Our study shows that antipsychotic polypharmacy is not correlated with metabolic syndrome but is correlated with the wider range of the syndrome when adjusting for the effects of lifestyle in outpatients with schizophrenia. These findings indicate that antipsychotic polypharmacy contributes in part to metabolic syndrome.
It remains unclear why antipsychotic polypharmacy is correlated with metabolic disturbance. Earlier studies suggested that various receptors effects, such as H1
, and M3
, might contribute to metabolic disturbance [20
]. We speculate that the complex receptor-binding profiles of antipsychotic polypharmacy might be one of the causes of metabolic disturbance.
Among earlier studies, the association between metabolic syndrome and antipsychotic polypharmacy was not certain. For example, Correll et al. [3
] observed that patients who receive antipsychotic polypharmacy had significantly higher rates of metabolic syndrome in univariate analyses, but antipsychotic polypharmacy was not independently associated with metabolic syndrome in logistic regression analyses which accounted for demographic and clinical variables. They speculated that antipsychotic polypharmacy was not a primary factor for metabolic syndrome, and that factors related to antipsychotic polypharmacy, such as inactivity, contributed to the risk of metabolic syndrome.
Physical activity was not associated with metabolic syndrome of any severity in this study. We infer that the association between metabolic syndrome and antipsychotic polypharmacy is not certain because of the effect of antipsychotic polypharmacy on lowering blood pressure, rather than because of the effect of inactivity. It was reported that polypharmacy was associated with a significantly higher drop in systolic pressure than monotherapy [21
]. This might be due to the effects of a higher dose than that received during monotherapy or a drug interaction which created dopaminergic and noradrenergic deficiency conditions, such as Shy-Drager syndrome. Similarly, in the present study, patients receiving antipsychotic polypharmacy were less likely to fulfil the criterion of elevated blood pressure. Consequently, because antipsychotic polypharmacy tended not to be associated with elevated blood pressure, which is one of the three criteria for metabolic syndrome, polypharmacy may not have been correlated with metabolic syndrome, which needs to fulfil two or more of the three criteria, but rather with pre-metabolic syndrome, which needs to fulfil one or more of the criteria. We speculate that antipsychotic polypharmacy is directly associated with metabolic disturbance and increases the risk for metabolic syndrome, but the effect on lowering blood pressure masks the diagnosis of metabolic syndrome.
Another reason for our finding that polypharmacy contributes in some way to metabolic syndrome is that psychiatrists might be reluctant to prescribe additional antipsychotics for patients with metabolic syndrome to avoid worsening their metabolic profiles; however, for patients with pre-metabolic syndrome, they might not hesitate to prescribe additional antipsychotic.
Antipsychotic polypharmacy was not significantly associated with the visceral fat obesity group. That may be why the sample size in the group was small. We speculate that the association between polypharmacy and the visceral fat obesity may become significant if the sample size is larger.
Among the lifestyle factors, smoking habit was associated with prevalence of metabolic syndrome. It is considered to be an important risk factor for metabolic syndrome in the general population [22
]. The prevalence of smoking in schizophrenia greatly exceeds that in the general population [24
]. For the prevention of metabolic syndrome, it is necessary to provide guidance for lifestyle, such as smoking cessation advice, to patients with schizophrenia, especially those receiving antipsychotic polypharmacy.
The limitations of our study were a cross-sectional design, moderate sample size, high rate of refusal to participate in the study, and non-assessment of other psychotropic drugs except antipsychotics. In addition, special conditions were imposed on antipsychotic treatment in Japan at the time of the study, that is, clozapine had not yet been launched and olanzapine and quetiapine were contraindicated for patients with diabetes or a history of diabetes. Clozapine and olanzapine, in particular, are known as high-risk drugs for metabolic syndrome [27
]. Therefore, the above special conditions are likely to have affected the results in this study.