Schizophrenia and increased risks of cardiovascular disease Charles H. Hennekens, MD,a,b,c Alissa R. Hennekens, MSW,d Danielle Hollar, PhD,a,b and Daniel E. Casey, MDe Boca Raton, FL Boston, MA and Portand, OR Objective The aim of the study is to review the absolute and relative impacts of the major causes for premature mortality among patients with schizophrenia. Data sources We reviewed published articles on causes of mortality in the general population as well as among patients with schizophrenia. Study selection We selected articles which published total and cause-specific mortality rates. Data extraction We reviewed the causes of mortality and their risk factors. Data synthesis The average life expectancy of the general population is 76 years (72 years in men, 80 years in women), whereas the corresponding figure is 61 years (57 years in men, 65 years in women) among patients with schizophrenia. Thus, patients with schizophrenia have approximately a 20% reduced life expectancy compared with the general population. Although patients with schizophrenia are 10 to 20 times more likely than the general population to commit suicide, more than two thirds of patients with schizophrenia, compared with approximately one-half in the general population, die of coronary heart disease (CHD). The chief risk factors for this excess risk of death are cigarette smoking, obesity leading to dyslipidemia, insulin resistance and diabetes, and hypertension. Conclusions The chief cause of excess premature mortality among patients with schizophrenia is CHD, caused mainly by their adverse risk factor profile. Because patients with schizophrenia have less access to medical care, consume less medical care, and are less compliant with their regimens, the choice of antipsychotic drug regimens that do not further adversely affect their risk factor for CHD is a major clinical and public health challenge among patients with schizophrenia. (Am Heart J 2005 150:1115-21.) Coronary heart disease (CHD) is far and away the leading cause of mortality in most developed countries, accounting for N1 in 3 total deaths. During the 21st century, CHD will remain the leading cause of death in developed countries, will become the leading cause of death in developing countries, and therefore, will emerge as the leading cause of death in the world. In the general US population, there are numerous large prospective cohort studies which quantitate the rela- tionship of various major risk factors with subsequent incidence of and mortality from CHD.1,2 Schizophrenia occurs in approximately 1% of the world���s population, including approximately 3 million in the US. Despite the relatively high and uniform preva- lence of schizophrenia, prospective data are sparse regarding the relationship of various major risk factors with subsequent incidence of and mortality from CHD. For these and other reasons, little attention has been given to the high frequency of CHD in patients with schizophrenia by generalists, specialists in other fields, or cardiovascular specialists. In this article, we describe the rates of death from CHD in the general population, as well as their major risk factors, to inform generalists as well as specialists in other fields of their relative and absolute importance. We also examine the high rates of death from CHD and their major risk factors among patients with schizophrenia for the cardiovascular specialist. Finally, for all health care providers, we emphasize the crucial importance for patients with From the aDepartment of Biomedical Science, Center of Excellence in Biomedical and Marine Biotechnology, Florida Atlantic University, Departments of bMedicine, and cEpidemiology and Public Health, University of Miami School of Medicine, dBoston University School of Social Work, and eDepartments of Psychiatry and Neurology, Oregon Health and Science University. This work was supported by research funds from the Agatston Research Institute (ARI), the Oregon Health and Science University, and the Danicas Foundation. Submitted May 25, 2004 accepted February 7, 2005. Reprint requests: Charles H. Hennekens, MD, 2800 S. Ocean Blvd, PH-A, Boca Raton, FL 33432. E-mail: profchhmd@prodigy.net 0002-8703/$ - see front matter n 2005, Mosby, Inc. All rights reserved. doi:10.1016/j.ahj.2005.02.007 Curriculum in Cardiology

