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Tamoxifen for Mania: Maybe It’s Not Just for Breast Cancer

Results from a small pilot study are promising.

Acute mania is treated with antipsychotics and with mood stabilizers (lithium and the anticonvulsants valproate and carbamazepine). Identifying the biochemical targets of these medications has been challenging. A recent hypothesis is that the protein kinase C (PKC) signaling cascade is a target of the mood stabilizers. This is supported by gene studies and animal models, suggesting that PKC activation is associated with mania-like behavior. PKC inhibitors block acute responses to cocaine and reduce risk-taking behavior. Tamoxifen, a nonsteroidal antiestrogen used to treat breast cancer, is a potent and selective PKC inhibitor that crosses the blood-brain barrier.

Investigators previously conducted a single-blind study of tamoxifen in acute mania. Now, in a double-blind study, they followed 16 inpatients (14 men; average age, 35) who had a diagnosis of bipolar disorder with a current manic or mixed episode. After a 2- to 7-day screening period and discontinuation of all medications except benzodiazepines, patients were randomized to 3 weeks of tamoxifen (20–140 mg/day) or placebo. The tamoxifen group showed significant improvement in mania starting on day 5 and continuing through day 21. Mania scores improved by more than 50% in five of eight patients in the tamoxifen group but in only one of eight in the placebo group. Loss of appetite was the only adverse effect that occurred more frequently with tamoxifen than with placebo.

Comment: Because tamoxifen has antiestrogenic as well as PKC-inhibiting effects, we cannot ascribe these therapeutic results to a specific mechanism of action. However, the results are intriguing and warrant replication in larger controlled trials. More specific PKC inhibitors should be developed and tested.

— Jonathan Silver, MD

Published in Journal Watch Psychiatry November 5, 2007

Citation(s):

Zarate CA Jr et al. Efficacy of a protein kinase C inhibitor (tamoxifen) in the treatment of acute mania: A pilot study. Bipolar Disord 2007 Sep; 9:561.

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