Nuvan Rathnayaka

Working memory fMRI activation in cocaine-dependent subjects: Association with treatment response

Functional magnetic resonance imaging (fMRI) studies of early abstinence cocaine users offer information about the state of the brain when most cocaine users seek treatment. This study examined the relationship between pretreatment brain function and subsequent treatment response in 19 treatment-seeking early abstinence cocaine-dependent (CD) subjects. These subjects and 14 non-drug-using control subjects underwent fMRI while performing a working memory task with three levels of difficulty. CD subjects were then randomized to treatment studies. Results showed CD subjects had significantly lower (random effects, corrected for multiple comparisons) brain activation in caudate, putamen, cingulate gyrus, middle and superior frontal gyri, inferior frontal gyrus pars triangularis and pars opercularis, precentral gyrus, and thalamus compared with non-drug-using controls. Within CD subjects, thalamic activation significantly correlated with treatment response. This study shows CD subjects in early abstinence have alterations of brain function in frontal, striatal, and thalamic brain regions known to be part of a circuit associated with motor control, reward, and cognition. Subjects with pretreatment thalamic deactivation showed the poorest treatment response, possibly related to thalamic involvement in mesocortical and mesolimbic dopamine projections.

Combination of Modafinil and d-amphetamine for the Treatment of Cocaine Dependence: A Preliminary Investigation

Background: Two stimulant medications, modafinil and d-amphetamine, when tested individually, have shown safety and efficacy for treatment of cocaine addiction. We hypothesized that the combination of modafinil and d-amphetamine, at low doses, would show equivalent or greater benefit in reducing cocaine use compared to higher doses of each individual medication or placebo. Methods: Sixteen week, randomized, parallel-group design with four treatment arms comparing placebo to modafinil 400 mg; d-amphetamine 60 mg; modafinil 200 mg plus d-amphetamine 30 mg. Primary outcome variables, retention and cocaine use, were analyzed on the sample of 73 participants who received the first dose of the study medication. Results: Retention rates did not differ between groups and were generally low, with 40% remaining in treatment at week 12 and 20% at week 16. Participants receiving the combination of modafinil and d-amphetamine showed a trend of increased cocaine use over time with a corresponding low Bayesian probability of benefit (33%). Relatively better cocaine outcomes were observed in the placebo and d-amphetamine only groups. The study medications were generally well-tolerated with few adverse effects, yet rates of adherence were suboptimal (≤80%). Conclusion: Data from this preliminary investigation fail to provide evidential support for conducting a larger study of this dual-agonist medication combination for treatment of cocaine dependence.

A two-phased screening paradigm for evaluating candidate medications for cocaine cessation or relapse prevention: Modafinil, levodopa-carbidopa, naltrexone

BACKGROUND Cocaine pharmacotherapy trials are often confounded by considerable variability in baseline cocaine-use levels, obscuring possible medication efficacy. Testing the feasibility of using a prerandomization, abstinence-induction protocol, we screened three candidate medications to explore treatment response in patients who did, or did not, achieve abstinence during an extended baseline phase. METHOD Eligible treatment-seeking, cocaine-dependent subjects entered a 4-week baseline period (Phase I) with high-value abstinence contingent vouchers and two motivational interviewing sessions, followed by a 12-week medication trial (Phase II) with random assignment stratified on Phase I abstinence status to (1) modafinil (400mg/d), (2) levodopa/carbidopa (800/200mg/d), (3) naltrexone (50mg/d), or (4) placebo. Treatment consisted of thrice-weekly clinic visits for urine benzoylecgonine testing and weekly cognitive behavioral therapy with contingency management targeting medication compliance. RESULTS Of the 118 subjects enrolled, 81 (80%) completed Phase I, with 33 (41%) achieving abstinence, defined a priori as 6 consecutive cocaine-negative urines. Tests of the interaction of each medication (active versus placebo) by baseline status (abstinent versus nonabstinent) permitted moderator effect analysis. Overall, baseline abstinence predicted better outcome. Cocaine-use outcomes for levodopa and naltrexone treatment differed as a function of Phase I abstinence status, with both medications producing benefit in nonabstinent but not baseline-abstinent subjects. There was no evidence of a moderator effect for modafinil. CONCLUSIONS The two-phase screening trial demonstrated that subgrouping of patients with respect to baseline abstinence status is feasible and clinically useful for exploring cocaine cessation and relapse-prevention effects of candidate medications.

