Tamoxifen Efficacy in Bipolar Mania Gets Additional Backing

By John Gever
IZMIR, Turkey, March 3 -- More evidence has suggested that protein kinase C inhibitors may be effective in the manic phase of bipolar disorder, researchers here said.
Point out that tamoxifen is not approved for bipolar disorder and carries safety risks in long-term use.
Explain that a smaller study last year had a similar finding.
Manic patients treated with the breast cancer drug tamoxifen for three weeks showed a mean decrease of 5.84 points on the Young Mania Rating Scale, compared with an increase of 1.50 points among patients receiving placebo (P<0.001), reported Aysegul Yildiz, M.D., of Dokuz Eylul University, and colleagues in the March issue of Archives of General Psychiatry.
In addition to its role as an estrogen-receptor antagonist used against breast caner, tamoxifen is an inhibitor of protein kinase C.
The 66-patient randomized, double-blind trial is the second to show that tamoxifen can reduce mania symptoms. Similar results were reported last September in a placebo-controlled trial of 16 patients. (See: Breast Cancer Drug Tames Acute Mania in Bipolar Disorder).
Dr. Yildiz and colleagues did not recommend tamoxifen as an appropriate drug for long-term management of bipolar disorder because the agent heightens the risk of endometrial cancer.
Rather, they suggested the findings validate "the protein kinase C system as a plausible target for novel mood-stabilizing treatments."
In the current trial, the patients had bipolar I disorder according to DSM-IV criteria, in a manic or mixed state with Young Mania Rating Scale scores of more than 20 at enrollment.
Patients received either tamoxifen or placebo for three weeks, along with up to 5 mg/day lorazepam if clinically indicated.
The starting dose of tamoxifen was 40 mg/day, which was then increased in 10-mg increments to 80 mg/day.
About four-fifths of patients had received some other type of psychiatric medication in the month before entering the study. Mean scores on the Young Mania Rating Scale at baseline were 38.6 (SD 5.0) among patients assigned to tamoxifen and 37.2 (SD 6.6) in the placebo group.
Patients were also assessed with the Clinical Global Impressions-Mania scale, with baseline scores of 6.0 (SD 0.9) and 5.9 (SD 1.0) in the tamoxifen and placebo groups, respectively.
About 17% of patients in the tamoxifen group and 32% of those receiving placebo discontinued treatment prematurely because of clinical worsening. The difference was not statistically significant.
On an intent-to-treat basis, scores on both the Young and Clinical Global Impressions mania evaluations decreased significantly with tamoxifen relative to placebo.
Clinical Global Impressions-Mania scores declined by a mean of 0.73 points with tamoxifen versus an increase of 0.10 points in the placebo group (P<0.001).
Fourteen of 29 patients completing three weeks of tamoxifen treatment showed at least 50% reduction in symptoms according to the Young scale, compared with 5% of patients in the placebo group (P=0.003).
Clinical remission (Young score of 12 or less) was seen in 28% of the tamoxifen group versus none of the placebo group.
Dr. Yildiz and colleagues also found that lorazepam use was significantly lower in the tamoxifen group. The three-week average total dose of lorazepam was 25.2 mg (SD 16.1) in the tamoxifen group and 41.8 mg (SD 36.0) in placebo-treated patients (P=0.04).
Use of lorazepam was similar in the two groups during the first treatment week, but usage diverged markedly after that.
One patient in each group attempted suicide during the trial. Both cases were associated with delusions and neither patient showed signs of depression or a mixed state.
Other adverse events were minor or moderate. They were reported in 20% of tamoxifen patients and 10% of those receiving placebo, with no clear pattern or significant difference between groups.
Dr. Yildiz and colleagues noted that the placebo response was "remarkably poor" relative to what has been reported in other short-term studies of manic patients.
The researchers had no definitive explanation for this finding. They said the placebo group mean may have been skewed by five patients who showed major worsening in Young scores during the trial. These patients had received antipsychotic medication a few weeks before entering the study and were still very ill.
On the other hand, the tamoxifen group included at least six patients with similar histories and illness severity at enrollment, and they all improved substantially with treatment, Dr. Yildiz and colleagues said.
Another possible influence was a significant baseline difference between the placebo and tamoxifen group in pre-trial drug treatment, the researchers said. Some 68% of placebo-group patients versus 49% of those assigned to tamoxifen had received anti-manic or antipsychotic medication prior to entry.
The researchers said a major limitation of their study was its short duration. Such trials, they wrote, "may demonstrate technical 'efficacy' (greater symptomatic improvement than with placebo) but usually are too brief to quantify clinically important rates of syndromal, symptomatic, or functional recovery, which typically evolve over several months."
In an accompanying commentary, Mauricio Tohen, M.D., Dr.P.H., a researcher at Lilly in Indianapolis, pointed to another unusual aspect of the study, which was that Dr. Yildiz conducted all the clinical ratings herself using "all available clinical information." He said that could have introduced subtle biases.
That the study was conducted at a single site is a limitation as well, he said.
"Reproducibility of the results needs to be considered before large multi-site studies are initiated," Dr. Tohen wrote.
But in combination with the earlier clinical trial and other studies, the Turkish study "support[s] further study of agents with central anti-protein kinase C activity," he said.
He observed that no drug has yet been developed for bipolar disorder based on understanding of its pathophysiology or on mechanisms of effective treatments.
"Undoubtedly, this will be an important step to conquer this devastating disorder that affects millions of patients around the globe," Dr. Tohen wrote.
The study was supported by the Stanley Medical Research Institute.
The authors reported no potential conflicts of interest.
Dr. Tohen is an employee and stockholder of Eli Lilly & Co.

Primary source: Archives of General PsychiatrySource reference:Yildiz A, et al "Protein kinase C inhibition in the treatment of mania: a double-blind, placebo-controlled trial of tamoxifen" Archives of General Psychiatry 2008; 65: 255-63.

Additional source: Archives of General PsychiatrySource reference: Tohen M, "Clinical trials in bipolar mania: implications in study design and drug development" Archives of General Psychiatry 2008; 65: 252-53.