Less than half of patients suffering from major depressive disorder, a leading cause of disability worldwide, achieve remission with current antidepressants, making it imperative to develop more effective treatment. A new therapeutic direction is emerging from the increased understanding of natural resilience as an active stress-coping process. It is known that potassium (K(+)) channels in the ventral tegmental area (VTA) are an active mediator of resilience. However, no druggable targets have been identified to potentiate active resilience mechanisms. In the chronic social defeat stress model of depression, we report that KCNQ-type K(+) channel openers, including FDA-approved drug retigabine (ezogabine), show antidepressant efficacy. We demonstrate that overexpression of KCNQ channels in the VTA dopaminergic neurons and either local infusion or systemic administration of retigabine normalized neuronal hyperactivity and depressive behaviours. These findings identify KCNQ as a target for conceptually novel antidepressants that function through the potentiation of active resilience mechanisms.

中文翻译：

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KCNQ通道开放剂通过主动的适应力机制逆转抑郁症状。

患有严重抑郁症（世界范围内导致残疾的主要原因）的患者中，只有不到一半的患者能够通过目前的抗抑郁药获得缓解，因此必须开发出更有效的治疗方法。对自然弹性作为一种积极的压力应对过程的理解日益加深，新的治疗方向正在出现。众所周知，腹侧被盖区（VTA）中的钾（K（+））通道是弹性的主动介体。但是，尚未发现可药物化的靶标能够增强主动的适应力机制。在抑郁症的慢性社会衰竭应激模型中，我们报告说KCNQ型K（+）通道开放剂，包括FDA批准的药物瑞替加滨（ezogabine），显示出抗抑郁功效。我们证明，在VTA多巴胺能神经元中过表达KCNQ通道，以及局部输注或全身使用瑞替加滨可归一化神经元过度活跃和抑郁行为。这些发现将KCNQ确定为概念上新型抗抑郁药的靶标，这些抗抑郁药通过增强活性弹性机制发挥功能。