Stacia M. DeSantis

A Double-Blind Randomized Controlled Trial of N-Acetylcysteine in Cannabis-Dependent Adolescents

OBJECTIVE Preclinical findings suggest that the over-the-counter supplement N-acetylcysteine (NAC), via glutamate modulation in the nucleus accumbens, holds promise as a pharmacotherapy for substance dependence. The authors investigated NAC as a novel cannabis cessation treatment in adolescents, a vulnerable group for whom existing treatments have shown limited efficacy. METHOD In an 8-week double-blind randomized placebo-controlled trial, treatment-seeking cannabis-dependent adolescents (ages 15-21 years; N=116) received NAC (1200 mg) or placebo twice daily as well as a contingency management intervention and brief (<10 minutes) weekly cessation counseling. The primary efficacy measure was the odds of negative weekly urine cannabinoid test results during treatment among participants receiving NAC compared with those receiving placebo, in an intent-to-treat analysis. The primary tolerability measure was frequency of adverse events, compared by treatment group. RESULTS Participants receiving NAC had more than twice the odds, compared with those receiving placebo, of having negative urine cannabinoid test results during treatment (odds ratio=2.4, 95% CI=1.1-5.2). Exploratory secondary abstinence outcomes favored NAC but were not statistically significant. NAC was well tolerated, with minimal adverse events. CONCLUSIONS This is the first randomized controlled trial of pharmacotherapy for cannabis dependence in any age group to yield a positive primary cessation outcome in an intent-to-treat analysis. Findings support NAC as a pharmacotherapy to complement psychosocial treatment for cannabis dependence in adolescents.

Plasma Biomarkers That Reflect Determinants of Matrix Composition Identify the Presence of Left Ventricular Hypertrophy and Diastolic Heart Failure

Background— Chronic pressure overload (such as arterial hypertension) may cause left ventricular (LV) remodeling, alterations in cardiac function, and the development of diastolic heart failure. Changes in the composition of the myocardial extracellular matrix may contribute to the development of pressure-overload–induced LV remodeling. We hypothesized that a specific pattern of plasma biomarker expression that reflected changes in these pathophysiological mechanisms would have diagnostic application to identify (1) patients who have development of LV hypertrophy (LVH) and (2) patients with LVH who have development of diastolic heart failure. Methods and Results— Plasma concentration of 17 biomarkers (matrix metalloproteinase [MMP]-1, -2, -3, -7, -8, and -9; tissue inhibitors -1, -2, -3, and -4; N-terminal propeptide of brain natriuretic peptide (NT-proBNP); cardiotrophin; osteopontin; soluble receptor for advanced glycation end products; collagen I teleopeptide; collagen I NT-proBNP; and collagen III N-terminal propetide [PIIINP]), an echocardiogram, and 6-minute hall walk were performed on 241 referent control subjects, 144 patients with LVH but no evidence of heart failure, and 61 patients with LVH and diastolic heart failure (DHF). A plasma multibiomarker panel consisting of increased MMP-7, MMP-9, TIMP-1, PIIINP, and NT-proBNP predicted the presence of LVH with an area under the curve of 0.80. A plasma multibiomarker panel consisting of increased MMP-2, TIMP-4, PIIINP, and decreased MMP-8 predicted the presence of DHF with an area under the curve of 0.79. These multibiomarker panels performed better than any single biomarker including NT-proBNP and better than using clinical covariates alone (area under the curve, 0.73 for LVH and 0.68 for DHF). Conclusions— Plasma biomarkers reflecting changes in extracellular matrix fibrillar collagen homeostasis, combined into a multibiomarker panel, have discriminative value in identifying the presence of structural remodeling (LVH) and clinical disease (DHF).

Relationship between the temporal profile of plasma microRNA and left ventricular remodeling in patients after myocardial infarction.

