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Effects of KCNQ potassium channel modulation on ventral tegmental area activity and connectivity in individuals with depression and anhedonia

Molecular Psychiatry volume 30, pages 3686–3694 (2025)Cite this article

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Abstract

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(1,34) = 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(56) = 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(1,33) = 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.

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Fig. 1: Study recruitment flow and the incentive flanker task.
Fig. 2: Ventral tegmental area hyper-activation during anticipation is associated with depression symptom severity and is reduced following treatment with ezogabine.
Fig. 3: Mesocortical functional connectivity at baseline in MDD and HC.
Fig. 4: Mesocortical functional connectivity at baseline and following ezogabine or placebo.

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Data availability

Data from the phased R61MH111932 clinical trial is available through the NIH Data Archive (NDA, #2582).

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Acknowledgements

Research reported in this publication was supported by the National Institute of Mental Health of the National Institutes of Health under Award Number R61MH111932. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Additional support was provided by the Ehrenkranz Laboratory of Human Resilience, the Freidman Brain Institute at the Icahn school of Medicine at Mount Sinai, and the Gottesman Foundation. RS was supported by VHA I01CX001937, this study is in part the result of work supported with resource at the Michael E. DeBakey VA Medical Center, the content does not represent the official views of the United States government. Scientific computing and data resources support was also provided in part by CTSA grant UL1TR004419.

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Authors and Affiliations

  1. Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, USA

    Laurel S. Morris, Sara Costi, Sara Hameed, Avijit Chowdhury & James W. Murrough

  2. Department of Psychiatry, University of Oxford, Oxford, UK

    Sara Costi

  3. Oxford Health NHS Foundation Trust, Warneford Hospital, Oxford, UK

    Sara Costi

  4. Nathan Kline Institute, Orangeburg, NY, USA

    Katherine A. Collins, Emily R. Stern & Dan V. Iosifescu

  5. New York University Grossman School of Medicine, New York, NY, USA

    Emily R. Stern & Dan V. Iosifescu

  6. Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, USA

    Carole Morel & James W. Murrough

  7. Menninger Department of Psychiatry & Behavioral Sciences, Baylor College of Medicine, Houston, TX, USA

    Ramiro Salas & Sanjay J. Mathew

  8. The Menninger Clinic, Houston, TX, USA

    Ramiro Salas & Sanjay J. Mathew

  9. Neuroscience Department, Baylor College of Medicine, Houston, TX, USA

    Ramiro Salas

  10. Center for Translational Research on Inflammatory Diseases, Michael E. Debakey VA Medical Center, Houston, TX, USA

    Ramiro Salas

  11. Department of Mental Health and Public Health, Faculty of Life and Health Sciences, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong, PR China

    Ming-Hu Han

  12. Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Ming-Hu Han

  13. Michael E. Debakey VA Medical Center, Houston, TX, USA

    Sanjay J. Mathew

  14. VISN 2 Mental Illness Research, Education, and Clinical Center (MIRECC), James J. Peters VA Medical Center, Bronx, NY, USA

    James W. Murrough

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JWM, SJM, MHH, DVI, KAC, ERS, SC, RS contributed to the conception or design of the work. LSM, SC, SH, KAC, AC, RS contributed to the acquisition of the data. LSM, AC contributed to the analysis of the data. LSM, CM, MHH, JWM contributed to the interpretation of data. LSM wrote the initial draft of the paper. All authors revised the paper for intellectual content. All authors provided final approval of the paper to be published.

Corresponding authors

Correspondence to Laurel S. Morris or James W. Murrough.

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Competing interests

Dr. Costi has provided consultation services for Boehringer Ingelheim, Guidepoint and TCG Crossover. In the last 10 years, Dr. Iosifescu has served as a consultant for Alkermes, Allergan, Angelini, Autobahn, Axsome, Biogen, Boehringer Ingelheim, the Centers for Psychiatric Excellence, Clexio, Delix, Jazz, LivaNova, Lundbeck, Neumora, Otsuka, Precision Neuroscience, Relmada, Sage, and Sunovion. He has received grant support (paid to his institutions) from Alkermes, AstraZeneca, BrainsWay, LiteCure, NeoSync, Otsuka, Roche, and Shire. In the past 24 months, Dr. Murrough has provided consultation services for LivaNova, KetaMed, Inc, Merk, Cliniclabs, Inc., Biohaven Pharmaceuticals, Inc., Compass Pathfinder, Xenon Pharmaceuticals, and Clexio Biosciences. Drs. Murrough and Han are named on a patent pending for the use of KCNQ channel openers to treat depression and related conditions. Dr. Collins has consulted for MedAvante-ProPhase, and A. Stein- Regulatory Affairs Consulting, Ltd. in the past, and currently serves as a consultant to Cronos Clinical Consulting Services, Inc. and Relmada Therapeutics, Inc. Dr. Mathew has received consultant fees from Abbott, Almatica Pharma, Beckley Psytech, Biohaven, BioXcel Therapeutics, Boehringer-Ingelheim, Brii Biosciences, Clexio Biosciences, COMPASS Pathways, Delix Therapeutics, Douglas Pharmaceuticals, Engrail Therapeutics, Freedom Biosciences, Liva Nova, Levo Therapeutics, Merck, Motif Neurotech, Neumora, Neurocrine, Perception Neurosciences, Praxis Precision Medicines, Relmada Therapeutics, Sage Therapeutics, Seelos Therapeutics, Signant Health, Sunovion Pharmaceuticals, Xenon Pharmaceuticals, Worldwide Clinical Trials, and XW Pharma. Dr. Mathew has received research support from Boehringer-Ingelheim, Engrail Therapeutics, Merck, Neurocrine, and Sage Therapeutics. Dr. Han is supported by the National Key R&D Program of China (Grant Nos. 2021ZD0202900 and 2021ZD0202902), Research Fund for International Senior Scientists (Grant No. T2250710685), Shenzhen Natural Science Foundation (Grant No. JCYJ20220818101600001), Shenzhen Key Laboratory of Precision Diagnosis and Treatment of Depression (Grant No. ZDSYS20220606100606014), Shenzhen Medical Research Fund (Grant No. SMRF B2303012), and Science and Technology Research and Development Foundation of Shenzhen (High-level Talent Innovation and Entrepreneurship Plan of Shenzhen Team Funding) (Grant No. KQTD20221101093608028). The other authors declare no other disclosures.

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Morris, L.S., Costi, S., Hameed, S. et al. Effects of KCNQ potassium channel modulation on ventral tegmental area activity and connectivity in individuals with depression and anhedonia. Mol Psychiatry 30, 3686–3694 (2025). https://doi.org/10.1038/s41380-025-02957-7

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