Percentage Of Heavy Drinking Days Research Articles

Sleep as an Important Target or Modifier in Alcohol Use Disorder Clinical Treatment: Example From a Recent Gabapentin Randomized Clinical Trial.

Alcohol consumption affects sleep both in healthy populations and in patients with alcohol use disorder (AUD). However, sleep has typically not been considered within AUD pharmacotherapy trials. We used data from a completed gabapentin clinical treatment trial to explore the medication's effect on patient-rated insomnia measured by a standard insomnia rating (Insomnia Severity Index [ISI]) and whether this influenced gabapentin's effects on alcohol consumption. This study included 90 individuals with current Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition AUD criteria reporting current or past alcohol withdrawal. Participants were assigned to placebo or gabapentin (up to 1200 mg/day) for a 16-week randomized controlled trial with percent heavy drinking days (PHDD) and percent abstinent days (PDA) as outcomes. Utilizing mixed-effects models, this study assessed medication effects on ISI over the trial. We then examined the interaction of baseline ISI and medication on drinking. Finally, given our previous finding of alcohol withdrawal influencing gabapentin efficacy, we added change in ISI as a potential "moderator" of the interaction of medication effects and alcohol withdrawal on drinking. Sleep (ISI) improved more in those treated with gabapentin (60.6% reduction) compared with placebo (37.8% reduction; P = 0.013). Higher baseline ISI predicted drinking in gabapentin-treated individuals (lower PHDD [P = 0.026] and higher (PDA [P = 0.047]). ISI was an independent predictor of PHDD decrease and PDA increase (P < 0.001; P = 0.002), but this did not significantly moderate gabapentin's effectiveness. Although gabapentin positively impacts both alcohol use and sleep, its effect on drinking is not fully dependent on sleep improvement, implying a direct biological mechanism on alcohol use.

Neural correlates of drinking reduction during a clinical trial of cognitive behavioral therapy for alcohol use disorder.

Cognitive behavioral therapy (CBT) is an effective treatment for alcohol use disorder (AUD). We hypothesized that the dorsolateral prefrontal cortex (DLPFC), a region implicated in cognitive control and goal-directed behavior, plays a role in behavior change during CBT by facilitating the regulation of craving (ROC). Treatment-seeking participants with AUD (N = 22) underwent functional magnetic resonance imaging (fMRI) scanning both before and after a 12-week, single-arm trial of CBT, using an ROC task that was previously shown to engage the DLPFC. We found that both the percentage of heavy drinking days (PHDD) and the overall self-reported alcohol craving measured during the ROC task were significantly reduced from pre- to post-CBT. However, we did not find significant changes over time in either the ability to regulate craving or regulation-related activity in any brain region. We found a significant 3-way interaction between the effects of cue-induced craving, cue-induced brain activity and timepoint of assessment (pre- or post-CBT) on PHDD in the left DLPFC. Follow-up analysis showed that cue-induced craving was associated with cue-induced activity in the left DLPFC among participants who ceased heavy drinking during CBT, both at pre-CBT and post-CBT timepoints. No such associations were present at either timepoint among participants who continued to drink heavily. These results suggest that patients in whom DLPFC functioning is more strongly related to cue-induced craving may preferentially respond to CBT.

The relationship between drinking and smoking in a clinical trial for smoking cessation and drinking reduction.

Heavy drinking smokers experience poorer smoking cessation outcomes. Less is known about the relationship between drinking and smoking among those who are trying to reduce or abstain from both substances. The present study used data from 115 heavy drinking smokers who completed a 12-week clinical trial comparing varenicline alone (1 mg/bid) versus varenicline (1 mg/bid) plus naltrexone (50 mg/day) for smoking cessation and drinking reduction. We tested whether drinking outcomes mediated the relationship between medication and cigarettes per smoking day (CPSD) during the active medication phase (Week 4, 8, and 12) and follow-up phase (Week 16 and 26). CPSD and drinking variables predicted respective use at subsequent time points (p's < .0001). Results revealed a nonsignificant mediation effect of our primary mediator drinks per drinking day (DPDD) at Week 12: 95% CI = [-1.03, .58] and Week 26: 95% CI = [-.09, .51], and our secondary mediators of percent heavy drinking days (PHDDs) and percent days abstinent (PDA) at Week 12: 95% CI = [-.14, .35] and Week 26: 95% CI = [-.15, .41]. Cross-lagged effects (e.g., Week 4 drinking predicting Week 8 smoking) were nonsignificant between DPDD and CPSD (p's ≥ .07), and PHDD and PDA and CPSD that met our a priori cutoff (p's ≥ .02). There was a significant relationship between drinking and smoking concurrently indicated by fixed error covariances (CPSD and DPDD: p < .01; CPSD and PDA p = .01). Our findings highlight an association between drinking and smoking behaviors, respectively, across the span of 6 months. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Relationship of negative emotionality, NIAAA recovery, and 3- and 6-month drinking outcomes among adults in treatment for alcohol use disorder

