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 Open Access

Kennedy, Ashley Paige (2011)

Permanent URL: https://etd.library.emory.edu/concern/etds/kw52j817r?locale=en
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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

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