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Treatment of major depressive disorder and bipolar mixed states.


Ramona is a 35-year-old unmarried woman who has recently relocated to the area and is seeking a psychiatrist. She works as a real estate attorney. Ramona describes herself as "depressed most of the time and manic." She reports having been depressed for 3 years. Over the last few months she has experienced depressed mood, loss of interest in personal pursuits such as piano and sculpting, and difficulty sleeping. When asked what she means by manic, she describes being physically "slowed down" but having a racing mind and pressure to keep talking to the point of disturbing others. Additionally, she describes periods of time when she is easily distracted. Ramona was initially treated with escitalopram, which her previous provider recently replaced with valproate.

Diagnosis of Bipolar Mixed States

Bipolar disorder maybe at times difficult to diagnose. It is not uncommon for years to transpire between the emergence of symptoms and an accurate diagnosis. (1) One of the challenges in making a correct and timely diagnosis of bipolar disorder is the heterogeneity of its manifestations. (2) Patients often present with mixed states, such as manic or hypomanic states with mixed depressive features or a major depressive episode combined with subsyndromal hypomania or mania. Mixed states, manifested by coexistence of mania or hypomania and depression, can at times lead to misdiagnosis, with potentially negative consequences. For example, treatment of bipolar disorder with antidepressants may be ineffective or trigger mood elevations and lability. (3,4) Failure to detect the mixed nature of manic episodes may have dire implications. In a study of 184 patients, suicidality (past, current, or recurrent) was far more common in the presence of mixed mania (defined in the study as mania combined with 2 or more prominent depressive features) than in patients with pure mania (57.9% vs 1.3%; P<.001). (5)

Mixed states are increasingly appreciated in the context of a disorder spectrum, rather than as discrete categories of illness. This is reflected by changes in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) mixed features specifiers, compared with the earlier designation of mixed episode in the DSM Fourth Edition, Text Revision (DSM-IV-TR). (6) In the DSM-IV-TR, mixed state was defined as a week of concomitantly meeting full criteria for mania and full criteria for depression, accompanied by impaired functioning, psychosis, or hospitalization. In the DSM-5, a mixed categorical-dimensional approach is employed. (7) Three or more clinically significant subthreshold symptoms of the opposite pole are included in the DSM-5 mixed features specifier. (6) These changes have implications not only for diagnosis and treatment, but also for epidemiology, research, and education. (8) It remains unclear what the ramifications will be for clinicians, researchers, and patients from diagnosing and treating major depressive disorder (MDD) with mixed features.

Hypomania and Mania With Mixed Depressive Features

Although mixed manic states occur frequently in patients with bipolar disorder, estimates of prevalence vary widely because of the heterogeneity of criteria used to define the condition. In a cross-sectional study performed in 76 centers, 368 inpatients with bipolar disorder were assessed for mixed episodes using various criteria. (9) The estimated prevalence of mixed episodes of mania was 12.9% according to the DSM-IV-TR, 9% according to the International Classification of Diseases, Tenth Edition (ICD-10), and 23.2% based on clinical judgement. In a review of 17 studies (n=981), the overall rate of mixed states was 31% among acutely manic patients with bipolar disorder. (10) Relative to "pure" mania without mixed symptoms, mixed mania occurs more frequently in women than men, and those with mixed mania had a hospitalization at a younger age. (11,12)

Mixed mania has a worse course and prognosis than pure mania. (13) Episodes tend to be more frequent and illness is of longer duration in patients with mixed mania. (11,14) Patients with mixed mania had an increased risk of subsequent depressive episodes and a much shorter interval until a new episode of depression than those with pure mania. (15) Further, patients who transitioned to a depressed episode without recovery from the index mania episode were more likely to have mixed mania than those who did not cycle into depression. (16) Mixed mania is also associated with more functional impairment, comorbid psychiatric disorder, substance use disorder, and suicidality. (5,12,17,19)

