Abstract
Anhedonia remains a major clinical issue for which there is few effective interventions. Untreated or poorly controlled anhedonia has been linked to worse disease course and increased suicidal behavior across disorders. Taking a proof-of-mechanism approach under the auspices of the National Institute of Mental Health FAST-FAIL initiative, we were the first to show that, in a transdiagnostic sample screened for elevated self-reported anhedonia, 8 weeks of treatment with a kappa-opioid receptor (KOR) antagonist resulted in significantly higher reward-related activation in one of the core hubs of the brain reward system (the ventral striatum), better reward learning in the Probabilistic Reward Task (PRT), and lower anhedonic symptoms, relative to 8 weeks of placebo. Here, we performed secondary analyses of the PRT data to investigate the putative effects of KOR antagonism on anhedonic behavior with more precision by using trial-level model-based Bayesian computational modeling and probability analyses. We found that, relative to placebo, KOR antagonism resulted in significantly higher learning rate (i.e., ability to learn from reward feedback) and a more sustained preference toward the more frequently rewarded stimulus, but unaltered reward sensitivity (i.e., the hedonic response to reward feedback). Collectively, these findings provide novel evidence that in a transdiagnostic sample characterized by elevated anhedonia, KOR antagonism improved the ability to modulate behavior as a function of prior rewards. Together with confirmation of target engagement in the primary report (Krystal et al., Nat Med, 2020), the current findings suggest that further transdiagnostic investigation of KOR antagonism for anhedonia is warranted.
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13 August 2021
A Correction to this paper has been published: https://doi.org/10.1038/s41386-021-01145-9
References
Trivedi MH, Rush AJ, Wisniewski SR, Nierenberg AA, Warden D, Ritz L, et al. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry. 2006;163:28–40.
DeRubeis RJ, Hollon S, Amsterdam J, et al. Cognitive therapy vs medications in the treatment of moderate to severe depression. Arch Gen Psychiatry. 2005;62:409–16.
American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 5th ed. Arlington, VA: American Psychiatric Association; 2013.
Insel T, Cuthbert B, Garvey M, Heinssen R, Pine DS, Quinn K, et al. Research domain criteria (RDoC): toward a new classification framework for research on mental disorders. Am J Psychiatry. 2010;167:748–51.
Loas G, Krystkowiak P, Godefroy O. Anhedonia in Parkinson’s disease: an overview. J Neuropsychiatry Clin Neurosci. 2012;24:444–51.
Whitton AE, Treadway MT, Pizzagalli DA. Reward processing dysfunction in major depression, bipolar disorder and schizophrenia. Curr Opin Psychiatry. 2015;28:7–12.
Nawijn L, van Zuiden M, Frijling JL, Koch SBJ, Veltman DJ, Olff M. Reward functioning in PTSD: a systematic review exploring the mechanisms underlying anhedonia. Neurosci Biobehav Rev. 2015;51:189–204.
Meehl PE. Hedonic capacity: some conjectures. Bull Menn Clin. 1975;39:295–307.
Klein DF. Endogenomorphic depression. A conceptual and terminological revision. Arch Gen Psychiatry. 1974;31:447–54.
Pizzagalli DA. Depression, stress, and anhedonia: toward a synthesis and integrated model. Annu Rev Clin Psychol. 2014;10:393–423.
Spijker J, Bijl RV, de Graaf R, Nolen WA. Determinants of poor 1-year outcome of DSM-III-R major depression in the general population: results of the Netherlands Mental Health Survey and Incidence Study (NEMESIS). Acta Psychiatr Scand. 2001;103:122–30.
Moos RH, Cronkite RC. Symptom-based predictors of a 10-year chronic course of treated depression. J Nerv Ment Dis. 1999;187:360–8.
Fawcett J, Scheftner WA, Fogg L, Clark DC, Young MA, Hedeker D, et al. Time-related predictors of suicide in major affective disorder. Am J Psychiatry. 1990;147:1189–94.
Berridge KC, Robinson TE. What is the role of dopamine in reward: hedonic impact, reward learning, or incentive salience? Brain Res Brain Res Rev. 1998;28:309–69.
Treadway MT, Zald DH. Reconsidering anhedonia in depression: lessons from translational neuroscience. Neurosci Biobehav Rev. 2011;35:537–55.
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.
