Weight gain is one of the most common and medically serious side effects of certain antipsychotic medications. For people living with schizophrenia, this added weight can raise the risk of heart disease and metabolic problems on top of an already demanding condition. Researchers have increasingly asked whether peptide-based treatments could address that burden without adding new complications.
A recent open-label trial published in Schizophrenia Research followed 26 adults with schizophrenia who were taking either clozapine or olanzapine, two antipsychotics strongly associated with weight gain. The study ran for 76 weeks total, including a 24-week semaglutide intervention followed by a full year of post-intervention follow-up. Alongside the weight data, the research team also tracked changes in the gut microbiome, an angle that is still relatively new in this area of psychiatry.
The peptide studied here, semaglutide, belongs to a class called GLP-1 receptor agonists. These compounds mimic a hormone the gut naturally releases after eating, influencing appetite signaling and glucose metabolism. What makes this trial notable is the specific population: people with a serious mental illness, managed in a public mental health setting, who are often excluded from mainstream metabolic research.
Trial design and participants
Participants were adults with schizophrenia who did not have diabetes but who had a body mass index above 27 kg per square meter, meaning they were classified as overweight or obese. The average age was 41.5 years, and 65.4 percent of participants were female. All were already receiving either clozapine or olanzapine as part of their psychiatric care.
The intervention itself lasted 24 weeks. For the first eight weeks, the dose was gradually increased to allow the body to adjust. The following 16 weeks used a full weekly dose of 1.0 mg, administered by a nurse in the clinical setting. After the intervention ended, researchers continued to track participants for an additional year, bringing the full trial window to 76 weeks. That follow-up period was designed to see what happened to the weight changes once the peptide was discontinued.
Weight and waist circumference findings
By the end of the 24-week intervention, the intention-to-treat analysis showed an average body weight reduction of 9.8 percent, which translated to roughly 10.1 kilograms. The 95 percent confidence interval ranged from 6.8 to 12.7 percent reduction, and the result was statistically significant. Waist circumference also fell by an average of 7.3 percent, again with a statistically significant result.
Glycated hemoglobin, a measure of average blood sugar levels over several months, showed a reduction of 5.3 percent, but this did not reach statistical significance. The researchers noted a trend in that direction without drawing firm conclusions from it.
The longer view was also informative. At the 76-week mark, one year after the intervention ended, participants who completed the trial still showed an average body weight reduction of 5.1 percent from their original baseline. That is a meaningful retention of benefit, but it was about half the reduction seen at 24 weeks, pointing to some attenuation of effect after the peptide was stopped.
Completion rates and tolerability
Of the 26 people who started the intervention, 17 completed the full 24 weeks, giving a completion rate of 65.4 percent. That figure is not unusual for this kind of trial in a population with complex needs, though the researchers acknowledged it as a limitation when interpreting the results. Among those 17 who completed the intervention, 15 went on to complete the 76-week follow-up, a retention rate of 88.2 percent.
The study was open-label, meaning both participants and clinicians knew what was being administered. This is a common approach in early-phase or feasibility research, particularly when working in community mental health settings where blinding can be logistically difficult. The open-label design does introduce the possibility of expectation effects on some secondary outcomes, and the researchers were transparent about this.
Gut microbiome observations
One of the more novel elements of this trial was the collection of microbiome data at three points: baseline, 10 weeks into the intervention, and at the 24-week endpoint. The researchers measured alpha diversity, a term that refers to the variety of different microbial species living within a single individual's gut.
The data showed that alpha diversity decreased as time on semaglutide increased. This is a somewhat counterintuitive finding, since higher microbial diversity is generally associated with better metabolic and immune health in the broader literature. However, the researchers also observed an enrichment of a specific bacterium called Parasutterella excrementihominis. The literature suggests this organism may be associated with certain favorable metabolic states, though the picture is still being worked out in ongoing research.
The authors framed these microbial compositional changes as potentially consistent with improvement in health outcomes, while being careful not to overclaim. The microbiome findings are exploratory and would need replication in larger, controlled studies before stronger conclusions could be drawn. What the data does suggest is that GLP-1 receptor agonists may exert some of their effects partly through changes in gut ecology, an area that researchers are actively investigating.
What happens after the peptide stops
The 76-week follow-up was designed specifically to address a practical question: does the weight reduction persist after semaglutide is discontinued? The answer from this trial is a qualified yes, with an important caveat. While participants still showed meaningful weight loss compared to where they started, the degree of reduction fell from roughly 10 percent at 24 weeks to around 5 percent at 76 weeks.
This attenuation after discontinuation is consistent with what the broader GLP-1 literature has observed in other populations. It raises questions about optimal duration of treatment and what supportive strategies might help people maintain benefits once the intervention ends. For a population already managing a complex psychiatric condition, those downstream questions carry real practical weight.
The researchers noted that this pattern does not necessarily diminish the value of the intervention. Even a sustained 5 percent reduction in body weight carries recognized cardiometabolic significance according to the existing literature on metabolic health, particularly for individuals at elevated baseline risk.
Limitations and next steps
The study was small, with 26 participants at the outset and fewer completing each phase. Without a control group receiving a placebo, it is not possible to fully separate the effects of semaglutide from natural variation, seasonal changes in behavior, or other factors. The open-label design adds a further layer of interpretive caution.
Despite these limitations, the trial contributes to a relatively sparse evidence base for metabolic interventions in people with serious mental illness. The combination of weight data, cardiometabolic markers, and microbiome sampling within a single study offers a more complete picture than any of those elements alone. The authors called for larger, randomized controlled trials to confirm these findings and to explore the microbiome changes in more depth.
