Effects of the KCNQ (Kv7) Channel Opener Ezogabine on Resting-State Functional Connectivity of Striatal Brain Reward Regions, Depression, and Anhedonia in Major Depressive Disorder: Results From a Randomized Controlled Trial
Open accessAbstract
Background Major depressive disorder (MDD) is a leading cause of disability worldwide, with available treatments often showing limited efficacy. Recent research suggests that targeting specific subtypes of depression and understanding the underlying brain mechanisms can improve treatment outcomes. This study investigates the potential of the potassium KCNQ (Kv7) channel opener ezogabine to modulate the resting-state functional connectivity (RSFC) of the brain's reward circuitry and alleviate depressive symptoms, including anhedonia, a core feature of MDD.Methods A double-blind, randomized, placebo-controlled clinical trial in individuals with MDD ages 18 to 65 years compared daily dosing with ezogabine (n= 19) with placebo (n = 21) for 5 weeks. Functional magnetic resonance imaging assessed RSFC of the brain's key reward regions (ventral caudate, nucleus accumbens) at baseline and posttreatment. Clinical symptoms were measured using the Snaith-Hamilton Pleasure Scale (SHAPS), Montgomery-Åsberg Depression Rating Scale (MADRS), and other clinical symptom scales.Results Ezogabine significantly reduced RSFC between the reward seeds and the posterior cingulate cortex (PCC)/precuneus compared with placebo, which was associated with a reduction in depression severity. Improvements in anhedonia (SHAPS) and depressive symptoms (MADRS) with ezogabine compared with placebo were also associated with decreased connectivity between the reward seeds and mid/posterior cingulate regions (midcingulate cortex, PCC, precuneus).Conclusions The findings suggest that ezogabine's antidepressant effects are mediated through modulation of striatal-mid/posterior cingulate connectivity, indicating a potential therapeutic mechanism for KCNQ-targeted drugs for MDD and anhedonia. Future studies should validate these results in larger trials.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In major depressive disorder with prominent anhedonia, ezogabine produced meaningful reductions in depressive symptoms and improved reward sensitivity in randomized and open-label studies, with parallel changes in ventral striatal connectivity and reward learning.
“In major depressive disorder with prominent anhedonia, ezogabine produced meaningful reductions in depressive symptoms and improved reward sensitivity in randomized and open-label studies, with parallel changes in ventral striatal connectivity and reward learning [259,260,261].”
From Synaptic Plasticity—Intrinsic Excitability and Antidepressant Discovery (2026) · cites this paper as [259]
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Diagnostic and Statistical Manual of Mental Disorders
American Psychiatric Association (2013) · doi:10.1176/appi.books.9780890425596 · Cited by 116,369 · see citing works
A new depression scale designed to be sensitive to change
Montgomery, S. A., & Åsberg, M. (1979) · British Journal of Psychiatry · doi:10.1192/bjp.134.4.382 · Cited by 13,962 · see citing works
AFNI: Software for analysis and visualization of functional magnetic resonance neuroimages
Cox, R. W. (1996) · Computers and Biomedical Research · doi:10.1006/cbmr.1996.0014 · Cited by 10,913 · see citing works
Mapping the structural core of human cerebral cortex
Hagmann, P., Cammoun, L., Gigandet, X., Meuli, R., Honey, C. J., Wedeen, V. J., & Sporns, O. (2008) · PLoS Biology · doi:10.1371/journal.pbio.0060159 · Cited by 4,173 · see citing works
The brain's default mode network
Raichle, M. E. (2015) · Annual Review of Neuroscience · doi:10.1146/annurev-neuro-071013-014030 · Cited by 3,904 · see citing works
Trivedi, M. H., Rush, A. J., Wisniewski, S. R., Nierenberg, A. A., Warden, D., Ritz, L., Norquist, G., Howland, R. H., Lebowitz, B., McGrath, P. J., et al. (2006) · American Journal of Psychiatry · doi:10.1176/appi.ajp.163.1.28 · Cited by 3,879 · see citing works
