Elizabeth J. Santa Ana

d-Cycloserine attenuates reactivity to smoking cues in nicotine dependent smokers: A pilot investigation

Increasing evidence indicates that smoking cues contribute to nicotine self-administration and attenuating conditioned reactivity to smoking cues may aid abstinence of smoking and prevention of smoking relapse in individuals with nicotine dependence. Based on prior studies showing that the partial N-methyl-D-aspartate (NMDA) agonist D-cycloserine (DCS) facilitates extinction of learned fear during behavioral exposure therapy in humans and facilitates extinction of cocaine-induced conditioned place preference in animals, we evaluated whether DCS would have potential for reducing reactivity to smoking cues when combined with cue exposure treatment in humans with nicotine dependence. In this double-blind placebo-controlled pilot laboratory study, 25 smokers were recruited from the general community and randomized to DCS or placebo, plus cue exposure therapy. DCS significantly attenuated smoking cue reactivity in response to in-vivo smoking cues based on physiological reactivity and subjective urge-to-smoke ratings and led to a significantly smaller expired carbon monoxide (CO) level at the one-week follow-up compared to placebo, although exploratory analyses indicated no effect on smoking behavior overall. These findings provide promising support for DCS combined with cue exposure therapy in attenuating conditioned reactivity to smoking cues.

PTSD and the HPA axis: differences in response to the cold pressor task among individuals with child vs. adult trauma.

Hypothalamic pituitary adrenal (HPA) axis and subjective stress response to a cold-water immersion task, the cold pressor task (CPT), in individuals (N=89) with post-traumatic stress disorder (PTSD) were examined. All tests were conducted at 08:00h after an overnight hospital stay. Plasma adrenocorticotrophin hormone (ACTH), cortisol, and subjective stress were examined at baseline and five post-task time points in controls (n=31), subjects with PTSD as a result of an index trauma during childhood (i.e. before age 18; n=25), and subjects with PTSD as a result of an index trauma as an adult (n=33). Approximately, 50% of individuals in both trauma groups were alcohol dependent, and the impact of this comorbidity was also examined. Subjects with PTSD, regardless of age of index trauma, had a less robust ACTH response as compared to controls. Regardless of the presence or absence of comorbid alcohol dependence, subjects with childhood trauma had lower cortisol at baseline and at all post-task measurement points and did not demonstrate the decrease in cortisol over the course of the 2h monitoring period seen in subjects with adult index trauma and controls. The findings reveal differences in the neuroendocrine response to the CPT in individuals with PTSD compared to control subjects, and differences in PTSD subjects when examined by age of index trauma.

Controlled Drinking: More Than Just a Controversy

Purpose of review We intend to provide clinicians and clinical scientists with an overview of developments in the controlled-drinking literature, primarily since 2000. A brief description of the controversy surrounding controlled drinking provides a context for a discussion of various approaches to controlled drinking intervention as well as relevant clinical research. Recent findings Consistent with previous research, behavioral self-control training continues to be the most empirically validated controlled-drinking intervention. Recent research has focused on increasing both the accessibility/availability and efficacy of behavioral self-control training. Moderation-oriented cue exposure is a recent development in behaviorally oriented controlled drinking that yields treatment outcomes comparable to behavioral self-control training. The relative efficacy of moderation-oriented cue exposure versus behavioral self-control training may vary depending on the format of treatment delivery (group versus individual) and level of drinking severity. In general, the efficacy of both techniques does not appear to vary as a function of drinking severity but may vary as a function of drinking-related self-efficacy. Guided-self change is a relatively new and brief cognitive-behavioral intervention that has demonstrated efficacy with problem drinkers. Interventions based on harm reduction principles have decreased alcohol use in various student populations. Finally, Moderation Management is the only self-help program that supports non-abstinence goals, a feature that makes it popular with problem drinkers who are avoidant of traditional treatment services. Summary The controversial past of controlled drinking is slowly giving way to a hopeful future in which individuals are less likely to be forced into an abstinence-only treatment scenario. The enhanced accessibility of effective controlled-drinking interventions should significantly expand the treatment options of individuals within the full spectrum of alcohol-related problems.

Differences in early onset alcohol use and heavy drinking among persons with childhood and adulthood trauma.

