Can the Initial Antipsychotic Influence Years of Weight Gain?

The first antipsychotic that is selected for a patient could influence the weight gained in subsequent years, according to investigators analyzing real-world data in a retrospective cohort study.¹

At some variance with meta-analyses that have ranked antipsychotics by weight gain reported in controlled trials, this analysis found that patients receiving either aripiprazole, quetiapine, olanzapine, or risperidone in the first year of treatment are most likely to have experienced weight gain in 5 years from a normal body mass index (BMI) at baseline. No significant weight gain from the normal baseline was found in that period after initial prescriptions of perphenazine, fluphenazine, or amisulpride.

“The implication of this longitudinal population study is that, while we know that in randomized controlled trials there is a clear hierarchy in relation to weight gain, in a real-world evaluation, the association between prescribing choice and cardiometabolic outcomes is determined by multiple other factors and is more complex,” Adrian Heald, DM, of the School of Medicine and Manchester Academic Health Sciences Center at Manchester University in the United Kingdom, and colleagues said.

The investigators previously reported on weight change over a 20-year period following diagnosis and treatment of serious mental illness. In the present study, they revisited that data, seeking to link the initial antipsychotic with weight gained over 5 years. However, they did not present data on either duration or dose of the initial agents or on the regimens in the intervening years, which could limit the comparative analysis. Regarding duration of use for the initial antipsychotic, the investigators only offered, “We have analyzed in detail the duration of antipsychotic prescribing in the first year after diagnosis/first prescription and have been able to describe the first antipsychotic agent prescribed.”

As for the absence of data on dosing, Heald et al acknowledge it is a limitation of the study but suggest that their findings remain relevant given the number of individuals they followed over that time. They also argue, “We did not include antipsychotic dose in the analysis as there is little evidence of a dose effect on weight change at clinically therapeutic doses.”

Their cohort comprised 17,570 adults treated with an antipsychotic for schizophrenia, schizotypal disorders, and delusional disorders during the period between 1998 and 2023. Data were extracted from the Greater Manchester Care Record database, an integrated regional database across primary, secondary, and mental health care.

The investigators applied both univariate and multivariate regression analyses to identify factors that might influence weight trajectory between BMI at baseline and 5-year follow-up. Six antipsychotics were omitted from the analysis due to low rates of prescription. The initially prescribed antipsychotic agents in the study period were olanzapine (54%), risperidone (12%), quetiapine (10%), aripiprazole (6%), amisulpride (4%), haloperidol (4%), chlorpromazine (2%), and other antipsychotics (8%).

In addition to the association with particular agents, weight gain in 5 years was also related to polypharmacy during the first year. Notably, weight gain was greater in women than in men and in younger patients than in older patients. Additionally, a greater percentage increase in BMI occurred in those who had obesity at baseline.

Aripiprazole was among the agents implicated in greater weight gain from normal baseline BMI, which was unexpected, as meta-analyses of clinical trials have demonstrated it to be relatively weight neutral. Heald et al suggested several possible contributing factors, although these do not necessarily comport with the reported change from normal BMI. “If aripiprazole is used as first line, it may be targeted toward people who are already overweight or obese, who already have a predisposition to weight gain; ie, the choice of aripiprazole may be based on the physical health profile of the individual,” investigators said.

“Some 75% of aripiprazole prescriptions were coprescribed or following other agents, which may account for the strong association with weight gain seen here,” Heald et al suggested. “Aripiprazole may be used as an augmentation agent in cases of treatment resistance, [and] aripiprazole may be added to combat weight gain when this has already occurred with a view to facilitating some weight reduction.”

The investigators concluded that, in addition to differences between agents in relation to the weight gain measured at 5 years, the interaction between drugs and disposition to weight gain is complex. They recommend regular physical health checks for all individuals prescribed antipsychotics, “with consideration of change in medication if the medication is thought to be a contributory factor to weight gain.”

Dr Bender reports on medical innovations and advances in practice and edits presentations for news and professional education publications. He previously taught and mentored pharmacy and medical students, and he provided and managed pharmacy care and drug information services.

Reference

1. Heald A, Tilston G, Warner-Levy JJ, et al. Impact of early antipsychotic prescription choice on weight gain in the first 5 years of psychotic illness: a retrospective cohort study. Neurol Ther. 2025;14(4):1657-1670.