A clinical trial and fMRI study of the cognitive neuroscience of cocaine addiction and of the efficacy of the cognitive enhancer D-Cycloserine for its treatment Public
Kennedy, Ashley Paige (2011)
Abstract
Cocaine dependence is a chronically relapsing disorder for which
its predominant behavioral
therapies are associated with only partial efficacy. The learning
objectives of my dissertation
research plan were primarily addressed by determining if the
N-methyl-D-aspartate glutamate
receptor partial agonist and cognitive enhancer, D-Cycloserine
(DCS), could boost the cocaine
abstinence and treatment retention goals of cognitive behavioral
therapy (CBT). The research
tested an overall hypothesis that enhanced brain glutamate
neurotransmission facilitates the
therapeutic learning and memory goals of addiction behavioral
therapies and thus promotes
recovery and relapse prevention in cocaine-dependent persons. The
first placebo-controlled,
randomized, double-blind study (Study 1) tested the safety and
efficacy of once-weekly oral DCS
(50 mg) combined with a condensed version of a manual-based CBT in
cocaine-dependent men
enrolled in the 4-week outpatient Substance Abuse Treatment Program
at the Atlanta Veteran's
Administration Medical Center. Relative to a 12-step based
treatment-as-usual, an under-dosed
CBT was associated with significant improvements in drug abstinence
and treatment retention at
4-weeks and enhanced maintenance of drug abstinence after four more
weeks of post-treatment
follow-up. However, the CBT response posed a ceiling effect and DCS
was no more effective
than placebo in enhancing the response to CBT at the treatment
endpoints of 4- and 8-weeks. The
second study was an extended replication of Study 1 that differed
in the dose of DCS (250 mg),
the use of computer- rather than therapist-delivered behavioral
therapy (cCBT) and repeated
measures of functional magnetic resonance imaging (fMRI) to
determine the impact of cCBT and
adjunct DCS on the neural processing correlates of attentional bias
for conditioned drug-
associated cues. DCS was ineffective in facilitating the cCBT
response and was associated with
an increase in the frequency of cocaine-positive urine samples
relative to placebo and did not
enhance treatment retention in a cocaine-dependent sample. Neural
responses to an addiction
Stroop task partially supported this measure as a neurocognitive
marker of relapse. These studies
provide a more definitive picture of the efficacy of cognitive
enhancement as a means of
facilitating behavioral therapy outcomes for drug addiction and of
the brain changes that code
therapeutic response to treatment in cocaine-dependent
populations.
Table of Contents
Introduction
1
Cocaine dependence and the neural basis of relapse
2
Current behavioral therapies for drug dependence
3
The role of DCS, a partial agonist at the NMDA glutamate receptor, in learning and memory
5
Facilitation of extinction with an NMDA receptor partial agonist
6
Augmentation of exposure-based therapy for anxiety disorders with a cognitive enhancer, DCS
8
D-Cycloserine as an adjunctive therapy for drug dependence
9
Estimating the incentive motivational properties of drug-conditioned stimuli in drug-dependent persons
10
Chapter 1: A common TPH2 haplotype regulates the neural processing of cognitive control for the Multi-Source Interference Task (MSIT)
11
Introduction
11
Material and Methods
14
Subjects
14
Genotyping
16
Multi-Source Interference Task (MSIT)
16
fMRI Acquisition and Image Analysis
20
Functional Connectivity Analysis
21
Results
23
Linkage Disequilibrium of TPH2 SNPs and Haplotype Frequencies
23
MSIT Performance
23
Main Effect of Task and Effect of TPH2 Haplotype
23
TPH2 Haplotype Effect on Functional Connectivity for MSIT-related Neural Pathways
25
Discussion
28
Conclusions
30
Chapter 2: Clinical correlates of attentional bias for a personalized addiction Stroop task in a cocaine-dependent population
31
Introduction
31
Material and Methods
32
Study Participants
32
Treatment Program
33
Assessment Instruments
33
Stroop Tasks
34
Personalized versus Generalized Drug Use Words
34
Statistical Analyses
36
Results
36
Subject demographic and clinical variables
36
Stroop task performance
37
Attentional Bias for Conditioned Drug Cues
37
Counting Stroop
37
Logistic Regression
37
Discussion
41
Conclusions
44
Chapter 3: The neural basis of attentional bias for drug-related stimuli associated with cocaine addiction
44
Introduction
44
Material and Methods
45
Subjects
45
Tasks
46
MRI Acquisition
47
Imaging Preprocessing and fMRI Analyses
47
Individual Subject Level Model Fitting
47
Random Effect Analysis
48
Correlation Analysis
48
Subgroup Analysis
48
Results
48
Task Performance
48
fMRI Responses
50
Word Counting Stroop Task: Cocaine versus Neutral Words
50
Relationship between Behavioral and Neural Cocaine Stroop Effects
50
Comparison of Neural Correlated for Phenotypic Extremes of Attentional Bias
50
Discussion
54
Limitations
58
Conclusions
59
Chapter 4: A randomized trial of the adjunct use of D-Cycloserine to facilitate cognitive
behavioral therapy outcomes in a cocaine-dependent population
59
Introduction
59
Material and Methods
62
Study Design
62
Randomization
63
Sample Size Calculation
65
Inclusion/Exclusion Criteria
65
Assessments Instruments
66
Cognitive Behavioral Therapy
66
Statistical Analyses
67
Results
68
Subjects
68
Demographics
68
Drug Abstinence and Treatment Retention
72
Discussion
74
Strengths and Limitations
75
Conclusions
76
Chapter 5: A controlled clinical trial and fMRI study of the adjunct use of D-Cycloserine with a computerized cognitive behavioral therapy for cocaine dependence
77
Introduction
77
Material and Methods
80
Inclusion/Exclusion Criteria
80
Randomization and Study Blind
82
Assessment Instruments
83
Drug Monitoring
85
Computerized Cognitive Behavioral Therapy (cCBT)
85
Group Therapy
87
Contingency Management Voucher System
89
Follow-up Visits
90
Stroop Tasks
90
Statistical Analyses
92
fMRI Acquisition and Analyses
93
General Linear Model (GLM)
94
Correlation Analyses
94
Results
94
Subjects
95
Baseline Demographic and Clinical Variables
95
Outcome Variables: Drug Abstinence and Treatment Retention
97
Stroop Task Performance
97
Baseline
97
Effect of Treatment
104
fMRI Responses
104
Baseline Stroop Tasks
104
Relationship between the Behavioral and Neural cocStroop Effects
112
Discussion
112
Clinical Use of DCS for Cocaine Dependence
112
Attentional Bias for Conditioned Drug Cues
118
Neural Correlates of Attentional Bias for a Stroop Task
119
Conclusions
120
Discussion
121
References
128
About this Dissertation
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