We examined predictors for age at onset of first alcohol use and onset of heaviest alcohol use among men (n = 43) and women (n = 46) with alcohol dependence and PTSD, PTSD only, alcohol dependence only, and controls, with a particular focus on individuals with child versus adult trauma. Using analysis of variance procedures, results showed differences in onset of first alcohol use and heaviest drinking between childhood and adulthood trauma victims. These preliminary results indicate that behavioral mechanisms associated with alcohol use patterns between individuals with childhood and adulthood trauma are dissimilar, suggesting greater psychopathological consequences for individuals with childhood trauma.

Effect of Treatment and Adherence on Ethnic Differences in Blood Pressure Control Among Adults with Hypertension

We evaluated whether hypertension control differs by ethnicity after accounting for patient characteristics, treatment, and adherence to treatment using the third National Health and Nutrition Examination Survey (US population estimate, 42,511,379). Outcome measures were prescribed treatment, treatment adherence, hypertension control (blood pressure [BP]<140/90 mm Hg). Multivariate logistic regression was performed with non-Hispanic whites (NHW) as the comparison group. Non-Hispanic blacks (NHB) were more likely to report medication prescription (odds ratio [OR] 1.6, 95% confidence interval [CI] 1.1-2.5) and being advised to restrict salt (OR 1.5, CI: 1.2-2.0). Among those advised, NHB were more likely to report salt restriction (OR 1.5, CI: 1.1-2.1) and weight-loss attempts (OR 1.7, CI: 1.3-2.3). Among persons advised to follow exercise, alcohol restriction, smoking cessation, tension reduction, or diet modification, NHB (OR 2.2, CI: 1.6-3.0) and Mexican Americans (OR 2.0, CI: 1.1-3.9) were more likely to report adherence. The likelihood of uncontrolled hypertension was higher in NHB (OR 1.4, CI: 1.1-1.7) and Mexican Americans (OR 1.5, CI 1.1-2.0) despite medication adherence. Even after adjustment for treatment and adherence, substantial ethnic differences in hypertension control were found. Initiating treatment, while crucial, is not sufficient and future guidelines should emphasize aggressive treatment escalation to achieve hypertension control.

Does Alexithymia Explain Variation in Cue-Elicited Craving Reported by Methamphetamine-Dependent Individuals?

Drug craving is an important motivational phenomenon among addicted individuals, and successful management of craving is essential to both the initiation and maintenance of abstinence. Although craving in response to drug cues is common in drug-dependent individuals, it is not universal. At the present time, it is not known why approximately 20-30% of all addicted persons fail to report appreciable craving in laboratory-based cue reactivity studies. This study examined the possibility that alexithymia, a personality attribute characterized by a difficulty identifying and describing emotions, may contribute to the impoverished cue-elicited craving experienced by some addicts. Specifically, we tested the hypothesis that alexithymia, as measured by the Toronto Alexithymia Scale (TAS), would be inversely related to the magnitude of cue-elicited craving obtained in a cue reactivity protocol. Forty methamphetamine-dependent individuals completed the TAS and provided craving ratings for methamphetamine after presentation of methamphetamine-associated cues. Thirteen participants (32%) reported no methamphetamine cue-elicited craving. Contrary to expectation, TAS factor 1 (a measure of difficulty identifying feelings) scores were positively associated with cue-elicited craving. Thus, the results suggest that increasing difficulty-identifying feelings may be associated with higher cue-elicited craving. Clinical implications for this finding are discussed.

Impact of DCS-facilitated cue exposure therapy on brain activation to cocaine cues in cocaine dependence

BACKGROUND The development of addiction is marked by a pathological associative learning process that imbues incentive salience to stimuli associated with drug use. Recent efforts to treat addiction have targeted this learning process using cue exposure therapy augmented with d-cycloserine (DCS), a glutamatergic agent hypothesized to enhance extinction learning. To better understand the impact of DCS-facilitated extinction on neural reactivity to drug cues, the present study reports fMRI findings from a randomized, double-blind, placebo-controlled trial of DCS-facilitated cue exposure for cocaine dependence. METHODS Twenty-five participants completed two MRI sessions (before and after intervention), with a cocaine-cue reactivity fMRI task. The intervention consisted of 50mg of DCS or placebo, combined with two sessions of cocaine cue exposure and skills training. RESULTS Participants demonstrated cocaine cue activation in a variety of brain regions at baseline. From the pre- to post-study scan, participants experienced decreased activation to cues in a number of regions (e.g., accumbens, caudate, frontal poles). Unexpectedly, placebo participants experienced decreases in activation to cues in the left angular and middle temporal gyri and the lateral occipital cortex, while DCS participants did not. CONCLUSIONS Three trials of DCS-facilitated cue exposure therapy for cocaine dependence have found that DCS either increases or does not significantly impact response to cocaine cues. The present study adds to this literature by demonstrating that DCS may prevent extinction to cocaine cues in temporal and occipital brain regions. Although consistent with past research, results from the present study should be considered preliminary until replicated in larger samples.

