’s thought content includes flight of ideas and delusions of grandeur; he claims to be a state boxing champion and a psychologist. He also claims that he will run for Congress in the near future. He reports that he’s started knocking on his neighbors’ doors, pitched the idea to buy their house, and convinced them to vote for him as their congressman. He denies any suicidal or homicidal ideations. There is no evidence of perceptual disturbance. Mr. X undergoes a Mini-Mental State Examination (MMSE) and scores 26/30, which suggests no cognitive impairment. However, his insight and judgment are poor.

Mr. X’s physical examination is unremarkable. His laboratory workup includes a complete blood count, comprehensive metabolic panel, urinalysis, thyroid function test, vitamin B12 and folate levels, urine drug screen, and blood alcohol level. All results are within normal limits. He has no history of alcohol or recreational drug use as evident by the laboratory results and collateral information from his wife. Further, a non-contrast CT scan of his head shows no abnormality.

Approximately 1 month ago, Mr. X was diagnosed with restless leg syndrome (RLS). Mr. X’s medication regimen consists of gabapentin, 300 mg 3 times daily, prescribed years ago by his neurologist for neuropathic pain; and ropinirole, 3 mg/d, for RLS. His neurologist had prescribed him ropinirole, which was started at 1 mg/d and titrated to 3 mg/d within a 1-week span. Two weeks after Mr. X started this medication regimen, his wife reports that she noticed changes in his behavior, including severe agitation, irritability, delusions of grandeur, decreased need for sleep, and racing of thoughts.

[polldaddy:10417490]

The authors’ observations

Mr. X was diagnosed with medication (ropinirole)-induced bipolar and related disorder with mood-congruent psychotic features.

To determine this diagnosis, we initially considered Mr. X’s age and medical conditions, including stroke and space-occupying lesions of the brain. However, the laboratory and neuroimaging studies, which included a CT scan of the head and MRI of the brain, were negative. Next, because Mr. X had sudden onset manic symptoms after ropinirole was initiated, we considered the possibility of a substance/medication-induced bipolar and related disorder. Further, ropinirole is capable of producing the symptoms in criterion A of DSM-5 criteria for substance/medication-induced bipolar and related disorder. Mr. X met all DSM-5 criteria for substance/medication-induced bipolar and related disorder (Table¹).

[polldaddy:10417494]

TREATMENT Medication adjustments and improvement

The admitting clinician discontinues ropinirole and initiates divalproex sodium, 500 mg twice a day. By Day 4, Mr. X shows significant improvement, including no irritable mood and regression of delusions of grandeur, and his sleep cycle returns to normal. At this time, the divalproex sodium is also discontinued.

Continue to: The authors' observations

Dopamine agonist agents are a standard treatment in the management of Parkinson’s disease and RLS.^2-5 Ropinirole, a dopamine receptor agonist, has a high affinity for dopamine D2 and D3 receptor subtypes.⁴ Published reports have linked dopamine agonists to mania with psychotic features.^6,7 In a study by Stoner et al,⁸ of 95 patients treated with ropinirole, 13 patients developed psychotic features that necessitated the use of antipsychotic medications or a lower dose of ropinirole.

The recommended starting dose for ropinirole is 0.25 mg/d. The dose can be increased to 0.5 mg in the next 2 days, and to 1 mg/d at the end of the first week.⁹ The mean effective daily dose is 2 mg/d, and maximum recommended dose is 4 mg/d.⁹ For Mr. X, ropinirole was quickly titrated to 3 mg/d over 1 week, which resulted in mania and psychosis. We suggest that when treating geriatric patients, clinicians should consider prescribing the lowest effective dose of psychotropic medications, such as ropinirole, to prevent adverse effects. Higher doses of dopamine agonists, especially in geriatric patients, increase the risk of common adverse effects, such as nausea (25% to 50%), headache (7% to 22%), fatigue (1% to 19%), dizziness (6% to 18%), and vomiting (5% to 11%).¹⁰ When prescribing dopamine agonists, clinicians should educate patients and their caregivers about the rare but potential risk of medication-induced mania and psychosis.

Mr. X’s case emphasizes the importance of a comprehensive psychiatric evaluation and medical workup to rule out a wide differential diagnosis when approaching new-onset mania and psychosis in geriatric patients.¹¹ Our case contributes to the evidence that dopamine agonist medications are associated with mania and psychotic symptoms.

OUTCOME A return to baseline

On Day 12, Mr. X is discharged home in a stable condition. Two weeks later, at an outpatient follow-up visit, Mr. X is asymptomatic and has returned to his baseline functioning.

Bottom Line

When approaching new-onset mania and psychosis in geriatric patients, a comprehensive psychiatric evaluation and medical workup are necessary to rule out a wide differential diagnosis. Ropinirole use can lead to mania and psychotic symptoms, especially in geriatric patients. As should be done with all other dopaminergic agents, increase the dose of ropinirole with caution, and be vigilant for the emergence of signs of mania and/or psychosis.

Continue to: Related Resources

• Adabie A, Jackson JC, Torrence CL. Older-age bipolar disorder: A case series. Current Psychiatry. 2019;18(2):24-29.
• Chen P, Dols A, Rej S, et al. Update on the epidemiology, diagnosis, and treatment of mania in older-age bipolar disorder. Curr Psychiatry Rep. 2017;19(8):46.

Drug Brand Names

Divalproex sodium • Depakote
Gabapentin • Neurontin
Ropinirole • Requip

CASE Agitated, uncooperative, and irritable

Mr. X, age 84, presents to the emergency department with agitation, mania-like symptoms, and mood-congruent psychotic symptoms that started 2 weeks ago. Mr. X, who is accompanied by his wife, has no psychiatric history.

On examination, Mr. X is easily agitated and uncooperative. His speech is fast, but not pressured, with increased volume and tone. He states, “My mood is fantastic” with mood-congruent affect. His thought process reveals circumstantiality and loose association. Mr. X’s thought content includes flight of ideas and delusions of grandeur; he claims to be a state boxing champion and a psychologist. He also claims that he will run for Congress in the near future. He reports that he’s started knocking on his neighbors’ doors, pitched the idea to buy their house, and convinced them to vote for him as their congressman. He denies any suicidal or homicidal ideations. There is no evidence of perceptual disturbance. Mr. X undergoes a Mini-Mental State Examination (MMSE) and scores 26/30, which suggests no cognitive impairment. However, his insight and judgment are poor.

Mr. X’s physical examination is unremarkable. His laboratory workup includes a complete blood count, comprehensive metabolic panel, urinalysis, thyroid function test, vitamin B12 and folate levels, urine drug screen, and blood alcohol level. All results are within normal limits. He has no history of alcohol or recreational drug use as evident by the laboratory results and collateral information from his wife. Further, a non-contrast CT scan of his head shows no abnormality.

Approximately 1 month ago, Mr. X was diagnosed with restless leg syndrome (RLS). Mr. X’s medication regimen consists of gabapentin, 300 mg 3 times daily, prescribed years ago by his neurologist for neuropathic pain; and ropinirole, 3 mg/d, for RLS. His neurologist had prescribed him ropinirole, which was started at 1 mg/d and titrated to 3 mg/d within a 1-week span. Two weeks after Mr. X started this medication regimen, his wife reports that she noticed changes in his behavior, including severe agitation, irritability, delusions of grandeur, decreased need for sleep, and racing of thoughts.

[polldaddy:10417490]

The authors’ observations

Mr. X was diagnosed with medication (ropinirole)-induced bipolar and related disorder with mood-congruent psychotic features.

To determine this diagnosis, we initially considered Mr. X’s age and medical conditions, including stroke and space-occupying lesions of the brain. However, the laboratory and neuroimaging studies, which included a CT scan of the head and MRI of the brain, were negative. Next, because Mr. X had sudden onset manic symptoms after ropinirole was initiated, we considered the possibility of a substance/medication-induced bipolar and related disorder. Further, ropinirole is capable of producing the symptoms in criterion A of DSM-5 criteria for substance/medication-induced bipolar and related disorder. Mr. X met all DSM-5 criteria for substance/medication-induced bipolar and related disorder (Table¹).

[polldaddy:10417494]

TREATMENT Medication adjustments and improvement

The admitting clinician discontinues ropinirole and initiates divalproex sodium, 500 mg twice a day. By Day 4, Mr. X shows significant improvement, including no irritable mood and regression of delusions of grandeur, and his sleep cycle returns to normal. At this time, the divalproex sodium is also discontinued.

Continue to: The authors' observations

Dopamine agonist agents are a standard treatment in the management of Parkinson’s disease and RLS.^2-5 Ropinirole, a dopamine receptor agonist, has a high affinity for dopamine D2 and D3 receptor subtypes.⁴ Published reports have linked dopamine agonists to mania with psychotic features.^6,7 In a study by Stoner et al,⁸ of 95 patients treated with ropinirole, 13 patients developed psychotic features that necessitated the use of antipsychotic medications or a lower dose of ropinirole.

The recommended starting dose for ropinirole is 0.25 mg/d. The dose can be increased to 0.5 mg in the next 2 days, and to 1 mg/d at the end of the first week.⁹ The mean effective daily dose is 2 mg/d, and maximum recommended dose is 4 mg/d.⁹ For Mr. X, ropinirole was quickly titrated to 3 mg/d over 1 week, which resulted in mania and psychosis. We suggest that when treating geriatric patients, clinicians should consider prescribing the lowest effective dose of psychotropic medications, such as ropinirole, to prevent adverse effects. Higher doses of dopamine agonists, especially in geriatric patients, increase the risk of common adverse effects, such as nausea (25% to 50%), headache (7% to 22%), fatigue (1% to 19%), dizziness (6% to 18%), and vomiting (5% to 11%).¹⁰ When prescribing dopamine agonists, clinicians should educate patients and their caregivers about the rare but potential risk of medication-induced mania and psychosis.

Mr. X’s case emphasizes the importance of a comprehensive psychiatric evaluation and medical workup to rule out a wide differential diagnosis when approaching new-onset mania and psychosis in geriatric patients.¹¹ Our case contributes to the evidence that dopamine agonist medications are associated with mania and psychotic symptoms.

OUTCOME A return to baseline

On Day 12, Mr. X is discharged home in a stable condition. Two weeks later, at an outpatient follow-up visit, Mr. X is asymptomatic and has returned to his baseline functioning.

Bottom Line

When approaching new-onset mania and psychosis in geriatric patients, a comprehensive psychiatric evaluation and medical workup are necessary to rule out a wide differential diagnosis. Ropinirole use can lead to mania and psychotic symptoms, especially in geriatric patients. As should be done with all other dopaminergic agents, increase the dose of ropinirole with caution, and be vigilant for the emergence of signs of mania and/or psychosis.

Continue to: Related Resources

• Adabie A, Jackson JC, Torrence CL. Older-age bipolar disorder: A case series. Current Psychiatry. 2019;18(2):24-29.
• Chen P, Dols A, Rej S, et al. Update on the epidemiology, diagnosis, and treatment of mania in older-age bipolar disorder. Curr Psychiatry Rep. 2017;19(8):46.

Drug Brand Names

Divalproex sodium • Depakote
Gabapentin • Neurontin
Ropinirole • Requip

Mr. Z, an obese adult with a history of portal hypertension and cirrhosis from alcoholism, visits your clinic because he is having difficulty sleeping and concentrating at work. He recently reduced his alcohol use and has improved support from his spouse. He walks into your office with an unremarkable gait before stopping to jot down a note in crisp, neat handwriting. He sits facing you, making good eye contact and exhibiting no involuntary movements. As has been the case at previous visits, Mr. Z is fully oriented to person, place, and time. You can follow one another’s train of thought and collaborate on treatment decisions. You’ve ruled out hepatic encephalopathy. Could you be missing something?

Hepatic encephalopathy is a neuropsychiatric condition caused by metabolic changes secondary to liver dysfunction and/or by blood flow bypassing the portal venous system. Signs and symptoms of hepatic encephalopathy range from subtle changes in cognition and affect to coma.Pathophysiologic mechanisms involved in hepatic encephalopathy include inflammation, neurotoxins, oxidative stress, permeability changes in the blood-brain barrier, and impaired brain energy metabolism.¹

Patients with poor liver function commonly have psychometrically detectable cognitive and psychomotor deficits that can substantially affect their lives. When such deficits are undetectable by routine physical and mental status examinations, the condition is called minimal hepatic encephalopathy (MHE), or latent hepatic encephalopathy. Minimal hepatic encephalopathy is associated with a reduced quality of life, sleep disturbances, fall risk, impaired ability to work and/or drive, and a risk of developing overt hepatic encephalopathy.¹

Approximately 22% to 74% of patients with liver dysfunction develop MHE.² Prevalence estimates vary widely because of the poor standardization of diagnostic criteria and potential underdiagnosis due to a lack of obvious symptoms.²

How is MHE diagnosed?

The most commonly administered psychometric test to assess for MHE is the Psychometric Hepatic Encephalopathy Score, a written test that measures motor speed and accuracy, concentration, attention, visual perception, visual-spatial orientation, visual construction, and memory.^3,4 Other methods for evaluating MHE, including EEG, MRI, single-photon emission CT, positron emission tomography, and determining a patient’s frequency threshold of perceiving a flickering light, have predictive power, but they do not have a well-defined, standardized role in the diagnosis of MHE.² Although ammonia levels can correlate with severity of impairment in episodic hepatic encephalopathy, they are not well correlated with the deficits in MHE, and often it is not feasible to properly measure ammonia concentrations in outpatient settings.²

Limited treatment options

Few studies have investigated interventions specifically for MHE. The best­studied treatments are lactulose⁵ and rifaximin.⁶ Lactulose reduces the formation of ammonia and the absorption of both ammonia and glutamine in the colonic lumen.⁵ In addition to improving MHE, lactulose helps prevent the recurrence of episodic overt hepatic encephalopathy.⁵ The antibiotic rifaximin kills ammonia-producing gut bacteria because it is minimally absorbed in the digestive system. No studies investigating rifaximin have observed antibiotic resistance, even with prolonged use. Rifaximin improves cognitive ability, driving ability, and quality of life in patients with MHE. Adding rifaximin to a treatment regimen that includes lactulose also can reduce the recurrence of overt hepatic encephalopathy.⁶ Branched chain amino acids, L-carnitine, L-ornithine aspartate, treating a comorbid zinc deficiency, probiotics, and increasing vegetable protein intake relative to animal protein intake may also have roles in treating MHE.²

Mr. Z, an obese adult with a history of portal hypertension and cirrhosis from alcoholism, visits your clinic because he is having difficulty sleeping and concentrating at work. He recently reduced his alcohol use and has improved support from his spouse. He walks into your office with an unremarkable gait before stopping to jot down a note in crisp, neat handwriting. He sits facing you, making good eye contact and exhibiting no involuntary movements. As has been the case at previous visits, Mr. Z is fully oriented to person, place, and time. You can follow one another’s train of thought and collaborate on treatment decisions. You’ve ruled out hepatic encephalopathy. Could you be missing something?

