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 2 drugs,
they said, exert their primary effect considerably upstream of protein kinase C & ultimately work through an indirect
cascade of events.
Although there have been substantial
gains with lithium, valproate, carbamazepine & atypical antipsychotic drugs, the researchers said, those drugs may take
more than a week to start working & 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
& two women, mean age 35.4, with a mean length of illness of 16.4 years & a mean duration of the current manic episode
of 33.9 days. Of these more than 1/2 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 3 weeks. Primary efficacy was assessed by the Young Mania Rating
Scale.
The 8 patients
on tamoxifen showed significant improvement in mania compared with placebo as early as 5 days (d=0.59, 95% CI, 0.17-1.00),
a 50% or greater effect that remained significant throughout the 3 week trial (d=1.11, CI, 0.59-1.64).
The placebo group
showed no significant change from baseline at any point.
After 3 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 (5 of 8 patients) & 13% (1 of 8) 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 & that of other recent studies
with tamoxifen, the researchers said.
Lorazepam (Ativan)
was used during the trial for 4 of the tamoxifen patients & 6 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 didn't 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 isn't entirely protein kinase C-selective & also has anti-estrogen
effects. Thus, they said, they couldn't 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, i.e., 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.
source: medpage today