Distress Tolerance Associations With Posttraumatic Stress Disorder Symptoms Among Trauma-Exposed, Cocaine-Dependent Adults

The present investigation examined associations between distress tolerance and posttraumatic stress disorder (PTSD) symptoms in a cocaine-dependent sample. Participants were comprised of 138 cocaine-dependent adults (Mage = 45.4, SD = 9.9; 81% male; 76.3% African American) who endorsed trauma exposure, defined according to Diagnostic and Statistical Manual of Mental Disorders (4th ed., text rev.; DSM-IV-TR) PTSD Criterion A. Participants were administered interview-based measures and completed a series of self-report questionnaires. Results indicated that distress tolerance was significantly, incrementally (negatively) associated with PTSD symptom severity, contributing 6.8% of unique variance to the model (p < .001); notably, the overall model explained 44.8% of variance in PTSD symptomatology. Distress tolerance also contributed between 2.7% and 6.8% of unique variance across each of the PTSD symptom clusters (ps < .05). Incremental effects were documented, after accounting for the variance explained by theoretically relevant covariates (i.e., gender, cocaine-use severity, depressive symptoms, trauma-exposure severity). Theoretical and clinical implications are discussed.

Anti-saccade error rates as a measure of attentional bias in cocaine dependent subjects

Cocaine-dependent (CD) subjects show attentional bias toward cocaine-related cues, and this form of cue-reactivity may be predictive of craving and relapse. Attentional bias has previously been assessed by models that present drug-relevant stimuli and measure physiological and behavioral reactivity (often reaction time). Studies of several CNS diseases outside of substance use disorders consistently report anti-saccade deficits, suggesting a compromise in the interplay between higher-order cortical processes in voluntary eye control (i.e., anti-saccades) and reflexive saccades driven more by involuntary midbrain perceptual input (i.e., pro-saccades). Here, we describe a novel attentional-bias task developed by using measurements of saccadic eye movements in the presence of cocaine-specific stimuli, combining previously unique research domains to capitalize on their respective experimental and conceptual strengths. CD subjects (N = 46) and healthy controls (N = 41) were tested on blocks of pro-saccade and anti-saccade trials featuring cocaine and neutral stimuli (pictures). Analyses of eye-movement data indicated (1) greater overall anti-saccade errors in the CD group; (2) greater attentional bias in CD subjects as measured by anti-saccade errors to cocaine-specific (relative to neutral) stimuli; and (3) no differences in pro-saccade error rates. Attentional bias was correlated with scores on the obsessive-compulsive cocaine scale. The results demonstrate increased saliency and differential attentional to cocaine cues by the CD group. The assay provides a sensitive index of saccadic (visual inhibitory) control, a specific index of attentional bias to drug-relevant cues, and preliminary insight into the visual circuitry that may contribute to drug-specific cue reactivity.

Bradycardia as a Marker of Chronic Cocaine Use: A Novel Cardiovascular Finding

Few studies have examined the effects of chronic cocaine use on the resting surface electrocardiogram (ECG) between exposures to cocaine. Researchers compared 12-lead ECGs from 97 treatment-seeking cocaine-dependent patients, with ECG parameters from 8,513 non-cocaine-using control patients from the Atherosclerosis Risk in Communities study. After matching and adjusting for relevant covariates, cocaine use demonstrated large and statistically reliable effects on early repolarization, bradycardia, severe bradycardia, and heart rate. Current cocaine dependence corresponds to an increased odds of demonstrating early repolarization by a factor of 4.92 and increased odds of bradycardia and severe bradycardia by factors 3.02 and 5.11, respectively. This study demonstrates the novel finding that long-lasting effects of cocaine use on both the cardiac conduction and the autonomic nervous system pose a risk of adverse cardiovascular events between episodes of cocaine use, and that bradycardia is a marker of chronic cocaine use.

