Morris Laurel S, Costi Sara, Hameed Sara, Collins Katherine A, Stern Emily R, Chowdhury Avijit, Morel Carole, Salas Ramiro, Iosifescu Dan V, Han Ming-Hu, Mathew Sanjay J, Murrough James W
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, USA.
Department of Psychiatry, University of Oxford, Oxford, UK.
Mol Psychiatry. 2025 Mar 25. doi: 10.1038/s41380-025-02957-7.
Up to half of individuals with depression do not respond to first-line treatments, possibly due to a lack of treatment interventions informed by neurobiology. A novel therapeutic approach for depression has recently emerged from translational work targeting aberrant activity of ventral tegmental area (VTA) dopamine neurons via modulation of the KCNQ voltage-gated potassium channels. In this study, individuals with major depressive disorder (MDD) with elevated anhedonia were randomized to five weeks of the KCNQ channel opener, ezogabine (up to 900 mg/day) or placebo. Participants completed functional MRI during a monetary anticipation task and resting-state at baseline and at end-of-treatment. The clinical results were reported previously. Here, we examined VTA activity during monetary anticipation and resting-state functional connectivity between the VTA and the ventromedial prefrontal cortex (mesocortical pathway) and ventral striatum (mesolimbic pathway) at baseline and end-of-treatment. Results indicated a significant drug-by-time interaction in VTA activation during anticipation (F = 4.36, p = 0.044), where VTA activation was reduced from pre-to-post ezogabine, compared to placebo. Mesocortical functional connectivity was also higher in depressed participants at baseline compared to a healthy control group (t = 2.68, p = 0.01) and associated with VTA hyper-activity during task-based functional MRI at baseline (R = 0.352, p = 0.033). Mesocortical connectivity was also reduced from pre-to-post ezogabine, compared to placebo (significant drug-by-time interaction, F = 4.317, p = 0.046). Together this translational work is consistent with preclinical findings highlighting VTA hyper-activity in depression, and suggesting a mechanism of action for KCNQ channel openers in normalizing this hyper-activity in individuals with both depression and anhedonia.
高达一半的抑郁症患者对一线治疗无反应，这可能是由于缺乏基于神经生物学的治疗干预措施。一种针对抑郁症的新型治疗方法最近从转化研究中出现，该研究通过调节KCNQ电压门控钾通道来靶向腹侧被盖区（VTA）多巴胺神经元的异常活动。在这项研究中，快感缺失程度较高的重度抑郁症（MDD）患者被随机分为接受为期五周的KCNQ通道开放剂依佐加滨（最高900毫克/天）或安慰剂治疗。参与者在金钱预期任务期间以及基线和治疗结束时的静息状态下完成功能磁共振成像。临床结果已在之前报道。在此，我们在基线和治疗结束时检查了金钱预期期间的VTA活动以及VTA与腹内侧前额叶皮质（中皮质通路）和腹侧纹状体（中边缘通路）之间的静息状态功能连接。结果表明，在预期期间VTA激活存在显著的药物×时间交互作用（F = 4.36，p = 0.044），与安慰剂相比，依佐加滨治疗前后VTA激活降低。与健康对照组相比，抑郁症患者在基线时的中皮质功能连接也更高（t = 2.68，p = 0.01），并且与基线时基于任务的功能磁共振成像期间的VTA过度活动相关（R = 0.352，p = 0.033）。与安慰剂相比，依佐加滨治疗前后中皮质连接也降低（显著的药物×时间交互作用，F = 4.317，p = 0.046）。这项转化研究工作与临床前研究结果一致，突出了抑郁症中VTA的过度活动，并提示KCNQ通道开放剂在使抑郁症和快感缺失患者的这种过度活动正常化方面的作用机制。
