Effects of the KCNQ channel opener ezogabine on functional connectivity of the ventral striatum and clinical symptoms in patients with major depressive disorder

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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References

  1. 1.

    Ferrari AJ, Charlson FJ, Norman RE, Patten SB, Freedman G, Murray CJL, et al. Burden of depressive disorders by country, sex, age, and year: findings from the Global Burden of Disease Study 2010. PLoS Med. 2013;10:e1001547.

    PubMed  PubMed Central  Article  Google Scholar 

  2. 2.

    Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW, Warden D, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163:1905–17.

    Article  PubMed  Google Scholar 

  3. 3.

    Tollefson GD, Holman S. How long to onset of antidepressant action: a meta-analysis of patients treated with fluoxetine or placebo. Int Clin Psychopharmacol. 1994;9:245–50.

    CAS  PubMed  Article  Google Scholar 

  4. 4.

    Ferguson JM. SSRI antidepressant medications: adverse effects and tolerability. Prim Care Companion J Clin Psychiatry. 2001;3:22–7.

    PubMed  PubMed Central  Article  Google Scholar 

  5. 5.

    Berton O, Nestler EJ. New approaches to antidepressant drug discovery: beyond monoamines. Nat Rev Neurosci. 2006;7:137–51.

    CAS  PubMed  Article  Google Scholar 

  6. 6.

    Millan MJ, Goodwin GM, Meyer-Lindenberg A, Ove Ogren S. Learning from the past and looking to the future: emerging perspectives for improving the treatment of psychiatric disorders. Eur Neuropsychopharmacol. 2015;25:599–656.

    CAS  PubMed  Article  Google Scholar 

  7. 7.

    Krishnan V, Han MH, Graham DL, Berton O, Renthal W, Russo SJ, et al. Molecular adaptations underlying susceptibility and resistance to social defeat in brain reward regions. Cell. 2007;131:391–404.

    CAS  PubMed  Article  Google Scholar 

  8. 8.

    Friedman AK, Juarez B, Ku SM, Zhang H, Calizo RC, Walsh JJ. et al. KCNQ channel openers reverse depressive symptoms via an active resilience mechanism. Nat Commun. 2016;7:11671

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  9. 9.

    Chaudhury D, Walsh JJ, Friedman AK, Juarez B, Ku SM, Koo JW, et al. Rapid regulation of depression-related behaviours by control of midbrain dopamine neurons. Nature. 2013;493:532–6.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Friedman AK, Walsh JJ, Juarez B, Ku SM, Chaudhury D, Wang J, et al. Enhancing depression mechanisms in midbrain dopamine neurons achieves homeostatic resilience. Science. 2014;344:313–9.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  11. 11.

    Pizzagalli DA, Jahn AL, O’Shea JP. Toward an objective characterization of an anhedonic phenotype: a signal-detection approach. Biol Psychiatry. 2005;57:319–27.

    PubMed  PubMed Central  Article  Google Scholar 

  12. 12.

    Han MH, Nestler EJ. Neural substrates of depression and resilience. Neurotherapeutics. 2017;14:677–86.

    PubMed  PubMed Central  Article  Google Scholar 

  13. 13.

    Connor KM, Davidson JRT. Development of a new resilience scale: the Connor-Davidson Resilience scale (CD-RISC). Depress Anxiety. 2003;18:76–82.

    PubMed  Article  Google Scholar 

  14. 14.

    Gunthorpe MJ, Large CH, Sankar R. The mechanism of action of retigabine (ezogabine), a first-in-class K+ channel opener for the treatment of epilepsy. Epilepsia. 2012;53:412–24.

    CAS  PubMed  Article  Google Scholar 

  15. 15.

    Brodie MJ, Lerche H, Gil-Nagel A, Elger C, Hall S, Shin P, et al. Efficacy and safety of adjunctive ezogabine (retigabine) in refractory partial epilepsy. Neurology. 2010;75:1817–24.

    CAS  PubMed  Article  Google Scholar 

  16. 16.

    French JA, Abou-Khalil BW, Leroy RF, Yacubian EM, Shin P, Hall S. et al. Randomized, double-blind, placebo-controlled trial of ezogabine (retigabine) in partial epilepsy. Neurology. 2011;76:1555–63.

    CAS  PubMed  Article  Google Scholar 

  17. 17.

    Stafstrom CE, Grippon S, Kirkpatrick P. Ezogabine (retigabine). Nat Rev Drug Discov. 2011;10:729–30.

    CAS  PubMed  Article  Google Scholar 

  18. 18.

    Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E, et al. The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry. 1998;59(SUPPL. 20):22–33.

