Bipolar Disorder

Bipolar disorder patients’ perceptions of their overall physical health can predict the severity of their functioning over the next 2 years, according to research published in the Journal of Affective Disorders.

Analyzing longitudinal data from the Systematic Treatment Enhancement Program for Bipolar Disorder on the physical subscales of the 36-Item Short Form Health Survey, Emily Bernstein and her colleagues at Harvard Medical School and Massachusetts General Hospital in Boston found that individuals with more negative views of their physical well-being tended to have more severe mood symptoms and worse functioning across 2 years of observation. “Perceptions of role limitations due to physical health problems predicted depressive symptoms and poor life satisfaction, while worse bodily pain predicted symptoms of mania and hypomania,” the authors wrote. Physical functioning was not a significant predictor of clinical outcomes.

“These data suggest that addressing broad attitudes or thoughts about physical health is important in treating individuals with bipolar disorder as subjective perceptions seem to impact course of illness,” Dr. Bernstein and her colleagues wrote. Introducing stress management or relaxation training into treatments for bipolar disorder could help reduce patients’ sensations of pain and their consequences for course of illness, particularly mania and hypomania, the investigators said. Psychotherapy also could play a beneficial role for such patients “in targeting and modifying the way they think about their health.”

Read the article in the Journal of Affective Disorders (doi: http://dx.doi.org/10.1016/j.jad.2015.09.052).

Bipolar disorder patients’ perceptions of their overall physical health can predict the severity of their functioning over the next 2 years, according to research published in the Journal of Affective Disorders.

Analyzing longitudinal data from the Systematic Treatment Enhancement Program for Bipolar Disorder on the physical subscales of the 36-Item Short Form Health Survey, Emily Bernstein and her colleagues at Harvard Medical School and Massachusetts General Hospital in Boston found that individuals with more negative views of their physical well-being tended to have more severe mood symptoms and worse functioning across 2 years of observation. “Perceptions of role limitations due to physical health problems predicted depressive symptoms and poor life satisfaction, while worse bodily pain predicted symptoms of mania and hypomania,” the authors wrote. Physical functioning was not a significant predictor of clinical outcomes.

“These data suggest that addressing broad attitudes or thoughts about physical health is important in treating individuals with bipolar disorder as subjective perceptions seem to impact course of illness,” Dr. Bernstein and her colleagues wrote. Introducing stress management or relaxation training into treatments for bipolar disorder could help reduce patients’ sensations of pain and their consequences for course of illness, particularly mania and hypomania, the investigators said. Psychotherapy also could play a beneficial role for such patients “in targeting and modifying the way they think about their health.”

Read the article in the Journal of Affective Disorders (doi: http://dx.doi.org/10.1016/j.jad.2015.09.052).

Bipolar disorder patients’ perceptions of their overall physical health can predict the severity of their functioning over the next 2 years, according to research published in the Journal of Affective Disorders.

Analyzing longitudinal data from the Systematic Treatment Enhancement Program for Bipolar Disorder on the physical subscales of the 36-Item Short Form Health Survey, Emily Bernstein and her colleagues at Harvard Medical School and Massachusetts General Hospital in Boston found that individuals with more negative views of their physical well-being tended to have more severe mood symptoms and worse functioning across 2 years of observation. “Perceptions of role limitations due to physical health problems predicted depressive symptoms and poor life satisfaction, while worse bodily pain predicted symptoms of mania and hypomania,” the authors wrote. Physical functioning was not a significant predictor of clinical outcomes.

“These data suggest that addressing broad attitudes or thoughts about physical health is important in treating individuals with bipolar disorder as subjective perceptions seem to impact course of illness,” Dr. Bernstein and her colleagues wrote. Introducing stress management or relaxation training into treatments for bipolar disorder could help reduce patients’ sensations of pain and their consequences for course of illness, particularly mania and hypomania, the investigators said. Psychotherapy also could play a beneficial role for such patients “in targeting and modifying the way they think about their health.”

Read the article in the Journal of Affective Disorders (doi: http://dx.doi.org/10.1016/j.jad.2015.09.052).

The burden of psychiatric comorbidity is greater in patients with multiple sclerosis (MS), compared with the general population, reported Dr. Ruth Ann Marrie and coauthors from the departments of psychiatry and medicine at the University of Manitoba, Winnipeg.

A study of 44,452 MS patients and 220,849 controls in four Canadian provinces from 1995 to 2005 found that the incidence of depression in the MS group was 0.98% (95% CI; 0.81%-1.15%), compared with 0.72% (95% CI; 0.67%-0.76%) in the control group. The prevalence of depression was 20.1% in MS patients (19.5%-20.6%), compared with 11.9% (11.8%-12.1%) in the matched population, the authors noted.

HUNG KUO CHUN/Thinkstock

Also, the incidence and prevalence of anxiety disorder in the MS population was 0.64% (0.54%-0.73%) and 8.7% (8.4%-9.1%), respectively, compared with 0.42% (0.39%-0.45%) and 5.1% (4.9%-5.2%) in controls .

For bipolar disorder, the MS group had an incidence of 0.33% (0.26%-0.39%), compared with 0.16% (0.14%-0.18%) in controls. Prevalence was 4.7% (4.4%-4.9%) in the MS group and 2.3% (2.2%-2.3%) in controls .

Lastly, in schizophrenia, MS patients had an incidence of 0.060% (0.031%-0.080%), compared with 0.018% (0.011%-0.024%) in controls. Prevalence was 1.28% (1.15%-1.41%), in the MS group and 1.03% (0.99%-1.08%) in controls, the investigators said.

The findings suggest a “nonspecific effect of MS on psychiatric comorbidity,” Dr. Marrie and colleagues said in the report.

“From a policy perspective, this implies the need for general psychiatric support rather than illness-specific strategies,” they concluded.

Read the study in Neurology.

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The burden of psychiatric comorbidity is greater in patients with multiple sclerosis (MS), compared with the general population, reported Dr. Ruth Ann Marrie and coauthors from the departments of psychiatry and medicine at the University of Manitoba, Winnipeg.

A study of 44,452 MS patients and 220,849 controls in four Canadian provinces from 1995 to 2005 found that the incidence of depression in the MS group was 0.98% (95% CI; 0.81%-1.15%), compared with 0.72% (95% CI; 0.67%-0.76%) in the control group. The prevalence of depression was 20.1% in MS patients (19.5%-20.6%), compared with 11.9% (11.8%-12.1%) in the matched population, the authors noted.

HUNG KUO CHUN/Thinkstock

Also, the incidence and prevalence of anxiety disorder in the MS population was 0.64% (0.54%-0.73%) and 8.7% (8.4%-9.1%), respectively, compared with 0.42% (0.39%-0.45%) and 5.1% (4.9%-5.2%) in controls .

For bipolar disorder, the MS group had an incidence of 0.33% (0.26%-0.39%), compared with 0.16% (0.14%-0.18%) in controls. Prevalence was 4.7% (4.4%-4.9%) in the MS group and 2.3% (2.2%-2.3%) in controls .

Lastly, in schizophrenia, MS patients had an incidence of 0.060% (0.031%-0.080%), compared with 0.018% (0.011%-0.024%) in controls. Prevalence was 1.28% (1.15%-1.41%), in the MS group and 1.03% (0.99%-1.08%) in controls, the investigators said.

The findings suggest a “nonspecific effect of MS on psychiatric comorbidity,” Dr. Marrie and colleagues said in the report.

“From a policy perspective, this implies the need for general psychiatric support rather than illness-specific strategies,” they concluded.

Read the study in Neurology.

[email protected]

The burden of psychiatric comorbidity is greater in patients with multiple sclerosis (MS), compared with the general population, reported Dr. Ruth Ann Marrie and coauthors from the departments of psychiatry and medicine at the University of Manitoba, Winnipeg.

A study of 44,452 MS patients and 220,849 controls in four Canadian provinces from 1995 to 2005 found that the incidence of depression in the MS group was 0.98% (95% CI; 0.81%-1.15%), compared with 0.72% (95% CI; 0.67%-0.76%) in the control group. The prevalence of depression was 20.1% in MS patients (19.5%-20.6%), compared with 11.9% (11.8%-12.1%) in the matched population, the authors noted.

HUNG KUO CHUN/Thinkstock

Also, the incidence and prevalence of anxiety disorder in the MS population was 0.64% (0.54%-0.73%) and 8.7% (8.4%-9.1%), respectively, compared with 0.42% (0.39%-0.45%) and 5.1% (4.9%-5.2%) in controls .

For bipolar disorder, the MS group had an incidence of 0.33% (0.26%-0.39%), compared with 0.16% (0.14%-0.18%) in controls. Prevalence was 4.7% (4.4%-4.9%) in the MS group and 2.3% (2.2%-2.3%) in controls .

Lastly, in schizophrenia, MS patients had an incidence of 0.060% (0.031%-0.080%), compared with 0.018% (0.011%-0.024%) in controls. Prevalence was 1.28% (1.15%-1.41%), in the MS group and 1.03% (0.99%-1.08%) in controls, the investigators said.

The findings suggest a “nonspecific effect of MS on psychiatric comorbidity,” Dr. Marrie and colleagues said in the report.

“From a policy perspective, this implies the need for general psychiatric support rather than illness-specific strategies,” they concluded.

Read the study in Neurology.

[email protected]

When screening for bipolar disorders, Mood Disorders Questionnaire scores proved more sensitive – but showed less specificity – in an inpatient mood disorders setting than an outpatient psychiatric population, a retrospective study shows. The results suggest that the MDQ can be used effectively on an inpatient psychiatry mood disorders unit, reported Dr. Simon Kung and his associates.

Dr. Kung of the Mayo Clinic in Rochester, Minn., and his associates evaluated 1,330 patients who checked into a mood disorders unit and administered the MDQ upon entry. After excluding patients with diagnoses that were neither unipolar or bipolar, 860 MDQs were ultimately used. Sensitivity and specificity were calculated for each number of questionnaire items checked positive.

The researchers determined that the optimal cutoff score for MDQs was 8, resulting in a sensitivity/specificity of 86%/71%, compared with 92%/64% using the recommended outpatient cutoff of 7.

Read the full article here: (J Affect Disord. 201515;188:97-100. doi:10.1016/j.jad.2015.08.060)

[email protected]

When screening for bipolar disorders, Mood Disorders Questionnaire scores proved more sensitive – but showed less specificity – in an inpatient mood disorders setting than an outpatient psychiatric population, a retrospective study shows. The results suggest that the MDQ can be used effectively on an inpatient psychiatry mood disorders unit, reported Dr. Simon Kung and his associates.

Dr. Kung of the Mayo Clinic in Rochester, Minn., and his associates evaluated 1,330 patients who checked into a mood disorders unit and administered the MDQ upon entry. After excluding patients with diagnoses that were neither unipolar or bipolar, 860 MDQs were ultimately used. Sensitivity and specificity were calculated for each number of questionnaire items checked positive.

The researchers determined that the optimal cutoff score for MDQs was 8, resulting in a sensitivity/specificity of 86%/71%, compared with 92%/64% using the recommended outpatient cutoff of 7.

Read the full article here: (J Affect Disord. 201515;188:97-100. doi:10.1016/j.jad.2015.08.060)

[email protected]

When screening for bipolar disorders, Mood Disorders Questionnaire scores proved more sensitive – but showed less specificity – in an inpatient mood disorders setting than an outpatient psychiatric population, a retrospective study shows. The results suggest that the MDQ can be used effectively on an inpatient psychiatry mood disorders unit, reported Dr. Simon Kung and his associates.

Dr. Kung of the Mayo Clinic in Rochester, Minn., and his associates evaluated 1,330 patients who checked into a mood disorders unit and administered the MDQ upon entry. After excluding patients with diagnoses that were neither unipolar or bipolar, 860 MDQs were ultimately used. Sensitivity and specificity were calculated for each number of questionnaire items checked positive.

