The second-generation antipsychotic (SGA) risperidone, widely used to treat patients with military-related posttraumatic stress disorder (PTSD) that is resistant to SSRI antidepressants, appears to be ineffective as an adjunctive treatment.

That surprising news comes from John Krystal, M.D., a professor and chair of the Department of Psychiatry at Yale School of Medicine, and his colleagues at the Department of Veterans Affairs National Center for PTSD. They made the determination after conducting a randomized, double-blind, placebo-controlled, multicenter study from February 2007 to February 2010 at 23 Veterans Administration (VA) outpatient medical centers.

There were no significant effects of adjunctive risperidone treatment on the primary outcome measure, the change in total score from baseline to 24 weeks on the Clinician Administered PTSD Scale. Risperidone was also not superior to placebo on the secondary outcomes, including the observer- and self-rated versions of the Clinical Global Impressions scale; quality of life; and measures of depression, anxiety, or paranoia/psychosis.

The researchers believe this study is the first large trial of a pharmacotherapy aimed at SSRI-resistant PTSD symptoms. "Overall, the data do not provide strong support for the current widespread prescription of risperidone to patients with chronic SSRI-resistant military-related PTSD symptoms," they said in the August 3 Journal of the American Medical Association.

That revelation may leave practitioners with few weapons in their pharmacotherapeutic arsenal. Two SSRI antidepressants, sertraline and paroxetine, are the only pharmacotherapies approved by the Food and Drug Administration for the treatment of PTSD. According to a 2008 study from the U.S. Department of Veterans Affairs, 89 percent of veterans diagnosed with PTSD and treated with pharmacotherapy are prescribed SSRIs.

But SSRIs appear to be less effective in men than in women, and less effective for chronic PTSD than acute PTSD. And SGAs, namely risperidone, were thought to be the next logical step in treatment.

"There were several paths to the widespread prescription of the SGA risperidone for SSRI-resistant PTSD symptoms," Krystal explained to Psychiatric News. "These medications were commonly prescribed as adjunctive therapy for people with PTSD and comorbid psychosis. Early reports suggested SGAs were more helpful than the first-generation antipsychotics for aggression, sleep disturbance, and mood symptoms. Adjunctive SGA therapy for SSRI-resistant symptoms emerged as a practice supported by case reports, case series, and studies."

"For many VA clinicians, the choice was also driven by the side-effect profile," he pointed out. "Most VA PTSD patients are Vietnam veterans, who are now in their 60s and 70s. This population has higher lifetime rates of smoking and alcohol use disorders than the general population, and is at risk for obesity, hypertension, diabetes, coronary artery disease, and cerebrovascular disease. Risperidone is associated with fewer contraindications for these patients and initially was the SGA most commonly prescribed for this population."

So what's next in light of these results? "The next step is to study the other commonly prescribed medications used as adjunctive treatments for PTSD," said Krystal. "We need to understand whether drugs like prazosin and trazodone and other similar medications that are widely prescribed to people with PTSD deliver on their promise. Some of those studies are already under way. We also need to continue our work studying the neurobiology of PTSD. We believe that better understanding of the underlying brain function will point us to new mechanisms for treatment of PTSD."

How do Krystal and his colleagues feel about their findings? "We're disappointed by the lack of overall benefit associated with risperidone in our study. There is real need for effective adjunctive pharmacotherapy for PTSD, and we had hoped to find more evidence of risperidone efficacy," he said. "However, we believe that there is a "silver lining." Progress in large-scale pharmacotherapy research is slow and expensive, but it has impact. Our findings will very likely influence the risk-benefit decisions that doctors make, increasing their caution in prescribing risperidone as an adjunctive medication for PTSD or in continuing risperidone prescriptions for patients who show little evidence of benefit."

This study was supported by the Cooperative Studies Program of the Department of Veterans Affairs Office of Research and Development. Risperidone and placebo were donated by Ortho-McNeil Janssen Scientific Affairs, which also contributed funds to the Baltimore Research and Education Foundation on behalf of the VA Cooperative Studies Program.

An abstract of "Adjunctive Risperidone Treatment for Antidepressant-Resistant Symptoms of Chronic Military Service-Related PTSD: A Randomized Trial" is posted at <http://jama.ama-assn.org/content/306/5/493.abstract>.