    PubMed  Google Scholar 

  19. 19.

    Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br J Psychiatry. 1979;134:382–9.

    CAS  PubMed  Article  Google Scholar 

  20. 20.

    Snaith RP, Hamilton M, Morley S, Humayan A, Hargreaves D, Trigwell P. A scale for the assessment of hedonic tone. The Snaith-Hamilton Pleasure Scale. Br J Psychiatry. 1995;167:99–103.

    CAS  PubMed  Article  Google Scholar 

  21. 21.

    Rush AJ, Trivedi MH, Ibrahim HM, Carmody TJ, Arnow B, Klein DN, et al. The 16-item Quick Inventory of Depressive Symptomatology (QIDS), clinician rating (QIDS-C), and self-report (QIDS-SR): a psychometric evaluation in patients with chronic major depression. Biol Psychiatry. 2003;54:573–83.

    PubMed  Article  Google Scholar 

  22. 22.

    Busner J, Targum SD. The clinical global impressions scale: applying a research tool in clinical practice. Psychiatry. 2007;4:28–37.

    PubMed  Google Scholar 

  23. 23.

    Gard DE, Gard MG, Kring AM, John OP. Anticipatory and consummatory components of the experience of pleasure: a scale development study. J Res Pers. 2006;40:1086–102.

    Article  Google Scholar 

  24. 24.

    Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, et al. The Columbia-suicide severity rating scale: initial validity and internal consistency findings from three multisite studies with adolescents and adults. Am J Psychiatry. 2011;168:1266–77.

    PubMed  PubMed Central  Article  Google Scholar 

  25. 25.

    Brown E, Wood L, Wood S. MedDRA - the medical dictionary for regulatory activities. Drug Saf. 2008;20:109–17.

    Article  Google Scholar 

  26. 26.

    Cox RW. AFNI: software for analysis and visualization of functional magnetic resonance neuroimages. Comput Biomed Res. 1996;29:162–73.

    CAS  PubMed  Article  Google Scholar 

  27. 27.

    Smith SM, Jenkinson M, Woolrich MW, Beckmann CF, Behrens TEJ, Johansen-Berg H, et al. Advances in functional and structural MR image analysis and implementation as FSL. Neuroimage. 2004;23(SUPPL. 1):208–19.

    Article  Google Scholar 

  28. 28.

    Pruim RHR, Mennes M, van Rooij D, Llera A, Buitelaar JK, Beckmann CF. ICA-AROMA: a robust ICA-based strategy for removing motion artifacts from fMRI data. Neuroimage. 2015;112:267–77.

    PubMed  Article  Google Scholar 

  29. 29.

    Jo HJ, Saad ZS, Simmons WK, Milbury LA, Cox RW. Mapping sources of correlation in resting state FMRI, with artifact detection and removal. Neuroimage. 2010;52:571–82.

    PubMed  PubMed Central  Article  Google Scholar 

  30. 30.

    Murty VP, Shermohammed M, Smith DV, Carter RMK, Huettel SA, Adcock RA. Resting state networks distinguish human ventral tegmental area from substantia nigra. Neuroimage. 2014;100:580–9.

    PubMed  PubMed Central  Article  Google Scholar 

  31. 31.

    Barry RL, Coaster M, Rogers BP, Newton AT, Moore J, Anderson AW, et al. On the origins of signal variance in FMRI of the human midbrain at high field. PLoS ONE. 2013;8:1–14.

    Google Scholar 

  32. 32.

    Eklund A, Nichols TE, Knutsson H. Cluster failure: why fMRI inferences for spatial extent have inflated false-positive rates. Proc Natl Acad Sci. 2016;113:7900–5.

    CAS  PubMed  Article  Google Scholar 

  33. 33.

    Cox RW, Chen G, Glen DR, Reynolds RC, Taylor PA. FMRI clustering and false positive rates. Proc Natl Acad Sci USA. 2017;114:E3370–1.

    CAS  Article  Google Scholar 

  34. 34.

    Whitton AE, Kakani P, Foti D, Van’T Veer A, Haile A, Crowley DJ, et al. Blunted neural responses to reward in remitted major depression: a high-density event-related potential study. Biol Psychiatry Cogn Neurosci Neuroimaging. 2016;1:87–95.

    PubMed  PubMed Central  Article  Google Scholar 

  35. 35.

    Pizzagalli DA, Iosifescu D, Hallett LA, Ratner KG, Fava M. Reduced hedonic capacity in major depressive disorder: evidence from a probabilistic reward task. J Psychiatr Res. 2008;43:76–87.

    PubMed  PubMed Central  Article  Google Scholar 

  36. 36.