Der-Avakian A, D’Souza MSS, Pizzagalli DAA, Markou A. Assessment of reward responsiveness in the response bias probabilistic reward task in rats: implications for cross-species translational research. Transl Psychiatry. 2013;3:e297.
Lamontagne SJ, Melendez SI, Olmstead MC. Investigating dopamine and glucocorticoid systems as underlying mechanisms of anhedonia. Psychopharmacology. 2018;235:3103–13.
Pizzagalli DA, Evins AE, Schetter EC, Frank MJ, Pajtas PE, Santesso DL, et al. Single dose of a dopamine agonist impairs reinforcement learning in humans: behavioral evidence from a laboratory-based measure of reward responsiveness. Psychopharmacology. 2008;196:221–32.
Kaiser RH, Treadway MT, Wooten DW, Kumar P, Goer F, Murray L, et al. Frontostriatal and dopamine markers of individual differences in reinforcement learning: a multi-modal investigation. Cereb Cortex. 2018;28:4281–90.
Vrieze E, Ceccarini J, Pizzagalli DA, Bormans G, Vandenbulcke M, Demyttenaere K, et al. Measuring extrastriatal dopamine release during a reward learning task. Hum Brain Mapp. 2013;34:575–86.
Santesso DL, Dillon DG, Birk JL, Holmes AJ, Goetz E, Bogdan R, et al. Individual differences in reinforcement learning: behavioral, electrophysiological, and neuroimaging correlates. Neuroimage. 2008;42:807–16.
Luking KR, Neiman JS, Luby JL, Barch DM. Reduced hedonic capacity/approach motivation relates to blunted responsivity to gain and loss feedback in children. J Clin Child Adolesc Psychol. 2017;46:450–62.
Bogdan R, Pizzagalli DA. Acute stress reduces reward responsiveness: implications for depression. Biol Psychiatry. 2006;60:1147–54.
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.
Liu W, Roiser JP, Wang L-Z, Zhu Y-H, Huang J, Neumann DL, et al. Anhedonia is associated with blunted reward sensitivity in first-degree relatives of patients with major depression. J Affect Disord. 2016;190:640–8.
Tan A, Costi S, Morris LS, Van Dam NT, Kautz M, Whitton AE, 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. 2018. https://doi.org/10.1038/s41380-018-0283-2.
Liu W, Chan RCK, Wang L, Huang J, Cheung EFC, Gong Q, et al. Deficits in sustaining reward responses in subsyndromal and syndromal major depression. Prog Neuropsychopharmacol Biol Psychiatry. 2011;35:1045–52.
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.
Pechtel P, Dutra SJ, Goetz EL, Pizzagalli DA. Blunted reward responsiveness in remitted depression. J Psychiatr Res. 2013;47:1864–9.
Whitton AE, Kakani P, Foti D, Veer AV, Haile A, Crowley DJ, et al. Blunted neural responses to reward in remitted major depression: a high-density event-related potential study. Biol Psychiatry Cognit Neurosci Neuroimaging. 2016;1:87–95.
Audrain-McGovern J, Wileyto EP, Ashare R, Cuevas J, Strasser AA. Reward and affective regulation in depression-prone smokers. Biol Psychiatry. 2014;76:689–97.
Fletcher K, Parker G, Paterson A, Fava M, Iosifescu D, Pizzagalli DA. Anhedonia in melancholic and non-melancholic depressive disorders. J Affect Disord. 2015;184:81–8.
Morris BH, Bylsma LM, Yaroslavsky I, Kovacs M, Rottenberg J. Reward learning in pediatric depression and anxiety: preliminary findings in a high-risk sample. Depression Anxiety. 2015;32:373–81.
Jacobson ML, Browne CA, Lucki I. Kappa opioid receptor antagonists as potential therapeutics for stress-related disorders. Annu Rev Pharmacol Toxicol. 2020;60:615–36.
McLaughlin JP, Li S, Valdez J, Chavkin TA, Chavkin C. Social defeat stress-induced behavioral responses are mediated by the endogenous kappa opioid system. Neuropsychopharmacology. 2006;31:1241–8.
Reindl JD, Rowan K, Carey AN, Peng X, Neumeyer JL, McLaughlin JP. Antidepressant-like effects of the novel kappa opioid antagonist MCL-144B in the forced-swim test. Pharmacology. 2008;81:229–35.