The researchers determined that the optimal cutoff score for MDQs was 8, resulting in a sensitivity/specificity of 86%/71%, compared with 92%/64% using the recommended outpatient cutoff of 7.

Read the full article here: (J Affect Disord. 201515;188:97-100. doi:10.1016/j.jad.2015.08.060)

[email protected]

Patients with bipolar disorder who perceive their overall physical health as poor experience worse disease outcomes, according to Emily E. Bernstein of Harvard University, Cambridge, Mass., and her associates.

Data were collected from the Systematic Treatment Enhancement Program for Bipolar Disorder and were analyzed via the Short Form Health Survey (SF-36). An increased sense of role limitation increased the risk of depressive symptoms, while increased physical pain raised the risk of mania/hypomania. “Reports of specific or concrete physical limitations in daily life showed no associations with psychiatric symptoms at concurrent assessments, but did predict worse course of illness” 1 year later, the researchers wrote.

“Though further research is warranted, changes in subjective physical health–related quality of life, even independent of objective health changes, may offer important insight into global well-being and be targets of psychotherapy treatment,” they concluded.

Find the study in the Journal of Affective Disorders (doi: 10.1016/j.jad.2015.09.052).

[email protected]

Patients with bipolar disorder who perceive their overall physical health as poor experience worse disease outcomes, according to Emily E. Bernstein of Harvard University, Cambridge, Mass., and her associates.

Data were collected from the Systematic Treatment Enhancement Program for Bipolar Disorder and were analyzed via the Short Form Health Survey (SF-36). An increased sense of role limitation increased the risk of depressive symptoms, while increased physical pain raised the risk of mania/hypomania. “Reports of specific or concrete physical limitations in daily life showed no associations with psychiatric symptoms at concurrent assessments, but did predict worse course of illness” 1 year later, the researchers wrote.

“Though further research is warranted, changes in subjective physical health–related quality of life, even independent of objective health changes, may offer important insight into global well-being and be targets of psychotherapy treatment,” they concluded.

Find the study in the Journal of Affective Disorders (doi: 10.1016/j.jad.2015.09.052).

[email protected]

Patients with bipolar disorder who perceive their overall physical health as poor experience worse disease outcomes, according to Emily E. Bernstein of Harvard University, Cambridge, Mass., and her associates.

Data were collected from the Systematic Treatment Enhancement Program for Bipolar Disorder and were analyzed via the Short Form Health Survey (SF-36). An increased sense of role limitation increased the risk of depressive symptoms, while increased physical pain raised the risk of mania/hypomania. “Reports of specific or concrete physical limitations in daily life showed no associations with psychiatric symptoms at concurrent assessments, but did predict worse course of illness” 1 year later, the researchers wrote.

“Though further research is warranted, changes in subjective physical health–related quality of life, even independent of objective health changes, may offer important insight into global well-being and be targets of psychotherapy treatment,” they concluded.

Find the study in the Journal of Affective Disorders (doi: 10.1016/j.jad.2015.09.052).

[email protected]

Both bipolar disorder (BD) patients and their first-degree relatives were slower than were healthy controls in an emotion recognition task, suggesting facial recognition may be an endophenotype in bipolar disorder, according to a study published in Psychiatry Research.

Dr. Esther Vierck of the University of Otago in New Zealand and her associates compared 36 BD patients and 40 healthy control participants in a computerized facial emotion recognition task – 24 of the BD patient group’s first-degree relatives also were measured.

The researchers noted that bipolar patients were less accurate in recognizing emotional expressions than were controls, but did not find any evidence for emotion specificity within the BD or BD relative groups.

Read the article here: doi:10.1016/j.psychres.2015.08.033.

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Both bipolar disorder (BD) patients and their first-degree relatives were slower than were healthy controls in an emotion recognition task, suggesting facial recognition may be an endophenotype in bipolar disorder, according to a study published in Psychiatry Research.

Dr. Esther Vierck of the University of Otago in New Zealand and her associates compared 36 BD patients and 40 healthy control participants in a computerized facial emotion recognition task – 24 of the BD patient group’s first-degree relatives also were measured.

The researchers noted that bipolar patients were less accurate in recognizing emotional expressions than were controls, but did not find any evidence for emotion specificity within the BD or BD relative groups.

Read the article here: doi:10.1016/j.psychres.2015.08.033.

[email protected]

Both bipolar disorder (BD) patients and their first-degree relatives were slower than were healthy controls in an emotion recognition task, suggesting facial recognition may be an endophenotype in bipolar disorder, according to a study published in Psychiatry Research.

Dr. Esther Vierck of the University of Otago in New Zealand and her associates compared 36 BD patients and 40 healthy control participants in a computerized facial emotion recognition task – 24 of the BD patient group’s first-degree relatives also were measured.

The researchers noted that bipolar patients were less accurate in recognizing emotional expressions than were controls, but did not find any evidence for emotion specificity within the BD or BD relative groups.

Read the article here: doi:10.1016/j.psychres.2015.08.033.

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Lithium appears to be both safe and effective for the management of bipolar I disorder symptoms in pediatric populations, a recently published study from Pediatrics confirms.

Lead author Dr. Robert L. Findling of Johns Hopkins University and his associates conducted a multicenter, randomized, placebo-controlled outpatient trial, gathering data from 153 participants between the ages of 7 and 17 with bipolar I disorder/manic or mixed episodes. Among the participants, 81 were randomized to receive lithium (n = 53) or placebo (n = 28), for up to 8 weeks. Symptoms of bipolar disorder were assessed using the Young Mania Rating Scale (YMRS) score.

Ultimately, the study found that lithium was effective in reducing manic symptoms in nearly one-half (47%) of these participants, with Overall Clinical Global Impression–Improvement scores favoring lithium (n = 25; 47% very much/much improved), compared with placebo (n = 6; 21% very much/much improved) after 8 weeks. The researchers also noted that lithium use was not associated with weight gain, although they observed a statistically significant increase in thyrotropin concentration among the lithium group. Nausea, headache, and vomiting were the most common side effects.

“This study provides evidence to support the efficacy of lithium in the acute treatment of youths with [bipolar I disorder] who are currently in a manic or mixed state. Lithium had an adverse effect profile that was acceptable for most patients,” the authors wrote.

Read the full article in Pediatrics.

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Lithium appears to be both safe and effective for the management of bipolar I disorder symptoms in pediatric populations, a recently published study from Pediatrics confirms.

Lead author Dr. Robert L. Findling of Johns Hopkins University and his associates conducted a multicenter, randomized, placebo-controlled outpatient trial, gathering data from 153 participants between the ages of 7 and 17 with bipolar I disorder/manic or mixed episodes. Among the participants, 81 were randomized to receive lithium (n = 53) or placebo (n = 28), for up to 8 weeks. Symptoms of bipolar disorder were assessed using the Young Mania Rating Scale (YMRS) score.

Ultimately, the study found that lithium was effective in reducing manic symptoms in nearly one-half (47%) of these participants, with Overall Clinical Global Impression–Improvement scores favoring lithium (n = 25; 47% very much/much improved), compared with placebo (n = 6; 21% very much/much improved) after 8 weeks. The researchers also noted that lithium use was not associated with weight gain, although they observed a statistically significant increase in thyrotropin concentration among the lithium group. Nausea, headache, and vomiting were the most common side effects.

“This study provides evidence to support the efficacy of lithium in the acute treatment of youths with [bipolar I disorder] who are currently in a manic or mixed state. Lithium had an adverse effect profile that was acceptable for most patients,” the authors wrote.

Read the full article in Pediatrics.

[email protected]

Lithium appears to be both safe and effective for the management of bipolar I disorder symptoms in pediatric populations, a recently published study from Pediatrics confirms.

Lead author Dr. Robert L. Findling of Johns Hopkins University and his associates conducted a multicenter, randomized, placebo-controlled outpatient trial, gathering data from 153 participants between the ages of 7 and 17 with bipolar I disorder/manic or mixed episodes. Among the participants, 81 were randomized to receive lithium (n = 53) or placebo (n = 28), for up to 8 weeks. Symptoms of bipolar disorder were assessed using the Young Mania Rating Scale (YMRS) score.

Ultimately, the study found that lithium was effective in reducing manic symptoms in nearly one-half (47%) of these participants, with Overall Clinical Global Impression–Improvement scores favoring lithium (n = 25; 47% very much/much improved), compared with placebo (n = 6; 21% very much/much improved) after 8 weeks. The researchers also noted that lithium use was not associated with weight gain, although they observed a statistically significant increase in thyrotropin concentration among the lithium group. Nausea, headache, and vomiting were the most common side effects.

“This study provides evidence to support the efficacy of lithium in the acute treatment of youths with [bipolar I disorder] who are currently in a manic or mixed state. Lithium had an adverse effect profile that was acceptable for most patients,” the authors wrote.

Read the full article in Pediatrics.

[email protected]

Bipolar disorder might include a distinct subphenotype characterized by externalizing symptoms and specific genetic variations, report Shanker Swaminathan, Ph.D., and his colleagues.

A study of 2,505 bipolar I disorder patients categorized participants into two groups: externalizing (those with comorbid externalizing disorders, plus a subgroup of patients with externalizing symptoms before 15 years of age) and nonexternalizing, wrote Dr. Swaminathan, formerly with the department of medical and molecular genetics at Indiana University, Indianapolis, and now with Baylor College of Medicine, Houston.

wildpixel/Thinkstock.com

Patients in the externalizing group showed significant differences in clinical features from the nonexternalizing group in multiple areas, including earlier age of onset of bipolar disorder, depression, and mania (P less than .001).

Additionally, those in the externalizing group had a higher frequency of self-harm incidents (P less than .001) and suicide attempts (P less than .008). These patients also were more likely to report a history of rapid switching and cycling (P less than .001), the authors reported.

Genetic analysis found numerous “nominally associated” SNPs, though none reached genome-wide significance, Dr. Swaminathan and his colleagues reported.

The findings “suggest the presence of an externalizing disorder subphenotype within [bipolar I disorder] warranting further investigation,” they concluded.

Read the full study here: J Affect Disord. 2015 Jun;178:206-14.

[email protected]

Bipolar disorder might include a distinct subphenotype characterized by externalizing symptoms and specific genetic variations, report Shanker Swaminathan, Ph.D., and his colleagues.

A study of 2,505 bipolar I disorder patients categorized participants into two groups: externalizing (those with comorbid externalizing disorders, plus a subgroup of patients with externalizing symptoms before 15 years of age) and nonexternalizing, wrote Dr. Swaminathan, formerly with the department of medical and molecular genetics at Indiana University, Indianapolis, and now with Baylor College of Medicine, Houston.

wildpixel/Thinkstock.com

Patients in the externalizing group showed significant differences in clinical features from the nonexternalizing group in multiple areas, including earlier age of onset of bipolar disorder, depression, and mania (P less than .001).

Additionally, those in the externalizing group had a higher frequency of self-harm incidents (P less than .001) and suicide attempts (P less than .008). These patients also were more likely to report a history of rapid switching and cycling (P less than .001), the authors reported.

Genetic analysis found numerous “nominally associated” SNPs, though none reached genome-wide significance, Dr. Swaminathan and his colleagues reported.

The findings “suggest the presence of an externalizing disorder subphenotype within [bipolar I disorder] warranting further investigation,” they concluded.

Read the full study here: J Affect Disord. 2015 Jun;178:206-14.

[email protected]

Bipolar disorder might include a distinct subphenotype characterized by externalizing symptoms and specific genetic variations, report Shanker Swaminathan, Ph.D., and his colleagues.

