The edition · Psychiatry
Semaglutide and metformin lead for antipsychotic weight gain, and ketamine helps treatment-resistant bipolar depression
A 95-trial network meta-analysis ranks the options for antipsychotic-associated weight gain; a midazolam-controlled trial supports ketamine in bipolar depression without switching to mania; and paliperidone discontinuation data question the idea of rebound relapse.
The edition in brief
Five findings for psychiatrists. A network meta-analysis of 95 randomised trials (5,898 people with schizophrenia-spectrum disorders on antipsychotics) found semaglutide (-10.98 kg), liraglutide (-5.43 kg), topiramate (-3.95 kg), metformin (-3.86 kg) and exenatide (-2.97 kg) produced the largest weight reductions against placebo, all with moderate certainty. The Ket-BD trial randomised 68 outpatients with treatment-resistant bipolar I or II depression to four ketamine or midazolam infusions over two weeks; ketamine lowered MADRS by 7.3 points more (95% CI -12.0 to -2.5), with no mania, hypomania or psychosis in either arm. A target trial emulation in TriNetX found GLP-1 receptor agonist initiation, versus SGLT2 inhibitors, was associated with lower four-year mortality in people with serious mental illness (4.91% vs 6.45%, HR 0.76), though residual confounding is likely. An individual participant data analysis of five paliperidone discontinuation trials found rapid relapse was not over-represented after stopping medication, arguing against a common pharmacological rebound. A perioperative trial in 306 older surgical patients found combined psychological and medication optimisation reduced depression and anxiety scores modestly at three months, with the benefit concentrated in cancer surgery.
Ketamine infusions beat midazolam in treatment-resistant bipolar depression, without switching
In bipolar depression that has failed two treatments, a short course of adjunctive IV ketamine is a reasonable specialist option with antimanic cover in place.
GLP-1 receptor agonists were associated with lower mortality than SGLT2 inhibitors in serious mental illness
This association supports raising GLP-1 receptor agonists when metabolic treatment is considered in serious mental illness, but it does not prove they save lives.
Rapid relapse after stopping paliperidone was not more common than during continued treatment
When deprescribing, monitor most closely those whose illness was more severe before stabilisation; fast relapse tracked severity, not stopping.
Perioperative mental health care modestly reduced depression and anxiety in older surgical patients
Screen older surgical patients for depression and anxiety before surgery, and prioritise liaison input for those having cancer operations.
Weigh at the first antipsychotic review, not the sixth
Weigh at baseline and at 12 weeks after starting an antipsychotic, and act on a 5% gain rather than waiting for obesity to appear.
For antipsychotic-associated weight gain, semaglutide and metformin have the best evidence
Treat antipsychotic weight gain actively: metformin first for most, semaglutide for the largest loss, rather than accepting it.
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