Rush, A. J., Trivedi, M. H., Ibrahim, H. M., Carmody, T. J., Arnow, B., Klein, D. N., Markowitz, J. C., Ninan, P. T., Kornstein, S., Manber, R., et al. (2003) · Biological Psychiatry · doi:10.1016/s0006-3223(02)01866-8 · Cited by 3,829 · see citing works
Meeting of minds: the medial frontal cortex and social cognition
Amodio, D. M., & Frith, C. D. (2006) · Nature Reviews Neuroscience · doi:10.1038/nrn1884 · Cited by 3,782 · see citing works
Circular analysis in systems neuroscience: the dangers of double dipping
Kriegeskorte, N., Simmons, W. K., Bellgowan, P. S. F., & Baker, C. I. (2009) · Nature Neuroscience · doi:10.1038/nn.2303 · Cited by 2,696 · see citing works
Krishnan, V., Han, M.-H., Graham, D. L., Berton, O., Renthal, W., Russo, S. J., LaPlant, Q., Graham, A., Lutter, M., Lagace, D. C., et al. (2007) · Cell · doi:10.1016/j.cell.2007.09.018 · Cited by 2,307 · see citing works
Self-citationThe role of the posterior cingulate cortex in cognition and disease
Leech, R., & Sharp, D. J. (2014) · Brain · doi:10.1093/brain/awt162 · Cited by 2,247 · see citing works
Resting-state connectivity biomarkers define neurophysiological subtypes of depression
Drysdale, A. T., Grosenick, L., Downar, J., Dunlop, K., Mansouri, F., Meng, Y., Fetcho, R. N., Zebley, B., Oathes, D. J., Etkin, A., et al. (2017) · Nature Medicine · doi:10.1038/nm.4246 · Cited by 2,170 · see citing works
The integration of negative affect, pain and cognitive control in the cingulate cortex
Shackman, A. J., Salomons, T. V., Slagter, H. A., Fox, A. S., Winter, J. J., & Davidson, R. J. (2011) · Nature Reviews Neuroscience · doi:10.1038/nrn2994 · Cited by 2,082 · see citing works
A scale for the assessment of hedonic tone the Snaith-Hamilton pleasure scale
Snaith, R. P., Hamilton, M., Morley, S., Humayan, A., Hargreaves, D., & Trigwell, P. (1995) · British Journal of Psychiatry · doi:10.1192/bjp.167.1.99 · Cited by 1,778 · see citing works
New approaches to antidepressant drug discovery: beyond monoamines
Berton, O., & Nestler, E. J. (2006) · Nature Reviews Neuroscience · doi:10.1038/nrn1846 · Cited by 1,589 · see citing works
Russo, S. J., Murrough, J. W., Han, M.-H., Charney, D. S., & Nestler, E. J. (2012) · Nature Neuroscience · doi:10.1038/nn.3234 · Cited by 1,206 · see citing works
Self-citationRapid regulation of depression-related behaviours by control of midbrain dopamine neurons
Chaudhury, D., Walsh, J. J., Friedman, A. K., Juarez, B., Ku, S. M., Koo, J. W., Ferguson, D., Tsai, H.-C., Pomeranz, L., Christoffel, D. J., et al. (2013) · Nature · doi:10.1038/nature11713 · Cited by 1,156 · see citing works
Self-citationDepression, Stress, and Anhedonia: Toward a Synthesis and Integrated Model
Pizzagalli, D. A. (2014) · Annual Review of Clinical Psychology · doi:10.1146/annurev-clinpsy-050212-185606 · Cited by 1,155 · see citing works
Resting-state functional connectivity in major depressive disorder: A review
Mulders, P. C., van Eijndhoven, P. F., Schene, A. H., Beckmann, C. F., & Tendolkar, I. (2015) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2015.07.014 · Cited by 884 · see citing works
The neuroscience of placebo effects: connecting context, learning and health
Wager, T. D., & Atlas, L. Y. (2015) · Nature Reviews Neuroscience · doi:10.1038/nrn3976 · Cited by 844 · see citing works
Insel, T. R., & Cuthbert, B. N. (2015) · Science · doi:10.1126/science.aab2358 · Cited by 840 · see citing works
Anhedonia in schizophrenia: Distinctions between anticipatory and consummatory pleasure
Gard, D. E., Kring, A. M., Gard, M. G., Horan, W. P., & Green, M. F. (2007) · Schizophrenia Research · doi:10.1016/j.schres.2007.03.008 · Cited by 817 · see citing works
Voltage-gated potassium channels as therapeutic targets
Wulff, H., Castle, N. A., & Pardo, L. A. (2009) · Nature Reviews Drug Discovery · doi:10.1038/nrd2983 · Cited by 798 · see citing works
Differentiating BOLD and non-BOLD signals in fMRI time series using multi-echo EPI
Kundu, P., Inati, S., Evans, J. W., Luh, W., & Bandettini, P. A. (2011) · NeuroImage · doi:10.1016/j.neuroimage.2011.12.028 · Cited by 604 · see citing works
Rumination as a common mechanism relating depressive risk factors to depression.