A study of 2,505 bipolar I disorder patients categorized participants into two groups: externalizing (those with comorbid externalizing disorders, plus a subgroup of patients with externalizing symptoms before 15 years of age) and nonexternalizing, wrote Dr. Swaminathan, formerly with the department of medical and molecular genetics at Indiana University, Indianapolis, and now with Baylor College of Medicine, Houston.

wildpixel/Thinkstock.com

Patients in the externalizing group showed significant differences in clinical features from the nonexternalizing group in multiple areas, including earlier age of onset of bipolar disorder, depression, and mania (P less than .001).

Additionally, those in the externalizing group had a higher frequency of self-harm incidents (P less than .001) and suicide attempts (P less than .008). These patients also were more likely to report a history of rapid switching and cycling (P less than .001), the authors reported.

Genetic analysis found numerous “nominally associated” SNPs, though none reached genome-wide significance, Dr. Swaminathan and his colleagues reported.

The findings “suggest the presence of an externalizing disorder subphenotype within [bipolar I disorder] warranting further investigation,” they concluded.

Read the full study here: J Affect Disord. 2015 Jun;178:206-14.

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When a known depressed patient newly develops signs of mania or hypomania, a cascade of diagnostic and therapeu­tic questions ensues: Does the event “automatically” signify the presence of bipolar disorder (BD), or could manic symptoms be secondary to another underlying medical problem, a prescribed anti­depressant or non-psychotropic medication, or illicit substances?

Even more questions confront the clinician: If mania symptoms are nothing more than an adverse drug reaction, will they go away by stop­ping the presumed offending agent? Or do symptoms always indicate the unmasking of a bipolar diathesis? Should anti-manic medication be prescribed immediately? If so, which one(s) and for how long? How extensive a medical or neurologic workup is indicated?

And, how do you differentiate ambiguous hypomania symptoms (irritability, insomnia, agitation) from other phenomena, such as akathisia, anxiety, and overstimulation?

In this article, we present an overview of how to approach and answer these key questions, so that you can identify, comprehend, and manage manic symptoms that arise in the course of your patient’s treatment for depression (Box).

Does disease exist on a unipolar−bipolar continuum?
There has been a resurgence of interest in Kraepelin’s original notion of mania and depression as falling along a continuum, rather than being distinct categories of pathology. True bipolar mania has its own identifiable epidemiology, familiality, and treatment, but symptomatic shades of gray often pose a formidable diagnostic and therapeutic challenge.

For example, DSM-5 relaxed its defini­tion of “mixed” episodes of BD to include subsyndromal mania features in unipolar depression. When a patient with unipolar depression develops a full, unequivocal manic episode, there usually isn’t much ambiguity or confusion about initial man­agement: assure a safe environment, stop any antidepressants, rule out drug- or medically induced causes, and begin an acute anti-manic medication.

Next steps can, sometimes, be murkier:
   • formulate a definitive, overarching diagnosis
   • provide psycho-education
   • forecast return to work or school
   • discuss prognosis and likelihood of relapse
   • address necessary lifestyle modifica­tions (eg, sleep hygiene, elimination of alcohol and illicit drug use)
   • determine whether indefinite mainte­nance pharmacotherapy is indicated— and, if so, with which medication(s).

CASE A diagnostic formulation isn’t always black and white
Ms. J, age 56, a medically healthy woman, has a 10-year history of depression and anxiety that has been treated effectively for most of that time with venlafaxine, 225 mg/d. The mother of 4 grown children, Ms. J has worked steadily for >20 years as a flight attendant for an international airline.

Today, Ms. J is brought by ambulance from work to the emergency department in a par­anoid and agitated state. The admission fol­lows her having e-blasted airline corporate executives with a voluminous manifesto that she worked on around the clock the preced­ing week, in which she explained her bold ideas to revolutionize the airline industry, under her leadership.

Ms. J’s family history is unremarkable for psychiatric illness.

How does one approach a case such as Ms. J’s?
Stark examples of classical mania, as depicted in this case vignette, are easy to recognize but not necessarily straightfor­ward, nosologically. Consider the follow­ing not-so-straightforward elements of Ms. J’s case:
   • a first-lifetime episode of mania or hypomania is rare after age 50
   • Ms. J took a serotonin-norepinephrine reuptake inhibitor (SNRI) for many years without evidence of mood destabilization
   • years of repetitive chronobiological stress (including probable frequent time zone changes with likely sleep disruption) appar­ently did not trigger mood destabilization
   • none of Ms. J’s 4 pregnancies led to postpartum mood episodes
   • at least on the surface, there are no obvious features that point to likely causes of a secondary mania (eg, drug-induced, toxic, metabolic, or medical)

• Ms. J has no known family history of BD or any other mood disorder.

Approaching a case such as Ms. J’s must involve a systematic strategy that can best be broken into 2 segments: (1) a period of acute initial assessment and treatment and (2) later efforts focused on broader diagnostic evalu­ation and longer-term relapse prevention.

Initial assessment and treatment
Immediate assessment and manage­ment hinges on initial triage and form­ing a working diagnostic impression. Although full-blown mania usually is obvious (sometimes even without a formal interview), be alert to patients who might minimize or altogether disavow mania symptoms—often because of denial of ill­ness, misidentification of symptoms, or impaired insight about changes in think­ing, mood, or behavior.

Because florid mania, by definition, impairs psychosocial functioning, the con­text of an initial presentation often holds diagnostic relevance. Manic patients who display disruptive behaviors often are brought to treatment by a third party, whereas a less severely ill patient might be more inclined to seek treatment for herself (himself) when psychosis is absent and insight is less compromised or when the patient feels she (he) might be depressed.

It is not uncommon for a manic patient to report “depression” as the chief complaint or to omit elements related to psychomo­tor acceleration (such as racing thoughts or psychomotor agitation) in the description of symptoms. An accurate diagnosis often requires clinical probing and clarification of symptoms (eg, differentiating simple insom­nia with consequent next-day fatigue from loss of the need for sleep with intact or even enhanced next-day energy) or discriminating racing thoughts from anxious ruminations that might be more intrusive than rapid.

Presentations of frank mania also can come to light as a consequence of symp­toms, rather than as symptoms per se (eg, conflict in relationships, problems at work, financial reversals).

Particularly in patients who do not have a history of mania, avoid the temptation to begin or modify existing pharmacother­apy until you have performed a basic ini­tial evaluation. Immediate considerations for initial assessment and management include the following:

Provide containment. Ensure a safe setting, level of care, and frequency of monitoring. Evaluate suicide risk (particularly when mixed features are present), and risk of with­drawal from any psychoactive substances.

Engage significant others. Close family members can provide essential history, particularly when a patient’s insight about her illness and need for treatment are impaired. Family members and significant others also often play important roles in helping to restrict access to finances, fos­tering medication adherence, preventing access to weapons in the home, and shar­ing information with providers about sub­stance use or high-risk behavior.

Systematically assess for DSM-5 symp­toms of mania and depression. DSM-5 modified criteria for mania/hypomania to necessitate increased energy, in addition to change in mood, to make a syndromal diag­nosis. Useful during a clinical interview is the popular mnemonic DIGFAST to aid recognition of core mania symptoms^a:
   • Distractibility
   • Indiscretion/impulsivity
   • Grandiosity
   • Flight of ideas
   • Activity increase
   • Sleep deficit
   • Talkativeness.

^aAlso see: “Mnemonics in a mnutshell: 32 aids to psychiatric diagnosis,” in the October 2008 issue Current Psychiatry and in the archive at CurrentPsychiatry.com.

These symptoms should represent a departure from normal baseline character­istics; it often is helpful to ask a significant other or collateral historian how the pres­ent symptoms differ from the patient’s usual state.

Assess for unstable medical conditions or toxicity states. When evaluating an acute change in mental status, toxicology screening is relatively standard and the absence of illicit substances should sel­dom, if ever, be taken for granted—espe­cially because occult substance use can lead to identification of false-positive BD “cases.”¹

Stop any antidepressant. During a manic episode, continuing antidepressant medi­cation serves no purpose other than to contribute to or exacerbate mania symp­toms. Nonetheless, observational studies demonstrate that approximately 15% of syndromally manic patients continue to receive an antidepressant, often when a clinician perceives more severe depression during mania, multiple prior depressive episodes, current anxiety, or rapid cycling.²

Importantly, antidepressants have been shown to harm, rather than alleviate, pre­sentations that involve a mixed state,³ and have no demonstrated value in preventing post-manic depression. Mere elimination of an antidepressant might ease symptoms during a manic or mixed episode.⁴

In some cases, it might be advisable to taper, not abruptly stop, a short half-life serotonergic antidepressant, even in the setting of mania, to minimize the potential for aggravating autonomic dysregulation that can result from antidepressant discon­tinuation effects. 

Begin anti-manic pharmacotherapy. Initiation of an anti-manic mood stabilizer, such as lithium and divalproex, has been standard in the treatment of acute mania.

In the 1990s, protocols for oral loading of divalproex (20 to 30 mg/kg/d) gained popularity for achieving more rapid symp­tom improvement than might occur with lithium. In the current era, atypical anti­psychotics have all but replaced mood sta­bilizers as an initial intervention to contain mania symptoms quickly (and with less risk than first-generation antipsychotics for acute adverse motor effects from so-called rapid neuroleptization).

Because atypical antipsychotics often rapidly subdue mania, psychosis, and agitation, regardless of the underlying process, many practitioners might feel more comfortable initiating them than a mood stabilizer when the diagnosis is ambiguous or provisional, although their longer-term efficacy and safety, relative to traditional mood stabilizers, remains contested. Considerations for choosing from among feasible anti-manic pharma­cotherapies are summarized in Table 1.⁵ 

Normalize the sleep-wake cycle. Chronobiological and circadian vari­ables, such as irregular sleep patterns, are thought to contribute to the pathophysiol­ogy of affective switch in BD. Behavioral and pharmacotherapeutic efforts to impose a normal sleep−wake schedule are considered fundamental to stabilizing acute mania.

Facilitate next steps after acute stabili­zation. For inpatients, this might involve step-down to a partial hospitalization or intensive outpatient program, alongside taking steps to ensure continued treatment adherence and minimize relapse.

What medical and neurologic workup is appropriate?
Not every first lifetime presentation of mania requires extensive medical and neurologic workup, particularly among patients who have a history of depression and those whose presentation neatly fits the demographic and clinical profile of newly emergent BD. Basic assessment should determine whether any new medication has been started that could plausibly contribute to abnormal mental sta­tus (Table 2).

Nevertheless, evaluation of almost all first presentations of mania should include:
   • urine toxicology screen 
   • complete blood count
   • comprehensive metabolic panel
   • thyroid-stimulating hormone assay
   • serum vitamin B₁₂ level assay
   • serum folic acid level assay
   • rapid plasma reagin test.

Clinical features that usually lead a cli­nician to pursue a more detailed medical and neurologic evaluation of first-episode mania include:
   • onset age >40
   • absence of a family history of mood disorder
   • symptoms arising during a major medical illness
   • multiple medications
   • suspicion of a degenerative or heredi­tary neurologic disorder
   • altered state of consciousness
   • signs of cortical or diffuse subcorti­cal dysfunction (eg, cognitive deficits, motor deficits, tremor)
   • abnormal vital signs.

Depending on the presentation, addi­tional testing might include:
   • tests of HIV antibody, immune auto­antibodies, and Lyme disease antibody
   • heavy metal screening (when sug­gested by environmental exposure)
   • lumbar puncture (eg, in a setting of manic delirium or suspected central nervous system infection or paraneoplastic syndrome)
   • neuroimaging (note: MRI provides bet­ter visualization than CT of white matter pathology and small vessel cerebrovascular disease) electroencephalography.