schizophrenia of particular antipsychotic drug regimens that do not adversely affect their already high prevalence of major risk factors for CHD. Mortality among patients with schizophrenia Whereas the average life expectancy in the general population of the United States is approximately 76 years (72 years in men and 80 years in women),1 that among patients with schizophrenia is approxi- mately 20% shorter or 61 years (57 years in men and 65 years in women).3,4 This significantly lower life expectancy for patients with schizophrenia is caused primarily by CHD and also by other etiologies, principally suicide.5 With respect to suicide, approxi- mately 50% of patients with schizophrenia attempt take their own lives and approximately 10% succeed��� a 10-fold higher relative risk than in the general population.6 In contrast, the relative risk of CHD among patients with schizophrenia is perhaps 2-fold higher than the general population. Nonetheless, because suicides occur in approximately 10% and CHD among perhaps 50% to 75% of patients with schizo- phrenia, there are more deaths attributable to CHD than suicide. This situation is analogous to cigarette smoking and lung cancer where the relative risk is 20, and smoking and CHD where the relative risk is 2. Because there are so many more deaths in the general population attributable to CHD than lung cancer, if smoking were abolished, there would be more CHD deaths than lung cancer deaths prevented.7 In a meta-analysis based on data since 1990, death rates from CHD were 90% higher in patients with schizo- phrenia than among the general population.4 In another recent analysis,8 patients with schizophrenia were twice as likely to die of CHD than the general population. Furthermore, when patients with schizophrenia have major CHD events such as acute myocardial infarction, they are significantly less likely to receive the standard of care received by the general population.9,10 Table I summarizes the mortality data just reviewed. Typical antipsychotic drugs, in particular haloperidol, are effective but cause a high frequency of troublesome and even embarrassing side effects to patients with schizophrenia. These side effects are principally extra- pyramidal symptoms and tardive dyskinesias. The advent of atypical antipsychotic drugs was a major advance in patients with schizophrenia, in part, because of their far lower risks for extrapyramidal symptoms and tardive dyskinesias. With respect to the Positive And Negative Syndrome Scale, the atypicals have superior efficacy in treating negative symptoms, improving mood and cognition, as well as preventing relapse. These include thioridazine, olanzapine, quetiapine, risperidone, as well as ziprasidone and, most recently, aripiprazole. Some but not all atypical antipsychotic drugs also cause adverse effects on risk factors for CHD including weight gain and a wide range of metabolic abnormalities.11 These side effects should be particularly worrisome to health care providers because patients with schizo- phrenia already have far higher risks of CHD than the general population. Major risk factors for CHD in the general population and among patients with schizophrenia Major risk factors for CHD, including cigarette smok- ing, blood cholesterol, hypertension, obesity, and dia- betes mellitus, are more common among patients with schizophrenia than in the general population. In the general population, patients often prefer prescription of pills to proscription of harmful lifestyles. Among patients with schizophrenia, compliance with pill taking is difficult to achieve, including their antipsychotic drug regimen. Thus, emphasis on the prescription of anti- psychotic drugs of proven benefit which do not adversely affect the major risk factors for CHD assumes great clinical and public health importance. Cigarette smoking In the general US population, cigarette smoking is the leading avoidable cause of all premature death,11 as well as mortality from cancer. In the general population of the United States, approximately 25% are current cigarette smokers compared with approximately 75% among patients with schizophrenia. Furthermore, patients with schizophrenia have great difficulty with smoking cessa- tion in the short term and with smoking avoidance in the long term.12 In addition, patients with schizophrenia tend to smoke more cigarettes daily than smokers in the general population. Thus, patients with schizophrenia are at markedly increased risk because amount currently smoked is the major risk factor for CHD. Blood cholesterol In most general populations in developed countries, elevated blood cholesterol is the leading avoidable cause Table I. Life expectancy and absolute risks of death in the general population and among patients with schizophrenia General population Patients with schizophrenia Life expectancy (y) 76 (72 men and 80 women) 61 (57 men and 65 women) Absolute risks of death Suicide (%) 1 10 CHD (%) 33 50-75 American Heart Journal December 2005 1116 Hennekens et al