Reward Processing Mechanisms of Negative Symptoms in Schizophrenia Gregory P. Strauss, Ph.D. Assistant Professor Department of Psychology University of Georgia Disclosures ACKNOWLEDGMENTS & DISCLOSURES ▪ Receive royalties and consultation fees from ProPhase LLC in connection with commercial use of the BNSS and other professional activities; these fees are donated to the Brain and Behavior Research Foundation. ▪ Last 12 Months: Speaking/consultation with Minerva, Lundbeck, Acadia What are negative symptoms and why are they important? Domains of psychopathology in schizophrenia Negative Symptoms ▪ Negative symptoms - reductions in goal-directed activity, social behavior, pleasure, and the outward expression of emotion or speech Cognitive Positive ▪ Long considered a core feature of psychotic disorders1,2 Deficits Symptoms ▪ Distinct from other domains of psychopathology (e.g., psychosis, disorganization) 3 ▪ Associated with a range of poor clinical outcomes (e.g., Disorganized Affective disease liability, quality of life, subjective well-being, Symptoms Symptoms recovery) 4-7 1. Bleuler E. [Dementia praecox or the group of schizophrenias]. Vertex Sep-Oct 2010;21(93):394-400. 2. Kraepelin E. Dementia praecox and paraphrenia (R. M. Barclay, Trans.). New York, NY: Krieger. 1919. 3. Peralta V, Cuesta MJ. How many and which are the psychopathological dimensions in schizophrenia? Issues influencing their ascertainment. Schizophrenia research Apr 30 2001;49(3):269-285. 4. Fervaha G, Remington G. Validation of an abbreviated quality of life scale for schizophrenia. Eur Neuropsychopharmacol Sep 2013;23(9):1072-1077. 5. Piskulic D, Addington J, Cadenhead KS, et al. Negative symptoms in individuals at clinical high risk of psychosis. Psychiatry research Apr 30 2012;196(2-3):220-224. 6. Strauss GP, Harrow M, Grossman LS, Rosen C. Periods of recovery in deficit syndrome schizophrenia: a 20-year multi-follow-up longitudinal study. Schizophrenia bulletin Jul 2010;36(4):788-799. 7. Strauss GP, Sandt AR, Catalano LT, Allen DN. Negative symptoms and depression predict lower psychological well-being in individuals with schizophrenia. Comprehensive psychiatry Nov 2012;53(8):1137-1144. Challenges in Treatment ▪ Psychosocial and pharmacological interventions have yielded limited effectiveness for improving negative symptoms in schizophrenia 8 ▪ No drug has received an indication for negative symptoms from the FDA ▪ 2005 NIMH Consensus Conference 9 ▪ 5 domains: blunted affect, alogia, anhedonia, avolition, asociality ▪ New assessments needed ▪ Need more studies on pathophysiology to identify treatment targets 8. Fusar-Poli P, Papanastasiou E, Stahl D, Rocchetti M, Carpenter W, Shergill S, McGuire P. Treatments of Negative Symptoms in Schizophrenia: Meta-Analysis of 168 Randomized Placebo-Controlled Trials. Schizophrenia bulletin Jul 2015;41(4):892-899. 9. Kirkpatrick B, Fenton WS, Carpenter WT, Jr., Marder SR. The NIMH-MATRICS consensus statement on negative symptoms. Schizophrenia bulletin Apr 2006;32(2):214-219. Early Identification and Prevention From Addington & Heinssen, 2012 Addington, J., & Heinssen, R. (2012). Prediction and prevention of psychosis in youth at clinical high risk. Annual review of clinical psychology, 8, 269-289. Negative Symptoms Occur Outside of Schizophrenia- we just don’t call them that 1.Schizophrenia 2. Schizoaffective Disorder From Strauss & Cohen, 2017 3. Schizophreniform Disorder 4. Schizotypal Personality Disorder 5. Schizoid Personality Disorder 6. Paranoid Personality Disorder 7. Avoidant Personality Disorder 8. Bipolar Disorder (I and II) 9. Major Depressive Disorder 10. Persistent Depressive Disorder (Dysthymia) 11. Premenstrual Dysphoric Disorder 12. Selective Mutism 13. Social Anxiety Disorder 14. Separation Anxiety Disorder 15. Reactive Attachment Disorder 16. Posttraumatic Stress Disorder 17. Depersonalization/Derealization Disorder 18. Autism Spectrum Disorder 19. Neurocognitive Disorders Strauss, G. P., & Cohen, A. S. (2017). A transdiagnostic review of negative symptom phenomenology and etiology. Schizophrenia bulletin, 43(4), 712-719. How severe are negative symptoms when they occur in the prodrome and outside of schizophrenia? Z-Scores Compared to Healthy Control Group Z-Scores Compared to Schizophrenia Group 6 0 -0.2 5 -0.4 -0.6 4 -0.8 3 -1 -1.2 2 -1.4 1 -1.6 score score Compared to Schizophrenia Group score score Compared to Healthy Control Group - - Z -1.8 Z 0 Blunted Alogia Avolition Anhed/Asoc EXP VOL Total Blunted Affect Alogia Avolition Anhed/Asoc EXP VOL Total Affect Schizoaffective Disorder Major Depressive Disorder Ultra High-Risk Schizophrenia Schizoaffective Disorder Major Depressive Disorder Bipolar Disorder Healthy Control Ultra High-Risk Bipolar Disorder Strauss, G. P., & Cohen, A. S. (2017). A