Faculty Bibliography

BACKGROUND:Relatively little is known about the prognostic value of comorbid mental disorders in alcohol use disorder (AUD) treatment for older adults (OA). AIMS/OBJECTIVE:This article aimed to investigate 1) the impact of current unipolar mood and anxiety disorders in AUD treatment success in OA, 2) the timing of this putative comorbidity impact over six months, and 3) the role of treatment length in comorbidity effects. METHODS:We analyzed baseline and one-, three-, and six-month follow-up data from the international multicenter RCT "ELDERLY-Study" (baseline n = 693, median age: 64.0 years) using mixed effects regression models. In adults aged 60+ with DSM-5 AUD "ELDERLY" compared outpatient motivational enhancement therapy (MET, four sessions) with outpatient MET plus community reinforcement approach for seniors (MET & CRA-S; up to 12 sessions). Aiming for abstinence or minimal alcohol use (AU), both conditions included CBT-elements. We assessed AU with Form 90, and mental disorders with the Mini International Neuropsychiatric Interview (M.I.N.I.). RESULTS:Mood-related disorders were associated with more drinks per day at baseline and greater reductions in drinks per day at one and six months (main effect mood disorder: Coef. 2.1, 95% CI 0.6-3.6; one month interaction effect: Coef. -1.9, 95% CI -3.3- -0.5; six months interaction effect: Coef. -2.1, 95% CI -3.5 - -0.6). These results were replicated within MET & CRA-S but not within MET. CONCLUSION/CONCLUSIONS:Comorbid mental disorders had modest effects on short-term outpatient treatment outcomes. OA with AUD and unipolar mood-related disorders may profit from short interventions based on motivational interviewing and CBT-elements. ClinicalTrials.gov:NCT02084173.

BACKGROUND:As the USA grapples with an opioid epidemic, medical emergency departments (EDs) have become a critical setting for intervening with opioid-dependent patients. Brief interventions designed to bridge the gap from acute ED care to longer-term treatment have shown limited efficacy for this population. Strength-based case management (SBCM) has shown strong effects on treatment linkage among patients with substance use disorders in other healthcare settings. This study aimed to investigate whether SBCM is an effective model for linking opioid-dependent ED patients with addiction treatment and pharmacotherapy. Here, we describe the implementation and challenges of adapting SBCM for the ED (SBCM-ED). Study rationale, design, and baseline characteristics are also described. METHODS:This study compared the effects of SBCM-ED to screening, assessment, and referral alone (SAR) on treatment linkage, substance use, and functioning. We recruited participants from a public hospital in NYC. Working alliance between case managers and participants and the feasibility of SBCM implementation were evaluated. Baseline data from the randomized sample were analyzed for group equivalency. Outcomes analyses are forthcoming. RESULTS:Three hundred adult participants meeting DSM-IV criteria for opioid dependence were randomly assigned to either SBCM, in which they received a maximum of six case management sessions within 90 days of enrollment, or SAR, in which they received a comprehensive referral list and pamphlet outlining drug use consequences. No significant differences were found between groups at baseline on demographic or substance use characteristics. All SAR participants and 92.6% of SBCM-ED participants initiated their assigned intervention. Over half of SBCM-ED first sessions occurred in the ED on the day of enrollment. Case managers developed a strong working alliance with SBCM-ED participants after just one session. CONCLUSION/CONCLUSIONS:Interventions that exceed SBIRT were accepted by an opioid-dependent patient population seen in an urban medical ED. At the time of study funding, this trial was one of the first to focus specifically on this population in this challenging setting. The successful implementation of SBCM demonstrates its adaptability to the ED and may serve as a potential model for EDs seeking to adopt an intervention that overcomes the barrier between the ED encounter and more intensive treatment. TRIAL REGISTRATION/BACKGROUND:ClinicalTrials.gov NCT02586896 . Registered on 27 October 2015.

BACKGROUND:We reanalyzed a multisite 26-week randomized double-blind placebo-controlled clinical trial of 600 mg twice-a-day Gabapentin Enacarbil Extended-Release (GE-XR), a gabapentin prodrug, designed to evaluate safety and efficacy for treating alcohol use disorder. In the original analysis (n = 338), published in 2019, GE-XR did not differ from placebo. Our aim is to advance precision medicine by identifying likely responders to GE-XR from the trial data and to determine for likely responders if GE-XR is causally superior to placebo. METHODS:The primary outcome measure in the reanalysis is the reduction from baseline of the number of heavy drinking days (ΔHDD). Baseline features including measures of alcohol use, anxiety, depression, mood states, sleep, and impulsivity were used in a random forest (RF) model to predict ΔHDD to treatment with GE-XR based on those assigned to GE-XR. The resulting RF model was used to obtain predicted outcomes for those randomized to GE-XR and counterfactually to those randomized to placebo. Likely responders to GE-XR were defined as those predicted to have a reduction of 14 days or more. Tests of causal superiority of GE-XR to placebo were obtained for likely responders and for the whole sample. RESULTS:For likely responders, GE-XR was causally superior to placebo (p < 0.0033), while for the whole sample, there was no difference. Likely responders exhibited improved outcomes for the related outcomes of percent HDD and drinks per week. Compared with unlikely responders, at baseline likely responders had higher HDDs; lower levels of anxiety, depression, and general mood disturbances; and higher levels of cognitive and motor impulsivity. CONCLUSIONS:There are substantial causal benefits of treatment with GE-XR for a subset of patients predicted to be likely responders. The likely responder statistical paradigm is a promising approach for analyzing randomized clinical trials to advance personalized treatment.

