24 October 2005. Antipsychotic drugs were originally introduced for the treatment of schizophrenia, but over the years they have crept into many a medicine cabinet. In nursing homes, it is estimated that about 25 percent of residents are prescribed antipsychotics (see Katz et al., 1992). Many patients suffering from Alzheimer disease and, less well-known, Parkinson disease, as well (Weintraub and Stern, 2005) receive such drugs to treat psychiatric aspects of their respective diseases. But while elderly dementia patients with aggression or delusions receive modest benefit from these drugs (see Schneider et al., 1991), are they paying a hidden price? Reporting in last Wednesday’s Journal of the American Medical Association, Lon Schneider and colleagues at the University of Southern California, Los Angeles, suggest that they may be. Their meta-analysis of 15 different randomized placebo-controlled trials reveals that antipsychotics slightly increase the risk of death in dementia patients.
Schneider and colleagues gathered and analyzed clinical data on over 5,000 elderly dementia patients that had either been published in the literature or reported at meetings. Over 3,300 of these patients had randomly been prescribed atypical, or second-generation, antipsychotics (including risperidone, olanzapine, quetiapine and aripiprazole, clozapine, and ziprasidone), while over 1,700 were given placebo. Schneider and colleagues found that over the course of these trials, more patients on these medications than on placebo died (3.5 percent of medicated patients died versus 2.3 percent of those on placebo). The odds ratio, or relative risk, for death among the patients on antipsychotics was 1.54 times normal.
These findings stand before a backdrop of continued warnings from the U.S. Food and Drug Administration (FDA) about adverse cerebrovascular effects of some of these drugs (see, for example, http://www.fda.gov/medwatch/SAFETY/2003/risperdal.htm) and are consistent with findings published by the Administration last April. Then, the FDA concluded that dementia patients taking these drugs have a 1.6- to 1.7-fold risk of death (see http://www.fda.gov/cder/drug/advisory/antipsychotics.htm). The report also comes out exactly a month after Jeff Lieberman and colleagues at Columbia University reported in the New England Journal of Medicine that atypical, or second-generation, antipsychotics are no more effective than the original, cheaper drugs (see related Schizophrenia Research Forum news story).
This analysis suggests that the increased risk is relatively small. In fact, it only becomes statistically significant when the data on the individual drugs are pooled (the analysis revealed that no single drug statistically increased the risk of death). Even so, it should be noted that all the trials were short, between 8 and 12 weeks long. This “implies a 4 percent to 5 percent risk difference over a year of treatment, with an upper bound for some drugs as high as 25 percent,” suggest Schneider and colleagues. However, the authors add that the risk may be highest early in treatment, then decrease over time. Long-term controlled trials are needed to address these issues, suggest the authors.
Where does this leave the physician treating dementia patients who have psychotic episodes? “The results do not contraindicate the use of antipsychotic drugs in the treatment of patients with dementia who have psychotic symptoms and agitation; instead, they change the risk-benefit analysis such that antipsychotic drugs should only be used when there is an identifiable risk of harm to the patient or others, when the distress caused by the illness is significant, or when alternate therapies have failed and symptom relief would be beneficial,” write Peter Rabins and Constantine Lyketsos of Johns Hopkins School of Medicine in Baltimore, Maryland, in a JAMA editorial. As for falling back on first-generation antipsychotics as an alternative, this doesn’t appear to be an option because Schneider and colleagues calculated that haloperidol, one of the earliest antipsychotics, doubles the risk for mortality in the elderly demented patients.
On the broader theme of drug safety, Rabins and Lyketsos suggest that the current requirements for drug approval—two randomized controlled trials (RCTs)—are unlikely to detect these rare events. For example, COX-2 inhibitors were widely used for years before serious cardiovascular side effects were reported (see ARF related news story). “The FDA must put more effort into formal postmarketing surveillance and require that data from all RCTs be made readily available within a specific time period after data collection is completed,” Rabins and Lyketsos write. One of the problems Schneider and colleagues faced in carrying out their analysis is that many of the trials have not been published, so they had to rely on data presented at meetings to strengthen the power of their study.
In addition, mortality should be an endpoint in all drug studies premarketing or postmarketing, and postmarketing assessment of mortality should be made mandatory for all newly approved drugs, suggest Rabins and Lyketsos.—Tom Fagan.
Schneider LS, Dagerman KS, Insel P. Risk of death with atypical antipsychotic drug treatment for dementia. Meta-analysis of randomized placebo-controlled trials. JAMA. 2005 October 19;294:1934-1943. Abstract
Rabins PV, Lyketsos CG. Antipsychotic drugs in dementia. What should be made of the risks? JAMA. 2005 October 19;294:1963-1965. Abstract