Hepatic encephalopathy is a neuropsychiatric condition caused by metabolic changes secondary to liver dysfunction and/or by blood flow bypassing the portal venous system. Signs and symptoms of hepatic encephalopathy range from subtle changes in cognition and affect to coma.Pathophysiologic mechanisms involved in hepatic encephalopathy include inflammation, neurotoxins, oxidative stress, permeability changes in the blood-brain barrier, and impaired brain energy metabolism.¹

Patients with poor liver function commonly have psychometrically detectable cognitive and psychomotor deficits that can substantially affect their lives. When such deficits are undetectable by routine physical and mental status examinations, the condition is called minimal hepatic encephalopathy (MHE), or latent hepatic encephalopathy. Minimal hepatic encephalopathy is associated with a reduced quality of life, sleep disturbances, fall risk, impaired ability to work and/or drive, and a risk of developing overt hepatic encephalopathy.¹

Approximately 22% to 74% of patients with liver dysfunction develop MHE.² Prevalence estimates vary widely because of the poor standardization of diagnostic criteria and potential underdiagnosis due to a lack of obvious symptoms.²

How is MHE diagnosed?

The most commonly administered psychometric test to assess for MHE is the Psychometric Hepatic Encephalopathy Score, a written test that measures motor speed and accuracy, concentration, attention, visual perception, visual-spatial orientation, visual construction, and memory.^3,4 Other methods for evaluating MHE, including EEG, MRI, single-photon emission CT, positron emission tomography, and determining a patient’s frequency threshold of perceiving a flickering light, have predictive power, but they do not have a well-defined, standardized role in the diagnosis of MHE.² Although ammonia levels can correlate with severity of impairment in episodic hepatic encephalopathy, they are not well correlated with the deficits in MHE, and often it is not feasible to properly measure ammonia concentrations in outpatient settings.²

Limited treatment options

Few studies have investigated interventions specifically for MHE. The best­studied treatments are lactulose⁵ and rifaximin.⁶ Lactulose reduces the formation of ammonia and the absorption of both ammonia and glutamine in the colonic lumen.⁵ In addition to improving MHE, lactulose helps prevent the recurrence of episodic overt hepatic encephalopathy.⁵ The antibiotic rifaximin kills ammonia-producing gut bacteria because it is minimally absorbed in the digestive system. No studies investigating rifaximin have observed antibiotic resistance, even with prolonged use. Rifaximin improves cognitive ability, driving ability, and quality of life in patients with MHE. Adding rifaximin to a treatment regimen that includes lactulose also can reduce the recurrence of overt hepatic encephalopathy.⁶ Branched chain amino acids, L-carnitine, L-ornithine aspartate, treating a comorbid zinc deficiency, probiotics, and increasing vegetable protein intake relative to animal protein intake may also have roles in treating MHE.²

Mr. Z, an obese adult with a history of portal hypertension and cirrhosis from alcoholism, visits your clinic because he is having difficulty sleeping and concentrating at work. He recently reduced his alcohol use and has improved support from his spouse. He walks into your office with an unremarkable gait before stopping to jot down a note in crisp, neat handwriting. He sits facing you, making good eye contact and exhibiting no involuntary movements. As has been the case at previous visits, Mr. Z is fully oriented to person, place, and time. You can follow one another’s train of thought and collaborate on treatment decisions. You’ve ruled out hepatic encephalopathy. Could you be missing something?

Hepatic encephalopathy is a neuropsychiatric condition caused by metabolic changes secondary to liver dysfunction and/or by blood flow bypassing the portal venous system. Signs and symptoms of hepatic encephalopathy range from subtle changes in cognition and affect to coma.Pathophysiologic mechanisms involved in hepatic encephalopathy include inflammation, neurotoxins, oxidative stress, permeability changes in the blood-brain barrier, and impaired brain energy metabolism.¹

Patients with poor liver function commonly have psychometrically detectable cognitive and psychomotor deficits that can substantially affect their lives. When such deficits are undetectable by routine physical and mental status examinations, the condition is called minimal hepatic encephalopathy (MHE), or latent hepatic encephalopathy. Minimal hepatic encephalopathy is associated with a reduced quality of life, sleep disturbances, fall risk, impaired ability to work and/or drive, and a risk of developing overt hepatic encephalopathy.¹

Approximately 22% to 74% of patients with liver dysfunction develop MHE.² Prevalence estimates vary widely because of the poor standardization of diagnostic criteria and potential underdiagnosis due to a lack of obvious symptoms.²

How is MHE diagnosed?

The most commonly administered psychometric test to assess for MHE is the Psychometric Hepatic Encephalopathy Score, a written test that measures motor speed and accuracy, concentration, attention, visual perception, visual-spatial orientation, visual construction, and memory.^3,4 Other methods for evaluating MHE, including EEG, MRI, single-photon emission CT, positron emission tomography, and determining a patient’s frequency threshold of perceiving a flickering light, have predictive power, but they do not have a well-defined, standardized role in the diagnosis of MHE.² Although ammonia levels can correlate with severity of impairment in episodic hepatic encephalopathy, they are not well correlated with the deficits in MHE, and often it is not feasible to properly measure ammonia concentrations in outpatient settings.²

Limited treatment options

Few studies have investigated interventions specifically for MHE. The best­studied treatments are lactulose⁵ and rifaximin.⁶ Lactulose reduces the formation of ammonia and the absorption of both ammonia and glutamine in the colonic lumen.⁵ In addition to improving MHE, lactulose helps prevent the recurrence of episodic overt hepatic encephalopathy.⁵ The antibiotic rifaximin kills ammonia-producing gut bacteria because it is minimally absorbed in the digestive system. No studies investigating rifaximin have observed antibiotic resistance, even with prolonged use. Rifaximin improves cognitive ability, driving ability, and quality of life in patients with MHE. Adding rifaximin to a treatment regimen that includes lactulose also can reduce the recurrence of overt hepatic encephalopathy.⁶ Branched chain amino acids, L-carnitine, L-ornithine aspartate, treating a comorbid zinc deficiency, probiotics, and increasing vegetable protein intake relative to animal protein intake may also have roles in treating MHE.²

Although all health care professionals are at risk for burnout, physicians have especially high rates of self-reported burnout—which is commonly understood as a work-related syndrome of emotional exhaustion, depersonalization, and a decreased sense of accomplishment that develops over time.¹ In a 2019 report investigating burnout in approximately 15,000 physicians, 39% of psychiatrists and nearly 50% of physicians from multiple other specialities described themselves as “burned out.”² In addition, 15% reported symptoms of clinical depression (4%) or subclinical depression (11%). In comparison, in 2017, 7.1% of US adults experienced at least 1 major depressive episode.³ Because physician burnout and depression can be associated with adverse outcomes in patient care and personal health, rapid identification and differentiation of the 2 conditions is paramount.

Differentiating burnout and depression

Burnout and depression are distinct but overlapping entities. Although burnout can be difficult to recognize and is not currently a DSM diagnosis, physicians can learn to identify the signs with reference to the more familiar features of depression (Table^4,5). Many features of burnout are work-related, while the negative feelings and thoughts of depression pertain to all areas of life. Furthermore, a major depressive episode often includes hopelessness, suicidality, or mood-congruent delusions; burnout does not. Shared symptoms of burnout and depression include extreme exhaustion, feeling unhappy, and reduced performance.

Surprisingly, there is no universally accepted definition of burnout.^4,5 Some researchers have proposed that physicians who are categorized as “burned out” may actually have underlying anxiety or depressive disorders that have been misdiagnosed and not appropriately treated.^4,5 Others claim that burnout is best formulated as a depressive condition in need of formal diagnostic criteria.^4,5 Because the definition of burnout is in question,^4,5 strategies to prevent and detect burnout in individual clinicians remain elusive.

Key areas that contribute to vulnerability to burnout include one’s sense of community, fairness, and control in the workplace; personal and organization values; and work-life balance. We propose the mnemonic WORK to help clinicians quickly assess their vulnerability to burnout in these areas.

Workload. Outside of working hours, are you satisfied with the amount of time you devote to self-care, recreation, and other activities that are important to you? Do you honor your “down time”?

Oversight. Are you satisfied with the flexibility and autonomy in your professional life? Are you able to cope with the systemic demands of your practice while upholding your priorities within these restrictions?

Reward. Are the mechanisms for feedback, opportunities for advancement, and financial compensation in your workplace fair? Do you find positive meaning in the work that you do?

Continue to: Kinship

Kinship. Does your place of work support cooperation and collaboration, rather than competition and isolation? Do you approach and receive support from your colleagues when you need assistance?

Persistent dissatisfaction in any of these aspects should prompt clinicians to further develop strategies that promote workplace engagement, job satisfaction, and resilience. We hope this mnemonic helps clinicians to take responsibility for their own well-being and ultimately reap the rewards of a fulfilling professional life.

Although all health care professionals are at risk for burnout, physicians have especially high rates of self-reported burnout—which is commonly understood as a work-related syndrome of emotional exhaustion, depersonalization, and a decreased sense of accomplishment that develops over time.¹ In a 2019 report investigating burnout in approximately 15,000 physicians, 39% of psychiatrists and nearly 50% of physicians from multiple other specialities described themselves as “burned out.”² In addition, 15% reported symptoms of clinical depression (4%) or subclinical depression (11%). In comparison, in 2017, 7.1% of US adults experienced at least 1 major depressive episode.³ Because physician burnout and depression can be associated with adverse outcomes in patient care and personal health, rapid identification and differentiation of the 2 conditions is paramount.

Differentiating burnout and depression

Burnout and depression are distinct but overlapping entities. Although burnout can be difficult to recognize and is not currently a DSM diagnosis, physicians can learn to identify the signs with reference to the more familiar features of depression (Table^4,5). Many features of burnout are work-related, while the negative feelings and thoughts of depression pertain to all areas of life. Furthermore, a major depressive episode often includes hopelessness, suicidality, or mood-congruent delusions; burnout does not. Shared symptoms of burnout and depression include extreme exhaustion, feeling unhappy, and reduced performance.

Surprisingly, there is no universally accepted definition of burnout.^4,5 Some researchers have proposed that physicians who are categorized as “burned out” may actually have underlying anxiety or depressive disorders that have been misdiagnosed and not appropriately treated.^4,5 Others claim that burnout is best formulated as a depressive condition in need of formal diagnostic criteria.^4,5 Because the definition of burnout is in question,^4,5 strategies to prevent and detect burnout in individual clinicians remain elusive.

Key areas that contribute to vulnerability to burnout include one’s sense of community, fairness, and control in the workplace; personal and organization values; and work-life balance. We propose the mnemonic WORK to help clinicians quickly assess their vulnerability to burnout in these areas.

Workload. Outside of working hours, are you satisfied with the amount of time you devote to self-care, recreation, and other activities that are important to you? Do you honor your “down time”?

Oversight. Are you satisfied with the flexibility and autonomy in your professional life? Are you able to cope with the systemic demands of your practice while upholding your priorities within these restrictions?

Reward. Are the mechanisms for feedback, opportunities for advancement, and financial compensation in your workplace fair? Do you find positive meaning in the work that you do?

Continue to: Kinship

Kinship. Does your place of work support cooperation and collaboration, rather than competition and isolation? Do you approach and receive support from your colleagues when you need assistance?

Persistent dissatisfaction in any of these aspects should prompt clinicians to further develop strategies that promote workplace engagement, job satisfaction, and resilience. We hope this mnemonic helps clinicians to take responsibility for their own well-being and ultimately reap the rewards of a fulfilling professional life.

Although all health care professionals are at risk for burnout, physicians have especially high rates of self-reported burnout—which is commonly understood as a work-related syndrome of emotional exhaustion, depersonalization, and a decreased sense of accomplishment that develops over time.¹ In a 2019 report investigating burnout in approximately 15,000 physicians, 39% of psychiatrists and nearly 50% of physicians from multiple other specialities described themselves as “burned out.”² In addition, 15% reported symptoms of clinical depression (4%) or subclinical depression (11%). In comparison, in 2017, 7.1% of US adults experienced at least 1 major depressive episode.³ Because physician burnout and depression can be associated with adverse outcomes in patient care and personal health, rapid identification and differentiation of the 2 conditions is paramount.

Differentiating burnout and depression

Burnout and depression are distinct but overlapping entities. Although burnout can be difficult to recognize and is not currently a DSM diagnosis, physicians can learn to identify the signs with reference to the more familiar features of depression (Table^4,5). Many features of burnout are work-related, while the negative feelings and thoughts of depression pertain to all areas of life. Furthermore, a major depressive episode often includes hopelessness, suicidality, or mood-congruent delusions; burnout does not. Shared symptoms of burnout and depression include extreme exhaustion, feeling unhappy, and reduced performance.

Surprisingly, there is no universally accepted definition of burnout.^4,5 Some researchers have proposed that physicians who are categorized as “burned out” may actually have underlying anxiety or depressive disorders that have been misdiagnosed and not appropriately treated.^4,5 Others claim that burnout is best formulated as a depressive condition in need of formal diagnostic criteria.^4,5 Because the definition of burnout is in question,^4,5 strategies to prevent and detect burnout in individual clinicians remain elusive.

Key areas that contribute to vulnerability to burnout include one’s sense of community, fairness, and control in the workplace; personal and organization values; and work-life balance. We propose the mnemonic WORK to help clinicians quickly assess their vulnerability to burnout in these areas.

Workload. Outside of working hours, are you satisfied with the amount of time you devote to self-care, recreation, and other activities that are important to you? Do you honor your “down time”?

Oversight. Are you satisfied with the flexibility and autonomy in your professional life? Are you able to cope with the systemic demands of your practice while upholding your priorities within these restrictions?

Reward. Are the mechanisms for feedback, opportunities for advancement, and financial compensation in your workplace fair? Do you find positive meaning in the work that you do?

Continue to: Kinship

Kinship. Does your place of work support cooperation and collaboration, rather than competition and isolation? Do you approach and receive support from your colleagues when you need assistance?

Persistent dissatisfaction in any of these aspects should prompt clinicians to further develop strategies that promote workplace engagement, job satisfaction, and resilience. We hope this mnemonic helps clinicians to take responsibility for their own well-being and ultimately reap the rewards of a fulfilling professional life.