Impairment in cognitive control in alcohol use disorder (AUD) contributes to difficulty controlling alcohol use and, in many populations, difficulties with emotion regulation. However, the most reliable and robust marker of clinically-relevant deficits in cognitive control in AUD is unclear. Our aims were to measure relationships between BOLD signal during a Stroop task and AUD severity and change in BOLD signal and change in drinking over three weeks. We also aimed to explore the relationships between BOLD signal and subjective negative affect. Thirty-three individuals with AUD underwent a multisensory Stroop task during functional magnetic resonance imaging (fMRI), as well as a battery of neuropsychological tests and self-report assessments of negative affect and AUD severity. Greater activation in temporal gyrus and cerebellum during incongruent trials compared to congruent trials was observed, and percent signal change (incongruent minus congruent) in both clusters was positively correlated with AUD severity and self-reported negative affect. Neuropsychological task performance and self-reported impulsivity were not highly correlated with AUD severity. Hierarchical regression analyses indicated that percent signal change (incongruent minus congruent) in cerebellum was independently associated with negative affect after controlling for recent and chronic drinking. In a subset of individuals (n = 23) reduction in cerebellar percent signal change (incongruent minus congruent) was correlated with increases in percent days abstinent over 3 weeks. BOLD activation during this Stroop task may therefore be an important objective marker of AUD severity and negative affect. The potential importance of the cerebellum in emotion regulation and AUD severity is highlighted.

BACKGROUND:Higher levels of anxiety, negative affect, and impaired emotion regulation are associated with alcohol use disorder (AUD) and contribute to relapse and worse treatment outcomes. Prazosin, while typically used to treat post-traumatic stress disorder (PTSD) and other anxiety disorders, has shown promise for treating AUD. In order to better understand these underlying neural processes in individuals with AUD, our aims in this study were to measure brain activation during an anticipatory anxiety task before treatment to determine whether observed patterns supported previous work. We then aimed to measure the effects of prazosin on patients with AUD and explore whether greater baseline anticipatory anxiety (as measured by subjective and neural measures) predicts better treatment outcomes. METHODS:Thirty-four individuals seeking treatment for AUD participated in a six-week placebo-controlled study of prazosin and underwent an anticipatory anxiety task during fMRI scans at baseline and three weeks. Alcohol use over six weeks was measured. RESULTS:Greater levels of subjective anxiety and deactivation in posterior cingulate cortex (PCC) and ventromedial prefrontal cortex (vmPFC) were observed during high-threat stimuli compared to low-threat stimuli. Compared to placebo, prazosin reduced subjective anxiety to high-threat stimuli but there were no observed significant effects of prazosin on brain activation during the task. However, AUD patients with greater vmPFC deactivation during high threat relative to low threat and patients with low baseline anticipatory anxiety during the task had worse clinical outcomes on prazosin. CONCLUSIONS:Deactivation in PCC and vmPFC to high-threat stimuli replicated previous work and shows promise for further study as a marker for AUD. Although prazosin did not affect brain activation in the regions of interest during the anticipatory anxiety task, subjective levels of anxiety and brain activation in vmPFC predicted treatment outcomes in individuals with AUD undergoing treatment with prazosin, highlighting individuals more likely to benefit from prazosin than others.

AIM/OBJECTIVE:To examine whether adding the Community Reinforcement Approach for Seniors (CRA-S) to Motivational Enhancement Therapy (MET) increases the probability of treatment success in people ≥ 60 years old with alcohol use disorder (AUD). DESIGN/METHODS:A single blind multi-centre multinational randomized (1:1) controlled trial. SETTING/METHODS:Outpatient settings (municipal alcohol treatment clinics in Denmark, specialized addiction care facilities in Germany, and a primary care clinic in the USA). PARTICIPANTS/METHODS:Between January 2014 and May 2016, 693 patients aged 60+ years and fulfilling DSM-5 criteria for AUD participated in comparing MET (n=351) and MET + CRA-S (n=342). INTERVENTION AND COMPARATOR/UNASSIGNED:MET (comparator) included four manualized sessions aimed at increasing motivation to change and establishing a change plan. CRA-S (intervention) consisted of up to eight further optional, manualized sessions aimed at helping patients to implement their change plan. CRA-S included a specially designed module on coping with age and age-related problems. MEASUREMENTS/METHODS:The primary outcome was either total alcohol abstinence or an expected blood alcohol concentration of ≤ 0.05% during the 30 days preceding the 26 weeks follow-up (defined as success) or blood alcohol concentration of >0.05% during the follow-up period (defined as failure). This was assessed by self-report using the Form 90 instrument. The main analysis involved complete cases. FINDINGS/RESULTS:The follow-up rate at 26 weeks was 76.2% (76.9% in the MET group and 76.0% in the MET+CRA-S group). The success rate in the MET group was 48.9% (95%CI=42.9%-54.9%) vs. 52.3% (95%CI=46.2%-58.3%) in the MET+CRA-S group. The odds of success in the two conditions did not differ (odds ratio 1.22. 95% CI=0.86-1.75, p = 0.26, Bayes factor=0.10). Sensitivity analyses involving alternative approaches to missing values did not change the results. CONCLUSIONS:In older adults with an alcohol use disorder diagnosis, adding the 'Community Reinforcement Approach for Seniors' intervention to brief outpatient Motivational Enhancement Therapy treatment did not improve drinking outcome.

