Abstract
Anhedonia is thought to reflect deficits in reward processing that are associated with abnormal activity in mesocorticolimbic brain regions. It is expressed clinically as a deficit in the interest or pleasure in daily activities. More severe anhedonia in major depressive disorder (MDD) is a negative predictor of antidepressant response. It is unknown, however, whether the pathophysiology of anhedonia represents a viable avenue for identifying biological markers of antidepressant treatment response. Therefore, this study aimed to examine the relationships between reward processing and response to antidepressant treatment using clinical, behavioral, and functional neuroimaging measures. Eighty-seven participants in the first Canadian Biomarker Integration Network in Depression (CAN-BIND-1) protocol received 8 weeks of open-label escitalopram. Clinical correlates of reward processing were assessed at baseline using validated scales to measure anhedonia, and a monetary incentive delay (MID) task during functional neuroimaging was completed at baseline and after 2 weeks of treatment. Response to escitalopram was associated with significantly lower self-reported deficits in reward processing at baseline. Activity during the reward anticipation, but not the reward consumption, phase of the MID task was correlated with clinical response to escitalopram at week 8. Early (baseline to week 2) increases in frontostriatal connectivity during reward anticipation significantly correlated with reduction in depressive symptoms after 8 weeks of treatment. Escitalopram response is associated with clinical and neuroimaging correlates of reward processing. These results represent an important contribution towards identifying and integrating biological, behavioral, and clinical correlates of treatment response. ClinicalTrials.gov: NCT01655706.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
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.
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.
Downar J, Geraci J, Salomons TV, Dunlop K, Wheeler S, McAndrews MP, et al. Anhedonia and reward-circuit connectivity distinguish nonresponders from responders to dorsomedial prefrontal repetitive transcranial magnetic stimulation in major depression. Biol Psychiatry. 2014;76:176–85.
Warden D, Rush AJ, Trivedi MH, Fava M, Wisniewski SR. The STAR*D Project results: a comprehensive review of findings. Curr Psychiatry Rep. 2007;9:449–59.
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.
Hägele C, Schlagenhauf F, Rapp M, Sterzer P, Beck A, Bermpohl F, et al. Dimensional psychiatry: reward dysfunction and depressive mood across psychiatric disorders. Psychopharmacology. 2015;232:331–41.
Dubol M, Trichard C, Leroy C, Sandu A-L, Rahim M, Granger B, et al. Dopamine transporter and reward anticipation in a dimensional perspective: a multimodal brain imaging study. Neuropsychopharmacology. 2018;43:820–7.
Stoy M, Schlagenhauf F, Sterzer P, Bermpohl F, Hägele C, Suchotzki K, et al. Hyporeactivity of ventral striatum towards incentive stimuli in unmedicated depressed patients normalizes after treatment with escitalopram. J Psychopharmacol. 2012;26:677–88.
Dichter GS, Kozink RV, McClernon FJ, Smoski MJ. Remitted major depression is characterized by reward network hyperactivation during reward anticipation and hypoactivation during reward outcomes. J Affect Disord. 2012;136:1126–34.
Zhang B, Lin P, Shi H, Öngür D, Auerbach RP, Wang X, et al. Mapping anhedonia-specific dysfunction in a transdiagnostic approach: an ALE meta-analysis. Brain Imaging Behav. 2016;10:920–39.
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, Nickerson LD, Dillon DG, Holmes AJ, Bogdan R, Kumar P, et al. Dissociable cortico-striatal connectivity abnormalities in major depression in response to monetary gains and penalties. Psychol Med. 2015;45:121–31.
Wacker J, Dillon DG, Pizzagalli DA. The role of the nucleus accumbens and rostral anterior cingulate cortex in anhedonia: integration of resting EEG, fMRI, and volumetric techniques. Neuroimage. 2009;46:327–37.
Prakash N, Stark CJ, Keisler MN, Luo L, Der-Avakian A, Dulcis D. Serotonergic plasticity in the dorsal raphe nucleus characterizes susceptibility and resilience to anhedonia. J Neurosci. 2020;40:569–84.
