Risk-Benefit Ratio Not Favorable for Use of Atypicals in Older Adults

Four atypical antipsychotics that are commonly prescribed to adults over age 40 were found to have a high rate of serious and nonserious side effects while offering little significant long-term improvement in psychopathology.

That was the finding from a study of safety and long-term effectiveness of four commonly prescribed atypical antipsychotics—aripiprazole, olanzapine, quetiapine, and risperidone—that was published online November 27 in the Journal of Clinical Psychiatry. Atypical antipsychotics are often prescribed off-label for older adults experiencing psychosis related to dementia.

But the results of the study call into question the long-term use of these medications, especially for off-label purposes.

“Our study suggests that off-label use of these drugs in older people should be short term and undertaken with caution,” said study author and APA President Dilip Jeste, M.D,. in an interview with Psychiatric News. He is distinguished professor of psychiatry and neuroscience at the University of California, San Diego, School of Medicine.

Medications Discontinued

In the study, 332 patients over age 40 were randomized to one of the four antipsychotics in a design that allowed patients or their treating psychiatrist to exclude one or two of the antipsychotics based on previous experience or anticipated risk (such as, for instance, if a patient was known to be at risk for metabolic syndrome). In this way, the study was designed to mimic as closely as possible real-life clinical situations.

Patients were followed for up to two years, with assessments at baseline, six weeks, 12 weeks, and every 12 weeks thereafter. Medications were administered using an open-label design and flexible dosages, but with blind raters. The study was conducted from October 2005 to October 2010.

Patients included those with psychosis related to schizophrenia, mood disorders, posttraumatic stress disorder (PTSD), or dementia diagnosed using DSM-IV-TR criteria. (Antipsychotics are approved by the Food and Drug Administration for schizophrenia and bipolar disorder, but not for PTSD or dementia.)

Serious Adverse Events Developed

Because of a high incidence of serious adverse events, quetiapine was discontinued midway through the trial. And there were significant differences among patients willing to be randomized to different atypical antipsychotics, suggesting that treating clinicians tended to exclude olanzapine and prefer aripiprazole as one of the possible choices in patients with metabolic problems.

Yet the four groups did not differ in longitudinal changes in metabolic parameters or on most other outcome measures. Overall results suggested a high rate of early medication discontinuation.

The proportion of patients who discontinued their randomized medication before the end of the two-year follow-up period ranged from 78.6 percent taking quetiapine to 81.5 percent taking aripiprazole. The median number of weeks to discontinuation of randomized medication was 26 weeks.

Jeste and colleagues noted that it is possible that the early discontinuation might have reflected significant clinical improvement or at least adherence to the treatment guidelines for using atypical antipsychotics for as short a period as possible, especially in patients with dementia. But there was no relationship between diagnosis and duration of atypical antipsychotic treatment—so discontinuation occurred in schizophrenia and mood disorder patients, too—and the majority of the patients whose randomized atypical antipsychotic was discontinued were switched to another atypical antipsychotic by their treating clinicians, indicating a continued need for treatment.

There was no significant improvement in psychopathology based on symptom measurement using the Brief Psychiatric Rating Scale. And study patients experienced a high cumulative incidence of metabolic syndrome (36.5 percent in one year) and of serious (23.7 percent) and nonserious (50.8 percent) adverse events associated with all of the medications.

Jeste and colleagues called the results “sobering.” They said, “While there were a few significant differences among the four atypical antipsychotics included in this study, the overall risk-benefit ratio for the atypical antipsychotics in patients over age 40 was not favorable, irrespective of diagnosis and drug.”

In comments to Psychiatric News, Jeste emphasized that the study results should not be interpreted to mean these antipsychotics should be banned, but that the results pertain to long-term safety and effectiveness, not to short-term use.

Jeste emphasized the importance of shared decision making involving patients and family members when prescribing antipsychotics for any condition, for any duration. And he urged clinicians to consider psychosocial treatments for psychosis related to dementia when possible and appropriate; he said mild symptoms of psychosis related to dementia can sometimes respond to old-fashioned “tender loving care.”

“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.” ■