Treatment with the anticonvulsant divalproex in combination with olanzapine or risperidone significantly enhances both efficacy and time to response in patients suffering from acute psychotic episodes of schizophrenia, investigators reported in the January issue of Neuropsychopharmacology. For patients with schizophrenia who have mood disorder symptoms, divalproex is a common treatment. “Physicians had been reporting that patients receiving combination therapy appeared to have more improvement in their schizophrenia symptoms than those on antipsychotic monotherapy,” said lead author Daniel E. Casey, MD, Associate Director in the VISN 20 Mental Illness Research, Education, and Clinical Center, Chief of Psychiatric Research at the Portland Veterans Affairs Medical Center, and Professor of Psychiatry and Neurology at Oregon Health and Science University in Portland. “We decided to study this phenomenon to see if it might open up new therapeutic insights.”

TANDEM TREATMENT

In the first large, multicenter, prospective, double-blind study examining the use of divalproex in combination with antipsychotic therapy, Dr. Casey and his colleagues enrolled 249 patients, ages 18 to 65, who had been hospitalized with an acute psychotic episode of schizophrenia. Those diagnosed with mood symptoms were excluded. The investigators randomly assigned 65 patients to olanzapine monotherapy, 66 to olanzapine and divalproex, 60 to risperidone monotherapy, and 58 to risperidone and divalproex. They observed the participants’ improvements during 28 days of treatment, using the Positive and Negative Syndrome Scale total score to measure changes in patient behavior.

All therapies were well tolerated and rates of adverse events and early exits from the study were similar among the treatment groups. Dr. Casey reported that by the third day, the investigators were seeing significant enhancement of efficacy in the combination therapy groups. They observed clinical improvement (defined as a 20% or greater improvement from baseline scores) in 53% of patients in the combination groups by day 7. A similar rate of improvement was not reached until day 14 in the monotherapy groups.

SIGNIFICANT REDUCTIONS, SIGNIFICANT CHALLENGES

As a 20% improvement in symptoms is a standard guideline to determine release from the hospital, Dr. Casey suggested that “for many patients combination therapy has the potential to cut in half the time they have to spend in the hospital.” He noted, however, that 25% to 30% of patients with schizophrenia do not respond well to antipsychotic drug therapy.

Dr. Casey proposed that long-term combination therapy in these patients should be studied. He also cited the need to study whether the enhanced improvements of combination therapy will be sustained, increased, or diminished over time.

—Bruce Sylvester

Suggested Reading
Casey DE, Daniel DG, Wassef AA, et al. Effect of divalproex combined with olanzapine or risperidone in patients with an acute exacerbation of schizophrenia. Neuropsychopharmacology. 2003;28:182-192.

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