Smith G C, McEwen H, Steinberg J D, Shepherd P R
Department of Molecular Medicine and Pathology, University of Auckland, Auckland, New Zealand,
Psychopharmacology (Berl). 2014 Dec;231(23):4553-60. doi: 10.1007/s00213-014-3608-0. Epub 2014 May 7.
The second generation antipsychotic drug clozapine is a much more effective therapy for schizophrenia than first generation compounds, but the reasons for this are poorly understood. We have previously shown that one distinguishing feature of clozapine is its ability to raise glucagon levels in animal models and thus causes prolonged hyperinsulinemia without inducing hypoglycaemia. Previous studies have provided evidence that defects in Akt/PKB and GSK3 signalling can contribute to development of psychiatric diseases. Clozapine is known to activate Akt/PKB in the brain, and some studies have indicated that this is due to a direct effect of the drug on the neurons. However, we provide strong evidence that elevated insulin levels induced by clozapine are in fact the real cause of the drug's effects on Akt/PKB and GSK3 in the brain. This suggests that the elevated levels of insulin induced by clozapine may contribute to this drug's therapeutic efficacy.
第二代抗精神病药物氯氮平对精神分裂症的治疗效果比第一代化合物要好得多，但其原因却鲜为人知。我们之前已经表明，氯氮平的一个显著特征是它能够在动物模型中提高胰高血糖素水平，从而导致长时间的高胰岛素血症而不诱发低血糖。先前的研究已经提供证据表明，Akt/PKB和GSK3信号通路的缺陷可能导致精神疾病的发展。已知氯氮平能在大脑中激活Akt/PKB，一些研究表明这是该药物对神经元的直接作用。然而，我们提供了强有力的证据表明，氯氮平诱导的胰岛素水平升高实际上是该药物对大脑中Akt/PKB和GSK3产生作用的真正原因。这表明氯氮平诱导的胰岛素水平升高可能有助于该药物的治疗效果。
