The Neurobiology of Anhedonia: Circuitry and Relevance to Drug Development & Patient Stratification Diego A. Pizzagalli, Ph.D. Professor of Psychiatry Harvard Medical School McLean Hospital ISCTM Reward Processing February 21, 2020
Disclosures • Grant/Research Support: • NIH, NARSAD, Dana Foundation • Speaker’s Bureau: • None • Consultant: • Akili, BlackThorn Therapeutics (licensed Probabilistic Reward Task ), Boehringer Ingelheim, Compass Pathway, Otsuka, Takeda • Stock Options: • BlackThorn Therapeutics • Patents: • None
Role of Anhedonia in MDD & Antidepressant Response 1) Anhedonia predicts: • Depression two years later (e.g., Wardenaar et al. 2012); • Poor outcome (e.g., Spijker et al. 2001; Uher et al. 2012) ; • Chronic course over 10 years (Moos & Cronkite 1999) . 2) Anhedonia and amotivation are poorly addressed by first- line treatments (Calabrese et al., 2014; Craske et al., 2019) . 3) Anhedonia predicts poor response to first-line pharmacological (e.g., SSRI; Vrieze et al., 2013 ) and psychological (e.g., CBT; McMakin et al. 2012 ) treatments as well as TMS (e.g., Downar et al., 2014 ).
Borrowing from the “Traditional” Approach…. 1) Since anhedonia has been associated with: • Reduced functional, structural, and neurochemical markers within DA-rich regions along the mesocorticolimbic pathways (e.g., ventral and dorsal striatum) (e.g., Auerbach et al., 2017; Gabbay et al., 2017; Keedwell et al., 2005; Pecina et al., 2017); 2) Dopamine plays a key role in several reward-related functions (incentive motivation, reinforcement learning) 1) + 2) Patients with anhedonic phenotypes might preferentially benefit from treatments hypothesized to increase DA signaling.
Parsing Reward Processing: From Hedonics to Motivated Behavior Barch et al., 2015
Barch et al., 2015
Reward Learning Barch et al., 2015
Reward Learning As a DA-sensitive Phenotype Probabilistic Reward Task 11.5 vs. 13 mm Athina Markou 0.9 vs. 1.6 sec tone Andre Der-Avakian
Decreased Dopamine Suppresses Reward Learning in Humans and Rats Response Bias [Single 0.5 mg dose] [Single 0.1 mg/kg dose] Hypothesized mechanism: Presynaptic autoreceptor activation → ↓DA
Psychostimulant Exposure Enhances Reward Learning in Humans and Rats Humans Rats N = 30 (14 mg) Response Bias Block 1 Block 2 Block 3 Der-Avakian et al. Translational Psychiatry 2013 Barr et al. Biological Psychiatry 2008 Barr et al. Biological Psychiatry 2008 Der-Avakian et al. Translational Psychiatry 2017 [14 mg path in non-smokers] [Single 0.5 mg/kg dose] Hypothesized mechanism: ↑ striatal DA transmission?
Nicotine Withdrawal Suppresses Reward Learning in Humans and Rats Humans Rats Barr et al. Biological Psychiatry 2008 Pergadia et al. JAMA Psychiatry 2014 Hypothesized mechanism: ↓ striatal DA transmission?
Reward Learning is Associated with Frontostriatal and Dopamine Markers Better reward learning: ↓ DAT availability (i.e., higher DA?) [ 11 C]Altropane (PET) r (31)= -0.43 p =0.01 Worse Better Learning
Reward Learning is Associated with Frontostriatal and Dopamine Markers Better reward learning: ↑ resting state FC between accumbens and vmPFC r (31)= 0.69 p <0.001
Interim Summary Reward learning: 1) Is associated with individual differences in frontostriatal and dopamine markers (healthy controls); 2) Is potentiated by pharmacological challenges hypothesized to increase striatal DA transmission (amphetamine, nicotine); 3) Is reduced by challenges hypothesized to decrease striatal DA transmission (single low dose of pramipexole, nicotine withdrawal, chronic social defeat); 4) Is reduced in individuals with MDD, especially with elevated anhedonia or melancholia (not shown; Pizzagalli et al., 2008; Liu et al., 2011; Vrieze et al., 2013; Fletcher et al., 2015 )
STUDY 1 Hypothesis: Patients with MDD failing to respond to SSRI treatment (sertraline) and characterized by pre-treatment anhedonic behaviors will preferentially benefit from bupropion treatment ( norepinephrine-dopamine reuptake inhibitor, NDRI ).
