A Reference Guide to Bipolar Depression

(Bipolar Depression: The Other Side of the Coin)

Tossing a coin is believed to be a 50/50 possibility of coming up either heads or tails. It doesn't really work that way and there is an imbalance in the results based on the minting of the coin, age, use, and many other factors. The results are always slightly skewed towards heads.1

The 'face' of bipolar disorder to many is mania; however, the 'down side' is truly the depressed phase. According to studies by Judd and colleagues, individuals with bipolar disorder spend most of their time symptomatic in a depressed phase; actually, a significant percentage of time is spent in a depressed mood as compared to either mania, hypomania or euthymia.2,3


The Diagnostic and Statistical Manual of the American Psychiatric Association (DSM) does not distinguish between the depressive symptoms of unipolar and bipolar depression5 however, studies that have compared the two generally find differences in the clinical presentations.4

Diagnostic criteria


Differential diagnosis

Differentiating major depressive disorder (MDD) from depression in bipolar disorder (BPD), particularly BPD II, can be a challenge. Several studies have demonstrated that BPD is associated with a significantly earlier age of onset, more recurrences, atypical and mixed depressions, and family history of BPD or completed suicide compared to MDD.6,7 Mixed states are highly predictive of a BPD diagnosis, especially BPD II.6 In addition, mixed states have been associated with an increased lifetime risk for comorbid psychiatric disorders, more mood episodes, higher rates of treatment, and lower rates of full-time employment compared to pure states.8 There is also commonly a history of adverse behavioral responses to antidepressants in individuals with bipolar depression.9

Mood Disorders Questionnaire

In conjunction with a clinical evaluation, evidence-based validated measures can be helpful to clinicians in both the initial assessment and the long-term management of bipolar depression. The Mood Disorder Questionnaire (MDQ) was developed specifically to help clinicians differentiate unipolar depression from bipolar depression.10 It comprises 15 questions that can be easily administered in an office setting. It is both sensitive and specific, correctly identifying seven out of 10 patients with bipolar disorder, while screening out nine out of 10 patients without the condition.11 The MDQ can be downloaded from the Depression and Bipolar Support Alliance (DBSA) website at http:// www.dbsalliance.org/pdfs/MDQ.pdf ‎ and is recommended for use by clinicians who may see patients with depressive symptomatology.


There is a relative lack of clinical evidence from studies in patients with acute bipolar I or bipolar II depression.12 This lack of clinical evidence may be that bipolar I disorder presents initially as mania is generally regarded as a more severe form of illness than acute bipolar depression4,13,14; however, this view may be ill-founded as patients with bipolar II disorder experience a greater frequency of episodes and a longer overall time spent in depression.2,14 It may also be related to the lack of recognition of this subtype in the community by both patients and clinicians.14

The treatment of bipolar depression has continued to challenge clinicians, essentially because there are so few treatments that demonstrate efficacy and substantial controversy remains about the role of antidepressant drugs in bipolar depression.15 Experts debate why antidepressants are so commonly used despite the scarce evidence for efficacy.16,17 Yet bipolar depression is commonly misdiagnosed by clinicians and often treated with an antidepressant.10 Gijsman and colleagues evaluated the evidence from randomized, controlled trials on the efficacy and safety of antidepressants in the short-term treatment of bipolar depression and describe that results from clinical trial data do not suggest that switching is a common early complication of treatment with antidepressants.18 However,  recent meta analyses by Sidor and colleagues demonstrated that although antidepressants do not present any safety issues, their lack of efficacy in bipolar depression limits their clinical utility.17 Additional studies are needed to clarify the appropriate role of antidepressants in bipolar depression, if at all. 18

Atypical Antipsychotics

The only currently Federal Drug Administration (FDA) approved medications for bipolar depression are atypical antipsychotics including: lurasidone as monotherapy or in combination with valproate or lithium19; quetiapine, in both original and extended release formulations20; and olanzapine and fluoxetine combination.21 Attempts to generalize across this class of medications have shown variable results with inconsistent efficacy data from clinical trials.22

The efficacy of quetiapine in patients with bipolar depression is established by five placebo-controlled studies, including two studies in which active controls (i.e., paroxetine or lithium) were not more effective than placebo.22 A study by Weisler showed that patients who responded to quetiapine therapy are more likely to stay well if they continue quetiapine therapy rather than switch to placebo or lithium for maintenance. Therefore, continuation can be of benefit in patients who can tolerate the drug’s most common adverse effects, including sedation and weight gain.23 The rapid onset of action quetiapine can be clinically useful as it offers clinicians and patients a treatment that can be initiated early in the course of worsening depression, similar to the way that antipsychotics are used for emerging manic symptoms.23

