Depression

Mrs. W, age 36, who is married, has a history of military service, and is currently employed as a paralegal, is referred to our practice by her family physician. She complains of severe depression that impairs her ability to function at work. She had seen several other psychiatrists in both military and civilian settings, and had been treated with multiple antidepressants, including fluoxetine, sertraline, bupropion, and paroxetine.

At the time of her initial psychiatric evaluation, she is taking duloxetine, 90 mg/d, but still is experiencing depressive symptoms. She is tearful, sad, lacks energy, spends too much time in bed, and is experiencing thoughts of hopelessness, despair, and escape, verging on thoughts of suicide. As a result, she needs to scale back her work schedule to part-time. When asked about how long she had been suffering from depression, she responds “I’ve been depressed all my life.” She had been briefly hospitalized at age 16, when she made a suicide attempt by overdose. There had been no subsequent suicide attempts or psychiatric hospitalizations, although she acknowledges having intermittent suicidal thoughts.

Mrs. W’s clinical presentation is similar to that of many patients entering our practice—patients who have recurrent depression that began in early life and a history of failure to respond to multiple antidepressants. She and other patients with similar presentations are not suffering from treatment-resistant depression and in need of a trial of electroconvulsive therapy, transcranial magnetic stimulation, direct current stimulation, vagus nerve stimulation, or intranasal esketamine. She has bipolar disorder, and had been repeatedly misdiagnosed and treated inappropriately with antidepressant monotherapy.

In a previous article¹ (“Controversies in bipolar disorder: Trust evidence or experience?,” Current Psychiatry, February 2009, p. 27-28,31-33,39), we endorsed the concept of a bipolar spectrum. We also argued that subthreshold hypomania is the rule and not the exception in bipolar II disorder, that antidepressant monotherapy rarely causes manic switches but is more likely to worsen depression, and that although antidepressant monotherapy usually destabilizes bipolar illness, antidepressants can be helpful when combined with mood stabilizers. We observed that bipolar disorder occurs frequently in children and adolescents and that psychosis is a common occurrence in patients with bipolar disorder. We also outlined what we consider to be the major clinical features of bipolar depression and noted the role of thyroid hormones in managing mood disorders.

In this article, based on our more than 25 years of experience in diagnosing and treating psychiatric disorders in patients of all ages, we expand on those observations.

Misdiagnosis is common

Bipolar depression is frequently misdiagnosed as unipolar depression in outpatient^2-8 and inpatient⁹ settings, and in children and adolescents.¹⁰ Mrs. W is typical of patients who have what we consider a bipolar spectrum disorder and receive an inaccurate diagnosis and treatment that is ineffective or may worsen the course of their illness.

Reliance on DSM-5¹¹ and its predecessor, DSM-IV, is a part of the problem of misdiagnosis because the diagnostic criteria for bipolar disorder fail to capture the clinical features of many patients with “softer” (less obvious manic and hypomanic) variants of the disorder.^12,13 For example, DSM-5 criteria for a hypomanic episode (the mild high experienced by patients with a soft bipolar disorder) require that the episode lasts “at least 4 consecutive days” and is “present most of the day, nearly every day.” In our experience, the majority of hypomanic episodes are shorter—ranging from a half-day to 2 days, averaging perhaps 1.5 days.

Continue to: DSM-5 also requires...

DSM-5 also requires severity criteria for hypomania that patients with unequivocal hypomanic episodes often do not meet. For example, they may fail to experience flight of ideas or racing thoughts, or engage in activities such as “unrestrained buying sprees, sexual indiscretions, or foolish business investments.” These patients usually describe these mild highs as feeling normal and report a happier mood, more smiles and laughter, increased energy, less sleepiness, increased talkativeness, increased socialization, and improved motivation to complete tasks left undone and projects left unfinished because of the previous depressive episode. These softer (subthreshold) hypomanic episodes are authentic and, if clinicians do not identify them, may lead to misdiagnosis and inappropriate treatment.

Patients who present with depression often fail to report these brief, subthreshold hypomanic episodes or consider them to be irrelevant to their diagnosis and treatment.^12,13 Probing questions can often elicit these unreported highs. For example, a patient with depression should be asked, “Have you had a single good day during the last month?” and “Where were you and what did you do during that day?” Eliciting a history of brief periods of improved mood is the key to differentiating between unipolar and bipolar depression. Screening instruments such as the Mood Disorders Questionnaire¹⁴ and the Bipolar Spectrum Diagnostic Scale¹⁵ may be helpful in distinguishing between unipolar and bipolar depression. However, we offer our thoughts on making that crucial distinction.

Distinguishing between these 2 types of depression

Although it may be difficult to distinguish between unipolar and bipolar depression, especially in the absence of a history of distinct manic or hypomanic episodes, we find the following criteria to be useful in making that determination.

Age of onset. Bipolar spectrum disorders typically begin earlier in life than unipolar depression.^10,16-19 A typical presentation of bipolar disorder in children and adolescents is depression or agitated mixed states with features of both mania and depression, often accompanied by rapid mood cycling.^20,21 Unipolar depression usually begins later in life, and patients do not have a history of significant depressive episodes or mood swings in childhood or adolescence. An important question to ask a patient with a chief complaint of depression is, “How old were you when you first experienced an episode of depression?”

Gender differences. Bipolar spectrum disorders with more subtle (softer) presentations, such as subthreshold highs, occur more often in women than men.²² However, overall rates of bipolar disorder may be slightly higher in men than in women.²³ Unipolar melancholic depression occurs at approximately the same frequency in men and women.²⁴

Continue to: Rapidity of onset

Rapidity of onset. Bipolar depressive episodes develop more rapidly than unipolar episodes. It is common for a patient with a bipolar spectrum disorder to transition from normal to very depressed virtually overnight, whereas in our clinical experience, unipolar episodes progress more slowly, often over several months.

Deliberate self-harm. Adolescents and young adults with a bipolar spectrum disorder frequently engage in self-injurious behavior, usually cutting with a knife, razor, or even sharp fingernails.²⁵ Although these patients may also have thoughts of suicide and make suicide attempts, the individual usually perceives cutting as a means of gaining relief from tension and distress. These behaviors are often associated with a diagnosis of a personality disorder; in our opinion, however, they are hallmarks of a bipolar spectrum disorder.

ADHD. Bipolar disorder frequently co-occurs with attention-deficit/hyperactivity disorder (ADHD).^26,27 Adults with bipolar disorder often have ADHD symptoms, which can complicate their treatment and cause functional impairment even after their mood disorder has been stabilized.²⁸

Substance use disorders. Excessive use of alcohol and drugs is common among people with a wide range of psychiatric disorders, but patients with bipolar disorder have an unusually high rate of co-occurring substance use disorders—40% to 50%.^29,30

Appetite and weight differences. Patients with unipolar depression usually experience loss of appetite and weight loss, whereas in our clinical experience, patients with bipolar depression often overeat, crave carbohydrates, and gain weight.

Continue to: Sleep problems

Sleep problems. Patients with bipolar depression have an increased need for sleep (the opposite of what they experience during highs), are sleepy during the day regardless of how many hours they sleep, and have difficulty getting up in the morning. Patients with unipolar depression also have a sleep disturbance: they may fall asleep easily, sleep for a few hours, and then awaken but are unable to fall back to sleep.³¹ Yet these patients usually do not complain of sleepiness during the day.

Diurnal variation of mood. Patients with unipolar depression often report that their depressive symptoms fluctuate in a circadian manner. For example, they may report that their depression is worse in the morning but improves toward evening.³¹ This regular alteration of circadian rhythm usually is not evident in patients with bipolar depression, whose mood may vary unpredictably or in response to stressors. Some patients with bipolar disorder, however, exhibit ultradian (ultra-rapid) mood cycling, which may be confused with the diurnal mood variation seen in patients with unipolar depression.

Tendency to recur. Although both unipolar and bipolar depressive episodes recur, a pattern of multiple recurring episodes beginning in early life is characteristic of bipolar spectrum disorders.

Behavioral history. Patients with bipolar depression are more likely than patients with unipolar depression to have a history of multiple marriages, multiple romantic relationships, episodes of promiscuity, legal problems, or financial extravagance.

Response to antidepressants. Patients with bipolar depression exhibit atypical responses to antidepressant monotherapy, such as worsening of depressive symptoms, initial improvement of mood with subsequent loss of effectiveness, premature response to an antidepressant (eg, improvement of mood within 1 to 2 days of beginning the antidepressant), fluctuation of depressive symptoms (mood cycling), or precipitation of a hypomanic or manic episode. We believe that a history of multiple failed antidepressant trials is compelling evidence of misdiagnosis of a bipolar spectrum disorder as unipolar depression.

Continue to: Genetics

Genetics. Bipolar disorder is one of the most heritable of illnesses.³² Family history is important, but affected relatives may have been misdiagnosed with unipolar depression or schizophrenia, or said to have experienced “nervous breakdowns.”

Consequences of misdiagnosis

Misdiagnosis of patients with bipolar disorder is not benign. We see patients who have suffered needlessly for years with severe depression and mood instability. After trying antidepressant after antidepressant without benefit, they begin to feel hopeless, believing they have tried everything and that nothing works for them. Often, these patients have dropped out of high school or college, or lost jobs, friends, and spouses due to their disabling but misdiagnosed psychiatric disorder. Patients with misdiagnosed bipolar disorder have an increased risk of suicide attempts and psychiatric hospitalization.^5,8

Misdiagnosis of patients with bipolar disorder is not limited to nonpsychiatric physicians. The majority of patients with bipolar spectrum disorders are misdiagnosed by outpatient psychiatrists as having unipolar depression.^2-7 At least 45% of patients hospitalized for depression have bipolar disorder—and most of these patients are treated inappropriately with antidepressants.⁹ The STAR*D study,^33,34 a large randomized clinical trial of antidepressants, concluded that more than one-third of patients had not remitted from their depression after treatment with 3 different antidepressants. In our opinion, many of the nonresponding patients may have undiagnosed bipolar depression, which predictably leads to a failure to respond adequately to antidepressants. We believe that the customary inclusion and exclusion criteria used to select participants for these research studies miss subtle (subthreshold) hypomanic episodes that fall short of meeting DSM criteria for duration and severity. This phenomenon may account for the results of studies that conclude that antidepressants are, at best, minimally more effective than placebo.³⁵

When a patient with a bipolar spectrum disorder is misdiagnosed and treated with an antidepressant, the usual result is mood destabilization. Reports of mood swings, increased crying, and suicidal thoughts and suicidal gestures in children, adolescents, and young adults treated with antidepressants led the FDA to issue a “black-box” warning.³⁶ Because bipolar depression typically begins in youth,^10,18,19 the behaviors cited in the warning may reflect misdiagnosis of bipolar depression as unipolar depression, and consequent mood destabilization as a result of treatment with an antidepressant in the absence of a mood stabilizer.

Depression and life stressors

Since many patients who are depressed present with a history of significant stressors, clinicians often face the problem of distinguishing between clinical depression and stress-induced depression. We believe that one typical symptom of depression—increased sensitivity to stressors—may help in making that distinction. A patient who is depressed will often attribute depression to stressors such as marital conflict, divorce, problems with a teenage child, work pressures, financial pressures, or the illness or death of a family member or pet. If clinical depression (unipolar or bipolar) is present, the symptoms are persistent, sometimes antedate the stressor by days or weeks, often outlast the stressor, increase in severity over time, and are disproportional to the stressor. Clinical depression can also cause the patient to become obsessed with traumatic events or losses that occurred many years earlier.

Continue to: Our approach to treatment

Patients with mood disorders often benefit from a combination of pharmacologic management and psychotherapy. Psychotherapy is particularly important in addressing the functional impairment, diminished self-worth, and interpersonal conflicts that often accompany clinical depression. Several styles or systems of psycho­therapy have been developed to benefit patients with mood disorders. Their effectiveness may depend on the patient’s ability to gain insight,³⁷ but in our opinion, the most important attribute of helpful psychotherapy is the rapport established between the patient and the therapist, and the therapist’s ability to empathize with the patient and instill in the patient a sense of optimism and hope. We often recommend that patients attend meetings of the Depression and Bipolar Support Alliance (DBSA), a national support group with chapters throughout the country. Patients often find that attending these meetings is both educational and emotionally rewarding.

The foundational pharmacologic treatment for bipolar disorder is a mood stabilizer. The medications we consider to be effective mood stabilizers (some with an FDA indication for bipolar maintenance, some without) are lithium carbonate, divalproex sodium, carbamazepine, oxcarbazepine, and lamotrigine.

Each of these mood stabilizers has its advantages, disadvantages, risks, and adverse effects. For example, although divalproex is a reliable mood stabilizer, it has a significant risk of causing birth defects if taken during pregnancy and can cause increased appetite and weight gain. Carbamazepine has significant drug interactions and the potential to cause neurologic adverse effects, while oxcarbazepine, a derivative of carbamazepine, has fewer drug interactions but is more likely to cause hyponatremia. Lamotrigine must be titrated very slowly to reduce the risk of a potentially fatal skin rash (ie, Stevens-Johnson syndrome or toxic epidermal necrolysis). Lithium is effective but has a significant adverse-effect burden: impairment of renal function with long-term use, nephrogenic diabetes insipidus, hypothyroidism, hyperparathyroidism, acne, and weight gain. Lithium also has potential interactions with multiple commonly prescribed medications, including antihypertensives and diuretics, as well as over-the-counter pain relievers such as ibuprofen and naproxen.

Second-generation antipsychotics (SGAs) have mood stabilizing, antidepressant, and anti-manic properties and are often useful in managing bipolar disorder. In our experience, for patients with bipolar disorder, SGAs are best used in combination with a mood stabilizer. Although virtually all SGAs have demonstrated effectiveness in the treatment of psychosis and some phases of bipolar disorder, the newer agents (aripiprazole, brexpiprazole, lurasidone, and cariprazine) are relatively free of metabolic adverse effects such as weight gain, abnormal cholesterol levels, increased prolactin levels, insulin resistance, and increased risk of diabetes.

Antidepressants may be effective in treating unipolar depression, but when treating bipolar depression, they should be used cautiously and only in combination with a mood stabilizer.

Continue to: As we observed...

As we observed in our previous article,¹ thyroid laboratory monitoring and supplementation are critical components of managing mood disorders (Box 1^38-41).

Box 1

Moving towards better diagnoses

The emergence of a criteria-based psychiatric system in 1980 with the publication of DSM-III, and its subsequent revisions and updates, constituted a major advance in psychiatric diagnosis. As we learn more about the pathophysiology, genetics, and epigenetics of psychiatric symptoms and syndromes, future diagnostic systems will improve problems of validity that have yet to be resolved. While we believe that, for the most part, DSM-5 was an advance over the previous diagnostic iteration, we have 2 issues with DSM-5 in terms of the diagnosis of bipolar disorder (Box 2^{10,12,13,18,19,42}).

Box 2

Patients with a chief complaint of depression are often given a diagnosis of “major depression, rule out bipolar disorder.” We believe that this formula should be turned on its head. In our opinion, based on our clinical experience, we think that most patients who present to a clinician’s office or psychiatric hospital with depression have bipolar depression, not unipolar depression. We hope that our experience and observations derived from treating thousands of patients over more than 25 years may be helpful to clinicians who sometimes struggle to bring relief to their patients with mood disorders.

CASE CONTINUED

Return to work

Mrs. W is now doing well. She is taking a lower dosage of duloxetine, 60 mg/d, in combination with the mood stabilizer lamotrigine, 200 mg/d. She returns to work full-time as a paralegal and no longer is experiencing depressive episodes.