Making an overarching diagnosis: Is mania always bipolar disorder?
Mania is considered a manifestation of BD when symptoms cannot be attributed to another psychiatric condition, another underlying medical or neurologic condi­tion, or a toxic-metabolic state (Table 3 and Table 4^6-9). Classification of mania that occurs soon after antidepressant exposure in patients without a known history of BD continues to be the subject of debate, vary­ing in its conceptualization across editions of DSM.

The National Institute of Mental Health (NIMH) Systematic Treatment Enhancement Program for Bipolar Disorder, or STEP-BD, observed a fairly low (approximately 10%) incidence of switch from depression to mania when an antidepressant is added to a mood stabilizer; the study authors con­cluded that much of what is presumed to be antidepressant-induced mania might simply be the natural course of illness.¹⁰

Notably, several reports suggest that antidepressants might pose a greater risk of mood destabilization in people with BD I than with either BD II or other sus­pected variants on the bipolar spectrum.

DSM-5 advises that a diagnosis of substance-induced mood disorder appro­priately describes symptoms that spontane­ously dissipate once an antidepressant has been discontinued, whereas a diagnosis of BD can be made when manic or hypomanic symptoms persist at a syndromal level after an antidepressant has been stopped and its physiological effects are no longer present. With respect to time course, the International Society of Bipolar Disorders proposes that, beyond 12 to 16 weeks after an antidepressant has been started or the dosage has been increased, it is unlikely that new-onset mania/hypomania can rea­sonably be attributed to “triggering” by an antidepressant¹¹ (although antidepressants should be stopped when symptoms of mania emerge).

Several clinical features have been linked in the literature with an increased suscepti­bility to BD after an initial depressive epi­sode, including:
   • early (pre-adolescent) age at onset of first mood disorder episode⁶
   • family history of BD, highly recurrent depression, or psychosis^12,13
   • psychosis when depressed.^7,14

A number of other characteristics of depressive illness—including seasonal depression, atypical depressive features, suicidality, irritability, anxiety or sub­stance use comorbidity, postpartum mood episodes, and brief recurrent depressive episodes—have been described in the lit­erature as potential correlates of a bipolar diathesis; none have proved to be robust or pathognomonic of a BD diagnosis, as opposed to a unipolar diagnosis.

Data from the NIMH Collaborative Depression Study suggest that recurrent mania/hypomania after an antidepressant-associated polarity switch is greater when a family history of BD is present; other clinical variables might hold less predictive value.¹⁵

In addition, although some practitioners consider a history of nonresponse to trials of multiple antidepressants suggestive of an underlying bipolar process, polarity is only one of many variables that must be considered in the differential diagnosis of antidepressant-resistant depression.^b Likewise, molecular genetic studies do not support a link between antidepressant nonresponse and the likelihood of a diag­nosis of BD.¹⁶

^bSee “A practical approach to subtyping depression among your patients” in the April 2014 issue of Current Psychiatry or in the archive at CurrentPsychiatry.com.

Indefinite pharmacotherapy for bipolar disorder?
An important but nagging issue when diag­nosing BD after a first manic (or hypomanic) episode is the implied need for indefinite pharmacotherapy to sustain remission and prevent relapse and recurrence.

The likelihood of subsequent depression or mania/hypomania remains high after an index manic/hypomanic episode, par­ticularly for 6 to 8 months after recovery.^8,17 Natural history data suggest that, during the year that follows a first lifetime mania, approximately 40% of patients experience a second manic episode.⁸ A second lifetime mania might be especially likely in patients whose index episode involved mood-congruent psychosis, low premorbid work functioning, and an initial manic episode, as opposed to a mixed episode¹⁷ or early age at onset.⁸

In the absence of randomized, placebo-controlled studies of maintenance phar­macotherapy after a first lifetime manic episode, clinical judgment often drives decisions about the duration of continuing pharmacotherapy after initial symptoms resolve. The Texas Medication Algorithm Project for BD advises that:

Similarly, in the most recent (2004) Expert Consensus Guideline Series for the Treatment of Bipolar Disorder,¹⁹ 84% of practitioner−respondents favored indefi­nite mood stabilizer therapy after a second lifetime manic episode. No recommen­dation was made about the duration of maintenance pharmacotherapy after a first lifetime manic/hypomanic episode.

Avoid or reintroduce an antidepressant if depression recurs after a first mania?
Controversies surrounding antidepressant use in BD are extensive; detailed discus­sion is beyond the scope of this review (Goldberg and Ghaemi provided a broader discussion of risks and benefits of antide­pressants in BD20). Although the main clinical concern regarding antidepres­sant use was, at one time, the potential to induce mania or accelerate the frequency of recurrent episodes, more recent, empiri­cal studies suggest that the greater risk of using antidepressants for BD is lack of efficacy.^10,21

If a careful longitudinal history and clin­ical evaluation reveal that an initial manic episode heralds the onset of BD, decisions about whether to avoid an antidepressant (as opposed to using other, more evidence-based interventions for bipolar depres­sion) depend on a number of variables, including establishing whether the index episode was manic or hypomanic; ruling out current subthreshold mixed features; and clarifying how recently mania devel­oped. Decisions about future antidepres­sant use (or avoidance) might be less clear if an index manic/hypomanic episode was brief and self-limited once the antidepres­sant was stopped.

Although some experts eschew antidepressant monotherapy after such occurrences, there is no body of litera­ture to inform decisions about the safety or efficacy of undertaking a future antidepressant trial in such patients. That said, reasonable judgment probably includes several considerations:
   • Re-exposure to the same antidepres­sant that was associated with an induction of mania is likely riskier than choosing a different antidepressant; in general, purely serotonergic antidepressants or bupropion are considered to pose less risk of mood destabilization than is seen with an SNRI or tricyclic antidepressant.
   • After a manic episode, a subsequent antidepressant trial generally shouldn’t be attempted without concurrent anti-manic medication.
   • Introducing any antidepressant is probably ill-advised in the recent (~2 months) aftermath of acute manic/ hypomanic symptoms.²²
   • Patients and their significant other should be apprised of the risk of emerg­ing symptoms of mania or hypomania, or mixed features, and should be familiar with key target symptoms to watch for. Prospective mood charting can be helpful.
   • Patients should be monitored closely both for an exacerbation of depression and recurrence of mania/hypomania symptoms.
   • Any antidepressant should be discon­tinued promptly at the first sign of psy­chomotor acceleration or the emergence of mixed features, as defined by DSM-5.

Psychoeducation and forecasting
Functional recovery from a manic episode can lag behind symptomatic recovery. Subsyndromal symptoms often persist after a full episode subsides.

Mania often is followed by a depres­sive episode, and questions inevitably arise about how to prevent and treat these epi­sodes. Because the median duration of a manic episode is approximately 13 weeks,²³ it is crucial for patients and their immedi­ate family to recognize that recovery might be gradual, and that it will likely take time before she (he) can resume full-time respon­sibilities at work or school or in the home.

Today, a patient who is hospitalized for severe acute mania (as Ms. J was, in the case vignette) seldom remains an inpa­tient long enough to achieve remission of symptoms; sometimes, she (he) might con­tinue to manifest significant symptoms, even though decisions about the “medical necessity” of ongoing inpatient care tend to be governed mainly by issues of safety and imminent danger. (This web exclusive Table^20,24,25 provides considerations when making the transition from the acute phase to the continuation phase of treatment.)

To minimize risk of relapse, psycho-education should include discussion of:
   • psychiatrically deleterious effects of alcohol and illicit drug use
   • suicide risk, including what to do in an emergency
   • protecting a regular sleep schedule and avoiding sleep deprivation
   • the potential for poor medication adherence and management of side effects
   • the need for periodic laboratory moni­toring, as needed
   • the role of adjunctive psychotherapy and effective stress management
   • familiarity with symptoms that serve as warning signs, and how to monitor their onset.

Bottom Line
When a patient being treated for depression develops signs of mania or hypomania, stop any antidepressant and consider initiating a mood stabilizer, antipsychotic, or both, to contain and stabilize symptoms. Entertain medical and substance-related causes of mania symptoms, and evaluate and treat as suggested by the patient’s presentation. Long-term drug therapy to prevent recurrence of mania/hypomania, as well as risks and benefits of future exposure to antidepressants, should be decided case by case.

Related Resources
• Proudfoot J, Whitton A, Parker G, et al. Triggers of mania and depression in young adults with bipolar disorder. J Affect Disord. 2012;143(1-3):196-202.
• Stange JP, Sylvia LG, Magalhães PV, et al. Extreme at­tributions predict transition from depression to ma­nia or hypomania in bipolar disorder. J Psychiatr Res. 2013;47(10):1329-1336.

Drug Brand Names
Albuterol • Proventil, Ventolin
Anastrozole • Arimidex
Aripiprazole • Abilify
Bupropion • Wellbutrin
Carbamazepine • Tegretol
Chloroquine • Aralen
Ciprofloxacin • Cipro
Clarithromycin • Biaxin
Clomiphene • Clomid
Digoxin • Digox, Lanoxin
Divalproex • Depakote
5-Fluorouracil • Carac, Efudex
Human chorionic gonadotropin • Novarel, Pregnyl
Ifosfamide • Ifex
Isoniazid • Nydrazid
Lamotrigine • Lamictal
Letrozole • Femara
Lithium • Eskalith, Lithobid
Lurasidone • Latuda
Mefloquine • Lariam
Olanzapine • Zyprexa
Olanzapine/fluoxetine combination • Symbyax
ramipexole • Mirapex
Procarbazine • Matulane
Quetiapine • Seroquel
Ropinirole • Requip
Rotigotine • Neupro
Venlafaxine • Effexor
Zidovudine • Retrovir

Disclosures
Dr. Goldberg is a consultant to Merck & Co. and Sunovion. He is a member of the speakers’ bureau of AstraZeneca, Janssen, Merck & Co., Takeda and Lundbeck, and Sunovion.

Dr. Ernst reports no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

When a known depressed patient newly develops signs of mania or hypomania, a cascade of diagnostic and therapeu­tic questions ensues: Does the event “automatically” signify the presence of bipolar disorder (BD), or could manic symptoms be secondary to another underlying medical problem, a prescribed anti­depressant or non-psychotropic medication, or illicit substances?

Even more questions confront the clinician: If mania symptoms are nothing more than an adverse drug reaction, will they go away by stop­ping the presumed offending agent? Or do symptoms always indicate the unmasking of a bipolar diathesis? Should anti-manic medication be prescribed immediately? If so, which one(s) and for how long? How extensive a medical or neurologic workup is indicated?

And, how do you differentiate ambiguous hypomania symptoms (irritability, insomnia, agitation) from other phenomena, such as akathisia, anxiety, and overstimulation?

In this article, we present an overview of how to approach and answer these key questions, so that you can identify, comprehend, and manage manic symptoms that arise in the course of your patient’s treatment for depression (Box).

Does disease exist on a unipolar−bipolar continuum?
There has been a resurgence of interest in Kraepelin’s original notion of mania and depression as falling along a continuum, rather than being distinct categories of pathology. True bipolar mania has its own identifiable epidemiology, familiality, and treatment, but symptomatic shades of gray often pose a formidable diagnostic and therapeutic challenge.

For example, DSM-5 relaxed its defini­tion of “mixed” episodes of BD to include subsyndromal mania features in unipolar depression. When a patient with unipolar depression develops a full, unequivocal manic episode, there usually isn’t much ambiguity or confusion about initial man­agement: assure a safe environment, stop any antidepressants, rule out drug- or medically induced causes, and begin an acute anti-manic medication.

Next steps can, sometimes, be murkier:
   • formulate a definitive, overarching diagnosis
   • provide psycho-education
   • forecast return to work or school
   • discuss prognosis and likelihood of relapse
   • address necessary lifestyle modifica­tions (eg, sleep hygiene, elimination of alcohol and illicit drug use)
   • determine whether indefinite mainte­nance pharmacotherapy is indicated— and, if so, with which medication(s).