Postpartum depression (PPD) is one of the most prevalent complications associated with pregnancy and childbirth in the United States, affecting more than 400,000 women annually.¹ Postpartum depression is most commonly treated with psychotherapy and antidepressants approved for the treatment of major depressive disorder. Until recently, there was no pharmacologic therapy approved by the FDA specifically for the treatment of PPD. Considering the adverse outcomes associated with untreated or inadequately treated PPD, and the limitations of existing therapies, there is a significant unmet need for pharmacologic treatment options for PPD.² To help address this need, the FDA recently approved brexanolone injection (brand name: ZULRESSO^™) (Table 1³) as a first-in-class therapy for the treatment of adults with PPD.³

Clinical implications

Postpartum depression can result in adverse outcomes for the patient, baby, and family when under- or untreated, and the need for rapid resolution of symptoms cannot be overstated.² Suicide is strongly associated with depression and is a leading cause of pregnancy-related deaths.⁴ Additionally, PPD can impact the health, safety, and well-being of the child, with both short- and long-term consequences, including greater rates of psychological or behavioral difficulties among children of patients with PPD.⁵ Postpartum depression can also have negative effects on the patient’s partner, with 24% to 50% of partners experiencing depression.⁶ Current PPD management strategies include the use of psychotherapy and pharmacologic interventions for major depressive disorder that may take up to 4 to 6 weeks for some patients, and may not achieve remission for all patients.^7-9

Brexanolone injection is a first-in-class medication with a novel mechanism of action. In clinical studies, it achieved rapid (by Hour 60) and sustained (through Day 30) reductions in depressive symptoms and could provide a meaningful new treatment option for adult women with PPD.^10,11

How it works

Animal and human studies have established the relevance of GABAergic signaling in the etiology and symptoms of depression, and supported the investigation of gamma-aminobutyric acid A receptor (GABA_AR) positive allosteric modulators (PAMs)—and particularly neuroactive steroids, such as brexanolone—as potential therapeutics in PPD (Table 2^12-14). Through pregnancy, the levels of allopregnanolone, a neuroactive steroid metabolite of progesterone, rise in concert with progesterone, before a precipitous decrease at childbirth. This fluctuation, as well as other perturbations of GABAergic signaling in the peripartum period, may contribute to the development of PPD.^12-15

Brexanolone is a neuroactive steroid that is chemically identical to endogenous allopregnanolone produced in the CNS. Brexanolone potentiates GABA-mediated currents from recombinant human GABA_ARs in mammalian cells expressing α1β2γ2 receptor subunits, α4β3δ receptor subunits, and α6β3δ receptor subunits.³ Positive allosteric modulation of both synaptic and extrasynaptic GABA_ARs differentiates brexanolone from other GABA_AR modulators, such as benzodiazepines.^10,11

Brexanolone’s mechanism of action in the treatment of PPD is not fully understood, but it is thought to be related to GABA_AR PAM activity.³

Supporting evidence

The FDA approval of brexanolone injection was based on the efficacy demonstrated in 2 Phase III multicenter, randomized, double-blind, placebo-controlled studies in adult women (age 18 to 45) with PPD (defined by DSM-IV criteria for a major depressive episode, with onset of symptoms in the third trimester or within 4 weeks of delivery). Exclusion criteria included the presence of bipolar disorder or psychosis. In these studies, 60-hour continuous IV infusions of brexanolone or placebo were given, followed by 4 weeks of observation. Study 1 (202B) enrolled patients with severe PPD (Hamilton Rating Scale for Depression [HAM-D] total score ≥26), and Study 2 (202C) enrolled patients with moderate PPD (HAM-D score 20 to 25). A titration to the recommended target dosage of 90 μg/kg/hour was evaluated in both studies. BRX90 patients received 30 μg/kg/hour for 4 hours, 60 μg/kg/hour for 20 hours, 90 μg/kg/hour for 28 hours, followed by a taper to 60 μg/kg/hour for 4 hours and then 30 μg/kg/hour for 4 hours. The primary endpoint in both studies was the mean change from baseline in depressive symptoms as measured by HAM-D total score at the end of the 60-hour infusion. A pre-specified secondary efficacy endpoint was the mean change from baseline in HAM-D total score at Day 30.

Continue to: Efficacy

Efficacy. In both placebo-controlled studies, titration to a target dose of brexanolone 90 μg/kg/hour was superior to placebo in improvement of depressive symptoms (Table 3³).

Pharmacological profile

Brexanolone exposure-response relationships and the time course of pharmacodynamic response are unknown.³

Adverse reactions. Safety was evaluated from all patients receiving brexanolone injection, regardless of dosing regimen (N = 140, including patients from a Phase IIb study, 202A).^3,11

The most common adverse reactions (incidence ≥5% and at least twice the rate of placebo) were sedation/somnolence, dry mouth, loss of consciousness, and flushing/hot flush.³ The incidence of patients discontinuing due to any adverse reaction was 2% for brexanolone vs 1% for placebo.³

Sedation, somnolence, and loss of consciousness. In clinical studies, brexanolone caused sedation and somnolence that required dose interruption or reduction in some patients during the infusion (5% of brexanolone-treated patients compared with 0% of placebo-treated patients).³ Some patients were also reported to have loss of consciousness or altered state of consciousness during the brexanolone infusion (4% of patients treated with brexanolone compared with 0% of patients treated with placebo).³ All patients with loss of or altered state of consciousness recovered fully 15 to 60 minutes after dose interruption.³ There was no clear association between loss or alteration of consciousness and pattern or timing of dose, and not all patients who experienced a loss or alteration of consciousness reported sedation or somnolence before the episode.

Continue to: Suicidality

Suicidality. The risk of developing suicidal thoughts and behaviors with brexanolone is unknown, due to the relatively low number of exposures to brexanolone injection during clinical development and a mechanism of action distinct from that of existing antidepressant medications.³

Pharmacokinetics

In clinical trials, brexanolone exhibited dose-proportional pharmacokinetics, and the terminal half-life is approximately 9 hours (Table 4³). Brexanolone is metabolized by non-cytochrome P450 (CYP)-based pathways, including keto-reduction, glucuronidation, and sulfation.³ No clinically significant differences in the pharmacokinetics of brexanolone were observed based on renal or hepatic impairment, and no studies were conducted to evaluate the effects of other drugs on brexanolone.³

Lactation. A population pharmacokinetics model constructed from studies in the clinical development program calculated the maximum relative infant dose for brexanolone during infusion as 1.3%.³ Given the low oral bioavailability of brexanolone (<5%) in adults, the potential for breastfed infant exposure is considered low.³

Clinical considerations

Risk Evaluation and Mitigation Strategies (REMS) requirements. Brexanolone injection is a Schedule IV controlled substance. It has a “black-box” warning regarding excessive sedation and sudden loss of consciousness, which has been taken into account within the REMS drug safety program. Health care facilities and pharmacies must enroll in the REMS program and ensure that brexanolone is administered only to patients who are enrolled in the REMS program. Staff must be trained on the processes and procedures to administer brexanolone, and the facility must have a fall precautions protocol in place and be equipped with a programmable peristaltic IV infusion pump and continuous pulse oximetry with alarms.³

Monitoring. A REMS-trained clinician must be available continuously on-site to oversee each patient for the duration of the continuous IV infusion, which lasts 60 hours (2.5 days) and should be initiated early enough in the day to allow for recognition of excessive sedation. Patients must be monitored for hypoxia using continuous pulse oximetry equipped with an alarm and should also be assessed for excessive sedation every 2 hours during planned, non-sleep periods. If excessive sedation occurs, the infusion should be stopped until symptoms resolve, after which the infusion may be resumed at the same or a lower dose as clinically appropriate. In case of overdosage, the infusion should be stopped immediately and supportive measures initiated as necessary. Patients must not be the primary caregiver of dependents, and must be accompanied during interactions with their child(ren).

Continue to: Contraindications

Contraindications. There are no contraindications for the use of brexanolone in adults with PPD.

End-stage renal disease (ESRD). Avoid using brexanolone in patients with ESRD because of the potential accumulation of the solubilizing agent, betadex sulfobutyl ether sodium.

Pregnancy. Brexanolone has not been studied in pregnant patients. Pregnant women and women of reproductive age should be informed of the potential risk to a fetus based on data from other drugs that enhance GABAergic inhibition.

Breastfeeding. There are no data on the effects of brexanolone on a breastfed infant. Breastfeeding should be a discussion of risk and benefit between the patient and her doctor. The developmental and health benefits of breastfeeding should be considered, along with the mother’s clinical need for brexanolone and any potential adverse effects on the breastfed child from brexanolone or from the underlying maternal condition. However, based on the low relative infant dose (<2%) and the low oral bioavailability in adults, the risk to breastfed infants is thought to be low.¹⁶

Potential for abuse. Brexanolone injection is a Schedule IV controlled substance. Although it was not possible to assess physical dependency in the registrational trials due to dose tapering at the end of treatment, clinicians should advise patients about the theoretical possibility for brexanolone to be abused or lead to dependence based on other medications with similar primary pharmacology.

Continue to: Concomitant medications

Concomitant medications. Caution patients that taking opioids or other CNS depressants, such as benzodiazepines, in combination with brexanolone may increase the severity of sedative effects.

Suicidal thoughts and behaviors. Advise patients and caregivers to look for the emergence of suicidal thoughts and behavior and instruct them to report such symptoms to their clinician. Consider changing the therapeutic regimen, including discontinuing brexanolone, in patients whose depression becomes worse or who experience emergent suicidal thoughts and behaviors.

Why Rx?

Postpartum depression is a common and often devastating medical complication of childbirth that can result in adverse outcomes for the patient, baby, and family when left undertreated or untreated. There is a great need to identify and treat women who develop PPD. Rapid and sustained resolution of symptoms in women who experience PPD should be the goal of treatment, and consequently, brexanolone injection presents an important new tool in available treatment options for PPD.

Bottom Line

Brexanolone injection is a neuroactive steroid gamma-aminobutyric acid (GABA) A receptor positive allosteric modulator that’s been FDA-approved for the treatment of postpartum depression (PPD). It is administered as a continuous IV infusion over 60 hours. The rapid and sustained improvement of PPD observed in clinical trials with brexanolone injection may support a new treatment paradigm for women with PPD.

Postpartum depression (PPD) is one of the most prevalent complications associated with pregnancy and childbirth in the United States, affecting more than 400,000 women annually.¹ Postpartum depression is most commonly treated with psychotherapy and antidepressants approved for the treatment of major depressive disorder. Until recently, there was no pharmacologic therapy approved by the FDA specifically for the treatment of PPD. Considering the adverse outcomes associated with untreated or inadequately treated PPD, and the limitations of existing therapies, there is a significant unmet need for pharmacologic treatment options for PPD.² To help address this need, the FDA recently approved brexanolone injection (brand name: ZULRESSO^™) (Table 1³) as a first-in-class therapy for the treatment of adults with PPD.³

Clinical implications

Postpartum depression can result in adverse outcomes for the patient, baby, and family when under- or untreated, and the need for rapid resolution of symptoms cannot be overstated.² Suicide is strongly associated with depression and is a leading cause of pregnancy-related deaths.⁴ Additionally, PPD can impact the health, safety, and well-being of the child, with both short- and long-term consequences, including greater rates of psychological or behavioral difficulties among children of patients with PPD.⁵ Postpartum depression can also have negative effects on the patient’s partner, with 24% to 50% of partners experiencing depression.⁶ Current PPD management strategies include the use of psychotherapy and pharmacologic interventions for major depressive disorder that may take up to 4 to 6 weeks for some patients, and may not achieve remission for all patients.^7-9

Brexanolone injection is a first-in-class medication with a novel mechanism of action. In clinical studies, it achieved rapid (by Hour 60) and sustained (through Day 30) reductions in depressive symptoms and could provide a meaningful new treatment option for adult women with PPD.^10,11

How it works

Animal and human studies have established the relevance of GABAergic signaling in the etiology and symptoms of depression, and supported the investigation of gamma-aminobutyric acid A receptor (GABA_AR) positive allosteric modulators (PAMs)—and particularly neuroactive steroids, such as brexanolone—as potential therapeutics in PPD (Table 2^12-14). Through pregnancy, the levels of allopregnanolone, a neuroactive steroid metabolite of progesterone, rise in concert with progesterone, before a precipitous decrease at childbirth. This fluctuation, as well as other perturbations of GABAergic signaling in the peripartum period, may contribute to the development of PPD.^12-15

Brexanolone is a neuroactive steroid that is chemically identical to endogenous allopregnanolone produced in the CNS. Brexanolone potentiates GABA-mediated currents from recombinant human GABA_ARs in mammalian cells expressing α1β2γ2 receptor subunits, α4β3δ receptor subunits, and α6β3δ receptor subunits.³ Positive allosteric modulation of both synaptic and extrasynaptic GABA_ARs differentiates brexanolone from other GABA_AR modulators, such as benzodiazepines.^10,11

Brexanolone’s mechanism of action in the treatment of PPD is not fully understood, but it is thought to be related to GABA_AR PAM activity.³

Supporting evidence

The FDA approval of brexanolone injection was based on the efficacy demonstrated in 2 Phase III multicenter, randomized, double-blind, placebo-controlled studies in adult women (age 18 to 45) with PPD (defined by DSM-IV criteria for a major depressive episode, with onset of symptoms in the third trimester or within 4 weeks of delivery). Exclusion criteria included the presence of bipolar disorder or psychosis. In these studies, 60-hour continuous IV infusions of brexanolone or placebo were given, followed by 4 weeks of observation. Study 1 (202B) enrolled patients with severe PPD (Hamilton Rating Scale for Depression [HAM-D] total score ≥26), and Study 2 (202C) enrolled patients with moderate PPD (HAM-D score 20 to 25). A titration to the recommended target dosage of 90 μg/kg/hour was evaluated in both studies. BRX90 patients received 30 μg/kg/hour for 4 hours, 60 μg/kg/hour for 20 hours, 90 μg/kg/hour for 28 hours, followed by a taper to 60 μg/kg/hour for 4 hours and then 30 μg/kg/hour for 4 hours. The primary endpoint in both studies was the mean change from baseline in depressive symptoms as measured by HAM-D total score at the end of the 60-hour infusion. A pre-specified secondary efficacy endpoint was the mean change from baseline in HAM-D total score at Day 30.

Continue to: Efficacy

Efficacy. In both placebo-controlled studies, titration to a target dose of brexanolone 90 μg/kg/hour was superior to placebo in improvement of depressive symptoms (Table 3³).