Bottom Line

Patients with bipolar depression are often misdiagnosed with unipolar depression and treated inappropriately with antidepressant monotherapy, which often results in mood destabilization. Based on our clinical experience, a careful assessment of select criteria, including age of onset, rapidity of onset, comorbidities, diurnal mood variations, and more, can be useful for distinguishing between unipolar and bipolar depression.

Related Resources

• Nasrallah HA. Misdiagnosing bipolar depression as major depressive disorder. Current Psychiatry. 2013;12(10):20-21,A.
• Ghaemi SN. Bipolar spectrum: a review of the concept and a vision for the future. Psychiatry Investig. 2013;10(3):218-224.

Drug Brand Names

Aripiprazole • Abilify
Brexpiprazole • Rexulti
Bupropion • Wellbutrin
Carbamazepine • Tegretol, Equetro
Cariprazine • Vraylar
Divalproex • Depakote
Duloxetine • Cymbalta
Esketamine • Spravato
Fluoxetine • Prozac
Lamotrigine • Lamictal
Levothyroxine • Synthroid, Levoxyl
Liothyronine • Cytomel
Lithium • Eskalith, Lithobid
Lurasidone • Latuda
Oxcarbazepine • Oxtellar XR, Trileptal
Paroxetine • Paxil
Sertraline • Zoloft

Mrs. W, age 36, who is married, has a history of military service, and is currently employed as a paralegal, is referred to our practice by her family physician. She complains of severe depression that impairs her ability to function at work. She had seen several other psychiatrists in both military and civilian settings, and had been treated with multiple antidepressants, including fluoxetine, sertraline, bupropion, and paroxetine.

At the time of her initial psychiatric evaluation, she is taking duloxetine, 90 mg/d, but still is experiencing depressive symptoms. She is tearful, sad, lacks energy, spends too much time in bed, and is experiencing thoughts of hopelessness, despair, and escape, verging on thoughts of suicide. As a result, she needs to scale back her work schedule to part-time. When asked about how long she had been suffering from depression, she responds “I’ve been depressed all my life.” She had been briefly hospitalized at age 16, when she made a suicide attempt by overdose. There had been no subsequent suicide attempts or psychiatric hospitalizations, although she acknowledges having intermittent suicidal thoughts.

Mrs. W’s clinical presentation is similar to that of many patients entering our practice—patients who have recurrent depression that began in early life and a history of failure to respond to multiple antidepressants. She and other patients with similar presentations are not suffering from treatment-resistant depression and in need of a trial of electroconvulsive therapy, transcranial magnetic stimulation, direct current stimulation, vagus nerve stimulation, or intranasal esketamine. She has bipolar disorder, and had been repeatedly misdiagnosed and treated inappropriately with antidepressant monotherapy.

In a previous article¹ (“Controversies in bipolar disorder: Trust evidence or experience?,” Current Psychiatry, February 2009, p. 27-28,31-33,39), we endorsed the concept of a bipolar spectrum. We also argued that subthreshold hypomania is the rule and not the exception in bipolar II disorder, that antidepressant monotherapy rarely causes manic switches but is more likely to worsen depression, and that although antidepressant monotherapy usually destabilizes bipolar illness, antidepressants can be helpful when combined with mood stabilizers. We observed that bipolar disorder occurs frequently in children and adolescents and that psychosis is a common occurrence in patients with bipolar disorder. We also outlined what we consider to be the major clinical features of bipolar depression and noted the role of thyroid hormones in managing mood disorders.

In this article, based on our more than 25 years of experience in diagnosing and treating psychiatric disorders in patients of all ages, we expand on those observations.

Misdiagnosis is common

Bipolar depression is frequently misdiagnosed as unipolar depression in outpatient^2-8 and inpatient⁹ settings, and in children and adolescents.¹⁰ Mrs. W is typical of patients who have what we consider a bipolar spectrum disorder and receive an inaccurate diagnosis and treatment that is ineffective or may worsen the course of their illness.

Reliance on DSM-5¹¹ and its predecessor, DSM-IV, is a part of the problem of misdiagnosis because the diagnostic criteria for bipolar disorder fail to capture the clinical features of many patients with “softer” (less obvious manic and hypomanic) variants of the disorder.^12,13 For example, DSM-5 criteria for a hypomanic episode (the mild high experienced by patients with a soft bipolar disorder) require that the episode lasts “at least 4 consecutive days” and is “present most of the day, nearly every day.” In our experience, the majority of hypomanic episodes are shorter—ranging from a half-day to 2 days, averaging perhaps 1.5 days.

Continue to: DSM-5 also requires...

DSM-5 also requires severity criteria for hypomania that patients with unequivocal hypomanic episodes often do not meet. For example, they may fail to experience flight of ideas or racing thoughts, or engage in activities such as “unrestrained buying sprees, sexual indiscretions, or foolish business investments.” These patients usually describe these mild highs as feeling normal and report a happier mood, more smiles and laughter, increased energy, less sleepiness, increased talkativeness, increased socialization, and improved motivation to complete tasks left undone and projects left unfinished because of the previous depressive episode. These softer (subthreshold) hypomanic episodes are authentic and, if clinicians do not identify them, may lead to misdiagnosis and inappropriate treatment.

Patients who present with depression often fail to report these brief, subthreshold hypomanic episodes or consider them to be irrelevant to their diagnosis and treatment.^12,13 Probing questions can often elicit these unreported highs. For example, a patient with depression should be asked, “Have you had a single good day during the last month?” and “Where were you and what did you do during that day?” Eliciting a history of brief periods of improved mood is the key to differentiating between unipolar and bipolar depression. Screening instruments such as the Mood Disorders Questionnaire¹⁴ and the Bipolar Spectrum Diagnostic Scale¹⁵ may be helpful in distinguishing between unipolar and bipolar depression. However, we offer our thoughts on making that crucial distinction.

Distinguishing between these 2 types of depression

Although it may be difficult to distinguish between unipolar and bipolar depression, especially in the absence of a history of distinct manic or hypomanic episodes, we find the following criteria to be useful in making that determination.

Age of onset. Bipolar spectrum disorders typically begin earlier in life than unipolar depression.^10,16-19 A typical presentation of bipolar disorder in children and adolescents is depression or agitated mixed states with features of both mania and depression, often accompanied by rapid mood cycling.^20,21 Unipolar depression usually begins later in life, and patients do not have a history of significant depressive episodes or mood swings in childhood or adolescence. An important question to ask a patient with a chief complaint of depression is, “How old were you when you first experienced an episode of depression?”

Gender differences. Bipolar spectrum disorders with more subtle (softer) presentations, such as subthreshold highs, occur more often in women than men.²² However, overall rates of bipolar disorder may be slightly higher in men than in women.²³ Unipolar melancholic depression occurs at approximately the same frequency in men and women.²⁴

Continue to: Rapidity of onset

Rapidity of onset. Bipolar depressive episodes develop more rapidly than unipolar episodes. It is common for a patient with a bipolar spectrum disorder to transition from normal to very depressed virtually overnight, whereas in our clinical experience, unipolar episodes progress more slowly, often over several months.

Deliberate self-harm. Adolescents and young adults with a bipolar spectrum disorder frequently engage in self-injurious behavior, usually cutting with a knife, razor, or even sharp fingernails.²⁵ Although these patients may also have thoughts of suicide and make suicide attempts, the individual usually perceives cutting as a means of gaining relief from tension and distress. These behaviors are often associated with a diagnosis of a personality disorder; in our opinion, however, they are hallmarks of a bipolar spectrum disorder.

ADHD. Bipolar disorder frequently co-occurs with attention-deficit/hyperactivity disorder (ADHD).^26,27 Adults with bipolar disorder often have ADHD symptoms, which can complicate their treatment and cause functional impairment even after their mood disorder has been stabilized.²⁸

Substance use disorders. Excessive use of alcohol and drugs is common among people with a wide range of psychiatric disorders, but patients with bipolar disorder have an unusually high rate of co-occurring substance use disorders—40% to 50%.^29,30

Appetite and weight differences. Patients with unipolar depression usually experience loss of appetite and weight loss, whereas in our clinical experience, patients with bipolar depression often overeat, crave carbohydrates, and gain weight.

Continue to: Sleep problems

Sleep problems. Patients with bipolar depression have an increased need for sleep (the opposite of what they experience during highs), are sleepy during the day regardless of how many hours they sleep, and have difficulty getting up in the morning. Patients with unipolar depression also have a sleep disturbance: they may fall asleep easily, sleep for a few hours, and then awaken but are unable to fall back to sleep.³¹ Yet these patients usually do not complain of sleepiness during the day.

Diurnal variation of mood. Patients with unipolar depression often report that their depressive symptoms fluctuate in a circadian manner. For example, they may report that their depression is worse in the morning but improves toward evening.³¹ This regular alteration of circadian rhythm usually is not evident in patients with bipolar depression, whose mood may vary unpredictably or in response to stressors. Some patients with bipolar disorder, however, exhibit ultradian (ultra-rapid) mood cycling, which may be confused with the diurnal mood variation seen in patients with unipolar depression.

Tendency to recur. Although both unipolar and bipolar depressive episodes recur, a pattern of multiple recurring episodes beginning in early life is characteristic of bipolar spectrum disorders.

Behavioral history. Patients with bipolar depression are more likely than patients with unipolar depression to have a history of multiple marriages, multiple romantic relationships, episodes of promiscuity, legal problems, or financial extravagance.

Response to antidepressants. Patients with bipolar depression exhibit atypical responses to antidepressant monotherapy, such as worsening of depressive symptoms, initial improvement of mood with subsequent loss of effectiveness, premature response to an antidepressant (eg, improvement of mood within 1 to 2 days of beginning the antidepressant), fluctuation of depressive symptoms (mood cycling), or precipitation of a hypomanic or manic episode. We believe that a history of multiple failed antidepressant trials is compelling evidence of misdiagnosis of a bipolar spectrum disorder as unipolar depression.

Continue to: Genetics

Genetics. Bipolar disorder is one of the most heritable of illnesses.³² Family history is important, but affected relatives may have been misdiagnosed with unipolar depression or schizophrenia, or said to have experienced “nervous breakdowns.”

Consequences of misdiagnosis

Misdiagnosis of patients with bipolar disorder is not benign. We see patients who have suffered needlessly for years with severe depression and mood instability. After trying antidepressant after antidepressant without benefit, they begin to feel hopeless, believing they have tried everything and that nothing works for them. Often, these patients have dropped out of high school or college, or lost jobs, friends, and spouses due to their disabling but misdiagnosed psychiatric disorder. Patients with misdiagnosed bipolar disorder have an increased risk of suicide attempts and psychiatric hospitalization.^5,8

Misdiagnosis of patients with bipolar disorder is not limited to nonpsychiatric physicians. The majority of patients with bipolar spectrum disorders are misdiagnosed by outpatient psychiatrists as having unipolar depression.^2-7 At least 45% of patients hospitalized for depression have bipolar disorder—and most of these patients are treated inappropriately with antidepressants.⁹ The STAR*D study,^33,34 a large randomized clinical trial of antidepressants, concluded that more than one-third of patients had not remitted from their depression after treatment with 3 different antidepressants. In our opinion, many of the nonresponding patients may have undiagnosed bipolar depression, which predictably leads to a failure to respond adequately to antidepressants. We believe that the customary inclusion and exclusion criteria used to select participants for these research studies miss subtle (subthreshold) hypomanic episodes that fall short of meeting DSM criteria for duration and severity. This phenomenon may account for the results of studies that conclude that antidepressants are, at best, minimally more effective than placebo.³⁵

When a patient with a bipolar spectrum disorder is misdiagnosed and treated with an antidepressant, the usual result is mood destabilization. Reports of mood swings, increased crying, and suicidal thoughts and suicidal gestures in children, adolescents, and young adults treated with antidepressants led the FDA to issue a “black-box” warning.³⁶ Because bipolar depression typically begins in youth,^10,18,19 the behaviors cited in the warning may reflect misdiagnosis of bipolar depression as unipolar depression, and consequent mood destabilization as a result of treatment with an antidepressant in the absence of a mood stabilizer.

Depression and life stressors

Since many patients who are depressed present with a history of significant stressors, clinicians often face the problem of distinguishing between clinical depression and stress-induced depression. We believe that one typical symptom of depression—increased sensitivity to stressors—may help in making that distinction. A patient who is depressed will often attribute depression to stressors such as marital conflict, divorce, problems with a teenage child, work pressures, financial pressures, or the illness or death of a family member or pet. If clinical depression (unipolar or bipolar) is present, the symptoms are persistent, sometimes antedate the stressor by days or weeks, often outlast the stressor, increase in severity over time, and are disproportional to the stressor. Clinical depression can also cause the patient to become obsessed with traumatic events or losses that occurred many years earlier.

Continue to: Our approach to treatment

Patients with mood disorders often benefit from a combination of pharmacologic management and psychotherapy. Psychotherapy is particularly important in addressing the functional impairment, diminished self-worth, and interpersonal conflicts that often accompany clinical depression. Several styles or systems of psycho­therapy have been developed to benefit patients with mood disorders. Their effectiveness may depend on the patient’s ability to gain insight,³⁷ but in our opinion, the most important attribute of helpful psychotherapy is the rapport established between the patient and the therapist, and the therapist’s ability to empathize with the patient and instill in the patient a sense of optimism and hope. We often recommend that patients attend meetings of the Depression and Bipolar Support Alliance (DBSA), a national support group with chapters throughout the country. Patients often find that attending these meetings is both educational and emotionally rewarding.

The foundational pharmacologic treatment for bipolar disorder is a mood stabilizer. The medications we consider to be effective mood stabilizers (some with an FDA indication for bipolar maintenance, some without) are lithium carbonate, divalproex sodium, carbamazepine, oxcarbazepine, and lamotrigine.

Each of these mood stabilizers has its advantages, disadvantages, risks, and adverse effects. For example, although divalproex is a reliable mood stabilizer, it has a significant risk of causing birth defects if taken during pregnancy and can cause increased appetite and weight gain. Carbamazepine has significant drug interactions and the potential to cause neurologic adverse effects, while oxcarbazepine, a derivative of carbamazepine, has fewer drug interactions but is more likely to cause hyponatremia. Lamotrigine must be titrated very slowly to reduce the risk of a potentially fatal skin rash (ie, Stevens-Johnson syndrome or toxic epidermal necrolysis). Lithium is effective but has a significant adverse-effect burden: impairment of renal function with long-term use, nephrogenic diabetes insipidus, hypothyroidism, hyperparathyroidism, acne, and weight gain. Lithium also has potential interactions with multiple commonly prescribed medications, including antihypertensives and diuretics, as well as over-the-counter pain relievers such as ibuprofen and naproxen.

Second-generation antipsychotics (SGAs) have mood stabilizing, antidepressant, and anti-manic properties and are often useful in managing bipolar disorder. In our experience, for patients with bipolar disorder, SGAs are best used in combination with a mood stabilizer. Although virtually all SGAs have demonstrated effectiveness in the treatment of psychosis and some phases of bipolar disorder, the newer agents (aripiprazole, brexpiprazole, lurasidone, and cariprazine) are relatively free of metabolic adverse effects such as weight gain, abnormal cholesterol levels, increased prolactin levels, insulin resistance, and increased risk of diabetes.

Antidepressants may be effective in treating unipolar depression, but when treating bipolar depression, they should be used cautiously and only in combination with a mood stabilizer.

Continue to: As we observed...

As we observed in our previous article,¹ thyroid laboratory monitoring and supplementation are critical components of managing mood disorders (Box 1^38-41).

