The treatment of bipolar depression is a major challenge, with few treatments of proven efficacy and, in particular, substantial controversy about the role of antidepressant drugs. Authors of guidelines and consensus statements on this topic often ponder why antidepressants are so commonly used despite the scarce evidence for efficacy.30–32
Until recently, after the work of Emil Kraepelin, bipolar depressive episodes were deemed phenomenologically and biologically similar to unipolar depressive episodes. Even as late as the 1990s, inclusion and exclusion criteria in clinical trials of antidepressants in patients with depressive disorder did not usually either select or stratify according to polarity. Earlier trials suggested that when given with antimanic treatment, selective serotonin reuptake inhibitor antidepressants were more effective and no more likely to induce mania than placebo, and were less likely to induce mania than tricyclic antidepressants.32
In 2007, a large trial found no benefit associated with the addition of paroxetine or bupropion to a mood stabiliser;33
another reported that paroxetine was no better at achieving a durable recovery than placebo.34
A recent updated meta-analysis of antidepressants in bipolar depression reported a pooled effect no different from placebo (relative risk [RR] of response 1·17, 95% CI 0·82–1·57) with statistically significant heterogeneity.35
Meta-analyses in patients with bipolar disorder have grouped antidepressant drugs together as one class, despite the observed statistically significant heterogeneity and the evidence in patients with unipolar disorder that antidepressant agents vary to a clinically significant degree in both efficacy and tolerability.36
Therefore, to conclude that no antidepressant agent is effective in bipolar depression is probably premature, although the emerging evidence suggests that paroxetine is ineffective.
The antiepileptic drug lamotrigine was investigated in patients with bipolar depression after a clinical benefit was seen after treatment with the drug in patients with bipolar disorder.37
A meta-analysis of individual patient-level data 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. Thus, the place of lamotrigine in acute treatment remains uncertain.38
Atypical antipsychotics have been investigated in bipolar depression with variable results.39
Treatment with quetiapine leads to more symptomatic improvement in patients with bipolar depression than do placebo, paroxetine, and lithium.39
Some evidence exists of a reduced risk of recurrence in patients who respond to acute-phase treatment and continue quetiapine rather than switch to placebo; thus, continuation could be of benefit in patients who can tolerate the drug’s adverse effects, including sedation and weight gain.40
The reasonably fast onset of action of quetiapine is clinically useful because it provides clinicians and patients with a treatment that can be initiated early in the course of a worsening depression in the same way that antipsychotics are used for emerging manic symptoms. Combined olanzapine and fluoxetine leads to more symptomatic improvement than does olanzapine or placebo alone, which could suggest that fluoxetine is an effective treatment of acute bipolar depression or that the combination of fluoxetine and olanzapine is synergistic.41
So far, the investigation of atypical antipsychotic drugs has been instructive for both clinical and methodological reasons. Quetiapine and olanzapine–fluoxetine combination have regulatory approval for bipolar depression in some countries and are included as first-line recommendations in recent guidelines. Emerging evidence suggests that lurasidone might also be efficacious, whereas aripiprazole does not seem to be so.39,42
The transdiagnostic benefits of a drug like quetiapine, which is antipsychotic, antimanic, and antidepressant in both unipolar and bipolar depression, emphasises the importance of the investigation of treatment effects across conventional diagnostic boundaries.9,40,43
However, this non-specificity and scarcity of convincing evidence of long-term disease modification by known mechanisms suggests that the effects are mediated by short-term alleviation of symptoms. Nonetheless, because bipolar depression is very difficult to treat, this relief is often useful for patients and clinicians. Further, combinations of atypical antipsychotics with selective serotonin-reuptake inhibitors, or with agents that have medium-term to long-term effects on depression (eg, lamotrigine) are often used in clinical practice and warrant investigation in clinical trials.
Up to a third of patients with bipolar disorder do not respond to treatments in naturalistic studies;4,5,7
these figures probably underestimate the proportion of treatment-resistant patients with depression in clinical practice. Even patients who receive adequate pharmacotherapy have lengthy and debilitating periods of subthreshold depressive symptoms after major episodes. Longitudinal studies estimate that patients with bipolar disorder type I spend as many as 3 weeks depressed for every 1 week (hypo)manic; the ratio in bipolar disorder type II is 37:1.5,44
Subthreshold depressive symptoms are associated with social and occupational impairment,45
and increased psychosocial impairment is prospectively associated with earlier recurrences.46,47
Very little evidence exists of effective strategies for patients who do not respond to first-line treatments. A recent review of strategies reported just seven small trials; one each for ketamine, pramipexole, lamotrigine, and risperidone, and two each for modafinil and electroconvulsive therapy.48
Therefore, recommendations in clinical practice guidelines for treatment-resistant bipolar depression are still often based on extrapolation from the evidence on augmentation and switching strategies in unipolar major depression. This situation might lead to an underestimation of the attendant risks of treatment-emergent hypomania or mania in patients with bipolar disorder.