    Vrieze E, Pizzagalli DA, Demyttenaere K, Hompes T, Sienaert P, De Boer P, et al. Reduced reward learning predicts outcome in major depressive disorder. Biol Psychiatry. 2013;73:639–45.

    PubMed  Article  Google Scholar 

  37. 37.

    Berton O, McClung CA, DiLeone RJ, Krishnan V, Renthal W, Russo SJ, et al. Essential role of BDNF in the mesolimbic dopamine pathway in social defeat stress. Science. 2006;311:864–8.

    CAS  Article  PubMed  Google Scholar 

  38. 38.

    Berton O, Mcclung CA, Dileone RJ, Krishnan V, Renthal W, Russo SJ, et al. Essential role of BDNF in the social defeat. Stress. 2008;864:864–9.

    Google Scholar 

  39. 39.

    Devinsky O, Morrell MJ, Vogt BA. Review article: Contributions of anterior cingulate cortex to behaviour. Brain. 1995;118:279–306.

    PubMed  Article  Google Scholar 

  40. 40.

    Bush G, Luu P, Posner MI. Cognitive and emotional influences in anterior cingulate cortex. Trends Cogn Sci. 2000;4:215–22.

    CAS  PubMed  Article  Google Scholar 

  41. 41.

    Shackman AJ, Salomons TV, Slagter HA, Fox AS, Winter JJ, Davidson RJ. The integration of negative affect, pain and cognitive control in the cingulate cortex. Nat Rev Neurosci. 2011;12:154–67.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  42. 42.

    Apps MAJ, Rushworth MFS, Chang SWC. The anterior cingulate gyrus and social cognition: tracking the motivation of others. Neuron. 2016;90:692–707.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  43. 43.

    Jensen J, McIntosh AR, Crawley AP, Mikulis DJ, Remington G, Kapur S. Direct activation of the ventral striatum in anticipation of aversive stimuli. Neuron. 2003;40:1251–7.

    CAS  PubMed  Article  Google Scholar 

  44. 44.

    Delgado MR, Li J, Schiller D, Phelps EA. The role of the striatum in aversive learning and aversive prediction errors. Philos Trans R Soc B Biol Sci. 2008;363:3787–800.

    Article  Google Scholar 

  45. 45.

    Brooks AM, Berns GS. Aversive stimuli and loss in the mesocorticolimbic dopamine system. Trends Cogn Sci. 2013;17:281–6.

    PubMed  Article  Google Scholar 

  46. 46.

    Quevedo K, Ng R, Scott H, Kodavaganti S, Smyda G, Diwadkar V, et al. Ventral striatum functional connectivity during rewards and losses and symptomatology in depressed patients. Biol Psychol. 2017;123:62–73.

    PubMed  Article  Google Scholar 

  47. 47.

    Raichle ME. The brain’s default mode network. Annu Rev Neurosci. 2015;38:433–47.

    CAS  PubMed  Article  Google Scholar 

  48. 48.

    Zhong X, Pu W, Yao S. Functional alterations of fronto-limbic circuit and default mode network systems in first-episode, drug-naïve patients with major depressive disorder: a meta-analysis of resting-state fMRI data. J Affect Disord. 2016;206:280–6.

    PubMed  Article  Google Scholar 

  49. 49.

    Hamilton JP, Furman DJ, Chang C, Thomason ME, Dennis E, Gotlib IH. Default-mode and task-positive network activity in major depressive disorder: implications for adaptive and maladaptive rumination. Biol Psychiatry. 2011;70:327–33.

    PubMed  PubMed Central  Article  Google Scholar 

  50. 50.

    Ho TC, Connolly CG, Henje Blom E, LeWinn KZ, Strigo IA, Paulus MP, et al. Emotion-dependent functional connectivity of the default mode network in adolescent depression. Biol Psychiatry. 2015;78:635–46.

    PubMed  Article  Google Scholar 

  51. 51.

    Haber SN, Fudge JL, McFarland NR. Striatonigrostriatal pathways in primates form an ascending spiral from the shell to the dorsolateral striatum. J Neurosci. 2000;20:2369–82.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  52. 52.

    Haber SN, Knutson B. The reward circuit: linking primate anatomy and human imaging. Neuropsychopharmacology. 2010;35:4–26.

    PubMed  Article  Google Scholar 

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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).

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Correspondence to 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.

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Tan, A., Costi, S., Morris, L.S. et al. Effects of the KCNQ channel opener ezogabine on functional connectivity of the ventral striatum and clinical symptoms in patients with major depressive disorder. Mol Psychiatry 25, 1323–1333 (2020). https://doi.org/10.1038/s41380-018-0283-2

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