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Antipsychotic Drug Use in the Elderly: An Update

Antipsychotic medications have been the subject of much discussion recently, with several new studies published and reports of these studies appearing in the general news media. This issue of Geriatric Clinical News provides an update on these recent stories and links for more information.

A study by Wayne Ray and colleagues in the New England Journal of Medicine1 reviewed the risk of sudden cardiac death with antipsychotic drugs. This was a retrospective cohort study of Medicaid enrollees in Tennessee between the ages of 30 and 74. The time period reviewed was prior to the implementation of Medicare Part D.

Typical antipsychotic drugs previously had been linked to an increased risk of sudden cardiac death. These medications block repolarizing potassium currents and can prolong the QT interval. This study reviewed both typical and atypical agents.

The authors found that users of typical antipsychotic medications had twice the risk of sudden cardiac death compared to nonusers of antipsychotics. Users of atypical antipsychotics had an incidence-rate ratio of 2.26. These differences were significantly different from the rate for nonusers, but not significantly different from one another. For users of both classes of drugs, the risk increased significantly with increasing doses.

In an accompanying editorial in the same issue2, Schneeweiss and Avorn conclude that consideration of benefits versus risks of these medications should lead to a sharp reduction in use for elderly individuals with dementia. They also suggest that it would seem reasonable to obtain an electrocardiogram before and shortly after initiation of therapy with these agents. They note that an incidence rate of 6.8 cases of agranulocytosis per 1,000 patient-years with clozapine lead to creation of a stringent risk management system. The risk of sudden cardiac death with antipsychotic agents is about 3 events per 1,000 patient-years.

Ballard and colleagues3 reached a similar conclusion, although with a very different study design, reported in The Lancet Neurology. They studied residents of care facilities in the United Kingdom with Alzheimer's disease. This was a randomized placebo-controlled trial in which individuals receiving antipsychotic medications were randomly assigned to either continue or discontinue therapy. They compared survival in the two groups and found that individuals randomized to placebo had a survival rate of 59% at 36 months. For those taking an antipsychotic, the survival rate was 30%. The difference in survival rates was less pronounced during measurements at shorter time intervals.

An accompanying editorial in The Lancet Neurology4 urges careful balancing of risks and benefits of antipsychotics in patients with dementia and suggests these drugs should be used only if alternative strategies do not work.

A meta-analysis comparing second-generation versus first-generation antipsychotic drugs was recently published in The Lancet. Leucht and colleagues5 examined 150 double-blind studies with over 21,000 participants. Nine second-generation agents were included in the review, of which six are available in the United States.

With respect to overall efficacy, only four of the nine second-generation agents have demonstrated better improvement of overall symptoms compared to first-generation agents (three in the U.S. — clozapine, olanzapine, and risperidone). These same agents also were the only ones demonstrated to be superior in management of negative symptoms compared to first-generation agents.

Only 17 studies reported on quality of life. Of the agents available in the United States, only clozapine was found to be better than first-generation agents. With respect to extrapyramidal side effects, all second-generation agents were found to be better than haloperidol. Low potency first-generation agents (e.g., chlorpromazine) are also better than haloperidol in this regard. Only clozapine, olanzapine, and risperidone have evidence of lower extrapyramidal side effects compared with the low potency first-generation agents.

All of the second-generation agents, except aripiprazole and ziprasidone, were associated with significantly more weight gain than haloperidol. Clozapine and quetiapine were significantly more sedating than haloperidol, whereas aripiprazole was significantly less sedating.

The authors conclude that neither first-generation nor second-generation antipsychotic medications constitute a homogenous class. Second-generation agents vary widely in efficacy, side effects, cost, and pharmacology. They suggest that generalization of the agents into these two classes is improper and ought to be abandoned.

An accompanying editorial in the same issue of the journal6 recommends that "the time has come to abandon the terms first-generation and second-generation antipsychotics, as they do not merit this distinction." Rather, clinicians should keep in mind the benefit–risk ratio of each antipsychotic medication and choose a medication for each patient that best meets the needs of that patient.


1. Ray WA, Chung CP, Murray KT, et al. Atypical antipsychotic drugs and the risk of sudden cardiac death. N Engl J Med 2009;360:225-35.

2. Schneeweiss S, Avorn J. Antipsychotic agents and sudden cardiac death?how should we manage the risk? N Engl J Med 2009;360:294-6.

3. Ballard C, Hanney ML, Theodoulou M, et al. The dementia antipsychotic withdrawal trial (DART-AD): long-term follow-up of a randomized placebo-controlled trial. The Lancet Neurology 2009;8(2):151-7.

4. Antipsychotic drugs for dementia: a balancing act. The Lancet Neurology 2009;8(2):125.

5. Leucht S, Corves C, Arbter D, et al. Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis. Lancet 2009;373:31-41.

6. Tyrer P, Kendall T. The spurious advance of antipsychotic drug therapy. Lancet 2009;373:4-5.

Some eye-opening facts and figures:

More than 44,000 deaths result each year from medication-related errors, 7,000 of which are due to mistakes in prescribing or dispensing the wrong drugs.

Nearly one in five elderly Americans living in the community is taking at least one drug generally deemed unsuitable for their age group because safer alternative medications are available.

Consultant pharmacists’ services are so important in safeguarding the health and safety of nursing home residents that regular pharmacist reviews of each resident’s drug therapy are mandated by law in federally funded facilities.

In nursing homes alone, patient counseling, medication monitoring, and other services provided by consultant pharmacists save close to $3.6 billion each year in prevented hospitalizations and reduced medication costs.