Pharmacological profile

Brexanolone exposure-response relationships and the time course of pharmacodynamic response are unknown.³

Adverse reactions. Safety was evaluated from all patients receiving brexanolone injection, regardless of dosing regimen (N = 140, including patients from a Phase IIb study, 202A).^3,11

The most common adverse reactions (incidence ≥5% and at least twice the rate of placebo) were sedation/somnolence, dry mouth, loss of consciousness, and flushing/hot flush.³ The incidence of patients discontinuing due to any adverse reaction was 2% for brexanolone vs 1% for placebo.³

Sedation, somnolence, and loss of consciousness. In clinical studies, brexanolone caused sedation and somnolence that required dose interruption or reduction in some patients during the infusion (5% of brexanolone-treated patients compared with 0% of placebo-treated patients).³ Some patients were also reported to have loss of consciousness or altered state of consciousness during the brexanolone infusion (4% of patients treated with brexanolone compared with 0% of patients treated with placebo).³ All patients with loss of or altered state of consciousness recovered fully 15 to 60 minutes after dose interruption.³ There was no clear association between loss or alteration of consciousness and pattern or timing of dose, and not all patients who experienced a loss or alteration of consciousness reported sedation or somnolence before the episode.

Continue to: Suicidality

Suicidality. The risk of developing suicidal thoughts and behaviors with brexanolone is unknown, due to the relatively low number of exposures to brexanolone injection during clinical development and a mechanism of action distinct from that of existing antidepressant medications.³

Pharmacokinetics

In clinical trials, brexanolone exhibited dose-proportional pharmacokinetics, and the terminal half-life is approximately 9 hours (Table 4³). Brexanolone is metabolized by non-cytochrome P450 (CYP)-based pathways, including keto-reduction, glucuronidation, and sulfation.³ No clinically significant differences in the pharmacokinetics of brexanolone were observed based on renal or hepatic impairment, and no studies were conducted to evaluate the effects of other drugs on brexanolone.³

Lactation. A population pharmacokinetics model constructed from studies in the clinical development program calculated the maximum relative infant dose for brexanolone during infusion as 1.3%.³ Given the low oral bioavailability of brexanolone (<5%) in adults, the potential for breastfed infant exposure is considered low.³

Clinical considerations

Risk Evaluation and Mitigation Strategies (REMS) requirements. Brexanolone injection is a Schedule IV controlled substance. It has a “black-box” warning regarding excessive sedation and sudden loss of consciousness, which has been taken into account within the REMS drug safety program. Health care facilities and pharmacies must enroll in the REMS program and ensure that brexanolone is administered only to patients who are enrolled in the REMS program. Staff must be trained on the processes and procedures to administer brexanolone, and the facility must have a fall precautions protocol in place and be equipped with a programmable peristaltic IV infusion pump and continuous pulse oximetry with alarms.³

Monitoring. A REMS-trained clinician must be available continuously on-site to oversee each patient for the duration of the continuous IV infusion, which lasts 60 hours (2.5 days) and should be initiated early enough in the day to allow for recognition of excessive sedation. Patients must be monitored for hypoxia using continuous pulse oximetry equipped with an alarm and should also be assessed for excessive sedation every 2 hours during planned, non-sleep periods. If excessive sedation occurs, the infusion should be stopped until symptoms resolve, after which the infusion may be resumed at the same or a lower dose as clinically appropriate. In case of overdosage, the infusion should be stopped immediately and supportive measures initiated as necessary. Patients must not be the primary caregiver of dependents, and must be accompanied during interactions with their child(ren).

Continue to: Contraindications

Contraindications. There are no contraindications for the use of brexanolone in adults with PPD.

End-stage renal disease (ESRD). Avoid using brexanolone in patients with ESRD because of the potential accumulation of the solubilizing agent, betadex sulfobutyl ether sodium.

Pregnancy. Brexanolone has not been studied in pregnant patients. Pregnant women and women of reproductive age should be informed of the potential risk to a fetus based on data from other drugs that enhance GABAergic inhibition.

Breastfeeding. There are no data on the effects of brexanolone on a breastfed infant. Breastfeeding should be a discussion of risk and benefit between the patient and her doctor. The developmental and health benefits of breastfeeding should be considered, along with the mother’s clinical need for brexanolone and any potential adverse effects on the breastfed child from brexanolone or from the underlying maternal condition. However, based on the low relative infant dose (<2%) and the low oral bioavailability in adults, the risk to breastfed infants is thought to be low.¹⁶

Potential for abuse. Brexanolone injection is a Schedule IV controlled substance. Although it was not possible to assess physical dependency in the registrational trials due to dose tapering at the end of treatment, clinicians should advise patients about the theoretical possibility for brexanolone to be abused or lead to dependence based on other medications with similar primary pharmacology.

Continue to: Concomitant medications

Concomitant medications. Caution patients that taking opioids or other CNS depressants, such as benzodiazepines, in combination with brexanolone may increase the severity of sedative effects.

Suicidal thoughts and behaviors. Advise patients and caregivers to look for the emergence of suicidal thoughts and behavior and instruct them to report such symptoms to their clinician. Consider changing the therapeutic regimen, including discontinuing brexanolone, in patients whose depression becomes worse or who experience emergent suicidal thoughts and behaviors.

Why Rx?

Postpartum depression is a common and often devastating medical complication of childbirth that can result in adverse outcomes for the patient, baby, and family when left undertreated or untreated. There is a great need to identify and treat women who develop PPD. Rapid and sustained resolution of symptoms in women who experience PPD should be the goal of treatment, and consequently, brexanolone injection presents an important new tool in available treatment options for PPD.

Bottom Line

Brexanolone injection is a neuroactive steroid gamma-aminobutyric acid (GABA) A receptor positive allosteric modulator that’s been FDA-approved for the treatment of postpartum depression (PPD). It is administered as a continuous IV infusion over 60 hours. The rapid and sustained improvement of PPD observed in clinical trials with brexanolone injection may support a new treatment paradigm for women with PPD.

Postpartum depression (PPD) is one of the most prevalent complications associated with pregnancy and childbirth in the United States, affecting more than 400,000 women annually.¹ Postpartum depression is most commonly treated with psychotherapy and antidepressants approved for the treatment of major depressive disorder. Until recently, there was no pharmacologic therapy approved by the FDA specifically for the treatment of PPD. Considering the adverse outcomes associated with untreated or inadequately treated PPD, and the limitations of existing therapies, there is a significant unmet need for pharmacologic treatment options for PPD.² To help address this need, the FDA recently approved brexanolone injection (brand name: ZULRESSO^™) (Table 1³) as a first-in-class therapy for the treatment of adults with PPD.³

Clinical implications

Postpartum depression can result in adverse outcomes for the patient, baby, and family when under- or untreated, and the need for rapid resolution of symptoms cannot be overstated.² Suicide is strongly associated with depression and is a leading cause of pregnancy-related deaths.⁴ Additionally, PPD can impact the health, safety, and well-being of the child, with both short- and long-term consequences, including greater rates of psychological or behavioral difficulties among children of patients with PPD.⁵ Postpartum depression can also have negative effects on the patient’s partner, with 24% to 50% of partners experiencing depression.⁶ Current PPD management strategies include the use of psychotherapy and pharmacologic interventions for major depressive disorder that may take up to 4 to 6 weeks for some patients, and may not achieve remission for all patients.^7-9

Brexanolone injection is a first-in-class medication with a novel mechanism of action. In clinical studies, it achieved rapid (by Hour 60) and sustained (through Day 30) reductions in depressive symptoms and could provide a meaningful new treatment option for adult women with PPD.^10,11

How it works

Animal and human studies have established the relevance of GABAergic signaling in the etiology and symptoms of depression, and supported the investigation of gamma-aminobutyric acid A receptor (GABA_AR) positive allosteric modulators (PAMs)—and particularly neuroactive steroids, such as brexanolone—as potential therapeutics in PPD (Table 2^12-14). Through pregnancy, the levels of allopregnanolone, a neuroactive steroid metabolite of progesterone, rise in concert with progesterone, before a precipitous decrease at childbirth. This fluctuation, as well as other perturbations of GABAergic signaling in the peripartum period, may contribute to the development of PPD.^12-15

Brexanolone is a neuroactive steroid that is chemically identical to endogenous allopregnanolone produced in the CNS. Brexanolone potentiates GABA-mediated currents from recombinant human GABA_ARs in mammalian cells expressing α1β2γ2 receptor subunits, α4β3δ receptor subunits, and α6β3δ receptor subunits.³ Positive allosteric modulation of both synaptic and extrasynaptic GABA_ARs differentiates brexanolone from other GABA_AR modulators, such as benzodiazepines.^10,11

Brexanolone’s mechanism of action in the treatment of PPD is not fully understood, but it is thought to be related to GABA_AR PAM activity.³

Supporting evidence

The FDA approval of brexanolone injection was based on the efficacy demonstrated in 2 Phase III multicenter, randomized, double-blind, placebo-controlled studies in adult women (age 18 to 45) with PPD (defined by DSM-IV criteria for a major depressive episode, with onset of symptoms in the third trimester or within 4 weeks of delivery). Exclusion criteria included the presence of bipolar disorder or psychosis. In these studies, 60-hour continuous IV infusions of brexanolone or placebo were given, followed by 4 weeks of observation. Study 1 (202B) enrolled patients with severe PPD (Hamilton Rating Scale for Depression [HAM-D] total score ≥26), and Study 2 (202C) enrolled patients with moderate PPD (HAM-D score 20 to 25). A titration to the recommended target dosage of 90 μg/kg/hour was evaluated in both studies. BRX90 patients received 30 μg/kg/hour for 4 hours, 60 μg/kg/hour for 20 hours, 90 μg/kg/hour for 28 hours, followed by a taper to 60 μg/kg/hour for 4 hours and then 30 μg/kg/hour for 4 hours. The primary endpoint in both studies was the mean change from baseline in depressive symptoms as measured by HAM-D total score at the end of the 60-hour infusion. A pre-specified secondary efficacy endpoint was the mean change from baseline in HAM-D total score at Day 30.

Continue to: Efficacy

Efficacy. In both placebo-controlled studies, titration to a target dose of brexanolone 90 μg/kg/hour was superior to placebo in improvement of depressive symptoms (Table 3³).

Pharmacological profile

Brexanolone exposure-response relationships and the time course of pharmacodynamic response are unknown.³

Adverse reactions. Safety was evaluated from all patients receiving brexanolone injection, regardless of dosing regimen (N = 140, including patients from a Phase IIb study, 202A).^3,11

The most common adverse reactions (incidence ≥5% and at least twice the rate of placebo) were sedation/somnolence, dry mouth, loss of consciousness, and flushing/hot flush.³ The incidence of patients discontinuing due to any adverse reaction was 2% for brexanolone vs 1% for placebo.³

Sedation, somnolence, and loss of consciousness. In clinical studies, brexanolone caused sedation and somnolence that required dose interruption or reduction in some patients during the infusion (5% of brexanolone-treated patients compared with 0% of placebo-treated patients).³ Some patients were also reported to have loss of consciousness or altered state of consciousness during the brexanolone infusion (4% of patients treated with brexanolone compared with 0% of patients treated with placebo).³ All patients with loss of or altered state of consciousness recovered fully 15 to 60 minutes after dose interruption.³ There was no clear association between loss or alteration of consciousness and pattern or timing of dose, and not all patients who experienced a loss or alteration of consciousness reported sedation or somnolence before the episode.

Continue to: Suicidality

Suicidality. The risk of developing suicidal thoughts and behaviors with brexanolone is unknown, due to the relatively low number of exposures to brexanolone injection during clinical development and a mechanism of action distinct from that of existing antidepressant medications.³

Pharmacokinetics

In clinical trials, brexanolone exhibited dose-proportional pharmacokinetics, and the terminal half-life is approximately 9 hours (Table 4³). Brexanolone is metabolized by non-cytochrome P450 (CYP)-based pathways, including keto-reduction, glucuronidation, and sulfation.³ No clinically significant differences in the pharmacokinetics of brexanolone were observed based on renal or hepatic impairment, and no studies were conducted to evaluate the effects of other drugs on brexanolone.³

Lactation. A population pharmacokinetics model constructed from studies in the clinical development program calculated the maximum relative infant dose for brexanolone during infusion as 1.3%.³ Given the low oral bioavailability of brexanolone (<5%) in adults, the potential for breastfed infant exposure is considered low.³

Clinical considerations

Risk Evaluation and Mitigation Strategies (REMS) requirements. Brexanolone injection is a Schedule IV controlled substance. It has a “black-box” warning regarding excessive sedation and sudden loss of consciousness, which has been taken into account within the REMS drug safety program. Health care facilities and pharmacies must enroll in the REMS program and ensure that brexanolone is administered only to patients who are enrolled in the REMS program. Staff must be trained on the processes and procedures to administer brexanolone, and the facility must have a fall precautions protocol in place and be equipped with a programmable peristaltic IV infusion pump and continuous pulse oximetry with alarms.³

Monitoring. A REMS-trained clinician must be available continuously on-site to oversee each patient for the duration of the continuous IV infusion, which lasts 60 hours (2.5 days) and should be initiated early enough in the day to allow for recognition of excessive sedation. Patients must be monitored for hypoxia using continuous pulse oximetry equipped with an alarm and should also be assessed for excessive sedation every 2 hours during planned, non-sleep periods. If excessive sedation occurs, the infusion should be stopped until symptoms resolve, after which the infusion may be resumed at the same or a lower dose as clinically appropriate. In case of overdosage, the infusion should be stopped immediately and supportive measures initiated as necessary. Patients must not be the primary caregiver of dependents, and must be accompanied during interactions with their child(ren).

Continue to: Contraindications

Contraindications. There are no contraindications for the use of brexanolone in adults with PPD.

End-stage renal disease (ESRD). Avoid using brexanolone in patients with ESRD because of the potential accumulation of the solubilizing agent, betadex sulfobutyl ether sodium.

Pregnancy. Brexanolone has not been studied in pregnant patients. Pregnant women and women of reproductive age should be informed of the potential risk to a fetus based on data from other drugs that enhance GABAergic inhibition.

Breastfeeding. There are no data on the effects of brexanolone on a breastfed infant. Breastfeeding should be a discussion of risk and benefit between the patient and her doctor. The developmental and health benefits of breastfeeding should be considered, along with the mother’s clinical need for brexanolone and any potential adverse effects on the breastfed child from brexanolone or from the underlying maternal condition. However, based on the low relative infant dose (<2%) and the low oral bioavailability in adults, the risk to breastfed infants is thought to be low.¹⁶

Potential for abuse. Brexanolone injection is a Schedule IV controlled substance. Although it was not possible to assess physical dependency in the registrational trials due to dose tapering at the end of treatment, clinicians should advise patients about the theoretical possibility for brexanolone to be abused or lead to dependence based on other medications with similar primary pharmacology.