Shirayama Y, Ishida H, Iwata M, Hazama GI, Kawahara R, Duman RS. Stress increases dynorphin immunoreactivity in limbic brain regions and dynorphin antagonism produces antidepressant-like effects. J Neurochem. 2004;90:1258–68.
Carlezon JrWA, Beguin C, DiNieri JA, Baumann MH, Richards MR, Todtenkopf MS, et al. Depressive-like effects of the kappa-opioid receptor agonist salvinorin A on behavior and neurochemistry in rats. J Pharmacol Exp Ther. 2006;316:440–7.
Pizzagalli DA, Holmes AJ, Dillon DG, Goetz EL, Birk JL, Bogdan R, et al. Reduced caudate and nucleus accumbens response to rewards in unmedicated individuals with major depressive disorder. Am J Psychiatry. 2009;166:702–10.
Admon R, Kaiser RH, Dillon DG, Beltzer M, Goer F, Olson DP, et al. Dopaminergic enhancement of striatal response to reward in major depression. Am J Psychiatry. 2017;174:378–86.
Forbes EE, Hariri AR, Martin SL, Silk JS, Moyles DL, Fisher PM, et al. Altered striatal activation predicting real-world positive affect in adolescent major depressive disorder. Am J Psychiatry. 2009;166:64–73.
Maisonneuve IM, Archer S, Glick SD. U50,488, a kappa opioid receptor agonist, attenuates cocaine-induced increases in extracellular dopamine in the nucleus accumbens of rats. Neurosci Lett. 1994;181:57–60.
Bruijnzeel AW. kappa-Opioid receptor signaling and brain reward function. Brain Res Rev. 2009;62:127–46.
Muschamp JW, Van’t Veer A, Carlezon WA. Tracking down the molecular substrates of stress: new roles for p38α mapk and kappa-opioid receptors. Neuron. 2011;71:383–5.
Carlezon WA, Krystal AD. Kappa-opioid antagonists for psychiatric disorders: from bench to clinical trials. Depression Anxiety. 2016;33:895–906.
Wee S, Koob GF. The role of the dynorphin-kappa opioid system in the reinforcing effects of drugs of abuse. Psychopharmacology. 2010;210:121–35.
Carlezon JrWA, Beguin C, Knoll AT, Cohen BM. Kappa-opioid ligands in the study and treatment of mood disorders. Pharmacol Ther. 2009;123:334–43.
Krystal AD, Pizzagalli DA, Smoski M, Mathew SJ, Nurnberger J, Lisanby SH, et al. A randomized proof-of-mechanism trial applying the ‘fast-fail’ approach to evaluating κ-opioid antagonism as a treatment for anhedonia. Nat Med. 2020. https://doi.org/10.1038/s41591-020-0806-7.
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.
Huys QJ, Pizzagalli DA, Bogdan R, Dayan P. Mapping anhedonia onto reinforcement learning: a behavioural meta-analysis. Biol Mood Anxiety Disord. 2013;3:12.
Waelti P, Dickinson A, Schultz W. Dopamine responses comply with basic assumptions of formal learning theory. Nature. 2001;412:43–8.
Montague PR, Hyman SE, Cohen JD. Computational roles for dopamine in behavioural control. Nature. 2004;431:760–7.
Bayer HM, Glimcher PW. Midbrain dopamine neurons encode a quantitative reward prediction error signal. Neuron. 2005;47:129–41.
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;59:22–33.
Diagnostic and statistical manual of mental disorders. 4th ed. text revision. Washington, DC: American Psychiatric Press; 2000.
Franken IH, Rassin E, Muris P. The assessment of anhedonia in clinical and non-clinical populations: further validation of the Snaith-Hamilton Pleasure Scale (SHAPS). J Affect Disord. 2007;99:83–9.
Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry. 1960;23:56–62.
Maier W, Buller R, Philipp M, Heuser I. The Hamilton Anxiety Scale: reliability, validity and sensitivity to change in anxiety and depressive disorders. J Affect Disord. 1988;14:61–8.
Rorick-Kehn LM, Witkin JM, Statnick MA, Eberle EL, McKinzie JH, Kahl SD, et al. LY2456302 is a novel, potent, orally-bioavailable small molecule kappa-selective antagonist with activity in animal models predictive of efficacy in mood and addictive disorders. Neuropharmacology. 2014;77:131–44.
