Keming Gao, MD, PhD

Slideshows

Useful information about mood disorders in 3 key areas-bipolar disorder, comorbid ADHD and depression, and suicide risk. 

Mood Disorders in 3 Clinical Reports

Depressive disorders and bipolar and related disorders have their own chapters in DSM-5, but the challenges for diagnosing and treating these disorders remain the same. Some of the most common challenges include the diagnosis of a mood disorder, especially a bipolar disorder, and the assessment and management of comorbidities and suicidalities in patients with a mood disorder. In this Special Report on mood disorders, the authors of the 3 articles have attempted to address these issues. The article on comorbid ADHD and depression by W. Burleson Daviss, MD, and Joseph B. Bond, MD, appears 

 and will be published in the September issue of 

As with any illness, a correct diagnosis is the first step toward treatment success. However, the same presentations of depressive symptoms with MDD (unipolar depression) and with bipolar disorder (bipolar depression) pose challenges for clinicians to differentiate unipolar depression from bipolar depression. Misdiagnosis of bipolar depression as unipolar depression is problematic.

 Although manic/hypomanic symptoms are prerequisites for diagnosing bipolar disorder, in some cases, the manic/hypomanic symptoms might not be obvious or straightforward.

Clinicians should help patients understand the presentations of manic/hypomanic symptoms to uncover any manic/hypomanic episode(s). A complete psychiatric interview with a longitudinal perspective is essential. Collateral information from family members and/or friends may be necessary to make a correct diagnosis for those who don’t have much insight into their illness or who are unwilling to share their manic/hypomanic experiences. Screening tools such as the Mood Disorder Questionnaire and Hypomania Checklist-32 item may be useful to uncover manic/hypomanic symptoms.

Among all the psychiatric conditions, bipolar disorder has the highest risk for suicide and suicide attempts.

phenotypic boundaries of bipolar disorder

, Dean F. MacKinnon, MD, uses 2 patients as examples to illustrate phenotypic differences in bipolar disorders. He concludes “soft” symptoms are not easily discerned. Clinicians should pay close attention to the “soft” symptoms during interviews.

 of other psychiatric disorders with mood disorders is the rule rather than the exception.

 A systematic diagnostic interview is essential to assess psychiatric comorbidities. Comorbid anxiety and substance use disorders are 

, especially in patients with a bipolar disorder.

 However, a significant number of patients with a mood disorder, especially those with bipolar I disorder, also have ADHD.

 Commonly used medications for ADHD have the potential to worsen anxiety symptoms and provoke mania or hypomania.

, W. Burleson Daviss, MD, and Joseph B. Bond, MD, review the prevalence, assessment, and treatment of comorbid ADHD and depression. Their review not only provides an update on this important topic, but also helps clinicians understand the challenges and unmet needs in this population.

Mood disorders are risk factors for suicide and suicide attempts. Among all the psychiatric conditions, bipolar disorder has the highest risk for suicide and suicide attempts. To reduce deaths by suicide in patients with bipolar disorder, the International Society for Bipolar Disorder Task Force on Suicide Risk and Prevention in Bipolar Disorder made a collaborative effort to study the risk factors for suicide and suicide attempt and to develop strategies to assess and manage suicide risk.

suicide risk and prevention in bipolar disorder

, Ayal Schaffer, MD, and Manuel Sanchez De Carmona, MD, share some findings from this collaboration. The authors first review the prevalence of suicide and suicide attempt and summarize the risk factors for suicide. They also provide a specific clinical model for bipolar disorder suicide risk assessment, and propose strategies for managing suicide risk.

In summary, these articles provide important clinically relevant information for diagnosing mood disorders, especially bipolar disorder, and assessing and managing comorbid ADHD in depression and suicide risk in bipolar disorder.

Dr. Gao is Professor of Psychiatry, Department of Psychiatry, Case Western Reserve University School of Medicine; Clinical Director of Mood Disorders Program, University Hospitals Case Medical Center, Cleveland, OH. He reports that he has received grant support from AstraZeneca, the Brain and Behavior Foundation, and the Cleveland Foundation; he is on the Speakers Bureau and Advisory Board for Sunovion.

 Hirschfeld RM, Lewis L, Vornik LA. Perceptions and impact of bipolar disorder: how far have we really come? Results of the National Depressive and Manic-Depressive Association 2000 survey of individuals with bipolar disorder. 

 Gao K, Kemp DE, Conroy C, et al. Comorbid anxiety and substance use disorders associated with a lower use of mood stabilizers in patients with rapid cycling bipolar disorder: a descriptive analysis of the cross-sectional data of 566 patients. 

 Angst J, Adolfsson R, Bennazzi F, et al. The HCL-32: towards a self assessment tool for hypomanic symptoms in outpatients. 

 Yang HC, Yuan CM, Liu TB, et al. Validity of the 32-item Hypomania Checklist (HCL-32) in a clinical sample with mood disorders in China. 

 Merikangas KR, Akiskal HS, Angst J, et al. Lifetime and 12-month prevalence of bipolar spectrum disorder in the National Comorbidity Survey replication. 

 Gao K, Wang Z, Chen J, et al. Should an assessment of axis I comorbidity be included in the initial diagnostic assessment of mood disorders? Role of QIDS-16-SR total score in predicting number of axis I comorbidity. 

 Schaffer A, Isometsa ET, Tondo L, et al. International Society for Bipolar Disorders Task Force on Suicide: meta-analyses and meta-regression of correlates of suicide attempts and suicide deaths in bipolar disorder. 

 Schaffer A, Isometsa ET, Azorin JM, et al. A review of factors associated with greater likelihood of suicide attempts and suicide deaths in bipolar disorder: part II of a report of the International Society for Bipolar Disorders Task Force on Suicide in Bipolar Disorder. 

Articles

Some of the most common challenges include the diagnosis of a mood disorder, especially a bipolar disorder, and the assessment and management of comorbidities and suicidalities in patients with a mood disorder. Here's an overview.

Introduction: A Focus on Differential Diagnoses, Comorbidity, and Suicide Risk

The comorbidity of anxiety disorders with bipolar disorder is a rule, not an exception, with a negative impact on both course and treatment outcome. So far, there are no guidelines or consensus for the treatment of this comorbidity. There are also no efficacy data that support the use of antidepressants or benzodiazepines in the treatment of anxiety disorder in this population. Benzodiazepines, the second-line agents for some primary anxiety disorders, may be riskier for patients with bipolar disorder because they are associated with a high rate of comorbid substance use disorder. Some preliminary data have shown that antipsychotics, especially atypical anti- psychotics, may be a viable alternative for patients with comorbid bipolar and anxiety disorders with or without substance use disorder.

