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Tamoxifen shows promise for acute mania.

ISTANBUL, TURKEY -- Tamoxifen, long a workhorse for the treatment and prevention of breast cancer, continues to show promise as a novel antimanic agent.

Findings from two separate, randomized, placebo-controlled clinical trials have shown tamoxifen to be an effective, fast-acting, and well-tolerated agent for the treatment of acute mania in patients with bipolar disorder, Dr. Aysegul Yildiz reported at the annual congress of the European College of Neuropsychopharmacology.

Tamoxifen is at present the only protein kinase C (PKC) inhibitor that crosses the blood-brain barrier available for human use. The evidence to date indicates that its antimanic effect is primarily attributable to this central inhibition of protein kinase C signaling rather than the antiestrogenic action that has long made the drug a mainstay in the field of breast cancer, according to Dr. Yildiz, a psychiatrist at Dokuz Eylul University, Izmir, Turkey.

PKC plays major roles in the regulation of neuronal excitability, neuroplasticity, and neurotransmitter release. The long-established antimanic agents, lithium and valproate, both inhibit PKC function even though they are structurally very dissimilar. Moreover, psychostimulants that can trigger manic episodes in susceptible patients activate PKC.

On the basis of animal studies suggesting that PKC signaling may be a promising new therapeutic target in mania, Dr. Yildiz conducted the first-ever randomized, double-blind, placebo-controlled clinical trial of tamoxifen in the treatment of mania. Sixty-six adults with bipolar I disorder in a manic or mixed state were randomized to tamoxifen or placebo for up to 3 weeks. A total of 83% of the tamoxifen group and 68% of the placebo group completed the 3-week study.

From a mean baseline Young Mania Rating Scale (YMRS) score of 38, the ta-moxifen-treated group averaged a drop of 5.84 points per week. This was accompanied by a mean 0.73-point drop per week in Clinical Global Impressions-Mania scores from a baseline of 6.0 points. In contrast, the control group experienced mean weekly increases of 1.5 points on the YMRS and 0.1 points on the Clinical Global Impressions-Mania instrument (Arch. Gen. Psychiatry 2008;65:255-63).

The clinical response rate as defined by at least a 50% reduction in YMRS was 48% in the tamoxifen arm and 5% in controls. The tamoxifen clinical response rate was comparable with that observed in short-term clinical trials of lithium and valproate, she continued.

Dr. Yildiz noted that a smaller yet similarly scientifically rigorous double-blind clinical trial of tamoxifen in acute mania has been conducted by investigators at the National Institute of Mental Health in Bethesda, Md.

Sixteen patients with manic or mixed bipolar disorder were randomized to tamoxifen at 20-140 mg/day or placebo for 3 weeks. During that time, the tamoxifen group experienced a mean 18.3-point drop in YMRS, compared with a 4.67-point increase in controls. Significant improvement in the tamoxifen-treated patients was seen as early as 5 days. After 3 weeks, 63% of patients in the tamoxifen arm and 13% of controls showed a significant response as measured by the YMRS (Bipolar Disord. 2007;9:561-70).


Major Findings: Patients on tamoxifen averaged a drop of 5.84 points per week on the Young Mania Rating Scale and a mean 0.73-point drop per week in Clinical Global Impressions-Mania scores, compared with the control group drop of 1.5 and 0.1 points, respectively.

Data Source: A double-blind, placebo-controlled clinical trial of 66 adults with bipolar I disorder in a manic or mixed state randomized to tamoxifen or placebo for up to 3 weeks.

Disclosures: The study was funded by the Stanley Medical Research Institute, Chevy Chase, Md. The investigator has no relevant disclosures.
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Author:Jancin, Bruce
Publication:Clinical Psychiatry News
Date:Feb 1, 2010
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