Dr. Robinson is a consultant with Worldwide Drug Development in Burlington, Vermont.

Disclosure: Dr. Robinson has served as a consultant to Bristol-Myers Squibb, CeNeRx, Epix, Genaissance, Johnson and Johnson, Medicinova, PGxHealth, Pfizer, and Somerset.

 

Patients with schizophrenia suffer mortality rates estimated to be twice that of the general population and have a foreshortened life expectancy.1,2 The excess mortality associated with the diagnosis of schizophrenia is attributable to greater numbers of fatalities due to both natural and unnatural causes of death.3 Increased suicide rates among patients with schizophrenia is well documented, but other causes of excess mortality in this patient population are less clear. Implicated as contributing factors to the high mortality rate are medical illnesses often associated with schizophrenic disorders and, in some instances, possible adverse effects of antipsychotic treatment.

 

Schizophrenia and Risk of Suicide

Nearly one-third of the excess mortality in schizophrenia is attributable to the significantly higher risk of suicide, with an additional 12% due to accidental death. Several large cohort studies clearly document the increased rate of suicide among patients with schizophrenia.3,4 Meta-analyses of studies of long-term outcomes over the course of the disorder estimate the incidence of death by suicide in schizophrenia to be 5% over the patient’s lifetime. Young male patients are particularly liable to commit suicide, especially during the early months following diagnosis of the disorder. 

 

Increased Mortality Due to Natural Causes

Mortality data indicate that patients with schizophrenia also have higher fatality rates due to natural causes of death compared with that of the United States general population.3 Cardiovascular, respiratory, and metabolic disorders are 2–3 times more prevalent in schizophrenia than in the population as a whole and contribute to moderately increased mortality rates from natural causes.5,6 Unhealthy life styles, polypharmacy, and suboptimal health care are all regarded as contributing factors to higher mortality risk. Pleas to implement preventive measures focus on reducing the dramatically increased mortality of schizophrenic patients by more diligent treatment of affective symptoms, improving overall treatment compliance, and greater vigilance in enforcing healthier lifestyles.7,8

 

Antipsychotics and Adverse Cardiac Effects

In addition to sequelae of medical problems associated with schizophrenia, antipsychotics have been implicated as contributing factors. There is some evidence that antipsychotics may cause sudden cardiac death or stroke. A case-controlled survey of medical practices within a network of 150 general practitioners over a 6-year period (1995–2001) found a 3-fold increase in the rate of sudden cardiac deaths associated with antipsychotics in primary care patients.9 The highest rate of sudden cardiac death was in patients receiving treatment with a butyrophenone, a class of antipsychotics known to prolong the QT interval and a particular concern with thioridazine.9 Increased rates of sudden cardiac death as compared with matched controls were apparent even at low doses of antipsychotics. Although in this study a majority of patients were receiving a conventional antipsychotic, adverse cardiac effects associated with atypical antipsychotic use were also noted.10

Atypical antipsychotics are established risk factors for development of diabetes mellitus and the metabolic syndrome. These adverse effects over time indirectly result in cardiovascular sequelae and higher death rates.5 Diabetes and dyslipidemias from extended exposure to atypical antipsychotics, especially clozapine and olanzapine, can lead to atherosclerosis, coronary artery disease, and other vascular lesions.

 

Antipsychotics in Elderly Patients

Increased rates of cerebrovascular events in dementia trials evident in 2001 for risperidone11 and in 2004 for olanzepine12 prompted the decision by the United Kingdom Committee on the Safety of Medicines to warn clinicians about potential risk of stroke with these two agents. In April 2005, the US Food and Drug Administration undertook a meta-analysis of 17 controlled clinical trials conducted for aripiprazole, olanzapine, quetiapine, and risperidone, involving >5,000 patients with dementia-related psychotic symptoms. Nearly all the clinical trials in the FDA analysis exhibited at least a small but significant increase in mortality compared with placebo treatment. This suggested that the finding was a class effect and not due to bias introduced by aberrant data from a few clinical trials.13 The FDA analyses found an approximately 50% higher incidence of stroke with atypical antipsychotics in dementia trials. It led to requiring “black box” warnings in the product labeling for all atypical antipsychotics. The FDA further admonished drug prescribers that atypical antipsychotics had not received approval for a dementia indication. Subsequent to the FDA meta-analysis, similar results were reported by a second group of investigators, which appeared to replicate the findings.13

Questions remain whether these stroke data associated with use of atypical antipsychotics are reliable.14 No mechanism accounting for this largely unexpected finding has been clearly delineated. Proposed theories for apparent increased risk of stroke include increased platelet aggregation due to increased prolactin levels; serotonin blocking effects of atypical antipsychotics; hypotension with small vessel disease; and increased coagulability caused by adverse metabolic effects of these agents on triglycerides, cholesterol, leptin, and glucose.

A cohort analysis of Medicare data of first-time recipients of conventional and atypical antipsychotics (22,000 patients ≥65 years of age) found a 37% higher mortality with conventional versus atypical antipsychotics.15 An unexpected finding of the study was the surprising fact that >25% of Medicare beneficiaries in nursing homes within the state where the survey was conducted received an antipsychotic. However, not all studies of hospitalizations for stroke involving dementia patients have confirmed an association of neurologic sequelae and treatment with conventional or atypical antipsychotics.16

The FDA analysis was confined to elderly patients in clinical trials for dementia and applied only to atypical antipsychotics. Consequently, more definitive data are needed to assess risk-benefit of antipsychotic use in older patients. Presently available information is largely extrapolated from experience with treatment of younger patients or elderly patients with dementia.

 

Mortality Risk of Atypical Antipsychotics in Younger Adults

A recent study examined mortality of patients with schizophrenia during treatment with an atypical antipsychotic in pre-approval clinical trials.17 This review of data derived from FDA summary documents in the public domain permitted assessment of mortality during treatment with several of the newer atypical antipsychotics in clinical trials conducted during the period from 1982–2002. It examined experience in >12,000 patients receiving atypical (investigational) antipsychotics, 2,900 receiving conventional antipsychotics, and 1,200 receiving placebo treatment. Mortality rates based on patient exposure years were 2,055/100,000 for atypical antipsychotics versus 8,081/100,000 for placebo (P<.05). The mortality rate for placebo treatment was significantly higher than that for either atypical or conventional antipsychotic treatment. Suicide was the leading cause of death (28%) during atypical antipsychotic treatment, followed by cardiovascular (18%) and respiratory (17%) disorders. Complete data were unavailable to assess causes of death with the other two treatments. Overall mortality rates for each of three treatment groups, however, exceeded the mortality rate for the general population (850/100,000), an outcome consistent with the finding of higher mortality risk for schizophrenia, as discussed above.

 

Conclusion

Patients with schizophrenia experience higher mortality rates than the general population. The excess mortality is due to both significant suicide risk and a higher likelihood of death from natural causes. Antipsychotics have been impugned as causing increased mortality and strokes in demented elderly patients, which led to the FDA warning included in the current labeling of atypical antipsychotics. No definitive mechanism for the purported adverse events of atypical antipsychotics in elderly dementia patients has been identified. Recent cohort studies suggest there is a similar increased mortality risk with use of conventional antipsychotics in dementia patients. Analyses of pre-approval clinical trial data for the atypical antipsychotics in schizophrenia find a lower mortality risk during treatment with antipsychotics compared with placebo treatment, although all of the groups experienced higher mortality than for the general population. PP

 

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