Reward Processing Mechanisms of Negative Symptoms in

Gregory P. Strauss, Ph.D. Assistant Professor Department of 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 Cognitive Positive ▪ Long considered a core feature of psychotic disorders1,2 Deficits Symptoms ▪ Distinct from other domains of psychopathology (e.g., , disorganization) 3 ▪ Associated with a range of poor clinical outcomes (e.g., Disorganized Affective liability, quality of life, subjective well-being, Symptoms Symptoms recovery) 4-7

1. Bleuler E. [ praecox or the group of ]. 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, , 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. From Strauss & Cohen, 2017 3. Schizophreniform Disorder 4. Schizotypal Personality Disorder 5. Schizoid Personality Disorder 6. Paranoid Personality Disorder 7. Avoidant Personality Disorder 8. (I and II) 9. Major Depressive Disorder 10. Persistent Depressive Disorder () 11. Premenstrual Dysphoric Disorder 12. Selective Mutism 13. Disorder 14. Separation Anxiety Disorder 15. Reactive Attachment Disorder 16. Posttraumatic Stress Disorder 17. Depersonalization/Derealization Disorder 18. 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 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 Comparedto Schizophrenia Group

score score Comparedto 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 is highly central, critically linked to functional outcome, and key to successful negative symptom treatment • Reward processing deficits exist in SZ, Mood Disorders, and CHR and are associated with avolition transdiagnostically • However, equifinality is present; different reward processing domains may be more critical targets in some disorders than others • Hitting the most “central” mechanism may be critical, leading to a cascading effect of improvement in multiple reward domains • That mechanism likely differs across disorders and within individuals within a diagnosis Practical Considerations for Clinical Trials

• Reward processing impairments represent intermediate phenotypes that could be targeted in clinical trials • Can you target a reward process (e.g., effort-cost computation) transdiagnostically using behavioral or neurophysiological variables as primary outcome measures? • Consider equifinality • Psychometrics mostly untested • Inclusion criteria based on task performance or neurophysiological response? • Is changing an intermediate phenotype enough for a negative symptom indication? Collaborators Acknowledgments • Anthony Ahmed, PhD • Brian Kirkpatrick, MD • Daniel N. Allen, PhD • Eric Granholm, PhD ACKNOWLEDGMENTS & DISCLOSURES• Jim Gold, PhD FUNDING CAN Lab Research Team • Alicia Nunez, MPH • Kimberly Barchard, PhD • NIMH • Cristina Gonzalez (lab manager) • Silvana Galderisi, MD • R01-MH116039 • Armida Mucci, MD • Alessandro Rossi, MD • R21-MH112925 • Sydney James (coordinator) • Alessandro Bertolino • K23-MH092530 • Paolo Rocca, PhD • Ian Raugh (Grad student) • Mario Maj, MD • NARSAD Young Investigator • Stefan Kaiser, PhD • Martin Bischof, PhD • Katie Visser (Grad student) • Matthias Hartman-Riemer, PhD • Matthias Kirschner, PhD • Lisa Bartolomeo (Grad student) • Karoline Schneider • Maria Paz Garcia-Portilla, PhD • Anna Mane • Miguel Bernardo • Emilio Fernandez-Egea • Cui Jiefeng, MD • Yao Jing, MD • Tan Shuping, MD • Farnaz Esfahlani, PhD • Wing Chung Chang, MD • Laura Rowland, PhD • Michael Davidson • Remy Luthringer • Jay Saoud • Vijay Mittal • Elaine Walker Thank you!