Zarate Carlos A, Singh Jaskaran B, Carlson Paul J, Quiroz Jorge, Jolkovsky Libby, Luckenbaugh David A, Manji Husseini K
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.
Bipolar Disord. 2007 Sep;9(6):561-70. doi: 10.1111/j.1399-5618.2007.00530.x.
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.
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.
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).
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.
大量临床前生化和行为学数据表明，蛋白激酶C抑制可产生抗躁狂作用。值得注意的是，结构上差异很大的抗躁狂药物锂盐和丙戊酸盐，在治疗相关模式下给药时，会减弱蛋白激酶C的功能。目前仅有一种相对选择性的可穿越血脑屏障供人类使用的蛋白激酶C抑制剂——他莫昔芬。我们小组最近对他莫昔芬治疗急性躁狂进行了一项单盲研究，发现其在短时间内（3 - 7天）能显著减轻躁狂症状。在本研究中，我们调查了在躁狂症患者中使用蛋白激酶C抑制剂是否能产生抗躁狂作用。
在一项双盲、安慰剂对照研究中，16名双相情感障碍、躁狂或混合发作、有或无精神病性特征的患者被随机分配接受他莫昔芬（20 - 140毫克/天；n = 8）或安慰剂（n = 8），为期三周。主要疗效通过杨氏躁狂量表进行评估。
与安慰剂相比，服用他莫昔芬的患者早在五天时躁狂症状就有显著改善，且在整个三周试验中这种效果一直显著。三周后药物差异的效应量非常大（d = 1.08，95%置信区间0.45 - 1.71）（p = 0.001）。在研究终点，他莫昔芬组的有效率为63%，安慰剂组为13%（p = 0.12）。
蛋白激酶C抑制剂产生了抗躁狂作用；起效时间在五天内。有必要对选择性蛋白激酶C抑制剂治疗急性躁狂进行大规模对照研究。