Drysdale AT, Grosenick L, Downar J, Dunlop K, Mansouri F, Meng Y, et al. Resting-state connectivity biomarkers define neurophysiological subtypes of depression. Nat Med. 2017;23:28–38.
Carl H, Walsh E, Eisenlohr-Moul T, Minkel J, Crowther A, Moore T, et al. Sustained anterior cingulate cortex activation during reward processing predicts response to psychotherapy in major depressive disorder. J Affect Disord. 2016;203:204–12.
Walsh E, Carl H, Eisenlohr-Moul T, Minkel J, Crowther A, Moore T, et al. Attenuation of frontostriatal connectivity during reward processing predicts response to psychotherapy in major depressive disorder. Neuropsychopharmacology. 2017;42:831–43.
Kujawa A, Burkhouse KL, Karich SR, Fitzgerald KD, Monk CS, Phan KL. Reduced reward responsiveness predicts change in depressive symptoms in anxious children and adolescents following treatment. J Child Adolesc Psychopharmacol. 2019;29:378–85.
Forbes EE, Olino TM, Ryan ND, Birmaher B, Axelson D, Moyles DL, et al. Reward-related brain function as a predictor of treatment response in adolescents with major depressive disorder. Cogn Affect Behav Neurosci. 2010;10:107–18.
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.
Cheng Y, Xu J, Arnone D, Nie B, Yu H, Jiang H, et al. Resting-state brain alteration after a single dose of SSRI administration predicts 8-week remission of patients with major depressive disorder. Psychol Med. 2017;47:438–50.
Burkhouse KL, Gorka SM, Klumpp H, Kennedy AE, Karich S, Francis J, et al. Neural responsiveness to reward as an index of depressive symptom change following cognitive-behavioral therapy and SSRI treatment. J Clin Psychiatry. 2018;79:17m11836.
Allen TA, Lam RW, Milev R, Rizvi SJ, Frey BN, MacQueen GM, et al. Early change in reward and punishment sensitivity as a predictor of response to antidepressant treatment for major depressive disorder: a CAN-BIND-1 report. Psychol Med. 2019;49:1629–38.
Whitton AE, Webb CA, Dillon DG, Kayser J, Rutherford A, Goer F, et al. Pretreatment rostral anterior cingulate cortex connectivity with salience network predicts depression recovery: findings from the EMBARC randomized clinical trial. Biol Psychiatry 2019;85:872–80.
Kennedy SH, Lam RW, Rotzinger S, Milev RV, Blier P, Downar J, et al. Symptomatic and functional outcomes and early prediction of response to escitalopram monotherapy and sequential adjunctive aripiprazole therapy in patients with major depressive disorder: a CAN-BIND-1 report. J Clin Psychiatry. 2019;80:18m12202.
Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br J Psychiatry. 1979;134:382–9.
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.
Rizvi SJ, Quilty LC, Sproule BA, Cyriac A, Michael Bagby R, Kennedy SH. Development and validation of the Dimensional Anhedonia Rating Scale (DARS) in a community sample and individuals with major depression. Psychiatry Res. 2015;229:109–19.
Alders GL, Davis AD, MacQueen G, Strother SC, Hassel S, Zamyadi M, et al. Reduced accuracy accompanied by reduced neural activity during the performance of an emotional conflict task by unmedicated patients with major depression: A CAN-BIND fMRI study. J Affect Disord. 2019;257:765–73.
Knutson B, Bhanji JP, Cooney RE, Atlas LY, Gotlib IH. Neural responses to monetary incentives in major depression. Biol Psychiatry. 2008;63:686–92.
Schiller CE, Minkel J, Smoski MJ, Dichter GS. Remitted major depression is characterized by reduced prefrontal cortex reactivity to reward loss. J Affect Disord. 2013;151:756–62.
Smoski MJ, Rittenberg A, Dichter GS. Major depressive disorder is characterized by greater reward network activation to monetary than pleasant image rewards. Psychiatry Res. 2011;194:263–70.
