Targeting Anhedonia in Cocaine Use Disorder

Study Overview
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Brief Summary
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The purpose of this study is to examine anhedonia as a potential moderator of treatment outcomes for Cocaine Use Disorder (CUD). Specifically, this study will investigate how anhedonia affects outcomes in contingency management (CM) treatment for CUD and whether anhedonia mediates the effects of adjunctive treatment with a dopaminergic (DAergic) drug, d-amphetamine, on outcomes in CM for CUD, as well as investigate the contribution of anhedonia to overall CUD severity.

Detailed Description
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Recent research suggests that anhedonia is a key neurobehavioral dysfunction in Cocaine Use Disorder (CUD) that contributes to treatment outcomes. Anhedonia, defined here as lack of interest or pleasure in non-drug rewards, is frequently found in CUD and is related to neural deficits, such as low striatal dopamine and deficient activation to non-drug rewards in mesocortical circuits. Interestingly, not all individuals in CUD have these deficits. Preliminary data suggests that the presence of self-reported anhedonia predicts worse outcome in contingency management (CM) treatment of CUD. Moreover, low baseline dopamine predicts failure to attain abstinence in CM while medications that enhance DA increase CM success rates and responsiveness to rewards. This study specifically aims to test the contribution of anhedonia to overall CUD severity, the relationship of anhedonia to outcomes in CM treatment, and the mediating role of anhedonia in medication enhancement of CM in CUD. To accomplish these aims, individuals with CUD will be enrolled and will undergo 4 weeks of intensive CM treatment, either with or without treatment with the dopaminergic drug, d-amphetamine. A medication only group will be included to solely measure the effects of d-amphetamine. Anhedonia will be assessed using multi-modal subjective, psychophysiological and behavioral measures of reward functioning at baseline, and each week of treatment. Functional magnetic resonance imaging (fMRI) measures of reward functioning will also be taken at baseline and week 4 in a subset of participants (n = 24)

Official Title
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Targeting Anhedonia in Cocaine Use Disorder - Treatment Study

Conditions
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Cocaine-Related Disorders, Anhedonia

