Antidepressant Medicines Drive Weight Gain
It's a pervasive problem.
I was doing a TikTok live this week, as part of my mission to provide information for public health that isn’t the same as medical care. I was asked a question about antidepressant-induced weight gain. Readers will recall I’ve covered the oft-devastating metabolic toll of antipsychotic augmentation previously. I’ve also addressed the role of add-on sleep medicines in weight gain. I’ve also touched on some of the more pernicious agents in the psychiatric pharmacopeia, like Remeron, Zyprexa, Seroquel, and, of course, sugar. Welcome to The Frontier Psychiatrists, a health-themed newsletter.
Today, I address the question of whether antidepressants cause weight gain. I’m suspicious that there is a drug class-wide effect that drives metabolic syndrome. Most approval trials for oral medicines in Psychiatry are brief. 6 weeks. 8 weeks. Not years. Humans, on the other hand, live over a timeframe of years. Thus, side effects that are only going to be seen after the course of many years will not show up in a six or eight study. The FDA label doesn’t have to reflect side effects that didn’t happen in these trials. Only in rigorous post-marketing assessments do we discover serious adverse effects that are either 1. rare or 2. take a long time to show up.
One of those side effects is weight gain. Anti-depressant medications? I'm afraid to tell you, dear readers, that they lead to significant weight gain and contribute to metabolic syndrome at an individual and population level. These are not the only drugs that have this problem; some others do even more harm (Ahem, antipsychotics!)
The issue with looking at post-marketing data, of course, is that is is not randomized. Thus, causality is harder to suss out. This doesn’t mean it’s impossible, however. One of my favorite books for lay audiences is The Book of Why (amazon affiliate link), on the topic of causal inference in statistics. In short, the math to determine cause and effect exists, even in statistics1.
The data on longer-term use suggests that oral medicines demonstrate that exposure to antidepressants is at the least associated with obesity:
The authors in the above study are looking at a 12-month period of time. The vertical axis is % change in weight. They compare antidepressants of various kinds to 3 anti-obesity medicines as a kind of control (one of which, sibutramine, is now off the market). Of note, in the second row down, on the right side, is the lack of weight change for patients on chronic bronchodilators as a sort of control.
It’s a huge sample:
A total of 22,610 patients were included in the analysis (Figure 1), including 19,244 adult patients treated with an antidepressant for at least three months and 3366 patients receiving a nonpsychiatric intervention.2
In summary: only Wellbutrin (bupropion) has no appreciable risk of weight gain. This compound is also part of the weight loss combo drug Contrave (with naltrexone).
One issue that confounds the interpretation of this data is that weight gain happens naturally in people who lost weight because they were so depressed! Quoting Mauricio Fava, M.D.:
“weight gain during antidepressant treatment can be a sign of improvement who have weight loss as a symptom of lack of appetite.”3
And we would misunderstand depression to think this was never possible. However, it’s also worth recalling— some “depressed” people have appetite suppression. Some overeat. On average, in a large depression trial of those seeking treatment:
16% of the study sample experienced major weight gain during the 6-year follow-up.4
Thus, given the very large sample represented in the graphic above, the “depressed people start eating again” is likely to wash out. Similarly, we’d expect the same trend to be present in all effective antidepressants, including bupropion…but it’s not. On its own, it’s not a weight loss drug—so that is less likely to be the rationale.