Data from the National Comorbidity Survey have shown that patients with bipolar I disorder (BPI) had high rates of lifetime Axis I comorbidity and that anxiety disorder and substance use disorder were the 2 most common comorbid conditions with BPI.

 Of the 59 patients with BPI, 93% had at least one anxiety disorder and 61% had at least one substance use disorder.

More recently, the findings from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) have shown that patients with BPI (n = 1411) had high rates of comorbid anxiety disorders with specific phobia (30%), panic disorder with/ without agoraphobia (26%), generalized anxiety disorder (GAD) (25%), and social phobia (24%).

 have reported that in clinical outpatient samples, the lifetime rates of anxiety disorder ranged from 24% to 53% with BPI and 16% to 46% with bipolar II disorder (BPII).

 Data from a cohort of patients with rapid cycling BPI or BPII (n = 566) have shown that 35% of patients had lifetime GAD, 27% had panic disorder, and 7% had obsessive-compulsive disorder (OCD).

Comorbid substance use disorder with bipolar disorder is also a rule, not an exception. In the Epidemiologic Catchment Area study, patients with BPI or BPII had the highest rates of substance use disorder among all patients with mental illness, with a lifetime incidence of alcohol use disorder of 44% and a lifetime incidence of drug use disorder of 34%.

 In the NESARC, more than half of the patients with BPI (58%) had a lifetime history of alcohol use disorder, and more than one third (37.5%) had a lifetime history of drug use disorder.

 In clinical outpatient studies, the rates of lifetime comorbid substance use disorder with bipolar disorder were 42% to 61% with BPI and 31% to 48% with BPII.

Although the exact rates of double or multiple comorbidities of anxiety disorders and substance use disorders in bipolar disorder are unknown, high rates of these comorbidities in bipolar disorder have been observed in various study populations. These include national surveys,

 In our sample, at least 31% of patients with rapid cycling bipolar disorder had both comorbid anxiety disorder and substance use disorder.

Comorbid anxiety disorder has a significantly negative impact on the quality of life of patients who have bipolar disorder, as manifested by earlier onset of illness,

 more rapid cycling, suicidal behavior, substance use disorder,

poorer response to lithium or anticonvulsants,

 The data from a study of patients with rapid cycling bipolar disorder have shown that comorbid anxiety disorder and/or substance use disorder was associated with an increased risk of hospitalization or suicide attempt(s).

Findings from the Systematic Treatment Enhancement Program-Bipolar Disorder (STEP-BP) have shown that comorbid anxiety and bipolar disorders were usually undertreated, although antidepressants were more commonly prescribed for patients with the comorbidity.

 More recently, data from the STEP-BP have shown that a current anxiety diagnosis at study entry was associated with the increased risk of depression recurrence; the proportion of days with anxiety in the previous year was an independent predictor for depression recurrence.

 However, it is still unclear whether adequate treatment of anxiety disorders will change the course and treatment outcome in patients with bipolar disorder.

Although newer antidepressants, especially SSRIs, have proved efficacious in the treatment of primary anxiety disorders and have commonly been prescribed for patients with bipolar disorder,

 there are no data to support their use in treating anxiety in bipolar disorder. The issue of antidepressant-induced mania remains controversial

 although there is evidence that antidepressants may trigger mania or destabilize the course of the bipolar disorder, especially without the concomitant use of a mood stabilizer.

In a 6-year follow-up study of patients with schizophrenia or bipolar and substance use disorders, treatment with a benzodiazepine was not associated with any of the measured outcomes other than increasing the likelihood of benzodiazepine abuse-15% in the treatment group versus 6% in the nontreatment group.

 Clearly, benzodiazepines for anxiety disorder should be used with caution in patients who have bipolar disorder and a substance use disorder.

EXPERIENCE WITH ANTIPSYCHOTICS Primary GAD

There is a long history of interest in antipsychotics for the treatment of anxiety disorders, but the data for the treatment of GADs are limited to the typical agents. In a large randomized, double-blind, placebo-controlled study, Mendels and colleagues

 found that trifluoperazine was superior to placebo in the acute treatment of 

 In this multicenter study, 415 patients with moderate to severe anxiety symptoms on the Hamilton Anxiety Rating Scale (HAM-A) equal to a score of 20 were randomly assigned to receive either 2 to 6 mg of trifluoperazine (n = 207) or placebo (n = 208) for 4 weeks. Efficacy was assessed using the HAM-A and other scales. Trifluoperazine showed superiority to placebo in all outcome measures including HAM-A total scores and subscores (

In less well-designed studies, other typical antipsychotics appeared to be superior to placebo or as effective as benzodiazepines in the treatment of GAD or other anxiety disorders.

 In terms of atypical antipsychotics, there is only one small randomized, placebo-controlled study (N = 20) of olanzapine in the treatment of refractory primary GAD.

OCD or chronic posttraumatic stress disorder

Before the introduction of newer atypical antipsychotics, the efficacy of haloperidol in the treatment of refractory OCD was explored with mixed results. One study found there were no differences among 3 groups: those receiving chlorimipramine, those receiving chlorimipramine-haloperidol, and those taking chlorimipramine-diazepam for the treatment of phobic-obsessive psychoneurosis as measured with the Brief Psychiatric Rating Scale and Inpatient Multidimensional Psychiatric Scale.

 Another study found that haloperidol adjunctive to fluvoxamine (n = 17) was superior to placebo (n = 17) in the treatment of refractory OCD.

With the introduction of newer atypical antipsychotics and the realization of the incomplete effect of SSRIs on the treatment of OCD, investigators have explored atypical antipsychotic augmentation to SSRI treatment in refractory OCD. After a small open-label study of risperidone augmentation for the treatment of refractory OCD with positive results,

 the efficacy of risperidone, olanzapine, and quetiapine was assessed in open-label or double-blind, placebo-controlled studies.

