Clozapine Weight Gain: What Metformin, Semaglutide, and Aripiprazole Have Shown

Creator: Ryan S. Sultan, MD
Published: 2026-11-12

By Ryan S. Sultan, MD
Psychiatrist · Columbia University Irving Medical Center
Published November 12, 2026 · 5-minute read

Weight gain on clozapine is common. In the pooled studies in the prescribing information, 236 of 669 adults with schizophrenia taking clozapine (35%) gained at least 7% of their body weight, over a median exposure of 609 days.¹ In a Canadian chart review of 396 patients starting clozapine, those not taking metformin had gained an average of 2.99 kg at 6 months and 4.72 kg at 12 months.²

Metformin, GLP-1 receptor agonists such as semaglutide, and aripiprazole have each been tested in randomized trials in people taking clozapine.

How much weight, and what happens to blood sugar

A 2020 network meta-analysis of 100 randomized trials, with a median treatment duration of 6 weeks, compared 18 antipsychotics. Clozapine was at the high end of the range, with 3.01 kg more weight gain than placebo and the largest rise in glucose.³

In a five-year naturalistic study of 82 outpatients on clozapine, weight gain continued until approximately month 46, and 30 patients (36.6%) were diagnosed with diabetes during follow-up.⁴ The label states that precise risk estimates for hyperglycemia with atypical antipsychotics aren't available, and it recommends monitoring weight during treatment.¹

Metformin lowered weight by about 3 kg, and the loss reversed after stopping in one trial

A 2016 meta-analysis pooled 8 placebo-controlled studies with 478 participants who were taking clozapine and did not have diabetes. Metformin produced 3.12 kg more weight loss than placebo (95% CI, 1.37 to 4.88 kg) and improved waist circumference, fasting glucose, and triglycerides.⁵

In a 24-week trial of 55 clozapine-treated patients randomized to metformin 1,500 mg/day or placebo, 8 patients on metformin (28.57%) lost more than 7% of their body weight. Mean body weight returned to baseline after they stopped it.⁶

Starting metformin at the same time as the antipsychotic

A 2025 guideline recommends starting metformin alongside an antipsychotic, or adding it when certain criteria are present. It states that starting the two together can reduce weight gain by 4.03 kg compared with controls.⁷ The same estimate appears in a Cochrane review, from 4 studies with 131 participants, rated as low-certainty evidence.⁸

A randomized trial of this approach at clozapine initiation closed early because of COVID-19 restrictions. Ten people were randomized to each group, and 8 on metformin and 5 on placebo completed. The difference in weight change, 0.09 kg with metformin and 2.88 kg with placebo, was not statistically significant (p = 0.231).⁹

In the Canadian chart review, patients co-prescribed metformin had lost an average of 0.67 kg at 12 months, compared with the 4.72 kg gain on clozapine alone. That comparison is observational.²

Semaglutide and other GLP-1 drugs lowered weight in four trials

Randomized trials of GLP-1 receptor agonists in people taking antipsychotics
Trial	Who was studied and what happened to weight
COaST 2025, semaglutide up to 2.0 mg weekly	31 adults with schizophrenia and obesity, all taking clozapine, randomized before recruitment stopped early. At 36 weeks, body weight fell 13.88% with semaglutide and 0.42% with placebo
Sass 2026, semaglutide	73 adults who had started clozapine or olanzapine within the past 5 years. At week 26, weight was 9.2 kg lower with semaglutide than with placebo
HISTORI 2025, semaglutide up to 1.0 mg weekly	154 adults with schizophrenia, prediabetes, and overweight or obesity on second-generation antipsychotics. Over 30 weeks, semaglutide reduced body weight by 9.21 kg
Larsen 2017, liraglutide	103 adults with prediabetes taking clozapine or olanzapine. Over 16 weeks, weight was 5.3 kg lower with liraglutide than with placebo

Sources: published trial reports.^{10, 11, 12, 13}

COaST enrolled only people taking clozapine. It randomized 31 of an intended 80 participants, because recruitment was suspended when the study drug became unavailable. No differences were observed in clozapine or norclozapine concentrations or in psychosis scores.¹⁰

The Sass trial and HISTORI were designed around blood sugar, with HbA1c as the primary outcome. HISTORI's abstract doesn't specify how many participants were taking clozapine.^{11, 12} Neither trial found a difference in psychiatric symptoms.^{11, 12} In HISTORI, a few semaglutide-treated patients were hospitalized more often than in the placebo group, and the number of serious adverse effects did not differ.¹²

In pooled data from three earlier trials of exenatide and liraglutide, nausea occurred in 53.6% of treated patients and 27.5% of controls.¹⁴

Aripiprazole added to clozapine: 1 to 2 kg in randomized trials

In a 16-week trial of 207 patients, adding aripiprazole 5 to 15 mg/day to clozapine produced 2.15 kg more weight loss than placebo, with no significant difference in total symptom scores.¹⁵ A meta-analysis of four trials (N = 347), three of which reported weight, put the difference at 1.36 kg and found that the combination was associated with agitation or akathisia.¹⁶ In a 2026 cohort of 80 inpatients, metformin was associated with less weight gain over time and aripiprazole was not.¹⁷

Limitations of the evidence

This evidence has limitations. First, the trials measured weight, glucose, and lipids over 36 weeks or less. Second, the semaglutide trial limited to clozapine randomized 31 people and stopped recruiting early, and in one trial metformin's benefit reversed when it was stopped. Nevertheless, the randomized trials point in the same direction, and weight gain on clozapine is a reason to raise these options with the prescriber.

The side effects page covers the rest of the monitoring, and the page on missed doses covers what happens after a gap. Stopping clozapine over weight is a decision made with the prescriber.

Frequently asked questions

How much weight do people gain on clozapine?

In pooled label data, 35% of adults on clozapine gained at least 7% of their body weight over a median exposure of 609 days. In a Canadian chart review, patients starting clozapine without metformin had gained an average of 2.99 kg at 6 months and 4.72 kg at 12 months.^{1, 2}

Does metformin help with clozapine weight gain?

In a meta-analysis of 8 studies with 478 participants on clozapine, metformin produced 3.12 kg more weight loss than placebo. In one 24-week trial, mean body weight returned to baseline after metformin was stopped.^{5, 6}

Can you take Ozempic (semaglutide) with clozapine?

In COaST, a small trial limited to people taking clozapine, 31 adults were randomized before recruitment stopped early. Body weight fell 13.88% with semaglutide and 0.42% with placebo at 36 weeks. The decision belongs with the prescriber.¹⁰

Does semaglutide affect clozapine blood levels?

In the COaST trial, no differences were observed in clozapine or norclozapine concentrations or in psychosis scores. The trial randomized 31 people and stopped recruiting early.¹⁰

Does adding aripiprazole (Abilify) to clozapine help with weight?

In a 16-week trial of 207 patients, adding aripiprazole to clozapine produced 2.15 kg more weight loss than placebo. A meta-analysis of four trials, three of which reported weight, put the difference at 1.36 kg.^{15, 16}

In a crisis: call or text 988, or go to the nearest emergency department. A first episode of psychosis belongs in a hospital-based or coordinated specialty care program.

I start and manage clozapine in an outpatient practice in Chelsea, Manhattan. Details are on the schizophrenia care in NYC page. Clozapine should not be stopped, skipped, or restarted without the prescriber. This page is general information and does not replace an evaluation.