Continue to: Concomitant medications

Concomitant medications. Caution patients that taking opioids or other CNS depressants, such as benzodiazepines, in combination with brexanolone may increase the severity of sedative effects.

Suicidal thoughts and behaviors. Advise patients and caregivers to look for the emergence of suicidal thoughts and behavior and instruct them to report such symptoms to their clinician. Consider changing the therapeutic regimen, including discontinuing brexanolone, in patients whose depression becomes worse or who experience emergent suicidal thoughts and behaviors.

Why Rx?

Postpartum depression is a common and often devastating medical complication of childbirth that can result in adverse outcomes for the patient, baby, and family when left undertreated or untreated. There is a great need to identify and treat women who develop PPD. Rapid and sustained resolution of symptoms in women who experience PPD should be the goal of treatment, and consequently, brexanolone injection presents an important new tool in available treatment options for PPD.

Bottom Line

Brexanolone injection is a neuroactive steroid gamma-aminobutyric acid (GABA) A receptor positive allosteric modulator that’s been FDA-approved for the treatment of postpartum depression (PPD). It is administered as a continuous IV infusion over 60 hours. The rapid and sustained improvement of PPD observed in clinical trials with brexanolone injection may support a new treatment paradigm for women with PPD.

For a patient with a major mental illness, the road to wellness is long and uncertain. The medications commonly used to treat mood and thought disorders can take weeks to months to start providing benefits, and they carry significant risks for adverse effects, such as weight gain, sexual dysfunction, and movement disorders. Patients often have to take psychotropic medications for the rest of their lives. In addition to these downsides, there is no guarantee that these medications will provide complete or even partial relief.^2,3

Recently, there has been growing excitement about new treatments that might be “miracle cures” for patients with mental illness, particularly for individuals with treatment-resistant depression (TRD). Two of these treatments—ketamine-related compounds, and hallucinogenic drugs—seem to promise therapeutic effects that are vastly different from those of other psychiatric medications: They appear to improve patients’ symptoms very quickly, and their effects may persist long after these drugs have been cleared from the body.

Intravenous ketamine is an older generic drug used in anesthesia; recently, it has been used off-label for TRD and other mental illnesses. On March 5, 2019, the FDA approved an intranasal formulation of esketamine—the S-enantiomer of ketamine—for TRD.⁴ Hallucinogens have also been tested in small studies and have seemingly significant effects in alleviating depression in patients with terminal illnesses⁵ and reducing smoking behavior in patients with tobacco use disorder.^6,7

These miracle cures are becoming increasingly available to patients and continue to gain credibility among clinicians and researchers. How should we evaluate the usefulness of these new treatments? And how should we talk to our patients about them? To answer these questions, this article:

• explores our duty to our patients, ourselves, and our colleagues
• describes the dilemma
• discusses ways to evaluate claims made about these new miracle cures.

Duty: Protecting and helping our patients

The physician–patient relationship is a fiduciary relationship. According to both common law and medical ethics, a physician who enters into a treatment relationship with a patient creates a bond of special trust and confidence. Such a relationship requires a physician to act in good faith and in the patient’s best interests.⁸ As physicians, we have a duty to evaluate the safety and efficacy of new treatments that are available for our patients, whether or not they are FDA-approved.

We should also protect our patients from the adverse consequences of relatively untested drugs. For example, ketamine and hallucinogens both produce dissociative effects, and may carry high risks for patients who have a predisposition to psychosis.⁹ We should protect our patients from any false hopes that might lead them to abandon their current treatment regimens due to adverse effects and imperfect results. At the same time, we also have a duty to acknowledge our patients’ suffering and to recognize that they might be desperate for new treatment options. We should remain open-minded about new treatments, and acknowledge that they might work. Finally, we have a duty to be mindful of any financial benefits that we may derive from the development, marketing, and administration of these medications.

Dilemma: The need for new treatments

This is not the first time that novel treatments in mental health have seemed to hold incredible promise. In the late 1800s, Sigmund Freud began to regularly use a compound that led him to feel “the normal euphoria of a healthy person.” He wrote that this substance produced:

…exhilaration and lasting euphoria, which does not differ in any way from the normal euphoria of a healthy person. The feeling of excitement which accompanies stimulus by alcohol is completely lacking; the characteristic urge for immediate activity which alcohol produces is also absent. One senses an increase of self-control and feels more vigorous and more capable of work; on the other hand, if one works, one misses that heightening of the mental powers which alcohol, tea, or coffee induce. One is simply normal, and soon finds it difficult to believe that one is under the influence of any drug at all.¹

Continue to: The compound Freud was describing...

The compound Freud was describing is cocaine, which we now know is an addictive and dangerous drug that can in fact worsen depression.¹⁰ Another treatment regarded as a miracle cure in its time involved placing patients with schizophrenia into an insulin-induced coma to treat their symptoms; this therapy was used from 1933 to 1960.¹¹ We now recognize that this practice is unacceptably dangerous.

The past is filled with cautionary tales of the enthusiastic adoption of treatments for mental illness that later turned out to be ineffective, counterproductive, dangerous, or inhumane. Yet, the long, arduous journeys our patients go through continue to weigh heavily on us. We would love to offer our patients newer, more efficacious, and longer-lasting treatments with fewer adverse effects.

Discussion: How to best evaluate miracle cures

To help quickly assess a new treatment, the following 5 categories can help guide and organize our thought process.

1. Evidence

What type of evidence do we have that a new treatment is safe and effective? Psychiatric research may be even more susceptible to a placebo effect than other medical research, particularly for illnesses with subjective symptoms, such as depression.¹² Double-blinded, placebo-controlled studies, such as the IV ketamine trial conducted by Singh et al,¹³ are the gold standard for separating a substance’s actual biologic effect from a placebo effect. Studies that do not include a control group should not be regarded as providing scientific evidence of efficacy.

2. Mechanism

If a new compound appears to have a beneficial effect on mental health, it is important to consider the potential mechanism underlying this effect to determine if it is biologically plausible. A compound that is claimed to be a panacea for every symptom of every mental illness should be heavily scrutinized. For example, based on available research, ketamine’s long-lasting effects seem to come from 2 mechanisms^14,15:

• Activation of endogenous opioid receptors, which is also responsible for the euphoria induced by heroin and oxycodone.
• Blockade of N-methyl-D-aspartate receptors. N-methyl-D-aspartate receptor activation is a key mechanism by which learning and memory function in the brain, and blocking these receptors may increase brain plasticity.

Continue to: Therefore, it seems plausible...

Therefore, it seems plausible that ketamine could produce both short- and long-term improvements in mood. Hallucinogenic drugs are thought to profoundly alter brain function through several mechanisms, including activating serotonin receptors, enhancing brain plasticity, and increasing brain connectivity.¹⁶

3. Reinforcement

Psychiatric medications that are acutely reinforcing have significant potential for abuse. Antidepressants and mood stabilizers are not acutely rewarding. They don’t make patients feel good right away. Medications such as stimulants and opioids do, and must be used with extreme care because of their abuse potential. The problem with acutely reinforcing medications is that in the long run, they can worsen depression by decreasing the brain’s ability to produce endogenous opioids.¹⁷

4. No single solution?

A mental disorder is unlikely to have a single solution. Rather than regarding a new treatment as capable of rapidly alleviating every symptom of a patient’s illness, it should be viewed as a tool that can be helpful when used in combination with other treatments and lifestyle practices. In an interview with the web site STAT, Cristina Cusin, MD, co-director of the Intravenous Ketamine Clinic for Depression at Massachusetts General Hospital, said, “You don’t treat an advanced disease with just an infusion and a ‘see you next time.’ If [doctors] replace your knee but [you] don’t do physical therapy, you don’t walk again.”¹⁸ To sustain the benefits of a novel medication, patients with serious mental illnesses need to maintain strong social supports, see a mental health care provider regularly, and abstain from illicit drug and alcohol use.

5. Context matters

For a medication to obtain approval to treat a specific indication, the FDA usually require 2 trials that demonstrate efficacy. Off-label use of generic medications such as ketamine may have benefits, but it is unlikely that a generic drug would be put through a costly FDA-approval process.¹⁹

When learning about new medications, remember that patients might assume that these agents have undergone a thorough review process for safety and effectiveness. When our patients request such treatments—whether FDA-approved or off-label—it is our responsibility as physicians to educate them about the benefits, risks, effectiveness, and limitations of these treatments, as well as to evaluate the appropriateness of a treatment for a specific patient’s symptoms.

Continue to: Tempering excitement with caution

Our patients are not the only ones desperate for a miracle cure. As psychiatrists, many of us are desperate, too. New compounds may ultimately change the way we treat mental illness. However, we have an obligation to temper our excitement with caution by remembering past mistakes, and systematically evaluating new miracle cures to determine if they are safe and effective.

For a patient with a major mental illness, the road to wellness is long and uncertain. The medications commonly used to treat mood and thought disorders can take weeks to months to start providing benefits, and they carry significant risks for adverse effects, such as weight gain, sexual dysfunction, and movement disorders. Patients often have to take psychotropic medications for the rest of their lives. In addition to these downsides, there is no guarantee that these medications will provide complete or even partial relief.^2,3

Recently, there has been growing excitement about new treatments that might be “miracle cures” for patients with mental illness, particularly for individuals with treatment-resistant depression (TRD). Two of these treatments—ketamine-related compounds, and hallucinogenic drugs—seem to promise therapeutic effects that are vastly different from those of other psychiatric medications: They appear to improve patients’ symptoms very quickly, and their effects may persist long after these drugs have been cleared from the body.

Intravenous ketamine is an older generic drug used in anesthesia; recently, it has been used off-label for TRD and other mental illnesses. On March 5, 2019, the FDA approved an intranasal formulation of esketamine—the S-enantiomer of ketamine—for TRD.⁴ Hallucinogens have also been tested in small studies and have seemingly significant effects in alleviating depression in patients with terminal illnesses⁵ and reducing smoking behavior in patients with tobacco use disorder.^6,7

These miracle cures are becoming increasingly available to patients and continue to gain credibility among clinicians and researchers. How should we evaluate the usefulness of these new treatments? And how should we talk to our patients about them? To answer these questions, this article:

• explores our duty to our patients, ourselves, and our colleagues
• describes the dilemma
• discusses ways to evaluate claims made about these new miracle cures.

Duty: Protecting and helping our patients

The physician–patient relationship is a fiduciary relationship. According to both common law and medical ethics, a physician who enters into a treatment relationship with a patient creates a bond of special trust and confidence. Such a relationship requires a physician to act in good faith and in the patient’s best interests.⁸ As physicians, we have a duty to evaluate the safety and efficacy of new treatments that are available for our patients, whether or not they are FDA-approved.

We should also protect our patients from the adverse consequences of relatively untested drugs. For example, ketamine and hallucinogens both produce dissociative effects, and may carry high risks for patients who have a predisposition to psychosis.⁹ We should protect our patients from any false hopes that might lead them to abandon their current treatment regimens due to adverse effects and imperfect results. At the same time, we also have a duty to acknowledge our patients’ suffering and to recognize that they might be desperate for new treatment options. We should remain open-minded about new treatments, and acknowledge that they might work. Finally, we have a duty to be mindful of any financial benefits that we may derive from the development, marketing, and administration of these medications.

Dilemma: The need for new treatments

This is not the first time that novel treatments in mental health have seemed to hold incredible promise. In the late 1800s, Sigmund Freud began to regularly use a compound that led him to feel “the normal euphoria of a healthy person.” He wrote that this substance produced:

…exhilaration and lasting euphoria, which does not differ in any way from the normal euphoria of a healthy person. The feeling of excitement which accompanies stimulus by alcohol is completely lacking; the characteristic urge for immediate activity which alcohol produces is also absent. One senses an increase of self-control and feels more vigorous and more capable of work; on the other hand, if one works, one misses that heightening of the mental powers which alcohol, tea, or coffee induce. One is simply normal, and soon finds it difficult to believe that one is under the influence of any drug at all.¹

Continue to: The compound Freud was describing...

The compound Freud was describing is cocaine, which we now know is an addictive and dangerous drug that can in fact worsen depression.¹⁰ Another treatment regarded as a miracle cure in its time involved placing patients with schizophrenia into an insulin-induced coma to treat their symptoms; this therapy was used from 1933 to 1960.¹¹ We now recognize that this practice is unacceptably dangerous.

The past is filled with cautionary tales of the enthusiastic adoption of treatments for mental illness that later turned out to be ineffective, counterproductive, dangerous, or inhumane. Yet, the long, arduous journeys our patients go through continue to weigh heavily on us. We would love to offer our patients newer, more efficacious, and longer-lasting treatments with fewer adverse effects.

Discussion: How to best evaluate miracle cures

To help quickly assess a new treatment, the following 5 categories can help guide and organize our thought process.

1. Evidence

What type of evidence do we have that a new treatment is safe and effective? Psychiatric research may be even more susceptible to a placebo effect than other medical research, particularly for illnesses with subjective symptoms, such as depression.¹² Double-blinded, placebo-controlled studies, such as the IV ketamine trial conducted by Singh et al,¹³ are the gold standard for separating a substance’s actual biologic effect from a placebo effect. Studies that do not include a control group should not be regarded as providing scientific evidence of efficacy.

2. Mechanism

If a new compound appears to have a beneficial effect on mental health, it is important to consider the potential mechanism underlying this effect to determine if it is biologically plausible. A compound that is claimed to be a panacea for every symptom of every mental illness should be heavily scrutinized. For example, based on available research, ketamine’s long-lasting effects seem to come from 2 mechanisms^14,15:

• Activation of endogenous opioid receptors, which is also responsible for the euphoria induced by heroin and oxycodone.
• Blockade of N-methyl-D-aspartate receptors. N-methyl-D-aspartate receptor activation is a key mechanism by which learning and memory function in the brain, and blocking these receptors may increase brain plasticity.

Continue to: Therefore, it seems plausible...

Therefore, it seems plausible that ketamine could produce both short- and long-term improvements in mood. Hallucinogenic drugs are thought to profoundly alter brain function through several mechanisms, including activating serotonin receptors, enhancing brain plasticity, and increasing brain connectivity.¹⁶

3. Reinforcement

Psychiatric medications that are acutely reinforcing have significant potential for abuse. Antidepressants and mood stabilizers are not acutely rewarding. They don’t make patients feel good right away. Medications such as stimulants and opioids do, and must be used with extreme care because of their abuse potential. The problem with acutely reinforcing medications is that in the long run, they can worsen depression by decreasing the brain’s ability to produce endogenous opioids.¹⁷

4. No single solution?

A mental disorder is unlikely to have a single solution. Rather than regarding a new treatment as capable of rapidly alleviating every symptom of a patient’s illness, it should be viewed as a tool that can be helpful when used in combination with other treatments and lifestyle practices. In an interview with the web site STAT, Cristina Cusin, MD, co-director of the Intravenous Ketamine Clinic for Depression at Massachusetts General Hospital, said, “You don’t treat an advanced disease with just an infusion and a ‘see you next time.’ If [doctors] replace your knee but [you] don’t do physical therapy, you don’t walk again.”¹⁸ To sustain the benefits of a novel medication, patients with serious mental illnesses need to maintain strong social supports, see a mental health care provider regularly, and abstain from illicit drug and alcohol use.

