Does Adjuvant Metformin Reduce Olanzapine-Induced Metabolic Adverse Effects in Patients Diagnosed With Schizophrenia

Olanzapine is an atypical antipsychotic used in the treatment of schizophrenia, bipolar disorder, and major depressive disorder. In comparison to conventional antipsychotics, it demonstrates superiority in binding to serotonin 5HT-2A than to dopamine D2 receptors, thus presenting as an alternative in having lower extrapyramidal side effects. However, over time, it has become clear that olanzapine carries other prominent adverse effects associated with its use. These relate to the endocrine system and include body weight gain, increased adiposity, insulin resistance, and dyslipidaemia, all of which contribute to metabolic syndrome. Several studies included in this review involved patients with these broader psychiatric diagnoses, not only schizophrenia. This systematic review, therefore, assesses the evidence for the effectiveness of utilizing adjuvant metformin to reduce olanzapine-induced metabolic adverse effects across these populations.

Due to the heterogeneity in available data, this systematic review was conducted via a narrative synthesis method. Initially, the search question was formulated utilizing the PICO tool, then a rigorous search strategy was applied to four search engines. Utilizing the PRISMA flow diagram for visualization of the flow of articles, the initial search revealed a total of 71 articles, whereby strict inclusion and exclusion criteria were applied, revealing the final six articles included in the review. Detailed analysis of the articles allowed key themes and outcomes to be drawn upon, including body weight/BMI, waist circumference, glucose/insulin level changes, and lipid profile. This allowed key data to be grouped and narratively analyzed, resulting in the confident formulation of conclusions regarding the ability of metformin to reduce the metabolic adverse effects of olanzapine.

Through this review, adjunctive metformin was shown to play a role in reducing metabolic adverse effects associated with olanzapine. Most notably, its positive effect in reducing weight gain/BMI, triglycerides, liver fat content, and insulin resistance-all of which contribute to metabolic syndrome. Furthermore, the addition of metformin was shown to have no impact on waist circumference and certain lipid parameters such as LDL and total cholesterol, warranting further research. However, employing this evidence in the production of guidelines to benefit patients with schizophrenia remains a challenge due to the lack of evidence in the form of randomized controlled trials surrounding the dose-dependent effects, as well as age and gender differences of metformin on olanzapine therapy.

Metformin addition to olanzapine therapy showed variable effects on some metabolic parameters such as waist circumference and certain lipid parameters. However, it did show consistent effects in managing body weight/BMI, insulin resistance, triglycerides, and liver fat content. This conforms to previous but limited evidence surrounding the use of metformin in reducing metabolic adverse effects of olanzapine therapy. Based on evidence gaps, this review also proposes areas of additional research and offers recommendations, including the use of longer RCTs, larger demographics to determine if the data can be extrapolated to a wider population, and the use of varying doses to ascertain the dose-dependent effects of metformin in alleviating metabolic adverse effects associated with olanzapine therapy.

PROSPERO registration ID: CRD420251015966.