Year 2021
October 2021


Abstract Title
A systematic review and meta-analysis of randomized controlled trials on the effect of pharmacological add-on therapy for clozapine-associated weight gain



Institute of Mental Health1, National University of Singapore2

Background & Hypothesis

Clozapine-associated weight gain is a common and problematic metabolic complication in patients with schizophrenia. An earlier review focused on the use of add-on metformin, yet the optimal treatment for clozapine-associated weight gain is not established.


We conducted a systematic review and meta-analysis of pharmacological add-on therapy to manage clozapine-associated weight gain. Pubmed, Embase, PsycINFO and Cochrane Library databases from their inception to June 18, 2020, were systematically searched for randomized controlled trials that compare the effect of change in body weight between pharmacological add-on therapy with placebo in people treated with clozapine.


Twelve studies examining seven different treatments were included in the review. Meta-analysis of the fluvoxamine and metformin studies showed weight reduction effect, however significant result was only observed from metformin add-on therapy. No worsening of psychiatric symptoms or severe adverse effects reported from these interventions. Aripiprazole, liraglutide and exenatide shown great potential in weight reduction in patients on clozapine therapy, but not from phenylpropanolamine and modafinil add-on therapy.

Discussion & Conclusion

We concluded that metformin is an effective add-on therapy for clozapine-associated weight gain. It is generally well tolerated without severe adverse effects reported. The potential of aripiprazole and glucagon-like peptide-1 receptor agonists warrants further investigation to expand the current limited pharmacological options. These pharmacological agents were tested in a diverse patient group and the results cannot be extrapolated outside of the trials.