The Case Against Antidepressants for Bipolar Depression: Findings from STEP-BD

Psychiatric TimesVol 37, Issue 6
Volume 37
Issue 6

Do you prescribe antidepressants for your patients with bipolar depression? If so, think again, and consider results from these studies.



Do you prescribe antidepressants for your patients with bipolar depression? If so, think again, and consider results from the Systematic Treatment Enhancement Program–Bipolar Disorder (STEP-BD) studies. This was the largest federally funded group of studies of bipolar disorder treatment, and they included important randomized clinical trials involving subsamples of the 4360 patients enrolled.

Among the significant findings were the following:

1. Antidepressants (bupropion, paroxetine) are not more effective than placebo for bipolar depression (24% for the antidepressants versus 27% for the placebo in a 6-month trial).1 The antidepressants, when added to a mood stabilizer, did not induce more switches into mania (10% versus 11%), but the patients who participated in the study were probably at very low risk for switching. However, patients with bipolar depression with mixed features (defined as having 2 or more manic symptoms [eg, agitation and racing thoughts] with their depression) developed manias over the next several months that were more severe as compared with placebo-treated patients.

2. A group of 86 patients with bipolar disorder who responded to an antidepressant when depressed were identified. Some were rapid cyclers (4 or more episodes per year). All of the patients were also prescribed mood stabilizers such as lithium, valproate, or a second-generation antipsychotic. These patients were randomized to stay on the antidepressants or discontinue them. The patients with rapid cycling who were continued on their antidepressant had triple the number of depressions per year compared with those without rapid cycling. Yet, there was no difference in the rate of depressions between rapid and non-rapid cycling in the antidepressant discontinuation group. Thus, depressive morbidity and cycling were worsened by continuation of an antidepressant in patients with rapid cycling.2

3. In another STEP-BD study, prospective data were collected on the first 1500 patients looking for evidence of the antidepressant-associated chronic irritable dysphoria (ACID) syndrome described in previous case reports.3 It had been proposed that ACID was caused by treating patients who had bipolar depression with an antidepressant. The patient sample included 63% bipolar I patients with depression; most of the remaining patients had bipolar II. The researchers identified 83 patients in whom a depressive episode developed during the study period and for whom there was at least 1 year of follow-up information. Those who received an antidepressant for their depression had a 10-fold higher risk for ACID than the patients who were antidepressant free. ACID did not seem to occur in the natural course of bipolar disorder; it only occurred in those who received antidepressants.

Findings from STEP-BD studies indicate that antidepressants should be avoided in most cases when treating acute depression in patients with bipolar disorder. Rather, one should choose from among 5 medications with a reasonable evidence-base for effectiveness and safety in treating or at least preventing bipolar depressions, namely: lithium, quetiapine, lamotrigine, lurasidone, and cariprazine—or combinations of these.


Dr Osser is Associate Professor of Psychiatry, Harvard Medical School, and Consulting Psychiatrist, US Department of Veterans Affairs, National Telemental Health Center, Bipolar Disorders Telehealth Program, Brockton, MA.


1. Sachs GS, Neirenberg AA, Calabrese JR, et al. Effectiveness of adjunctive antidepressant treatment for bipolar depression. N Engl J Med. 2007;356:1711-1722.
2. El-Mallakh RH, Vöhringer PA, Ostacher MM, et al. Antidepressants worsen rapid cycling course in bipolar depression: a STEP-BD randomized clinical trial. J Affect Disord. 2015;184:318-321.
3 El-Mallakh RH, Ghaemi SN, Sagduyu K, et al. Antidepressant-associated chronic irritable dysphoria (ACID) in STEP-BD patients. J Affect Disord. 2008;111;372-377.

This article was originally posted on April 24, 2020, and has since been updated. -Ed

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