Reduced cardiovascular fitness associated with exposure to clozapine in individuals with chronic schizophrenia

Studies show that individuals with schizophrenia have impaired cardiovascular fitness (i.e., low peak aerobic power (VO2peak)). It is speculated that antipsychotics with adverse cardiovascular and metabolic profiles, in particular clozapine, have a significant impact on VO2peak. In this cross-sectional study, we examined whether exposure to clozapine was associated with further reduced VO2peak compared with non-clozapine antipsychotics. Thirty participants with chronic schizophrenia or schizoaffective disorder were divided into clozapine and non-clozapine groups. Mean daily doses of antipsychotics were standardized to chlorpromazine equivalents and haloperidol equivalents for antagonism of alpha1- and alpha2-adrenergic receptors. Participants completed an incremental-to-maximal symptom-limited exercise test on a cycle ergometer for the assessment of VO2peak. The clozapine group demonstrated significantly lower VO2peak than the non-clozapine group. Haloperidol equivalents for alpha-adrenergic receptor antagonism, but not chlorpromazine equivalents, demonstrated significant inverse associations with VO2peak. The clozapine group had a significantly higher amount of antagonistic activity at alpha-adrenergic receptors than the non-clozapine group. In conclusion, exposure to clozapine was associated with further reduced cardiovascular fitness, which may be explained by the drug's greater antagonistic activity at alpha-adrenergic receptors. Cardiovascular fitness needs to be promoted in individuals treated with antipsychotics, particularly clozapine, to prevent the risk of cardiovascular disease and mortality.