Development of an in-home telehealth program for outpatient veterans with substance use disorders.

A variety of obstacles (e.g., lack of transportation, less availability of treatment in rural districts) contribute to underutilization of treatment among patients with substance use disorders, warranting the need to develop innovative strategies for enhancing access to treatment for these patients. The telehealth in-home-messaging-device is a small message-delivering and monitoring device connected via landline phone to a secure server that provides assessment and disease self-management education to patients in their homes. We describe the development of a Substance Use Disorder telehealth management program (SUD program) for use on this device and a feasibility pilot of the program with six outpatient veterans with substance use disorders referred by their primary medical care providers. These patients indicated that the SUD program was acceptable, easy to use, and helpful toward addressing their substance use problems. Home telehealth technology may be an innovative and feasible approach for providing substance abuse evidence-based treatment either as an adjunct to specialty treatment for substance use disorders or as a stand-alone intervention within primary care for a larger number of patients who may otherwise not access traditional treatment services.

D-cycloserine combined with cue exposure therapy fails to attenuate subjective and physiological craving in cocaine dependence

BACKGROUND Based on preclinical studies showing that the partial N-methyl-D-aspartate (NMDA) agonist D-cycloserine (DCS) facilitates extinction of cocaine self-administration and cocaine-induced conditioned place preference, we evaluated whether 50 mg of DCS would reduce craving to cocaine cues when combined with cue exposure (CE) in cocaine dependent humans. METHODS In this double-blind placebo-controlled pilot study, 47 cocaine dependent participants were randomized to DCS or placebo (PBO), plus CE. Participants received DCS or PBO 30 minutes prior to two CE sessions, conducted one day apart. Craving and heart rate was assessed prior to CE sessions, during CE trials, and after CE trials. These measures were assessed again at a 1-week follow-up (session 3) after the second CE session. RESULTS DCS failed to significantly attenuate cocaine cue reactivity based on subjective craving and physiological reactivity (heart rate) compared to PBO. The CE protocol, consisting of repeated exposure to drug cues combined with skills training, resulted in extinction to cocaine cues as suggested by decreased craving within and between sessions in both treatment conditions. All participants exhibited elevated heart rate with repeated exposures, demonstrating a potentiation in heart rate between sessions. CONCLUSIONS 50 mg of DCS may not be effective for extinguishing reactivity to drug cues for individuals with cocaine dependence. SCIENTIFIC SIGNIFICANCE Future studies examining the effect of DCS on facilitating extinction to drug cues should examine variations in cue exposure length, number of CE presentations, and timing of DCS dose administration prior to cue exposures, which may differentially impact drug cue reactivity.

Weibull mixture regression for marginal inference in zero-heavy continuous outcomes.

Continuous outcomes with preponderance of zero values are ubiquitous in data that arise from biomedical studies, for example studies of addictive disorders. This is known to lead to violation of standard assumptions in parametric inference and enhances the risk of misleading conclusions unless managed properly. Two-part models are commonly used to deal with this problem. However, standard two-part models have limitations with respect to obtaining parameter estimates that have marginal interpretation of covariate effects which are important in many biomedical applications. Recently marginalized two-part models are proposed but their development is limited to log-normal and log-skew-normal distributions. Thus, in this paper, we propose a finite mixture approach, with Weibull mixture regression as a special case, to deal with the problem. We use extensive simulation study to assess the performance of the proposed model in finite samples and to make comparisons with other family of models via statistical information and mean squared error criteria. We demonstrate its application on real data from a randomized controlled trial of addictive disorders. Our results show that a two-component Weibull mixture model is preferred for modeling zero-heavy continuous data when the non-zero part are simulated from Weibull or similar distributions such as Gamma or truncated Gauss.