In addition, these 3 agents were explored for the treatment of chronic posttraumatic stress disorder (PTSD). Most of the studies showed that adding risperidone, olanzapine, or quetiapine to an SSRI produced results superior to those achieved with placebo in the treatment of refractory OCD or chronic PTSD. However, the sample sizes of these studies were relatively small, ranging from 15 to 66 patients.

Comorbid anxiety symptoms in bipolar disorder

There are 2 large randomized, double-blind, placebo-controlled studies, one with olanzapine and the other with quetiapine, for the acute treatment of bipolar depression.

 In both studies, changes in HAM-A scores were used as secondary outcome measures. Tohen and colleagues

 analyzed HAM-A scores of 695 patients (placebo, n = 315; olanzapine, n = 309; olanzapine-fluoxetine combination [OFC], n = 71). At baseline, HAM-A scores were comparable among the 3 groups with a mean range of 15.8 to 17.1 points. After the 8-week treatment, both olanzapine and OFC were significantly superior to placebo in reducing HAM-A total scores. However, there was no difference between olanzapine monotherapy and OFC (

In the quetiapine study, patients were randomized to treatment with 600 mg/d of quetiapine (n = 180), 300 mg/d of quetiapine (n = 181), or placebo (n = 181).

 The changes in HAM-A scores of 511 patients (342, BPI; 169, BPII) were analyzed. Similar to the olanzapine study, the baseline HAM-A mean scores were comparable among the 3 groups, ranging from 18.6 to 18.9 points. At the end of week 8, both dosages of quetiapine significantly reduced HAM-A total scores compared with placebo (

). In a post hoc analysis, quetiapine significantly decreased HAM-A items of anxious mood, tension, fear, insomnia, and depressed mood and intellectual, somatic (muscular), and genitourinary symptoms compared with placebo.

 However, only the patients with BPI showed a significant and robust reduction in HAM-A total scores compared with placebo (

The neuronal basis for anxiety is complex and unclear, although the serotonergic system may play a role. Recently, the involvement of the dopamine system in anxiogenesis has been speculated. The amygdala and the mesolimbic dopaminergic systems are believed to play an important role in conditioned fear and anxiety in animals and anxiety disorder in humans.

Anxiety-provoking environments increased dopamine release in the amygdala,

 The increase in dopamine in the prefrontal cortex during stress or anxiogenic administration could be totally blocked by anxiolytics, such as diazepam

 The anxiogenic-like response induced by chronic amphetamine treatment in rats could be totally blocked by haloperidol injection.

 Similarly, other antipsychotics could also block the acquisition of conditioned fear.

Neuroimaging studies in humans have demonstrated that an increased release of dopamine caused by stimulants was positively correlated with an increase in anxiety symptoms in healthy persons.

 These data from animal and human studies suggest that direct blockade of dopamine action with antipsychotic drugs may be an alternative way to reduce anxiety symptoms.

IS USE OF ANTIPSYCHOTICS FOR ANXIETY JUSTIFIED?

Good quality data for antipsychotics in the treatment of anxiety disorder are limited to trifluoperazine. It is the only antipsychotic that has been approved by the FDA for the short-term treatment of primary GAD. At present, the use of other antipsychotics in primary or comorbid anxiety disorder should be considered off-label.

Although adjunctive atypical antipsychotics appeared to be useful in refractory OCD or chronic PTSD, and monotherapy appeared useful in bipolar depression with anxiety symptoms, the results were confounded by small sample sizes or lack of systematic assessment of the nature of anxiety. Therefore, caution should be followed in the use of these agents for primary or comorbid anxiety symptoms/disorders.

Anxiety is a very complicated phenomenon. So far, there is no single agent that can be used effectively and safely by all patients. A systemic consideration of the risks and benefits of antidepressants, antipsychotics, benzodiazepines, and other agents should be carried out before the initiation of treatment.

Since there are no efficacy data supporting the use of any agent in the treatment of comorbid anxiety disorder in patients with bipolar disorder, attention should be paid to the potential adverse effects. For antidepressants, in addition to the common adverse effects experienced by patients who are not bipolar, patients with bipolar disorder may experience treatment-related mania/hypomania. To minimize this risk, adequate treatment with a mood stabilizer is essential when an antidepressant is indicated. Benzodiazepine use in patients with bipolar disorder and a history of substance use disorder, especially current substance use disorder, should be carefully documented and monitored because of the abuse/dependence potential of benzodiazepines. Using an agent with a long half-life may minimize the risk of abuse or withdrawal.	

Although antipsychotics do not pose a risk for mania/hypomania or abuse/ dependence with bipolar disorder, the burden of potential adverse effects cannot be ignored. The lower prevalence of atypical antipsychotic-induced extrapyramidal symptoms (EPS) compared with typical agents has led clinicians to prioritize their use, but atypical antipsychotic-induced EPS do occur in the treatment of schizophrenia or acute mania. More important, there is evidence, although inconsistent, that bipolar disorder is a risk factor for EPS. Similarly, metabolic abnormalities have been reported in patients with schizophrenia who are treated with typical or atypical antipsychotics. Therefore, patients treated with antipsychotics should be closely monitored for metabolic syndrome and movement disorders regardless of the drug classes.

There is no pharmacological study designed for a cohort of patients with bipolar disorder and a specific comorbid anxiety disorder. Low-dose trifluoperazine was well tolerated and superior to placebo in the short-term treatment of primary GAD.

 Adjunctive therapy with an atypical antipsychotic (risperidone, olanzapine, or quetiapine) was superior to placebo in the treatment of refractory OCD or chronic PTSD, but these studies were confounded by small sample sizes.

The preliminary data on olanzapine and quetiapine in reducing anxiety symptoms in patients with bipolar depression suggest that this class of agents may have promise for the treatment of comorbid anxiety disorders with bipolar disorder. There exists an urgent need for large randomized controlled trials of the various atypical antipsychotic agents in patients who have bipolar disorder and comorbid specific anxiety disorders, especially in those with substance use disorder.

 Kessler RC, Rubinow DR, Holmes C, et al. The epidemiology of 

 bipolar I disorder in a general population survey. Psychol Med. 1997;27:1079-1089.	


 Grant BF, Stinson FS, Hasin DS, et al. Prevalence, correlates, and comorbidity of bipolar I disorder and axis I and II disorders: results from the National Epidemiologic Survey on Alcohol and Related Conditions. 