Box 1

Moving towards better diagnoses

The emergence of a criteria-based psychiatric system in 1980 with the publication of DSM-III, and its subsequent revisions and updates, constituted a major advance in psychiatric diagnosis. As we learn more about the pathophysiology, genetics, and epigenetics of psychiatric symptoms and syndromes, future diagnostic systems will improve problems of validity that have yet to be resolved. While we believe that, for the most part, DSM-5 was an advance over the previous diagnostic iteration, we have 2 issues with DSM-5 in terms of the diagnosis of bipolar disorder (Box 2^{10,12,13,18,19,42}).

Box 2

Patients with a chief complaint of depression are often given a diagnosis of “major depression, rule out bipolar disorder.” We believe that this formula should be turned on its head. In our opinion, based on our clinical experience, we think that most patients who present to a clinician’s office or psychiatric hospital with depression have bipolar depression, not unipolar depression. We hope that our experience and observations derived from treating thousands of patients over more than 25 years may be helpful to clinicians who sometimes struggle to bring relief to their patients with mood disorders.

CASE CONTINUED

Return to work

Mrs. W is now doing well. She is taking a lower dosage of duloxetine, 60 mg/d, in combination with the mood stabilizer lamotrigine, 200 mg/d. She returns to work full-time as a paralegal and no longer is experiencing depressive episodes.

Bottom Line

Patients with bipolar depression are often misdiagnosed with unipolar depression and treated inappropriately with antidepressant monotherapy, which often results in mood destabilization. Based on our clinical experience, a careful assessment of select criteria, including age of onset, rapidity of onset, comorbidities, diurnal mood variations, and more, can be useful for distinguishing between unipolar and bipolar depression.

Related Resources

• Nasrallah HA. Misdiagnosing bipolar depression as major depressive disorder. Current Psychiatry. 2013;12(10):20-21,A.
• Ghaemi SN. Bipolar spectrum: a review of the concept and a vision for the future. Psychiatry Investig. 2013;10(3):218-224.

Drug Brand Names

Aripiprazole • Abilify
Brexpiprazole • Rexulti
Bupropion • Wellbutrin
Carbamazepine • Tegretol, Equetro
Cariprazine • Vraylar
Divalproex • Depakote
Duloxetine • Cymbalta
Esketamine • Spravato
Fluoxetine • Prozac
Lamotrigine • Lamictal
Levothyroxine • Synthroid, Levoxyl
Liothyronine • Cytomel
Lithium • Eskalith, Lithobid
Lurasidone • Latuda
Oxcarbazepine • Oxtellar XR, Trileptal
Paroxetine • Paxil
Sertraline • Zoloft

Mrs. W, age 36, who is married, has a history of military service, and is currently employed as a paralegal, is referred to our practice by her family physician. She complains of severe depression that impairs her ability to function at work. She had seen several other psychiatrists in both military and civilian settings, and had been treated with multiple antidepressants, including fluoxetine, sertraline, bupropion, and paroxetine.

At the time of her initial psychiatric evaluation, she is taking duloxetine, 90 mg/d, but still is experiencing depressive symptoms. She is tearful, sad, lacks energy, spends too much time in bed, and is experiencing thoughts of hopelessness, despair, and escape, verging on thoughts of suicide. As a result, she needs to scale back her work schedule to part-time. When asked about how long she had been suffering from depression, she responds “I’ve been depressed all my life.” She had been briefly hospitalized at age 16, when she made a suicide attempt by overdose. There had been no subsequent suicide attempts or psychiatric hospitalizations, although she acknowledges having intermittent suicidal thoughts.

Mrs. W’s clinical presentation is similar to that of many patients entering our practice—patients who have recurrent depression that began in early life and a history of failure to respond to multiple antidepressants. She and other patients with similar presentations are not suffering from treatment-resistant depression and in need of a trial of electroconvulsive therapy, transcranial magnetic stimulation, direct current stimulation, vagus nerve stimulation, or intranasal esketamine. She has bipolar disorder, and had been repeatedly misdiagnosed and treated inappropriately with antidepressant monotherapy.

In a previous article¹ (“Controversies in bipolar disorder: Trust evidence or experience?,” Current Psychiatry, February 2009, p. 27-28,31-33,39), we endorsed the concept of a bipolar spectrum. We also argued that subthreshold hypomania is the rule and not the exception in bipolar II disorder, that antidepressant monotherapy rarely causes manic switches but is more likely to worsen depression, and that although antidepressant monotherapy usually destabilizes bipolar illness, antidepressants can be helpful when combined with mood stabilizers. We observed that bipolar disorder occurs frequently in children and adolescents and that psychosis is a common occurrence in patients with bipolar disorder. We also outlined what we consider to be the major clinical features of bipolar depression and noted the role of thyroid hormones in managing mood disorders.

In this article, based on our more than 25 years of experience in diagnosing and treating psychiatric disorders in patients of all ages, we expand on those observations.

Misdiagnosis is common

Bipolar depression is frequently misdiagnosed as unipolar depression in outpatient^2-8 and inpatient⁹ settings, and in children and adolescents.¹⁰ Mrs. W is typical of patients who have what we consider a bipolar spectrum disorder and receive an inaccurate diagnosis and treatment that is ineffective or may worsen the course of their illness.

Reliance on DSM-5¹¹ and its predecessor, DSM-IV, is a part of the problem of misdiagnosis because the diagnostic criteria for bipolar disorder fail to capture the clinical features of many patients with “softer” (less obvious manic and hypomanic) variants of the disorder.^12,13 For example, DSM-5 criteria for a hypomanic episode (the mild high experienced by patients with a soft bipolar disorder) require that the episode lasts “at least 4 consecutive days” and is “present most of the day, nearly every day.” In our experience, the majority of hypomanic episodes are shorter—ranging from a half-day to 2 days, averaging perhaps 1.5 days.

Continue to: DSM-5 also requires...

DSM-5 also requires severity criteria for hypomania that patients with unequivocal hypomanic episodes often do not meet. For example, they may fail to experience flight of ideas or racing thoughts, or engage in activities such as “unrestrained buying sprees, sexual indiscretions, or foolish business investments.” These patients usually describe these mild highs as feeling normal and report a happier mood, more smiles and laughter, increased energy, less sleepiness, increased talkativeness, increased socialization, and improved motivation to complete tasks left undone and projects left unfinished because of the previous depressive episode. These softer (subthreshold) hypomanic episodes are authentic and, if clinicians do not identify them, may lead to misdiagnosis and inappropriate treatment.

Patients who present with depression often fail to report these brief, subthreshold hypomanic episodes or consider them to be irrelevant to their diagnosis and treatment.^12,13 Probing questions can often elicit these unreported highs. For example, a patient with depression should be asked, “Have you had a single good day during the last month?” and “Where were you and what did you do during that day?” Eliciting a history of brief periods of improved mood is the key to differentiating between unipolar and bipolar depression. Screening instruments such as the Mood Disorders Questionnaire¹⁴ and the Bipolar Spectrum Diagnostic Scale¹⁵ may be helpful in distinguishing between unipolar and bipolar depression. However, we offer our thoughts on making that crucial distinction.

Distinguishing between these 2 types of depression

Although it may be difficult to distinguish between unipolar and bipolar depression, especially in the absence of a history of distinct manic or hypomanic episodes, we find the following criteria to be useful in making that determination.

Age of onset. Bipolar spectrum disorders typically begin earlier in life than unipolar depression.^10,16-19 A typical presentation of bipolar disorder in children and adolescents is depression or agitated mixed states with features of both mania and depression, often accompanied by rapid mood cycling.^20,21 Unipolar depression usually begins later in life, and patients do not have a history of significant depressive episodes or mood swings in childhood or adolescence. An important question to ask a patient with a chief complaint of depression is, “How old were you when you first experienced an episode of depression?”

Gender differences. Bipolar spectrum disorders with more subtle (softer) presentations, such as subthreshold highs, occur more often in women than men.²² However, overall rates of bipolar disorder may be slightly higher in men than in women.²³ Unipolar melancholic depression occurs at approximately the same frequency in men and women.²⁴

Continue to: Rapidity of onset

Rapidity of onset. Bipolar depressive episodes develop more rapidly than unipolar episodes. It is common for a patient with a bipolar spectrum disorder to transition from normal to very depressed virtually overnight, whereas in our clinical experience, unipolar episodes progress more slowly, often over several months.

Deliberate self-harm. Adolescents and young adults with a bipolar spectrum disorder frequently engage in self-injurious behavior, usually cutting with a knife, razor, or even sharp fingernails.²⁵ Although these patients may also have thoughts of suicide and make suicide attempts, the individual usually perceives cutting as a means of gaining relief from tension and distress. These behaviors are often associated with a diagnosis of a personality disorder; in our opinion, however, they are hallmarks of a bipolar spectrum disorder.

ADHD. Bipolar disorder frequently co-occurs with attention-deficit/hyperactivity disorder (ADHD).^26,27 Adults with bipolar disorder often have ADHD symptoms, which can complicate their treatment and cause functional impairment even after their mood disorder has been stabilized.²⁸

Substance use disorders. Excessive use of alcohol and drugs is common among people with a wide range of psychiatric disorders, but patients with bipolar disorder have an unusually high rate of co-occurring substance use disorders—40% to 50%.^29,30

Appetite and weight differences. Patients with unipolar depression usually experience loss of appetite and weight loss, whereas in our clinical experience, patients with bipolar depression often overeat, crave carbohydrates, and gain weight.

Continue to: Sleep problems

Sleep problems. Patients with bipolar depression have an increased need for sleep (the opposite of what they experience during highs), are sleepy during the day regardless of how many hours they sleep, and have difficulty getting up in the morning. Patients with unipolar depression also have a sleep disturbance: they may fall asleep easily, sleep for a few hours, and then awaken but are unable to fall back to sleep.³¹ Yet these patients usually do not complain of sleepiness during the day.

Diurnal variation of mood. Patients with unipolar depression often report that their depressive symptoms fluctuate in a circadian manner. For example, they may report that their depression is worse in the morning but improves toward evening.³¹ This regular alteration of circadian rhythm usually is not evident in patients with bipolar depression, whose mood may vary unpredictably or in response to stressors. Some patients with bipolar disorder, however, exhibit ultradian (ultra-rapid) mood cycling, which may be confused with the diurnal mood variation seen in patients with unipolar depression.

Tendency to recur. Although both unipolar and bipolar depressive episodes recur, a pattern of multiple recurring episodes beginning in early life is characteristic of bipolar spectrum disorders.

Behavioral history. Patients with bipolar depression are more likely than patients with unipolar depression to have a history of multiple marriages, multiple romantic relationships, episodes of promiscuity, legal problems, or financial extravagance.

Response to antidepressants. Patients with bipolar depression exhibit atypical responses to antidepressant monotherapy, such as worsening of depressive symptoms, initial improvement of mood with subsequent loss of effectiveness, premature response to an antidepressant (eg, improvement of mood within 1 to 2 days of beginning the antidepressant), fluctuation of depressive symptoms (mood cycling), or precipitation of a hypomanic or manic episode. We believe that a history of multiple failed antidepressant trials is compelling evidence of misdiagnosis of a bipolar spectrum disorder as unipolar depression.

Continue to: Genetics

Genetics. Bipolar disorder is one of the most heritable of illnesses.³² Family history is important, but affected relatives may have been misdiagnosed with unipolar depression or schizophrenia, or said to have experienced “nervous breakdowns.”

Consequences of misdiagnosis

Misdiagnosis of patients with bipolar disorder is not benign. We see patients who have suffered needlessly for years with severe depression and mood instability. After trying antidepressant after antidepressant without benefit, they begin to feel hopeless, believing they have tried everything and that nothing works for them. Often, these patients have dropped out of high school or college, or lost jobs, friends, and spouses due to their disabling but misdiagnosed psychiatric disorder. Patients with misdiagnosed bipolar disorder have an increased risk of suicide attempts and psychiatric hospitalization.^5,8

Misdiagnosis of patients with bipolar disorder is not limited to nonpsychiatric physicians. The majority of patients with bipolar spectrum disorders are misdiagnosed by outpatient psychiatrists as having unipolar depression.^2-7 At least 45% of patients hospitalized for depression have bipolar disorder—and most of these patients are treated inappropriately with antidepressants.⁹ The STAR*D study,^33,34 a large randomized clinical trial of antidepressants, concluded that more than one-third of patients had not remitted from their depression after treatment with 3 different antidepressants. In our opinion, many of the nonresponding patients may have undiagnosed bipolar depression, which predictably leads to a failure to respond adequately to antidepressants. We believe that the customary inclusion and exclusion criteria used to select participants for these research studies miss subtle (subthreshold) hypomanic episodes that fall short of meeting DSM criteria for duration and severity. This phenomenon may account for the results of studies that conclude that antidepressants are, at best, minimally more effective than placebo.³⁵

When a patient with a bipolar spectrum disorder is misdiagnosed and treated with an antidepressant, the usual result is mood destabilization. Reports of mood swings, increased crying, and suicidal thoughts and suicidal gestures in children, adolescents, and young adults treated with antidepressants led the FDA to issue a “black-box” warning.³⁶ Because bipolar depression typically begins in youth,^10,18,19 the behaviors cited in the warning may reflect misdiagnosis of bipolar depression as unipolar depression, and consequent mood destabilization as a result of treatment with an antidepressant in the absence of a mood stabilizer.

Depression and life stressors

Since many patients who are depressed present with a history of significant stressors, clinicians often face the problem of distinguishing between clinical depression and stress-induced depression. We believe that one typical symptom of depression—increased sensitivity to stressors—may help in making that distinction. A patient who is depressed will often attribute depression to stressors such as marital conflict, divorce, problems with a teenage child, work pressures, financial pressures, or the illness or death of a family member or pet. If clinical depression (unipolar or bipolar) is present, the symptoms are persistent, sometimes antedate the stressor by days or weeks, often outlast the stressor, increase in severity over time, and are disproportional to the stressor. Clinical depression can also cause the patient to become obsessed with traumatic events or losses that occurred many years earlier.

Continue to: Our approach to treatment

Patients with mood disorders often benefit from a combination of pharmacologic management and psychotherapy. Psychotherapy is particularly important in addressing the functional impairment, diminished self-worth, and interpersonal conflicts that often accompany clinical depression. Several styles or systems of psycho­therapy have been developed to benefit patients with mood disorders. Their effectiveness may depend on the patient’s ability to gain insight,³⁷ but in our opinion, the most important attribute of helpful psychotherapy is the rapport established between the patient and the therapist, and the therapist’s ability to empathize with the patient and instill in the patient a sense of optimism and hope. We often recommend that patients attend meetings of the Depression and Bipolar Support Alliance (DBSA), a national support group with chapters throughout the country. Patients often find that attending these meetings is both educational and emotionally rewarding.

The foundational pharmacologic treatment for bipolar disorder is a mood stabilizer. The medications we consider to be effective mood stabilizers (some with an FDA indication for bipolar maintenance, some without) are lithium carbonate, divalproex sodium, carbamazepine, oxcarbazepine, and lamotrigine.

