Potential Toxic Effects of Olanzapine on Metabolic Parameters in de Novo Paranoid Schizophrenic Patients. The Role of Adjunctive Aripeprazole: Clinical and Experimental Study

Background: Approximately 75% of all deaths in people with schizophrenia are caused by physical illness with cardiovascular disease [CVD] being the commonest cause of death. Factors predisposing people with schizophrenia to CVD include antipsychotic medication. Aim of Work: The aim of this study was to detect metabolic syndrome and its components in de novo paranoid schizophrenics on olanzapine therapy and the metabolic benefits of addition of aripeprazole, clinically and experimentally. Methodology: 1) Clinical study: 200 Outpatients suffered from de novo paranoid schizophrenia according to 10th International Classification of Psychiatric Disorders, Research Criteria [ICD10 RC] were included in the study. None of them had any component of metabolic syndrome. They were maintained on olanzapine [10 - 20 mg]. Patients were assessed clinically, psychometrically using Scale for the Assessment of Negative [SANS] and Positive [SAPS] Symptoms and metabolically at base line and after 6 months. Patients who had metabolic syndrome after 6 month of starting olanzapine therapy, were randomly divided into two groups according to added regime to maintained olanzapine: Group 1: olanzapine [10 mg/day] + placebo [empty hard gelatin capsule]. Group II: olanzapine [10 mg/day] + aripeprazole [10 mg/day]. 2) Experimental study: 40 male albino rats were randomly equally divided into 4 groups: Group 1 [control group]: received a standard diet, Group II [olanzapine treated]: received olanzapine at a dose of 0.5 mg/kg/day, Group III [aripiprazole treatd]: received aripiprazole at a dose of 2 mg/kg/day, Group IV [combined olanzapine and aripiprazole treated]: received olanzapine at a dose of 0.5 mg/kg/day combined with aripiprazole at a dose of 2 mg/kg/day orally. The duration of the study was 16 weeks. All treated rat groups were assessed for metabolic parameters, liver enzymes and histopathology. Results: Clinically, after the 6 months of olanzapine treatment [mean dose 12.75 mg], there was significant increase [p < 0.001] in weight, body mass index, triglyceride, total cholesterol, and fasting blood glucose level compared to base line level of these parameters (Table 1). 32 patients [16%] suffered from metabolic syndrome after 6 months of olanzapine therapy. After 3 months of aripeprazole, [10 mg/day], addition to maintained olanzapine therapy to patients suffered from metabolic syndrome, there was significant [p < 0.001] improvement in tested parameters (Table 2). Experimentally, the rats in group II [olanzapine treated rats] had significantly higher body weight [p = 0.002], liver weight [p < 0.001], metabolic parameters [p < 0.001] and liver enzymes [p < 0.001] than controls. Group 1v [combined olanzapine and aripeprazole treated rats] had significant decrease in metabolic parameters and liver enzymes in comparison to olanzapine treated rats (Table 3). Histopathologically, liver fat cells were significantly [p < 0.001] present in the olanzapine-only [8 rats] treatment group compared to group 1v [3 rats] and group 11 [zero]. Liver fat cells were higher in number and larger in size in group 1 compared to group 1v and group 1. Conclusion and Recommendation: Olanzapine treatment was found to be associated with risk factors of metabolic syndrome clinically and experimentally and its hepatic manifestation of non-alcoholic fatty liver disease in wister rats. Improvements were observed clinically and experimentally in metabolic measures, liver enzymes and liver histopathology by addition of aripeprazole. Patients on olanzapine therapy must be followed regularly regarding metabolic parameters, hepatic, cardiac and cerebrovascular morbidity, with urgent interference with early manifestations. It is recommended to check liver enzymes regularly for those patients kept on atypical antipsychotic drug [olanzapine].