CASE A diagnostic formulation isn’t always black and white
Ms. J, age 56, a medically healthy woman, has a 10-year history of depression and anxiety that has been treated effectively for most of that time with venlafaxine, 225 mg/d. The mother of 4 grown children, Ms. J has worked steadily for >20 years as a flight attendant for an international airline.

Today, Ms. J is brought by ambulance from work to the emergency department in a par­anoid and agitated state. The admission fol­lows her having e-blasted airline corporate executives with a voluminous manifesto that she worked on around the clock the preced­ing week, in which she explained her bold ideas to revolutionize the airline industry, under her leadership.

Ms. J’s family history is unremarkable for psychiatric illness.

How does one approach a case such as Ms. J’s?
Stark examples of classical mania, as depicted in this case vignette, are easy to recognize but not necessarily straightfor­ward, nosologically. Consider the follow­ing not-so-straightforward elements of Ms. J’s case:
   • a first-lifetime episode of mania or hypomania is rare after age 50
   • Ms. J took a serotonin-norepinephrine reuptake inhibitor (SNRI) for many years without evidence of mood destabilization
   • years of repetitive chronobiological stress (including probable frequent time zone changes with likely sleep disruption) appar­ently did not trigger mood destabilization
   • none of Ms. J’s 4 pregnancies led to postpartum mood episodes
   • at least on the surface, there are no obvious features that point to likely causes of a secondary mania (eg, drug-induced, toxic, metabolic, or medical)

• Ms. J has no known family history of BD or any other mood disorder.

Approaching a case such as Ms. J’s must involve a systematic strategy that can best be broken into 2 segments: (1) a period of acute initial assessment and treatment and (2) later efforts focused on broader diagnostic evalu­ation and longer-term relapse prevention.

Initial assessment and treatment
Immediate assessment and manage­ment hinges on initial triage and form­ing a working diagnostic impression. Although full-blown mania usually is obvious (sometimes even without a formal interview), be alert to patients who might minimize or altogether disavow mania symptoms—often because of denial of ill­ness, misidentification of symptoms, or impaired insight about changes in think­ing, mood, or behavior.

Because florid mania, by definition, impairs psychosocial functioning, the con­text of an initial presentation often holds diagnostic relevance. Manic patients who display disruptive behaviors often are brought to treatment by a third party, whereas a less severely ill patient might be more inclined to seek treatment for herself (himself) when psychosis is absent and insight is less compromised or when the patient feels she (he) might be depressed.

It is not uncommon for a manic patient to report “depression” as the chief complaint or to omit elements related to psychomo­tor acceleration (such as racing thoughts or psychomotor agitation) in the description of symptoms. An accurate diagnosis often requires clinical probing and clarification of symptoms (eg, differentiating simple insom­nia with consequent next-day fatigue from loss of the need for sleep with intact or even enhanced next-day energy) or discriminating racing thoughts from anxious ruminations that might be more intrusive than rapid.

Presentations of frank mania also can come to light as a consequence of symp­toms, rather than as symptoms per se (eg, conflict in relationships, problems at work, financial reversals).

Particularly in patients who do not have a history of mania, avoid the temptation to begin or modify existing pharmacother­apy until you have performed a basic ini­tial evaluation. Immediate considerations for initial assessment and management include the following:

Provide containment. Ensure a safe setting, level of care, and frequency of monitoring. Evaluate suicide risk (particularly when mixed features are present), and risk of with­drawal from any psychoactive substances.

Engage significant others. Close family members can provide essential history, particularly when a patient’s insight about her illness and need for treatment are impaired. Family members and significant others also often play important roles in helping to restrict access to finances, fos­tering medication adherence, preventing access to weapons in the home, and shar­ing information with providers about sub­stance use or high-risk behavior.

Systematically assess for DSM-5 symp­toms of mania and depression. DSM-5 modified criteria for mania/hypomania to necessitate increased energy, in addition to change in mood, to make a syndromal diag­nosis. Useful during a clinical interview is the popular mnemonic DIGFAST to aid recognition of core mania symptoms^a:
   • Distractibility
   • Indiscretion/impulsivity
   • Grandiosity
   • Flight of ideas
   • Activity increase
   • Sleep deficit
   • Talkativeness.

^aAlso see: “Mnemonics in a mnutshell: 32 aids to psychiatric diagnosis,” in the October 2008 issue Current Psychiatry and in the archive at CurrentPsychiatry.com.

These symptoms should represent a departure from normal baseline character­istics; it often is helpful to ask a significant other or collateral historian how the pres­ent symptoms differ from the patient’s usual state.

Assess for unstable medical conditions or toxicity states. When evaluating an acute change in mental status, toxicology screening is relatively standard and the absence of illicit substances should sel­dom, if ever, be taken for granted—espe­cially because occult substance use can lead to identification of false-positive BD “cases.”¹

Stop any antidepressant. During a manic episode, continuing antidepressant medi­cation serves no purpose other than to contribute to or exacerbate mania symp­toms. Nonetheless, observational studies demonstrate that approximately 15% of syndromally manic patients continue to receive an antidepressant, often when a clinician perceives more severe depression during mania, multiple prior depressive episodes, current anxiety, or rapid cycling.²

Importantly, antidepressants have been shown to harm, rather than alleviate, pre­sentations that involve a mixed state,³ and have no demonstrated value in preventing post-manic depression. Mere elimination of an antidepressant might ease symptoms during a manic or mixed episode.⁴

In some cases, it might be advisable to taper, not abruptly stop, a short half-life serotonergic antidepressant, even in the setting of mania, to minimize the potential for aggravating autonomic dysregulation that can result from antidepressant discon­tinuation effects. 

Begin anti-manic pharmacotherapy. Initiation of an anti-manic mood stabilizer, such as lithium and divalproex, has been standard in the treatment of acute mania.

In the 1990s, protocols for oral loading of divalproex (20 to 30 mg/kg/d) gained popularity for achieving more rapid symp­tom improvement than might occur with lithium. In the current era, atypical anti­psychotics have all but replaced mood sta­bilizers as an initial intervention to contain mania symptoms quickly (and with less risk than first-generation antipsychotics for acute adverse motor effects from so-called rapid neuroleptization).

Because atypical antipsychotics often rapidly subdue mania, psychosis, and agitation, regardless of the underlying process, many practitioners might feel more comfortable initiating them than a mood stabilizer when the diagnosis is ambiguous or provisional, although their longer-term efficacy and safety, relative to traditional mood stabilizers, remains contested. Considerations for choosing from among feasible anti-manic pharma­cotherapies are summarized in Table 1.⁵ 

Normalize the sleep-wake cycle. Chronobiological and circadian vari­ables, such as irregular sleep patterns, are thought to contribute to the pathophysiol­ogy of affective switch in BD. Behavioral and pharmacotherapeutic efforts to impose a normal sleep−wake schedule are considered fundamental to stabilizing acute mania.

Facilitate next steps after acute stabili­zation. For inpatients, this might involve step-down to a partial hospitalization or intensive outpatient program, alongside taking steps to ensure continued treatment adherence and minimize relapse.

What medical and neurologic workup is appropriate?
Not every first lifetime presentation of mania requires extensive medical and neurologic workup, particularly among patients who have a history of depression and those whose presentation neatly fits the demographic and clinical profile of newly emergent BD. Basic assessment should determine whether any new medication has been started that could plausibly contribute to abnormal mental sta­tus (Table 2).

Nevertheless, evaluation of almost all first presentations of mania should include:
   • urine toxicology screen 
   • complete blood count
   • comprehensive metabolic panel
   • thyroid-stimulating hormone assay
   • serum vitamin B₁₂ level assay
   • serum folic acid level assay
   • rapid plasma reagin test.

Clinical features that usually lead a cli­nician to pursue a more detailed medical and neurologic evaluation of first-episode mania include:
   • onset age >40
   • absence of a family history of mood disorder
   • symptoms arising during a major medical illness
   • multiple medications
   • suspicion of a degenerative or heredi­tary neurologic disorder
   • altered state of consciousness
   • signs of cortical or diffuse subcorti­cal dysfunction (eg, cognitive deficits, motor deficits, tremor)
   • abnormal vital signs.

Depending on the presentation, addi­tional testing might include:
   • tests of HIV antibody, immune auto­antibodies, and Lyme disease antibody
   • heavy metal screening (when sug­gested by environmental exposure)
   • lumbar puncture (eg, in a setting of manic delirium or suspected central nervous system infection or paraneoplastic syndrome)
   • neuroimaging (note: MRI provides bet­ter visualization than CT of white matter pathology and small vessel cerebrovascular disease) electroencephalography.

Making an overarching diagnosis: Is mania always bipolar disorder?
Mania is considered a manifestation of BD when symptoms cannot be attributed to another psychiatric condition, another underlying medical or neurologic condi­tion, or a toxic-metabolic state (Table 3 and Table 4^6-9). Classification of mania that occurs soon after antidepressant exposure in patients without a known history of BD continues to be the subject of debate, vary­ing in its conceptualization across editions of DSM.

The National Institute of Mental Health (NIMH) Systematic Treatment Enhancement Program for Bipolar Disorder, or STEP-BD, observed a fairly low (approximately 10%) incidence of switch from depression to mania when an antidepressant is added to a mood stabilizer; the study authors con­cluded that much of what is presumed to be antidepressant-induced mania might simply be the natural course of illness.¹⁰

Notably, several reports suggest that antidepressants might pose a greater risk of mood destabilization in people with BD I than with either BD II or other sus­pected variants on the bipolar spectrum.

DSM-5 advises that a diagnosis of substance-induced mood disorder appro­priately describes symptoms that spontane­ously dissipate once an antidepressant has been discontinued, whereas a diagnosis of BD can be made when manic or hypomanic symptoms persist at a syndromal level after an antidepressant has been stopped and its physiological effects are no longer present. With respect to time course, the International Society of Bipolar Disorders proposes that, beyond 12 to 16 weeks after an antidepressant has been started or the dosage has been increased, it is unlikely that new-onset mania/hypomania can rea­sonably be attributed to “triggering” by an antidepressant¹¹ (although antidepressants should be stopped when symptoms of mania emerge).

Several clinical features have been linked in the literature with an increased suscepti­bility to BD after an initial depressive epi­sode, including:
   • early (pre-adolescent) age at onset of first mood disorder episode⁶
   • family history of BD, highly recurrent depression, or psychosis^12,13
   • psychosis when depressed.^7,14

A number of other characteristics of depressive illness—including seasonal depression, atypical depressive features, suicidality, irritability, anxiety or sub­stance use comorbidity, postpartum mood episodes, and brief recurrent depressive episodes—have been described in the lit­erature as potential correlates of a bipolar diathesis; none have proved to be robust or pathognomonic of a BD diagnosis, as opposed to a unipolar diagnosis.

Data from the NIMH Collaborative Depression Study suggest that recurrent mania/hypomania after an antidepressant-associated polarity switch is greater when a family history of BD is present; other clinical variables might hold less predictive value.¹⁵

In addition, although some practitioners consider a history of nonresponse to trials of multiple antidepressants suggestive of an underlying bipolar process, polarity is only one of many variables that must be considered in the differential diagnosis of antidepressant-resistant depression.^b Likewise, molecular genetic studies do not support a link between antidepressant nonresponse and the likelihood of a diag­nosis of BD.¹⁶

^bSee “A practical approach to subtyping depression among your patients” in the April 2014 issue of Current Psychiatry or in the archive at CurrentPsychiatry.com.

Indefinite pharmacotherapy for bipolar disorder?
An important but nagging issue when diag­nosing BD after a first manic (or hypomanic) episode is the implied need for indefinite pharmacotherapy to sustain remission and prevent relapse and recurrence.

