Dec. 26, 2002 PORTLAND, Oregon, December 20, 2002 -- Reporting in the January issue of the journal Neuropsychopharmacology, Portland Veterans Affairs Medical Center researchers and colleagues have found that combining the anticonvulsant drug divalproex with either olanzapine or risperidone-two commonly used antipsychotic drugs-significantly enhanced and hastened responses in patients suffering from acute psychotic episodes of schizophrenia.
"Our findings suggest that combination therapy with divalproex can decrease the mental pain and suffering for many patients with schizophrenia and shorten the time they need to be in the hospital," said study leader Daniel E. Casey, M.D., Associate Director of Research for the VA Northwest Network's Mental Illness Research, Education and Clinical Center, Chief of Psychiatric Research at the Portland VAMC and Professor of Psychiatry and Neurology at Oregon Health & Science University.
Compared to patients treated with either antipsychotic drug alone, the researchers found, those treated with the combination showed an enhanced reduction of symptoms as early as the third day of therapy. Further, the combination therapy was as well tolerated as either antipsychotic drug used alone, with no additional side effects.
More than 2 million Americans suffer from schizophrenia. One of the world's most common and potentially devastating of all mental illnesses, this chronic disorder is characterized by symptoms such as delusions, hallucinations and grossly disorganized behavior. Patients often have difficulty recognizing reality, thinking logically and behaving normally in social situations. Antipsychotic medications can help many schizophrenia patients lead normal lives, Casey pointed out, but the disorder's causes are incompletely understood and there is no cure.
Although divalproex is commonly used to treat mood disorders, seizures and migraine headache, scientists long ago found the drug ineffective if used alone to treat schizophrenia. Since about 10 percent of patients suffering from schizophrenia also have mood-disorder symptoms, however, divalproex is often used in combination with antipsychotics that target the schizophrenia symptoms.
"We've been getting a clinical signal from physicians that patients receiving this combination seem to improve more in their schizophrenia symptoms than those being treated with an antipsychotic alone," Casey said. "We needed to find out if this signal pointed to something real." The resultant study is the first large-scale trial to assess divalproex in combination with an antipsychotic agent in the treatment of schizophrenia.
In their multi-center trial, Casey and his colleagues studied 249 patients between ages 18-65 who were hospitalized with an acute psychotic episode (exacerbation) of schizophrenia. Patients who also suffered from mood symptoms were excluded from the trial. Sixty-five participants were randomly assigned to receive the antipsychotic olanzapine, 66 received olanzapine with divalproex, 60 received the antipsychotic risperidone alone and 58 got risperidone plus divalproex.
Olanzapine and risperidone belong to two different classes of antipsychotic drugs, Casey noted. Patients were treated for 28 days and evaluated at 3, 5, 7, 10, 14, 21 and 28 days with the Positive and Negative Syndrome Scale total score, a common psychiatric diagnostic tool used to measure changes in patient behavior. Improvements from baseline scores were observed throughout the treatment period in all four groups.
"At day 3 we were already seeing significant enhancement of benefits in the combination groups," Casey said. Clinical improvement, defined as a 20 percent or greater improvement from baseline scores, was seen in 53 percent of patients in the combination groups on day 7, but this degree of improvement was not achieved until day 14 in the groups being treated by either antipsychotic drug alone. A 20 percent improvement in symptoms is commonly used as a threshold to determine that a patient is ready to leave the hospital, Casey pointed out, "so for many patients the combination therapy has the potential to cut in half the time they have to spend in the hospital."
Both combination and single-drug therapy were well tolerated. Adverse effects and rates of discontinued therapy were similar among all treatment groups.
About 25-30 percent of schizophrenia patients respond poorly to antipsychotic drug therapy, Casey noted. Potential results of longer combination therapy in these patients remains to be explored, he said, as well as whether the enhanced improvements of combination therapy observed in this study will be sustained, increased or diminished over longer periods of follow-up.
In addition to Casey, the research team included David G. Daniel, M.D., of George Washington University and Bioniche Development; Adel Wassef, M.D., of the University of Texas, Houston; Katherine Tracy, M.D., Ph.D., of the University of Illinois, Chicago, and Abbott Laboratories; and Patricia Wozniak, Ph.D., and Kenneth W. Sommerville, M.D., of Abbott Laboratories, as well as many other investigators in the divalproex study group. The research was supported in part by Abbott Laboratories.
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