Spasojevic, J., & Alloy, L. B. (2001) · Emotion · doi:10.1037/1528-3542.1.1.25 · Cited by 599 · see citing works
Depression, rumination and the default network
Berman, M. G., Peltier, S., Nee, D. E., Kross, E., Deldin, P. J., & Jonides, J. (2011) · Social Cognitive and Affective Neuroscience · doi:10.1093/scan/nsq080 · Cited by 568 · see citing works
Preclinical models: status of basic research in depression
Nestler, E. J., Gould, E., & Manji, H. K. (2002) · Biological Psychiatry · doi:10.1016/s0006-3223(02)01405-1 · Cited by 559 · see citing works
Linear mixed-effects modeling approach to FMRI group analysis
Chen, G., Saad, Z. S., Britton, J. C., Pine, D. S., & Cox, R. W. (2013) · NeuroImage · doi:10.1016/j.neuroimage.2013.01.047 · Cited by 440 · see citing works
Integrated strategy for improving functional connectivity mapping using multiecho fMRI
Kundu, P., Brenowitz, N. D., Voon, V., Worbe, Y., Vértes, P. E., Inati, S. J., Saad, Z. S., Bandettini, P. A., & Bullmore, E. T. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1301725110 · Cited by 399 · see citing works
Craske, M. G., Meuret, A. E., Ritz, T., Treanor, M., & Dour, H. J. (2016) · Depression and Anxiety · doi:10.1002/da.22490 · Cited by 387 · see citing works
Common and Dissociable Dysfunction of the Reward System in Bipolar and Unipolar Depression
Satterthwaite, T. D., Kable, J. W., Vandekar, L., Katchmar, N., Bassett, D. S., Baldassano, C. F., Ruparel, K., Elliott, M. A., Sheline, Y. I., Gur, R. C., et al. (2015) · Neuropsychopharmacology · doi:10.1038/npp.2015.75 · Cited by 249 · see citing works
Borsini, A., Wallis, A. S. J., Zunszain, P., Pariante, C. M., & Kempton, M. J. (2020) · Cognitive, Affective, & Behavioral Neuroscience · doi:10.3758/s13415-020-00804-6 · Cited by 207 · see citing works
Pizzagalli, D. A. (2022) · American Journal of Psychiatry · doi:10.1176/appi.ajp.20220423 · Cited by 204 · see citing works
KCNQ channel openers reverse depressive symptoms via an active resilience mechanism
Friedman, A. K., Juarez, B., Ku, S. M., Zhang, H., Calizo, R. C., Walsh, J. J., Chaudhury, D., Zhang, S., Hawkins, A., Dietz, D. M., et al. (2016) · Nature Communications · doi:10.1038/ncomms11671 · Cited by 172 · see citing works
Self-citationLundberg, J., Cars, T., Lööv, S., Söderling, J. K., Sundström, J., Tiihonen, J., Levál, A., Gannedahl, A., Björkholm, C., Själin, M., et al. (2022) · JAMA Psychiatry · doi:10.1001/jamapsychiatry.2022.3860 · Cited by 168 · see citing works
Gabbay, V., Johnson, A. R., Alonso, C. M., Evans, L. K., Babb, J. S., & KLEIN, R. G. (2015) · Journal of Child and Adolescent Psychopharmacology · doi:10.1089/cap.2014.0105 · Cited by 148 · see citing works
Millan, M. J., Goodwin, G. M., Meyer-Lindenberg, A., & Ove Ögren, S. (2015) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2015.01.016 · Cited by 132 · see citing works
A causal role for the anterior mid-cingulate cortex in negative affect and cognitive control
Tolomeo, S., Christmas, D. M., Jentzsch, I., Johnston, B. A., Sprengelmeyer, R., Matthews, K., & Steele, J. D. (2016) · Brain · doi:10.1093/brain/aww069 · Cited by 128 · see citing works
Retigabine: Chemical Synthesis to Clinical Application
Blackburn-Munro, G., Dalby‐Brown, W., Mirza, N. R., Mikkelsen, J. D., & Blackburn-Munro, R. E. (2006) · CNS Drug Reviews · doi:10.1111/j.1527-3458.2005.tb00033.x · Cited by 127 · see citing works
Cheng, W., Rolls, E. T., Qiu, J., Xie, X., Wei, D., Huang, C., Yang, A. C., Tsai, S., Li, Q., Meng, J., et al. (2018) · Translational Psychiatry · doi:10.1038/s41398-018-0139-1 · Cited by 123 · see citing works
Chronic social defeat stress mouse model: Current view on its behavioral deficits and modifications.