Each of these mood stabilizers has its advantages, disadvantages, risks, and adverse effects. For example, although divalproex is a reliable mood stabilizer, it has a significant risk of causing birth defects if taken during pregnancy and can cause increased appetite and weight gain. Carbamazepine has significant drug interactions and the potential to cause neurologic adverse effects, while oxcarbazepine, a derivative of carbamazepine, has fewer drug interactions but is more likely to cause hyponatremia. Lamotrigine must be titrated very slowly to reduce the risk of a potentially fatal skin rash (ie, Stevens-Johnson syndrome or toxic epidermal necrolysis). Lithium is effective but has a significant adverse-effect burden: impairment of renal function with long-term use, nephrogenic diabetes insipidus, hypothyroidism, hyperparathyroidism, acne, and weight gain. Lithium also has potential interactions with multiple commonly prescribed medications, including antihypertensives and diuretics, as well as over-the-counter pain relievers such as ibuprofen and naproxen.

Second-generation antipsychotics (SGAs) have mood stabilizing, antidepressant, and anti-manic properties and are often useful in managing bipolar disorder. In our experience, for patients with bipolar disorder, SGAs are best used in combination with a mood stabilizer. Although virtually all SGAs have demonstrated effectiveness in the treatment of psychosis and some phases of bipolar disorder, the newer agents (aripiprazole, brexpiprazole, lurasidone, and cariprazine) are relatively free of metabolic adverse effects such as weight gain, abnormal cholesterol levels, increased prolactin levels, insulin resistance, and increased risk of diabetes.

Antidepressants may be effective in treating unipolar depression, but when treating bipolar depression, they should be used cautiously and only in combination with a mood stabilizer.

Continue to: As we observed...

As we observed in our previous article,¹ thyroid laboratory monitoring and supplementation are critical components of managing mood disorders (Box 1^38-41).

Box 1

Moving towards better diagnoses

The emergence of a criteria-based psychiatric system in 1980 with the publication of DSM-III, and its subsequent revisions and updates, constituted a major advance in psychiatric diagnosis. As we learn more about the pathophysiology, genetics, and epigenetics of psychiatric symptoms and syndromes, future diagnostic systems will improve problems of validity that have yet to be resolved. While we believe that, for the most part, DSM-5 was an advance over the previous diagnostic iteration, we have 2 issues with DSM-5 in terms of the diagnosis of bipolar disorder (Box 2^{10,12,13,18,19,42}).

Box 2

Patients with a chief complaint of depression are often given a diagnosis of “major depression, rule out bipolar disorder.” We believe that this formula should be turned on its head. In our opinion, based on our clinical experience, we think that most patients who present to a clinician’s office or psychiatric hospital with depression have bipolar depression, not unipolar depression. We hope that our experience and observations derived from treating thousands of patients over more than 25 years may be helpful to clinicians who sometimes struggle to bring relief to their patients with mood disorders.

CASE CONTINUED

Return to work

Mrs. W is now doing well. She is taking a lower dosage of duloxetine, 60 mg/d, in combination with the mood stabilizer lamotrigine, 200 mg/d. She returns to work full-time as a paralegal and no longer is experiencing depressive episodes.

Bottom Line

Patients with bipolar depression are often misdiagnosed with unipolar depression and treated inappropriately with antidepressant monotherapy, which often results in mood destabilization. Based on our clinical experience, a careful assessment of select criteria, including age of onset, rapidity of onset, comorbidities, diurnal mood variations, and more, can be useful for distinguishing between unipolar and bipolar depression.

Related Resources

• Nasrallah HA. Misdiagnosing bipolar depression as major depressive disorder. Current Psychiatry. 2013;12(10):20-21,A.
• Ghaemi SN. Bipolar spectrum: a review of the concept and a vision for the future. Psychiatry Investig. 2013;10(3):218-224.

Drug Brand Names

Aripiprazole • Abilify
Brexpiprazole • Rexulti
Bupropion • Wellbutrin
Carbamazepine • Tegretol, Equetro
Cariprazine • Vraylar
Divalproex • Depakote
Duloxetine • Cymbalta
Esketamine • Spravato
Fluoxetine • Prozac
Lamotrigine • Lamictal
Levothyroxine • Synthroid, Levoxyl
Liothyronine • Cytomel
Lithium • Eskalith, Lithobid
Lurasidone • Latuda
Oxcarbazepine • Oxtellar XR, Trileptal
Paroxetine • Paxil
Sertraline • Zoloft

SAN FRANCISCO – Serial ketamine infusions eliminated suicidal ideation in more than two-thirds of patients at a psychiatry office in Connecticut but at significantly higher doses than those recently approved for Janssen’s new esketamine nasal spray (Spravato).

M. Alexander Otto/MDedge News

The patients were treated by Lori V. Calabrese, MD, at Innovative Psychiatry, her private outpatient practice in South Windsor. She presented her first 235 IV ketamine cases at the American Psychiatric Association annual meeting. It was likely the largest real-world series to date of ketamine infusions for treatment-resistant depression and suicidality.

The patients, 14-84 years old but mostly middle-aged, received six infusions over 2-3 weeks, starting at 0.5 mg/kg over 40-50 minutes, then titrated upward for dissociative effect to a maximum of 1.7 mg/kg. Subjects filled out the nine-item Patient Health Questionnaire (PHQ-9) at baseline and before each infusion. Item nine – “thoughts that you would be better off dead or of hurting yourself in some way” – was used to gauge suicidality. That item has been validated as a predictor of suicide risk.

Among 144 patients (62%) who were markedly suicidal, ketamine infusions were tied to diminished ideation in 118 (82%) and eliminated ideation in 98 (68%). They were severely depressed at baseline; PHQ-9 scores fell in 127 (89%), and depression went into remission in 89 (62%). There were no suicide attempts, ED visits, or hospitalizations during treatment and at 4-week follow-up.

“Even if they had been suicidal for a long time, been hospitalized, and made suicide attempts, 68% had full remission of suicidality. This is a life-saving treatment, a breakthrough option for psychiatrists,” Dr. Calabrese said.

The results are “fabulous,” said Jaskaran Singh, MD, who said he was clinical leader of the esketamine program at Janssen.

M. Alexander Otto/MDedge News

aotto@mdedge.com

SAN FRANCISCO – Serial ketamine infusions eliminated suicidal ideation in more than two-thirds of patients at a psychiatry office in Connecticut but at significantly higher doses than those recently approved for Janssen’s new esketamine nasal spray (Spravato).

M. Alexander Otto/MDedge News

The patients were treated by Lori V. Calabrese, MD, at Innovative Psychiatry, her private outpatient practice in South Windsor. She presented her first 235 IV ketamine cases at the American Psychiatric Association annual meeting. It was likely the largest real-world series to date of ketamine infusions for treatment-resistant depression and suicidality.

The patients, 14-84 years old but mostly middle-aged, received six infusions over 2-3 weeks, starting at 0.5 mg/kg over 40-50 minutes, then titrated upward for dissociative effect to a maximum of 1.7 mg/kg. Subjects filled out the nine-item Patient Health Questionnaire (PHQ-9) at baseline and before each infusion. Item nine – “thoughts that you would be better off dead or of hurting yourself in some way” – was used to gauge suicidality. That item has been validated as a predictor of suicide risk.

Among 144 patients (62%) who were markedly suicidal, ketamine infusions were tied to diminished ideation in 118 (82%) and eliminated ideation in 98 (68%). They were severely depressed at baseline; PHQ-9 scores fell in 127 (89%), and depression went into remission in 89 (62%). There were no suicide attempts, ED visits, or hospitalizations during treatment and at 4-week follow-up.

“Even if they had been suicidal for a long time, been hospitalized, and made suicide attempts, 68% had full remission of suicidality. This is a life-saving treatment, a breakthrough option for psychiatrists,” Dr. Calabrese said.

The results are “fabulous,” said Jaskaran Singh, MD, who said he was clinical leader of the esketamine program at Janssen.

M. Alexander Otto/MDedge News

aotto@mdedge.com

SAN FRANCISCO – Serial ketamine infusions eliminated suicidal ideation in more than two-thirds of patients at a psychiatry office in Connecticut but at significantly higher doses than those recently approved for Janssen’s new esketamine nasal spray (Spravato).

M. Alexander Otto/MDedge News

The patients were treated by Lori V. Calabrese, MD, at Innovative Psychiatry, her private outpatient practice in South Windsor. She presented her first 235 IV ketamine cases at the American Psychiatric Association annual meeting. It was likely the largest real-world series to date of ketamine infusions for treatment-resistant depression and suicidality.

The patients, 14-84 years old but mostly middle-aged, received six infusions over 2-3 weeks, starting at 0.5 mg/kg over 40-50 minutes, then titrated upward for dissociative effect to a maximum of 1.7 mg/kg. Subjects filled out the nine-item Patient Health Questionnaire (PHQ-9) at baseline and before each infusion. Item nine – “thoughts that you would be better off dead or of hurting yourself in some way” – was used to gauge suicidality. That item has been validated as a predictor of suicide risk.

Among 144 patients (62%) who were markedly suicidal, ketamine infusions were tied to diminished ideation in 118 (82%) and eliminated ideation in 98 (68%). They were severely depressed at baseline; PHQ-9 scores fell in 127 (89%), and depression went into remission in 89 (62%). There were no suicide attempts, ED visits, or hospitalizations during treatment and at 4-week follow-up.

“Even if they had been suicidal for a long time, been hospitalized, and made suicide attempts, 68% had full remission of suicidality. This is a life-saving treatment, a breakthrough option for psychiatrists,” Dr. Calabrese said.

The results are “fabulous,” said Jaskaran Singh, MD, who said he was clinical leader of the esketamine program at Janssen.

M. Alexander Otto/MDedge News

aotto@mdedge.com

SEATTLE – Initial treatment of multiple sclerosis (MS) with a high-efficacy therapy may reduce depressive symptoms, according to an interim analysis described at the annual meeting of the Consortium of Multiple Sclerosis Centers.

Depression, a common psychiatric comorbidity in MS, is associated with excess morbidity and mortality in that population. Treatment with disease-modifying therapy (DMT) could influence the cause and symptoms of depression.

Youkyung S. Roh, a medical student at Johns Hopkins University in Baltimore, and colleagues hypothesized that lower-efficacy DMTs may increase the risk of depression, whereas higher-efficacy DMTs may have antidepressive properties, possibly because of their anti-inflammatory effects.

To test this hypothesis, Ms. Roh and her colleagues examined data from MS Partners Advancing Technology and Health Solutions (MS PATHS), an ongoing, 10-site, longitudinal study. They compared the rates of change in depressive symptom severity, as measured by the Quality of Life in Neurological Disorders (Neuro-QoL) depression subscale, between patients initiating a lower-efficacy DMT and those initiating a higher-efficacy DMT. Eligible participants had relapsing-remitting MS, were new initiators of DMTs, and completed baseline and follow-up Neuro-QoL depression scales. The researchers defined lower-efficacy DMTs as interferons, glatiramer acetate, fingolimod, and dimethyl fumarate. Higher-efficacy DMTs were defined as natalizumab, rituximab, ocrelizumab, and alemtuzumab.

The investigators used multivariable-adjusted, mixed-effects regression models to compare the rates of change in Neuro-QoL depression scores for patients with MS who were initiating higher-efficacy DMTs versus those initiating lower-efficacy DMTs. Secondary analyses excluded interferons from the lower-efficacy DMT category.

In addition, the investigators compared the rates of depression between therapies within each class of DMT efficacy. Other analyses were stratified by sex, race, disability status, and antidepressant use.

The investigators’ interim analyses included 1,501 participants who initiated a new therapy and who had baseline and follow-up Neuro-QoL depression scores. The mean age of the study population was 45.1 years, and 76% of participants were women. Average follow-up duration was just under 1 year.

In all, 922 participants initiated lower-efficacy DMTs, and 579 participants initiated higher-efficacy DMTs. In preliminary analyses, initiation of higher-efficacy DMT was associated with a multivariable-adjusted 0.58-points/year reduction in Neuro-QoL depression scores, compared with initiation of lower-efficacy DMT. The result was statistically significant.

In addition, results were consistent in analyses that excluded interferons from the category of lower-efficacy DMTs. In those analyses, the reduction in depression scores was 0.63 points/year, which was also statistically significant.

Analyses incorporating additional follow-up data from this cohort are ongoing, said the authors.

The study was not supported by outside funding. Ellen M. Mowry, MD, one of the investigators, reported having performed contracted research for Biogen, Genzyme, and Sun Pharma. Ms Youkyung and another two investigators reported no disclosures or conflicts of interest.

egreb@mdedge.com.

SEATTLE – Initial treatment of multiple sclerosis (MS) with a high-efficacy therapy may reduce depressive symptoms, according to an interim analysis described at the annual meeting of the Consortium of Multiple Sclerosis Centers.

Depression, a common psychiatric comorbidity in MS, is associated with excess morbidity and mortality in that population. Treatment with disease-modifying therapy (DMT) could influence the cause and symptoms of depression.

Youkyung S. Roh, a medical student at Johns Hopkins University in Baltimore, and colleagues hypothesized that lower-efficacy DMTs may increase the risk of depression, whereas higher-efficacy DMTs may have antidepressive properties, possibly because of their anti-inflammatory effects.

To test this hypothesis, Ms. Roh and her colleagues examined data from MS Partners Advancing Technology and Health Solutions (MS PATHS), an ongoing, 10-site, longitudinal study. They compared the rates of change in depressive symptom severity, as measured by the Quality of Life in Neurological Disorders (Neuro-QoL) depression subscale, between patients initiating a lower-efficacy DMT and those initiating a higher-efficacy DMT. Eligible participants had relapsing-remitting MS, were new initiators of DMTs, and completed baseline and follow-up Neuro-QoL depression scales. The researchers defined lower-efficacy DMTs as interferons, glatiramer acetate, fingolimod, and dimethyl fumarate. Higher-efficacy DMTs were defined as natalizumab, rituximab, ocrelizumab, and alemtuzumab.

The investigators used multivariable-adjusted, mixed-effects regression models to compare the rates of change in Neuro-QoL depression scores for patients with MS who were initiating higher-efficacy DMTs versus those initiating lower-efficacy DMTs. Secondary analyses excluded interferons from the lower-efficacy DMT category.

In addition, the investigators compared the rates of depression between therapies within each class of DMT efficacy. Other analyses were stratified by sex, race, disability status, and antidepressant use.

The investigators’ interim analyses included 1,501 participants who initiated a new therapy and who had baseline and follow-up Neuro-QoL depression scores. The mean age of the study population was 45.1 years, and 76% of participants were women. Average follow-up duration was just under 1 year.

In all, 922 participants initiated lower-efficacy DMTs, and 579 participants initiated higher-efficacy DMTs. In preliminary analyses, initiation of higher-efficacy DMT was associated with a multivariable-adjusted 0.58-points/year reduction in Neuro-QoL depression scores, compared with initiation of lower-efficacy DMT. The result was statistically significant.

In addition, results were consistent in analyses that excluded interferons from the category of lower-efficacy DMTs. In those analyses, the reduction in depression scores was 0.63 points/year, which was also statistically significant.

Analyses incorporating additional follow-up data from this cohort are ongoing, said the authors.

The study was not supported by outside funding. Ellen M. Mowry, MD, one of the investigators, reported having performed contracted research for Biogen, Genzyme, and Sun Pharma. Ms Youkyung and another two investigators reported no disclosures or conflicts of interest.

egreb@mdedge.com.

SEATTLE – Initial treatment of multiple sclerosis (MS) with a high-efficacy therapy may reduce depressive symptoms, according to an interim analysis described at the annual meeting of the Consortium of Multiple Sclerosis Centers.

Depression, a common psychiatric comorbidity in MS, is associated with excess morbidity and mortality in that population. Treatment with disease-modifying therapy (DMT) could influence the cause and symptoms of depression.

