Anhedonia — the loss of drive rather than the presence of sadness — is the part of depression that responds worst to existing drugs. A randomized trial at a Toronto mood disorders unit tested whether semaglutide changes it, in 72 adults with major depressive disorder and a BMI of 25 or above, randomized to oral semaglutide 14 mg or placebo alongside whatever treatment they were already on [1]. The observational literature on these drugs and mood is messier, as depression risk against two comparators shows.
The measure was the Effort-Expenditure for Rewards Task, in which people repeatedly choose between an easy option for a small payout and a hard one for a larger payout at some stated probability. Participants on semaglutide became more willing to take the hard option as the expected value rose, with a treatment by visit by expected value interaction reaching P = .02.
Computational modeling then split that into parts, and this is where the result becomes interesting rather than merely positive. Sensitivity to effort fell significantly on semaglutide (β = -1.737, P = .03), meaning the cost of trying felt lower. Sensitivity to probability did not move (β = -0.776, P = .51). A drug that simply made people press more buttons, or feel generally better, would be expected to shift both.
The scale deserves equal weight. Seventy-two people at one center, split 35 and 37, with the result coming from a secondary analysis — preregistered, which matters a great deal, but still one task in one small trial. The journal's title calls it a randomized clinical trial and the abstract calls it a secondary analysis; both are accurate and the second is the one that should govern how much is built on it.
What makes it worth reporting anyway is that it is a mechanism claim with a null attached, tested prospectively against placebo, in a population where the drug was not being given for weight. That is a rarer thing in this field than the volume of publication suggests, and it sits alongside the other evidence that these drugs act on reward circuitry rather than only on the stomach — the appetite side of which is in nausea and appetite on one circuit, and the substance-use side in what happens when you stop and the overdose comparison.