Intervention / Treatment
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* Drug: d-amphetamine
* Behavioral: Contingency management
* Drug: Placebo (for d-amphetamine)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: be between 18 and 60 years of age meet Diagnostic and Statistical Manual V (DSM-5) criteria for current cocaine use disorder of at least moderate severity (≥ 4 symptoms) have at least 1 cocaine positive urine sample during the baseline screening period be in acceptable health on the basis of interview, medical history and physical exam, per the judgment of our study physician be able to understand the consent form and provide written informed consent be able to provide the names of at least 2 persons who can generally locate their whereabouts. if female, agree to use an acceptable method of birth control during study (surgical sterilization, approved hormonal contraceptives, barrier methods with spermicide, or intrauterine device). Exclusion Criteria: current DSM-5 diagnosis for substance use disorder of least moderate severity (≥ 4 symptoms), other than cocaine, nicotine, marijuana, or alcohol Physical dependence on alcohol requiring medically supervised detoxification, in the judgment of the study physician current amphetamine use (by self-report in past 30 days or positive urine drug screen), more than 50 lifetime uses of amphetamine, or history of DSM-5 Amphetamine Use Disorder a current DSM-5 axis I psychiatric disorder or neurological disease or disorder requiring ongoing treatment and/or making study participation unsafe significant current suicidal or homicidal ideation medical conditions contraindicating d-amphetamine (e.g., significant cardiovascular disease, liver or kidney disease, seizure disorder, hypotension or hypertension) taking medications known to have effects on the central nervous system or that could cause significant drug interactions with d-amphetamine (e.g., clonidine, prazosin) having conditions of probation or parole requiring reports of drug use to officers of the court impending incarceration pregnant or nursing for female patients inability to read, write, or speak English Additional Exclusion Criteria for the functional magnetic resonance (fMRI) Sub-Study (in addition to all listed criteria above for the Main Treatment Study): body mass index (BMI) >30, as this may be incompatible with the magnetic resonance scanner gantry any retained metals in the body, including implants and metallic substances (e.g. aneurysm clips, retained metal particles in metal workers, magnetic dental implants, ferromagnetic ocular implants, iron-based facial tattoos), as this may cause adverse effects to participants and interfere with data collection in the MR magnetic field inability to tolerate small, enclosed spaces (such as the magnetic resonance scanner bore)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: d-Amphetamine and Contingency Management<br>Participants in this group will receive 4 weeks of treatment with 60mg of sustained release d-amphetamine with contingency management treatment for cocaine use disorder. | Drug: d-amphetamine<br>* Participants in this group will receive 60 mg of d-amphetamine daily for 4 weeks. There will be a 1 week run up dosing and a 1 week run-down medication period.<br>* Other names: dexedrine;Behavioral: Contingency management<br>* Contingency management is an established cocaine use disorder treatment in which individuals receive monetary rewards for abstinence.<br>|
| Active Comparator: d-Amphetamine alone<br>Participants in this group will receive 4 weeks of treatment with 60mg of sustained release d-amphetamine but will not receive contingency management treatment for cocaine use disorder. | Drug: d-amphetamine<br>* Participants in this group will receive 60 mg of d-amphetamine daily for 4 weeks. There will be a 1 week run up dosing and a 1 week run-down medication period.<br>* Other names: dexedrine;|
| Active Comparator: Placebo and Contingency Management<br>Participants in this group will receive 4 weeks of of placebo treatment, paired with contingency management treatment for cocaine use disorder. | Behavioral: Contingency management<br>* Contingency management is an established cocaine use disorder treatment in which individuals receive monetary rewards for abstinence.<br>Drug: Placebo (for d-amphetamine)<br>* 60 mg of riboflavin and cornstarch as needed.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants who were Cocaine Abstinent as Assessed by Urine Screening (Measure of Treatment Efficacy) | Subjects will complete a urine drug screen each visit. Achievement of cocaine abstinence will be defined as two consecutive weeks of cocaine-negative urine samples. | At end of active treatment (Treatment week 4) | 
| Change in Consummatory Reward Composite (Anhedonia) | Principal components analysis will be used to determine whether consummatory anhedonia measures (SHAPS, TEPS-Consummatory, EPRT, Corrugator and Zygomatic EMG) can be reduced into one composite representing consummatory reward functioning. If this is inappropriate, we will use individual measures (see below under Secondary Outcome Measures) with pessimistic priors to address multiplicity. | Baseline and weeks 1, 2, 3, and 4 of treatment | 
| Change in Motivational Reward Composite (Anhedonia) | Principal components analysis will be used to determine whether motivational anhedonia measures (TEPS-Motivational, EPKT, EEfRT) can be reduced into one composite representing motivational reward functioning. If this is inappropriate, we will use individual measures (see below under Secondary Outcome Measures) with pessimistic priors to address multiplicity. | Baseline and weeks 1, 2, 3, and 4 of treatment | 
| Change in Reward Learning Composite (Anhedonia) | Principal components analysis will be used to determine whether reward learning measures (PRT and PCT) can be reduced into one composite representing reward learning. If this is inappropriate, we will use individual measures (see below under Secondary Outcome Measures) with pessimistic priors to address multiplicity. | Baseline and weeks 1, 2, 3, and 4 of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment Effectiveness Score | Subjects will complete a urine drug screen each visit. The Treatment Effectiveness Score is defined as the total number of cocaine negative urines across treatment. | At end of active treatment (Treatment week 4) | 
| Consummatory Reward as Assessed by The Emotional Picture Rating Task (EPRT) | The Emotional Picture Rating Task (EPRT) is a behavioral measure of consummatory reward where participants are asked to report positive, negative and aroused feelings while viewing emotional pictures. Valence and arousal ratings of positive pictures are the outcomes. | Baseline and weeks 1, 2, 3, and 4 of treatment | 
| Motivational Reward as Assessed by the Emotional Picture Keypress Task (EPKT) | The Emotional Picture Key-press Task (EPKT) is a measure of motivational reward in which participants expend effort via key-pressing to extend or reduce viewing times for emotional pictures. Key-pressing to extend time viewing positive pictures is the outcome. | Baseline and weeks 1, 2, 3, and 4 of treatment | 