Background— microRNAs (miRs) are small noncoding RNAs that recognize and bind to mRNAs and inhibit protein translation or degrade mRNA. Studies in animal models have suggested that miRs play a translational or posttranslational regulatory role in myocardial growth, fibrosis, viability, and remodeling. However, whether specific temporal changes in miRs occur in patients during the left ventricular (LV) remodeling process that follows a myocardial infarction (post-MI) remains unknown. The current pilot study tested the hypotheses that plasma miRs could be reliably measured in post-MI patients and that there is a relationship between temporal changes in specific miRs and post-MI LV structural remodeling. Methods and Results— LV end-diastolic volume (echocardiography) and plasma miR were measured in age-matched referent controls (CTLs, n=12) and post-MI patients (n=12) from day 2 through day 90 post-MI. Selected miRs (miR-1, miR-21, miR-29a, miR-133a, and miR-208) were measured using quantitative reverse transcription–polymerase chain reaction and normalized for endogenous small nuclear RNA U6. After MI, LV end-diastolic volume increased progressively compared with CTL; this was accompanied by time-dependent changes in specific miRs. For example, miR-21 initially decreased 2 days post-MI (0.3±0.1-fold versus CTL; P<0.05), increased 5 days post-MI (2±1-fold versus CTL; P<0.05), and returned to CTL values at later post-MI time points. In contrast, miR-29a increased 5 days post-MI (4±1-fold versus CTL; P<0.05) and then decreased to CTL at later time points. miR-208 increased 5 days post-MI (3±1-fold versus CTL; P<0.05) and remained elevated up to 90 days post-MI. Conclusions— A time-dependent change in miRs occurred in post-MI patients, including an early and robust increase in miRs that has affected myocardial growth, fibrosis, and viability. Thus, serially profiling miRs in the plasma of post-MI patients may hold both mechanistic and prognostic significance.

The effect of neuromuscular blockade on mask ventilation

We wished to test the hypothesis that neuromuscular blockade facilitates mask ventilation. In order reliably and reproducibly to assess the efficiency of mask ventilation, we developed a novel grading scale (Warters scale), based on attempts to generate a standardised tidal volume. Following induction of general anaesthesia, a blinded anaesthesia provider assessed mask ventilation in 90 patients using our novel grading scale. The non‐blinded anaesthesiologist then randomly administered rocuronium or normal saline. After 2 min, mask ventilation was reassessed by the blinded practitioner. Rocuronium significantly improved ventilation scores on the Warters scale (mean (SD) 2.3 (1.6) vs 1.2 (0.9), p < 0.001). In a subgroup of patients with a baseline Warters scale value of > 3 (i.e. difficult to mask ventilate; n = 14), the ventilation scores also showed significant improvement (4.2 (1.2) vs 1.9 (1.0), p = 0.0002). Saline administration had no effect on ventilation scores. Our data indicate that neuromuscular blockade facilitates mask ventilation. We discuss the implications of this finding for unexpected difficult airway management and for the practice of confirming adequate mask ventilation before the administration of neuromuscular blockade.

Gender Differences in Craving and Cue Reactivity to Smoking and Negative Affect/Stress Cues

There is evidence that women may be less successful when attempting to quit smoking than men. One potential contributory cause of this gender difference is differential craving and stress reactivity to smoking- and negative affect/stress-related cues. The present human laboratory study investigated the effects of gender on reactivity to smoking and negative affect/stress cues by exposing nicotine dependent women (n = 37) and men (n = 53) smokers to two active cue types, each with an associated control cue: (1) in vivo smoking cues and in vivo neutral control cues, and (2) imagery-based negative affect/stress script and a neutral/relaxing control script. Both before and after each cue/script, participants provided subjective reports of smoking-related craving and affective reactions. Heart rate (HR) and skin conductance (SC) responses were also measured. Results indicated that participants reported greater craving and SC in response to smoking versus neutral cues and greater subjective stress in response to the negative affect/stress versus neutral/relaxing script. With respect to gender differences, women evidenced greater craving, stress and arousal ratings and lower valence ratings (greater negative emotion) in response to the negative affect/stressful script. While there were no gender differences in responses to smoking cues, women trended towards higher arousal ratings. Implications of the findings for treatment and tobacco-related morbidity and mortality are discussed.

Gender differences in the effect of early life trauma on hypothalamic–pituitary–adrenal axis functioning†

Background: The objective of this study was to examine the modifying effect of gender on the association between early life trauma and the hypothalamic–pituitary–adrenal (HPA) axis response to a pharmacologic challenge and a social stress task in men and women. Participants (16 men, 23 women) were the control sample of a larger study examining HPA axis function. Individuals with major depressive disorder, posttraumatic stress disorder, bipolar disorder, or psychotic or eating disorders were excluded. Methods: In two test sessions, subjects received 1 µg/kg of corticotropin‐releasing hormone (CRH) intravenously and participated in the Trier Social Stress Test (TSST). Primary outcomes included plasma cortisol and corticotropin levels measured at baseline and more than five time points following the challenges. Predictors included gender and early life trauma, as measured by the Early Trauma Index. Using factor analysis, the domains general trauma, severe trauma, and the effects of trauma were established. Using regression, these constructs were used to predict differential HPA reactivity in men and women following the challenges. Results: The three factors accounted for the majority of the variance in the ETI. Following the CRH challenge, women had higher overall corticotropin response as dictated by the area under the curve analysis. There were no significant associations between trauma and neuroendocrine response to the TSST. Conclusions: CRH challenge results indicate that gender differences in the impact of early trauma may help explain the differential gender susceptibility to psychopathology following adverse childhood events. This may help explain gender differences in some stress‐sensitive psychiatric disorders. Depression and Anxiety, 2011.