Mixed mania states are often more severe and clinically complex than pure mania. The treatment of mixed mania is challenging because of the lack of prospective, randomized trials in homogeneous cohorts of patients with bipolar disorder and mixed manic episodes. The majority of evidence stems from subgroup or post hoc analyses. In general, patients with mixed manic episodes have a diminished response to pharmacologic therapy, in particular monotherapy, compared with patients with pure mania episodes. (20) Most available evidence evaluates atypical antipsychotics and mood stabilizers. (20-22) In the absence of demonstrated superior efficacy in mixed mania, the selection of pharmacologic therapy is based on individual considerations and factors such as tolerability, safety, and long-term maintenance. One study of patients meeting criteria for DSM-IV-TR mixed episodes evaluated a mood stabilizer alone versus a mood stabilizer combined with an atypical antipsychotic. (23) Patients with inadequate response to divalproex were randomized to receive adjunctive olanzapine 5-20 mg/d (n=100) or placebo (n=101) for 6 weeks. Compared with placebo, adjunctive olanzapine achieved significantly greater decreases in mean scores on the Hamilton Depression Rating Scale (P=.02) and the Young Mania Rating Scale (YMRS; P<.001). Times to partial and full response were significantly shorter with adjunctive olanzapine. Increases in body weight, clinically significant weight gain ([greater than or equal to] 7% of total weight), and fasting plasma glucose were significantly greater with olanzapine than placebo.

Bipolar Depressive State With Mixed Mania

It has been recognized that the DSM-IV-TR criteria for mixed episode did not reflect the most common phenomenology of patients with bipolar depression and admixture of hypomania. The DSM-5 mixed features specifier addresses the idea that these symptoms are not necessarily divergent, but more often complementary. Therefore, it is important to appreciate mixed features because they have significant bearing on treatment decisions. Criteria for a major depressive episode did not change in the DSM-5. For patients with bipolar disorder, diagnosis of a major depressive episode with mixed features requires at least 3 manic or hypomanic symptoms during the majority of days of the current or most recent episode of depression. (6) In the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study, 1380 patients who met the criteria for bipolar I or II depression were evaluated for co-occurring manic symptoms. (24) Less than one-third of patients had no manic symptoms (31.2%). Approximately half (54.0%) had subsyndromal mania (1-3 symptoms of mania) and 14.8% had a full mixed episode according to DSM-IV criteria (Figure l).24 The most common (hypo)manic symptoms, folded into the context of depressive episode, were distractibility, flight of ideas, racing thoughts, and psychomotor agitation. In the STEP-BD study, patients with bipolar depressive episodes with mixed features of mania were more likely than those with pure depressive episodes to have an earlier age of onset, rapid cycling, bipolar I subtype, and history of suicide attempts. (24) As with patients with mixed mania, those with mixed depression are prone to more severe and frequent episodes of longer duration. (25,26)

Patients with bipolar depression and mixed features are often resistant to treatment; therefore, combination therapy with mood stabilizers and atypical antipsychotics has been recommended. (2,21) Although combination therapy may be needed, the role of antidepressants remains controversial. A recent review of the literature indicated that there is insufficient evidence to draw conclusions about safety and tolerability of antidepressants in patients with depressive mixed states. (27) Antidepressant monotherapy has limited efficacy but has the potential to worsen mixed depressive episodes.