Data shows that combined olanzapine and fluoxetine leads to more symptomatic improvement than does olanzapine or placebo alone. This may suggest that either fluoxetine is an effective treatment for acute bipolar depression or that the fluoxetine plus olanzapine combination may be synergistic.24

Recently approved in 2013 for bipolar depression is lurasidone. Efficacy was demonstrated through two clinical trials, one for lurasidone as an adjunctive therapy and the other as monotherapy.19,25,26 Data also strongly suggests a more promising metabolic profile than the other approved agents.27 A study by Hassan and colleagues demonstrated that patients who switched from another antipsychotic to lurasidone had a reduction in cardiometabolic parameters including BMI, triglycerides, fasting glucose, blood pressure and HDL.28 These reductions are important in the overall health of patients. Interestingly, other antipsychotics such has aripiprazole29* and ziprasidone30* have failed to demonstrate efficacy in bipolar depression over placebo.

*Not an FDA-approved indication for this agent.

Mood Stabilizers

The antiepileptic drug lamotrigine* has been studied in patients with bipolar depression after a clinical benefit was seen with bipolar disorder.31 A meta-analysis from five trials of lamotrigine in bipolar depression reported a modest treatment effect; however, no one trial showed statistically significant benefits of treatment with lamotrigine in comparison with placebo. When lamotrigine and placebo were studied as an add-on therapy to ongoing treatment with lithium in patients with bipolar depression, the addition of lamotrigine to lithium improved outcomes in patients with acute bipolar depression.32 Thus, the place of lamotrigine monotherapy in acute treatment of bipolar depression remains uncertain.33

Other mood stabilizers such as lithium and valproate have not demonstrated efficacy in acute treatment of bipolar depression. Lithium has been used for decades as maintenance treatment of mania to reduce the risk of manic relapses as well as and depressive relapses.34 Valproate has been used in the past two decades; however, placebo controlled evidence for valproate in acute depression or long-term prevention remains scarce.35

Response to treatment

It is estimated that up to a one-third of patients with bipolar disorder do not respond to treatments in naturalistic studies and this is considered to be a conservative estimate.3,36 Many patients who receive adequate pharmacotherapy still may have lengthy and debilitating periods of subthreshold depressive symptoms after major episodes. This was evident in the longitudinal studies mentioned earlier that estimate that patients with bipolar disorder type I spend as many as three weeks depressed for every one week hypomanic or manic; the ratio of depression to hypomania in bipolar disorder type II is 37:1.2,3

These pervasive but subthreshold depressive symptoms have been associated with social and occupational impairment.37 There is little evidence to date that offers any effective strategies for patients who do not respond to first-line treatments. A recent review of strategies reported just several small trials; one each for ketamine*, pramipexole*, lamotrigine*, and risperidone*, and two each for modafinil* and electroconvulsive therapy.38 Stimulants (e.g., amphetamines*, methylphenidate*) have also been studied for their potential antidepressant effects in bipolar depression.  As a result, recommendations in clinical practice guidelines for treatment-resistant bipolar depression are still often based on the evidence on augmentation and switching strategies in unipolar depression.15

The need for additional effective drugs for bipolar depression remains an unmet clinical need and clinicians who treat this disorder should be aware of the current and emerging evidence to facilitate best practices for patients with bipolar disorder.40

*Not an FDA-approved indication for this agent.

Psychosocial treatments for bipolar disorder

Treatment guidelines increasingly recommend the combination of pharmacotherapy with targeted psychotherapy to optimize the management of bipolar disorder.41,42 A number of randomized trials have studied the effect of combined pharmacological and psychological interventions and various health-service interventions in bipolar disorder43,44 but few of the trials have specifically investigated the early stages of bipolar disorder.  Observational studies suggest that early intervention may improve both course and outcomes. Delay to first treatment is associated with more time depressed, greater severity of depression, more episodes, and fewer days euthymic.45

A recent randomized trial in Denmark has shown clinical benefits from this approach. Kessing and colleagues studied patients with bipolar disorder (n=158) who were randomized to either a specialized mood disorder clinic that offered combined intervention with evidence-based pharmacological treatment and group psychoeducation or a standard treatment outpatient clinic and followed for 2.5 years. Results demonstrated significantly that the combined treatment prevented relapse and showed improved functioning and patient satisfaction with treatment.46

The various psychological approaches build on evidence that psychosocial stressors, including negative life events, excessive family discord, or events that disrupt sleep and wake rhythms or accelerate goal attainment are associated with worsening symptomatic states or relapses.47 The main goals of adjunctive psychotherapy for bipolar disorder include the education of patients, and when possible, caregivers, about strategies to manage stress, identification of early signs of recurrence, and how to keep regular lifestyle (e.g., sleep and exercise) habits.47