The likelihood of subsequent depression or mania/hypomania remains high after an index manic/hypomanic episode, par­ticularly for 6 to 8 months after recovery.^8,17 Natural history data suggest that, during the year that follows a first lifetime mania, approximately 40% of patients experience a second manic episode.⁸ A second lifetime mania might be especially likely in patients whose index episode involved mood-congruent psychosis, low premorbid work functioning, and an initial manic episode, as opposed to a mixed episode¹⁷ or early age at onset.⁸

In the absence of randomized, placebo-controlled studies of maintenance phar­macotherapy after a first lifetime manic episode, clinical judgment often drives decisions about the duration of continuing pharmacotherapy after initial symptoms resolve. The Texas Medication Algorithm Project for BD advises that:

Similarly, in the most recent (2004) Expert Consensus Guideline Series for the Treatment of Bipolar Disorder,¹⁹ 84% of practitioner−respondents favored indefi­nite mood stabilizer therapy after a second lifetime manic episode. No recommen­dation was made about the duration of maintenance pharmacotherapy after a first lifetime manic/hypomanic episode.

Avoid or reintroduce an antidepressant if depression recurs after a first mania?
Controversies surrounding antidepressant use in BD are extensive; detailed discus­sion is beyond the scope of this review (Goldberg and Ghaemi provided a broader discussion of risks and benefits of antide­pressants in BD20). Although the main clinical concern regarding antidepres­sant use was, at one time, the potential to induce mania or accelerate the frequency of recurrent episodes, more recent, empiri­cal studies suggest that the greater risk of using antidepressants for BD is lack of efficacy.^10,21

If a careful longitudinal history and clin­ical evaluation reveal that an initial manic episode heralds the onset of BD, decisions about whether to avoid an antidepressant (as opposed to using other, more evidence-based interventions for bipolar depres­sion) depend on a number of variables, including establishing whether the index episode was manic or hypomanic; ruling out current subthreshold mixed features; and clarifying how recently mania devel­oped. Decisions about future antidepres­sant use (or avoidance) might be less clear if an index manic/hypomanic episode was brief and self-limited once the antidepres­sant was stopped.

Although some experts eschew antidepressant monotherapy after such occurrences, there is no body of litera­ture to inform decisions about the safety or efficacy of undertaking a future antidepressant trial in such patients. That said, reasonable judgment probably includes several considerations:
   • Re-exposure to the same antidepres­sant that was associated with an induction of mania is likely riskier than choosing a different antidepressant; in general, purely serotonergic antidepressants or bupropion are considered to pose less risk of mood destabilization than is seen with an SNRI or tricyclic antidepressant.
   • After a manic episode, a subsequent antidepressant trial generally shouldn’t be attempted without concurrent anti-manic medication.
   • Introducing any antidepressant is probably ill-advised in the recent (~2 months) aftermath of acute manic/ hypomanic symptoms.²²
   • Patients and their significant other should be apprised of the risk of emerg­ing symptoms of mania or hypomania, or mixed features, and should be familiar with key target symptoms to watch for. Prospective mood charting can be helpful.
   • Patients should be monitored closely both for an exacerbation of depression and recurrence of mania/hypomania symptoms.
   • Any antidepressant should be discon­tinued promptly at the first sign of psy­chomotor acceleration or the emergence of mixed features, as defined by DSM-5.

Psychoeducation and forecasting
Functional recovery from a manic episode can lag behind symptomatic recovery. Subsyndromal symptoms often persist after a full episode subsides.

Mania often is followed by a depres­sive episode, and questions inevitably arise about how to prevent and treat these epi­sodes. Because the median duration of a manic episode is approximately 13 weeks,²³ it is crucial for patients and their immedi­ate family to recognize that recovery might be gradual, and that it will likely take time before she (he) can resume full-time respon­sibilities at work or school or in the home.

Today, a patient who is hospitalized for severe acute mania (as Ms. J was, in the case vignette) seldom remains an inpa­tient long enough to achieve remission of symptoms; sometimes, she (he) might con­tinue to manifest significant symptoms, even though decisions about the “medical necessity” of ongoing inpatient care tend to be governed mainly by issues of safety and imminent danger. (This web exclusive Table^20,24,25 provides considerations when making the transition from the acute phase to the continuation phase of treatment.)

To minimize risk of relapse, psycho-education should include discussion of:
   • psychiatrically deleterious effects of alcohol and illicit drug use
   • suicide risk, including what to do in an emergency
   • protecting a regular sleep schedule and avoiding sleep deprivation
   • the potential for poor medication adherence and management of side effects
   • the need for periodic laboratory moni­toring, as needed
   • the role of adjunctive psychotherapy and effective stress management
   • familiarity with symptoms that serve as warning signs, and how to monitor their onset.

Bottom Line
When a patient being treated for depression develops signs of mania or hypomania, stop any antidepressant and consider initiating a mood stabilizer, antipsychotic, or both, to contain and stabilize symptoms. Entertain medical and substance-related causes of mania symptoms, and evaluate and treat as suggested by the patient’s presentation. Long-term drug therapy to prevent recurrence of mania/hypomania, as well as risks and benefits of future exposure to antidepressants, should be decided case by case.

Related Resources
• Proudfoot J, Whitton A, Parker G, et al. Triggers of mania and depression in young adults with bipolar disorder. J Affect Disord. 2012;143(1-3):196-202.
• Stange JP, Sylvia LG, Magalhães PV, et al. Extreme at­tributions predict transition from depression to ma­nia or hypomania in bipolar disorder. J Psychiatr Res. 2013;47(10):1329-1336.

Drug Brand Names
Albuterol • Proventil, Ventolin
Anastrozole • Arimidex
Aripiprazole • Abilify
Bupropion • Wellbutrin
Carbamazepine • Tegretol
Chloroquine • Aralen
Ciprofloxacin • Cipro
Clarithromycin • Biaxin
Clomiphene • Clomid
Digoxin • Digox, Lanoxin
Divalproex • Depakote
5-Fluorouracil • Carac, Efudex
Human chorionic gonadotropin • Novarel, Pregnyl
Ifosfamide • Ifex
Isoniazid • Nydrazid
Lamotrigine • Lamictal
Letrozole • Femara
Lithium • Eskalith, Lithobid
Lurasidone • Latuda
Mefloquine • Lariam
Olanzapine • Zyprexa
Olanzapine/fluoxetine combination • Symbyax
ramipexole • Mirapex
Procarbazine • Matulane
Quetiapine • Seroquel
Ropinirole • Requip
Rotigotine • Neupro
Venlafaxine • Effexor
Zidovudine • Retrovir

Disclosures
Dr. Goldberg is a consultant to Merck & Co. and Sunovion. He is a member of the speakers’ bureau of AstraZeneca, Janssen, Merck & Co., Takeda and Lundbeck, and Sunovion.

Dr. Ernst reports no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

When a known depressed patient newly develops signs of mania or hypomania, a cascade of diagnostic and therapeu­tic questions ensues: Does the event “automatically” signify the presence of bipolar disorder (BD), or could manic symptoms be secondary to another underlying medical problem, a prescribed anti­depressant or non-psychotropic medication, or illicit substances?

Even more questions confront the clinician: If mania symptoms are nothing more than an adverse drug reaction, will they go away by stop­ping the presumed offending agent? Or do symptoms always indicate the unmasking of a bipolar diathesis? Should anti-manic medication be prescribed immediately? If so, which one(s) and for how long? How extensive a medical or neurologic workup is indicated?

And, how do you differentiate ambiguous hypomania symptoms (irritability, insomnia, agitation) from other phenomena, such as akathisia, anxiety, and overstimulation?

In this article, we present an overview of how to approach and answer these key questions, so that you can identify, comprehend, and manage manic symptoms that arise in the course of your patient’s treatment for depression (Box).

Does disease exist on a unipolar−bipolar continuum?
There has been a resurgence of interest in Kraepelin’s original notion of mania and depression as falling along a continuum, rather than being distinct categories of pathology. True bipolar mania has its own identifiable epidemiology, familiality, and treatment, but symptomatic shades of gray often pose a formidable diagnostic and therapeutic challenge.

For example, DSM-5 relaxed its defini­tion of “mixed” episodes of BD to include subsyndromal mania features in unipolar depression. When a patient with unipolar depression develops a full, unequivocal manic episode, there usually isn’t much ambiguity or confusion about initial man­agement: assure a safe environment, stop any antidepressants, rule out drug- or medically induced causes, and begin an acute anti-manic medication.

Next steps can, sometimes, be murkier:
   • formulate a definitive, overarching diagnosis
   • provide psycho-education
   • forecast return to work or school
   • discuss prognosis and likelihood of relapse
   • address necessary lifestyle modifica­tions (eg, sleep hygiene, elimination of alcohol and illicit drug use)
   • determine whether indefinite mainte­nance pharmacotherapy is indicated— and, if so, with which medication(s).

CASE A diagnostic formulation isn’t always black and white
Ms. J, age 56, a medically healthy woman, has a 10-year history of depression and anxiety that has been treated effectively for most of that time with venlafaxine, 225 mg/d. The mother of 4 grown children, Ms. J has worked steadily for >20 years as a flight attendant for an international airline.

Today, Ms. J is brought by ambulance from work to the emergency department in a par­anoid and agitated state. The admission fol­lows her having e-blasted airline corporate executives with a voluminous manifesto that she worked on around the clock the preced­ing week, in which she explained her bold ideas to revolutionize the airline industry, under her leadership.

Ms. J’s family history is unremarkable for psychiatric illness.

How does one approach a case such as Ms. J’s?
Stark examples of classical mania, as depicted in this case vignette, are easy to recognize but not necessarily straightfor­ward, nosologically. Consider the follow­ing not-so-straightforward elements of Ms. J’s case:
   • a first-lifetime episode of mania or hypomania is rare after age 50
   • Ms. J took a serotonin-norepinephrine reuptake inhibitor (SNRI) for many years without evidence of mood destabilization
   • years of repetitive chronobiological stress (including probable frequent time zone changes with likely sleep disruption) appar­ently did not trigger mood destabilization
   • none of Ms. J’s 4 pregnancies led to postpartum mood episodes
   • at least on the surface, there are no obvious features that point to likely causes of a secondary mania (eg, drug-induced, toxic, metabolic, or medical)

• Ms. J has no known family history of BD or any other mood disorder.

Approaching a case such as Ms. J’s must involve a systematic strategy that can best be broken into 2 segments: (1) a period of acute initial assessment and treatment and (2) later efforts focused on broader diagnostic evalu­ation and longer-term relapse prevention.

Initial assessment and treatment
Immediate assessment and manage­ment hinges on initial triage and form­ing a working diagnostic impression. Although full-blown mania usually is obvious (sometimes even without a formal interview), be alert to patients who might minimize or altogether disavow mania symptoms—often because of denial of ill­ness, misidentification of symptoms, or impaired insight about changes in think­ing, mood, or behavior.

Because florid mania, by definition, impairs psychosocial functioning, the con­text of an initial presentation often holds diagnostic relevance. Manic patients who display disruptive behaviors often are brought to treatment by a third party, whereas a less severely ill patient might be more inclined to seek treatment for herself (himself) when psychosis is absent and insight is less compromised or when the patient feels she (he) might be depressed.

It is not uncommon for a manic patient to report “depression” as the chief complaint or to omit elements related to psychomo­tor acceleration (such as racing thoughts or psychomotor agitation) in the description of symptoms. An accurate diagnosis often requires clinical probing and clarification of symptoms (eg, differentiating simple insom­nia with consequent next-day fatigue from loss of the need for sleep with intact or even enhanced next-day energy) or discriminating racing thoughts from anxious ruminations that might be more intrusive than rapid.

