Treatment with semaglutide appears to improve glycaemic control and weight outcomes in patients with schizophrenia receiving second-generation antipsychotics, as shown in a study.
After 26 weeks of treatment, HbA1c levels decreased by 0.25 percent (95 percent confidence interval [CI], −0.33 to −0.16) with semaglutide vs placebo (p<0.001). Notably, 43 percent of semaglutide-treated participants achieved low-risk HbA1c levels (<5.4 percent) as opposed to only 3 percent of those who received placebo. [JAMA Psychiatry 2025;doi:10.1001/jamapsychiatry.2025.3639]
Compared with placebo, semaglutide was also associated with significantly greater reductions in body weight (−9.2 kg, 95 percent CI, −13.3 to −5.1; p<0.001), waist circumference (−7 cm, 95 percent CI, −10.6 to −3.3; p<0.001), and fat mass (−6.1 kg, 95 percent CI, −10.2 to −1.9; p=0.006).
There were no differences observed in lipid levels, liver function, blood pressure, or psychiatric symptoms.
“These findings underscore the potential utility of GLP-1RAs as early interventions to mitigate the substantial metabolic burden associated with second-generation antipsychotics, particularly clozapine and olanzapine,” the investigators said.
They emphasized that GLP-1RAs may offer additional therapeutic potential by addressing nicotine dependence, as evidenced by semaglutide treatment reducing the Fagerström Test for Nicotine Dependence scores compared with placebo (mean difference, –1.4, 95 percent CI, –2.7 to –0.1). This has important implications, given the high prevalence of smoking and substance use among individuals with schizophrenia. [Addict Health 2009;1:38-42; Br J Pharmacol 2022;179:625-641]
“We did not observe a clear effect of semaglutide on alcohol or drug use,” they noted.
The analysis included 73 adult participants (mean age 35 years, 65 percent female, mean BMI 36.1 kg/m2) with schizophrenia spectrum disorders who were initiated on clozapine or olanzapine treatment within the past 5 years. All of them had early-stage glycaemic dysregulation (HbA1c of between 5.4 percent and 7.4 percent) and were not receiving antidiabetic therapy.
The participants were randomly assigned to receive semaglutide 1 mg or matching placebo, administered subcutaneously once weekly for 26 weeks as an adjunct to second-generation antipsychotic therapy. The primary outcome was change in HbA1c level from baseline to week 26. A total of 57 participants (78 percent) completed the trial.
In terms of safety, gastrointestinal adverse events were frequently reported in both treatment arms. Nausea occurred in 47 percent of participants in the semaglutide arm and in 41 percent of those in the placebo arm. Vomiting was reported in 39 percent and 14 percent, and constipation in 33 percent and 19 percent, respectively.
Serious adverse events occurred in 14 participants in the semaglutide arm and 16 in the placebo arm. Treatment was discontinued prematurely in eight participants in each treatment arm, with four participants in the semaglutide arm discontinuing due to adverse events. One participant who received semaglutide had a sudden cardiac death that was not related to treatment.
“This study contributes novel data to an underserved field and may help inform future preventive and therapeutic applications of GLP-1RAs in psychiatry,” the investigators said.
However, they also acknowledged several barriers to using the drugs in psychiatry. First is the lack of large-scale trials specifically evaluating the effects of GLP-1RAs in individuals with antipsychotic-induced metabolic disturbances. Another is the high cost of GLP-1RA therapy, which limits access, particularly among people with severe mental illness who already face multiple structural barriers to care.
“As patents expire and generic formulations become available, costs may decrease. In the meantime, public health systems should consider subsidizing GLP-1RA therapy for high-risk psychiatric populations, particularly individuals treated with clozapine, where switching to an antipsychotic medication with lower cardiometabolic risk is often not viable,” they said.