Impact of the KCNQ2/3 Channel Opener Ezogabine on Reward Circuit Activity and Clinical Symptoms in Depression: Results From a Randomized Controlled Trial
Publication: American Journal of Psychiatry
Abstract
Objective:
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.
Methods:
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.
Results:
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.
Conclusions:
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.
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History
Received: 13 May 2020
Revision received: 20 September 2020
Published online: 3 March 2021
Published in print: May 01, 2021
Accepted: 21 October 2021
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Competing Interests
Dr. Pizzagalli has received consulting fees from Akili Interactive Labs, BlackThorn Therapeutics, Boehringer Ingelheim, Compass Pathway, Posit Science, Otsuka Pharmaceuticals, and Takeda Pharmaceuticals; he has received an honorarium from Alkermes; he has stock options with BlackThorn Therapeutics; he has received research grant support from the Brain and Behavior Research Foundation, the Dana Foundation, Millennium Pharmaceuticals, and NIMH; and he has a financial interest in BlackThorn Therapeutics, which has licensed the copyright to the probabilistic reward task through Harvard University. Dr. Jha has received contract research grant support from Acadia Pharmaceuticals and Janssen Research and Development, as well as honoraria for CME presentations from North American Center for Continuing Medical Education and Global Medical Education. Dr. Swann is supported through the use of facilities and resources at the Michael E. DeBakey VA Medical Center; he has received research grant support from the American Foundation for Suicide Prevention, the Department of Defense, and the Veterans Administration; he has served as a consultant to Lundbeck and Otsuka; and he has received royalties from Oxford University Press. Dr. Collins is a paid independent rater for MedAvante-ProPhase. Dr. Iosifescu has received consulting fees from Alkermes, Axsome, the Centers for Psychiatric Excellence, Global Medical Education, MyndAnalytics (CNS Response), Jazz, Lundbeck, Otsuka, Precision Neuroscience, Sage, and Sunovion; and he has received research grant support (through his academic institutions) from Alkermes, AstraZeneca, BrainsWay, LiteCure, NeoSync, Roche, and Shire. Dr. Han is named on a patent pending for the use of ezogabine to treat depression and related conditions. Dr. Mathew is supported through the use of facilities and resources at the Michael E. Debakey VA Medical Center; he has served as a consultant to Alkermes, Allergan, Axsome Therapeutics, Clexio Biosciences, EMA Wellness, Greenwich Biosciences, Intra-Cellular Therapies, Janssen, Perception Neuroscience, Praxis Precision Medicines, Sage Therapeutics, Seelos Therapeutics, and Signant Health; and he has received research grant support from Biohaven Pharmaceuticals and VistaGen Therapeutics. Dr. Murrough has provided consultation services and/or served on advisory boards for Allergan, Boehringer Ingelheim, Clexio Biosciences, Fortress Biotech, FSV7, Global Medical Education, Impel Neuropharma, Janssen Research and Development, MedAvante-ProPhase, Novartis, Otsuka, and Sage Therapeutics; and he is named on a patent pending for neuropeptide Y as a treatment for mood and anxiety disorders and on a patent pending for the use of ezogabine and other KCNQ channel openers to treat depression and related conditions. The other authors report no financial relationships with commercial interests.
Funding Information
Supported by NIMH grant R61MH111932, grant UL1TR001433 from the NIH National Center for Advancing Translational Sciences, and the Ehrenkranz Laboratory for Human Resilience, a component of the Depression and Anxiety Center for Discovery and Treatment at the Icahn School of Medicine at Mount Sinai.
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