Beijing Anding Hospital, Capital Medical University, 1720 Seventh Avenue South, Beijing, China.
Bipolar Disord. 2010 Nov;12(7):741-52. doi: 10.1111/j.1399-5618.2010.00866.x.
Bipolar disorder is a debilitating psychiatric illness presenting with recurrent mania and depression. The pathophysiology of bipolar disorder is poorly understood, and molecular targets in the treatment of bipolar disorder remain to be identified. Preclinical studies have suggested that glycogen synthase kinase-3 (GSK3) is a potential therapeutic target in bipolar disorder, but evidence of abnormal GSK3 in human bipolar disorder and its response to treatment is still lacking.
This study was conducted in acutely ill type I bipolar disorder subjects who were hospitalized for a manic episode. The protein level and the inhibitory serine phosphorylation of GSK3 in peripheral blood mononuclear cells of bipolar manic and healthy control subjects were compared, and the response of GSK3 to antimanic treatment was evaluated.
The levels of GSK3α and GSK3β in this group of bipolar manic subjects were higher than healthy controls. Symptom improvement during an eight-week antimanic treatment with lithium, valproate, and atypical antipsychotics was accompanied by a significant increase in the inhibitory serine phosphorylation of GSK3, but not the total level of GSK3, whereas concomitant electroconvulsive therapy treatment during a manic episode appeared to dampen the response of GSK3 to pharmacological treatment.
Results of this study suggest that GSK3 can be modified during the treatment of bipolar mania. This finding in human bipolar disorder is in agreement with preclinical data suggesting that inhibition of GSK3 by increasing serine phosphorylation is a response of GSK3 to psychotropics used in bipolar disorder, supporting the notion that GSK3 is a promising molecular target in the pharmacological treatment of bipolar disorder.
双相情感障碍是一种使人衰弱的精神疾病，表现为反复发作的躁狂和抑郁。双相情感障碍的病理生理学尚不清楚，治疗双相情感障碍的分子靶点仍有待确定。临床前研究表明，糖原合成酶激酶-3（GSK3）是双相情感障碍的潜在治疗靶点，但人类双相情感障碍中异常 GSK3 及其对治疗的反应的证据仍然缺乏。
本研究在因躁狂发作而住院的急性 I 型双相情感障碍患者中进行。比较双相躁狂患者和健康对照者外周血单个核细胞中 GSK3 的蛋白水平和抑制性丝氨酸磷酸化，评估 GSK3 对抗躁狂治疗的反应。
该组双相躁狂患者的 GSK3α 和 GSK3β 水平高于健康对照组。锂、丙戊酸和非典型抗精神病药物 8 周抗躁狂治疗后症状改善，同时 GSK3 的抑制性丝氨酸磷酸化显著增加，但 GSK3 的总水平没有增加，而躁狂发作时同时进行电惊厥治疗似乎抑制了 GSK3 对药物治疗的反应。
本研究结果表明，GSK3 可以在双相躁狂的治疗过程中被修饰。这一在人类双相情感障碍中的发现与临床前数据一致，即通过增加丝氨酸磷酸化抑制 GSK3 是 GSK3 对双相情感障碍中使用的精神药物的反应，支持 GSK3 是双相情感障碍药物治疗中一个有前途的分子靶点的观点。
