In older adults, antipsychotic drugs are commonly prescribed off-label for a number of disorders outside of their Food and Drug Administration (FDA)-approved indications -- schizophrenia and bipolar disorder. The largest number of antipsychotic prescriptions in older adults is for behavioral disturbances associated with dementia, some of which carry FDA warnings on prescription information for these drugs.

In a new study -- led by researchers at the University of California, San Diego School of Medicine, Stanford University and the University of Iowa, and funded by the National Institute of Mental Health -- four of the antipsychotics most commonly prescribed off label for use in patients over 40 were found to lack both safety and effectiveness. The results will be published November 27 in The Journal of Clinical Psychiatry.

The study looked at four atypical antipsychotics (AAPs) -- aripiprazole (Abilify), olanzapine (Zyprexa), quetiapine (Seroquel), and risperidone (Risperdal) -- in 332 patients over the age of 40 diagnosed with psychosis associated with schizophrenia, mood disorders, PTSD, or dementia.

"Our study suggests that off-label use of these drugs in older people should be short-term, and undertaken with caution," said Dilip V. Jeste, MD, Estelle and Edgar Levi Chair in Aging, Distinguished Professor of Psychiatry and Neurosciences, and director of the Stein Institute for Research on Aging at UC San Diego.

Results of the five-year study led by Jeste, who is also current president of the American Psychiatric Association (which was not involved in this research), showed that within one year of treatment, one-third of the patients enrolled in the study developed metabolic syndrome (medical disorders that can increase the risk of cardiovascular disease or diabetes). Within two years, nearly a quarter of the patients developed serious adverse effects and just over half developed non-serious adverse effects.

Because the patients enrolled in the study were all diagnosed with conditions with psychotic symptoms that required antipsychotic drug treatment according to their treating physicians, no placebo was used in the trial. Instead, the researchers used a technique called "equipoise stratified randomization" which is a hybrid of complete randomization and a clinician's choice method.

"Our goal was to ensure clinical relevance," said Jeste. Patients had to agree to be randomized to 2, 3 or 4 of the study drugs, as they or their physicians were allowed to exclude one or two of the study AAPs, due to past experience or anticipated risk of the particular drug. Treating clinicians could determine the optimal dosage. "We attempted to make the study as 'user-friendly' as possible, to allow the drugs the best chance of success, while seeking to minimize the amount of bias," he explained.

While the researchers' intent was to continue the patients on the randomized medications for two years, the average length turned out to be only six months, after which the medications were halted or switched because they didn't work and/or had side effects.

Because of a notably high incidence of serious adverse events, quetiapine had to be discontinued midway through the trial. The researchers found that there were significant differences among patients willing to be randomized to different AAPs -- thus, treating clinicians tended to exclude olanzapine and prefer aripiprazole as one of the possible choices in patients with existing metabolic problems. Yet, the different AAP groups did not appreciably differ in most outcome measures.

Using a common scale called the Brief Psychiatric Rating Scale (BPRS), to measure symptoms such as delusions, hallucinations, unusual behavior, depression, and anxiety, assessments were made at 6 weeks, 12 weeks, and then every 12 weeks. Results using "blind" raters showed no significant improvement in BPRS over a six-month period.

"While there were a few significant differences among the four drugs, the overall risk-benefit ratio for the AAPs in patients over age 40 was not favorable, irrespective of diagnosis and drug," said Jeste.

Jeste points out that clinicians, patients, and caregivers are often left with difficult and unclear choices for treatment for older persons with psychosis, such as that associated with dementia. Not only are psychosis and agitation common in persons with dementia but they also frequently cause considerable caregiver distress and hasten institutionalization of patients. At the same time, there are no FDA-approved alternatives to antipsychotics for this population, and the high cost of newer AAPs also makes their use problematic.

While the researchers say their findings do not suggest that these AAPs should be banned in older patients with psychiatric disorders, they do indicate that considerable caution is warranted in off-label, long-term use of the drugs in older persons.

"When these medications are used off-label, they should be given in low dosages and for short durations, and their side effects monitored closely," said Jeste. "Clearly, there is also a critical need to develop and test new interventions that are safe and effective in older people with psychotic disorders."

Other authors of this paper are Hua Jin, MD, Pei-an Betty Shih, PhD, Shahrokh Golshan, PhD, Sunder Mudaliar, MD, Robert Henry, MD, and Danielle K. Glorioso, MSW, from University of California, San Diego; Helena C. Kraemer, PhD, emerita professor of biostatistics in psychiatry at Stanford University, and Stephan Arndt, PhD, professor of psychiatry and biostatistics at the University of Iowa.

The study was supported in part by National Institutes of Health grants MH071536, P30 MH080002-01, 1K01DK087813-01, NCRS UL1RR031980 and by the Department of Veteran Affairs.