Modern antidepressants could be effective for long-term treatment of some patients with bipolar disorder, a new trial suggests.

Current guidelines discourage use of antidepressants in these patients, over concerns that the drugs will trigger a manic episode.

But bipolar patients who remained on antidepressants for a whole year had fewer mood episodes than those who were switched to a placebo after two months, the investigators found.

These results “should change practice and it should convert more people that were nonbelievers to saying, yeah, at least for some patients, continuing antidepressants is a good strategy,” said lead researcher Dr. Lakshmi Yatham, head of psychiatry at the University of British Columbia, in Canada.

However, the clinical trial doesn’t provide cut-and-dried support for antidepressants.

The trial failed its primary goal of showing a statistically significant benefit for using antidepressants long-term versus short-term, because too few patients participated, noted Dr. Michael Thase, a psychiatrist with Penn Medicine in Philadelphia.

“You have an effect on the main primary outcome that is in the direction of a clinically meaningful effect in favor of staying on the antidepressants, but it’s below the threshold of statistical significance because the study didn’t get to the size that it was supposed to be,” explained Thase, who was not part of the research.

Depressive episodes are of great concern to doctors because they bring with them an increased risk of suicide. Suicide attempts and deaths are at least 18 times more common during depressive episodes than manic episodes in bipolar patients, the researchers said in background notes.

Yatham and his colleagues conducted the new trial because recent surveys have shown that nearly three in five bipolar patients are being prescribed antidepressants, despite guidelines discouraging their use.

“They’re quite commonly used, regardless of what experts think,” Yatham said.

In fact, Yatham was the lead author of the Canadian guidelines for bipolar disorder, which are the most recent North American treatment guidelines.

“The concern has always been among us experts, are the antidepressants going to switch people from depression to mania? The drugs might pull them out of the depression, but will this switch them into mania?” Yatham said.

Experts also have been concerned that the drugs might promote rapid cycling among bipolar patients, causing them to swing in and out of mood episodes as they swing between depression and mania, he added.

But these concerns are based on the effects that older tricyclic antidepressants produced in bipolar patients, Yatham noted.

Modern antidepressants like selective serotonin reuptake inhibitors (SSRIs) might be more effective, particularly if they are prescribed in conjunction with mood-stabilizing drugs aimed at controlling manic episodes, Yatham said.

The clinical trial enrolled 178 patients with bipolar disorder who had just recovered from a depressive episode following treatment with a modern antidepressant.

The patients were randomly assigned to continue antidepressant treatment for 52 weeks, or to begin tapering off the drugs at six weeks and switch to a placebo by eight weeks.

Analysis of the full 52-week period found no statistically significant benefit for staying on the drugs long-term. About 46% of placebo patients had a mood relapse, versus 31% of those on long-term antidepressants.

But when researchers focused on the specific period during which patients were taking either a placebo or an antidepressant, a benefit did emerge, Yatham said.

“When we look at the data from week six onwards, 27% of patients in the 52-week group had a relapse of a mood episode versus 45% in the 8-week group, and that difference is significant statistically,” he said. “In other words, when both groups are receiving different treatment, there is a difference between the groups.”

Differences in depressive and manic episodes also emerged in closer analysis of the data, Thase noted.

Only 17% of patients in the 52-week group had a depressive event, compared with 40% in the 8-week group, and that “was a statistically significant finding,” Thase said.

Patients on long-term antidepressants also had a higher risk of a manic episode — 12% versus 6% — but Thase pointed out that the actual number of patients who swung manic was small and statistically insignificant.

In the trial, 11 patients in the long-term antidepressant group had a manic event versus 5 in the short-term group.

“It’s a little risk, but it is an apparent risk,” Thase said. “You would need to do an 800-patient study to be able to declare that that doubling of the risk is statistically significant.”

Overall, experts “will be unlikely to advocate a change in the next practice guidelines on the basis of this finding of the study, because it did not have a statistically significant protective effect on the main outcome,” Thase said.

The study was published Aug. 3 in the New England Journal of Medicine.

Yatham believes the findings might not change the minds of naysayers, but they do provide support for those doctors who’ve chosen to prescribe antidepressants to bipolar patients despite treatment guidelines.

“I think a lot of clinicians are going to look at our study and say, ‘Yep, you know, I’ve been right, because these medicines stop depression and that’s why I’ve been using these things,’” Yatham said.

However, he emphasized that antidepressants should not be used by themselves.

“If anyone says you should think about using antidepressants for bipolar disorder, the recommendation would be not to use them as monotherapy on their own, but use them in conjunction with a mood-stabilizing agent such as lithium or valproate or antipsychotics, all of which are supposed to stop manias,” Yatham said.

More information

Here’s more on bipolar disorder.

SOURCES: Lakshmi Yatham, MBBS, head, psychiatry, University of British Columbia, Vancouver, Canada; Michael Thase, MD, psychiatrist, Penn Medicine, Philadelphia; New England Journal of Medicine, Aug. 3, 2023