Several atypical antipsychotics have been evaluated in patients with bipolar depression and mixed features, and a meta-analysis showed that treatment with atypical antipsychotics resulted in significant improvements in Montgomery-Asberg Depression Rating Scale (MADRS) and YMRS scores versus placebo. (28) A post hoc study evaluated asenapine and olanzapine in a subgroup of patients with bipolar I disorder and moderate-to-severe mixed major depressive episodes who met DSM-IV-TR criteria for mixed episodes. (29) Data came from subgroup analyses of results from two 3-week, randomized, placebo-controlled trials (N=489 and N=488). Decreases in MADRS scores were significantly greater in the group randomized to asenapine compared with placebo, from baseline to study endpoint (Figure 2). (29) From baseline to Day 7, decreases in MADRS scores were significantly greater with asenapine than with olanzapine (P=.04). In another study, olanzapine monotherapy was evaluated in patients with bipolar I depression and mixed features using pooled data from 2 studies (N=1214). (30) The mean MADRS total scores were significantly decreased in patients with 0, 1-2, or [greater than or equal to] 3 manic symptoms at baseline: -3.76 (P=.002), -3.20 (P<.001), and -3.44 (P=.002), respectively. Maintenance of response with olanzapine was studied in a post hoc analysis of 121 patients who achieved remission after a mixed episode and were then randomized to olanzapine or placebo. (31) Compared with placebo, olanzapine was associated with a longer time to symptomatic relapse (46 vs 15 days; P<.001). Another post hoc study evaluated the efficacy and safety of lurasidone monotherapy in patients with bipolar I depression who presented with mixed features (YMRS >4 at baseline). (32) Lurasidone was associated with a greater decrease in MADRS score at Week 6 versus placebo (-15.7 vs -10.9; P=.001) in the group with mixed features. The incidence rates of treatment-emergent hypomania and mania were similar for patients with and without mixed features in the placebo and lurasidone groups (0% to 3.4%).

Major Depressive Disorder With Subsyndromal Hypomania or Mania

The prevalence of mixed features in predominantly depressive patients was evaluated in the French EPIDEP study of 493 consecutive patients with MDD based on 2 semi-structured interviews. Mixed depression was identified in 23.8% of patients. (25) A study of nearly 600 patients with recurrent MDD and no family history of bipolar disorder evaluated the clinical outcomes of patients with subthreshold manic symptoms. Lifetime history of subthreshold symptoms of mania occurred in 9.6% of the sample. (33) Compared to those with MDD alone, patients with MDD and subthreshold mania were significantly more likely to have previous psychosis, poor response to antidepressants, more depressive episodes, and more hospitalizations. Other studies confirm that compared with patients with "pure" depression, those with subthreshold manic symptoms have more suicide attempts, more episodes, and more comorbidity (anxiety and substance use disorders). (33-37) Patients with MDD and mixed features have a greater likelihood of conversion to bipolar disorder. In the National Institute of Mental Health Collaborative Depression Study, 550 patients with MDD were screened for manic symptoms at baseline and monitored for a mean of 17.5 years. (38) The cumulative probability of developing hypomania or mania was 26.3%, resulting in a revised diagnosis of bipolar II disorder in 12.2% and bipolar I disorder in 7.5% of the patients. Clinical characteristics of MDD and subthreshold hypomania were evaluated among 211 participants in a large placebo-controlled trial. (39) The most common DSM-5-endorsed manic symptoms among patients with mixed major depression were flight of ideas or racing thoughts (66.8%), pressured speech (61.1%), and decreased need for sleep (40.8%). Also reported were distractibility (59.2%) and irritability (57.3%), although these symptoms are not specific for hypomania as they may occur within the context of a depressive episode. In another study, the composition of mood symptoms was compared in 117 patients with recurrent unipolar depression and 106 patients with bipolar I disorder. (40) In both groups, the number of hypomanic or manic symptoms reported was closely correlated with the number of depressive items reported.

Given the relatively recent incorporation of a mixed features specifier for subthreshold symptoms of hypomania or mania in patients with MDD, evidence for treatment is limited. In a claims analysis, patients with MDD and subthreshold hypomania were receiving antidepressants, mood stabilizers, and atypical antipsychotics; 72.1% received combination therapies with multiple drug classes. (37) Antidepressants are the most commonly used pharmacotherapy for MDD, but their efficacy and safety in patients with MDD and mixed features are not established. Antidepressants may not be efficacious in patients with depression and subthreshold symptoms of hypomania or mania, and they may be associated with treatment-emergent mood switching. (41,42) Therefore, although antidepressants remain the most common therapeutic choice for depression with mixed features, there are significant safety concerns associated with their use in these patients. (43)