transdiagnostic review of negative symptom phenomenology and etiology. Schizophrenia bulletin, 43(4), 712-719. Strauss et al. JAMA Psychiatry (2019) Which domain(s) should be targeted? Is one domain more central than the others? Control Bipolar Disorder Schizophrenia What was most central? What was most central? What was most central? Anhedonia Anhedonia Avolition, alogia Strauss et al., in press. Schizophr Bulletin Avolition– Key for Functional Outcome Total Social Work Blunted Affect -.43*** -.38*** -.30*** Alogia -.42*** -.39*** -.28*** Anhedonia -.52*** -.44*** -.30*** Avolition -.63*** -.46*** -.51*** Asociality -.62*** -.60*** -.39*** Avolition- the key domain for treatment Data from MIN-101 (Roluperidone) Clinical Trial (Davidson et al., 2017, AJP) Centrality Measures: Key symptom that leads to improvement: AVOLITION INTERNAL EXPERIENCE Strauss et al., in press Schiz Bull Etiological Models of Avolition in Schizophrenia • Several etiological Reward Responsiveness 3. Reward Learning Prediction models have been Error DA, VS, PFC 1. Initial Response 2. Reward Anticipation developed for Opioid & GABA in DA, BG, ACC Implicit Explicit BG, OFC (Gold et al., 2008; DA, BG ACC, OFC, avolition DLPFC Barch & Dowd, 2010; Kring & Ellis, 2013; Strauss et al., 2014; 2017) • The NIMH RDoC “positive valence 4. Delay 5. Effort system” offers a OFC DA, VS, ACC useful conceptual Reward Valuation framework Modified from Barch & Dowd, 2010 Motivated Behavior Barch, D. M., & Dowd, E. C. (2010). Goal representations and motivational drive in schizophrenia: the role of prefrontal– striatal interactions. Schizophrenia bulletin, 36(5), 919-934. Summary Construct/Sub-construct Mechanism Mood Schizophrenia Clinical High-Risk Reward Responsiveness Initial Response Opioid & GABA Impaired Intact Impaired in BG, OFC Anticipation DA; BG & ACC Impaired Impaired Impaired Reward Learning Reinforcement Learning Implicit DA; BG Impaired Intact Impaired Reinforcement Learning Explicit DA; ACC; OFC, Intact Impaired Impaired DLPFC Reward Prediction Error DA, 5HT; BG, Impaired Intact* Impaired ACC, OFC Reward Valuation Delay OFC, MPFC, BG Impaired Impaired Impaired Effort DA, GABA; BG, Impaired Impaired Impaired ACC, Amygdala For transdiagnostic reviews see Strauss & Cohen, 2019; Barch et al., 2019 How inter-connected are the domains? If you target reward processing broadly, will all reward domains be expected to improve? SZ vs. CN Strauss et al., under review 3.40 SZ: n = 54 3.50 2.79 CN: n = 54 3.00 2.50 2.00 0.88 1.50 0.78 0.72 0.59 1.00 0.50 0.00 Avg. Clustering Avg. Shortest Path Density Coefficient Length Group SZ Group CN SZ vs. SZ Affective Diagnosis SZ Neg. High vs. Neg Low 3.00 2.44 2.51 2.48 3.00 2.52 2.50 2.00 2.00 1.50 0.92 0.90 0.89 0.89 0.81 0.79 0.82 0.80 1.00 1.00 0.50 0.00 Avg. Clustering Avg. Shortest Path Density 0.00 Coefficient Length Avg. Clustering Avg. Shortest Path Density Coefficient Length High Negative Low Negative SZ SZOA Is one reward processing domain more central than the others and thus a more critical target? Strauss et al., in prep SZ: n = 54 CN: n = 54 Is it possible to stratify patients into clinically meaningful subgroups based on reward processing task performance? 3 Clusters 1.00 • Cluster 1: Global reward processing impairment (9%) 0.00 • Cluster 2: Hedonic and effort impairment (66%) • Cluster 3: Intact reward processing (25%) -1.00 -2.00 score - Z -3.00 -4.00 Strauss et al., in prep -5.00 SZ: n = 54 Hedonic ValueRep Effort RewLearn CHR: n = 68 Cluster 1 Cluster 2 Cluster 3 CN: n = 112 9% 66% 25% Do the reward-based subgroups differ on external validators? Diagnoses Cluster 1 Cluster 2 Cluster 3 • Cluster 1: Global reward processing impairment (9%) % SZ 100% 59% 38.5% • Cluster 2: Hedonic and effort impairment (66%) • Cluster 3: Intact reward processing (25%) % CHR 0% 41% 61.5% Clinical Characteristics Cluster 1 Cluster 2 Cluster 3 Post hoc BNSS Avolition 4.4 (2.7) 3.4 (3.1) 2.8 (3.0)* 1>3 BNSS Anhedonia 4.8 (3.5) 4.1 (3.8) 3.7 (4.7)* 1>3 BNSS Asociality 3.4 (2.8) 2.4 (2.5) 1.8 (2.4) n.s. BNSS Alogia 0.4 (0.8) 0.9 (2.1) 0.4 (0.7) n.s. BNSS Blunted Affect 0.3 (0.5) 2.5 (3.6) 1.3 (2.1) n.s. EMA % Goal-Directed Time 34% (31) 43% (23) 45% (22)* 1<2,3 Geolocation % Home Time 64% (13) 58% (31) 55% (31)* 1>2,3 Strauss et al., in prep Ambient Sound Speech Detected 43 (21) 47 (75) 162 (37)* 3>1,2 SZ: n = 54 CHR: n = 68 MATRICS Global Cognition 27 (19) 43 (14) 48 (12)* 1<2,3 CN: n = 112 Equifinality within reward domains in SZ? Cooper, J. A., Barch, D. M., Reddy, L. F., Horan, W. P., Green, M. F., & Treadway, M. T. (2019). Effortful goal-directed behavior in schizophrenia: Computational subtypes and associations with cognition. Journal of abnormal psychology, 128(7), 710. Literature Summary • Avolition