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Differentiating major depressive disorder and bipolar depression.


Amrita is a 28-year-old woman previously diagnosed with major depressive disorder (MDD). She has had several depressive episodes from ages 18 to 21 years. Amrita is currently employed as a loan officer at a community bank and has a 3-year-old daughter. She has been referred to your psychiatric practice by her primary care provider, who is concerned that her depression is nonresponsive to treatment. Amrita complains of feeling sad and "empty" on most days and reports anhedonia and insomnia. She describes "moving slowly" and has had difficulties working and caring for her daughter. She has a history of migraines and hypothyroidism managed with levothyroxine. She has had a partial response to sertraline but still reports being "down most days."

An important question for this patient with symptoms of depression is whether she has had episodes of feeling energetic and times when she was not her usual self. When asked, Amrita reports a 2-week period when her depression "improved"; this interval was characterized by high productivity and lack of need for sleep (sleeping only 3 or 4 hours per night).

Diagnosing Bipolar Depression

Diagnosing bipolar depression can be challenging, and it is probably the most misdiagnosed phase of the bipolar disorder spectrum. Many patients with bipolar depression are initially diagnosed and treated for MDD. (1) The consequences of misdiagnosis and improper treatment of bipolar depression can be considerable. Patients misdiagnosed with MDD are usually treated with antidepressant monotherapy, which is not efficacious and may be associated with a risk of mood switching. (1,2)

The extent of misdiagnosis was highlighted by the results of a survey of 600 patients with bipolar disorder in the National Depressive and Manic-Depressive Association advocacy group. (3) Although more than one-third sought professional care within 1 year of symptom onset, 69% were misdiagnosed, principally with unipolar depression. Among those misdiagnosed, patients consulted an average of 4 psychiatrists before being correctly diagnosed. For one-third of patients, it took at least 10 years to receive an accurate diagnosis. Another study showed that among outpatients (n=649) receiving treatment for depression, 21% screened positive for bipolar disorder, most of whom had never been diagnosed. (4) In a study of 501 patients with bipolar disorder, the mean interval between the first episode and treatment was 9.6 years. (5) Longer duration of untreated bipolar depression was associated with more mood episodes and suicidal behavior, (5) and an increasing number of previous episodes was associated with poorer outcomes once treatment was started. (6,7)

Bipolar depression has a considerable impact on patients. Two long-term prospective studies that assessed the natural history of weekly symptom status in patients with bipolar disorder demonstrated the burden of depression in these patients. (8,9) In a study of 146 patients with bipolar I disorder, depressive symptoms were 3 times as frequent as manic/hypomanic symptoms (31.9% vs 8.9% of follow-up weeks) and 5 times more frequent than cycling/mixed symptoms (5.9% of follow-up weeks). (8) In a companion study of 86 patients with bipolar II disorder, depressive symptoms were even more predominant (50.3% of follow-up weeks), compared with hypomanic symptoms (1.3%) and cycling/mixed symptoms (2.3%). (9) Although bipolar I disorder is characterized by episodic mania, the severity of bipolar depression is greater in patients with bipolar II disorder (50.3% vs 31.9% of follow-up weeks). (8,9) Depressive symptoms are also more troublesome to social adjustment than are manic symptoms. In a survey of 593 patients with bipolar disorder, self-reported depressive symptoms were more frequent than manic symptoms and were associated with significantly greater disruption of occupational, social, and family functioning. (10) Further, an increasing body of evidence suggests that the predominant mood polarity is an important prognostic indicator in patients with bipolar disorder and may have implications for long-term treatment. (11-13) Recent research has shown that depressive-predominant bipolar disorder is associated with longer delay until diagnosis and a higher number of suicide attempts. (11-13)

According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria, differentiating bipolar from unipolar depression requires documentation of a past episode of hypomania or mania. (14) Flowever, patients frequently underreport previous hypomanic and manic episodes and/or may not perceive these periods as being outside of the ordinary. As shown in the case presentation, Amrita presented with a major complaint of depression, but only when probed for a hypomanic or manic history did she reveal an episode suggesting symptoms of mania. In the absence of pathognomonic characteristics of bipolar depression, it is possible to take a probabilistic approach to the diagnosis based on numerous patient characteristics associated with an increased likelihood of bipolar disorder. (15) Outside of a prior history of mania, one of the most informative questions that one can ask a patient is whether he or she has a family history of bipolar disorder. (16-18) Additional characteristics of the patient's history and clinical episodes may increase the likelihood of bipolar versus unipolar depression. In a study of 306 patients undergoing a major depressive episode, the most significant predictive factors for bipolar disorder were seasonality, number of past episodes, hospitalization for psychiatric disorders, mixed states, and mood reactivity. (19) Another study that examined diagnostic conversion from MDD to bipolar depression found that earlier age at onset and treatment-resistant depression were significantly associated with conversion. (20) Another presentation that is associated with bipolar depression is antidepressant-related emergent mania or hypomania. (21) The risk of antidepressant-emergent mania was much higher among patients with bipolar depression, compared with MDD (13.8% vs 1.24%). (21)