Presentations of frank mania also can come to light as a consequence of symp­toms, rather than as symptoms per se (eg, conflict in relationships, problems at work, financial reversals).

Particularly in patients who do not have a history of mania, avoid the temptation to begin or modify existing pharmacother­apy until you have performed a basic ini­tial evaluation. Immediate considerations for initial assessment and management include the following:

Provide containment. Ensure a safe setting, level of care, and frequency of monitoring. Evaluate suicide risk (particularly when mixed features are present), and risk of with­drawal from any psychoactive substances.

Engage significant others. Close family members can provide essential history, particularly when a patient’s insight about her illness and need for treatment are impaired. Family members and significant others also often play important roles in helping to restrict access to finances, fos­tering medication adherence, preventing access to weapons in the home, and shar­ing information with providers about sub­stance use or high-risk behavior.

Systematically assess for DSM-5 symp­toms of mania and depression. DSM-5 modified criteria for mania/hypomania to necessitate increased energy, in addition to change in mood, to make a syndromal diag­nosis. Useful during a clinical interview is the popular mnemonic DIGFAST to aid recognition of core mania symptoms^a:
   • Distractibility
   • Indiscretion/impulsivity
   • Grandiosity
   • Flight of ideas
   • Activity increase
   • Sleep deficit
   • Talkativeness.

^aAlso see: “Mnemonics in a mnutshell: 32 aids to psychiatric diagnosis,” in the October 2008 issue Current Psychiatry and in the archive at CurrentPsychiatry.com.

These symptoms should represent a departure from normal baseline character­istics; it often is helpful to ask a significant other or collateral historian how the pres­ent symptoms differ from the patient’s usual state.

Assess for unstable medical conditions or toxicity states. When evaluating an acute change in mental status, toxicology screening is relatively standard and the absence of illicit substances should sel­dom, if ever, be taken for granted—espe­cially because occult substance use can lead to identification of false-positive BD “cases.”¹

Stop any antidepressant. During a manic episode, continuing antidepressant medi­cation serves no purpose other than to contribute to or exacerbate mania symp­toms. Nonetheless, observational studies demonstrate that approximately 15% of syndromally manic patients continue to receive an antidepressant, often when a clinician perceives more severe depression during mania, multiple prior depressive episodes, current anxiety, or rapid cycling.²

Importantly, antidepressants have been shown to harm, rather than alleviate, pre­sentations that involve a mixed state,³ and have no demonstrated value in preventing post-manic depression. Mere elimination of an antidepressant might ease symptoms during a manic or mixed episode.⁴

In some cases, it might be advisable to taper, not abruptly stop, a short half-life serotonergic antidepressant, even in the setting of mania, to minimize the potential for aggravating autonomic dysregulation that can result from antidepressant discon­tinuation effects. 

Begin anti-manic pharmacotherapy. Initiation of an anti-manic mood stabilizer, such as lithium and divalproex, has been standard in the treatment of acute mania.

In the 1990s, protocols for oral loading of divalproex (20 to 30 mg/kg/d) gained popularity for achieving more rapid symp­tom improvement than might occur with lithium. In the current era, atypical anti­psychotics have all but replaced mood sta­bilizers as an initial intervention to contain mania symptoms quickly (and with less risk than first-generation antipsychotics for acute adverse motor effects from so-called rapid neuroleptization).

Because atypical antipsychotics often rapidly subdue mania, psychosis, and agitation, regardless of the underlying process, many practitioners might feel more comfortable initiating them than a mood stabilizer when the diagnosis is ambiguous or provisional, although their longer-term efficacy and safety, relative to traditional mood stabilizers, remains contested. Considerations for choosing from among feasible anti-manic pharma­cotherapies are summarized in Table 1.⁵ 

Normalize the sleep-wake cycle. Chronobiological and circadian vari­ables, such as irregular sleep patterns, are thought to contribute to the pathophysiol­ogy of affective switch in BD. Behavioral and pharmacotherapeutic efforts to impose a normal sleep−wake schedule are considered fundamental to stabilizing acute mania.

Facilitate next steps after acute stabili­zation. For inpatients, this might involve step-down to a partial hospitalization or intensive outpatient program, alongside taking steps to ensure continued treatment adherence and minimize relapse.

What medical and neurologic workup is appropriate?
Not every first lifetime presentation of mania requires extensive medical and neurologic workup, particularly among patients who have a history of depression and those whose presentation neatly fits the demographic and clinical profile of newly emergent BD. Basic assessment should determine whether any new medication has been started that could plausibly contribute to abnormal mental sta­tus (Table 2).

Nevertheless, evaluation of almost all first presentations of mania should include:
   • urine toxicology screen 
   • complete blood count
   • comprehensive metabolic panel
   • thyroid-stimulating hormone assay
   • serum vitamin B₁₂ level assay
   • serum folic acid level assay
   • rapid plasma reagin test.

Clinical features that usually lead a cli­nician to pursue a more detailed medical and neurologic evaluation of first-episode mania include:
   • onset age >40
   • absence of a family history of mood disorder
   • symptoms arising during a major medical illness
   • multiple medications
   • suspicion of a degenerative or heredi­tary neurologic disorder
   • altered state of consciousness
   • signs of cortical or diffuse subcorti­cal dysfunction (eg, cognitive deficits, motor deficits, tremor)
   • abnormal vital signs.

Depending on the presentation, addi­tional testing might include:
   • tests of HIV antibody, immune auto­antibodies, and Lyme disease antibody
   • heavy metal screening (when sug­gested by environmental exposure)
   • lumbar puncture (eg, in a setting of manic delirium or suspected central nervous system infection or paraneoplastic syndrome)
   • neuroimaging (note: MRI provides bet­ter visualization than CT of white matter pathology and small vessel cerebrovascular disease) electroencephalography.

Making an overarching diagnosis: Is mania always bipolar disorder?
Mania is considered a manifestation of BD when symptoms cannot be attributed to another psychiatric condition, another underlying medical or neurologic condi­tion, or a toxic-metabolic state (Table 3 and Table 4^6-9). Classification of mania that occurs soon after antidepressant exposure in patients without a known history of BD continues to be the subject of debate, vary­ing in its conceptualization across editions of DSM.

The National Institute of Mental Health (NIMH) Systematic Treatment Enhancement Program for Bipolar Disorder, or STEP-BD, observed a fairly low (approximately 10%) incidence of switch from depression to mania when an antidepressant is added to a mood stabilizer; the study authors con­cluded that much of what is presumed to be antidepressant-induced mania might simply be the natural course of illness.¹⁰

Notably, several reports suggest that antidepressants might pose a greater risk of mood destabilization in people with BD I than with either BD II or other sus­pected variants on the bipolar spectrum.

DSM-5 advises that a diagnosis of substance-induced mood disorder appro­priately describes symptoms that spontane­ously dissipate once an antidepressant has been discontinued, whereas a diagnosis of BD can be made when manic or hypomanic symptoms persist at a syndromal level after an antidepressant has been stopped and its physiological effects are no longer present. With respect to time course, the International Society of Bipolar Disorders proposes that, beyond 12 to 16 weeks after an antidepressant has been started or the dosage has been increased, it is unlikely that new-onset mania/hypomania can rea­sonably be attributed to “triggering” by an antidepressant¹¹ (although antidepressants should be stopped when symptoms of mania emerge).

Several clinical features have been linked in the literature with an increased suscepti­bility to BD after an initial depressive epi­sode, including:
   • early (pre-adolescent) age at onset of first mood disorder episode⁶
   • family history of BD, highly recurrent depression, or psychosis^12,13
   • psychosis when depressed.^7,14

A number of other characteristics of depressive illness—including seasonal depression, atypical depressive features, suicidality, irritability, anxiety or sub­stance use comorbidity, postpartum mood episodes, and brief recurrent depressive episodes—have been described in the lit­erature as potential correlates of a bipolar diathesis; none have proved to be robust or pathognomonic of a BD diagnosis, as opposed to a unipolar diagnosis.

Data from the NIMH Collaborative Depression Study suggest that recurrent mania/hypomania after an antidepressant-associated polarity switch is greater when a family history of BD is present; other clinical variables might hold less predictive value.¹⁵

In addition, although some practitioners consider a history of nonresponse to trials of multiple antidepressants suggestive of an underlying bipolar process, polarity is only one of many variables that must be considered in the differential diagnosis of antidepressant-resistant depression.^b Likewise, molecular genetic studies do not support a link between antidepressant nonresponse and the likelihood of a diag­nosis of BD.¹⁶

^bSee “A practical approach to subtyping depression among your patients” in the April 2014 issue of Current Psychiatry or in the archive at CurrentPsychiatry.com.

Indefinite pharmacotherapy for bipolar disorder?
An important but nagging issue when diag­nosing BD after a first manic (or hypomanic) episode is the implied need for indefinite pharmacotherapy to sustain remission and prevent relapse and recurrence.

The likelihood of subsequent depression or mania/hypomania remains high after an index manic/hypomanic episode, par­ticularly for 6 to 8 months after recovery.^8,17 Natural history data suggest that, during the year that follows a first lifetime mania, approximately 40% of patients experience a second manic episode.⁸ A second lifetime mania might be especially likely in patients whose index episode involved mood-congruent psychosis, low premorbid work functioning, and an initial manic episode, as opposed to a mixed episode¹⁷ or early age at onset.⁸

In the absence of randomized, placebo-controlled studies of maintenance phar­macotherapy after a first lifetime manic episode, clinical judgment often drives decisions about the duration of continuing pharmacotherapy after initial symptoms resolve. The Texas Medication Algorithm Project for BD advises that:

Similarly, in the most recent (2004) Expert Consensus Guideline Series for the Treatment of Bipolar Disorder,¹⁹ 84% of practitioner−respondents favored indefi­nite mood stabilizer therapy after a second lifetime manic episode. No recommen­dation was made about the duration of maintenance pharmacotherapy after a first lifetime manic/hypomanic episode.

Avoid or reintroduce an antidepressant if depression recurs after a first mania?
Controversies surrounding antidepressant use in BD are extensive; detailed discus­sion is beyond the scope of this review (Goldberg and Ghaemi provided a broader discussion of risks and benefits of antide­pressants in BD20). Although the main clinical concern regarding antidepres­sant use was, at one time, the potential to induce mania or accelerate the frequency of recurrent episodes, more recent, empiri­cal studies suggest that the greater risk of using antidepressants for BD is lack of efficacy.^10,21

If a careful longitudinal history and clin­ical evaluation reveal that an initial manic episode heralds the onset of BD, decisions about whether to avoid an antidepressant (as opposed to using other, more evidence-based interventions for bipolar depres­sion) depend on a number of variables, including establishing whether the index episode was manic or hypomanic; ruling out current subthreshold mixed features; and clarifying how recently mania devel­oped. Decisions about future antidepres­sant use (or avoidance) might be less clear if an index manic/hypomanic episode was brief and self-limited once the antidepres­sant was stopped.

Although some experts eschew antidepressant monotherapy after such occurrences, there is no body of litera­ture to inform decisions about the safety or efficacy of undertaking a future antidepressant trial in such patients. That said, reasonable judgment probably includes several considerations:
   • Re-exposure to the same antidepres­sant that was associated with an induction of mania is likely riskier than choosing a different antidepressant; in general, purely serotonergic antidepressants or bupropion are considered to pose less risk of mood destabilization than is seen with an SNRI or tricyclic antidepressant.
   • After a manic episode, a subsequent antidepressant trial generally shouldn’t be attempted without concurrent anti-manic medication.
   • Introducing any antidepressant is probably ill-advised in the recent (~2 months) aftermath of acute manic/ hypomanic symptoms.²²
   • Patients and their significant other should be apprised of the risk of emerg­ing symptoms of mania or hypomania, or mixed features, and should be familiar with key target symptoms to watch for. Prospective mood charting can be helpful.
   • Patients should be monitored closely both for an exacerbation of depression and recurrence of mania/hypomania symptoms.
   • Any antidepressant should be discon­tinued promptly at the first sign of psy­chomotor acceleration or the emergence of mixed features, as defined by DSM-5.

