In clinical practice, 50% to 80% of bipolar patients receive long-term antidepressants,1 although potential benefits probably outweigh risks in 20% to 40%. This gap suggests that psychiatrists could do more to stay out of trouble when prescribing antidepressants for patients with bipolar depression.
Antidepressants have not shown efficacy in long-term treatment, and evidence of their effectiveness in acute bipolar depression is limited. They appear to pose greater risk of switching and mood destabilization for some patients and certain types of bipolar illness, and some antidepressant classes are more worrisome than others.
Because carefully analyzing risks and benefits is essential when considering antidepressants for a patient with bipolar illness, this article clarifies that delicate balance and offers evidence-based recommendations for using antidepressants in bipolar depression.
ACUTE THERAPY
Clinical trials support antidepressants as the treatment of choice for unipolar depression, but less evidence supports efficacy and safety in acute bipolar depression. Depressive episodes predominate in bipolar disorder, with chronic subsyndromal symptoms being most characteristic.2,3 Compared with mania or hypomania, depressive episodes:
- last longer and are more frequent
- contribute to greater morbidity and mortality
- pose a greater treatment challenge.
Antidepressants have shown benefit in multiple double-blind, bipolar depression trials and were as effective as mood stabilizers in one small study.4 Even so, no trials have found them more effective than mood stabilizers in acute bipolar depression.
Controlled trials. Two randomized, double-blind, placebo-controlled trials have examined antidepressant use in bipolar depression.5,6 The larger and better designed—a prospective 10-week study by Nemeroff et al6—examined 117 outpatients with type I bipolar disorder.
Subjects who had been taking lithium (serum levels 0.5 to 1.2 mEq/L) for ≥6 weeks and were experiencing moderate breakthrough depression then received paroxetine (mean dosage 32.6 mg/d), imipramine (mean dosage 166.7 mg/d), or placebo. Therapeutic response was defined as ≤7 on the Hamilton Rating Scale for Depression (HRSD) or ≤2 on the Clinical Global Impression (CGI) scale—normally considered criteria for depressive remission.
The authors hoped to show a statistically significant medication-placebo difference, but the antidepressants’ effects were similar to those of placebo. Thus, adding antidepressants to lithium conferred no added benefit, though the small sample size may have created a false negative.
Interestingly, a post-hoc analysis found different treatment outcomes when patients were separated into two groups by lithium serum levels:
- low therapeutic (≤0.8 mEq/L)
- high therapeutic (>0.8 mEq/L).
Adding antidepressants significantly reduced HRSD scores compared with placebo in the low lithium group but not in the high lithium group. Thus, therapeutic lithium levels may have moderate antidepressant effects, and adding antidepressants may help patients who cannot tolerate therapeutic lithium levels.
MAINTENANCE THERAPY
Antidepressants may have modest efficacy in acute bipolar depression, but they have not shown benefit—with or without mood stabilizers—in 7 studies of bipolar depression maintenance therapy. Most were double-blind, long-term trials comparing tricyclic antidepressants (TCAs) with lithium or adding TCAs to lithium; 3 were placebo-controlled.7 Antidepressants were not more effective than mood stabilizers such as lithium or lamotrigine in preventing bipolar depression.
Type II patients. For depression in type II bipolar disorder, the only data on using antidepressants as acute or maintenance therapy come from post-hoc analyses of unipolar depression trials and retrospective assessments of “manic switches.” No specific mania rating scales have been used.8,9
Long-term antidepressants. Two naturalistic studies by Altshuler et al10,11 explored continuing antidepressants as bipolar depression maintenance treatment. The larger trial11 included 84 patients (most with type I bipolar disorder) who experienced breakthrough depression while taking a mood stabilizer. This subset (15%) of the Stanley Foundation Bipolar Network had tolerated antidepressants at least 2 months without switching into hypomania/mania and remained in remission at least 6 weeks. None were rapid cyclers.
With counseling from clinicians, patients chose to continue or discontinue taking antidepressants. Relapse rates after 1 year were 70% in patients who stopped antidepressants after <6 months, compared with 24% in those who continued taking them for 1 year. The authors concluded that bipolar patients may benefit from staying on antidepressants at least 6 months and perhaps 12 or more months after depressive remission.
Keep in mind, however, that these findings may not apply to all bipolar patients. This study pertains to a minority of robust responders—none of whom were rapid cyclers—who tolerated the medication well and were not randomly assigned to continue or discontinue antidepressants. Other evidence suggests that depressed bipolar patients are three times more likely than unipolar patients (54% vs 16%) to develop tolerance to antidepressants.12
ANTIDEPRESSANT RISKS
Risks of using antidepressants in bipolar patients include acute switches into hypo/mania, usually within 8 weeks of starting an antidepressant, and new-onset mood destabilization—with cycle acceleration or rapid cycling—or worsening of pre-existing rapid cycling (Table 1).1