Reuters reported on a study by the National Institute of Mental Health that showed breast cancer drug tamoxifen may have an effect on the “manic” symptoms of bipolar disorder. The researchers used tamoxifen because of its effect on protein kinase C (PKC), an enzyme that has many effects on cells, including brain cells. PKC may be overactive in bipolar mania. The study was published in the September 2007 issue of the medical journal, Bipolar Disorders.

My major concern about this study is that it is extremely small: only 16 patients. These 16 patients were then given either tamoxifen or placebo for 3 weeks, and 10 out of the 16 patients had reduced mania symptoms compared with placebo. According to the study, effects were observable within 5 days. According to Reuters, tamoxifen is “too dangerous” of a drug for use in bipolar disorder, and this study is meant to encourage the search for bipolar disorder drugs that target PKC. One of the study investigators believes that targeting PKC may allow for faster effects of antimania drugs.

Zarate Jr CA, Singh JB, Carlson PJ, Quiroz J, Jolkovsky L, Luckenbaugh DA, Manji HK. Efficacy of a protein kinase C inhibitor (tamoxifen) in the treatment of acute mania: a pilot study.
Bipolar Disord 2007: 9: 561–570. © Blackwell Munksgaard, 2007 (free text is available as of September 12, 2007)

Objectives: Considerable preclinical biochemical and behavioral data suggest that protein kinase C inhibition would bring about antimanic effects. Notably, the structurally highly dissimilar antimanic agents lithium and valproate, when administered in therapeutically relevant paradigms, attenuate protein kinase C inhibition function. There is currently only one relatively selective protein kinase C inhibitor that crosses the blood–brain barrier available for human use – tamoxifen. Our group recently conducted a single-blind study with tamoxifen in acute mania and found that it significantly decreased manic symptoms within a short period of time (3–7 days). In this study, we investigated whether antimanic effects can be achieved with a protein kinase C inhibitor in subjects with mania.

Methods: In a double-blind, placebo-controlled study, 16 subjects with bipolar disorder, manic or mixed, with or without psychotic features, were randomly assigned to receive tamoxifen (20–140 mg/day; n = 8 ) or placebo (n = 8 ) for three weeks. Primary efficacy was assessed by the Young Mania Rating Scale.

Results: Subjects on tamoxifen showed significant improvement in mania compared to placebo as early as five days, an effect that remained significant throughout the three-week trial. The effect size for the drug difference was very large (d = 1.08, 95% confidence interval 0.45–1.71) after three weeks (p = 0.001). At study endpoint, response rates were 63% for tamoxifen and 13% for placebo (p = 0.12).

Conclusions: Antimanic effects resulted from a protein kinase C inhibitor; onset occurred within five days. Large, controlled studies with selective protein kinase C inhibitors in acute mania are warranted.

Original source: Reuters Health