MacQueen GM, Hassel S, Arnott SR, Jean A, Bowie CR, Bray SL, et al. The Canadian Biomarker Integration Network in Depression (CAN-BIND): magnetic resonance imaging protocols. J Psychiatry Neurosci. 2019;44:223–36.
Jenkinson M, Beckmann CF, Behrens TEJ, Woolrich MW, Smith SM. FSL. Neuroimage 2012;62:782–90.
Costumero V, Barrós-Loscertales A, Bustamante JC, Ventura-Campos N, Fuentes P, Ávila C. Reward sensitivity modulates connectivity among reward brain areas during processing of anticipatory reward cues. Eur J Neurosci. 2013;38:2399–407.
Desikan RS, Ségonne F, Fischl B, Quinn BT, Dickerson BC, Blacker D, et al. An automated labeling system for subdividing the human cerebral cortex on MRI scans into gyral based regions of interest. Neuroimage. 2006;31:968–80.
Uher R, Perlis RH, Henigsberg N, Zobel A, Rietschel M, Mors O, et al. Depression symptom dimensions as predictors of antidepressant treatment outcome: replicable evidence for interest-activity symptoms. Psychol Med. 2012;42:967–80.
Beck AT, Steer RA, Ball R, Ranieri W. Comparison of Beck Depression Inventories -IA and -II in psychiatric outpatients. J Pers Assess. 1996;67:588–97.
Hamilton MC. A rating scale for depression. J Neurol Neurosurg Psychiatry. 1960;23:56–62.
Baskaran A, Farzan F, Milev R, Brenner CA, Alturi S, Pat McAndrews M, et al. The comparative effectiveness of electroencephalographic indices in predicting response to escitalopram therapy in depression: a pilot study. J Affect Disord. 2018;227:542–9.
Wagner S, Engel A, Engelmann J, Herzog D, Dreimüller N, Müller MB, et al. Early improvement as a resilience signal predicting later remission to antidepressant treatment in patients with Major Depressive Disorder: Systematic review and meta-analysis. J Psychiatr Res. 2017;94:96–106.
Olgiati P, Serretti A, Souery D, Dold M, Kasper S, Montgomery S, et al. Early improvement and response to antidepressant medications in adults with major depressive disorder. Meta-analysis and study of a sample with treatment-resistant depression. J Affect Disord. 2018;227:777–86.
Hunter AM, Nghiem TX, Cook IA, Krantz DE, Minzenberg MJ, Leuchter AF. Change in quantitative EEG theta cordance as a potential predictor of repetitive transcranial magnetic stimulation clinical outcome in major depressive disorder. Clin EEG Neurosci. 2018;49:306–15.
Karim HT, Wang M, Andreescu C, Tudorascu D, Butters MA, Karp JF, et al. Acute trajectories of neural activation predict remission to pharmacotherapy in late-life depression. NeuroImage Clin. 2018;19:831–9.
Targum SD. Early symptomatic improvement affects treatment outcome in a study of major depressive disorder. J Psychiatr Res. 2017;95:276–81.
Khan A, Cohen S, Dager S, Avery DH, Dunner DL. Onset of response in relation to outcome in depressed outpatients with placebo and imipramine. J Affect Disord. 1989;17:33–8.
Quitkin FM, Rabkin JG, Ross D, Stewart JW. Identification of true drug response to antidepressants. Use of pattern analysis. Arch Gen Psychiatry. 1984;41:782–6.
Kemp DE, Ganocy SJ, Brecher M, Carlson BX, Edwards S, Eudicone JM, et al. Clinical value of early partial symptomatic improvement in the prediction of response and remission during short-term treatment trials in 3369 subjects with bipolar I or II depression. J Affect Disord. 2011;130:171–9.
Knutson B, Westdorp A, Kaiser E, Hommer D. FMRI visualization of brain activity during a monetary incentive delay task. Neuroimage. 2000;12:20–7.