Youkyung S. Roh, a medical student at Johns Hopkins University in Baltimore, and colleagues hypothesized that lower-efficacy DMTs may increase the risk of depression, whereas higher-efficacy DMTs may have antidepressive properties, possibly because of their anti-inflammatory effects.

To test this hypothesis, Ms. Roh and her colleagues examined data from MS Partners Advancing Technology and Health Solutions (MS PATHS), an ongoing, 10-site, longitudinal study. They compared the rates of change in depressive symptom severity, as measured by the Quality of Life in Neurological Disorders (Neuro-QoL) depression subscale, between patients initiating a lower-efficacy DMT and those initiating a higher-efficacy DMT. Eligible participants had relapsing-remitting MS, were new initiators of DMTs, and completed baseline and follow-up Neuro-QoL depression scales. The researchers defined lower-efficacy DMTs as interferons, glatiramer acetate, fingolimod, and dimethyl fumarate. Higher-efficacy DMTs were defined as natalizumab, rituximab, ocrelizumab, and alemtuzumab.

The investigators used multivariable-adjusted, mixed-effects regression models to compare the rates of change in Neuro-QoL depression scores for patients with MS who were initiating higher-efficacy DMTs versus those initiating lower-efficacy DMTs. Secondary analyses excluded interferons from the lower-efficacy DMT category.

In addition, the investigators compared the rates of depression between therapies within each class of DMT efficacy. Other analyses were stratified by sex, race, disability status, and antidepressant use.

The investigators’ interim analyses included 1,501 participants who initiated a new therapy and who had baseline and follow-up Neuro-QoL depression scores. The mean age of the study population was 45.1 years, and 76% of participants were women. Average follow-up duration was just under 1 year.

In all, 922 participants initiated lower-efficacy DMTs, and 579 participants initiated higher-efficacy DMTs. In preliminary analyses, initiation of higher-efficacy DMT was associated with a multivariable-adjusted 0.58-points/year reduction in Neuro-QoL depression scores, compared with initiation of lower-efficacy DMT. The result was statistically significant.

In addition, results were consistent in analyses that excluded interferons from the category of lower-efficacy DMTs. In those analyses, the reduction in depression scores was 0.63 points/year, which was also statistically significant.

Analyses incorporating additional follow-up data from this cohort are ongoing, said the authors.

The study was not supported by outside funding. Ellen M. Mowry, MD, one of the investigators, reported having performed contracted research for Biogen, Genzyme, and Sun Pharma. Ms Youkyung and another two investigators reported no disclosures or conflicts of interest.

egreb@mdedge.com.

SEATTLE – Multiple sclerosis (MS) adds a layer of complexity to psychiatric illnesses such as depression, and the usual rules of treatment do not necessarily apply, a neuropsychiatrist cautioned colleagues who treat MS.

Randy Dotinga/MDedge News

For example, depression may strike a patient as a primary condition, just as it could in anyone. But it may also be a manifestation of MS itself, or a side effect of an MS medication, or spurred by the fatigue and pain caused by MS, said Laura T. Safar, MD, a psychiatrist affiliated with Brigham and Women's Hospital, Boston*. As a result, popular psychiatric treatments such as SSRIs might not necessarily be the best approach, said Dr. Safar, who spoke in an interview and during a presentation at the annual meeting of the Consortium of Multiple Sclerosis Centers.

“You need to follow the why,” she said in the interview, adding that it is crucial to view neurologic and mental health as one and the same in MS. “More integration,” she said, “continues to be the way to go.”

Here are some pearls and tips from Dr. Safar’s presentation on treating psychiatric conditions in patients with MS:

Mental illness incidence

Depression is estimated to affect 25%-45% of people with MS over their lifetimes, while bipolar disorder is thought to affect 6% of patients and a quarter are estimated to have anxiety.

Researchers also believe as many as 10% of patients are affected by pathological laughing and crying during their lives.
 

Psychiatric side effects

Interferon drugs are notoriously linked to depression and psychosis. Glatiramer acetate (Copaxone) and natalizumab (Tysabri) are also thought to cause psychiatric side effects in some cases – anxiety and depression, respectively. But drug-modifying therapies can also provide relief on the psychiatric front, Dr. Safar said.

Meanwhile, dozens of other drugs used to treat aspects of MS such as spasticity, pain, and fatigue have possible psychiatric side effects.
 

Alternatives to SSRIs

SSRIs are often a first option in psychiatric patients, but those with MS may need another option because so many – an estimated 80% – also have fatigue, Dr. Safar said.

Alternatives for patients with MS include serotonin and norepinephrine reuptake inhibitors (SNRIs), which may have an advantage over SSRIs, she said. Specifically, SNRIs and bupropion (Wellbutrin) may be better for patients with fatigue and cognitive problems, she said, while vortioxetine (Trintellix) may benefit cognition.
 

Treating anxiety

There are no data regarding the best drug treatment for anxiety in patients with MS, she said, and SSRIs are typically the starting point. Consider SNRIs and duloxetine, respectively, when patients also have significant fatigue and cognitive symptoms. Use benzodiazepines only in occasional cases (such as anxiety regarding an MRI) and severe cases, she said.

MS-specific side effects

Beware of MS-specific side effects, Dr. Safar said. Some common psychiatric drugs, especially citalopram (Celexa) and escitalopram (Lexapro), may increase the QTc interval and shouldn’t be used in combination with the MS drug fingolimod (Gilenya).

And, she said, bupropion is “a very helpful agent” but poses a rare risk of seizures. Dr. Safar said she has seen this side effect a couple times over 10 years, but both were in patients with “other factors involved.” Still, “it’s something to keep in mind.”

Also understand that serotonergic agents can worsen restless legs syndrome, which is more common in patients with MS. Dr. Safar advises monitoring for the condition.
 

Pathological laughing, crying

Episodes of so-called pathological laughing, crying, or both tend to be brief, frequent, and intense. They may be sparked by nothing at all, and more often feature crying.

Certain SSRIs have proved helpful for the condition in MS, Dr. Safar said. Research also supports a combination of dextromethorphan (cough suppressant) and quinidine (a drug used to treat arrhythmias and malaria). The combination is sold together as Nuedexta.

Other agents such as venlafaxine (Effexor) and duloxetine (Cymbalta) have very limited data and shouldn’t be first-line treatment, she said.

Dr. Safar reports no relevant disclosures.

Correction, 5/31/19: An earlier version of this article misstated Dr. Safar's hospital affiliation.

SEATTLE – Multiple sclerosis (MS) adds a layer of complexity to psychiatric illnesses such as depression, and the usual rules of treatment do not necessarily apply, a neuropsychiatrist cautioned colleagues who treat MS.

Randy Dotinga/MDedge News

For example, depression may strike a patient as a primary condition, just as it could in anyone. But it may also be a manifestation of MS itself, or a side effect of an MS medication, or spurred by the fatigue and pain caused by MS, said Laura T. Safar, MD, a psychiatrist affiliated with Brigham and Women's Hospital, Boston*. As a result, popular psychiatric treatments such as SSRIs might not necessarily be the best approach, said Dr. Safar, who spoke in an interview and during a presentation at the annual meeting of the Consortium of Multiple Sclerosis Centers.

“You need to follow the why,” she said in the interview, adding that it is crucial to view neurologic and mental health as one and the same in MS. “More integration,” she said, “continues to be the way to go.”

Here are some pearls and tips from Dr. Safar’s presentation on treating psychiatric conditions in patients with MS:

Mental illness incidence

Depression is estimated to affect 25%-45% of people with MS over their lifetimes, while bipolar disorder is thought to affect 6% of patients and a quarter are estimated to have anxiety.

Researchers also believe as many as 10% of patients are affected by pathological laughing and crying during their lives.
 

Psychiatric side effects

Interferon drugs are notoriously linked to depression and psychosis. Glatiramer acetate (Copaxone) and natalizumab (Tysabri) are also thought to cause psychiatric side effects in some cases – anxiety and depression, respectively. But drug-modifying therapies can also provide relief on the psychiatric front, Dr. Safar said.

Meanwhile, dozens of other drugs used to treat aspects of MS such as spasticity, pain, and fatigue have possible psychiatric side effects.
 

Alternatives to SSRIs

SSRIs are often a first option in psychiatric patients, but those with MS may need another option because so many – an estimated 80% – also have fatigue, Dr. Safar said.

Alternatives for patients with MS include serotonin and norepinephrine reuptake inhibitors (SNRIs), which may have an advantage over SSRIs, she said. Specifically, SNRIs and bupropion (Wellbutrin) may be better for patients with fatigue and cognitive problems, she said, while vortioxetine (Trintellix) may benefit cognition.
 

Treating anxiety

There are no data regarding the best drug treatment for anxiety in patients with MS, she said, and SSRIs are typically the starting point. Consider SNRIs and duloxetine, respectively, when patients also have significant fatigue and cognitive symptoms. Use benzodiazepines only in occasional cases (such as anxiety regarding an MRI) and severe cases, she said.

MS-specific side effects

Beware of MS-specific side effects, Dr. Safar said. Some common psychiatric drugs, especially citalopram (Celexa) and escitalopram (Lexapro), may increase the QTc interval and shouldn’t be used in combination with the MS drug fingolimod (Gilenya).

And, she said, bupropion is “a very helpful agent” but poses a rare risk of seizures. Dr. Safar said she has seen this side effect a couple times over 10 years, but both were in patients with “other factors involved.” Still, “it’s something to keep in mind.”

Also understand that serotonergic agents can worsen restless legs syndrome, which is more common in patients with MS. Dr. Safar advises monitoring for the condition.
 

Pathological laughing, crying

Episodes of so-called pathological laughing, crying, or both tend to be brief, frequent, and intense. They may be sparked by nothing at all, and more often feature crying.

Certain SSRIs have proved helpful for the condition in MS, Dr. Safar said. Research also supports a combination of dextromethorphan (cough suppressant) and quinidine (a drug used to treat arrhythmias and malaria). The combination is sold together as Nuedexta.

Other agents such as venlafaxine (Effexor) and duloxetine (Cymbalta) have very limited data and shouldn’t be first-line treatment, she said.

Dr. Safar reports no relevant disclosures.

Correction, 5/31/19: An earlier version of this article misstated Dr. Safar's hospital affiliation.

SEATTLE – Multiple sclerosis (MS) adds a layer of complexity to psychiatric illnesses such as depression, and the usual rules of treatment do not necessarily apply, a neuropsychiatrist cautioned colleagues who treat MS.

Randy Dotinga/MDedge News

For example, depression may strike a patient as a primary condition, just as it could in anyone. But it may also be a manifestation of MS itself, or a side effect of an MS medication, or spurred by the fatigue and pain caused by MS, said Laura T. Safar, MD, a psychiatrist affiliated with Brigham and Women's Hospital, Boston*. As a result, popular psychiatric treatments such as SSRIs might not necessarily be the best approach, said Dr. Safar, who spoke in an interview and during a presentation at the annual meeting of the Consortium of Multiple Sclerosis Centers.

“You need to follow the why,” she said in the interview, adding that it is crucial to view neurologic and mental health as one and the same in MS. “More integration,” she said, “continues to be the way to go.”

Here are some pearls and tips from Dr. Safar’s presentation on treating psychiatric conditions in patients with MS:

Mental illness incidence

Depression is estimated to affect 25%-45% of people with MS over their lifetimes, while bipolar disorder is thought to affect 6% of patients and a quarter are estimated to have anxiety.

Researchers also believe as many as 10% of patients are affected by pathological laughing and crying during their lives.
 

Psychiatric side effects

Interferon drugs are notoriously linked to depression and psychosis. Glatiramer acetate (Copaxone) and natalizumab (Tysabri) are also thought to cause psychiatric side effects in some cases – anxiety and depression, respectively. But drug-modifying therapies can also provide relief on the psychiatric front, Dr. Safar said.

Meanwhile, dozens of other drugs used to treat aspects of MS such as spasticity, pain, and fatigue have possible psychiatric side effects.
 

Alternatives to SSRIs

SSRIs are often a first option in psychiatric patients, but those with MS may need another option because so many – an estimated 80% – also have fatigue, Dr. Safar said.

Alternatives for patients with MS include serotonin and norepinephrine reuptake inhibitors (SNRIs), which may have an advantage over SSRIs, she said. Specifically, SNRIs and bupropion (Wellbutrin) may be better for patients with fatigue and cognitive problems, she said, while vortioxetine (Trintellix) may benefit cognition.
 

Treating anxiety

There are no data regarding the best drug treatment for anxiety in patients with MS, she said, and SSRIs are typically the starting point. Consider SNRIs and duloxetine, respectively, when patients also have significant fatigue and cognitive symptoms. Use benzodiazepines only in occasional cases (such as anxiety regarding an MRI) and severe cases, she said.

MS-specific side effects

Beware of MS-specific side effects, Dr. Safar said. Some common psychiatric drugs, especially citalopram (Celexa) and escitalopram (Lexapro), may increase the QTc interval and shouldn’t be used in combination with the MS drug fingolimod (Gilenya).

And, she said, bupropion is “a very helpful agent” but poses a rare risk of seizures. Dr. Safar said she has seen this side effect a couple times over 10 years, but both were in patients with “other factors involved.” Still, “it’s something to keep in mind.”

Also understand that serotonergic agents can worsen restless legs syndrome, which is more common in patients with MS. Dr. Safar advises monitoring for the condition.
 

Pathological laughing, crying

Episodes of so-called pathological laughing, crying, or both tend to be brief, frequent, and intense. They may be sparked by nothing at all, and more often feature crying.

Certain SSRIs have proved helpful for the condition in MS, Dr. Safar said. Research also supports a combination of dextromethorphan (cough suppressant) and quinidine (a drug used to treat arrhythmias and malaria). The combination is sold together as Nuedexta.

Other agents such as venlafaxine (Effexor) and duloxetine (Cymbalta) have very limited data and shouldn’t be first-line treatment, she said.

Dr. Safar reports no relevant disclosures.

Correction, 5/31/19: An earlier version of this article misstated Dr. Safar's hospital affiliation.

SAN FRANCISCO – In a proof-of-concept study, music provided an alternative to oral psychotropic medication in calming agitated patients at an inpatient psychiatric facility. Music has been studied as a treatment for agitation in dementia patients but not so much in psychiatric patients, according to Trevor Scudamore, MD, who is a resident fellow at State University of New York, Syracuse.

Jim Kling/MDedge News

“The other thing is that music has been more looked at in group therapy settings than as adjunct therapy, or as an option as an as-needed medication for agitation,” Dr. Scudamore said in an interview. He presented the study at a poster session at the annual meeting of the American Psychiatric Association.

When agitation arose, the program allowed patients to choose between an oral medication or music, which entailed a 30-minute session listening to a preset playlist using a wireless headphone. Playlist options included a variety of musical genres, and participants could sit in one place or roam around while listening.

Traditionally, agitated patients had the choice of an oral medication. If the patient refused and then escalated, they had to accept an intravenous medication. “Now there’s a choice between an oral medication and music, almost like a third layer in defusing agitation in the patient. If they refuse music, then they could go for oral medication, and then [IV medication]. They’re given a little bit more options. Maybe they don’t feel so confined, which is an interesting way of helping possibly defuse anxiety from a situation. That needs to be explored further,” Dr. Scudamore said.

The study had a two-phase, cross-sectional design. The first 3 months, the study included 71 patients, who were used to establish a baseline of agitation and psychotropic medication use. They introduced the music intervention during the second 3-month period, with 101 participants. After they listened to music, the patients completed a self-report form using the Likert scale, and nursing staff observed the patients status during the initial anxiety/agitation, while they listened to music, and 15 minutes after the listening session.

