Antidepressants Equal to Placebo in Bipolar Depression

BOSTON, March 29 -- If a depressed patient with bipolar disorder is taking a mood stabilizer such as lithium, adding an antidepressant has no more effect than a placebo, according to researchers here.

In a study of 366 depressed bipolar patients, durable recoveries were nearly identical, whether patients were randomized to an antidepressant or placebo, found Gary Sachs, M.D., of Massachusetts General Hospital here, and colleagues.

Also, there were no significant differences in a range of secondary endpoints of the 26-week trial, part of the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) collaboration, the investigators reported online in the New England Journal of Medicine, scheduled for the April 26 print issue.

American physicians have been generally cautious about using antidepressants in bipolar patients, fearing that the drugs would spark manic episodes, Dr. Sachs and colleagues noted.

There had been only limited evidence that medications effective in treating unipolar depression are beneficial in depressed bipolar patients, they said.

To attempt to fill that gap, they recruited the 366 participants at 22 sites across the U.S. Participants were included in the study even if they were being treated for co-existing disorders, such as substance abuse or psychotic symptoms, in order to make the results more widely applicable.

Participants were randomized to one of two antidepressants -- bupropion (Wellbutrin) or paroxetine (Paxil) -- or to a placebo, and they were also treated with a mood stabilizer.

The study found:

• Forty-two of the 179 patients (23.5%) receiving a mood stabilizer plus an antidepressant had a durable recovery, defined as eight weeks of euthymia.
• At the same time, 51 of the 187 patients (27.3%) getting a mood stabilizer and placebo had a durable recovery. The difference between the two arms was non-significant at P=0.40.
• Rates of transient recovery, treatment-emergent affective switching, and discontinuation because of adverse events were also not significantly different between the arms.

The results suggested that antidepressants are safe, but not effective in these patients, Dr. Sachs said. Instead, "careful management of mood stabilizer medications is a reasonable alternative to adding an antidepressant medication for treating bipolar depression," he said.

The finding "comes as a surprise," according to R.H. Belmaker, M.D., of Beersheva Mental Health Center in Beersheva, Israel. Writing in an accompanying editorial, Dr. Belmaker said the study appears to contradict European research on the same question.

But while the study widens the clinical gap between Europe and the U.S. on the issue of efficacy and closes it on the issue of safety, he said, it's unlikely that the findings of Dr. Sachs and colleagues will change how doctors treat their patients.

Both the investigators and Dr. Belmaker noted an important limitation of the study.

The authors wrote that "patients who had recently had a manic episode were likely to be underrepresented in our study. Clinicians caring for these potential subjects might have judged them to be at high risk for a switch from depression to mania or hypomania and therefore might have avoided enrolling them into our double-blind study that exposed subjects to a standard antidepressant. Thus, our results are likely to be applicable only to those patients with bipolar depression who are considered appropriate candidates for treatment with standard antidepressants."

For this reason, Dr. Belmaker wrote "treatment will continue to be individualized."

Dr. Sachs reported consultant and speaker fees from Abbott Labs, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Merck, Pfizer, Sanofi, and Wyeth and grant support from the NIMH, Abbott Labs, GlaxoSmithKline, Memory Pharmaceuticals, and Repligen. Other authors reported support in various forms from Abbott Laboratories, Brain Cells, Bristol-Myers Squibb, Genaissance, GlaxoSmithKline, Innapharma, Janssen, Eli Lilly, Novartis, Pfizer, Sepracor, Shire, Somerset, Cederroth, Cyberonics, Forest, Janssen, Lichter Pharma, Eli Lilly, NARSAD, Pfizer, the Stanley Foundation, Wyeth, AstraZeneca, Solvay, Seriver, Sanofi-Aventis, the Cleveland Foundation, Medtronics, Aspect Medical Systems, the American Foundation for Suicide Prevention, Sanofi, Neuronetics, JDS Pharmaceuticals, UCB Pharma, Elan Pharmaceuticals, Parke-Davis, the R.W. Johnson Pharmaceutical Institute, SmithKline Beecham, the Cohen Family Foundation, and Pfizer, Memory Pharmaceuticals, Repligen, Roche Labs, the University of Toledo College of Medicine, Alexza Molecular Delivery, the Robert Sutherland Foundation, and Organon.

Dr. Belmaker said he had no potential conflict of interest.