| Motivational Reward as Assessed by the Effort Expenditure for Rewards Task (EEfRT) | The Effort Expenditure for Rewards Task (EEfRT) is a measure of motivational reward where, on each trial, participants choose between a hard task requiring many key-presses but worth more money and an easy task requiring few key-presses but worth less money. Percent of hard task choices is the outcome. | Baseline and weeks 1, 2, 3, and 4 of treatment | 
| Consummatory Reward as Assessed by the Snaith-Hamilton Pleasure Scale (SHAPS) Score | The Snaith-Hamilton Pleasure Scale (SHAPS) is a measure of consummatory reward consisting of 14 hedonic capacity statements (e.g. I would enjoy my favorite television program). The sum of these scores is the outcome. | Baseline and weeks 1, 2, 3, and 4 of treatment | 
| Consummatory Reward as Assessed by the Temporal Experience of Pleasure Scale (TEPS) | The Temporal Experience of Pleasure Scale (TEPS) contains 18 statements measuring both motivational and consummatory experiences of reward. Half of those statements comprise a subscale for consummatory reward, which is the outcome. | Baseline and weeks 1, 2, 3, and 4 of treatment | 
| Motivational Reward as Assessed by the Temporal Experience of Pleasure Scale (TEPS) Motivational Score | The Temporal Experience of Pleasure Scale (TEPS) contains 18 statements measuring both motivational and consummatory experiences of reward. Half of those statements comprise a subscale for consummatory reward, which is the outcome. | Baseline and weeks 1, 2, 3, and 4 of treatment | 
| Reward Learning as Assessed by the Probabilistic Classification Task (PCT) | The Probabilistic Classification Task is a measure of reward learning in which participants repeatedly guess whether an image belongs to Category A or B. For half of stimuli from each category, correct answers are rewarded with points (no change for incorrect) and for the other half incorrect guesses are punished with point removal (no change for correct). Learning rates for rewarded stimuli are the outcome. | Baseline and weeks 1, 2, 3, and 4 of treatment | 
| Reward Learning as Assessed by the Probabilistic Reward Task (PRT) | The Probabilistic Reward Task (PRT) is a measure of reward learning consisting of trials in which participants must identify whether a cartoon face has a short or long mouth over a brief presentation. Correct identification of one category (short or long) is rewarded more often. Response bias for the rewarded category is the outcome. | Baseline and weeks 1, 2, 3, and 4 of treatment | 
| Change in Consummatory Reward Activity as Assessed by fMRI | Consummatory reward will be measured by activity in nucleus accumbens and ventral pallidum and psychophysiological from nucleus accumbens to ventral pallidum, orbitofrontal cortex and rostral anterior cingulate cortex during reward/positive pictures vs. non-reward/neutral pictures during the Emotional Picture fMRI Task and the delay portions of Monetary Incentive Delay Task. Note: fMRI data will be collected in only 24 participants (12 in CM/Placebo arm and 12 in CM/Sustained Release-Amphetamine arm) | Measured 2 times (Baseline and week 4 of treatment) | 
| Change in Motivational Reward Activity as Assessed by fMRI | Motivational reward will be measured by activity in nucleus accumbens, and psychophysiological interactions from accumbens to ventromedial prefrontal cortex, accumbens and amygdala during anticipation of reward vs. non-reward during the anticipation phases of the Monetary Incentive Delay Task. Note: fMRI data will be collected in only 24 participants (12 in CM/Placebo arm and 12 in CM/Sustained Release-Amphetamine arm) | Measured 2 times (Baseline and week 4 of treatment) | 
| Change in Reward Learning as Assessed by fMRI | Reward learning will be measured by Prediction Error signals in neural accumbens, and Psychophysiological Interactions from neural accumbens to dorsolateral prefrontal cortex during prediction errors in the Probabilistic Classification fMRI Task. Note: fMRI data will be collected in only 24 participants (12 in CM/Placebo arm and 12 in CM/Sustained Release-Amphetamine arm) | Measured 2 times (Baseline and week 4 of treatment) | 
| Magnitude of Zygomatic Activity as a Physiological Measure of Anhedonia | Activity in the zygomatic (smile) muscle will be recorded using electromyography (EMG) during the EPRT (see above) to measure consummatory reward. Positive pictures enhance zygomatic activity. Magnitude of zygomatic responses during positive pictures is the outcome. | Baseline and weeks 1, 2, 3, and 4 of treatment | 
| Magnitude of Corrugator Activity as a Physiological Measure of Anhedonia | Activity in the corrugator (frown) muscle will be recorded using electromyography (EMG) during the EPRT (see above) to measure consummatory reward. Positive pictures suppress corrugator activity. Magnitude of corrugator responses during positive pictures is the outcome. | Measured 5 times (Baseline and once each treatment week) | 
| Heart Rate Variability as a Physiological Measure of Arousal | Heart rate will be recorded using Electrocardiogram (EKG) during the EPRT (see above) to measure arousal responses to stimuli. High heart rate variability is associated with blunted arousal to positive stimuli and higher rates of depressive symptoms, but its relationship to our other measures of anhedonia, or to cocaine use, is unknown. Thus, this is included as an exploratory variable. Heart rate variability responses during positive, neutral, and negative pictures is the outcome. | Baseline and weeks 1, 2, 3, and 4 of treatment | 
| Skin Conductance as a Physiological Measure of Arousal | Skin conductance measures activity in the eccrine sweat glands during the EPRT (see above). Activity in this gland serves as a measure of arousal responses to stimuli, but its relationship to our other measures of anhedonia, or to cocaine use, is unknown. Thus, this is included as an exploratory variable. The outcome measure is the skin conductance response during positive, neutral, and negative pictures. | Baseline and weeks 1, 2, 3, and 4 of treatment | 
| Delay Discounting as a Measure of Impulsivity | In the event that our hypothesis is disconfirmed and anhedonia does not predict outcomes, we have included impulsivity, as measured by delay discounting, as another possible predictor of treatment outcome in CM. The outcome will be steepness of discounting (k). | Baseline and weeks 1, 2, 3, and 4 of treatment | 
| The Avoidance and Inflexibility Scale | In the event that our hypothesis is disconfirmed and anhedonia does not predict outcomes, we have included avoidance and inflexibility as another possible predictor of treatment outcome in CM. The outcome will be the scale total. | Baseline and weeks 1, 2, 3, and 4 of treatment | 
| The Cocaine Selective Severity Assessment | In the event that our hypothesis is disconfirmed and anhedonia does not predict outcomes, we have included severity of withdrawal as another possible predictor of treatment outcome in CM. The outcome will be the scale total. | Baseline and weeks 1, 2, 3, and 4 of treatment |