Examination of the Wisconsin Inventory of Smoking Dependence Motives (WISDM-68) Factor Structure in a Sample of Pregnant Smokers

INTRODUCTION Smoking during pregnancy poses known risks to fetal and infant development. Women who continue to smoke during pregnancy exhibit higher levels of nicotine dependence than women who quit. Increased understanding of the construct of nicotine dependence in pregnant smokers may aid in the development of effective treatments. Research has suggested that nicotine dependence is a multifaceted construct, driven not only by withdrawal and tolerance processes, but also by reinforcement, sensory, and contextual processes. The Wisconsin inventory of smoking dependence motives (WISDM-68) assesses 13 varied smoking motives in order to assess processes that may lead to nicotine dependence. METHODS The factor structure of the WISDM-68 was explored using an ethnically diverse sample of 294 pregnant women who had been screened and/or enrolled in a smoking cessation treatment study. Confirmatory analyses were conducted with previously published models. An exploratory factor analysis and exploratory structural equation modeling (ESEM) were conducted to develop and validate a measurement model for the WISDM-68 in this sample. RESULTS Previously established models were not a good fit for the present data. Using ESEM, a 9-factor model exhibiting both predictive and concurrent validity emerged. Two factors predicted abstinence 6 months posttreatment. Several factors were associated with smoking heaviness, the Fagerström test for cigarette dependence and time to first cigarette. CONCLUSIONS In contrast to previously published studies, a 9-factor model best characterizes the WISDM in the present sample. These findings may reflect smoking motivations unique to young, pregnant women who continue to smoke during pregnancy.

Demographic and Psychological Factors Associated With Lifetime Cocaine Use: An Exploratory Factor Analysis of Baseline Questionnaires

OBJECTIVES Underlying heterogeneity among individuals with cocaine dependence is widely postulated in the literature, however, identification of a group of factors that explain risk of cocaine use severity has yet to be confirmed. METHODS Latent mixture modeling evaluated 338 cocaine-dependent individuals recruited from the community to assess the evidence for the presence of distinct subgroups. Variables included 5 baseline questionnaires measuring cognitive function (Shipley), impulsivity (BIS), mood (BDI), affective lability (ALS), and addiction severity (ASI). Results failed to suggest multiple subgroups. Given a lack of evidence for discrete latent classes, an exploratory factor analysis (EFA) followed by exploratory structural equation modeling (ESEM) was implemented to identify functional dimensions to enhance interpretation of these variables. RESULTS Findings from the EFA indicated a 3-factor model as the best fit, and the subsequent ESEM solution resulted in associations with lifetime cocaine use. Factor 1, best characterized by demographic factors (gender, age), is associated with less lifetime cocaine use. Psychological problems best characterize factor 2, which is associated with higher lifetime cocaine use. Finally, factor 3 is characterized by other substance use (alcohol and marijuana). Although this factor did not demonstrate a statistically reliable relation with self-reported, lifetime cocaine use, it did indicate a potentially meaningful positive association. CONCLUSIONS These 3 factors delineate dimensions of functioning that likewise help characterize the variability found in previously established associations with self-reported cocaine use.

Drop-The-Loser: A practical bayesian adaptive design for a clinical trial of citalopram for cocaine use disorder

Background: Bayesian adaptive designs have the potential to change the way clinical research is conducted. These novel study designs can answer the same questions as traditional efficacy trials but with potential advantages in terms of flexibility and efficiency. The Bayesian adaptive drop-the-loser (DTL) design is particularly applicable in trials where there are uncertainties regarding which treatment/dose level to test further. Aims: This paper describes steps taken in planning an ongoing DTL randomized clinical trial of citalopram for the treatment of cocaine use disorder, including the design rationale, simulation study, and pruning criteria. Method and results: Participants of this single site, double-blind, randomized controlled trial are assigned to either citalopram 20 mg/day, 40 mg/day, or placebo for 9 weeks. The primary outcome measure is longest duration of abstinence (LDA) based on urine drug screens. A planned interim analysis at 50% of data gathering will drop or “prune” the active medication group that is performing least well, based on pre-specified decision rules. Bayesian simulation results show that this adaptive design allocates more subjects to the ‘best efficacy’ dose condition with satisfactory power and Type I error rates. Discussion: Employing the proposed DTL design is likely to yield the same conclusions as the classical fixed (non-adaptive) design, but with greater statistical precision for estimating treatment effects. We discuss advantages of DTL for speeding up efforts underway to identify and test new medications to treat cocaine dependence. We also discuss logistical considerations and lessons learned from designing and implementing this trial. Correspondence to: Joy M. Schmitz, Center for Neurobehavioral Research on Addiction, Department of Psychiatry and Behavioral Sciences, UTMcGovern Medical School, Houston TX 77054, USA, Tel: 713-486-2867; Email: Joy.M.Schmitz@uth.tmc.edu