 Bauer MS, Altshuler L, Evans DR, et al; VA Cooperative Study No. 430 Team. Prevalence and distinct correlates of anxiety, substance, and combined comorbidity in a multi-site public sector sample with bipolar disorder. 

Ganocy SJ, Bilali S, et al. Pragmatic consideration in the comorbid presentations of anxiety disorder and substance use disorder in patients with rapid cycling bipolar disorder. Presented at:

 159th Annual Meeting of the American Psychiatric Association;

 May 20-25, 2006; Toronto. Abstract NR 51.


 Regier DA, Farmer ME, Rae DS, et al. Comorbidity of mental disorders with alcohol and other drug abuse: results from the Epidemiologic Catchment Area (ECA) Study. 

 Brown ES, Suppes T, Adinoff B, et al. Drug abuse and bipolar disorder: comorbidity or misdiagnosis? 

 McElroy SL, Altshuler LL, Suppes T, et al. Axis I psychiatric comorbidity and its relationship to historical illness variables in 288 patients with bipolar disorder. 

 Chengappa KNR, Levine J, Gershon S, Kupfer DJ. Lifetime prevalence of substance or alcohol abuse and dependence among subjects with bipolar I and II disorders in a voluntary registry. 

 Simon NM, Otto MW, Wisniewski SR, et al. Anxiety disorder comorbidity in bipolar disorder patients: data from the first 500 participants in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BP). 

 Schurhoff F, Bellivier F, Jouvent R, et al. Early and later onset bipolar disorders: two different forms of manic-depressive illness? 

 Carter TD, Mundo E, Parikh SV, Kennedy JL. Early age at onset as a risk factor for poor outcome of bipolar disorder. 

 Perlis RH, Miyahara S, Marangell LB, et al. Long-term implications of early onset in bipolar disorder: data from the first 1000 participants in the systematic treatment enhancement program for bipolar disorder (STEP-BP). 

 Young LT, Cooke RG, Robb JC, et al. Anxious and non-anxious bipolar disorder. 

 Frank E, Cyranowski JM, Rucci P, et al. Clinical significance of lifetime panic spectrum symptoms in the treatment of patients with bipolar disorder. 

 Feske U, Frank E, Mallinger A, et al. Anxiety as a correlate of response to the acute treatment of bipolar disorder. 

The comorbidity of anxiety disorders with bipolar disorder is a rule, not an exception, with a negative impact on both course and treatment outcome. So far, there are no guidelines or consensus for the treatment of this comorbidity.

Antipsychotics in the Treatment of Comorbid Anxiety in Bipolar Disorder

Some of the most challenging facets of bipolar disorder involve the management of its depressive symptoms. This article will focus on the pharmacologic management of this phase of bipolar disorder, describing the evidence base for controlled studies, emerging treatments, and expert recommendations.

An unmet need exists for acute and maintenance treatments that target depressive symptoms in bipolar disorder. Depression predominates over the course of both bipolar I (BP I) and bipolar II (BP II) disorders, occurring more than 3 times as frequently as manic and hypomanic symptoms combined in BP I,

 and nearly 40 times as frequently as hypomania in BP II.

 Patients repeatedly attribute greater impairment in their work, family life, and psychosocial functioning to depressive symptoms than to mania.

 Even more problematic, the majority of attempted suicides occur in states of depression, in which the rate is 20 times higher than in the general population.

A significant challenge facing clinicians is the misdiagnosis or underdiagnosis of bipolar depression. Perhaps this is because it presents itself less dramatically and is more difficult to recognize. A large French multicentered study of patients experiencing a major depressive episode, as classified by 

, found that when systematic methods for identifying hypomania were employed, the rate of BP II disorder nearly doubled, increasing from 22% to 40% of such patients.

 was used in a primary care clinic, more than one fifth of patients receiving antidepressants for the treatment of depression screened positive for bipolar disorder.

 Before this assessment, bipolar disorder had not been diagnosed in the majority of these patients. It is clear that early discrimination between bipolar disorder and other psychiatric illnesses, particularly major depressive disorder, is essential to minimize misdiagnosis and provide safe and effective care.

Acute and maintenance effects of lamotrigine

A rigorous and methodical evaluation of a pharmacologic treatment for bipolar depression emerged in 1999, when Calabrese and associates

 published the first randomized, parallel group, placebo-controlled trial of lamotrigine in the treatment of patients with BP I depression. Conducted over 7 weeks, the study randomized patients to lamotrigine 50 mg/d (n = 66), lamotrigine 200 mg/d (n = 63), or placebo (n = 66). Significant improvements were seen in patients receiving both dosages of lamotrigine over patients in the placebo group in observed change on the 

On the Montgomery-sberg Depression Rating Scale (MADRS) total score, significant improvement over placebo was evident for only the lamotrigine 200 mg/d group (

 < .05). However, a responder analysis-where response is defined as 50% or greater improvement in MADRS tota score-showed that 54% of the patients receiving lamotrigine 200 mg/d and 48% of the patients receiving lamotrigine 50 mg/d met criteria for response. Response rates for patients treated with both dosages of lamotrigine were significantly greater than the 29% response rate observed for placebo-treated patients (

Not all controlled studies of lamotrigine have demonstrated superior efficacy over placebo.

 Some trial results suggested improvement with lamotrigine in the core symptoms of depression but failed to detach from placebo on the primary outcome measure. Collectively, results demonstrated that lamotrigine was effective in treating bipolar depression, although dosages of 200 mg/d may be needed for maximum benefit.

In terms of safety, lamotrigine has generally been shown to have a sideeffect profile similar to that of placebo. The primary concern is the rare development of a serious rash, such as Stevens-Johnson syndrome and toxic epidermal necrolysis.

Perhaps even more challenging than the acute relief of depressive symptoms in bipolar disorder is the prevention of depression recurrence. To address this concern, lamotrigine was studied over an 18-month period in recently depressed patients with BP I.

 After completing an open-label phase with lamotrigine for 8 to 16 weeks, 463 patients were randomized to lamotrigine, 50, 200, or 400 mg/d; lithium, 0.8 to 1.1 mEq/L/d; or placebo.

Both lamotrigine and lithium were more effective than placebo at delaying the time to intervention for any mood episode, and lamotrigine (but not lithium) was more effective than placebo at delaying the time to intervention for a depressive episode. In a complementary fashion, lithium (but not lamotrigine) was superior to placebo at delaying the time to intervention for a manic episode. Similar results were observed in another 18-month maintenance study that evaluated recently manic or hypomanic patients.

