April 29, 2026

expert reaction to RCT which looks at semaglutide and motivation in depression

A randomised controlled trial published in JAMA Psychiatry looks at semaglutide use and motivation in depression. 

Prof Ciara McCabe, Professor of Neuroscience, Psychopharmacology and Mental Health, University of Reading, said:

“This is an interesting first step examining the effects of semaglutide on motivation (effort for reward task) and suggests that GLP-1 R agonists might increase motivation in MDD. However, the study is limited by its small sample size and the absence of any anhedonia assessment. It would be interesting to see whether treatment effects were moderated by baseline depression severity, which would increase the generalizability and clinical applicability of the findings.”

Dr Atheeshaan Arumuham, Academic Clinical Fellow, Institute of Psychiatry, Psychology & Neuroscience (IoPPN), King’s College London, said:

“This is a well-conducted randomised, placebo-controlled study, and the authors are careful not to overstate what their data show. Namely, that this paper reports a secondary analysis of an existing trial, which was not originally designed to test whether semaglutide treats depression. Instead, the original trial examined how semaglutide affected cognitive dysfunction that is present in people with depression.

“Semaglutide is a GLP 1 receptor agonist, a class of medications better known to the public through drugs such as Wegovy and Ozempic, which are widely prescribed for weight loss and metabolic conditions. These drugs act on hormonal systems involved in appetite and energy balance, but growing evidence suggests they may also influence brain circuits linked to reward and motivation.

“The key finding in this study is that semaglutide appeared to improve motivation, measured using a laboratory-based task called the Effort Expenditure for Rewards Task. This task involves choosing on each trial between an easy option with a small, guaranteed reward and a harder option that requires more effort but offers a larger reward with a stated probability. This allowed researchers to see how willing someone is to expend effort when the payoff is higher. In previous studies using this task, patients with depression have been found to have less motivation to spend effort for higher rewards, while also being less able to weight up the information of the size and chance of getting the rewards.

“Rather than simply making people work harder in general, semaglutide shifted how participants weighed up effort against reward, making them more willing to engage in harder tasks when higher rewards were at stake. Further analysis suggested this was driven by a reduced perceived ‘cost’ of effort, rather than changes in how likely people thought they were to win a reward.

“This is clinically interesting because reduced motivation and difficulty initiating effort are among the most disabling and persistent features of depression. Many patients describe this as one of the aspects of depression least well addressed by existing treatments, even when mood symptoms improve, so understanding how motivation can be modified is an important research goal.

“However, this does not mean semaglutide is an antidepressant. The study was not powered to detect overall improvements in depressive symptoms, and changes in motivation were independent of changes in depression severity. In other words, the results speak to one specific process linked to depression, not to treatment of the disorder itself.

“The findings fit with growing biological evidence that GLP 1 drugs can influence brain systems involved in reward and motivation, such as dopamine pathways, but the clinical relevance remains uncertain. That said, there are important limitations, including the modest sample size, restriction to overweight or obese participants, and evidence of possible unblinding, all of which introduces bias to the study. This means the findings would benefit from being replicated taking these limitations into consideration.

“In real world terms, this study opens up promising research questions rather than changing clinical practice. Any suggestion that semaglutide should currently be prescribed to treat depression would be premature, but the work does help clarify how metabolic treatments might influence motivation, which remains a major unmet need in mental health care.”

Prof Stella Chan, Charlie Waller Chair in Evidence-based Psychological Treatment, University of Reading, said:

“This study showed that Semaglutide, when used in conjunction with usual treatment, can improve motivation in patients. Given that anhedonia (reduced pleasure in things we usually enjoy) is one of the core symptoms of clinical depression, these findings are encouraging. However, readers should be aware that these findings were based on a relatively small sample of depressed patients with Body Mass Index (BMI) over 25 and hence they should be treated with caution until more research on a wider range of patient populations is conducted.”

Dr Francesco Tamagnini, Neurophysiologist, University of Reading’s School of Pharmacy, said:

“GLP-1 receptors have long been investigated for their role in regulating motivation and mood. Their therapeutic use in weight management and type 2 diabetes extends beyond effects on glucose metabolism, as these agents also appear to influence motivational processes. This study provides a useful example of how randomised controlled trials can be expanded to assess outcomes that were not originally included in the study design. While the findings suggest that semaglutide may have potential as a treatment for major depressive disorder, they also open the way for broader investigations into the functional overlap between glucose metabolism and the regulation of mental functions, including motivation.”

‘Semaglutide and Effort-Based Decision-Making in Major Depressive Disorder’ by Hartej Gill et al. was published in JAMA Psychiatry at 16:00 UK time on Wednesday 29^th April. 

DOI: 10.1001/jamapsychiatry.2026.0594

Declared interests

Prof Ciara McCabe: Ciara has received funding from EPC flavoring Ltd. for her work on the neural response to taste rewards.

Dr Atheeshaan Arumuham: No conflicts of interest to declare.

Prof Stella Chan: No COI

Dr Francesco Tamagnini: No conflicts to declare.