Does Antipsychotic Polypharmacy Increase the Risk for Metabolic Syndrome

The prescribing of more than one antipsychotic at the same time is becoming common in the treatment of patients with severe mental illnesses, despite authoritative treatment guidelines that advocate for antipsychotic monotherapy, recommending antipsychotic cotreatment as the last option after other strategies, including clozapine, have failed (1–3). Depending on treatment settings, populations, time of study and study methodology, prevalence rates of antipsychotic polytherapy for schizophrenia and other chronic psychotic disorders range between 3% and 71% (4–19). The increased cost of combining two atypical antipsychotics and the lack of substantial proof of the efficacy and safety of antipsychotic polytherapy has raised considerable reservations regarding this practice (20–22). Among the four controlled studies in patients with clozapine-refractory schizophrenia, two trials demonstrated a moderate benefit of augmentation with sulpiride (23) and risperidone (24), while the other two trials did not find clozapine augmentation with risperidone to be superior compared to augmentation with placebo (25,26). However, since only less than 5% of patients are treated with clozapine in the US, these controlled trials are limited in addressing the efficacy of combining two antipsychotics in patients with schizophrenia and other severe mental disorders who are either not considered fully treatment refractory, or in those unwilling or unable to benefit from clozapine. On the other hand, the safety of antipsychotic polytherapy has received scant attention in published work. In several studies, antipsychotic combination treatment has been associated with higher rates of extrapyramidal side effects, as well as increased use of anticholinergic agents (12,17,27) compared to antipsychotic monotherapy. In addition, sedation (25) and hyperprolactinemia (23,28) have been observed more often in patients treated with antipsychotic polytherapy. In addition, recent data suggest that antipsychotic polytherapy may be associated with greater metabolic risk. In a case-control study of patients treated with antipsychotics, including 181 cases with new antidiabetic prescriptions and 1,448 matched controls, an elevated risk for treatment-emergent diabetes mellitus was found in association with antipsychotic combination treatment (29). The association of antipsychotic treatment with weight gain, hyperglycemia, dyslipidemia, and the metabolic syndrome (30–34), as well as naturalistic reports linking cardiovascular mortality to antipsychotic polytherapy (35,36), suggest that combining antipsychotics, particularly second-generation antipsychotics, could be associated with an increased risk of metabolic syndrome, which is linked with coronary heart disease and diabetes (37,38). However, the antipsychotics used in polytherapy may produce different effects on the prevalence of metabolic syndrome (39,40), because clozapine and olanzapine are associated with greater weight increase and metabolic abnormalities than other SGAs, particularly ziprasidone and aripiprazole (41). The relationship between antipsychotic polytherapy and metabolic syndrome has not been examined. In this cross-sectional study of an inpatient population treated with second-generation antipsychotics, we aimed to determine whether antipsychotic polytherapy is associated with an increased point prevalence of metabolic syndrome and lipid markers of insulin resistance. We hypothesized that the frequency of metabolic syndrome and insulin resistance would be elevated in patients receiving more than one antipsychotic for the treatment of a severe mental disorder.