 Taken together, these studies support the use of lamotrigine for the prophylaxis of depressive episodes in bipolar disorder.

Atypical antipsychotics for acute bipolar depression

In addition to lamotrigine, the atypical antipsychotics olanzapine

 have been evaluated in randomized, placebo-controlled trials for the treatment of bipolar depression. The antidepressant efficacy of olanzapine was studied over the course of 8 weeks in patients with BP I disorder who were experiencing a major depressive episode.

Patients were randomized to olanzapine (n = 370), an olanzapine-fluoxetine combination (n = 86), or placebo (n = 377). The monotherapy group received a mean modal olanzapine dosage of 9.7 mg/d. The combination group received a mean modal olanzapine dosage of 7.4 mg/d and a fluoxetine dosage of 39.3 mg/d.

Beginning at week 1 and continuing throughout the duration of the study, patients receiving olanzapine and the olanzapine-fluoxetine combination demonstrated significantly greater mean improvement over placebo in MADRS total scores. Olanzapine monotherapy was superior to placebo on measures of response (39.0% vs 30.4%; 

However, when fluoxetine was added to olanzapine, the antidepressant efficacy became even more vigorous. The combination of olanzapine and fluoxetine was significantly better on all efficacy measures of depression than either olanzapine monotherapy or placebo, including higher rates of response (56.1%; 

< .001 vs placebo), remission (MADRS < 12; 48.8%; 

< .001 vs placebo), study completion, and times to response and remission.

Treatment with olanzapine was associated with somnolence, weight gain, increased appetite, dry mouth, and asthenia. The side-effect profile of the olanzapine-fluoxetine combination was similar to that seen with olanzapine monotherapy, except for higher rates of nausea and diarrhea. Weight gain, cholesterol levels, and nonfasting glucose levels were higher in patients taking olanzapine or an olanzapine- fluoxetine combination, compared with placebo. No differences were observed among the 3 groups in the rate of treatment-emergent glucose elevations of 200 mg/dL or greater.

To date, quetiapine is the only other atypical antipsychotic studied in the treatment of bipolar depression.

 In an 8-week trial termed the BOLDER (BipOLar DEpRession) I study, patients with BP I and BP II disorder were randomly assigned to receive quetiapine, 600 mg/d (n = 180); quetiapine, 300 mg/d (n = 181); or placebo (n = 181). Patients with BP II disorder were not excluded as in the olanzapine-fluoxetine trial and composed 34% of the study population.

As early as week 1, both dosages of quetiapine resulted in significantly greater mean improvement in MADRS total scores compared with placebo and at all time points in the intent-to-treat group of patients (

 < .001). The mean change in MADRS total score from baseline to last assessment was –16.73 in the 600 mg/d group, –16.39 in the 300 mg/d group, and –10.26 in the placebo group (

 < .001 for both quetiapine dosages vs placebo). The response rate was approximately 58% for patients treated with either dosages of quetiapine, compared with 36.1% for placebo (

 < .001). Remission rates were also significantly higher in patients treated with quetiapine, namely 52.9% for quetiapine at both 600 and 300 mg/d, compared with 28.4% for placebo (

< .001). Adverse effects that occurred at significantly higher rates with the drug than with placebo included dry mouth, sedation, somnolence, dizziness, constipation, headache, and weight gain.

Cross-study comparisons of olanzapine and quetiapine should be interpreted with caution because of methodologic and sample differences. However, some distinct differences have emerged among atypical antipsychotics in their efficacy for treating symptoms of bipolar depression. The magnitude of clinical effect in comparison to placebo can be calculated through measurement of Cohen’s deffect size.

 The effect size for 600 mg/d of quetiapine was 1.09 in patients with BP I depression and 0.91 for a dosage of 300 mg/d. Since both values were 0.8 or greater, they were considered to represent a large treatment effect. Olanzapine, on the other hand, achieved an effect size of 0.32, but this increased to 0.68 when it was combined with fluoxetine.

Other notable differences in medications relate to findings on the MADRS individual item analysis. Patients receiving quetiapine or an olanzapine-fluoxetine combination improved on the core mood items of depression: representing apparent sadness, reporting sadness, inability to feel, and pessimistic thoughts. Olanzapine monotherapy was not more effective than placebo at improving the core mood items of depression. In addition, both dosages of quetiapine were found to reduce suicidal thoughts compared with placebo, whereas both olanzapine groups did not differ from placebo in reducing suicidal thinking.

A replication study of quetiapine in the treatment of bipolar depression (BOLDER II) has recently been completed. 

 The results are yet to be formally published, but a preliminary analysis showed for a second time that quetiapine monotherapy at dosages of both 300 and 600 mg/d was superior to placebo at improving depressive symptoms. In contrast to the BOLDER I study, treatment effect sizes in the replication study were found to decrease in the BP I subgroup of patients. However, significantly greater mean improvement compared to placebo on the MADRS was observed not only in the BP I subgroup but also in patients with BP II disorder.

Challenges in the treatment of bipolar depression

Improving tolerability and treatment effectiveness remain crucial challenges when using pharmacologic agents for the management of bipolar depression. Thirty-four percent of patients receiving olanzapine,

 and 18% of patients receiving lamotrigine7 discontinued treatment because of adverse events, lack of efficacy, or relapse into a mood episode.

In the lamotrigine study, the rate of withdrawals due to adverse events was similar with active drug and placebo. In the olanzapine trial, patients receiving olanzapine monotherapy were most likely to discontinue treatment because of excessive somnolence, and had higher dropout rates because of adverse events than did patients who received an olanzapine- fluoxetine combination or placebo. Analysis of dropouts in patients who received quetiapine also showed higher rates of withdrawal because of sedation and somnolence.

Such data help to answer the question, “When is it best to use lamotrigine or an atypical antipsychotic in the acute treatment of bipolar depression?” In our experience, nonresponders to lamotrigine are typically responders to quetiapine and vice versa. Those who may respond best to quetiapine are typically agitated, restless, anxious, and suicidal patients who benefit from the anxiolytic and sedating properties of quetiapine.

