Depression and Anxiety Center for Discovery and Treatment, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York (Costi, Morris, Corniquel, Bevilacqua, Jha, Collins, Murrough); Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York (Kirkwood, Bagiella); Department of Psychology, University of California Los Angeles (Hoch); Mood and Anxiety Disorders Program, Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston (Vo-Le, Iqbal, Ursu, Swann, Salas, Mathew); Michael E. Debakey VA Medical Center, Houston (Vo-Le, Iqbal, Ursu, Swann, Salas, Mathew); Department of Ophthalmology, Icahn School of Medicine at Mount Sinai, New York (Chadha); Department of Psychiatry, Harvard Medical School, Boston, and McLean Hospital, Belmont, Mass. (Pizzagallli, Whitton); School of Medical Sciences, University of Sydney, Australia (Whitton); Montefiore Medical Center/Albert Einstein College of Medicine, New York (Parides); Department of Psychiatry, New York University School of Medicine, New York (Stern, Iosifescu); Nathan Kline Institute for Psychiatric Research, Orangeburg, N.Y. (Collins, Stern, Iosifescu); Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York (Han, Murrough); Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York (Han); Center for Affective Neuroscience, Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York (Han).
Am J Psychiatry. 2021 May 1;178(5):437-446. doi: 10.1176/appi.ajp.2020.20050653. Epub 2021 Mar 3.
Preclinical studies point to the KCNQ2/3 potassium channel as a novel target for the treatment of depression and anhedonia, a reduced ability to experience pleasure. The authors conducted the first randomized placebo-controlled trial testing the effect of the KCNQ2/3 positive modulator ezogabine on reward circuit activity and clinical outcomes in patients with depression.
Depressed individuals (N=45) with elevated levels of anhedonia were assigned to a 5-week treatment period with ezogabine (900 mg/day; N=21) or placebo (N=24). Participants underwent functional MRI during a reward flanker task at baseline and following treatment. Clinical measures of depression and anhedonia were collected at weekly visits. The primary endpoint was the change from baseline to week 5 in ventral striatum activation during reward anticipation. Secondary endpoints included depression and anhedonia severity as measured using the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Snaith-Hamilton Pleasure Scale (SHAPS), respectively.
The study did not meet its primary neuroimaging endpoint. Participants in the ezogabine group showed a numerical increase in ventral striatum response to reward anticipation following treatment compared with participants in the placebo group from baseline to week 5. Compared with placebo, ezogabine was associated with a significantly larger improvement in MADRS and SHAPS scores and other clinical endpoints. Ezogabine was well tolerated, and no serious adverse events occurred.
The study did not meet its primary neuroimaging endpoint, although the effect of treatment was significant on several secondary clinical endpoints. In aggregate, the findings may suggest that future studies of the KCNQ2/3 channel as a novel treatment target for depression and anhedonia are warranted.
临床前研究表明，KCNQ2/3 钾通道是治疗抑郁症和快感缺失（即体验愉悦的能力下降）的一种新靶点。作者进行了首次随机安慰剂对照试验，以测试 KCNQ2/3 正变构调节剂依佐加滨对抑郁症患者奖赏回路活动和临床结局的影响。
有快感缺失的抑郁个体（N=45），其快感缺失水平升高，被分配到依佐加滨（900mg/天；N=21）或安慰剂（N=24）的 5 周治疗期。参与者在基线和治疗后进行奖赏侧翼任务的功能磁共振成像。每周就诊时收集抑郁和快感缺失的临床测量值。主要终点是从基线到第 5 周时，在奖赏预期期间腹侧纹状体激活的变化。次要终点包括使用蒙哥马利-Åsberg 抑郁评定量表（MADRS）和 Snaith-Hamilton 快感量表（SHAPS）分别测量的抑郁和快感缺失严重程度。
该研究未达到其主要神经影像学终点。与安慰剂组相比，依佐加滨组参与者在治疗后对奖赏预期的腹侧纹状体反应从基线到第 5 周呈现出数值上的增加。与安慰剂相比，依佐加滨与 MADRS 和 SHAPS 评分以及其他临床终点的显著更大改善相关。依佐加滨耐受性良好，没有发生严重不良事件。
该研究未达到其主要神经影像学终点，尽管治疗效果在几个次要临床终点上显著。总的来说，这些发现可能表明，未来对 KCNQ2/3 通道作为治疗抑郁症和快感缺失的新靶点的研究是合理的。