Psychoeducation and forecasting
Functional recovery from a manic episode can lag behind symptomatic recovery. Subsyndromal symptoms often persist after a full episode subsides.

Mania often is followed by a depres­sive episode, and questions inevitably arise about how to prevent and treat these epi­sodes. Because the median duration of a manic episode is approximately 13 weeks,²³ it is crucial for patients and their immedi­ate family to recognize that recovery might be gradual, and that it will likely take time before she (he) can resume full-time respon­sibilities at work or school or in the home.

Today, a patient who is hospitalized for severe acute mania (as Ms. J was, in the case vignette) seldom remains an inpa­tient long enough to achieve remission of symptoms; sometimes, she (he) might con­tinue to manifest significant symptoms, even though decisions about the “medical necessity” of ongoing inpatient care tend to be governed mainly by issues of safety and imminent danger. (This web exclusive Table^20,24,25 provides considerations when making the transition from the acute phase to the continuation phase of treatment.)

To minimize risk of relapse, psycho-education should include discussion of:
   • psychiatrically deleterious effects of alcohol and illicit drug use
   • suicide risk, including what to do in an emergency
   • protecting a regular sleep schedule and avoiding sleep deprivation
   • the potential for poor medication adherence and management of side effects
   • the need for periodic laboratory moni­toring, as needed
   • the role of adjunctive psychotherapy and effective stress management
   • familiarity with symptoms that serve as warning signs, and how to monitor their onset.

Bottom Line
When a patient being treated for depression develops signs of mania or hypomania, stop any antidepressant and consider initiating a mood stabilizer, antipsychotic, or both, to contain and stabilize symptoms. Entertain medical and substance-related causes of mania symptoms, and evaluate and treat as suggested by the patient’s presentation. Long-term drug therapy to prevent recurrence of mania/hypomania, as well as risks and benefits of future exposure to antidepressants, should be decided case by case.

Related Resources
• Proudfoot J, Whitton A, Parker G, et al. Triggers of mania and depression in young adults with bipolar disorder. J Affect Disord. 2012;143(1-3):196-202.
• Stange JP, Sylvia LG, Magalhães PV, et al. Extreme at­tributions predict transition from depression to ma­nia or hypomania in bipolar disorder. J Psychiatr Res. 2013;47(10):1329-1336.

Drug Brand Names
Albuterol • Proventil, Ventolin
Anastrozole • Arimidex
Aripiprazole • Abilify
Bupropion • Wellbutrin
Carbamazepine • Tegretol
Chloroquine • Aralen
Ciprofloxacin • Cipro
Clarithromycin • Biaxin
Clomiphene • Clomid
Digoxin • Digox, Lanoxin
Divalproex • Depakote
5-Fluorouracil • Carac, Efudex
Human chorionic gonadotropin • Novarel, Pregnyl
Ifosfamide • Ifex
Isoniazid • Nydrazid
Lamotrigine • Lamictal
Letrozole • Femara
Lithium • Eskalith, Lithobid
Lurasidone • Latuda
Mefloquine • Lariam
Olanzapine • Zyprexa
Olanzapine/fluoxetine combination • Symbyax
ramipexole • Mirapex
Procarbazine • Matulane
Quetiapine • Seroquel
Ropinirole • Requip
Rotigotine • Neupro
Venlafaxine • Effexor
Zidovudine • Retrovir

Disclosures
Dr. Goldberg is a consultant to Merck & Co. and Sunovion. He is a member of the speakers’ bureau of AstraZeneca, Janssen, Merck & Co., Takeda and Lundbeck, and Sunovion.

Dr. Ernst reports no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Higher positivity ratings for current self-images were associated with lower depression and anxiety scores among young adults with Bipolar Spectrum Disorder (BPSD), suggesting that BPSD phenotype can shape the relationship between affect and current and future self-images.

As reported in the Journal of Affective Disorders, lead author Dr. Martina Di Simplicio of MRC Cognition and Brain Sciences Unit, Cambridge, England, and her associates assessed a nonclinical sample of 47 participants (66% female; mean age, 23) for hypomanic experiences and BPSD vulnerability, split into two groups based on their Mood Disorders Questionnaire (MDQ) score. Seventy-five percent of the participants in the high MDQ group generated at least one negative current self-image, compared with 48% of participants in the low MDQ group (P = .055).

The investigators noted that, for those with high MDQ scores, the relationship between affect and perception of the stability of negative self-images is different compared with those with low MDQ scores. And while 75% participants in the BPSD phenotype group were likely to endorse negative images of the current self (compared with less than 50% of the group without hypomanic experiences, almost none of the patients from either group had negative images of the future self).

“BPSD phenotype presents with both alterations and resilience in how self-images and mood shape each other. Further investigations could elucidate how this relationship is affected by illness progression and offer targets for early interventions based on experimental cognitive models,” the investigators wrote.

Read the article in Journal of Affective Disorders (doi: 10.1016/j.jad.2015.08.042).

[email protected]

Higher positivity ratings for current self-images were associated with lower depression and anxiety scores among young adults with Bipolar Spectrum Disorder (BPSD), suggesting that BPSD phenotype can shape the relationship between affect and current and future self-images.

As reported in the Journal of Affective Disorders, lead author Dr. Martina Di Simplicio of MRC Cognition and Brain Sciences Unit, Cambridge, England, and her associates assessed a nonclinical sample of 47 participants (66% female; mean age, 23) for hypomanic experiences and BPSD vulnerability, split into two groups based on their Mood Disorders Questionnaire (MDQ) score. Seventy-five percent of the participants in the high MDQ group generated at least one negative current self-image, compared with 48% of participants in the low MDQ group (P = .055).

The investigators noted that, for those with high MDQ scores, the relationship between affect and perception of the stability of negative self-images is different compared with those with low MDQ scores. And while 75% participants in the BPSD phenotype group were likely to endorse negative images of the current self (compared with less than 50% of the group without hypomanic experiences, almost none of the patients from either group had negative images of the future self).

“BPSD phenotype presents with both alterations and resilience in how self-images and mood shape each other. Further investigations could elucidate how this relationship is affected by illness progression and offer targets for early interventions based on experimental cognitive models,” the investigators wrote.

Read the article in Journal of Affective Disorders (doi: 10.1016/j.jad.2015.08.042).

[email protected]

Higher positivity ratings for current self-images were associated with lower depression and anxiety scores among young adults with Bipolar Spectrum Disorder (BPSD), suggesting that BPSD phenotype can shape the relationship between affect and current and future self-images.

As reported in the Journal of Affective Disorders, lead author Dr. Martina Di Simplicio of MRC Cognition and Brain Sciences Unit, Cambridge, England, and her associates assessed a nonclinical sample of 47 participants (66% female; mean age, 23) for hypomanic experiences and BPSD vulnerability, split into two groups based on their Mood Disorders Questionnaire (MDQ) score. Seventy-five percent of the participants in the high MDQ group generated at least one negative current self-image, compared with 48% of participants in the low MDQ group (P = .055).

The investigators noted that, for those with high MDQ scores, the relationship between affect and perception of the stability of negative self-images is different compared with those with low MDQ scores. And while 75% participants in the BPSD phenotype group were likely to endorse negative images of the current self (compared with less than 50% of the group without hypomanic experiences, almost none of the patients from either group had negative images of the future self).

“BPSD phenotype presents with both alterations and resilience in how self-images and mood shape each other. Further investigations could elucidate how this relationship is affected by illness progression and offer targets for early interventions based on experimental cognitive models,” the investigators wrote.

Read the article in Journal of Affective Disorders (doi: 10.1016/j.jad.2015.08.042).

[email protected]

Anatomical connectivity in discreet frontal regions of the brain is disrupted in bipolar I disorder patients, but not in mentally healthy relatives of such patients, according to a study.

©Purestock/thinkstockphotos.com

The researchers looked for connectivity abnormalities in the brains of multiply affected bipolar I disorder families “to assess the utility of dysconnectivity as a biomarker and its endophenotypic potential.” Tractography was done on magnetic resonance diffusion images of the brains of 19 bipolar I patients in remission, 21 of the patients’ first-degree relatives who did not have bipolar I, and 18 unrelated controls who also did not have bipolar I. A connectivity matrix was generated for each patient, and the Brain Connectivity Toolbox was used to extract neural network metrics.

“Whole brain analysis revealed no differences between groups,” according to Natalie J. Forde, a PhD candidate at the University Medical Centre Gronigen (the Netherlands) and her colleagues. “Analysis of specific mainly frontal regions, previously implicated as potentially endophenotypic by functional magnetic resonance imaging analysis of the same cohort, revealed a significant effect of group in the right medial superior frontal gyrus and left middle frontal gyrus driven by reduced [organization] in [bipolar I] patients, compared with controls.”

Read the full study in Psychiatry Research: Neuroimaging (doi: 10.1016/j.pscychresns.2015.08.004).

[email protected]

Anatomical connectivity in discreet frontal regions of the brain is disrupted in bipolar I disorder patients, but not in mentally healthy relatives of such patients, according to a study.

©Purestock/thinkstockphotos.com

The researchers looked for connectivity abnormalities in the brains of multiply affected bipolar I disorder families “to assess the utility of dysconnectivity as a biomarker and its endophenotypic potential.” Tractography was done on magnetic resonance diffusion images of the brains of 19 bipolar I patients in remission, 21 of the patients’ first-degree relatives who did not have bipolar I, and 18 unrelated controls who also did not have bipolar I. A connectivity matrix was generated for each patient, and the Brain Connectivity Toolbox was used to extract neural network metrics.

“Whole brain analysis revealed no differences between groups,” according to Natalie J. Forde, a PhD candidate at the University Medical Centre Gronigen (the Netherlands) and her colleagues. “Analysis of specific mainly frontal regions, previously implicated as potentially endophenotypic by functional magnetic resonance imaging analysis of the same cohort, revealed a significant effect of group in the right medial superior frontal gyrus and left middle frontal gyrus driven by reduced [organization] in [bipolar I] patients, compared with controls.”

Read the full study in Psychiatry Research: Neuroimaging (doi: 10.1016/j.pscychresns.2015.08.004).

[email protected]

Anatomical connectivity in discreet frontal regions of the brain is disrupted in bipolar I disorder patients, but not in mentally healthy relatives of such patients, according to a study.

©Purestock/thinkstockphotos.com

The researchers looked for connectivity abnormalities in the brains of multiply affected bipolar I disorder families “to assess the utility of dysconnectivity as a biomarker and its endophenotypic potential.” Tractography was done on magnetic resonance diffusion images of the brains of 19 bipolar I patients in remission, 21 of the patients’ first-degree relatives who did not have bipolar I, and 18 unrelated controls who also did not have bipolar I. A connectivity matrix was generated for each patient, and the Brain Connectivity Toolbox was used to extract neural network metrics.

“Whole brain analysis revealed no differences between groups,” according to Natalie J. Forde, a PhD candidate at the University Medical Centre Gronigen (the Netherlands) and her colleagues. “Analysis of specific mainly frontal regions, previously implicated as potentially endophenotypic by functional magnetic resonance imaging analysis of the same cohort, revealed a significant effect of group in the right medial superior frontal gyrus and left middle frontal gyrus driven by reduced [organization] in [bipolar I] patients, compared with controls.”

Read the full study in Psychiatry Research: Neuroimaging (doi: 10.1016/j.pscychresns.2015.08.004).

[email protected]