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
- Update 5/1/2026: Read a new finding from this trial.
—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?
