Reality: Most practice guidelines advise administering antimanic mood stabilizers before initiating an antidepressant. Clinicians widely interpret this recommendation as reinforcing the assumption that a mood stabilizer will diminish mania risk when introducing an antidepressant. (Less often, clinicians interpret it as meaning that a mood stabilizer itself may provide antidepressant efficacy.) In fact, whether (and which) antimanic agents mitigate the risk for antidepressant-induced mania has received little empirical study. The largest dataset on this topic—the randomized controlled data from Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD)12—found that the risk for treatment-emergent manic switch with paroxetine or bupropion was almost identical (about 10%) with or without an FDA-approved antimanic agent.
In a retrospective study, Henry et al6 found that cotherapy with lithium but not divalproex or carbamazepine protects against antidepressant-induced mania, and that switch rates to mania were the same whether or not an antidepressant was taken with an anticonvulsant. In a naturalistic retrospective study (n=158), Bottlender et al24 revealed that mood stabilizers (lithium, carbamazepine, or divalproex) prevented switches from depression to mania during treatment with TCAs but not SSRIs or MAOIs.
I favor incorporating lithium or other antimanic agents in the regimens of patients with bipolar depression not primarily to guard against antidepressant-induced mania but more for pharmacodynamic synergy—complementary mechanisms of action that collectively may produce more substantial antidepressant effects—especially when the patient’s illness course has included manic or hypomanic features in the preceding year.
MYTH 6: Antidepressants cause or worsen rapid cycling.
Reality: Wehr et al25 reported that antidepressants may accelerate cycling frequency (ie, inter-episode durations become shorter) in a small subgroup (N=10) of patients. By contrast, use of TCAs was not more likely in the weeks preceding shifts from depression to mania or hypomania in a 14-year follow-up study of bipolar rapid cycling from the NIMH Collaborative Depression Study.26 In fact, rapid-cycling patients spent more weeks depressed when taking lithium without a TCA than with 1.
Findings from STEP-BD indicate that prospectively observed rapid cycling, as defined by DSM-IV criteria, is relatively rare, although subjects taking antidepressants often had multiple episodes per year.27 These naturalistic data could suggest that antidepressant use leads to more depressive episodes, or that more depressive episodes lead to more antidepressant use. Causal relationships cannot be inferred from the nonrandomized study design. Nevertheless, antidepressant use was not associated with reduced depressive episodes over 1 year.
I believe that, in general, antidepressants are unlikely to improve a truly rapid-cycling illness course. In this scenario, a more “panoramic” understanding of the need to treat multiple relapses and polarity changes over time likely warrants using multiple anti-cycling agents. Rapid cycling is treated over the course of 1 year, rather than 1 episode.
MYTH 7: Antidepressants should never be used without a mood stabilizer for bipolar depression.
Reality: This admonition is widely cited as a general recommendation from modern practice guidelines; however, it mainly pertains to depression treatment in patients with bipolar I disorder, for whom most controlled trial data exist. For example, relatively high rates of treatment-emergent mania have been reported with TCA or MAOI monotherapy in bipolar I disorder patients (Table 2). Yet for bipolar II disorder, controlled trials demonstrate superior outcomes with venlafaxine monotherapy compared with lithium monotherapy, with no increase in mood destabilization.20
Neither the safety nor the efficacy of antidepressants with vs without mood stabilizers has been studied systematically in cyclothymic or mood disorder patients who may fall within the so-called bipolar spectrum but have never met DSM-IV criteria for a lifetime manic or hypomanic episode (ie, bipolar disorder not otherwise specified). Extrapolation from findings based on bipolar I disorder patients may not be valid for all bipolar subtypes.
Clinical strategies
In constructing a rationale-based approach to bipolar depression, consider these steps:
Step 1: Assess candidacy for antidepressant use. A number of key features can help you delineate the current illness state and context in which depressive symptoms arise—features that may influence you patient’s vulnerability to mood destabilization, and therefore are pertinent for gauging the likelihood that antidepressants may help or harm (Table 4).
Step 2: Consider mood stabilizers with antidepressant properties. Determine whether your patient is taking any mood stabilizers that possess robust antidepressant properties, or whether it may be beneficial to introduce one of these agents before initiating adjunctive antidepressants. Mood stabilizers with antidepressant efficacy are compelling options for patients presenting with any of the features listed in the right-hand column of Table 4, as well as those with: