Clozapine and olanzapine cause substantial weight gain and are frequently not substitutable, because for many people they are the antipsychotics that work. That leaves a population carrying drug-induced obesity with no option to simply stop the cause. A 24-week open-label study tested semaglutide in that group and, unusually, kept following them afterwards[1].
During treatment it worked about as expected. Weight fell 9.8% on an intention-to-treat basis (95% CI -12.7% to -6.8%), around 10.1 kg, with waist circumference down 7.3%. HbA1c fell too but did not reach significance (P = 0.055). The dose was 1.0 mg weekly, which is a diabetes dose rather than the 2.4 mg used for weight management, so these figures are not comparable to obesity-trial numbers — a distinction that changes the ranking of these drugs, as the network meta-analysis of nineteen drugs sets out.
The scale demands caution about all of it. Twenty-six people enrolled, 17 completed the intervention and 15 completed the trial, with no control group and no blinding. In a population where medication adherence is the central clinical difficulty, a 65% completion rate is itself a finding, and it means the weight figures describe those who stayed.
One result points in an unexpected direction. Gut microbial alpha diversity — a broad measure of how many different organisms are present — decreased as time on semaglutide increased, with enrichment of one particular species. Lower diversity is usually characterized as unfavorable in metabolic research, so this is not the result the field would have predicted. Nobody measured a health outcome from it, so it is an observation rather than a harm, and it belongs alongside the other things these drugs turn out to do that nobody designed them for, as in the inflammation substudy.
What this does establish is feasibility in a group usually excluded from obesity trials altogether: nurse-administered treatment in a public mental health setting produced real weight loss in people taking the most metabolically damaging antipsychotics. Whether it should be continued indefinitely rather than for 24 weeks is the question the 76-week figure raises and cannot answer — the same question running through what happens when you stop and the effort and reward trial.