D-cycloserine and Cocaine Cue Reactivity: Preliminary Findings

Background: D-cycloserine (DCS), a partial glutamate N-methyl-D-aspartic acid (NMDA) receptor agonist, enhances extinction of conditioned fear responding in rodents and facilitates exposure-based learning in humans with anxiety disorders. Objectives: This preliminary study investigates DCS pretreatment on response to cocaine cues in cocaine-dependent subjects. Methods: Ten cocaine-dependent subjects were randomly assigned to receive either 50 mg DCS or matching placebo two hours before each of two 1-hour cocaine cue exposure sessions one day apart. HR and craving ratings were obtained before and during cue exposure sessions. Results: There was a trend towards increased craving to cocaine cues in cocaine-dependent individuals after administration of DCS. Conclusions: The administration of DCS prior to cue exposure sessions may facilitate response activation. Scientific Significance: While facilitation of extinction-based learning by DCS may have therapeutic potential for cocaine dependence, this drug may exhibit a different profile in cocaine-dependent individuals as compared to those with anxiety disorders.

A randomized, double-blind, placebo-controlled clinical trial of acamprosate in alcohol-dependent individuals with bipolar disorder: a preliminary report

Tolliver BK, DeSantis SM, Brown DG, Prisciandaro JJ, Brady KT. A randomized, double‐blind, placebo‐controlled clinical trial of acamprosate in alcohol‐dependent individuals with bipolar disorder: a preliminary report. Bipolar Disord 2012: 14: 54–63.

Laboratory-based, cue-elicited craving and cue reactivity as predictors of naturally occurring smoking behavior

Cigarette craving, one hallmark sign of nicotine dependence, is often measured in laboratory settings using cue reactivity methods. How lab measures of cue reactivity relate to real world smoking behavior is unclear, particularly among non-treatment seeking smokers. Within a larger study of hormonal effects on cue reactivity (N=78), we examined the predictive relationship of cue reactivity to smoking, each measured in several ways. Results indicated that cue-evoked craving in response to stressful imagery, and to a lesser extent, in vivo smoking cues, significantly predicted smoking behavior during the week following testing. However, this predictive relationship was absent upon controlling for reactivity to neutral cues. Nicotine dependence may moderate the relationship between cue reactivity and actual smoking, such that this predictive relationship is less robust among highly dependent smokers than among smokers low in nicotine dependence. The question of whether cue-elicited craving predicts smoking among smokers not in treatment is best answered with a qualified yes, depending on how craving is manipulated and measured. Our findings highlight important methodological and theoretical considerations for cue reactivity research.

High-osmolarity saline in neurocritical care: systematic review and meta-analysis.

Background and Purpose:Intracranial hypertension and cerebral edema are known contributors to secondary brain injury and to poor neurologic outcomes. Small volume solutions of exceedingly high osmolarity, such as 23.4% saline, have been used for the management of intracranial hypertension crises and as a measure to prevent or reverse acute brain tissue shifts. We conducted a systematic literature review on the use of 23.4% saline in neurocritically ill patients and a meta-analysis of the effect of 23.4% saline on intracranial pressure reduction. Design:We searched computerized databases, reference lists, and personal files to identify all clinical studies in which 23.4% saline has been used for the treatment of neurocritical care patients. Studies that did not directly involve either effects on cerebral hemodynamics or the treatment of patients with clinical or radiographic evidence of intracranial hypertension and/or cerebral swelling were eliminated. Measurements and Main Results:We identified 11 clinical studies meeting eligibility criteria. A meta-analysis was performed to evaluate the percent decrease in intracranial pressure and the 95% confidence intervals, from baseline to 60 minutes or nadir from the six studies from which this information could be extracted. A fixed effects meta-analysis estimated that the percent decrease in intracranial pressure from baseline to either 60 minutes or nadir after administration of 23.4% saline was 55.6% (se 5.90; 95% confidence interval, 43.99–67.12; p < 0.0001). Conclusions:Highly concentrated hypertonic saline such as 23.4% provides a small volume solution with low cost and an over 50% reduction effect on raised intracranial pressure. Side effects reported are minor overall in view of the potentially catastrophic event that is being treated. High quality data are still needed to define the most appropriate osmotherapeutic agent, the optimal dose, the safest and most effective mode of administration and to further elucidate the mechanism of action of 23.4% saline and of osmotherapy in general.