Likewise, nonresponders to quetiapine usually demonstrate symptoms of fatigue, psychomotor retardation, and hypersomnolence; these patients may benefit most from lamotrigine. While these observations are speculative, they could assist the physician in determining which initial agent to prescribe based on the available data linking differences in dropout rates to adverse events.

 and the olanzapine-fluoxetine combination

 the response rates approximated 50%. These figures are similar to the response rate (47%) reported in the recent Sequenced Treatment Alternatives to Relieve Depression (STAR*D) effectiveness trial

 of unipolar depression. Still, this indicates that available treatments for bipolar depression appear to be effective for only about 50% of patients, leaving significant numbers of individuals with debilitating symptoms, including suicidality.

Even among patients who had achieved recovery from a bipolar mood episode, a recent Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) report determined that when followed prospectively, 144 (22.4%) of 644 patients experienced a depressive recurrence within 1 year.

 A greater percentage of days depressed over the past year, residual depressive symptoms at recovery, and a higher lifetime number of depressive episodes were all indications of recurrence of depressive episodes. Data from the STEP-BD report support the need for alternative therapeutic agents that offer complete recovery from a major depressive episode and can sustain these effects over the maintenance phase.

Other treatment strategies for bipolar depression that have been evaluated in controlled trials are reviewed elsewhere.

 In this article, we have included a summary of agents studied in the depressed phase of bipolar disorder based on the strength of trial methodology .

Not to be overlooked is the use of lithium, a cornerstone in the management of bipolar disorder, with proven antidepressant effects dating back more than 30 years.

 Placebo-controlled studies of lithium, however, have generally enrolled small numbers of patients and are limited by methodologic concerns, such as use of crossover designs. A more recent study of lithium indicates that higher blood levels may be most useful, since no additional antidepressant benefit was achieved by the administration of paroxetine or imipramine when blood levels of lithium were maintained above 0.8 mEq/L.

 With long-term use, another advantage of lithium is its ability to protect patients from suicide.

 have also been studied in placebo-controlled trials of acute bipolar depression, albeit studies involving these drugs have enrolled only limited numbers of patients. Use of a doubleblind, placebo-controlled, off-on-off design found that treatment with carbamazepine achieved response in 63% (15/24) of bipolar patients at an average dosage of 971 mg/d.

 The results of a placebo-controlled trial of divalproex in BPI depression have been published.

 The data from this trial (which consisted of 25 patients) indicated that the rate of improvement over time in depressive symptoms was about twice as high in patients who received divalproex as it was in those who received placebo.

Two unpublished studies have evaluated the antidepressant effects of divalproex in patients with BP I, BP II, or bipolar disorder not otherwise specified. In the first trial, conducted over 8 weeks, patients treated with divalproex showed improvement over placebo at weeks 2 and 5, but not at the study’s end point, as assessed by mean change in 

 In a 6-week trial of divalproex extended release, significant improvement over placebo was demonstrated on the MADRS despite the small sample size of 18 patients.

Taken as a whole, the evidence for divalproex and carbamazepine as monotherapy in the treatment of acute bipolar depression is less substantial than the evidence that exists for lithium, lamotrigine, or the antipsychotics quetiapine and olanzapine. For this reason, expert guidelines often suggest divalproex and carbamazepine as third-

Algorithms for the acute treatment of depressive episodes in bipolar disorder have been developed by the American Psychiatric Association,

 the Texas Implementation of Medication Algorithms Panel,

 and the Canadian Network for Mood and Anxiety Treatments.

 Expert recommendations concur that antidepressants should not be used as monotherapy in BP I depression. It is generally agreed that mood stabilizer treatment should be optimized before beginning a specific antidepressant regimen.

For patients taking lithium, this entails reaching a blood level equal to 0.8 mEq/L, and for patients with a history of severe or recent mania, beginning or continuing an antimanic agent. For patients not taking an antimanic agent or for those without a history of severe or recent mania, lamotrigine would be an appropriate initial choice. Next step treatments include switching to quetiapine or a combination of olanzapinefluoxetine. If patients still remain symptomatic, treatment strategies would incorporate combinations of lithium, lamotrigine, divalproex, carbamazepine, quetiapine, olanzapine, selective serotonin reuptake inhibitors (SSRIs), or bupropion. Electroconvulsive therapy has also shown positive results in treatment of bipolar depression,

Treatment with the SSRI venlafaxine has been associated with higher rates of mania or hypomania,

 as has treatment with tricyclic antidepressants.

 Long-term use of antidepressants in bipolar disorder is an ongoing controversy. Benefits from the addition of an antidepressant may be limited to the first 6 months of treatment,

 with some investigators advocating the withdrawal of antidepressants after resolution of the acute depressive episode.

 Still others argue that antidepressants should not be discontinued if they were used successfully in conjunction with a mood stabilizer during an acute depressive episode. This is based on retrospective data indicating that withdrawal of the antidepressant was associated with significantly higher 1-year relapse rates.

Depressive symptoms are a prominent concern in the care of patients with bipolar disorder. Accurate diagnosis and rapid introduction of treatment in the acute phase are essential to achieving favorable outcomes. There is solid evidence for the use of atypical antipsychotics, lithium, and anticonvulsants in the initial management of bipolar depression. How frequently traditional antidepressants should be prescribed in bipolar disorder and the appropriate duration of their use remains unclear.

For now, the task is to better define optimal treatments that are effective for a majority of patients, that are well tolerated, that do not result in cycling, and are successful at maintaining a lasting response. Given the limitations or partial efficacy of the reviewed monotherapies, future investigation of combined pharmacotherapies for acute bipolar depression seems warranted. Focusing our attention on the depressed phase of bipolar disorder remains the fundamental challenge.

Drs Kemp and Gao are research fellows in the department of psychiatry at Case Western Reserve University and University Hospitals of Cleveland. Dr Kemp has no conflicts of interest to report. Dr Gao reports that he has received honoraria from AstraZeneca.

Dr Muzina is vice chair for research and education in the department of psychiatry at the Cleveland Clinic Foundation. He reports that he has received honoraria, consulting fees, or research support from the following: AstraZeneca, Eli Lilly, GlaxoSmithKline, Pfizer, Abbott Laboratories, and Repligen.