OBJECTIVES/OBJECTIVE:To investigate the psychometric properties of the frequently used Alcohol Dependence Scale (ADS) in older adults and the associations between ADS scores and alcohol use and DSM-5 AUD symptom counts. METHODS:Using baseline data from an international multicenter RCT on outpatient AUD treatment for adults aged 60+ with DSM-5 alcohol use disorder (AUD; n = 529), we computed Cronbach's alpha (α) and applied confirmatory (CFA) and exploratory factor analysis (EFA) to determine the underlying factor structure. A structural equation model (SEM) explored the interrelationship of latent ADS factors with alcohol use and number of DSM-5 criteria endorsed. RESULTS:Internal consistency of the ADS (α = 0.81) was good. EFA revealed a three-factor structure. Factor 1 ("Severe withdrawal symptoms") consisted of severe psychoperceptual and psychophysical consequences of excessive drinking, Factor 2 ("Loss of control") consisted of acute physical reactions of intoxication, and Factor 3 ("Obsessive-compulsive drinking") described habitual drinking. The SEM suggested that only Factor 3 had large effects on DSM-5 symptom score and drinking behavior. CONCLUSION/CONCLUSIONS:Lowering the ADS threshold or focusing on ADS items from Factor 3 may be more suitable measures of severity of alcohol dependence in treatment-seeking older adults as ADS scores are low and not closely related to DSM-5 AUD.

Background and aims: Given the enormous global burden of depressive illness, there is an urgent need to develop novel and more effective treatments for major depressive disorder (MDD). Recent findings have suggested that psychedelic drugs may have a role in the treatment of depressive symptoms, and a number of groups are in the process of developing protocols to study this question systematically. Given the subjective quality of both the psychedelic experience and depressive symptomatology, great care must be taken when designing a protocol to study the clinical efficacy of psychedelic drugs. This study will discuss many factors to consider when designing a clinical trial of psilocybin for MDD. Methods: We provide a thorough review of pertinent research into antidepressant clinical trial methodology and review practical considerations that are relevant to the study of psychedelic-Assisted treatment for depression. Results: We discuss participant selection (including diagnostic accuracy, exclusion criteria, characteristics of the depressive episode, and the use of concurrent medications), study interventions (including dosing regimens, placebo selection, non-pharmacological components of treatment, and the importance of blinding), trial duration, outcome measures, and safety considerations. Conclusions: Careful and transparent study design and data analysis will maximize the likelihood of generating meaningful, reproducible results, and identifying a treatment-specific effect. Meeting the highest standards for contemporary trial design may also broaden the acceptance of psychedelic research in the scientific community at large.

OBJECTIVES/OBJECTIVE:The noradrenergic system plays an important role in the pathophysiology of alcohol use disorder (AUD). Medications in this class may reduce drinking. Our aims were to investigate this in a unique sample of individuals with AUD. METHODS:Thirty-six individuals with AUD were randomized to treatment with prazosin, an alpha-1 noradrenergic antagonist, or placebo, for 6 weeks (target daily dose 16 mg). Hierarchical linear modeling was used to examine the effect of treatment group on rate of change in primary (drinks per week [DPW]) and several secondary outcome measures. RESULTS:Prazosin did not significantly affect rate of reduction in alcohol use in the intent to treat sample (n = 36) compared with placebo, but did significantly increase the rate of reduction in DPW in an optimal treatment exposure subgroup (beta = -0.3; P = 0.01; event rate ratio 0.74; confidence interval 0.59, 0.93; n = 27). Poor adherence and tolerability may have contributed to null effects. Diastolic blood pressure (DBP) moderated the effects of treatment group on rate of reduction in drinks per drinking day, supporting previous work in doxazosin, another alpha-1 antagonist. Specifically, prazosin was associated with greater rates of reduction in drinking compared with placebo in individuals with high but not low DBP. CONCLUSIONS:Our findings do not support the clinical utility of prazosin for all treatment-seeking AUD, but post hoc analyses indicate that it might have some efficacy in individuals who can tolerate it. Further work exploring the clinical utility of DBP as a treatment matching variable, and defining optimal values using sensitivity and specificity analyses, is warranted.