Wang, W., Liu, W., Duan, D.-X., Bai, H., Wang, Z., & Xing, Y. (2020) · Behavioral Neuroscience · doi:10.1037/bne0000418 · Cited by 112 · see citing works
Structured Clinical Interview for DSM-IV (SCID)
Glasofer, D. R., Brown, A. J., & Riegel, M. (2015) · Springer eBooks · doi:10.1007/978-981-287-087-2_80-1 · Cited by 95 · see citing works
Tan, A., Costi, S., Morris, L. S., Dam, N. T. V., Kautz, M. M., Whitton, A. E., Friedman, A. K., Collins, K. A., Ahle, G. M., Chadha, N., et al. (2018) · Molecular Psychiatry · doi:10.1038/s41380-018-0283-2 · Cited by 83 · see citing works
Self-citationFan, J., Liu, W., Xia, J., Li, S., Gao, F., Zhu, J., Han, Y., Zhou, H., Liao, H., Yi, J., et al. (2020) · Human Brain Mapping · doi:10.1002/hbm.25222 · Cited by 83 · see citing works
Liu, R., Wang, Y., Chen, X., Zhang, Z., Xiao, L., & Zhou, Y. (2021) · NeuroImage Clinical · doi:10.1016/j.nicl.2021.102599 · Cited by 79 · see citing works
Costi, S., Morris, L. S., Kirkwood, K. A., Hoch, M., Corniquel, M. B., Vo‐Le, B., Iqbal, T., Chadha, N., Pizzagalli, D. A., Whitton, A. E., et al. (2021) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2020.20050653 · Cited by 79 · see citing works
Self-citationLi, L., Sun, H., Ding, J., Niu, C., Su, M., Zhang, L., Li, Y., Wang, C., Gamper, N., Du, X., et al. (2017) · British Journal of Pharmacology · doi:10.1111/bph.14026 · Cited by 51 · see citing works
Auerbach, R. P., Pagliaccio, D., & Kirshenbaum, J. S. (2022) · Current topics in behavioral neurosciences · doi:10.1007/7854_2022_358 · Cited by 47 · see citing works
Zhao, K., Xie, H., Fonzo, G. A., Tong, X.-Y., Carlisle, N. B., Chidharom, M., Etkin, A., & Zhang, Y. (2022) · Molecular Psychiatry · doi:10.1038/s41380-023-01958-8 · Cited by 47 · see citing works
The Potential of KCNQ Potassium Channel Openers as Novel Antidepressants
Costi, S., Han, M., & Murrough, J. W. (2022) · CNS Drugs · doi:10.1007/s40263-021-00885-y · Cited by 36 · see citing works
Self-citationWang, L., An, J., Gao, H., Zhang, P., Chen, C., Li, K., Mitchell, P. B., & Si, T. (2019) · Human Brain Mapping · doi:10.1002/hbm.24601 · Cited by 32 · see citing works
Alexander, L., Hawkins, P. C. T., Evans, J. W., Mehta, M. A., & Zarate, C. A. (2023) · Translational Psychiatry · doi:10.1038/s41398-023-02674-1 · Cited by 29 · see citing works
The computational structure of consummatory anhedonia
Hall, A., Browning, M. D., & Huys, Q. J. M. (2024) · Trends in Cognitive Sciences · doi:10.1016/j.tics.2024.01.006 · Cited by 29 · see citing works
Feng, M., Crowley, N. A., Patel, A., Guo, Y., Bugni, S. E., & Luscher, B. (2019) · Neuroscience · doi:10.1016/j.neuroscience.2019.03.003 · Cited by 20 · see citing works
Rengasamy, M. L., Mathew, S. J., Howland, R. H., Griffo, A., Panny, B., & Price, R. B. (2023) · EBioMedicine · doi:10.1016/j.ebiom.2023.104902 · Cited by 15 · see citing works
Self-citationCarver, C. M., Hastings, S. D., Cook, M. E., & Shapiro, M. S. (2019) · Hippocampus · doi:10.1002/hipo.23163 · Cited by 12 · see citing works
Vaccarino, S. R., Wang, S., Rizvi, S. J., Lou, W. Y. W., Hassel, S., MacQUEEN, G. M., Ho, K. T., Frey, B. N., Lam, R. W. M., Milev, R. V., et al. (2024) · BJPsych Open · doi:10.1192/bjo.2023.588 · Cited by 12 · see citing works