Dr Calabrese is a professor of psychiatry, and director of the mood disorders program and the bipolar disorders research center in the department of psychiatry at Case Western Reserve University and University Hospitals of Cleveland. He reports that he receives funding from Abbott Laboratories, AstraZeneca, Merck, GlaxoSmithKline, Janssen, Eli Lilly, and Pfizer. He is on the advisory boards or has consulting agreements with Abbott Laboratories, AstraZeneca, Bristol-Myers Squibb/Otsuka, Eli Lilly, GlaxoSmithKline, Janssen, and Teva.

Amitriptyline (Elavil, Norfranil, others)  
Bupropion (Wellbutrin, Zyban)  
Carbamazepine (Carbatrol, Tegretol, others)  
Citalopram (Celexa)  
Desipramine (Norpramin, others)  
Divalproex (Depacon, Depakene, Depakote)  
Escitalopram (Lexapro)  
Fluoxetine (Prozac, Sarafem)  
Gabapentin (Neurontin)  
Imipramine (Endep, Tofranil, others)  
Lamotrigine (Lamictal)  
Lithium (Eskalith, Lithane, others)  
Moclobemide (Manerix)  
Olanzapine (Zyprexa)  
Paroxetine (Paxil)  
Pramipexole (Mirapex)  
Quetiapine (Seroquel)  
Riluzole (Rilutek)  
Risperidone (Risperdal)  
Sertraline (Zoloft)  
Topiramate (Topamax)  
Tranylcypromine (Parnate)  
Venlafaxine (Effexor)  
Zonisamide (Zonegran)

