Abstract

Major depressive disorder (MDD) is a leading cause of disability worldwide, yet current treatment strategies remain limited in their mechanistic diversity. Recent evidence has highlighted a promising novel pharmaceutical target—the KCNQ-type potassium channel—for the treatment of depressive disorders, which may exert a therapeutic effect via functional changes within the brain reward system, including the ventral striatum. The current study assessed the effects of the KCNQ channel opener ezogabine (also known as retigabine) on reward circuitry and clinical symptoms in patients with MDD. Eighteen medication-free individuals with MDD currently in a major depressive episode were enrolled in an open-label study and received ezogabine up to 900 mg/day orally over the course of 10 weeks. Resting-state functional magnetic resonance imaging data were collected at baseline and posttreatment to examine brain reward circuitry. Reward learning was measured using a computerized probabilistic reward task. After treatment with ezogabine, subjects exhibited a significant reduction of depressive symptoms (Montgomery–Asberg Depression Rating Scale score change: −13.7 ± 9.7, p < 0.001, d = 2.08) and anhedonic symptoms (Snaith–Hamilton Pleasure Scale score change: −6.1 ± 5.3, p < 0.001, d = 1.00), which remained significant even after controlling for overall depression severity. Improvement in depression was associated with decreased functional connectivity between the ventral caudate and clusters within the mid-cingulate cortex and posterior cingulate cortex (n = 14, voxel-wise p < 0.005). In addition, a subgroup of patients tested with a probabilistic reward task (n = 9) showed increased reward learning following treatment. These findings highlight the KCNQ-type potassium channel as a promising target for future drug discovery efforts in mood disorders.

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Acknowledgements

We would like to thank the Icahn School of Medicine at Mount Sinai research pharmacists, including Ivy Cohen, Alla Khodzhayeva, and Giuseppe Difiore, for their extensive work on this project.

Funding

Funding for this study was provided by the Friedman Brain Institute and by the Ehrenkranz Laboratory for Human Resilience, both components of the Icahn School of Medicine at Mount Sinai. Additional research support was provided by Doris Duke Charitable Foundation (to JWM) and the National Institute of Mental Health (MH112081, to M-HH; K23MH094707, to JWM).

Author information

Author notes

  1. These authors contributed equally: Aaron Tan, Sara Costi

Affiliations

  1. Mood and Anxiety Disorders Program, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    • Aaron Tan
    • , Sara Costi
    • , Laurel S. Morris
    • , Nicholas T. Van Dam
    • , Marin Kautz
    • , Katherine A. Collins
    •  & James W. Murrough
  2. Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    • Aaron Tan
    • , Eric J. Nestler
    • , Ming-Hu Han
    •  & James W. Murrough
  3. Melbourne School of Psychological Sciences, University of Melbourne, Melbourne, VIC, Australia

    • Nicholas T. Van Dam
  4. Department of Psychiatry, Harvard Medical School, Belmont, MA, USA

    • Alexis E. Whitton
    •  & Diego A. Pizzagalli
  5. Department of Biological Sciences, Hunter College, The City University of New York, New York, NY, USA

    • Allyson K. Friedman
  6. Department of Psychology, Thomas Jefferson University, Philadelphia, PA, USA

    • Gabriella Ahle
  7. Department of Ophthalmology, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    • Nisha Chadha
  8. Roski Eye Institute, Keck School of Medicine at the University of Southern California, Los Angeles, CA, USA

    • Brian Do
  9. Department of Psychiatry, New York University School of Medicine, New York, NY, USA

    • Dan V. Iosifescu
  10. Nathan Kline Institute for Psychiatric Research, Orangeburg, NY, USA

    • Dan V. Iosifescu
  11. Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    • Eric J. Nestler
    •  & Ming-Hu Han
  12. Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    • Eric J. Nestler
    • , Ming-Hu Han
    •  & James W. Murrough

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Conflict of interest

In the past 5 years, JWM has provided consultation services to Sage Therapeutics, Boehreinger Ingelheim, Novartis, Allergan, Fortress Biotech, Janssen Research and Development, Genentech, MedAvante-ProPhase, and Global Medical Education (GME) and has received research support from Avanir Pharmaceuticals, Inc. JWM is named on a patent pending for neuropeptide Y as a treatment for mood and anxiety disorders. The Icahn School of Medicine (employer of JWM) is named on a patent and has entered into a licensing agreement and will receive payments related to the use of ketamine if it is approved for the treatment of depression. JWM is not named on this patent and will not receive any payments. KCA has received consulting fees from MedAvante-ProPhase for services unrelated to this study. In the past 3 years, DAP has received consulting fees from Akili Interactive Labs, BlackThorn Therapeutics, Boehreinger Ingelheim, Pfizer, and Posit Science for activities unrelated to the present study. In the past 3 years, DVI has provided consultations to Alkermes, Axsome, MyndAnalytics (CNS Response), Jazz, Lundbeck, Otsuka, and Sunovion and has received research support (through his academic institutions) from Alkermes, Astra Zeneca, Brainsway, LiteCure, Neosync, Roche, and Shire. The other authors declare that they have no conflict of interest.

Corresponding author

Correspondence to James W. Murrough.

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DOI

https://doi.org/10.1038/s41380-018-0283-2