Antipsychotic-Induced Metabolic and Cardiovascular Side Effects in Schizophrenia: A Novel Mechanistic Hypothesis

The use of antipsychotics is hindered by the frequent occurrence of metabolic and cardiovascular side effects, resulting in worsened quality of life and greater mortality as a result of cardiovascular and cerebrovascular disorders in schizophrenia patients than the comparable general population. The various antipsychotics induce extrapyramidal symptoms, impaired glucose and lipid metabolism, weight gain, hypertension and arrhythmias, with variable frequency. Second-generation antipsychotics appear to have several advantages over first-generation antipsychotics, including a claimed better action on cognitive function and the negative symptoms of schizophrenia, and lower frequency of extrapyramidal side effects; however, their use is associated with a greater frequency of metabolic and cardiovascular disturbances. The mechanisms of these important side effects are not well understood, and generic approaches (psychoeducational programmes and symptomatic therapies) have been proposed to limit their severity. Extensive data from the literature indicate that autonomic nervous system dysfunction-intrinsic to schizophrenia and strongly exacerbated by antipsychotic treatment-is the cause of the pervasive metabolic and vascular dysfunctions associated with schizophrenia. In this article, we marshal further literature data to argue that the metabolic and cardiovascular side effects of antipsychotics are primarily mediated by their ability to block peripheral dopamine receptors, which physiologically modulate sympathetic activity. We also propose that these effects might be overcome by providing peripheral dopaminergic stimulation.