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Using Antidepressants in Patients With Bipolar Disorder

September 23, 2020

(Part 3 of 5)

In this video, Joseph F. Goldberg, MD, explains the role of antidepressants in the treatment of bipolar disorder, including when their use may be acceptable and when they should be avoided.

Dr. Goldberg, Clinical Professor of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, gave a presentation at Psych Congress 2020 titled "Tailoring Individualized Pharmacotherapy for Bipolar Disorder: How to Translate Findings from Clinical Trials to a Single Patient."


Read the transcript:

It's often been said that in the world of bipolar disorder, depression is most oftentimes the more dominant mood state that we contend with. It's only been fairly recently that we've had FDA‑approved treatments for the depressed phase of bipolar illness.

Presently, there are 4 FDA‑approved treatments. Lurasidone, cariprazine, olanzapine‑fluoxetine combination, and quetiapine are all FDA‑approved treatments. We have more limited data with other kinds of treatments. Lamotrigine has some off‑label data. Other mood stabilizers have some off‑label data. Some of the other second‑generation antipsychotics, some but not all, have some off‑label data.

How about antidepressants? The real 2 key questions in using antidepressants in bipolar disorder are number one, "Are they safe?" and number two, "Are they effective?" I guess number three is "Do we have enough information to know with certainty if there's a class effect?"

We don't have a class effect with second‑generation antipsychotics when it comes to bipolar depression. Some work, and some don't. We sure don't have a class effect with mood stabilizers when it comes to bipolar depression. Many work more on mania than on depression. Really, lamotrigine is an exception. It works better for depression than for mania.

Is it fair to even assume a class effect with antidepressants? We have SSRIs. We have SNRIs. We have novel drugs like bupropion or mirtazapine. We have the older tricyclic antidepressants. We have MAOIs.

Just one caveat to all this is it's hard to know if there's really a class effect. What we do know is that of the fairly small number of SSRIs, mainly that have been studied in placebo‑controlled trials.

There have not been placebo‑controlled trials with any SNRIs. There have not been many placebo‑controlled trials with bupropion. There have been no placebo‑controlled trials with mirtazapine. There are no controlled trials at all with the newer antidepressants, such as vortioxetine or vilazodone.

With those caveats, we can say that of the small database for the older early SSRIs, there's no clear signal that they're beneficial. That is to say that the chance of success on an overall basis is really not notably better than just using a mood stabilizer alone.

The biggest of studies, the STEP‑BD trial, would say about a 1 in 4 chance you'll get undepressed with a mood stabilizer. Adding on an antidepressant doesn't really change that very much.

Concept called the Number Needed to Treat. How many people do you have to expose to a treatment before you will see an improvement? A big meta‑analysis said with antidepressants, it's a fairly high number, it's 29. You've got to treat 29 people before you're going to see a success. That's the efficacy question.

Then the safety question is, "Do they make you manic, or do they speed your cycles over time?" The answer there seems a little more comforting. While there was a time where our field was mainly concerned that antidepressants posed a hazard for inducing destabilization, that can happen, but it's hard to know if that's different from the natural course of illness.

The best way to know is to do a prospective placebo‑controlled study. Meta‑analyses would say that if you line up a lot of those studies, the chance of saying you're going to get into a mania when you take an antidepressant, compared to just taking mood stabilizer alone, isn't that high. It's about 12 percent.

Put another way, the Number Needed to Harm. How many people do you give an antidepressant to in the bipolar world before somebody has an undeniable mania? It's pretty high. It's about 200. That means you've got to treat 200 people before you're going to see somebody incontrovertibly get manic or hypomanic with an antidepressant.

In other words, for most depressed bipolar patients, antidepressants are not that relevant. They neither help nor hurt. Where does that leave us? It leaves us with asking, "Are there any clinical characteristics that might guide our thinking?"

Are there any subtypes of patients where antidepressants are more useful or less useful rather than an all‑or‑none, "are they good or are they bad" kind of way?

Here's what we know. Antidepressants are not a wise idea in somebody who's manic. You don't need an antidepressant while you're manic. If there are mixed features present, antidepressants can inflame even low‑grade mania symptoms without helping the depression symptoms.

In bipolar patients with many episodes per year, rapid cycling, antidepressants have never been shown to help and may make things worse. In people with recent mania or hypomania, antidepressants could make things worse, destabilize mood.

In people that have historically gotten manic with an antidepressant, they may have a higher risk, maybe even a genetic vulnerability, for antidepressants to destabilize mood. There's some pharmacogenetics data for the serotonin transporter speaking to that.

In people with a history of substance abuse, the risk is somewhat higher for mood destabilization. Some studies would say in bipolar I depression, antidepressants pose a higher hazard for destabilization than bipolar II.

What does that mean? It means the next pure depressed phase, non‑mixed, non‑rapid cycling, non‑substance‑abusing, not recently manic, never antidepressant‑induced mania, bipolar II patient that you encounter who's now depressed might be a candidate for an antidepressant, but that's small minority of patients.

Last but not least, initial response counts for a lot. It always does in psychopharmacology, but there's some nice research saying if a bipolar depressed patient takes an antidepressant and they have a very robust response and no signs of mania, that bodes very well for staying well on that regimen.

Whereas anything less than a robust response, a partial improvement, a nonimprovement, sticking around with the antidepressant is of no value. It will not kick in months later. It's not going to make you undepressed more so down the road if it doesn't do it up front. It may even increase the chance of seeing more cycles of either polarity over time.

Carefully judge an acute response. Judge a patient's candidacy for antidepressants. Pay attention to these risk factors for destabilization. Keep in mind the role of the FDA‑approved treatments which are much more standard of care.


More with Dr. Goldberg:
Clinical Characteristics Affecting Response to Bipolar Disorder Treatment
Optimizing Response to Bipolar Disorder Treatment


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