Depression with Psychosis

Depression with psychotic features is a subtype of MDD in the DSM-5. (14) However, researchers have proposed that psychotic depression may be a distinct diagnostic classification based on biologic, clinical, therapeutic, and prognostic differences between psychotic and nonpsychotic depression. (22) Unipolar psychotic depression is closely related to bipolar disorder (22); for example, psychotic symptoms are more common in bipolar depression than in unipolar depression. (23) Psychotic features of depression are predictive of a bipolar disorder diagnosis and are associated with emergent mania in depressed patients. (24,25) In a meta-analysis of prospective studies, patients with major depression and psychotic symptoms were almost 5 times more likely to transition to bipolar disorder than those without psychotic symptoms (odds ratio [OR], 4.76; 95% confidence interval [CI], 1.79-12.66). (26) Additionally, bipolar disorder was more prevalent among those with a family history of psychotic depression than those with a family history of nonpsychotic depression. (27) The presence of psychosis in bipolar disorder is associated with neurocognitive impairment and poorer prognosis. (28)

One of the outstanding questions in treating patients with psychotic depression is diagnostic stability. A study monitored 49 patients with a first episode of MDD and psychotic features to determine rates of remission and recovery and to evaluate diagnostic stability. (29) After being followed for >2 years from first hospitalization, 41% of patients had a different diagnosis. Of those with a new diagnosis, 70% of the new diagnoses were bipolar disorder and 30% were schizoaffective disorder. Notably, those patients with psychotic depression and a change in diagnosis had a 2.4-fold higher baseline score on the Young Mania Rating Scale than patients without a diagnostic change (score of 5.05 vs 2.12; OR, 1.18; 95% CI, 1.01-1.38; P=.036), and the presence of manic symptoms predicted a switch to bipolar disorder. Of those retaining the initial diagnosis of psychotic depression for 2 years, 42% remained symptomatic.

Pharmacotherapy for Bipolar Depression

Four treatments for bipolar depression are currently approved by the US Food and Drug Administration (FDA): olanzapine/fluoxetine combination, quetiapine, lurasidone monotherapy, and lurasidone adjunctive to lithium or valproate. Although there have been no direct head-to-head comparisons to date, studies have shown that these medications appear to have comparable efficacy with different adverse effects.

The efficacy of olanzapine and olanzapine-fluoxetine combination was evaluated in a randomized, double-blind, 8-week trial.-30 The study enrolled 833 adults with bipolar I depression and a Montgomery-Asberg Depression Rating Scale (MADRS) total score of at least 20. Patients received placebo (n=377), olanzapine 5-20 mg/d (n=370), or daily olanzapine-fluoxetine 6 mg/25 mg, 6 mg/50 mg, or 12 mg/50 mg (n=86). The olanzapine and olanzapine-fluoxetine groups demonstrated significantly better improvement in depressive symptoms compared with the placebo group in each of the 8 weeks (P<.001 for all) (Figure 1). (30) Compared with olanzapine, the combination olanzapine-fluoxetine group showed significantly greater improvement at Weeks 4 through 8 (P<.02). A significantly higher percentage of patients had potentially clinically significant weight gain (greater than 7% from baseline) with olanzapine (18.7%) and olanzapine-fluoxetine (19.5%) compared with placebo (0.3%; P<.001 for all).

FDA approval of quetiapine monotherapy for bipolar depression was based on efficacy and tolerability in 2 trials: BOLDER I and II. (31,32) These two 8-week studies showed that quetiapine 300 mg/d or 600 mg/d significantly improved symptoms of depression according to a decrease in MADRS scores compared with placebo. Head-to-head comparisons between established and newer treatments were evaluated in the EMBOLDEN I and II studies. (33,34) EMBOLDEN I was a double-blind, placebo-controlled study to evaluate quetiapine or lithium monotherapy in 802 adult patients with bipolar disorder and recent depression (499 with bipolar I and 303 with bipolar II).33 Patients were randomly assigned to quetiapine 300 mg/d (n=265), quetiapine 600 mg/d (n=268), lithium 600-1800 mg/d (n=136), or placebo (n=133) for 8 weeks. From Week 1 through Week 8, both doses of quetiapine were significantly more effective than placebo based on decreases in MADRS scores (P<.05) (Figure 2A). (33) The improvement in MADRS score in patients receiving lithium was not statistically significant compared with placebo. The most commonly reported adverse events with quetiapine were somnolence, dry mouth, and dizziness; for example, dizziness occurred in 18.1% and 17.6% for quetiapine 300 mg/d and 600 mg/d, respectively, compared with 8.8% for lithium and 3.8% for placebo.