Wilson RP, Colizzi M, Bossong MG, Allen P, Kempton M, MTAC, et al. The neural substrate of reward anticipation in health: a meta-analysis of fMRI findings in the monetary incentive delay task. Neuropsychol Rev. 2018;28:496–506.
Sankar A, Yttredahl AA, Fourcade EW, Mickey BJ, Love TM, Langenecker SA, et al. Dissociable neural responses to monetary and social gain and loss in women with major depressive disorder. Front Behav Neurosci. 2019;13:149.
Dillon DG, Bogdan R, Fagerness J, Holmes AJ, Perlis RH, Pizzagalli DA. Variation in TREK1 gene linked to depression-resistant phenotype is associated with potentiated neural responses to rewards in humans. Hum Brain Mapp. 2010;31:210–21.
Acknowledgements
We are indebted to all participants and clinicians for the time and effort they dedicated to this research. We thank Dr Diego Pizzagalli (Harvard Medical School, Belmont, MA, USA) for consultation and assistance with study design. We also thank Keith Ho (University Health Network, Toronto, Ontario, Canada) and Zahra Moazamigoudarzi (St. Michael’s Hospital, Toronto, Ontario, Canada) for their assistance in preparation of data for this manuscript. The authors wish to thank all members of the CAN-BIND Investigator team for their contribution to this work. Members of the CAN-BIND Investigator Team are listed here: www.canbind.ca/our-team/.
Author information
Authors and Affiliations
Contributions
KD: Data curation, formal analysis, writing (original draft), writing (review, editing, and approval); SJR: formal analysis, writing (original draft), writing (review, editing & approval); SHK: Study concept, data collection, formal analysis, writing (review, editing, and approval); SH: Data collection, data curation, writing (review, editing & approval); SCS: Data curation, writing (review, editing & approval); JKH: Data collection, data curation, writing (review, editing, and approval); MZ: Data collection, data curation, writing (review, editing, and approval); SRA: Data curation, writing (review, editing, and approval); ADD: Data collection, data curation, writing (review, editing, and approval); FM: Formal analysis, writing (review, editing, and approval); LS: Formal analysis, writing (review, editing, and approval); AKC: Data collection, data curation, writing (review, editing, and approval); RWL: Study concept, data collection, writing (review, editing & approval); RM: Study concept, data collection, writing (review, editing & approval); SR: Study concept, data collection, data curation, writing (review, editing, and approval); JAF: Data collection, data curation, writing (review, editing, and approval); BNF: Study concept, data collection, data curation, writing (review, editing, and approval); SVP: Study concept, writing (review, editing, and approval); CNS: Data collection, data curation, writing (review, editing, and approval); RU: Writing (review, editing, and approval); GT: Writing (review, editing and approval); GMM: Study concept, data collection, data curation, writing (review, editing, and approval); JD: Data collection, data curation, formal analysis, writing (review, editing, and approval).
Corresponding author
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Dunlop, K., Rizvi, S.J., Kennedy, S.H. et al. Clinical, behavioral, and neural measures of reward processing correlate with escitalopram response in depression: a Canadian Biomarker Integration Network in Depression (CAN-BIND-1) Report. Neuropsychopharmacol. 45, 1390–1397 (2020). https://doi.org/10.1038/s41386-020-0688-x
Published:
Issue date:
DOI: https://doi.org/10.1038/s41386-020-0688-x
This article is cited by
-
Neuroimaging for precision medicine in psychiatry
Neuropsychopharmacology (2025)
-
Breakthroughs and challenges for generating brain network-based biomarkers of treatment response in depression
Neuropsychopharmacology (2025)
-
The association between anhedonia and prefrontal cortex activation in patients with major depression: a functional near-infrared spectroscopy study
European Archives of Psychiatry and Clinical Neuroscience (2025)
-
Beyond the serotonin deficit hypothesis: communicating a neuroplasticity framework of major depressive disorder
Molecular Psychiatry (2024)
-
Neuronally-enriched exosomal microRNA-27b mediates acute effects of ibuprofen on reward-related brain activity in healthy adults: a randomized, placebo-controlled, double-blind trial
Scientific Reports (2022)
