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Impact of the KCNQ2/3 Channel Opener Ezogabine on Reward Circuit Activity and Clinical Symptoms in Depression: Results From a Randomized Controlled Trial. | LitMetric
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).
Published: May 2021
AI Article Synopsis
Article 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.
