Individuals with schizophrenia experience high rates of premature death. Recent time-series analyses and meta-analytic reviews suggest that premature mortality has increased in recent decades in this vulnerable population. Natural causes of death, most notably cardiovascular disease, are the leading cause of this excess mortality. Atypical antipsychotics have been suggested as one factor contributing to this excess cardiovascular mortality. To date, studies attempting to quantify the relationship between antipsychotic treatment and premature mortality have been small and inconclusive. Larger observational studies are required to answer this important issue. The VA National Psychosis Registry (NPR) provides a large and rich data source for the study of schizophrenia care and outcomes. The NPR is uniquely suited for conducting sophisticated and detailed health service analyses to improve mental health service outcomes. The findings from this study were designed to inform decisions and efforts to minimize treatment-associated morbidity and mortality among Veterans with schizophrenia.
The management of serious mental illnesses (SMI) such as schizophrenia involves a complex balance between the prescription of effective psychopharmacological medications and management of medication side effects. Therefore, we sought to understand risks associated with distinct treatment options and to identify opportunities to minimize these risks to maximize safety and outcomes. With these goals in mind, our study aims were to determine trends of cardiometabolic morbidity and mortality among Veterans with schizophrenia from 2000 through 2007 in comparison to a comparison cohort of Veterans without SMI and determine the association between cardiometabolic morbidity and mortality relative to antipsychotic medication exposure among Veterans with schizophrenia.
This retrospective cohort study examined a subset of the VA NPR population with schizophrenia and active VA service use in fiscal years 2000 through 2007. We identified a group of 65,362 patients with schizophrenia to follow over an 8-year observation period to compare with a matched comparison group of same size of Veterans without SMI. Registry data included patient socio-demographics, diagnoses, utilization, medication fills, Global Assessment of Functioning scores, and prescription fill records. Mortality data were obtained from the National Death Index Plus database while diagnostic codes were used to determine prevalence of five cardiometabolic diseases: dyslipidemia, coronary artery disease (CAD), hypertension, obesity, and type 2 diabetes. Patient clinical values such as blood pressure, weight, body mass index were obtained from VA Corporate Data Warehouse and administrative databases codes were examined. Descriptive statistics were used to compare the schizophrenia and comparison population with regard to demographic characteristics, non-SMI psychiatric diagnoses, tobacco exposure and inpatient and outpatient services use. Comparisons were conducted using methods for paired designs such as paired t tests. For each year and group, we calculated the prevalence of each cardiometabolic morbidity, proportion of the group with BMI 30, and annual all-cause, and cause-specific mortality. The number of years of potential life lost (YPLLs) was calculated for each deceased Veteran using current government life expectancy tables for the US population. Cox proportional hazards models were used to measure the association between medication exposure and morbidity and mortality. Multiple regression models were calculated to examine the relationship between cardiometabolic health and facilities associated with best cardiometabolic disease control and outcomes.
Diabetes and obesity were more prevalent among the schizophrenia group relative to the comparison group in earlier study periods. Diabetes affected 17.9% to 21.1% of the schizophrenia group in the first three study years and 15.8% to 18.5% of the comparison group. The prevalence of obesity was also greater among the schizophrenia patients (25.6% to 29.2%) relative to the comparison group (24.1% to 27.7%). These differences diminished in later years. Mortality rates varied substantially between the two groups; however, cardiovascular disease was the leading cause of death for both groups. The schizophrenia group experienced significantly higher rates of all-cause mortality than the non-SMI group, with elevated rates attributed to higher rates from trauma/accidents and suicide in most years. The findings from Cox proportional hazards models showed that cumulative exposures to antipsychotic medications were associated with a variety of cardiometabolic morbidities after adjustments for covariates. Both clozapine and olanzapine were associated to a higher dyslipidemia occurrence. Notably, for every 12-point increase in cumulative exposure scores for clozapine and olanzapine, the risk for dyslipidemia increased by 10% and 2.5% for these two agents, respectively. Similarly, olanzapine and clozapine were both associated with a higher incidence of both hypertension and diabetes. Aripiprazole was found to have a positive correlation with cerebrovascular accidents as well as diabetes incidence. Quetiapine was only found to be correlated with higher diabetes incidence. Among the two most commonly prescribed first generation antipsychotics in this study population (i.e., haloperidol and fluphenazine), fluphenazine was associated with a higher incidence of CAD. No significant correlations were found between the cumulative first or second generation antipsychotic use and incidence of acute myocardial infarction.
Understanding the effects of atypical antipsychotics on cardiometabolic-related morbidity and mortality of Veterans informs treatment decisions within the VA and helps maximize the safety for this severely ill population. Current findings suggest that VA guidelines have targeted the appropriate antipsychotic medication for ongoing cardiometabolic monitoring and risk assessment. Our findings suggest that cardiometabolic morbidity and mortality has a similar impact on Veterans with and without SMI.
- Penfold RB, Kilbourne AM, Mohr DC, Lai Z, Seibert MN, Bauer MS. Heterogeneity in aripiprazole diffusion for bipolar disorder treatment in the Veterans Health Administration. Psychiatric services (Washington, D.C.). 2012 Dec 1; 63(12):1178-85.
- Morden NE, Lai Z, Goodrich DE, MacKenzie T, McCarthy JF, Austin K, Welsh DE, Bartels S, Kilbourne AM. Eight-year trends of cardiometabolic morbidity and mortality in patients with schizophrenia. General hospital psychiatry. 2012 Jul 1; 34(4):368-79.