Q&A: The Risks of Long-Term Antidepressant Treatment

Charles Raison, MD

Psych Congress cochair Charles Raison, MD, sees big changes coming in the treatment of depression. At Psych Congress 2019, he will discuss how the limitations of standard antidepressants could help set the stage for a new generation of interventions.

Here, in part 2 of a 4-part Q&A series, Dr. Raison discusses the problems which can result from long-term antidepressant treatment. Check back soon at DepressionCare360 for part 3, in which he details the factors clinicians should consider when trying to decide whether to continue or stop an antidepressant treatment in a patient.

Go to Part 1: The Role of Antidepressants in the Treatment of Depression

Dr. Raison is the Mary Sue and Mike Shannon Chair for Healthy Minds, Children & Families; Professor, Human Development and Family Studies, School of Human Ecology; and Professor, Department of Psychiatry, School of Medicine and Public Health, University of Wisconsin- Madison. He is also Director of Clinical and Translational Research for the Usona Institute, which conducts research on the therapeutic effects of psilocybin.

His session, “Faded Love: A Critical Look at the Strengths and Weaknesses of Antidepressants for the Treatment of Major Depression,” will be held from 4:15 p.m. to 5:30 p.m. on Saturday, Oct. 5. 

Q: What problems can result from long-term antidepressant treatment?

A: There is circumstantial evidence that long-term antidepressant treatment in some patients may actually induce treatment resistance, so that the longer you take it, you become more and more resistant to antidepressants in general. We have some evidence that the longer you take it, the more dependent your brain becomes upon it not to get depressed.

So in other words, over time there's what's called oppositional tolerance; the brain pushes back against the changes that are being induced by the antidepressant and when that happens, sometimes the brain overrides those changes and the person gets depressed again, even on the medicine. If the brain overrides the effects while the person is on the antidepressant, they can start getting depressed even while they're on the antidepressant. There's data showing that lots of people over time need higher and higher doses of the antidepressant.

There's not very good data that early in treatment, the higher doses of SSRIs are better than lower doses. But there are data showing that over time many people who are on an antidepressant and lose a response at one dose will get it again if you increase the dose. That's a little bit like an opioid, right? That means that your brain is compensating against the medicine in ways that require higher doses of the medicine to overcome the compensation.

Go to Part 3: Deciding When to Stop an Antidepressant

That seems to be a pattern you see with all medications in the serotonergic system that are chronically active at the receptor, as antidepressants are, as opposed to things that are episodic, which actually may induce the opposite effect. The hope is that some of these new treatments will push the brain in a way where the brain becomes more well all on its own without the antidepressants.

That really is the core behind this talk [at Psych Congress.] There's tons of information about what we know about the limitations of antidepressants: How well do they work? Who do they respond for? What should we do if you don't respond? What do we know about their risks in terms of preventing relapse? What do we know about the risks in terms of accelerating the recurrence of depression in some people? What do we know about the risks of relapse when we discontinue them?

We go into all this, but it's really in the service of articulating a vision of the future based on what's happening now with these new agents. The limitations of how we use antidepressants themselves point to a profound paradigm shift I believe that we're right on the edge of in psychiatry and this talk is about that paradigm shift.

—Terri Airov