There is unfortunately a high rate of non-adherence to drug treatments, as great as 60% after acute episodes,48 psychosocial treatments can help emphasize consistency with pharmacotherapy. Evidence-based models of psychotherapy include cognitive behavioral therapy, family-focused therapy, interpersonal and social rhythm therapy, group psychoeducation, and systematic care management. Although these models have common objectives, their methods, approaches, and structure differ in approach.47,49

Adjunctive psychotherapy in acute treatment

Studies have examined whether psychotherapy enhances remission from acute depression.50  The STEP-BD study compared up to 30 sessions of family-focused therapy, interpersonal and social rhythm therapy, or cognitive behavioral therapy (i.e., intensive treatment) with a brief psychoeducational therapy (three individual sessions) for 293 patients with acute depression who also received mood stabilizers. Over 1 year, patients in intensive therapy recovered more rapidly and were more likely to be clinically well in any study month than those in brief treatment. Effects extended to relationship functioning and life satisfaction.51 There were no differences among the three intensive modalities in symptoms or psychosocial functioning over 1 year. Interestingly, patients with depression in STEP-BD who were treated with mood stabilizers and randomly assigned to adjunctive antidepressant treatment did not recover faster than patients who were assigned to adjunctive placebo treatment.52 Therefore, it is possible that psychosocial treatment might be an effective adjunct to mood stabilizers rather than antidepressants after a bipolar depressive episode.52

Family-focused therapy develops communication skills and problem solving skills in caregivers and the patients. The premise is the association between criticism and hostility in caregivers and an increased likelihood of relapse in mood disorders and schizophrenia.53 There are approximately 21 sessions of psychoeducation, communication and problem-solving skills training.47 Two randomized controlled trials including symptomatic patients with bipolar I and II found that, in the one to two years after a manic, mixed, or depressive episode, patients with bipolar disorder who received family-focused therapy in addition to pharmacotherapy had 30% to 35% lower rates of relapse and rehospitalization and fewer severe symptoms than did patients in case management48 or equally intensive individualized treatment.54

Cognitive behavioral therapy presumes that recurrences of mood disorder are determined by negative thinking in response to life events and from general dysfunctional beliefs about the self, the world, and the future.55 Cognitive behavioral therapy (CBT) to treat depression has been adapted for patients with bipolar disorder.56 One randomized controlled trial reported that patients who received 12 to 14 sessions of CBT were less likely to have depressive episodes and had better social functioning than patients in routine care for 30 months.46 Yet another trial of effectiveness (n=252) comparing cognitive behavioral therapy with treatment as usual in five UK community care centers found no advantage for cognitive behavioral therapy over 18 months, except among patients with fewer than 12 previous episodes.57

Interpersonal and social rhythm therapy, is an adaptation of the interpersonal psychotherapy for depression and approaches interpersonal problems through problem-solving by encouraging patients to regulate and maintain daily routines and sleep and wake rhythms.58 In a large (n=175) randomized clinical trial,58 acutely manic, mixed, or depressed patients with bipolar I disorder were assigned to weekly interpersonal and social rhythm therapy, or to equally intensive clinical management, both with pharmacotherapy. After acute stabilization, patients were randomly assigned to the two groups for a two-year maintenance phase. While there were no differences in time-to-recovery between the groups in the acute phase, patients who received interpersonal and social rhythm therapies during the acute phase had longer times to recurrence and better vocational functioning in the maintenance phase than did patients who received treatment as usual. In addition, this group was better able to regulate their daily or nightly routines. This suggests that helping patients to stabilize their sleep and wake rhythms after an acute episode might provide some downstream effects on prevention of future mood instability.58

Group psychoeducation

The approach to psychoeducation in mental health care has been based on utilizing established curricula that emphasize an awareness of illness, treatment adherence, early detection of recurrences, and sleep and wake regularity. In a study of euthymic bipolar I and bipolar II, patients were randomly assigned to pharmacotherapy along with 21 sessions of structured group psychoeducation or 21 sessions of an unstructured support group. After five years, patients in the structured groups had fewer relapses and were ill for less time than those who had been in the unstructured groups.56


If we return to the concept of a two-sided coin and relate it to bipolar disorder, there is truly little left to chance.  The chance of being symptomatic versus asymptomatic in BPD would be close to chance (47%); unfortunately, 67% of that 47% would be in a depressed state. For BP II, like the coin toss, the outcomes would be greater than chance (54%) of being symptomatic with a striking 93% of that time in a depressed state.

Timely assessment of bipolar disorder in patients who present with major depressive symptoms is critical. Evidence-based screening tools such as the MDQ can assist clinicians in making a diagnosis of bipolar depression. Treatment of bipolar depression can be complex and requires a more sophisticated approach than major depressive disorder. There is surprisingly little evidence to guide clinicians and the viable psychopharmacological options are different than in MDD. Combined pharmacological and non-pharmacological strategies appear to be an optimal approach to treatment.

Clinical Connections


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