5. Context matters

For a medication to obtain approval to treat a specific indication, the FDA usually require 2 trials that demonstrate efficacy. Off-label use of generic medications such as ketamine may have benefits, but it is unlikely that a generic drug would be put through a costly FDA-approval process.¹⁹

When learning about new medications, remember that patients might assume that these agents have undergone a thorough review process for safety and effectiveness. When our patients request such treatments—whether FDA-approved or off-label—it is our responsibility as physicians to educate them about the benefits, risks, effectiveness, and limitations of these treatments, as well as to evaluate the appropriateness of a treatment for a specific patient’s symptoms.

Continue to: Tempering excitement with caution

Our patients are not the only ones desperate for a miracle cure. As psychiatrists, many of us are desperate, too. New compounds may ultimately change the way we treat mental illness. However, we have an obligation to temper our excitement with caution by remembering past mistakes, and systematically evaluating new miracle cures to determine if they are safe and effective.

For a patient with a major mental illness, the road to wellness is long and uncertain. The medications commonly used to treat mood and thought disorders can take weeks to months to start providing benefits, and they carry significant risks for adverse effects, such as weight gain, sexual dysfunction, and movement disorders. Patients often have to take psychotropic medications for the rest of their lives. In addition to these downsides, there is no guarantee that these medications will provide complete or even partial relief.^2,3

Recently, there has been growing excitement about new treatments that might be “miracle cures” for patients with mental illness, particularly for individuals with treatment-resistant depression (TRD). Two of these treatments—ketamine-related compounds, and hallucinogenic drugs—seem to promise therapeutic effects that are vastly different from those of other psychiatric medications: They appear to improve patients’ symptoms very quickly, and their effects may persist long after these drugs have been cleared from the body.

Intravenous ketamine is an older generic drug used in anesthesia; recently, it has been used off-label for TRD and other mental illnesses. On March 5, 2019, the FDA approved an intranasal formulation of esketamine—the S-enantiomer of ketamine—for TRD.⁴ Hallucinogens have also been tested in small studies and have seemingly significant effects in alleviating depression in patients with terminal illnesses⁵ and reducing smoking behavior in patients with tobacco use disorder.^6,7

These miracle cures are becoming increasingly available to patients and continue to gain credibility among clinicians and researchers. How should we evaluate the usefulness of these new treatments? And how should we talk to our patients about them? To answer these questions, this article:

• explores our duty to our patients, ourselves, and our colleagues
• describes the dilemma
• discusses ways to evaluate claims made about these new miracle cures.

Duty: Protecting and helping our patients

The physician–patient relationship is a fiduciary relationship. According to both common law and medical ethics, a physician who enters into a treatment relationship with a patient creates a bond of special trust and confidence. Such a relationship requires a physician to act in good faith and in the patient’s best interests.⁸ As physicians, we have a duty to evaluate the safety and efficacy of new treatments that are available for our patients, whether or not they are FDA-approved.

We should also protect our patients from the adverse consequences of relatively untested drugs. For example, ketamine and hallucinogens both produce dissociative effects, and may carry high risks for patients who have a predisposition to psychosis.⁹ We should protect our patients from any false hopes that might lead them to abandon their current treatment regimens due to adverse effects and imperfect results. At the same time, we also have a duty to acknowledge our patients’ suffering and to recognize that they might be desperate for new treatment options. We should remain open-minded about new treatments, and acknowledge that they might work. Finally, we have a duty to be mindful of any financial benefits that we may derive from the development, marketing, and administration of these medications.

Dilemma: The need for new treatments

This is not the first time that novel treatments in mental health have seemed to hold incredible promise. In the late 1800s, Sigmund Freud began to regularly use a compound that led him to feel “the normal euphoria of a healthy person.” He wrote that this substance produced:

…exhilaration and lasting euphoria, which does not differ in any way from the normal euphoria of a healthy person. The feeling of excitement which accompanies stimulus by alcohol is completely lacking; the characteristic urge for immediate activity which alcohol produces is also absent. One senses an increase of self-control and feels more vigorous and more capable of work; on the other hand, if one works, one misses that heightening of the mental powers which alcohol, tea, or coffee induce. One is simply normal, and soon finds it difficult to believe that one is under the influence of any drug at all.¹

Continue to: The compound Freud was describing...

The compound Freud was describing is cocaine, which we now know is an addictive and dangerous drug that can in fact worsen depression.¹⁰ Another treatment regarded as a miracle cure in its time involved placing patients with schizophrenia into an insulin-induced coma to treat their symptoms; this therapy was used from 1933 to 1960.¹¹ We now recognize that this practice is unacceptably dangerous.

The past is filled with cautionary tales of the enthusiastic adoption of treatments for mental illness that later turned out to be ineffective, counterproductive, dangerous, or inhumane. Yet, the long, arduous journeys our patients go through continue to weigh heavily on us. We would love to offer our patients newer, more efficacious, and longer-lasting treatments with fewer adverse effects.

Discussion: How to best evaluate miracle cures

To help quickly assess a new treatment, the following 5 categories can help guide and organize our thought process.

1. Evidence

What type of evidence do we have that a new treatment is safe and effective? Psychiatric research may be even more susceptible to a placebo effect than other medical research, particularly for illnesses with subjective symptoms, such as depression.¹² Double-blinded, placebo-controlled studies, such as the IV ketamine trial conducted by Singh et al,¹³ are the gold standard for separating a substance’s actual biologic effect from a placebo effect. Studies that do not include a control group should not be regarded as providing scientific evidence of efficacy.

2. Mechanism

If a new compound appears to have a beneficial effect on mental health, it is important to consider the potential mechanism underlying this effect to determine if it is biologically plausible. A compound that is claimed to be a panacea for every symptom of every mental illness should be heavily scrutinized. For example, based on available research, ketamine’s long-lasting effects seem to come from 2 mechanisms^14,15:

• Activation of endogenous opioid receptors, which is also responsible for the euphoria induced by heroin and oxycodone.
• Blockade of N-methyl-D-aspartate receptors. N-methyl-D-aspartate receptor activation is a key mechanism by which learning and memory function in the brain, and blocking these receptors may increase brain plasticity.

Continue to: Therefore, it seems plausible...

Therefore, it seems plausible that ketamine could produce both short- and long-term improvements in mood. Hallucinogenic drugs are thought to profoundly alter brain function through several mechanisms, including activating serotonin receptors, enhancing brain plasticity, and increasing brain connectivity.¹⁶

3. Reinforcement

Psychiatric medications that are acutely reinforcing have significant potential for abuse. Antidepressants and mood stabilizers are not acutely rewarding. They don’t make patients feel good right away. Medications such as stimulants and opioids do, and must be used with extreme care because of their abuse potential. The problem with acutely reinforcing medications is that in the long run, they can worsen depression by decreasing the brain’s ability to produce endogenous opioids.¹⁷

4. No single solution?

A mental disorder is unlikely to have a single solution. Rather than regarding a new treatment as capable of rapidly alleviating every symptom of a patient’s illness, it should be viewed as a tool that can be helpful when used in combination with other treatments and lifestyle practices. In an interview with the web site STAT, Cristina Cusin, MD, co-director of the Intravenous Ketamine Clinic for Depression at Massachusetts General Hospital, said, “You don’t treat an advanced disease with just an infusion and a ‘see you next time.’ If [doctors] replace your knee but [you] don’t do physical therapy, you don’t walk again.”¹⁸ To sustain the benefits of a novel medication, patients with serious mental illnesses need to maintain strong social supports, see a mental health care provider regularly, and abstain from illicit drug and alcohol use.

5. Context matters

For a medication to obtain approval to treat a specific indication, the FDA usually require 2 trials that demonstrate efficacy. Off-label use of generic medications such as ketamine may have benefits, but it is unlikely that a generic drug would be put through a costly FDA-approval process.¹⁹

When learning about new medications, remember that patients might assume that these agents have undergone a thorough review process for safety and effectiveness. When our patients request such treatments—whether FDA-approved or off-label—it is our responsibility as physicians to educate them about the benefits, risks, effectiveness, and limitations of these treatments, as well as to evaluate the appropriateness of a treatment for a specific patient’s symptoms.

Continue to: Tempering excitement with caution

Our patients are not the only ones desperate for a miracle cure. As psychiatrists, many of us are desperate, too. New compounds may ultimately change the way we treat mental illness. However, we have an obligation to temper our excitement with caution by remembering past mistakes, and systematically evaluating new miracle cures to determine if they are safe and effective.

Approximately 20% to 30% of patients with major depressive disorder do not respond to pharmacotherapy.¹ For patients with treatment-resistant depression (TRD)—typically defined as an inadequate response to at least 1 antidepressant trial of adequate dose and duration—neurostimulation may be an effective treatment option.

Two forms of neurostimulation used to treat TRD are deep brain stimulation (DBS) and transcranial magnetic stimulation (TMS). In DBS, electrodes are placed within the patient’s cranium and affixed to specific target locations. These electrodes are electrically stimulated at various frequencies. Transcranial magnetic stimulation is a noninvasive treatment in which a magnetic field is produced over a patient’s cranium, stimulating brain tissue via electromagnetic induction.

Media portrayals of most alternative therapies are inacurate.² In addition, the negative cognitive changes seen in depression mean patients are less likely to effectively compare the advantages and disadvantages of alternative treatment options. Therefore, both patients and clinicians require education on these treatment options and their adverse effects.

In this article, I compare DBS and TMS, and offer suggestions for educating patients about the potential adverse effects and therapeutic outcomes of each modality.

Deep brain stimulation

Deep brain stimulation is FDA-approved for treating Parkinson’s disease, essential tremor, dystonia, and obsessive-compulsive disorder (OCD).³ It has been used off-label for TRD, and some preliminary evidence suggests it is effective for this purpose. A review of 22 studies found that for patients with TRD, the rate of response to DBS (defined as >50% improvement on Hamilton Depression Rating Scale score) ranges from 40% to 70%.¹ Additional research, including larger, randomized, sham-controlled trials, is needed.

A consensus on the optimal target location for DBS has not yet been reached. Studies have had varying degrees of symptom improvement targeting the subgenual cingulate gyrus, posterior gyrus rectus, nucleus accumbens, ventral capsule/ventral striatum, inferior thalamic peduncle, and lateral habenula.¹

A worsening of depressive symptoms and increased risk of suicide have been reported in—but are not exclusive to—DBS. Patients treated with DBS may still meet the criteria for treatment resistance.

Continue to: The lack of insurance coverage...

The lack of insurance coverage for DBS for treating depression is a deterrent to its use. Because DBS is not FDA-approved for treating depression, the costs (approximately $65,000) that are not covered by a facility or study will fall on the patient.⁴ Patients may abandon hope for a positive therapeutic outcome if they must struggle with the financial responsibility for procedures and follow-up.⁴

Serious potential adverse events of DBS include infections, skin erosions, and postoperative seizure.⁴ Patients who are treated with DBS should be educated about these adverse effects, and how they may affect outcomes.

Transcranial magnetic stimulation

Transcranial magnetic stimulation is FDA-approved for treating depression, OCD, and migraine. Randomized, sham-controlled trials have found that TMS is effective for TRD.⁵ Studies have demonstrated varying degrees of efficacy, with response rates ranging from 47% to 58%.⁶

The most commonly used target area for TMS for patients with depression is the left dorsolateral prefrontal cortex.⁷ Potential adverse effects are relatively few and benign. The most serious adverse effect of TMS is a risk for seizure, which is reported to occur at a frequency of <0.1%.⁷

Although it varies by practice and location, the cost for an acute course of TMS (20 to 30 sessions) may range from $6,000 to $12,000.⁸ Most insurance companies cover TMS treatment for depression.

Continue to: TMS

TMS: A more accessible option

Compared with DBS, TMS is a more affordable and accessible therapy for patients with TRD. Further studies are needed to learn more about the therapeutic potential of DBS for TRD, and to develop methods that help decrease the risk of adverse effects. In addition, insurance coverage needs to be expanded to DBS to avoid having patients be responsible for the full costs of this treatment. Until then, TMS should be a recommended therapy for patients with TRD. If TRD persists in patients treated with TMS, consider electroconvulsive therapy.

Approximately 20% to 30% of patients with major depressive disorder do not respond to pharmacotherapy.¹ For patients with treatment-resistant depression (TRD)—typically defined as an inadequate response to at least 1 antidepressant trial of adequate dose and duration—neurostimulation may be an effective treatment option.

Two forms of neurostimulation used to treat TRD are deep brain stimulation (DBS) and transcranial magnetic stimulation (TMS). In DBS, electrodes are placed within the patient’s cranium and affixed to specific target locations. These electrodes are electrically stimulated at various frequencies. Transcranial magnetic stimulation is a noninvasive treatment in which a magnetic field is produced over a patient’s cranium, stimulating brain tissue via electromagnetic induction.

Media portrayals of most alternative therapies are inacurate.² In addition, the negative cognitive changes seen in depression mean patients are less likely to effectively compare the advantages and disadvantages of alternative treatment options. Therefore, both patients and clinicians require education on these treatment options and their adverse effects.

In this article, I compare DBS and TMS, and offer suggestions for educating patients about the potential adverse effects and therapeutic outcomes of each modality.

Deep brain stimulation

Deep brain stimulation is FDA-approved for treating Parkinson’s disease, essential tremor, dystonia, and obsessive-compulsive disorder (OCD).³ It has been used off-label for TRD, and some preliminary evidence suggests it is effective for this purpose. A review of 22 studies found that for patients with TRD, the rate of response to DBS (defined as >50% improvement on Hamilton Depression Rating Scale score) ranges from 40% to 70%.¹ Additional research, including larger, randomized, sham-controlled trials, is needed.

A consensus on the optimal target location for DBS has not yet been reached. Studies have had varying degrees of symptom improvement targeting the subgenual cingulate gyrus, posterior gyrus rectus, nucleus accumbens, ventral capsule/ventral striatum, inferior thalamic peduncle, and lateral habenula.¹

A worsening of depressive symptoms and increased risk of suicide have been reported in—but are not exclusive to—DBS. Patients treated with DBS may still meet the criteria for treatment resistance.