A randomized, double-blind, placebo-controlled trial investigated the efficacy and safety of lurasidone in patients with MDD and mixed features. (44) Patients who met DSM-IV-TR criteria for MDD and had 2 or 3 manic symptoms were randomized to treatment with either lurasidone (20-60 mg/d, n=109) or placebo (n=100) for 6 weeks. For the primary endpoint of change from baseline in MADRS total score, the decrease was significantly greater for lurasidone compared with placebo (-20.5 vs -13.0, respectively; P<.001; effect size=0.8) (Figure 3). (44) When endpoints were defined as treatment response ([greater than or equal to]50% decline in MADRS score) and treatment remission (MADRS score <12), significantly greater proportions of patients randomized to lurasidone versus placebo met the criteria for response (64.8% vs 30.0%; number needed to treat [NNT]=3; P<.001) and remission (49.1% vs 23.0%; NNT=4; P<.001). The most common adverse events occurring in [greater than or equal to] 5% of the lurasidone group were nausea and somnolence. At Week 6, change in weight was minimal for both the lurasidone and placebo groups (1.9% vs 1.0% for a [greater than or equal to] 7% increase in weight).

A double-blind, placebo-controlled study evaluated patients with MDD or bipolar II disorder meeting DSM-IV criteria for a major depressive episode and 2 or 3 criteria for mania. (45) In this study, 73 patients were randomized to receive ziprasidone (40-160 mg/d) or placebo for 6 weeks. Decrease in MADRS score with ziprasidone was superior to placebo (P=.0038) (Figure 4). (45) Patients with bipolar II disorder had greater treatment efficacy than those with MDD and subthreshold mania. Adverse events reported in [greater than or equal to] 5% of patients in the ziprasidone group were headache and drowsiness; weight change at 6 weeks was not significantly different between the ziprasidone and placebo groups (0.5 vs 0.6 lb).


The diagnostic and clinical manifestations of mood disorders increasingly support a spectrum of disorders rather than discrete categories. Mixed episodes of mania or depression often portend worse outcomes and can be a challenge to treat. In particular, the role of antidepressants appears to be limited by lack of evidence for efficacy and concerns about safety. Patients with MDD and subthreshold hypomania or mania often have more severe illness than those with "pure" depression, and these patients may need different management approaches.


Ramona could have bipolar I or bipolar II disorder with mixed states, or MDD with subsyndromal hypomania. If, in addition to her major depressive episodes, she has experienced a lifetime episode of mania, she would be diagnosed with bipolar I disorder; if she has had a lifetime episode of hypomania, but no mania, she would have bipolar II disorder. In the absence of an episode of hypomania or mania, her diagnosis would be MDD with mixed features based on the presence of subthreshold mania or hypomania. Notably, she reported pressured speech and racing thoughts, 2 prominent clinical characteristics of MDD with subsyndromal mania or hypomania. Additional clinical insights are needed. What is her specific sleep pattern? Does she have insomnia or a decreased need for sleep? It is important to determine the age at onset of her depression because older onset points toward unipolar depression. Duration of mood elevation and family history are also important elements of a diagnosis. Clarifying Ramona's diagnosis is crucial to treatment decision making.


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Vladimir Maletic, MD, MS

Clinical Professor of Neuropsychiatry and Behavioral Science

University of South Carolina School of Medicine

Greenville, South Carolina

Consulting Associate, Division of Child and Adolescent Psychiatry

Department of Psychiatry

Duke University

Durham, North Carolina

Caption: FIGURE 1 Number of DSM-IV manic symptoms occurring during an index episode of bipolar depression in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study (n=1380). (24)

Caption: FIGURE 2 Improvement in depressive symptoms as assessed by mean changes from baseline in MADRS total scores in a study of asenapine and olanzapine versus placebo in patients with bipolar I disorder and mixed depression (n=98). (29)

Caption: FIGURE 3 Mean change from baseline in MADRS total score in a study of lurasidone versus placebo for treatment of major depressive disorder with mixed features (n=208). (44)

Caption: FIGURE 4 Mean change from baseline in MADRS scores in a study of ziprasidone versus placebo in patients with major depressive or bipolar II disorder and mixed features (n=73). (45)
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Author:Maletic, Vladimir
Publication:Current Psychiatry
Article Type:Case study
Geographic Code:1USA
Date:Aug 1, 2017
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