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A one-year maintenance study of divalproex sodium suggests that it is effective in long-term treatment of bipolar disorder, according to research presented in November at the United States Psychiatric and Mental Health Congress in Orlando, Fla.
The study was conducted by Charles Bowden, M.D., the Karren Professor of Psychiatry and Pharmacology at the University of Texas at San Antonio. Bowden is APA’s Area 5 Trustee and the Board liaison to the Council on Research. The research was funded by Abbott Laboratories, which manufactures the only available form of divalproex sodium under the brand name Depakote. An inexpensive generic of the active metabolite, valproic acid, is available, but it is associated with more gastrointestinal upset than divalproex, according to Bowden.
The study is the only long-term study of divalproex sodium for bipolar disorder, Bowden noted. It involved a sample of 372 patients with bipolar disorder randomized to either divalproex, lithium, or placebo. Although divalproex was more effective than either lithium or placebo, all three had high dropout rates, from slightly more than 60 percent for divalproex to just under 76 percent for lithium and 71 percent for placebo.
The data are being reviewed for possible publication in a peer-reviewed journal; they were presented publicly in three forums, according to Bowden. In addition to the psychiatric congress, the data were presented last year at the annual meeting of the Canadian Psychiatric Association in Calgary and at the meeting of the European College of Neuropsychopharmacology in Vienna .
The study has received a significant amount of attention because it is the longest controlled study of divalproex to date, said Bowden. Because of ethical and logistical concerns, conducting long-term controlled studies of therapies for bipolar disorder is difficult, Bowden observed. Longer term studies involving lithium, for example, have been naturalistic, he noted.
Early studies of lithium in bipolar disorder had design flaws, according to Bowden. "They took people who had been on lithium and abruptly stopped them," he explained. "It’s now understood that this causes a rebound increase in depressive and manic episodes." That skewed the outcome for subjects on placebo and made the lithium look more effective than it was, he noted. It also "made the so-called natural course of the illness look worse" than it really was, he added.
"The fact of the matter is that in this study we just completed, lithium looks better than placebo, but it doesn’t look substantially better for a good percentage of patients with bipolar disorder," Bowden commented. "On most measures, it looks significantly less effective than divalproex sodium." One caveat is that "on a number of measures neither divalproex nor lithium were [statistically] significantly better than placebo, although there were trends," Bowden noted.
The study included "educational and close patient support," observed Bowden, which may account for positive outcomes even with pharmacological placebo. Although this complicates data analysis, it supports a long-standing APA position that pharmacotherapy and psychotherapy not be separated, he noted.
The drug should be studied in people with mixed impulsivity disorders and in adolescents, he said. These groups are likely to include a substantial number of people with substance abuse disorders, and it may be possible to test not only the impact of the drug on bipolar disorder, but also whether it will reduce substance abuse in comorbid patients, he noted. Bowden would also like to see further research on subgroups within bipolar disorder, he said. He and colleagues will do some post-hoc analyses of subgroups using the data from the current study.
For any relatively new treatment in which research data are limited, it is necessary to be cautious in interpreting the data, Bowden observed. But he anticipated that the research would "encourage broader and more long-term use of divalproex" in bipolar disorder.
James Jefferson, M.D., is a clinical professor of psychiatry at the University of Wisconsin Medical School and distinguished senior scientist at the nonprofit Dean Foundation for Health, Research, and Education in Madison, Wis. The Dean Foundation was one of the sites for the Bowden study.
Jefferson noted in an interview that the complete study has yet to be published, and that it is difficult to comment without having seen all of the data. But he offered an assessment based on the information presented by Bowden.
"With this current study, there is a high dropout rate, but this is an extremely difficult patient group to treat," Jefferson said. "I think Abbott is to be commended" for funding these kinds of studies, which involve data that "may be more difficult to interpret due to the high dropout rate."
It is reasonable to assume that most psychiatric medications that are effective short term are likely to be effective over the long term, said Jefferson. "My assumption is that [medications] that work acutely work long term."
Although the study did reveal a statistically significant difference between divalproex, lithium, and placebo, it was not pronounced, Jefferson pointed out. "The bottom line, however, is that divalproex is another drug effective in treating bipolar disorder." It is not, according to the data, an ideal maintenance drug, said Jefferson. "An ideal maintenance drug would reduce recurrence of both manic and depressive episodes," he noted, but the data show divalproex to be more effective for mania than for depression.
The study design excludes patients who have a history of treatment cessation due to adverse effects to divalproex or lithium. But clinicians are unlikely to refer patients to a study if the patients are reacting well to a medication, which suggests that the subjects for the current study may have been more difficult to treat than a randomly selected group of bipolar patients, Jefferson said.