Continue to: The lack of insurance coverage...

The lack of insurance coverage for DBS for treating depression is a deterrent to its use. Because DBS is not FDA-approved for treating depression, the costs (approximately $65,000) that are not covered by a facility or study will fall on the patient.⁴ Patients may abandon hope for a positive therapeutic outcome if they must struggle with the financial responsibility for procedures and follow-up.⁴

Serious potential adverse events of DBS include infections, skin erosions, and postoperative seizure.⁴ Patients who are treated with DBS should be educated about these adverse effects, and how they may affect outcomes.

Transcranial magnetic stimulation

Transcranial magnetic stimulation is FDA-approved for treating depression, OCD, and migraine. Randomized, sham-controlled trials have found that TMS is effective for TRD.⁵ Studies have demonstrated varying degrees of efficacy, with response rates ranging from 47% to 58%.⁶

The most commonly used target area for TMS for patients with depression is the left dorsolateral prefrontal cortex.⁷ Potential adverse effects are relatively few and benign. The most serious adverse effect of TMS is a risk for seizure, which is reported to occur at a frequency of <0.1%.⁷

Although it varies by practice and location, the cost for an acute course of TMS (20 to 30 sessions) may range from $6,000 to $12,000.⁸ Most insurance companies cover TMS treatment for depression.

Continue to: TMS

TMS: A more accessible option

Compared with DBS, TMS is a more affordable and accessible therapy for patients with TRD. Further studies are needed to learn more about the therapeutic potential of DBS for TRD, and to develop methods that help decrease the risk of adverse effects. In addition, insurance coverage needs to be expanded to DBS to avoid having patients be responsible for the full costs of this treatment. Until then, TMS should be a recommended therapy for patients with TRD. If TRD persists in patients treated with TMS, consider electroconvulsive therapy.

Approximately 20% to 30% of patients with major depressive disorder do not respond to pharmacotherapy.¹ For patients with treatment-resistant depression (TRD)—typically defined as an inadequate response to at least 1 antidepressant trial of adequate dose and duration—neurostimulation may be an effective treatment option.

Two forms of neurostimulation used to treat TRD are deep brain stimulation (DBS) and transcranial magnetic stimulation (TMS). In DBS, electrodes are placed within the patient’s cranium and affixed to specific target locations. These electrodes are electrically stimulated at various frequencies. Transcranial magnetic stimulation is a noninvasive treatment in which a magnetic field is produced over a patient’s cranium, stimulating brain tissue via electromagnetic induction.

Media portrayals of most alternative therapies are inacurate.² In addition, the negative cognitive changes seen in depression mean patients are less likely to effectively compare the advantages and disadvantages of alternative treatment options. Therefore, both patients and clinicians require education on these treatment options and their adverse effects.

In this article, I compare DBS and TMS, and offer suggestions for educating patients about the potential adverse effects and therapeutic outcomes of each modality.

Deep brain stimulation

Deep brain stimulation is FDA-approved for treating Parkinson’s disease, essential tremor, dystonia, and obsessive-compulsive disorder (OCD).³ It has been used off-label for TRD, and some preliminary evidence suggests it is effective for this purpose. A review of 22 studies found that for patients with TRD, the rate of response to DBS (defined as >50% improvement on Hamilton Depression Rating Scale score) ranges from 40% to 70%.¹ Additional research, including larger, randomized, sham-controlled trials, is needed.

A consensus on the optimal target location for DBS has not yet been reached. Studies have had varying degrees of symptom improvement targeting the subgenual cingulate gyrus, posterior gyrus rectus, nucleus accumbens, ventral capsule/ventral striatum, inferior thalamic peduncle, and lateral habenula.¹

A worsening of depressive symptoms and increased risk of suicide have been reported in—but are not exclusive to—DBS. Patients treated with DBS may still meet the criteria for treatment resistance.

Continue to: The lack of insurance coverage...

The lack of insurance coverage for DBS for treating depression is a deterrent to its use. Because DBS is not FDA-approved for treating depression, the costs (approximately $65,000) that are not covered by a facility or study will fall on the patient.⁴ Patients may abandon hope for a positive therapeutic outcome if they must struggle with the financial responsibility for procedures and follow-up.⁴

Serious potential adverse events of DBS include infections, skin erosions, and postoperative seizure.⁴ Patients who are treated with DBS should be educated about these adverse effects, and how they may affect outcomes.

Transcranial magnetic stimulation

Transcranial magnetic stimulation is FDA-approved for treating depression, OCD, and migraine. Randomized, sham-controlled trials have found that TMS is effective for TRD.⁵ Studies have demonstrated varying degrees of efficacy, with response rates ranging from 47% to 58%.⁶

The most commonly used target area for TMS for patients with depression is the left dorsolateral prefrontal cortex.⁷ Potential adverse effects are relatively few and benign. The most serious adverse effect of TMS is a risk for seizure, which is reported to occur at a frequency of <0.1%.⁷

Although it varies by practice and location, the cost for an acute course of TMS (20 to 30 sessions) may range from $6,000 to $12,000.⁸ Most insurance companies cover TMS treatment for depression.

Continue to: TMS

TMS: A more accessible option

Compared with DBS, TMS is a more affordable and accessible therapy for patients with TRD. Further studies are needed to learn more about the therapeutic potential of DBS for TRD, and to develop methods that help decrease the risk of adverse effects. In addition, insurance coverage needs to be expanded to DBS to avoid having patients be responsible for the full costs of this treatment. Until then, TMS should be a recommended therapy for patients with TRD. If TRD persists in patients treated with TMS, consider electroconvulsive therapy.

CASE Vague symptoms; no clear etiology

Mr. W, age 53, presents to the emergency department (ED) describing acute mid-sternal chest pain (severity: 8 out of 10). His medical history is significant for pulmonary embolism and ascending aortic aneurysm in the context of Takayasu’s arteritis, an inflammatory condition of the large arterial blood vessels characterized by lesions that can lead to vascular stenosis, occlusion, or aneurysm. Takayasu’s arteritis is also known as pulseless disease due to the weak or absent pulses the condition produces.

A review of Mr. W’s medical records reveals that this is his 23rd visit to this hospital within a year; the year before that, he had 22 visits. At each of these previous visits, he had similar vague symptoms, including dizziness, chest pain, lightheadedness, fainting, bilateral knee weakness, and left-arm numbness/weakness, and no clear acute etiology for his reported symptoms. Each time, after the treating clinicians ruled out possible acute complications of a flare-up of Takayasu’s arteritis through a physical examination, laboratory tests, and imaging studies, Mr. W was discharged with recommendations that he follow-up with his primary care physician and specialists. At each discharge, he would leave the hospital with hesitation.

At this present visit, the ED physician recognizes Mr. W as someone who visits the ED often with no profound acute issues, and reviews the substantial medical records available to the hospital. He suspects Mr. W is feigning symptoms, and orders a psychiatric consultation.

EVALUATION Psychiatric interview and mental status exam

On examination, Mr. W is not in acute distress. Despite reporting an 8 out of 10 for chest pain severity, he displays no psychomotor agitation, and his pulse rate and blood pressure are within normal limits. He makes appropriate eye contact and describes his mood as “great.” He reports no problems with sleep, appetite, or disinterest in pleasurable activities, and denies being depressed or having any symptoms consistent with a mood disorder, anxiety disorder, or psychosis. He denies a history of panic attacks or excessive worrying that interferes with his sleep or activities of daily living. Additionally, Mr. W describes a stable, peaceful, and stress-free life within the limitations of his Takayasu’s arteritis, which he has been managing well since his diagnosis 6 years earlier.

Mr. W denies having any psychiatric symptoms, apprehensive feelings, or beliefs/fears that would be considered delusional, and he has no previous legal issues aside from an occasional driving citation. During the assessment, his affect remains broad and he denies having thoughts of suicide or homicide, or auditory or visual hallucinations.

Mr. W’s drug screen results are negative, and he denies using any illicit drugs. He uses only the medications that are prescribed by his clinicians. Overall, he seems to be a well-functioning individual. Mr. W reports that work is generally not stressful.

When the psychiatric team asks him about his frequent hospitalizations and ED visits, Mr. W is insistent that he is “just doing what my doctors said for me to do.” He repeats that he does not have any mental illness and did not see the point of seeing a psychiatrist.

In pursuit of collateral information, the psychiatry team accesses a regional medical record database that allows registered medical institutions and practices to track patients’ medical encounters within the region. According to this database, within approximately 5.5 years, Mr. W had 163 clinical encounters (ED visits and inpatient admissions) and 376 radiological studies in our region (Table 1 and Table 2).

[polldaddy:10394110]

Continue to: The authors' observations

The psychiatry team’s investigation of Mr. W’s medical records revealed the extent of his care-seeking behavior, and provided evidence for a diagnosis of factitious disorder.

Factitious disorder is an elusive psychiatric condition in which an individual chronically stimulates, induces, or aggravates illnesses to gain the status of being a patient. Although its exact cause has not been fully deciphered, it is seen mostly among individuals with knowledge of the workings of the medical field, such as a health care worker.¹ Factitious disorder is taxing on the health care system, with an estimated cost in the thousands of dollars per patient visit.² The condition has an estimated prevalence of 0.8% to 1.0% of patients seen by psychiatric consult services³ and is reported to be more prevalent among women than men.¹ Its cardinal features include health care site hopping and hospital shopping, vagueness about the patient’s history and symptoms, and discrepancy among reported symptoms, the patient’s behaviors, and objective clinical findings.^4,5 Although not all patients with factitious disorder have a legitimate medical reason for seeking care, some individuals with an established medical diagnosis use their condition as a tool to chronically seek care and play the sick role.

Factitious disorder should not be confused with malingering, which is differentiated by the patient’s search for a secondary gain, such as financial reward or avoiding jail; or conversion disorder, which is marked by true physical or neurologic symptoms and clinical findings triggered by psychological stressors. Patients with factitious disorder usually are cooperative during hospital stays and resume their normal daily routine shortly after discharge.⁴ In this case, Mr. W denied any psychiatric symptoms, apprehensive feelings, or beliefs or fears that would be considered delusional. He had no previous or pending legal issues, which ruled out malingering to avoid legal repercussions.

Mr. W’s presentation was complicated by his Takayasu’s arteritis diagnosis. Because Takayasu’s arteritis has a serious list of potential complications, ED physicians have a low threshold for ordering diagnostic studies for a patient with Takayasu’s arteritis who presents with a chief complaint of chest pain. In other words, when a patient with this condition presents to an acute setting (such as the ED) with chest pain, his/her chief complaint is taken with extreme seriousness. Conventional angiography is the standard diagnostic tool for Takayasu’s arteritis; CT angiography and magnetic resonance angiography are used for monitoring the disease’s progression.⁶

[polldaddy:10394113]

The authors’ observations

Currently, there are no FDA-approved treatments for factitious disorder, and patients with this condition generally are resistant to psychiatric and/or psychological care when discovered and offered treatment.⁷ Among those who consent to psychiatric care, psychoeducation, or psychotherapy, which have shown some efficacy for the condition, the dropout rate is high.⁸

Continue to: Although the instinctive approach...

Although the instinctive approach is to confront the patient once the deception has been uncovered, expert recommendations are contradictory. Some recommend confrontation as part of a treatment protocol,⁸ while others advise against such an approach.⁹

Because of how often patients with factitious disorder seek medical care, secondary iatrogenic consequences are possible. For example, for years, Mr. W has been unknowingly exposing himself to the iatrogenic consequences of the cumulative effect of diagnostic imaging for years. In 3 years alone, Mr. W had undergone an average of 125 diagnostic imaging studies per year—with and without contrast—and many unnecessary rounds of treatment with steroids and other interventions known to have secondary iatrogenic consequences.¹⁰ Excessive radiation exposure is known to be carcinogenic over time,¹⁰ and excessive use of steroids is associated with weight gain, physical habitus changes, and increased risk of infections.¹¹ In addition, the renal effects of the contrast materials from repeated imaging studies over so many years on Mr. W’s future kidney function are unknown.

TREATMENT Psychoeducation and referral for psychotherapy

We counsel Mr. W about factitious disorder and the risks of excessive hospitalizations, and refer him for follow-up at our local psychiatric clinic, as well as for individual psychotherapy. Mr. W is discharged because his medical work-up does not reveal any significant acute medical issues.

The authors’ observations

Because of the poor insight associated with factitious disorder and the limited treatment options available, a patient with factitious disorder is unlikely to enter psychiatric treatment on his/her own. The prognosis for a patient with factitious disorder remains poor unless the patient is forced into treatment. More intervention-focused research is needed to help improve outcomes for patients with factitious disorder.

OUTCOME Failure to follow up

Mr. W fails to attend individual psychotherapy as recommended. According to our regional record database, Mr. W continues to present to other EDs regularly.

Continue to: Bottom Line

A patient with factitious disorder stimulates, induces, or aggravates illnesses to gain the status of being a patient. Treatment options include psychiatric care, psychoeducation, or psychotherapy. However, due to poor insight, a patient with factitious disorder is unlikely to enter psychiatric treatment on his/her own.

Related Resources

• Yates GP, Feldman MD. Factitious disorder: a systematic review of 455 cases in the professional literature. Gen Hosp Psychiatry. 2016;41:20-28.
• Galli S, Tatu L, Bogousslavsky J, et al. Conversion, factitious disorder and malingering: a distinct pattern or a continuum? Front Neurol Neurosci. 2018;42:72-80.

CASE Vague symptoms; no clear etiology

Mr. W, age 53, presents to the emergency department (ED) describing acute mid-sternal chest pain (severity: 8 out of 10). His medical history is significant for pulmonary embolism and ascending aortic aneurysm in the context of Takayasu’s arteritis, an inflammatory condition of the large arterial blood vessels characterized by lesions that can lead to vascular stenosis, occlusion, or aneurysm. Takayasu’s arteritis is also known as pulseless disease due to the weak or absent pulses the condition produces.

A review of Mr. W’s medical records reveals that this is his 23rd visit to this hospital within a year; the year before that, he had 22 visits. At each of these previous visits, he had similar vague symptoms, including dizziness, chest pain, lightheadedness, fainting, bilateral knee weakness, and left-arm numbness/weakness, and no clear acute etiology for his reported symptoms. Each time, after the treating clinicians ruled out possible acute complications of a flare-up of Takayasu’s arteritis through a physical examination, laboratory tests, and imaging studies, Mr. W was discharged with recommendations that he follow-up with his primary care physician and specialists. At each discharge, he would leave the hospital with hesitation.

At this present visit, the ED physician recognizes Mr. W as someone who visits the ED often with no profound acute issues, and reviews the substantial medical records available to the hospital. He suspects Mr. W is feigning symptoms, and orders a psychiatric consultation.