That need for commitment from nurses presented a challenge to implementation. They had to hand out headphones, keep track of them, and make sure they got the headphones back. “It is a lot more work than just giving 50 mg of hydroxyzine,” said coauthor Christopher Botash, MD, who also is a resident at the university.

Study participants had a range of psychiatric ills, including substance abuse (61%), depression (51%), psychosis (28%), trauma (26%), personality disorder (20%), and anxiety (17%).

As part of a preliminary report, the researchers presented data from surveys completed by nine nurses and 31 patients. After the music implementation, the average length of stay declined (10.49 to 8.20 days; difference, 2.29 days), as did the median length of stay (6.5 to 5.0 days). The two most commonly prescribed antipsychotics saw a decrease in administrations, from 3.37 to 2.93/month for haloperidol, and from 3.83 to 2.73 administrations/month for olanzapine.

A total of 56% of the nursing staff stated that the music therapy program helped calm down the patients. Nurses who disagreed cited the tendency for patients to intrude at the nursing station asking for the music, though this improved as patients learned the routine. Ninety-six percent of the patients reported satisfaction with the experience.

It was challenging for the researchers to implement the study, since offering music was a break in the routine. “The staff really does rely a lot on the meds, so oftentimes we would have to say, ‘Hey, have you offered the music yet?’ It’s a bit of a culture change,” Dr. Botash said.

The study, which Dr. Scudamore and Dr. Botash coauthored with Nekpen S. Ekure, MD, did not receive external funding. Dr. Scudamore and Dr. Botash had no relevant financial disclosures.

SAN FRANCISCO – In a proof-of-concept study, music provided an alternative to oral psychotropic medication in calming agitated patients at an inpatient psychiatric facility. Music has been studied as a treatment for agitation in dementia patients but not so much in psychiatric patients, according to Trevor Scudamore, MD, who is a resident fellow at State University of New York, Syracuse.

Jim Kling/MDedge News

“The other thing is that music has been more looked at in group therapy settings than as adjunct therapy, or as an option as an as-needed medication for agitation,” Dr. Scudamore said in an interview. He presented the study at a poster session at the annual meeting of the American Psychiatric Association.

When agitation arose, the program allowed patients to choose between an oral medication or music, which entailed a 30-minute session listening to a preset playlist using a wireless headphone. Playlist options included a variety of musical genres, and participants could sit in one place or roam around while listening.

Traditionally, agitated patients had the choice of an oral medication. If the patient refused and then escalated, they had to accept an intravenous medication. “Now there’s a choice between an oral medication and music, almost like a third layer in defusing agitation in the patient. If they refuse music, then they could go for oral medication, and then [IV medication]. They’re given a little bit more options. Maybe they don’t feel so confined, which is an interesting way of helping possibly defuse anxiety from a situation. That needs to be explored further,” Dr. Scudamore said.

The study had a two-phase, cross-sectional design. The first 3 months, the study included 71 patients, who were used to establish a baseline of agitation and psychotropic medication use. They introduced the music intervention during the second 3-month period, with 101 participants. After they listened to music, the patients completed a self-report form using the Likert scale, and nursing staff observed the patients status during the initial anxiety/agitation, while they listened to music, and 15 minutes after the listening session.

That need for commitment from nurses presented a challenge to implementation. They had to hand out headphones, keep track of them, and make sure they got the headphones back. “It is a lot more work than just giving 50 mg of hydroxyzine,” said coauthor Christopher Botash, MD, who also is a resident at the university.

Study participants had a range of psychiatric ills, including substance abuse (61%), depression (51%), psychosis (28%), trauma (26%), personality disorder (20%), and anxiety (17%).

As part of a preliminary report, the researchers presented data from surveys completed by nine nurses and 31 patients. After the music implementation, the average length of stay declined (10.49 to 8.20 days; difference, 2.29 days), as did the median length of stay (6.5 to 5.0 days). The two most commonly prescribed antipsychotics saw a decrease in administrations, from 3.37 to 2.93/month for haloperidol, and from 3.83 to 2.73 administrations/month for olanzapine.

A total of 56% of the nursing staff stated that the music therapy program helped calm down the patients. Nurses who disagreed cited the tendency for patients to intrude at the nursing station asking for the music, though this improved as patients learned the routine. Ninety-six percent of the patients reported satisfaction with the experience.

It was challenging for the researchers to implement the study, since offering music was a break in the routine. “The staff really does rely a lot on the meds, so oftentimes we would have to say, ‘Hey, have you offered the music yet?’ It’s a bit of a culture change,” Dr. Botash said.

The study, which Dr. Scudamore and Dr. Botash coauthored with Nekpen S. Ekure, MD, did not receive external funding. Dr. Scudamore and Dr. Botash had no relevant financial disclosures.

SAN FRANCISCO – In a proof-of-concept study, music provided an alternative to oral psychotropic medication in calming agitated patients at an inpatient psychiatric facility. Music has been studied as a treatment for agitation in dementia patients but not so much in psychiatric patients, according to Trevor Scudamore, MD, who is a resident fellow at State University of New York, Syracuse.

Jim Kling/MDedge News

“The other thing is that music has been more looked at in group therapy settings than as adjunct therapy, or as an option as an as-needed medication for agitation,” Dr. Scudamore said in an interview. He presented the study at a poster session at the annual meeting of the American Psychiatric Association.

When agitation arose, the program allowed patients to choose between an oral medication or music, which entailed a 30-minute session listening to a preset playlist using a wireless headphone. Playlist options included a variety of musical genres, and participants could sit in one place or roam around while listening.

Traditionally, agitated patients had the choice of an oral medication. If the patient refused and then escalated, they had to accept an intravenous medication. “Now there’s a choice between an oral medication and music, almost like a third layer in defusing agitation in the patient. If they refuse music, then they could go for oral medication, and then [IV medication]. They’re given a little bit more options. Maybe they don’t feel so confined, which is an interesting way of helping possibly defuse anxiety from a situation. That needs to be explored further,” Dr. Scudamore said.

The study had a two-phase, cross-sectional design. The first 3 months, the study included 71 patients, who were used to establish a baseline of agitation and psychotropic medication use. They introduced the music intervention during the second 3-month period, with 101 participants. After they listened to music, the patients completed a self-report form using the Likert scale, and nursing staff observed the patients status during the initial anxiety/agitation, while they listened to music, and 15 minutes after the listening session.

That need for commitment from nurses presented a challenge to implementation. They had to hand out headphones, keep track of them, and make sure they got the headphones back. “It is a lot more work than just giving 50 mg of hydroxyzine,” said coauthor Christopher Botash, MD, who also is a resident at the university.

Study participants had a range of psychiatric ills, including substance abuse (61%), depression (51%), psychosis (28%), trauma (26%), personality disorder (20%), and anxiety (17%).

As part of a preliminary report, the researchers presented data from surveys completed by nine nurses and 31 patients. After the music implementation, the average length of stay declined (10.49 to 8.20 days; difference, 2.29 days), as did the median length of stay (6.5 to 5.0 days). The two most commonly prescribed antipsychotics saw a decrease in administrations, from 3.37 to 2.93/month for haloperidol, and from 3.83 to 2.73 administrations/month for olanzapine.

A total of 56% of the nursing staff stated that the music therapy program helped calm down the patients. Nurses who disagreed cited the tendency for patients to intrude at the nursing station asking for the music, though this improved as patients learned the routine. Ninety-six percent of the patients reported satisfaction with the experience.

It was challenging for the researchers to implement the study, since offering music was a break in the routine. “The staff really does rely a lot on the meds, so oftentimes we would have to say, ‘Hey, have you offered the music yet?’ It’s a bit of a culture change,” Dr. Botash said.

The study, which Dr. Scudamore and Dr. Botash coauthored with Nekpen S. Ekure, MD, did not receive external funding. Dr. Scudamore and Dr. Botash had no relevant financial disclosures.

SEATTLE – A small new study suggests that patients with multiple sclerosis (MS) who use cannabis in a hazardous way are more likely to suffer from symptoms of anxiety and depression, although it is not clear whether there is a cause-and-effect relationship. “We highly recommend screening for hazardous cannabis use in clinical settings,” said study lead author and rehabilitation psychologist Abbey J. Hughes, PhD, an assistant professor at Johns Hopkins University, Baltimore, in an interview. She spoke prior to the presentation of the study findings at the annual meeting of the Consortium of Multiple Sclerosis Centers.

According to Dr. Hughes, research suggests that patients with MS are using cannabis more now than in the past, especially for medical reasons. It is not clear, however, how cannabis is affecting neurobehavior in patients with MS who use it, said Dr. Hughes, who works with patients with MS.

For the new study, researchers gave surveys to 100 patients with MS (76% female; mean age, 46 years) who sought outpatient care at an MS center. Of those, 31 said they had used cannabis within the past month.

The patients were screened via several tools: the Cannabis Use Disorders Identification Test–Revised (CUDIT-R) Fatigue Severity Scale; Patient Health Questionnaire–8; Generalized Anxiety Disorders Scale–7; and Brief International Cognitive Assessment for Multiple Sclerosis.

Subjects were considered to have a problem with “hazardous cannabis use” if they met or exceeded the CUDIT-R’s clinical cut-off of 8 points. The test asks about topics such as hazardous behavior while using cannabis, problems with memory or concentration after using it, and inability to stop using it. Twelve participants met this criteria, and they were more likely to have more symptoms of depression (beta = 0.32; P less than .01) and anxiety (beta = 0.24; P = .02), after researchers controlled for age, years of education, and MS subtype.

They also were slightly more likely to have more severe fatigue (beta = 0.20; P = .07) and poor sleep (beta = 0.20; P = .07).

The researchers found no link between cannabis use and scores on the cognitive test, although Dr. Hughes noted that other research has suggested such a link.

The study is cross-sectional and does not offer insight into cause and effect, Dr. Hughes said. She noted that it is possible that patients used cannabis because they had higher levels of anxiety and depression.

No study funding was reported and the authors report no relevant disclosures.

SEATTLE – A small new study suggests that patients with multiple sclerosis (MS) who use cannabis in a hazardous way are more likely to suffer from symptoms of anxiety and depression, although it is not clear whether there is a cause-and-effect relationship. “We highly recommend screening for hazardous cannabis use in clinical settings,” said study lead author and rehabilitation psychologist Abbey J. Hughes, PhD, an assistant professor at Johns Hopkins University, Baltimore, in an interview. She spoke prior to the presentation of the study findings at the annual meeting of the Consortium of Multiple Sclerosis Centers.

According to Dr. Hughes, research suggests that patients with MS are using cannabis more now than in the past, especially for medical reasons. It is not clear, however, how cannabis is affecting neurobehavior in patients with MS who use it, said Dr. Hughes, who works with patients with MS.

For the new study, researchers gave surveys to 100 patients with MS (76% female; mean age, 46 years) who sought outpatient care at an MS center. Of those, 31 said they had used cannabis within the past month.

The patients were screened via several tools: the Cannabis Use Disorders Identification Test–Revised (CUDIT-R) Fatigue Severity Scale; Patient Health Questionnaire–8; Generalized Anxiety Disorders Scale–7; and Brief International Cognitive Assessment for Multiple Sclerosis.

Subjects were considered to have a problem with “hazardous cannabis use” if they met or exceeded the CUDIT-R’s clinical cut-off of 8 points. The test asks about topics such as hazardous behavior while using cannabis, problems with memory or concentration after using it, and inability to stop using it. Twelve participants met this criteria, and they were more likely to have more symptoms of depression (beta = 0.32; P less than .01) and anxiety (beta = 0.24; P = .02), after researchers controlled for age, years of education, and MS subtype.

They also were slightly more likely to have more severe fatigue (beta = 0.20; P = .07) and poor sleep (beta = 0.20; P = .07).

The researchers found no link between cannabis use and scores on the cognitive test, although Dr. Hughes noted that other research has suggested such a link.

The study is cross-sectional and does not offer insight into cause and effect, Dr. Hughes said. She noted that it is possible that patients used cannabis because they had higher levels of anxiety and depression.

No study funding was reported and the authors report no relevant disclosures.

SEATTLE – A small new study suggests that patients with multiple sclerosis (MS) who use cannabis in a hazardous way are more likely to suffer from symptoms of anxiety and depression, although it is not clear whether there is a cause-and-effect relationship. “We highly recommend screening for hazardous cannabis use in clinical settings,” said study lead author and rehabilitation psychologist Abbey J. Hughes, PhD, an assistant professor at Johns Hopkins University, Baltimore, in an interview. She spoke prior to the presentation of the study findings at the annual meeting of the Consortium of Multiple Sclerosis Centers.

According to Dr. Hughes, research suggests that patients with MS are using cannabis more now than in the past, especially for medical reasons. It is not clear, however, how cannabis is affecting neurobehavior in patients with MS who use it, said Dr. Hughes, who works with patients with MS.

For the new study, researchers gave surveys to 100 patients with MS (76% female; mean age, 46 years) who sought outpatient care at an MS center. Of those, 31 said they had used cannabis within the past month.

The patients were screened via several tools: the Cannabis Use Disorders Identification Test–Revised (CUDIT-R) Fatigue Severity Scale; Patient Health Questionnaire–8; Generalized Anxiety Disorders Scale–7; and Brief International Cognitive Assessment for Multiple Sclerosis.

Subjects were considered to have a problem with “hazardous cannabis use” if they met or exceeded the CUDIT-R’s clinical cut-off of 8 points. The test asks about topics such as hazardous behavior while using cannabis, problems with memory or concentration after using it, and inability to stop using it. Twelve participants met this criteria, and they were more likely to have more symptoms of depression (beta = 0.32; P less than .01) and anxiety (beta = 0.24; P = .02), after researchers controlled for age, years of education, and MS subtype.

They also were slightly more likely to have more severe fatigue (beta = 0.20; P = .07) and poor sleep (beta = 0.20; P = .07).

The researchers found no link between cannabis use and scores on the cognitive test, although Dr. Hughes noted that other research has suggested such a link.

The study is cross-sectional and does not offer insight into cause and effect, Dr. Hughes said. She noted that it is possible that patients used cannabis because they had higher levels of anxiety and depression.

No study funding was reported and the authors report no relevant disclosures.

SEATTLE – Pain, fatigue, depression, and anxiety are common among patients with multiple sclerosis (MS) in the 12 months after diagnosis, researchers reported at the annual meeting of the Consortium of Multiple Sclerosis Centers. In a novel study, about half of patients with MS reported clinically significant symptoms of depression or pain, and approximately 60% reported fatigue during that time.

Michigan Medicine

Pain, fatigue, depression, and anxiety are common in MS, but their prevalence in the first year after diagnosis is not well understood. To examine the rates of these conditions and how often they co-occur during that period, Anna L. Kratz, PhD, associate professor of physical medicine and rehabilitation at the University of Michigan in Ann Arbor, and her research colleagues had 231 adults with MS complete validated surveys at 1, 2, 3, 6, 9, and 12 months after diagnosis to assess symptoms of these conditions.

Overall, 47.2% of patients reported clinically significant levels of depression, 38.5% reported clinically significant levels of anxiety, 50.4% reported clinically significant pain, and 62.2% reported clinically significant fatigue at any point during the year after diagnosis. “Of those who did not have clinically significant symptoms at time of diagnosis, 21.3% went on to develop clinically significant depression, 17.0% anxiety, 30.9% pain, and 34.1% fatigue,” the authors reported.

About 23% of patients did not have clinically significant symptoms for any condition, while 20% had clinically significant symptoms for one condition, 21% for two, 19% for three, and 17% for all four.