STUDY 1: Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care (EMBARC) N = 262 MDD Patients Wk 0 (completed PRT) N = 127 N = 135 Sertraline Wks 1 - 8 Placebo Non- Non- Responders Responders responders responders Sertraline Bupropion XL Sertraline Placebo Wks 9 - 16 N = 60 N = 52 N = 73 N = 46 Does pre-treatment reward learning differentiate between eventual responders and non-responders to sertraline and bupropion in Phase 2? Yuen Ang
STUDY 1: Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care (EMBARC) ANCOVA (Phase 2) : • Drug (SER, BUP) x Response (yes, no) x Site (CU, MG, TX, UM) [covariates: age, gender and education]. Results (Phase 2) : Results (Phase 2) : • • Drug x Response: p<0.05 Drug x Response: p<0.05 • Bupropion responders have significantly greater response bias than non-responders (SERT: ns). • Phase 2 bupropion responders and non-responders: no Week 0 or Week 8 HAMD differences Ang et al., under review
STUDY 1: Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care (EMBARC) ANCOVA (Phase 1) : • Drug (SER, PLA) x Response (yes, no) x Site (CU, MG, TX, UM) [covariates: age, gender and education]. Results (Phase 1) : • Drug x Response: p>0.45 Ang et al., under review
STUDY 2 Hypothesis: Patients with MDD and characterized by pre- treatment anhedonic behaviors will preferentially benefit from pramipexole treatment ( D2/3 DA agonist )
STUDY 2: Ventrostriatal Dopamine Release and Reward Motivation in MDD (PI: F. Schneier, Columbia) Study Design : • 26 medication-naïve MDD patients and 26 controls • Patients received open-label treatment with pramipexole (ranging 0.5-2.5 mg/day) for 6 weeks • Before and after treatment: • Probabilistic reward task (behavior) • Ventral striatal reward prediction error signals (fMRI) • Before treatment : Ventral striatal DA release in response to oral dextroamphetamine ([ 11 C]-(+)-PHNO PET) • A priori outcome measures (administered weekly) • Depressive symptom severity (HAM-D) • Anhedonia severity (SHAPS) • Improvement in global illness severity (CGI-Change Scale)
STUDY 2: I. Significant symptomatic improvement following six weeks of treatment with pramipexole • 72.7% classified as responders at week 6 • Largest effect sizes for depressive symptoms (HAM-D: d =2.2; MASQ depressive distress subscale: d =1.4) and anhedonia (MASQ anhedonic depression subscale: d =1.3)
STUDY 2: II. Abnormal reward learning, VS reward PE signaling and VS DA release in MDD at baseline C C Franklin Alexis Schneier Whitton
STUDY 2: III. Better (i.e., more normative) reward learning and stronger reward sensitivity predicts lower post-treatment anhedonia PI: Franklin Schneier, Columbia University Whitton et al., Brain , 2020
STUDY 2: IV. Stronger (i.e., more normative) VS reward PE signals predict greater improvement in global illness severity A VS gain PE 3.5 3 Predicted CGI scores 2.5 2 1.5 X=-12 X = 12 1 High PE Mean Prediction-error signal 0.5 Low PE extracted from ventral striatum (HC group mean) 0 1 2 3 4 5 6 Week PI: Franklin Schneier, Columbia University Whitton et al., Brain , 2020
STUDY 2: V. Less (i.e., more normative) VS DA release predicts greater improvement in global illness severity C VS DA release 3.5 3 Predicted CGI scores 2.5 2 X=-12 1.5 X = 12 High DA release 1 Percentage change from baseline Mean binding potential relative to 0.5 Low DA release nondisplaceable compartment (HC group mean) (∆BP ND ) computed from ventral 0 1 2 3 4 5 6 striatum Week PI: Franklin Schneier, Columbia University Whitton et al., Brain , 2020
STUDY 3: FAST-MAS Study (PI: A. Krystal, Duke/UCSF) Kappa Opioid Antagonist for Anhedonia? B) Monetary Incentive Delay Task Reward Cue T arget Feedback Loss Cue No-incentive Cue (500 ms) (150 ms) (1,230 ms) You won You lost No +$ -$ 0$ $5 $1 change
STUDY 3: FAST-MAS Study (PI: A. Krystal, Duke/UCSF) Snaith Hamilton Pleasure Scale Intent-to-treat sample: JNJ-67953964 (Kappa Opioid Antagonist, 10 mg) [N=45] Placebo [N=44] Baseline-adjusted post-treatment scores: (F(1,86)=3.35; p=0.035; Hedges’ g=0.44 Krystal et al., Nature Medicine , in press
STUDY 3: FAST-MAS Study (PI: A. Krystal, Duke/UCSF) Primary Measure : Nucleus Accumbens Secondary Measures : Activation to Reward-predicting Cues Self-reported anhedonia (SHAPS) Behavior: Response Bias Baseline-adjusted post-treatment scores: Treatment Arm x Time: F(1,86)=5.58; p<0.01; Hedges’ g=0.58 F(1,52)=4.69, p=0.035 [covariate: baseline SHAPS]
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