The role of KCNQ channel activators in management of major depressive disorder
Meshkat, S., Kwan, A. T. H., Le, G. H., Wong, S., Rhee, T. G., Ho, R., Teopiz, K. M., Cao, B., & McIntyre, R. S. (2024) · Journal of Affective Disorders · doi:10.1016/j.jad.2024.05.067 · Cited by 12 · see citing works
A Key Noradrenergic Brainstem-Mesolimbic Circuit: Resilience to Social Stress
Zhang, H., Chaudhury, D., Ma, Y., et al. (2019) · Chronic Stress · doi:10.1177/2470547019850186 · Cited by 5 · see citing works
Flagged first, then by citations
Research works printed but not linked: 1
- [5]Ferguson JM (2001): SSRI antidepressant medications: adverse effects and tolerability. Prim Care Companion J Clin Psychiatry 3: 22. 15014625 PMC181155
Cited by
Sorted by citations
Synaptic Plasticity—Intrinsic Excitability and Antidepressant Discovery
Tanaka, M. (2026) · Biomedicines · doi:10.3390/biomedicines14061265
- Authors
- Chowdhury, A., Boukezzi, S., Costi, S., Hameed, S., Jacob, Y., Salas, R., Iosifescu, D. V., Han, M.-H., Swann, A., Mathew, S. J., Morris, L., & Murrough, J. W.
- Affiliations
- Icahn School of Medicine at Mount Sinai (US)
- Oxford Health NHS Foundation Trust (GB)
- Michael E. DeBakey VA Medical Center (US)
- Nathan Kline Institute for Psychiatric Research (US)
- Shenzhen Institutes of Advanced Technology (CN)
- Baylor College of Medicine (US)
- James J. Peters VA Medical Center (US)
- Corresponding author
- Murrough, James W.
- ORCID
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2025-10
- Volume
- 98
- Issue
- 7
- Pages
- 568-577
- ISSN
- 0006-3223 (ISSN-L)
- PMC
- PMC12353514
- OpenAlex
- W4408149262
- Cited by
- 10
- References
- 60
- Citations by year
- 2026: 8 · 2025: 2
- FWCI
- 5.65
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Biological Psychiatry (acceptedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Digital Commons-TMC (Texas Medical Center) (submittedVersion)
- Funders
- National Institutes of Health
- National Institute of Mental Health (R61MH111932)
- National Key Research and Development Program of China (2021ZD0202902, T2250710685, 2021ZD0202900)
- National Center for Advancing Translational Sciences (UL1TR001433)
- Wellcome Trust
- Natural Science Foundation of Shenzhen Municipality (JCYJ20220818101600001)
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Cognitive Neuroscience › Functional Brain Connectivity Studies
- Life Sciences › Neuroscience › Neurology › Transcranial Magnetic Stimulation Studies
- Keywords
- ezogabine, Kv7 channels, major depressive disorder, anhedonia, resting-state functional connectivity, nucleus accumbens, posterior cingulate cortex, precuneus, midcingulate cortex, antidepressant mechanism
- MeSH terms
- Adolescent, Adult, Aged, Antidepressive Agents, Carbamates, Major Depressive Disorder, Depressive Disorder, Major, Double-Blind Method, Female, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Phenylenediamines, Reward, KCNQ Potassium Channels, Young Adult, Anhedonia
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
