Cardiac risk and schizophrenia.

Sudden cardiac death, which is defined as death from a cardiac cause within a short time (minutes to hours) after symptoms initially appear, often without warning, is a major public health problem, accounting for about 10% of all natural deaths and over 50% of all coronary mortality. Most individuals who die a sudden cardiac death have no history of heart disease. Patients with schizophrenia have been reported to be 3 times as likely to experience sudden unexpected death than individuals from the general population, although the specific aspects contributing to this increased risk of death remain unclear. Different factors related to the underlying pathology, antipsychotic medications and lifestyle (e.g., smoking, general neglect of health, poor diet and decreased access to health care services) may contribute to the increased mortality in these patients. A recent study found that patients who received antipsychotic medication were 1.4 times more likely to die unexpectedly than individuals who were antipsychotic drug free. However, this study did not include patients who were taking any of the atypical (secondgeneration) antipsychotic drugs. Cases of sudden death have been reported in subjects taking atypical antipsychotic drugs, but a recent review of these drugs indicates that they are generally safe. The situation with regard to these drugs is confounded by the fact that there is an excess risk of mortality in schizophrenia even when patients are not treated with antipsychotic drugs, and a number of other medications that may be co-administered with antipsychotic drugs may also be associated with QTc prolongation, as discussed below. A number of cardiac measures shown to predict sudden cardiac death and other arrhythmias in non-diseased individuals have also been observed in patients with schizophrenia. For example, a prolonged QT interval (increased time taken for the heart to recover from the previous contraction) or QTc interval (QT interval corrected for cardiac rate) has been shown to be a risk factor for such cardiac events, and has been observed in some individuals with schizophrenia. Low heart rate variability (HRV), a marker of abnormal cardiac autonomic function that has been shown to predict potentially fatal ventricular tachycardias in a number of disease conditions, has also been observed in patients with psychosis. However, as most of the patients in these studies were either currently being treated with antipsychotic drugs or had previously received these medications, it is unclear whether the prolonged QT interval and the low HRV observed resulted from the antipsychotic drugs or from the disease itself. Some, but not all, antipsychotic drugs have been shown to prolong the QTc interval, but interpretation of data is complicated by the finding that prolonged QTc intervals are often associated with high drug doses or combinations of drugs. Patients treated with clozapine have been reported to exhibit significantly lower HRV than patients treated with olanzapine, sertindole or amisulpride. Moreover, HRV has been reported to be negatively correlated with the serum levels of clozapine. In a study of healthy volunteers, short-term administration of olanzapine, thioridazine and risperidone increased, decreased and had no effect, respectively, on HRV. Some antipsychotic medications have also been reported to be associated with an increased risk of diabetes and an illdefined metabolic syndrome, sometimes referred to as syndrome X, which typically includes weight gain and abnormalities in lipid, glucose and insulin regulation. Some or all of these conditions could indirectly play a role in the increased cardiac risk observed in patients with schizophrenia. It should be noted, however, that abnormalities in glucose regulation have also been observed in medication-naïve individuals with schizophrenia. Autonomic dysfunction, that is, an imbalance between the sympathetic and parasympathetic systems, in schizophrenia