It takes off weight, but fails to improve cognition or depression
STUDY: Badulescu S et al, Med 2026;7:100916, PMID: 39826355
STUDY TYPE: Randomized, double-blind, placebo-controlled trial
FUNDING: Physicians’ Services Incorporated Foundation
Background
There are many ways that metabolic health impairs mood and cognition: insulin resistance, obesity, inflammation, and vascular disease. In line with that, a large body of research links GLP-1 receptor agonists to better mood and cognition, including uncontrolled trials in depression. But the first randomized trial makes a break with that line.
The Study
Seventy-two overweight adults with major depression and cognitive impairment were randomized to oral semaglutide (titrated to 14 mg/day) or placebo for 16 weeks, added to their existing regimens. The primary outcome was an executive function composite score (Digit Symbol Substitution Test, Stroop, n-back). Secondary outcomes included global cognition, functioning, depressive symptoms, and body weight.
Semaglutide did not improve executive function (adjusted Z score difference: 0.32, p = 0.60) or depression:
It did, however, cause weight loss in this obese population (losing 5.2 kg versus a 1 kg gain on placebo, p < 0.001):
That is surprising, given most intervention that improve weight also provide at least a little boost to mood and cognition. In secondary analyses, semaglutide did improve global cognition (adjusted Z score difference: 2.39, p = 0.03) — and this effect was fully mediated by weight loss. Functioning improved as well, also tracking closely with weight loss.
Gastrointestinal side effects were common — nausea in 69% of the semaglutide group versus 14% on placebo — but no serious adverse events occurred.
Practice Implications
- GLP-1 agonists are wonder drugs for weight, but their psychiatric promise is unfulfilled
- This negative trial joins a handful of other small randomized trials where GLP-1 agonists failed in dementia, addictions, and binge eating, although each of those disorders has positive signals as well, making conclusions murky
—Chris Aiken, MD
Director, Psych Partners
Editor in Chief, Carlat Psychiatry Report
What’s Your Take? Share in Comments
- Are you seeing psychiatric benefits with GLP-1 agonists?
- How do you interpret negative trials when anecdotal data — or your own experience — is positive?
