Antidepressants in bipolar disorder: 7 myths and realities

A retrospective review of bipolar (n=41) and unipolar (n=37) depressed patients by Ghaemi et al⁸ found no significant difference in acute nonresponse rates between the groups. Similarly, Bottlender et al⁹ found no differences in treatment response when comparing naturalistic antidepressant outcomes for 50 unipolar and 50 bipolar patients matched for age, sex, and illness duration. Comparable antidepressant response outcomes also were reported in a retrospective study of 2,032 unipolar and bipolar inpatients conducted by Möller et al,¹⁰ and between unipolar (n=31) vs bipolar II (n=17) depressed patients receiving venlafaxine monotherapy for 6 weeks.¹¹

Antidepressant response may depend on factors such as episode chronicity or the number of failed medication trials within a given episode, regardless of illness polarity. This was suggested by the remarkably low response rates after 2 failed initial antidepressant treatments in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) unipolar depression trials. In my experience, antidepressant efficacy is more often a function of factors in addition to polarity, including:

• illness severity
• chronicity
• psychiatric, medical, or substance use comorbidity
• psychosocial skills, such as the capacity to tolerate distress, utilize effective coping techniques, and maintain appropriate relationships with others.

MYTH 3: Most antidepressants have been systematically studied for treatment of depression in bipolar disorder.

Reality: Only paroxetine,^12,13 bupropion,¹² and imipramine¹³ have been studied in randomized, large-scale, adequately powered placebo-controlled trials. Studies of other antidepressants suffer from small sample sizes (inadequate statistical power), lack of placebo controls, or failure to control for possible confounding factors, such as lack of stratification for bipolar I vs II subtype or presence vs absence of rapid cycling.

One large randomized trial showed comparable antidepressant efficacy with a mood stabilizer plus adjunctive venlafaxine (43%) vs sertraline (55%) vs bupropion (49%) over 10 weeks,¹⁴ but the lack of a mood stabilizer monotherapy comparison group limits the ability to anticipate whether adjunctive antidepressants increase response or remission rates more than mood stabilizers alone. Adjunctive imipramine,¹³ paroxetine,^12,13,15 and bupropion¹² yield no greater improvement in depressive symptoms than is seen with optimally dosed mood stabilizers alone.

Mirtazapine, a serotonergic/noradrenergic antidepressant that is sometimes prescribed off-label as a sleep aid, has not been systematically studied for safety or efficacy in bipolar depression. In case reports, mirtazapine has induced mania in patients with unipolar depression.^16-18 Using mirtazapine to counteract insomnia may be safer in patients with unipolar depression than in those with bipolar disorder. Because poor sleep is a core feature of mania, be certain to differentiate complaints that reflect simple insomnia from a loss of need for sleep:

• daytime fatigue is more common in insomnia than loss of need for sleep
• nocturnal hyperactivity is more often associated with loss of need for sleep.

Using an antidepressant to treat sleep problems that may derive from emerging mania or hypomania runs counter to basic pharmacodynamic principles and may pose greater risk than benefit.

Generally, using a medication that has been studied for treating a specific clinical entity such as bipolar depression is preferable to using one that has not. Avoid medications that have multiple negative placebo-controlled trials—such as paroxetine—unless you have evidence of efficacy in an individual patient.

MYTH 4: Risk for inducing mania is higher with noradrenergic antidepressants.

Reality: This popular belief arose from a unifying hypothesis offered by Sachs et al¹ and Leverich et al¹⁴ to explain higher rates of mania following treatment with desipramine than bupropion,¹ SSRIs compared with TCAs,² or venlafaxine compared with bupropion or sertraline.¹⁴ However, while plausible, this hypothesis does not fully account for the putative noradrenergic properties of bupropion—presumably via increased pre-synaptic norepinephrine outflow, rather than noradrenergic reuptake inhibition¹⁹—which reportedly has a lower risk of switching than desipramine1 or venlafaxine.¹⁴

The risk for venlafaxine monotherapy to induce mania or hypomania in patients with bipolar II depression has been reported to be nonexistent¹¹ or no higher than seen with lithium.²⁰ Also, some noradrenergic agents, such as duloxetine, have not been shown to induce mania in major depression,²¹ although duloxetine’s potential to destabilize mood is unknown because of the absence of data in bipolar disorder. Finally, although large-scale clinical trials have not examined the safety and efficacy of the noradrenergic reuptake inhibitor atomoxetine, several case reports have suggested its potential for inducing mania or hypomania.^22,23

Likely, all-or-none admonitions against using noradrenergic antidepressants are oversimplifications.

MYTH 5: Coadministering an antimanic mood stabilizer reliably prevents antidepressant-induced mania.