Depression and fatigue had the highest rate of comorbidity, whereas pain and anxiety had the lowest rate of comorbidity.

“Important clinical symptoms associated with MS are present at high levels in the first year post diagnosis,” Dr. Kratz and colleagues concluded. “While the rates and severity are marginally lower than have been identified in studies of individuals farther into the MS disease course, this study is a reminder that early MS intervention should incorporate interventions for these symptoms that are known to have strong associations with quality of life.”

The researchers had no disclosures.

jremaly@mdedge.com

SEATTLE – Pain, fatigue, depression, and anxiety are common among patients with multiple sclerosis (MS) in the 12 months after diagnosis, researchers reported at the annual meeting of the Consortium of Multiple Sclerosis Centers. In a novel study, about half of patients with MS reported clinically significant symptoms of depression or pain, and approximately 60% reported fatigue during that time.

Michigan Medicine

Pain, fatigue, depression, and anxiety are common in MS, but their prevalence in the first year after diagnosis is not well understood. To examine the rates of these conditions and how often they co-occur during that period, Anna L. Kratz, PhD, associate professor of physical medicine and rehabilitation at the University of Michigan in Ann Arbor, and her research colleagues had 231 adults with MS complete validated surveys at 1, 2, 3, 6, 9, and 12 months after diagnosis to assess symptoms of these conditions.

Overall, 47.2% of patients reported clinically significant levels of depression, 38.5% reported clinically significant levels of anxiety, 50.4% reported clinically significant pain, and 62.2% reported clinically significant fatigue at any point during the year after diagnosis. “Of those who did not have clinically significant symptoms at time of diagnosis, 21.3% went on to develop clinically significant depression, 17.0% anxiety, 30.9% pain, and 34.1% fatigue,” the authors reported.

About 23% of patients did not have clinically significant symptoms for any condition, while 20% had clinically significant symptoms for one condition, 21% for two, 19% for three, and 17% for all four.

Depression and fatigue had the highest rate of comorbidity, whereas pain and anxiety had the lowest rate of comorbidity.

“Important clinical symptoms associated with MS are present at high levels in the first year post diagnosis,” Dr. Kratz and colleagues concluded. “While the rates and severity are marginally lower than have been identified in studies of individuals farther into the MS disease course, this study is a reminder that early MS intervention should incorporate interventions for these symptoms that are known to have strong associations with quality of life.”

The researchers had no disclosures.

jremaly@mdedge.com

SEATTLE – Pain, fatigue, depression, and anxiety are common among patients with multiple sclerosis (MS) in the 12 months after diagnosis, researchers reported at the annual meeting of the Consortium of Multiple Sclerosis Centers. In a novel study, about half of patients with MS reported clinically significant symptoms of depression or pain, and approximately 60% reported fatigue during that time.

Michigan Medicine

Pain, fatigue, depression, and anxiety are common in MS, but their prevalence in the first year after diagnosis is not well understood. To examine the rates of these conditions and how often they co-occur during that period, Anna L. Kratz, PhD, associate professor of physical medicine and rehabilitation at the University of Michigan in Ann Arbor, and her research colleagues had 231 adults with MS complete validated surveys at 1, 2, 3, 6, 9, and 12 months after diagnosis to assess symptoms of these conditions.

Overall, 47.2% of patients reported clinically significant levels of depression, 38.5% reported clinically significant levels of anxiety, 50.4% reported clinically significant pain, and 62.2% reported clinically significant fatigue at any point during the year after diagnosis. “Of those who did not have clinically significant symptoms at time of diagnosis, 21.3% went on to develop clinically significant depression, 17.0% anxiety, 30.9% pain, and 34.1% fatigue,” the authors reported.

About 23% of patients did not have clinically significant symptoms for any condition, while 20% had clinically significant symptoms for one condition, 21% for two, 19% for three, and 17% for all four.

Depression and fatigue had the highest rate of comorbidity, whereas pain and anxiety had the lowest rate of comorbidity.

“Important clinical symptoms associated with MS are present at high levels in the first year post diagnosis,” Dr. Kratz and colleagues concluded. “While the rates and severity are marginally lower than have been identified in studies of individuals farther into the MS disease course, this study is a reminder that early MS intervention should incorporate interventions for these symptoms that are known to have strong associations with quality of life.”

The researchers had no disclosures.

jremaly@mdedge.com

SAN FRANCISCO – Ketamine and the more recently Food and Drug Administration–approved esketamine have generated a great deal of excitement in psychiatry over their potential to treat depression and other psychiatric disorders. However, the mechanism of action is not completely understood, and efforts are underway to better understand the drugs.

Much has been made of ketamine’s interaction with the N-methyl-D-aspartate (NMDA) receptors. One belief is that chronic stress leads to the accumulation of extracellular glutamate, which leads to a range of negative consequences. Ketamine blocks excess glutamate in the synapse and may thus reverse these downstream effects.

But it may not be so clear cut, according to Nolan Williams, MD. During a session on ketamine’s mechanism of action at the annual meeting of the American Psychiatric Association, Dr. Williams, assistant professor of psychiatry and behavioral sciences at Stanford (Calif.) University, noted that ketamine is “one of the most dirty drugs we know. It affects most neurotransmitter systems and has all sorts of downstream effects.”

Pain research has already shown that ketamine’s mechanisms can be complex. It affects the opioid system, both directly and indirectly, and an opioid receptor antagonist blocks ketamine’s pain-relieving effect.

Since opioids are also known to have antidepressant effects, it’s natural to wonder if ketamine’s mechanism also involves the opioid system. The opioid antagonist naltrexone provides a tool to study the problem. Dr. Williams reasoned that if ketamine relies in whole or in part on the opioid system for its antidepressive effect, then administering naltrexone ahead of ketamine should blunt or even eliminate its efficacy.

To examine the question, the team conducted a study of 11 patients with treatment-resistant depression. Right away, it was clear that the participants had some bias toward the treatment. “They all said the same thing to me: ‘My psychiatrist said that your study doesn’t make any sense because this is an NMDA antagonist. I’m going to get two free ketamine infusions.’ So they were preloaded with this idea that they were going to get very potent antidepressant effects (even with naltrexone),” said Dr. Williams.

The study had a crossover design and included two ketamine infusions. Participants were randomized to get either naltrexone or placebo 1 hour before the first ketamine infusion, and then were allowed to relapse back to within 20% of their baseline depression score before receiving the second ketamine infusion, when they received naltrexone or placebo, whichever hadn’t been given in the first treatment.

Of 12 who completed the study, seven responded to placebo plus ketamine treatment, and six remitted. But when they crossed over to the naltrexone arm, the result was very different: In three of four measures, there was no significant difference between the pretreatment and posttreatment results. “The same people who were almost exclusively in remission during the ketamine plus placebo condition got nothing out of ketamine plus naltrexone,” said Dr. Williams. Naltrexone had a similar negating effect on the positive response to ketamine on the suicide item of the 17-item Hamilton Rating Scale for Depression.

The researchers also looked at whether ketamine’s dissociative effect could be responsible for its activity through altering the participant’s mental state, but determined that it may be necessary for the antidepressant effect – but it is not sufficient.

“What we concluded pretty strongly was that the opioid properties of ketamine are necessary to have the antidepressive effect. We’re not saying it’s sufficient, but it appears to be quite necessary,” Dr. Williams said. He added that the results don’t mean that ketamine’s effect on NMDA is unimportant. In fact, “it’s probable that the ketamine is driving the mood in a direction, and these glutamine-related changes are probably what’s maintaining the mood in that direction,” he added.

As to the clinical impacts of his findings, Dr. Williams emphasized the need to understand the mechanisms behind the ketamine class. He pointed out that in pivotal trials of esketamine, there were six deaths, three by suicide, all of them in the esketamine group. Surprisingly, two of those who took their own lives had scored a 0 on the Columbia-Suicide Severity Scale, both at baseline and at the visit immediately preceding their deaths. The score wasn’t available for the third. “These weren’t people who were particularly dangerously suicidal. So understanding the mechanism is really important to understanding the safety of this drug, who we should give it to, and what sorts of things we should watch out for,” Dr. Williams said.

The study was funded by the National Institutes of Health, Spectrum, the Brain and Behavior Research Foundation, and Stanford Bio-X. Dr. Williams had no disclosures.
 

SAN FRANCISCO – Ketamine and the more recently Food and Drug Administration–approved esketamine have generated a great deal of excitement in psychiatry over their potential to treat depression and other psychiatric disorders. However, the mechanism of action is not completely understood, and efforts are underway to better understand the drugs.

Much has been made of ketamine’s interaction with the N-methyl-D-aspartate (NMDA) receptors. One belief is that chronic stress leads to the accumulation of extracellular glutamate, which leads to a range of negative consequences. Ketamine blocks excess glutamate in the synapse and may thus reverse these downstream effects.

But it may not be so clear cut, according to Nolan Williams, MD. During a session on ketamine’s mechanism of action at the annual meeting of the American Psychiatric Association, Dr. Williams, assistant professor of psychiatry and behavioral sciences at Stanford (Calif.) University, noted that ketamine is “one of the most dirty drugs we know. It affects most neurotransmitter systems and has all sorts of downstream effects.”

Pain research has already shown that ketamine’s mechanisms can be complex. It affects the opioid system, both directly and indirectly, and an opioid receptor antagonist blocks ketamine’s pain-relieving effect.

Since opioids are also known to have antidepressant effects, it’s natural to wonder if ketamine’s mechanism also involves the opioid system. The opioid antagonist naltrexone provides a tool to study the problem. Dr. Williams reasoned that if ketamine relies in whole or in part on the opioid system for its antidepressive effect, then administering naltrexone ahead of ketamine should blunt or even eliminate its efficacy.

To examine the question, the team conducted a study of 11 patients with treatment-resistant depression. Right away, it was clear that the participants had some bias toward the treatment. “They all said the same thing to me: ‘My psychiatrist said that your study doesn’t make any sense because this is an NMDA antagonist. I’m going to get two free ketamine infusions.’ So they were preloaded with this idea that they were going to get very potent antidepressant effects (even with naltrexone),” said Dr. Williams.

The study had a crossover design and included two ketamine infusions. Participants were randomized to get either naltrexone or placebo 1 hour before the first ketamine infusion, and then were allowed to relapse back to within 20% of their baseline depression score before receiving the second ketamine infusion, when they received naltrexone or placebo, whichever hadn’t been given in the first treatment.

Of 12 who completed the study, seven responded to placebo plus ketamine treatment, and six remitted. But when they crossed over to the naltrexone arm, the result was very different: In three of four measures, there was no significant difference between the pretreatment and posttreatment results. “The same people who were almost exclusively in remission during the ketamine plus placebo condition got nothing out of ketamine plus naltrexone,” said Dr. Williams. Naltrexone had a similar negating effect on the positive response to ketamine on the suicide item of the 17-item Hamilton Rating Scale for Depression.

The researchers also looked at whether ketamine’s dissociative effect could be responsible for its activity through altering the participant’s mental state, but determined that it may be necessary for the antidepressant effect – but it is not sufficient.

“What we concluded pretty strongly was that the opioid properties of ketamine are necessary to have the antidepressive effect. We’re not saying it’s sufficient, but it appears to be quite necessary,” Dr. Williams said. He added that the results don’t mean that ketamine’s effect on NMDA is unimportant. In fact, “it’s probable that the ketamine is driving the mood in a direction, and these glutamine-related changes are probably what’s maintaining the mood in that direction,” he added.

As to the clinical impacts of his findings, Dr. Williams emphasized the need to understand the mechanisms behind the ketamine class. He pointed out that in pivotal trials of esketamine, there were six deaths, three by suicide, all of them in the esketamine group. Surprisingly, two of those who took their own lives had scored a 0 on the Columbia-Suicide Severity Scale, both at baseline and at the visit immediately preceding their deaths. The score wasn’t available for the third. “These weren’t people who were particularly dangerously suicidal. So understanding the mechanism is really important to understanding the safety of this drug, who we should give it to, and what sorts of things we should watch out for,” Dr. Williams said.

The study was funded by the National Institutes of Health, Spectrum, the Brain and Behavior Research Foundation, and Stanford Bio-X. Dr. Williams had no disclosures.
 

SAN FRANCISCO – Ketamine and the more recently Food and Drug Administration–approved esketamine have generated a great deal of excitement in psychiatry over their potential to treat depression and other psychiatric disorders. However, the mechanism of action is not completely understood, and efforts are underway to better understand the drugs.

Much has been made of ketamine’s interaction with the N-methyl-D-aspartate (NMDA) receptors. One belief is that chronic stress leads to the accumulation of extracellular glutamate, which leads to a range of negative consequences. Ketamine blocks excess glutamate in the synapse and may thus reverse these downstream effects.

But it may not be so clear cut, according to Nolan Williams, MD. During a session on ketamine’s mechanism of action at the annual meeting of the American Psychiatric Association, Dr. Williams, assistant professor of psychiatry and behavioral sciences at Stanford (Calif.) University, noted that ketamine is “one of the most dirty drugs we know. It affects most neurotransmitter systems and has all sorts of downstream effects.”

Pain research has already shown that ketamine’s mechanisms can be complex. It affects the opioid system, both directly and indirectly, and an opioid receptor antagonist blocks ketamine’s pain-relieving effect.

Since opioids are also known to have antidepressant effects, it’s natural to wonder if ketamine’s mechanism also involves the opioid system. The opioid antagonist naltrexone provides a tool to study the problem. Dr. Williams reasoned that if ketamine relies in whole or in part on the opioid system for its antidepressive effect, then administering naltrexone ahead of ketamine should blunt or even eliminate its efficacy.

To examine the question, the team conducted a study of 11 patients with treatment-resistant depression. Right away, it was clear that the participants had some bias toward the treatment. “They all said the same thing to me: ‘My psychiatrist said that your study doesn’t make any sense because this is an NMDA antagonist. I’m going to get two free ketamine infusions.’ So they were preloaded with this idea that they were going to get very potent antidepressant effects (even with naltrexone),” said Dr. Williams.

The study had a crossover design and included two ketamine infusions. Participants were randomized to get either naltrexone or placebo 1 hour before the first ketamine infusion, and then were allowed to relapse back to within 20% of their baseline depression score before receiving the second ketamine infusion, when they received naltrexone or placebo, whichever hadn’t been given in the first treatment.

Of 12 who completed the study, seven responded to placebo plus ketamine treatment, and six remitted. But when they crossed over to the naltrexone arm, the result was very different: In three of four measures, there was no significant difference between the pretreatment and posttreatment results. “The same people who were almost exclusively in remission during the ketamine plus placebo condition got nothing out of ketamine plus naltrexone,” said Dr. Williams. Naltrexone had a similar negating effect on the positive response to ketamine on the suicide item of the 17-item Hamilton Rating Scale for Depression.

The researchers also looked at whether ketamine’s dissociative effect could be responsible for its activity through altering the participant’s mental state, but determined that it may be necessary for the antidepressant effect – but it is not sufficient.

“What we concluded pretty strongly was that the opioid properties of ketamine are necessary to have the antidepressive effect. We’re not saying it’s sufficient, but it appears to be quite necessary,” Dr. Williams said. He added that the results don’t mean that ketamine’s effect on NMDA is unimportant. In fact, “it’s probable that the ketamine is driving the mood in a direction, and these glutamine-related changes are probably what’s maintaining the mood in that direction,” he added.

As to the clinical impacts of his findings, Dr. Williams emphasized the need to understand the mechanisms behind the ketamine class. He pointed out that in pivotal trials of esketamine, there were six deaths, three by suicide, all of them in the esketamine group. Surprisingly, two of those who took their own lives had scored a 0 on the Columbia-Suicide Severity Scale, both at baseline and at the visit immediately preceding their deaths. The score wasn’t available for the third. “These weren’t people who were particularly dangerously suicidal. So understanding the mechanism is really important to understanding the safety of this drug, who we should give it to, and what sorts of things we should watch out for,” Dr. Williams said.

The study was funded by the National Institutes of Health, Spectrum, the Brain and Behavior Research Foundation, and Stanford Bio-X. Dr. Williams had no disclosures.
 

SAN FRANCISCO – It’s a common scenario, and it’s going to become more common: Psychiatric patients will be coming into the office not quite satisfied with their current treatment and wanting to try cannabis.

With laws varying from state to state and a limited but growing body of evidence, the situation “presents a complicated, often difficult clinical situation,” said David A. Gorelick, MD, PhD, professor of psychiatry at the University of Maryland, Baltimore.

There is some evidence supporting cannabis for chronic pain, neuropathic pain, spasticity in multiple sclerosis, and chemotherapy-induced nausea and vomiting. Cannabidiol is also Food and Drug Administration approved for two severe forms of pediatric epilepsy.

When it comes to psychiatric disorders, however, evidence is largely lacking. There have been suggestions of cannabis increasing anxiety and worsening posttraumatic stress, depression, bipolar disorder, and psychosis. On the other hand, some patients swear by marijuana for psychiatric symptom relief.

So what to do? Dr. Gorelick, editor of the Journal of Cannabis Research, had some advice in a video interview at the annual meeting of the American Psychiatric Association.

Where it’s legal, a cannabis recommendation for pain and sleep problems is reasonable, but it’s important to figure out what’s lacking in the patients’ treatment regimen that makes them want to try cannabis, and to first try to maximize treatment with approved, evidence-based options. As with any medication, a talk about risks and benefits is also essential. There’s an increased risk of motor vehicle accidents, acute panic attacks, and other issues with cannabis. Also, keep in mind that cannabinoids, particularly tetrahydrocannabinol, are metabolized in the liver and can interfere with concentrations of other liver-metabolized drugs, including some antidepressants and anticonvulsants. It’s not clear how significant the clinical interactions are, “but if patients are on warfarin, I would be very careful,” he said.

Dr. Gorelick disclosed speaking fees from hospitals and organizations for presentations on medical cannabis and royalties from Up-to-Date for cannabis topics. He also disclosed receiving honoraria from Colorado State University, Pueblo, and from Springer for his work on the Journal of Cannabis Research.

aotto@mdedge.com

SAN FRANCISCO – It’s a common scenario, and it’s going to become more common: Psychiatric patients will be coming into the office not quite satisfied with their current treatment and wanting to try cannabis.

With laws varying from state to state and a limited but growing body of evidence, the situation “presents a complicated, often difficult clinical situation,” said David A. Gorelick, MD, PhD, professor of psychiatry at the University of Maryland, Baltimore.

There is some evidence supporting cannabis for chronic pain, neuropathic pain, spasticity in multiple sclerosis, and chemotherapy-induced nausea and vomiting. Cannabidiol is also Food and Drug Administration approved for two severe forms of pediatric epilepsy.

When it comes to psychiatric disorders, however, evidence is largely lacking. There have been suggestions of cannabis increasing anxiety and worsening posttraumatic stress, depression, bipolar disorder, and psychosis. On the other hand, some patients swear by marijuana for psychiatric symptom relief.

So what to do? Dr. Gorelick, editor of the Journal of Cannabis Research, had some advice in a video interview at the annual meeting of the American Psychiatric Association.

Where it’s legal, a cannabis recommendation for pain and sleep problems is reasonable, but it’s important to figure out what’s lacking in the patients’ treatment regimen that makes them want to try cannabis, and to first try to maximize treatment with approved, evidence-based options. As with any medication, a talk about risks and benefits is also essential. There’s an increased risk of motor vehicle accidents, acute panic attacks, and other issues with cannabis. Also, keep in mind that cannabinoids, particularly tetrahydrocannabinol, are metabolized in the liver and can interfere with concentrations of other liver-metabolized drugs, including some antidepressants and anticonvulsants. It’s not clear how significant the clinical interactions are, “but if patients are on warfarin, I would be very careful,” he said.

Dr. Gorelick disclosed speaking fees from hospitals and organizations for presentations on medical cannabis and royalties from Up-to-Date for cannabis topics. He also disclosed receiving honoraria from Colorado State University, Pueblo, and from Springer for his work on the Journal of Cannabis Research.

aotto@mdedge.com

SAN FRANCISCO – It’s a common scenario, and it’s going to become more common: Psychiatric patients will be coming into the office not quite satisfied with their current treatment and wanting to try cannabis.

With laws varying from state to state and a limited but growing body of evidence, the situation “presents a complicated, often difficult clinical situation,” said David A. Gorelick, MD, PhD, professor of psychiatry at the University of Maryland, Baltimore.

There is some evidence supporting cannabis for chronic pain, neuropathic pain, spasticity in multiple sclerosis, and chemotherapy-induced nausea and vomiting. Cannabidiol is also Food and Drug Administration approved for two severe forms of pediatric epilepsy.

When it comes to psychiatric disorders, however, evidence is largely lacking. There have been suggestions of cannabis increasing anxiety and worsening posttraumatic stress, depression, bipolar disorder, and psychosis. On the other hand, some patients swear by marijuana for psychiatric symptom relief.

So what to do? Dr. Gorelick, editor of the Journal of Cannabis Research, had some advice in a video interview at the annual meeting of the American Psychiatric Association.

Where it’s legal, a cannabis recommendation for pain and sleep problems is reasonable, but it’s important to figure out what’s lacking in the patients’ treatment regimen that makes them want to try cannabis, and to first try to maximize treatment with approved, evidence-based options. As with any medication, a talk about risks and benefits is also essential. There’s an increased risk of motor vehicle accidents, acute panic attacks, and other issues with cannabis. Also, keep in mind that cannabinoids, particularly tetrahydrocannabinol, are metabolized in the liver and can interfere with concentrations of other liver-metabolized drugs, including some antidepressants and anticonvulsants. It’s not clear how significant the clinical interactions are, “but if patients are on warfarin, I would be very careful,” he said.

Dr. Gorelick disclosed speaking fees from hospitals and organizations for presentations on medical cannabis and royalties from Up-to-Date for cannabis topics. He also disclosed receiving honoraria from Colorado State University, Pueblo, and from Springer for his work on the Journal of Cannabis Research.

aotto@mdedge.com

Please join us Monday, June 3, at 8:00 p.m. ET as we discuss depression in physicians and the resulting tragedies, as well as how to help physicians receive the treatment they need to prevent suicide.

Our special guests include physicians with expertise on the triggers of physician depression and solutions for fighting this epidemic, Sarah Candler, MD, (@sarahgcandler) and Elisabeth Poorman, MD, (@DrPoorman). We hope you will participate in our Twitter chat on June 3 at 8 p.m. ET. #MDedgeChats

Physicians have higher rates of depression and suicide, compared with the general population, according to the American Foundation for Suicide Prevention. Suicide rates for male physicians are 1.41 times higher than in the general population and, for female physicians, 2.27 times greater.

“But these numbers come from only those deaths that are reported publicly,” Dr. Poorman wrote in an article that was published by WBUR, Boston’s NPR News Station. In fact, as Dr. Poorman was writing this story, she learned of five separate deaths that were widely known to be suicides, but never publicly identified as such, she said.

One possible explanation for physicians’ higher likelihood of becoming depressed or dying by suicide, compared with other professionals, is their hesitance to receive mental health treatment, experts have suggested. Psychiatrist Michael F. Myers, MD, found anecdotal evidence of this tendency when he interviewed the loved ones, friends, and colleagues of physicians who took their own lives.

In this chat we will discuss this topic and other possible reasons for the high rate of depression and suicide among physicians.

Topics of conversation

Question 1: What are the causes of physician depression and suicide in training and practice?

Question 2: How can we end stigma against seeking mental health treatment among physicians?

Question 3: How can we prevent depression and suicide among medical students and physicians?

Question 4: Which institutions or programs are exemplars in providing resources to improve mental health?

Question 5: What organizational and political changes are likely to reduce physician suicides?

Resources

1. Getting Back to Medicine as a Community

2. What stops physicians from getting mental health care?

3. Risk considerations for suicidal physicians

4. Two more and counting: Suicide in medical trainees

5. How to talk with a struggling physician colleague

6. Healthcare industry takes on high physician suicide rates, mental health stigma

7. The Curbsiders episode #129 Depression and Suicide: Occupational Hazards of Practicing Medicine

8. Creating Joy in Medicine in St. Paul, MN: A Case Study

9. Stress and rigorous work schedules push a doctor to commit suicide every day in the US: 'We need them, but they need us'
 

About Dr. Poorman

Dr. Poorman (@DrPoorman) is a primary care physician at the University of Washington in Seattle, a freelance journalist covering issues related to medicine, and a frequent speaker on the causes of and solutions to mental illness among providers.

Her writing has been featured in Self, The Guardian. Medpage Today’s KevinMD.com, and other publications. She produces the blog: https://www.drpoorman.org/what-we-do.

About Dr. Candler

Dr. Candler (@sarahgcandler) is a primary care physician in Houston. She is coeditor of the Annals Fresh Look blog, and a member of Internal Medicine News’ Editorial Advisory Board.

She is currently consulting for a tech firm and will later be joining Iora Health to start a Medicare Advantage clinic.

klennon@mdedge.com

Please join us Monday, June 3, at 8:00 p.m. ET as we discuss depression in physicians and the resulting tragedies, as well as how to help physicians receive the treatment they need to prevent suicide.

Our special guests include physicians with expertise on the triggers of physician depression and solutions for fighting this epidemic, Sarah Candler, MD, (@sarahgcandler) and Elisabeth Poorman, MD, (@DrPoorman). We hope you will participate in our Twitter chat on June 3 at 8 p.m. ET. #MDedgeChats

Physicians have higher rates of depression and suicide, compared with the general population, according to the American Foundation for Suicide Prevention. Suicide rates for male physicians are 1.41 times higher than in the general population and, for female physicians, 2.27 times greater.

“But these numbers come from only those deaths that are reported publicly,” Dr. Poorman wrote in an article that was published by WBUR, Boston’s NPR News Station. In fact, as Dr. Poorman was writing this story, she learned of five separate deaths that were widely known to be suicides, but never publicly identified as such, she said.

One possible explanation for physicians’ higher likelihood of becoming depressed or dying by suicide, compared with other professionals, is their hesitance to receive mental health treatment, experts have suggested. Psychiatrist Michael F. Myers, MD, found anecdotal evidence of this tendency when he interviewed the loved ones, friends, and colleagues of physicians who took their own lives.

In this chat we will discuss this topic and other possible reasons for the high rate of depression and suicide among physicians.

Topics of conversation

Question 1: What are the causes of physician depression and suicide in training and practice?

Question 2: How can we end stigma against seeking mental health treatment among physicians?

Question 3: How can we prevent depression and suicide among medical students and physicians?

Question 4: Which institutions or programs are exemplars in providing resources to improve mental health?

Question 5: What organizational and political changes are likely to reduce physician suicides?

Resources

1. Getting Back to Medicine as a Community

2. What stops physicians from getting mental health care?

3. Risk considerations for suicidal physicians

4. Two more and counting: Suicide in medical trainees

5. How to talk with a struggling physician colleague

6. Healthcare industry takes on high physician suicide rates, mental health stigma

7. The Curbsiders episode #129 Depression and Suicide: Occupational Hazards of Practicing Medicine

8. Creating Joy in Medicine in St. Paul, MN: A Case Study

9. Stress and rigorous work schedules push a doctor to commit suicide every day in the US: 'We need them, but they need us'
 

About Dr. Poorman

Dr. Poorman (@DrPoorman) is a primary care physician at the University of Washington in Seattle, a freelance journalist covering issues related to medicine, and a frequent speaker on the causes of and solutions to mental illness among providers.

Her writing has been featured in Self, The Guardian. Medpage Today’s KevinMD.com, and other publications. She produces the blog: https://www.drpoorman.org/what-we-do.

About Dr. Candler

Dr. Candler (@sarahgcandler) is a primary care physician in Houston. She is coeditor of the Annals Fresh Look blog, and a member of Internal Medicine News’ Editorial Advisory Board.

She is currently consulting for a tech firm and will later be joining Iora Health to start a Medicare Advantage clinic.

klennon@mdedge.com

Please join us Monday, June 3, at 8:00 p.m. ET as we discuss depression in physicians and the resulting tragedies, as well as how to help physicians receive the treatment they need to prevent suicide.

Our special guests include physicians with expertise on the triggers of physician depression and solutions for fighting this epidemic, Sarah Candler, MD, (@sarahgcandler) and Elisabeth Poorman, MD, (@DrPoorman). We hope you will participate in our Twitter chat on June 3 at 8 p.m. ET. #MDedgeChats

Physicians have higher rates of depression and suicide, compared with the general population, according to the American Foundation for Suicide Prevention. Suicide rates for male physicians are 1.41 times higher than in the general population and, for female physicians, 2.27 times greater.

“But these numbers come from only those deaths that are reported publicly,” Dr. Poorman wrote in an article that was published by WBUR, Boston’s NPR News Station. In fact, as Dr. Poorman was writing this story, she learned of five separate deaths that were widely known to be suicides, but never publicly identified as such, she said.

One possible explanation for physicians’ higher likelihood of becoming depressed or dying by suicide, compared with other professionals, is their hesitance to receive mental health treatment, experts have suggested. Psychiatrist Michael F. Myers, MD, found anecdotal evidence of this tendency when he interviewed the loved ones, friends, and colleagues of physicians who took their own lives.

In this chat we will discuss this topic and other possible reasons for the high rate of depression and suicide among physicians.

Topics of conversation

Question 1: What are the causes of physician depression and suicide in training and practice?

Question 2: How can we end stigma against seeking mental health treatment among physicians?

Question 3: How can we prevent depression and suicide among medical students and physicians?

Question 4: Which institutions or programs are exemplars in providing resources to improve mental health?

Question 5: What organizational and political changes are likely to reduce physician suicides?

Resources

1. Getting Back to Medicine as a Community

2. What stops physicians from getting mental health care?

3. Risk considerations for suicidal physicians

4. Two more and counting: Suicide in medical trainees

5. How to talk with a struggling physician colleague

6. Healthcare industry takes on high physician suicide rates, mental health stigma

7. The Curbsiders episode #129 Depression and Suicide: Occupational Hazards of Practicing Medicine

8. Creating Joy in Medicine in St. Paul, MN: A Case Study

9. Stress and rigorous work schedules push a doctor to commit suicide every day in the US: 'We need them, but they need us'
 

About Dr. Poorman

Dr. Poorman (@DrPoorman) is a primary care physician at the University of Washington in Seattle, a freelance journalist covering issues related to medicine, and a frequent speaker on the causes of and solutions to mental illness among providers.

Her writing has been featured in Self, The Guardian. Medpage Today’s KevinMD.com, and other publications. She produces the blog: https://www.drpoorman.org/what-we-do.

About Dr. Candler

Dr. Candler (@sarahgcandler) is a primary care physician in Houston. She is coeditor of the Annals Fresh Look blog, and a member of Internal Medicine News’ Editorial Advisory Board.

She is currently consulting for a tech firm and will later be joining Iora Health to start a Medicare Advantage clinic.

klennon@mdedge.com