The edition · Psychiatry
Semaglutide and metformin lead the evidence for antipsychotic weight gain
A network meta-analysis ranks weight-loss drugs in schizophrenia; ketamine outperformed midazolam in treatment-resistant bipolar depression; rapid relapse after stopping paliperidone looks like illness, not withdrawal; and GLP-1 agonists were associated with lower mortality in serious mental illness.
The edition in brief
A network meta-analysis of 95 randomised trials (5,898 people with schizophrenia on antipsychotics) found semaglutide produced the largest weight loss versus placebo (−11.0 kg, 95% CI −13.3 to −8.6), followed by liraglutide, topiramate, metformin (−3.9 kg, 16 trials) and exenatide, all at moderate certainty. Only semaglutide and metformin reached 5% weight loss. In the Ket-BD trial, 68 outpatients with treatment-resistant bipolar depression on a mood stabiliser or antipsychotic received four ketamine or midazolam infusions over two weeks; MADRS was 7.3 points lower with ketamine (−12.0 to −2.5), with no mania or psychosis. An individual-participant analysis of five paliperidone discontinuation trials found rapid relapse was no more common after stopping than during continued treatment, arguing against a pharmacological withdrawal effect and pointing to baseline severity. A target-trial emulation of 195,184 matched pairs with serious mental illness found GLP-1 receptor agonist initiation was associated with lower four-year mortality than SGLT2 inhibitors (4.91% vs 6.45%, HR 0.76), an observational finding that needs trials. FDA recorded a supplement to a generic olanzapine application from Macleods on 16 September; this is administrative, not a safety or efficacy action.
Four ketamine infusions lowered depression scores in treatment-resistant bipolar depression
In treatment-resistant bipolar depression on a mood stabiliser, a short ketamine course is a reasonable specialist option; do not expect evidence on durability yet.
Rapid relapse after stopping paliperidone tracked severity, not withdrawal
When deprescribing antipsychotics, use baseline severity to decide who needs the closest early monitoring.
GLP-1 agonists were associated with lower mortality than SGLT2 inhibitors in serious mental illness
When a patient with serious mental illness and diabetes needs a second agent, discuss a GLP-1 receptor agonist with their physician.
FDA records a supplement to a generic olanzapine application
No action needed: this is an administrative supplement to a generic olanzapine licence, not a safety finding.
Start metformin with the antipsychotic, not after the weight has gone on
In high-risk patients starting olanzapine or clozapine, consider metformin at initiation rather than waiting for weight gain.
For antipsychotic weight gain, semaglutide and metformin have the strongest case
Treat antipsychotic weight gain actively: start with metformin, and step up to semaglutide where needed and affordable.
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