Efficacy of a protein kinase C inhibitor (tamoxifen) in the treatment of acute mania: a pilot study.
OBJECTIVE
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 [corrected] 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.
Zarate
Carlos A
CA
Laboratory of Molecular Pathophysiology and Experimental Therapeutics, Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA. zaratec@mail.nih.gov
Singh
Jaskaran B
JB
Carlson
Paul J
PJ
Quiroz
Jorge
J
Jolkovsky
Libby
L
Luckenbaugh
David A
DA
Manji
Husseini K
HK
D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D001714:Bipolar Disorder / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D011569:Psychiatric Status Rating Scales; D015398:Signal Transduction / Q000187:drug effects; D013629:Tamoxifen / Q000008:administration & dosage* / Q000009:adverse effects; D016896:Treatment Outcome
D013629:Tamoxifen; D011493:Protein Kinase C