Effect of add-on Aripiprazole on Cardiometabolic Profile in Treatment Resistant Schizophrenia With Metabolic Syndrome: A Randomized Controlled Trial

Schizophrenia (SCZ) is a chronic severe mental illness usually having an unremitting course and associated with gross socio occupational deterioration. Patients of SCZ and other severe mental illness experience higher prevalence of physical morbidity like cardiovascular diseases, weight gain, obesity, dyslipidaemia, diabetes mellitus and metabolic syndrome as compared to general population. Life expectancy of patients with SCZ is reduced by approximately 20 years than general population because of cardiovascular morbidities. In patients with SCZ, data suggests that 1 in every 3 patients have metabolic syndrome, 1 in every 2 patients are overweight, 1 in 5 have significant hyperglycaemia and 2 in every 5 patients have dyslipidaemia. Atypical antipsychotics like Olanzapine and Clozapine used to treat patients of SCZ have highest association with obesity, metabolic syndrome and other cardiovascular complications. Significant percentage (25%) of patients with SCZ tends to show poor response to antipsychotics, eventually requiring Clozapine treatment. Clozapine is the only US FDA approved treatment for treatment resistant schizophrenia (TRS), but around 28-45% of patients on long term Clozapine use eventually tend to develop metabolic syndrome during the treatment course. Hence, there is a need to search for drugs which can be used in combination with Clozapine for the treatment of Clozapine induced metabolic syndrome. Metformin, an oral hypoglycaemic agent has been a recommended treatment for type 2 diabetes mellitus and also for antipsychotic induced metabolic syndrome. In a metanalysis of 4 RCTs on TRS patients on Clozapine with metabolic syndrome, it has been found that add-on Metformin is consistently found to have superior efficacy over placebo in reducing metabolic syndrome. However, metformin use causes subclinical lactic acidosis and hence it's use has been discouraged in patients with hepatic impairment, heart failure and chronic kidney disease as it requires close monitoring of renal function test and serum B12. The exact duration of metformin treatment for antipsychotic induced metabolic syndrome has been inconsistent. Hence, there is a need for searching alternative which can reduce Clozapine associated metabolic side effects along with beneficial effects on psychopathology in treatment resistant scenarios. Aripiprazole, a partial D2 agonist and post synaptic D2 antagonist is used as a successful augmenting agent in TRS. In patients with schizophrenia with metabolic syndrome, add-on Aripiprazole has been found to be superior to placebo in reducing metabolic syndrome in a metanalysis of 4 RCTs. They have measured biochemical parameters like CRP, Insulin resistance (HOMA IR), LDL/TG ratio as outcome measures to substantiate their findings.

In this study the investigators would like to evaluate the effect of add on Aripiprazole in reducing the metabolic parameters in patients of TRS on Clozapine with metabolic syndrome. In our study the investigators would measure the cardiovascular risk by calculating the change in QRISK3 score and the metabolic parameters by change in LDL/HDL ratio, hs CRP, Insulin resistance (HOMA IR) and fasting plasma glucose level.

3.RESEARCH HYPOTHESIS: Null hypothesis: There will be no significant difference in the change in cardiovascular risk score between the study groups in TRS on Clozapine with metabolic syndrome.

Alternative hypothesis: There will be significant difference in the change in cardiovascular risk score between the study groups in TRS on Clozapine with metabolic syndrome.

4. OBJECTIVES: Primary