EMBOLDEN II compared the efficacy and tolerability of quetiapine and paroxetine monotherapy with placebo in an 8-week, double-blind trial in patients with bipolar depression. (34) A total of 740 patients (478 with bipolar I and 262 with bipolar II) were randomized to quetiapine 300 mg/d (n=245), quetiapine 600 mg/d (n=247), paroxetine 20 mg/d (n=122), or placebo (n=126) for 8 weeks. Improvement in MADRS scores from baseline was significantly greater for quetiapine-treated patients at both doses compared with placebo, but was not significant for those receiving paroxetine (Figure 2B). (34) Adverse events were comparable to those in EMBOLDEN I; the most common adverse events in patients receiving quetiapine were dry mouth, somnolence, sedation, and dizziness.

Lurasidone was approved by the FDA in June 2013 as monotherapy or adjunctive therapy (with lithium or valproate) for adults with bipolar I disorder. Efficacy and safety of lurasidone in patients with depression associated with bipolar I disorder were studied in 2 PREVAIL trials. The primary end point of the studies was reduction in depressive symptoms as indicated by changes from baseline in MADRS score. (35-36) In the lurasidone monotherapy trial (PREVAIL 2), 505 patients with bipolar disorder who were currently experiencing a major depressive episode were randomized to 6 weeks of double-blind treatment with lurasidone 20-60 mg/d (n=166), 80-120 mg/d (n=169), or placebo (n=170). (35) Both dose groups showed a significantly greater improvement on the MADRS total score compared with placebo (Figure 3A). (35) The effect size was 0.51 for both lurasidone dose groups. The most common adverse events in patients receiving lurasidone were nausea, headache, akathisia, and somnolence. There were no clinically significant differences in metabolic parameters or body weight between lurasidone and placebo.

In the PREVAIL 1 adjunctive therapy trial, patients were randomized to 6 weeks of double-blind treatment with lurasidone 20-120 mg/d (n=183) or placebo (n=165) as add-on therapy to mood stabilizers (lithium or valproate). (36) Compared with placebo, lurasidone achieved a significantly lower mean MADRS total score at 6 weeks, with an effect size of 0.34 (Figure 3B). (36) The most commonly reported adverse effects were nausea, somnolence, tremor, akathisia, and insomnia, while minimal changes were noted in body weight and metabolic parameters.

The adverse-event profiles of FDA-approved pharmacotherapies for bipolar depression are summarized in Table 2. (37,39)


Bipolar depression is often undiagnosed or misdiagnosed. Depression is frequently the presenting mood state for patients with bipolar disorder, so screening for hypomania or mania is essential in patients with depression. It is important to remember that patients may be reluctant to disclose symptoms of hypomania or mania, or may find these episodes unremarkable. Several additional cues may point to bipolar depression, such as early onset of depression, family history, treatment-resistant depression, and number of past episodes. Psychotic features of depression may herald future transition to bipolar disorder. There are currently 3 FDA-approved antipsychotic agents for treatment of bipolar depression. While comparable in efficacy, they vary in their adverse-event profiles.


Amrita was diagnosed with bipolar depression. She currently has symptoms of MDD. Her depression was preceded by a manic episode that lasted approximately 2 weeks, during which she demonstrated flight of ideas, pressured speech, lack of need for sleep, and increased goal-directed activity. Her young age at onset and number of depressive episodes are further clues to her diagnosis of bipolar depression.


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Mauricio Tohen, MD, DrPH, MBA

Professor and Chair

Department of Psychiatry and Behavioral Sciences

University of New Mexico School of Medicine

Albuquerque, New Mexico

Caption: FIGURE 1 Mean changes in MADRS scores in an 8-week study. Reductions in MADRS scores with the use of olanzapine and olanzapine-fluoxetine were significantly greater than with placebo throughout the study. (30)

Caption: FIGURE 2 Mean changes in MADRS scores in an 8-week study comparing (A) placebo versus quetiapine and lithium (EMBOLDEN I) and versus (B) quetiapine and paroxetine (EMBOLDEN II). (33,34)

Caption: FIGURE 3 Mean changes in MADRS scores in a 6-week study comparing (A) placebo with lurasidone monotherapy (PREVAIL 2) or comparing (B) placebo with lurasidone adjunctive to lithium or valproate (PREVAIL 1). (35,36)
Adverse Effects With Antipsychotics
That Are FDA-Approved for Bipolar Depression (37-39)

Adverse Effect          Olanzapine   Quetiapine   Lurasidone

  Weight gain              +++           ++          +/0
  Dyslipidemia             +++           +            0
    dysregulation           ++           +            0
    sedation               +++          +++          +/0
  EPS                       +            0           +/0
    cardiomyopathy          0            0            0
  QTc prolongation         +/0           +            0
  Prolactin elevation      +/0           0            0

Abbreviations: EPS, extrapyramidal symptoms; FDA, US Food and Drug

Data from: McIntyre RS, Konarski JZ.JClin Psychiatry. 2005;66(Suppl
3):28-36. Cha DS, McIntyre RS. Expert Opin Pharmacother. 2012;13:
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Title Annotation:Depression Across the Spectrum of Mood Disorders: Advanced Strategies in Major Depressive Disorder and Bipolar Disorder
Author:Tohen, Mauricio
Publication:Current Psychiatry
Article Type:Case study
Geographic Code:1USA
Date:Aug 1, 2017
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