EVALUATION Psychiatric interview and mental status exam

On examination, Mr. W is not in acute distress. Despite reporting an 8 out of 10 for chest pain severity, he displays no psychomotor agitation, and his pulse rate and blood pressure are within normal limits. He makes appropriate eye contact and describes his mood as “great.” He reports no problems with sleep, appetite, or disinterest in pleasurable activities, and denies being depressed or having any symptoms consistent with a mood disorder, anxiety disorder, or psychosis. He denies a history of panic attacks or excessive worrying that interferes with his sleep or activities of daily living. Additionally, Mr. W describes a stable, peaceful, and stress-free life within the limitations of his Takayasu’s arteritis, which he has been managing well since his diagnosis 6 years earlier.

Mr. W denies having any psychiatric symptoms, apprehensive feelings, or beliefs/fears that would be considered delusional, and he has no previous legal issues aside from an occasional driving citation. During the assessment, his affect remains broad and he denies having thoughts of suicide or homicide, or auditory or visual hallucinations.

Mr. W’s drug screen results are negative, and he denies using any illicit drugs. He uses only the medications that are prescribed by his clinicians. Overall, he seems to be a well-functioning individual. Mr. W reports that work is generally not stressful.

When the psychiatric team asks him about his frequent hospitalizations and ED visits, Mr. W is insistent that he is “just doing what my doctors said for me to do.” He repeats that he does not have any mental illness and did not see the point of seeing a psychiatrist.

In pursuit of collateral information, the psychiatry team accesses a regional medical record database that allows registered medical institutions and practices to track patients’ medical encounters within the region. According to this database, within approximately 5.5 years, Mr. W had 163 clinical encounters (ED visits and inpatient admissions) and 376 radiological studies in our region (Table 1 and Table 2).

[polldaddy:10394110]

Continue to: The authors' observations

The psychiatry team’s investigation of Mr. W’s medical records revealed the extent of his care-seeking behavior, and provided evidence for a diagnosis of factitious disorder.

Factitious disorder is an elusive psychiatric condition in which an individual chronically stimulates, induces, or aggravates illnesses to gain the status of being a patient. Although its exact cause has not been fully deciphered, it is seen mostly among individuals with knowledge of the workings of the medical field, such as a health care worker.¹ Factitious disorder is taxing on the health care system, with an estimated cost in the thousands of dollars per patient visit.² The condition has an estimated prevalence of 0.8% to 1.0% of patients seen by psychiatric consult services³ and is reported to be more prevalent among women than men.¹ Its cardinal features include health care site hopping and hospital shopping, vagueness about the patient’s history and symptoms, and discrepancy among reported symptoms, the patient’s behaviors, and objective clinical findings.^4,5 Although not all patients with factitious disorder have a legitimate medical reason for seeking care, some individuals with an established medical diagnosis use their condition as a tool to chronically seek care and play the sick role.

Factitious disorder should not be confused with malingering, which is differentiated by the patient’s search for a secondary gain, such as financial reward or avoiding jail; or conversion disorder, which is marked by true physical or neurologic symptoms and clinical findings triggered by psychological stressors. Patients with factitious disorder usually are cooperative during hospital stays and resume their normal daily routine shortly after discharge.⁴ In this case, Mr. W denied any psychiatric symptoms, apprehensive feelings, or beliefs or fears that would be considered delusional. He had no previous or pending legal issues, which ruled out malingering to avoid legal repercussions.

Mr. W’s presentation was complicated by his Takayasu’s arteritis diagnosis. Because Takayasu’s arteritis has a serious list of potential complications, ED physicians have a low threshold for ordering diagnostic studies for a patient with Takayasu’s arteritis who presents with a chief complaint of chest pain. In other words, when a patient with this condition presents to an acute setting (such as the ED) with chest pain, his/her chief complaint is taken with extreme seriousness. Conventional angiography is the standard diagnostic tool for Takayasu’s arteritis; CT angiography and magnetic resonance angiography are used for monitoring the disease’s progression.⁶

[polldaddy:10394113]

The authors’ observations

Currently, there are no FDA-approved treatments for factitious disorder, and patients with this condition generally are resistant to psychiatric and/or psychological care when discovered and offered treatment.⁷ Among those who consent to psychiatric care, psychoeducation, or psychotherapy, which have shown some efficacy for the condition, the dropout rate is high.⁸

Continue to: Although the instinctive approach...

Although the instinctive approach is to confront the patient once the deception has been uncovered, expert recommendations are contradictory. Some recommend confrontation as part of a treatment protocol,⁸ while others advise against such an approach.⁹

Because of how often patients with factitious disorder seek medical care, secondary iatrogenic consequences are possible. For example, for years, Mr. W has been unknowingly exposing himself to the iatrogenic consequences of the cumulative effect of diagnostic imaging for years. In 3 years alone, Mr. W had undergone an average of 125 diagnostic imaging studies per year—with and without contrast—and many unnecessary rounds of treatment with steroids and other interventions known to have secondary iatrogenic consequences.¹⁰ Excessive radiation exposure is known to be carcinogenic over time,¹⁰ and excessive use of steroids is associated with weight gain, physical habitus changes, and increased risk of infections.¹¹ In addition, the renal effects of the contrast materials from repeated imaging studies over so many years on Mr. W’s future kidney function are unknown.

TREATMENT Psychoeducation and referral for psychotherapy

We counsel Mr. W about factitious disorder and the risks of excessive hospitalizations, and refer him for follow-up at our local psychiatric clinic, as well as for individual psychotherapy. Mr. W is discharged because his medical work-up does not reveal any significant acute medical issues.

The authors’ observations

Because of the poor insight associated with factitious disorder and the limited treatment options available, a patient with factitious disorder is unlikely to enter psychiatric treatment on his/her own. The prognosis for a patient with factitious disorder remains poor unless the patient is forced into treatment. More intervention-focused research is needed to help improve outcomes for patients with factitious disorder.

OUTCOME Failure to follow up

Mr. W fails to attend individual psychotherapy as recommended. According to our regional record database, Mr. W continues to present to other EDs regularly.

Continue to: Bottom Line

A patient with factitious disorder stimulates, induces, or aggravates illnesses to gain the status of being a patient. Treatment options include psychiatric care, psychoeducation, or psychotherapy. However, due to poor insight, a patient with factitious disorder is unlikely to enter psychiatric treatment on his/her own.

Related Resources

• Yates GP, Feldman MD. Factitious disorder: a systematic review of 455 cases in the professional literature. Gen Hosp Psychiatry. 2016;41:20-28.
• Galli S, Tatu L, Bogousslavsky J, et al. Conversion, factitious disorder and malingering: a distinct pattern or a continuum? Front Neurol Neurosci. 2018;42:72-80.

CASE Vague symptoms; no clear etiology

Mr. W, age 53, presents to the emergency department (ED) describing acute mid-sternal chest pain (severity: 8 out of 10). His medical history is significant for pulmonary embolism and ascending aortic aneurysm in the context of Takayasu’s arteritis, an inflammatory condition of the large arterial blood vessels characterized by lesions that can lead to vascular stenosis, occlusion, or aneurysm. Takayasu’s arteritis is also known as pulseless disease due to the weak or absent pulses the condition produces.

A review of Mr. W’s medical records reveals that this is his 23rd visit to this hospital within a year; the year before that, he had 22 visits. At each of these previous visits, he had similar vague symptoms, including dizziness, chest pain, lightheadedness, fainting, bilateral knee weakness, and left-arm numbness/weakness, and no clear acute etiology for his reported symptoms. Each time, after the treating clinicians ruled out possible acute complications of a flare-up of Takayasu’s arteritis through a physical examination, laboratory tests, and imaging studies, Mr. W was discharged with recommendations that he follow-up with his primary care physician and specialists. At each discharge, he would leave the hospital with hesitation.

At this present visit, the ED physician recognizes Mr. W as someone who visits the ED often with no profound acute issues, and reviews the substantial medical records available to the hospital. He suspects Mr. W is feigning symptoms, and orders a psychiatric consultation.

EVALUATION Psychiatric interview and mental status exam

On examination, Mr. W is not in acute distress. Despite reporting an 8 out of 10 for chest pain severity, he displays no psychomotor agitation, and his pulse rate and blood pressure are within normal limits. He makes appropriate eye contact and describes his mood as “great.” He reports no problems with sleep, appetite, or disinterest in pleasurable activities, and denies being depressed or having any symptoms consistent with a mood disorder, anxiety disorder, or psychosis. He denies a history of panic attacks or excessive worrying that interferes with his sleep or activities of daily living. Additionally, Mr. W describes a stable, peaceful, and stress-free life within the limitations of his Takayasu’s arteritis, which he has been managing well since his diagnosis 6 years earlier.

Mr. W denies having any psychiatric symptoms, apprehensive feelings, or beliefs/fears that would be considered delusional, and he has no previous legal issues aside from an occasional driving citation. During the assessment, his affect remains broad and he denies having thoughts of suicide or homicide, or auditory or visual hallucinations.

Mr. W’s drug screen results are negative, and he denies using any illicit drugs. He uses only the medications that are prescribed by his clinicians. Overall, he seems to be a well-functioning individual. Mr. W reports that work is generally not stressful.

When the psychiatric team asks him about his frequent hospitalizations and ED visits, Mr. W is insistent that he is “just doing what my doctors said for me to do.” He repeats that he does not have any mental illness and did not see the point of seeing a psychiatrist.

In pursuit of collateral information, the psychiatry team accesses a regional medical record database that allows registered medical institutions and practices to track patients’ medical encounters within the region. According to this database, within approximately 5.5 years, Mr. W had 163 clinical encounters (ED visits and inpatient admissions) and 376 radiological studies in our region (Table 1 and Table 2).

[polldaddy:10394110]

Continue to: The authors' observations

The psychiatry team’s investigation of Mr. W’s medical records revealed the extent of his care-seeking behavior, and provided evidence for a diagnosis of factitious disorder.

Factitious disorder is an elusive psychiatric condition in which an individual chronically stimulates, induces, or aggravates illnesses to gain the status of being a patient. Although its exact cause has not been fully deciphered, it is seen mostly among individuals with knowledge of the workings of the medical field, such as a health care worker.¹ Factitious disorder is taxing on the health care system, with an estimated cost in the thousands of dollars per patient visit.² The condition has an estimated prevalence of 0.8% to 1.0% of patients seen by psychiatric consult services³ and is reported to be more prevalent among women than men.¹ Its cardinal features include health care site hopping and hospital shopping, vagueness about the patient’s history and symptoms, and discrepancy among reported symptoms, the patient’s behaviors, and objective clinical findings.^4,5 Although not all patients with factitious disorder have a legitimate medical reason for seeking care, some individuals with an established medical diagnosis use their condition as a tool to chronically seek care and play the sick role.

Factitious disorder should not be confused with malingering, which is differentiated by the patient’s search for a secondary gain, such as financial reward or avoiding jail; or conversion disorder, which is marked by true physical or neurologic symptoms and clinical findings triggered by psychological stressors. Patients with factitious disorder usually are cooperative during hospital stays and resume their normal daily routine shortly after discharge.⁴ In this case, Mr. W denied any psychiatric symptoms, apprehensive feelings, or beliefs or fears that would be considered delusional. He had no previous or pending legal issues, which ruled out malingering to avoid legal repercussions.

Mr. W’s presentation was complicated by his Takayasu’s arteritis diagnosis. Because Takayasu’s arteritis has a serious list of potential complications, ED physicians have a low threshold for ordering diagnostic studies for a patient with Takayasu’s arteritis who presents with a chief complaint of chest pain. In other words, when a patient with this condition presents to an acute setting (such as the ED) with chest pain, his/her chief complaint is taken with extreme seriousness. Conventional angiography is the standard diagnostic tool for Takayasu’s arteritis; CT angiography and magnetic resonance angiography are used for monitoring the disease’s progression.⁶

[polldaddy:10394113]

The authors’ observations

Currently, there are no FDA-approved treatments for factitious disorder, and patients with this condition generally are resistant to psychiatric and/or psychological care when discovered and offered treatment.⁷ Among those who consent to psychiatric care, psychoeducation, or psychotherapy, which have shown some efficacy for the condition, the dropout rate is high.⁸

Continue to: Although the instinctive approach...

Although the instinctive approach is to confront the patient once the deception has been uncovered, expert recommendations are contradictory. Some recommend confrontation as part of a treatment protocol,⁸ while others advise against such an approach.⁹

Because of how often patients with factitious disorder seek medical care, secondary iatrogenic consequences are possible. For example, for years, Mr. W has been unknowingly exposing himself to the iatrogenic consequences of the cumulative effect of diagnostic imaging for years. In 3 years alone, Mr. W had undergone an average of 125 diagnostic imaging studies per year—with and without contrast—and many unnecessary rounds of treatment with steroids and other interventions known to have secondary iatrogenic consequences.¹⁰ Excessive radiation exposure is known to be carcinogenic over time,¹⁰ and excessive use of steroids is associated with weight gain, physical habitus changes, and increased risk of infections.¹¹ In addition, the renal effects of the contrast materials from repeated imaging studies over so many years on Mr. W’s future kidney function are unknown.

TREATMENT Psychoeducation and referral for psychotherapy

We counsel Mr. W about factitious disorder and the risks of excessive hospitalizations, and refer him for follow-up at our local psychiatric clinic, as well as for individual psychotherapy. Mr. W is discharged because his medical work-up does not reveal any significant acute medical issues.

The authors’ observations

Because of the poor insight associated with factitious disorder and the limited treatment options available, a patient with factitious disorder is unlikely to enter psychiatric treatment on his/her own. The prognosis for a patient with factitious disorder remains poor unless the patient is forced into treatment. More intervention-focused research is needed to help improve outcomes for patients with factitious disorder.

OUTCOME Failure to follow up

Mr. W fails to attend individual psychotherapy as recommended. According to our regional record database, Mr. W continues to present to other EDs regularly.

Continue to: Bottom Line

A patient with factitious disorder stimulates, induces, or aggravates illnesses to gain the status of being a patient. Treatment options include psychiatric care, psychoeducation, or psychotherapy. However, due to poor insight, a patient with factitious disorder is unlikely to enter psychiatric treatment on his/her own.

Related Resources

• Yates GP, Feldman MD. Factitious disorder: a systematic review of 455 cases in the professional literature. Gen Hosp Psychiatry. 2016;41:20-28.
• Galli S, Tatu L, Bogousslavsky J, et al. Conversion, factitious disorder and malingering: a distinct pattern or a continuum? Front Neurol Neurosci. 2018;42:72-80.