1. Judd LL, Akiskal HS, Schettler PJ, et al. The longterm natural history of the weekly symptomatic status of bipolar I disorder. Arch Gen Psychiatry. 2002; 59:530-537.  
2. Judd LL, Akiskal HS, Schettler PJ, et al. A prospective investigation of the natural history of the longterm weekly symptomatic status of bipolar II disorder. Arch Gen Psychiatry. 2003;60:261-269.  
3. Calabrese JR, Hirschfeld RM, Frye MA, Reed ML. Impact of depressive symptoms compared with manic symptoms in bipolar disorder: results of a US community-based sample. J Clin Psychiatry. 2004; 65:1499-1504.  
4. Tondo L, Isacsson G, Baldessarini R. Suicidal behaviour in bipolar disorder: risk and prevention. CNS Drugs. 2003;17:491-511.  
5. Hantouche EG, Akiskal HS, Lancrenon S, et al. Systematic clinical methodology for validating bipolar- II disorder: data in mid-stream from a French national multi-site study (EPIDEP). J Affect Disord. 1998;50:163-173.  
6. Hirschfeld RM, Cass AR, Holt DC, Carlson CA. Screening for bipolar disorder in patients treated for depression in a family medicine clinic. J Am Board Fam Pract. 2005;18:233-239.  
7. Calabrese JR, Bowden CL, Sachs GS, et al. A doubleblind placebo-controlled study of lamotrigine monotherapy in outpatients with bipolar I depression. Lamictal 602 study group. J Clin Psychiatry. 1999;60:79-88.  
8. Calabrese J, Sachs G, Hirschfeld RM, et al. Efficacy and safety of lamotrigine in acute bipolar depression: findings from three completed studies. Poster presented at: 45th Annual New Clinical Drug Evaluation Unit (NCDEU) Meeting. June 6-9, 2005; Boca Raton, Fla.  
9. Gao K, Calabrese JR. Newer treatment studies for bipolar depression. Bipolar Disord. 2005;7(suppl 5): 13-23.  
10. Ketter TA, Wang PW, Chandler RA, et al. Dermatology precautions and slower titration yield low incidence of lamotrigine treatment-emergent rash. J Clin Psychiatry. 2005;66:642-645.  
11. Calabrese JR, Bowden CL, Sachs G, et al. A placebo- controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently depressed patients with bipolar I disorder. J Clin Psychiatry. 2003; 64:1013-1024.  
12. Bowden CL, Calabrese JR, Sachs G, et al. A placebo- controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently manic or hypomanic patients with bipolar I disorder. Arch Gen Psychiatry. 2003;60:392-400.  
13. Tohen M, Vieta E, Calabrese J, et al. Efficacy of olanzapine and olanzapine-fluoxetine combination in the treatment of bipolar I depression. Arch Gen Psychiatry. 2003;60:1079-1088.  
14. Calabrese JR, Keck PE Jr, Macfadden W, et al. A randomized, double-blind, placebo-controlled trial of quetiapine in the treatment of bipolar I or II depression. Am J Psychiatry. 2005;162:1351-1360.  
15. Cohen J. Statistical Power Analysis for Behavioral Sciences. Hillsdale, NJ: Erlbaum; 1987.  
16. Thase ME, Macfadden W, McCoy R, et al. Confirmation of the efficacy of quetiapine monotherapy in bipolar depression in a second double-blind, placebocontrolled study: The BOLDER II study. Poster presented at: 159th American Psychiatric Association Annual Meeting. May 20-25, 2006; Toronto.  
17. Trivedi MH, Rush AJ, Wisniewski SR, et al. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry. 2006; 163:28-40.  
18. Perlis RH, Ostacher MJ, Patel JK, et al. Predictors of recurrence in bipolar disorder: primary outcomes from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). Am J Psychiatry. 2006;163:217-224.  
19. Gao K, Gajwani P, Elhaj O, Calabrese JR. Typical and atypical antipsychotics in bipolar depression. J Clin Psychiatry. 2005;66:1376-1385.  
20. Goodwin FK, Murphy DL, Dunner DL, Bunney WE Jr. Lithium response in unipolar versus bipolar depression. Am J Psychiatry. 1972;129:44-47.  
21. Nemeroff CB, Evans DL, Gyulai L, et al. Doubleblind, placebo-controlled comparison of imipramine and paroxetine in the treatment of bipolar depression. Am J Psychiatry. 2001;158:906-912.  
22. Baldessarini RJ, Tondo L, Hennen J. Effects of lithium treatment and its discontinuation on suicidal behavior in bipolar manic-depressive disorders. J Clin Psychiatry. 1999;60(suppl 2):77-84, discussion 111-116.  
23. Post RM, Uhde TW, Roy-Byrne PP, Joffe RT. Antidepressant effects of carbamazepine. Am J Psychiatry. 1986;143:29-34.  
24. Ballenger JC, Post RM. Carbamazepine in manicdepressive illness: a new treatment. Am J Psychiatry. 1980;137:782-790.  
25. Davis LL, Bartolucci A, Petty F. Divalproex in the treatment of bipolar depression: a placebo-controlled study. J Affect Disord. 2005;85:259-266.  
26. Dunn RT, Gilmer W, Fleck J, et al. Efficacy of divalproex in the treatment of acute bipolar depression: a randomized clinical trial. Poster presented at: 159th American Psychiatric Association Annual Meeting. May 20-25, 2006; Toronto.  
27. Sachs GS, Altshuler LL, Ketter T, et al. Divalproex versus placebo for the treatment of bipolar depression. Poster presented at: American College of Neuropsychopharmacology 40th Meeting. December 9-13, 2001; Waikoloa, Hawaii.  
28. Yatham LN, Kennedy SH, O’Donovan C, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) guidelines for the management of patients with bipolar disorder: consensus and controversies. Bipolar Disord. 2005;7(suppl 3):5-69.  
29. Suppes T, Dennehy EB, Hirschfeld RM, et al. The Texas implementation of medication algorithms: update to the algorithms for treatment of bipolar I disorder. J Clin Psychiatry. 2005;66:870-886.  
30. American Psychiatric Association. Practice guideline for the treatment of patients with bipolar disorder (revision). Am J Psychiatry. 2002;159(suppl 4): 1-50.  
31. Ciapparelli A, Dell’Osso L, Tundo A, et al. Electroconvulsive therapy in medication-nonresponsive patients with mixed mania and bipolar depression. J Clin Psychiatry. 2001;62:552-555.  
32. Vieta E, Martinez-Aran A, Goikolea JM, et al. A randomized trial comparing paroxetine and venlafaxine in the treatment of bipolar depressed patients taking mood stabilizers. J Clin Psychiatry. 2002; 63:508-512.  
33. Leverich GS, Altshuler LL, Frye MA, et al. Risk of switch in mood polarity to hypomania or mania in patients with bipolar depression during acute and continuation trials of venlafaxine, sertraline, and bupropion as adjuncts to mood stabilizers. Am J Psychiatry. 2006;163:232-239.  
34. Goodwin FK, Jamison KR. Manic-Depressive Illness. New York: Oxford University Press; 1990.  
35. Prien RF, Kupfer DJ, Mansky PA, et al. Drug therapy in the prevention of recurrences in unipolar and bipolar affective disorders. Report of the NIMH Collaborative Study Group comparing lithium carbonate, imipramine, and a lithium carbonate-imipramine combination. Arch Gen Psychiatry. 1984;41: 1096-1104.  
36. Ghaemi SN, Hsu DJ, Soldani F, Goodwin FK. Antidepressants in bipolar disorder: the case for caution. Bipolar Disord. 2003;5:421-433.  
37. Altshuler L, Kiriakos L, Calcagno J, et al. The impact of antidepressant discontinuation versus antidepressant continuation on 1-year risk for relapse of bipolar depression: a retrospective chart review. J Clin Psychiatry. 2001;62:612-616.  
38. Frye MA, Ketter TA, Kimbrell TA, et al. A placebocontrolled study of lamotrigine and gabapentin monotherapy in refractory mood disorders. J Clin Psychopharmacol. 2000;20:607-614.  
39. Zornberg GL, Pope HG Jr. Treatment of depression in bipolar disorder: new directions for research. J Clin Psychopharmacol. 1993;13:397-408.  
40. Himmelhoch JM, Fuchs CZ, Symons BJ. A double-blind study of tranylcypromine treatment of major anergic depression. J Nerv Ment Dis. 1982; 170:628-634.  
41. Bocchetta A, Bernardi F, Burrai C, et al. A doubleblind study of L-sulpiride versus amitriptyline in lithium-maintained bipolar depressives. Acta Psychiatr Scand. 1993;88:434-439.  
42. McIntyre RS, Mancini DA, McCann S, et al. Topiramate versus bupropion SR when added to mood stabilizer therapy for the depressive phase of bipolar disorder: a preliminary single-blind study. Bipolar Disord. 2002;4:207-213.  
43. Sachs GS, Lafer B, Stoll AL, et al. A double-blind trial of bupropion versus desipramine for bipolar depression. J Clin Psychiatry. 1994;55:391-393.  
44. Silverstone T. Moclobemide vs. imipramine in bipolar depression: a multicenter double-blind clinical trial. Acta Psychiatr Scand. 2001;104:104-109.  
45. Goldberg JF, Burdick KE, Endick CJ. Preliminary randomized, double-blind, placebo-controlled trial of pramipexole added to mood stabilizers for treatment- resistant bipolar depression. Am J Psychiatry. 2004;161:564-566.  
46. Shelton RC, Stahl SM. Risperidone and paroxetine given singly and in combination for bipolar depression. J Clin Psychiatry. 2004;65:1715-1719.  
47. Post RM, Altshuler LL, Leverich GS, et al. Higher switch rate on venlafaxine than bupropion or sertraline in bipolar depression. Br J Psychiatry. In press.  
48. Kupfer DJ, Chengappa KN, Gelenberg AJ, et al. Citalopram as adjunctive therapy in bipolar depression. J Clin Psychiatry. 2001;62:985-990.  
49. Fonseca M, Soares JC, Hatch JP, et al. An open trial of adjunctive escitalopram in bipolar depression. J Clin Psychiatry. 2006;67:81-86.  
50. Osher Y, Bersudsky Y, Belmaker RH. Omega-3 eicosapentaenoic acid in bipolar depression: report of a small open-label study. J Clin Psychiatry. 2005; 66:726-729.  
51. Zarate CA, Jr, Quiroz JA, Singh JB, et al. An openlabel trial of the glutamate-modulating agent riluzole in combination with lithium for the treatment of bipolar depression. Biol Psychiatry. 2005;57:430-432.  
52. Anand A, Bukhari L, Jennings SA, et al. A preliminary open-label study of zonisamide treatment for bipolar depression in 10 patients. J Clin Psychiatry. 2005;66:195-198.

A discussion of the pharmacologic management of bipolar depression, including emerging treatments and expert recommendations.

Keming Gao, MD, PhD

Articles

Mood Disorders in 3 Clinical Reports

Introduction: A Focus on Differential Diagnoses, Comorbidity, and Suicide Risk

Antipsychotics in the Treatment of Comorbid Anxiety in Bipolar Disorder

Progress in the Treatment of Bipolar Depression: Advances and Challenges