Negative Symptoms in in Schizophrenia Gregory P. Strauss, Ph.D. - - PowerPoint PPT Presentation

Reward Processing Mechanisms of Negative Symptoms in in Schizophrenia

Gregory P. Strauss, Ph.D. Assistant Professor Department of Psychology University of Georgia

ACKNOWLEDGMENTS & DISCLOSURES

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?

Negative Symptoms Affective Symptoms Positive Symptoms Cognitive Deficits Disorganized Symptoms Domains of psychopathology in schizophrenia

▪ Negative symptoms - reductions in goal-directed activity, social behavior, pleasure, and the outward expression of emotion or speech ▪ Long considered a core feature of psychotic disorders1,2 ▪ Distinct from other domains of psychopathology (e.g., psychosis, disorganization) 3 ▪ Associated with a range of poor clinical outcomes (e.g., disease liability, quality of life, subjective well-being, 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.

▪ 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

Challenges in Treatment

• 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 Id 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

• f clinical psychology, 8, 269-289.

1.Schizophrenia

• 2. Schizoaffective Disorder
• 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

From Strauss & Cohen, 2017

Negative Symptoms Occur Outside of f Schizophrenia- we just don’t call them that

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

• ccur in

in the prodrome and outside of f schiz izophrenia?

• 1.8
• 1.6
• 1.4
• 1.2
• 1
• 0.8
• 0.6
• 0.4
• 0.2

Blunted Affect Alogia Avolition Anhed/Asoc EXP VOL Total

Z-score Compared to Schizophrenia Group

Z-Scores Compared to Schizophrenia Group

Schizoaffective Disorder Major Depressive Disorder Ultra High-Risk Bipolar Disorder Healthy Control 1 2 3 4 5 6 Blunted Affect Alogia Avolition Anhed/Asoc EXP VOL Total

Z-score Compared to Healthy Control Group

Z-Scores Compared to Healthy Control Group

Schizophrenia Schizoaffective Disorder Major Depressive Disorder 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.

• l. JAMA Psychiatry

ry (2 (2019)

Which domain(s) should be targeted? Is Is one domain more central than the others?

Control Bipolar Disorder Schizophrenia What was most central? Anhedonia What was most central? Anhedonia What was most central? 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

Strauss et al., in press Schiz Bull Centrality Measures: Key symptom that leads to improvement: AVOLITION INTERNAL EXPERIENCE Data from MIN-101 (Roluperidone) Clinical Trial (Davidson et al., 2017, AJP)

• 4. Delay

OFC

• 5. Effort

DA, VS, ACC

Reward Valuation Reward Responsiveness

• 1. Initial Response

Opioid & GABA in BG, OFC

• 2. Reward Anticipation

DA, BG, ACC

• 3. Reward Learning

Prediction Error DA, VS, PFC Implicit DA, BG Explicit ACC, OFC, DLPFC

Motivated Behavior

Modified from Barch & Dowd, 2010

• Several etiological

models have been developed for avolition (Gold et al., 2008;

Barch & Dowd, 2010; Kring & Ellis, 2013; Strauss et al., 2014; 2017)

• The NIMH RDoC

“positive valence system” offers a useful conceptual framework

Etiological Models of f Avolition in Schizophrenia

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.

Construct/Sub-construct Mechanism Mood Schizophrenia Clinical High-Risk Reward Responsiveness Initial Response Opioid & GABA in BG, OFC Impaired Intact Impaired Anticipation DA; BG & ACC Impaired Impaired Impaired Reward Learning Reinforcement Learning Implicit DA; BG Impaired Intact Impaired Reinforcement Learning Explicit DA; ACC; OFC, DLPFC Intact Impaired Impaired Reward Prediction Error DA, 5HT; BG, ACC, OFC Impaired Intact* Impaired Reward Valuation Delay OFC, MPFC, BG Impaired Impaired Impaired Effort DA, GABA; BG, ACC, Amygdala Impaired Impaired Impaired

Summary ry

For transdiagnostic reviews see Strauss & Cohen, 2019; Barch et al., 2019

How in inter-connected are the domains? If If you target reward processing broadly, wil ill all ll reward domains be expected to im improve?

0.00 0.50 1.00 1.50 2.00 2.50 3.00 3.50

• Avg. Clustering

Coefficient

• Avg. Shortest Path

Length Density 0.88 2.79 0.72 0.78 3.40 0.59

SZ vs. CN

Group SZ Group CN 0.00 1.00 2.00 3.00

• Avg. Clustering

Coefficient

• Avg. Shortest Path

Length Density 0.89 2.48 0.81 0.89 2.52 0.79

SZ Neg. High vs. Neg Low

High Negative Low Negative 0.00 0.50 1.00 1.50 2.00 2.50 3.00

• Avg. Clustering

Coefficient

• Avg. Shortest Path

Length Density 0.92 2.44 0.82 0.90 2.51 0.80

SZ vs. SZ Affective Diagnosis

SZ SZOA

Strauss et al., under review SZ: n = 54 CN: n = 54

Is Is one reward processing domain more central than the others and thus a more cri ritical target?

Strauss et al., in prep SZ: n = 54 CN: n = 54

Is Is it it possib ible to stratify fy patients in into cli linically meaningful subgroups based on reward processing task performance?

• 5.00
• 4.00
• 3.00
• 2.00
• 1.00

0.00 1.00 Hedonic ValueRep Effort RewLearn Z-score

3 Clusters

Cluster 1 Cluster 2 Cluster 3 9% 66% 25%

• Cluster 1: Global reward processing impairment (9%)
• Cluster 2: Hedonic and effort impairment (66%)
• Cluster 3: Intact reward processing (25%)

Strauss et al., in prep SZ: n = 54 CHR: n = 68 CN: n = 112

Do the reward-based subgroups differ on ext xternal validators?

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 Ambient Sound Speech Detected 43 (21) 47 (75) 162 (37)* 3>1,2 MATRICS Global Cognition 27 (19) 43 (14) 48 (12)* 1<2,3 Diagnoses Cluster 1 Cluster 2 Cluster 3 % SZ 100% 59% 38.5% % CHR 0% 41% 61.5%

• Cluster 1: Global reward processing impairment (9%)
• Cluster 2: Hedonic and effort impairment (66%)
• Cluster 3: Intact reward processing (25%)

Strauss et al., in prep SZ: n = 54 CHR: n = 68 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 ry

• 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?

ACKNOWLEDGMENTS & DISCLOSURES

Acknowledgments

FUNDING

• NIMH
• R01-MH116039
• R21-MH112925
• K23-MH092530
• NARSAD Young Investigator

CAN Lab Research Team

• Cristina Gonzalez (lab manager)
• Sydney James (coordinator)
• Ian Raugh (Grad student)
• Katie Visser (Grad student)
• Lisa Bartolomeo (Grad student)

Collaborators

• Anthony Ahmed, PhD
• Brian Kirkpatrick, MD
• Daniel N. Allen, PhD
• Eric Granholm, PhD
• Jim Gold, PhD
• Alicia Nunez, MPH
• Kimberly Barchard, PhD
• Silvana Galderisi, MD
• Armida Mucci, MD
• Alessandro Rossi, MD
• Alessandro Bertolino
• Paolo Rocca, PhD
• Mario Maj, MD
• Stefan Kaiser, PhD
• Martin Bischof, PhD
• Matthias Hartman-Riemer, PhD
• Matthias Kirschner, PhD
• 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!