Lowe SL, Wong CJ, Witcher J, Gonzales CR, Dickinson GL, Bell RL, et al. Safety, tolerability, and pharmacokinetic evaluation of single- and multiple-ascending doses of a novel kappa opioid receptor antagonist LY2456302 and drug interaction with ethanol in healthy subjects. J Clin Pharmacol. 2014;54:968–78.
Zheng M-Q, Nabulsi N, Kim SJ, Tomasi G, Lin S-F, Mitch C, et al. Synthesis and evaluation of 11C-LY2795050 as a κ-opioid receptor antagonist radiotracer for PET imaging. J Nucl Med. 2013;54:455–63.
Nelson BD, Perlman G, Klein DN, Kotov R, Hajcak G. Blunted neural response to rewards as a prospective predictor of the development of depression in adolescent girls. Am J Psychiatry. 2016;173:1223–30.
Lemke MR. Depressive symptoms in Parkinson’s disease. Eur J Neurol. 2008;15 Suppl 1:21–5.
Poewe W. Non-motor symptoms in Parkinson’s disease. Eur J Neurol. 2008;15:14–20.
Stone MD, Audrain-McGovern J, Leventhal AM. Association of anhedonia with adolescent smoking susceptibility and initiation. Nicotine Tob Res. 2017;19:738–42.
Ilyutchenok RY, Dubrovina NI. Memory retrieval enhancement by kappa opioid agonist and mu, delta antagonists. Pharmacol Biochem Behav. 1995;52:683–7.
Tejeda HA, Counotte DS, Oh E, Ramamoorthy S, Schultz-Kuszak KN, Bäckman CM, et al. Prefrontal cortical kappa-opioid receptor modulation of local neurotransmission and conditioned place aversion. Neuropsychopharmacology. 2013;38:1770–9.
Kelsey JE, Verhaak AMS, Schierberl KC. The kappa-opioid receptor antagonist, nor-binaltorphimine (nor-BNI), decreases morphine withdrawal and the consequent conditioned place aversion in rats. Behav Brain Res. 2015;283:16–21.
Meng F, Xie GX, Thompson RC, Mansour A, Goldstein A, Watson SJ, et al. Cloning and pharmacological characterization of a rat κ opioid receptor. Proc Natl Acad Sci USA. 1993;90:9954–8.
Simonin F, Gavériaux-Ruff C, Befort K, Matthes H, Lannes B, Micheletti G, et al. κ-Opioid receptor in humans: cDNA and genomic cloning, chromosomal assignment, functional expression, pharmacology, and expression pattern in the central nervous system. Proc Natl Acad Sci USA. 1995;92:7006–10.
Zhu J, Chen C, Xue JC, Kunapuli S, DeRiel JK, Liu-Chen LY. Cloning of a human κ opioid receptor from the brain. Life Sci. 1995;56:PL201–7. https://doi.org/10.1016/0024-3205(94)00507-o.
Kumar P, Goer F, Murray L, Dillon DG, Beltzer ML, Cohen AL, et al. Impaired reward prediction error encoding and striatal-midbrain connectivity in depression. Neuropsychopharmacology. 2018;43:1581–8.
Trivedi MH, South C, Jha MK, Rush AJ, Cao J, Kurian B, et al. A novel strategy to identify placebo responders: prediction index of clinical and biological markers in the EMBARC trial. Psychother Psychosom. 2018;87:285–95.
Webb CA, Dillon DG, Pechtel P, Goer FK, Murray L, Huys QJQJM, et al. Neural correlates of three promising endophenotypes of depression: evidence from the EMBARC study. Neuropsychopharmacology. 2016;41:454–63.
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Substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work: all authors. Drafting the work or revising it critically for important intellectual content: DAP, MS, Y-SA, AEW, GS, SJM, DVI, JWN, ADK. Final approval of the version to be published: all authors. Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved: DAP, ADK.
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Pizzagalli, D.A., Smoski, M., Ang, YS. et al. Selective kappa-opioid antagonism ameliorates anhedonic behavior: evidence from the Fast-fail Trial in Mood and Anxiety Spectrum Disorders (FAST-MAS). Neuropsychopharmacol. 45, 1656–1663 (2020). https://doi.org/10.1038/s41386-020-0738-4
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DOI: https://doi.org/10.1038/s41386-020-0738-4
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