Breast Cancer Drug Tames Acute Mania in Bipolar Disorder

BETHESDA, Md., Sept. 12 -- Tamoxifen significantly decreased symptoms of acute mania beginning as early as five days in patients with bipolar disorder in a small pilot study.

The drug, approved to treat breast cancer, maintained its effect throughout a three-week trial with a response rate of 63% for tamoxifen versus 13% for placebo, Carlos A. Zarate, Jr., M.D., of the National Institute of Mental Health, and colleagues reported online in the Sept. issue of Bipolar Disorders.

Tamoxifen is a relatively selective protein kinase C inhibitor with the advantage that it crosses the blood-brain barrier, the researchers wrote.

They reasoned that because tamoxifen inhibits protein kinase C directly, it would produce anti-manic effects more rapidly than previously achieved with lithium or valproate (Depacon).

Those two drugs, they said, exert their primary effect considerably upstream of protein kinase C and ultimately work through an indirect cascade of events.

Although there have been substantial gains with lithium, valproate, carbamazepine, and atypical antipsychotic drugs, the researchers said, those drugs may take more than a week to start working and many patients don't respond adequately to or can't tolerate the side effects of the treatment.

The researchers acknowledge that tamoxifen is unlikely to become the drug of choice because it may cause endometrial cancer if taken for extended periods. However, they noted, by pointing to protein kinase C as a target for new medications, the study raises the possibility of developing faster-acting treatments for the often-destructive early manic phase of the illness.

The tamoxifen findings came from a double-blind, placebo-controlled pilot study of 16 patients with manic or mixed bipolar disorder, with or without psychotic features.

The study included 14 men and two women, mean age 35.4, with a mean length of illness of 16.4 years, and a mean duration of the current manic episode of 33.9 days. Of these more than half had a lifetime diagnosis of any substance abuse or dependence.

The patients were randomly assigned to receive tamoxifen (20-140 mg/day) or placebo for three weeks. Primary efficacy was assessed by the Young Mania Rating Scale.

The eight patients on tamoxifen showed significant improvement in mania compared with placebo as early as five days (d=0.59, 95% CI, 0.17-1.00), a 50% or greater effect that remained significant throughout the three-week trial (d=1.11, CI, 0.59-1.64).

The placebo group showed no significant change from baseline at any point.

After three weeks, the researchers said, the effect size for the drug difference was "very large" (d=1.08, 95% C.I., 0.45 to 1.71 (P=0.001).

At the end of the study, response rates were 63% for tamoxifen (five of eight patients) and 13% (one of eight) for placebo (Fisher's Exact P=0.12), the researchers reported.

The tamoxifen group showed a decrease of 18.3 points from baseline to endpoint on the Young Mania scale, while the placebo patients' mania worsened 4.7 points. These findings support the results of an earlier single-blind study and that of other recent studies with tamoxifen, the researchers said.

Lorazepam (Ativan) was used during the trial for four of the tamoxifen patients and six of the placebo patients. And it has been suggested that the anti-manic effects seen with tamoxifen were related to the lorazepam, which also has anti-manic effects. However, the researchers noted, lorazepam dose as a time-dependent covariate did not alter the tamoxifen results.

Overall, tamoxifen was well tolerated, they said, with loss of appetite the main side effect. Contrary to previous reports that tamoxifen might cause depression, the researchers said they found no such effect.

An unavoidable limitation of the study, the researchers noted, is that tamoxifen is not entirely protein kinase C-selective and also has anti-estrogen effects. Thus, they said, they could not clearly exclude the potential contributory effect of estrogen receptor blockade.

The preliminary results of this pilot study need to be interpreted with caution, Dr. Zarate said. First, the group size was small, although the results were sufficiently positive to suggest pursuing larger controlled trials with protein kinase inhibitors in mania.

Second, the results may not be generalizable to patients with certain characteristics, for example, those with current substance abuse disorders. Finally, he said, these results may not apply beyond the acute treatment phase of bipolar mania.

The findings of this pilot study suggest that protein kinase inhibition might be relevant to the anti-manic effects of lithium and valproate. Large controlled studies with selective protein kinase C inhibitors in acute bipolar mania are warranted, the researchers said.

The study was supported by the Intramural Research Program at the National Institute of Mental Health, the National Institutes of Health, and the Department of Health & Human Services. Co-author Jaskaran B. Singh, M.D., is currently at Johnson & Johnson Pharmaceutical Research and Development L.L.C.