The Debate Goes On: Are Antidepressants for Bipolar Moot?



Should bipolar disorder be treated with antidepressants? There is no short answer, but that was the topic in a Medical Crossfire® at the Annual Psychiatric Times® World CME ConferenceTM. A lively discussion was had by all in this session moderated by Roger McIntyre, MD, and joined by Chris Aiken, MD; S. Nassir Ghaemi, MD; and Joseph F. Goldberg, MD.

Chris Aiken, MD, shared his experience working with patients with bipolar disorder who are prescribed antidepressants. “In bipolar depression, about 90% of the responses you see with antidepressants are due to the placebo,” said Aiken, director of the Mood Treatment Center; instructor in clinical psychiatry at Wake Forest University School of Medicine in Winston-Salem, NC; editor in chief of Carlat Psychiatry; and mood disorders section editor at Psychiatric Times®. “Bipolar depressions last 2 to 3 months on average, so if you start an antidepressant in the middle of an episode, you’re likely to think that it worked when it was just the natural ebb and flow of the illness. If it were a sugar pill, this wouldn’t be a problem, but over time, these antidepressants can cause rapid cycling, mixed states, and mania.”

Chris Aiken, MD

Among those risks, rapid cycling is the most difficult to detect because it has a slow build. “In the Step-BD trial, antidepressants sped up the frequency of episodes three-fold in patients who were prone to rapid cycling.” Aiken recommended using mood charts to detect these subtle changes in episode frequency.

Systemic issues

S. Nassir Ghaemi, MD, professor of psychiatry at Tufts University School of Medicine, and lecturer on psychiatry, Harvard Medical School, Boston, MA, addressed the complexities in resolving bipolar depression with antidepressants. “The majority of patients with bipolar illness are getting an antidepressant. They have been since I entered the field in 1995. Over 25 years of my talking about this and writing about this, it hasn't changed; it has gotten worse,” he told the audience.

The larger problem is in the profession of psychiatry, said Ghaemi. Historically, psychiatry’s orientation was psychoanalytic, but in the 1980s the field shifted toward psychopharmacology. “It seems as if we say that a particular subclass of our drugs are not effective, or are not as effective as we thought, we are somehow harming the profession of psychiatry itself.”

S. Nassir Ghaemi, MD

“This psychopharmacological efficacy is seen as equivalent to professional competence, which of course is false,” said Ghaemi. In any other area of medicine, some drugs work for some things and they do not work for others, he explained. It is nothing bad to say that a certain class of drug does not work for a certain disorder. And herein lies the controversy: “Psychiatrists are almost unwilling to say that about anything. And if there's one place where it's clear, it is that antidepressants are not effective in bipolar depression.”

Personalized treatment

Joseph F. Goldberg, MD, took a different view, stating that antidepressants may work in a subset of patients with bipolar depression like “someone who has never had rapid cycling, substance abuse, recent manic symptoms . . . But you don’t see that too often.” Dr Goldberg, clinical professor of psychiatry at Icahn School of Medicine at Mount Sinai, New York, NY, and director of the Affective Disorders Research Program at Silver Hill Hospital in New Canaan, CT, added that we know very little about antidepressants in bipolar depression because the studies are so few.

Joseph F. Goldberg, MD

Rather than trying to figure out whether antidepressants work in bipolar depression, Goldberg called for research to better characterize who responds to antidepressants and who gets worse on them. As an example, he cited a meta-analysis by Ghaemi that found patients who were homozygous for the short arm of the serotonin transporter gene (S/S at 5-HTTLPR) were 135% more likely to have antidepressant-induced mania.1

He warned against lumping all antidepressants into one category given their varied mechanisms of action. “None of the newer agents have been studied in bipolar depression—including vortioxetine and vilazodone—so we can’t say what they would do.”

An area of agreement

Roger McIntyre, MD, the moderator of the Plenary Session: Special Report on Bipolar Disorder and program co-chair of the conference weighed in. “My own view is that antidepressants have been, frankly, largely useless to most people that I have seen—and useless would be considered a good outcome.”

Roger McIntyre, MD

Some consensus emerged around 2 opposing facts. While antidepressants carry a significant risk of mood destabilization, they are effective in a small minority of bipolar patients, which Ghaemi estimated at fewer than 20%. “The problem is that 60% of patients with bipolar disorder are taking them, and most of those antidepressants are prescribed without a mood stabilizer,” said Ghaemi.2

All agreed that antidepressants have meager benefits and clear risks in bipolar disorder. What is less clear is when to use them and when to come off them, and therein lies the controversy.

Save the date! Annual Psychiatric Times® World CME ConferenceTM - September 30-October 2, 2021.


1. Daray FM, Thommi SB, Ghaemi SN. The pharmacogenetics of antidepressant-induced mania: a systematic review and meta-analysis. Bipolar Disord. 2010;12(7):702-706.

2. Rhee TG, Olfson M, Nierenberg AA, Wilkinson ST. 20-Year Trends in the Pharmacologic Treatment of Bipolar Disorder by Psychiatrists in Outpatient Care Settings. Am J Psychiatry. 2020 Aug 1;177(8):706-715.

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