Metformin ameliorates recognition and working memory in antipsychotic-treated rats

Background: Olanzapine and clozapine are effective in controlling psychiatric symptoms. However, cognitive improvement remains outside their therapeutic scope, and both disturb glucose regulation and lipid metabolism. A widely used oral hypoglycemic drug, metformin, has emerging evidence supporting its role in enhancing cognition alongside maintaining glucose and lipid homeostasis. This study evaluated whether early co-administration of metformin with olanzapine or clozapine could protect against cognitive deterioration and metabolic side effects. Methods: Sprague-Dawley female rats were divided into treatment groups receiving olanzapine (2 mg/kg, i.p., twice daily), clozapine (12 mg/kg, i.p., twice daily), olanzapine combined with metformin (300 mg/kg, p.o., once daily), clozapine combined with metformin, or vehicle alone as control (n = 6 per group, over 6 weeks). Parameters monitored included body weight, food consumption, spontaneous locomotor activity, lipid panel values, and adipose tissue histomorphology. Cognitive domains of recognition memory and spatial working memory were assessed using novel object recognition task and T-maze paradigm, respectively. Results: Co-administration of metformin with either olanzapine or clozapine produced statistically significant improvements (p<0.001) in discrimination ratio and object interaction time in the novel object recognition test, as well as in the percentage of correct alternations in the T-maze, relative to antipsychotic treated groups. Furthermore, metformin attenuated the weight gain observed with olanzapine. Both antipsychotics reduced spontaneous locomotor activity, which was reversed upon metformin co-treatment. Metformin additionally ameliorated glucose intolerance induced by olanzapine and clozapine. Conclusion: Early metformin co-administration with olanzapine or clozapine effectively mitigated antipsychotic-induced cognitive impairment and metabolic disturbances in rats, supporting its potential to improve both cognitive outcomes and metabolic function.