BackgroundThe National Institute of Alcohol Abuse and Alcoholism (NIAAA) recently released a new definition of recovery from alcohol use disorder (AUD). A patient is considered recovered if they are remitted from DSM-5 AUD and report cessation of heavy drinking. The NIAAA has also recently proposed the Addictions Neuroclinical Assessment (ANA) to guide treatment research. Negative emotionality is one of three domains of the ANA and theory proposes that AUD is maintained by negative reinforcement via the relief of negative affect. The purpose of the current study was to examine: (1) the relationship of end-of-treatment negative emotionality and NIAAA recovery, and (2) the ability of NIAAA recovery at the end of treatment to predict three- and six-month drinking outcomes. MethodAt baseline and end-of-treatment, women and men (n = 181) in treatment for AUD completed measures of negative emotionality, drinking, and were assessed for DSM-5 AUD diagnostic criteria. At three- and six-months post-treatment, drinking was re-assessed. Results22.5% (n = 24) of participants met full criteria for NIAAA recovery at end-of-treatment. Lower levels of end of treatment negative emotionality were associated with increased odds of achieving NIAAA recovery. Meeting NIAAA recovery predicted greater percent days abstinent (PDA) and lower percent heavy drinking days (PHDD) at 3-months, but not at 6-months post-treatment. ConclusionsThis study is among the first to report a relationship between the negative emotionality domain of the ANA and NIAAA recovery. Results underscore the importance of addressing negative emotionality in treatment. Findings also suggest that NIAAA recovery predicts positive short term drinking outcomes.

Percentage of Heavy Drinking Days Following Psilocybin-Assisted Psychotherapy vs Placebo in the Treatment of Adult Patients With Alcohol Use Disorder

Although classic psychedelic medications have shown promise in the treatment of alcohol use disorder (AUD), the efficacy of psilocybin remains unknown. To evaluate whether 2 administrations of high-dose psilocybin improve the percentage of heavy drinking days in patients with AUD undergoing psychotherapy relative to outcomes observed with active placebo medication and psychotherapy. In this double-blind randomized clinical trial, participants were offered 12 weeks of manualized psychotherapy and were randomly assigned to receive psilocybin vs diphenhydramine during 2 day-long medication sessions at weeks 4 and 8. Outcomes were assessed over the 32-week double-blind period following the first dose of study medication. The study was conducted at 2 academic centers in the US. Participants were recruited from the community between March 12, 2014, and March 19, 2020. Adults aged 25 to 65 years with a DSM-IV diagnosis of alcohol dependence and at least 4 heavy drinking days during the 30 days prior to screening were included. Exclusion criteria included major psychiatric and drug use disorders, hallucinogen use, medical conditions that contraindicated the study medications, use of exclusionary medications, and current treatment for AUD. Study medications were psilocybin, 25 mg/70 kg, vs diphenhydramine, 50 mg (first session), and psilocybin, 25-40 mg/70 kg, vs diphenhydramine, 50-100 mg (second session). Psychotherapy included motivational enhancement therapy and cognitive behavioral therapy. The primary outcome was percentage of heavy drinking days, assessed using a timeline followback interview, contrasted between groups over the 32-week period following the first administration of study medication using multivariate repeated-measures analysis of variance. A total of 95 participants (mean [SD] age, 46 [12] years; 42 [44.2%] female) were randomized (49 to psilocybin and 46 to diphenhydramine). One participant (1.1%) was American Indian/Alaska Native, 3 (3.2%) were Asian, 4 (4.2%) were Black, 14 (14.7%) were Hispanic, and 75 (78.9%) were non-Hispanic White. Of the 95 randomized participants, 93 received at least 1 dose of study medication and were included in the primary outcome analysis. Percentage of heavy drinking days during the 32-week double-blind period was 9.7% for the psilocybin group and 23.6% for the diphenhydramine group, a mean difference of 13.9%; (95% CI, 3.0-24.7; F1,86 = 6.43; P = .01). Mean daily alcohol consumption (number of standard drinks per day) was also lower in the psilocybin group. There were no serious adverse events among participants who received psilocybin. Psilocybin administered in combination with psychotherapy produced robust decreases in percentage of heavy drinking days over and above those produced by active placebo and psychotherapy. These results provide support for further study of psilocybin-assisted treatment for AUD. ClinicalTrials.gov Identifier: NCT02061293.

Using peers to increase veterans' engagement in a smartphone application for unhealthy alcohol use: A pilot study of acceptability and utility.

Mobile apps can only increase access to alcohol treatment if patients actively engage with them. Peers may be able to facilitate such engagement by providing supportive accountability and instruction and encouragement for app use. We developed a protocol for peers to support engagement in the Stand Down app for unhealthy alcohol use in veterans and tested the acceptability and utility of the protocol. Thirty-one veteran primary care patients who screened positive for unhealthy alcohol use and were not currently in addiction treatment were given access to Stand Down for four weeks and concurrently received weekly phone support from a Department of Veterans Affairs peer specialist to facilitate engagement with the app. App usage was extracted daily, and pre/post treatment assessments measured changes in drinking patterns, via the Timeline Followback interview, and satisfaction with care, via quantitative and qualitative approaches. A priori benchmarks for acceptability were surpassed: time spent in the app (M = 93.89 min, SD = 92.1), days of app use (M = 14.05, SD = 8.0), and number of daily interviews completed for tracking progress toward a drinking goal (M = 12.64, SD = 9.7). Global satisfaction, per the Client Satisfaction Questionnaire, was high (M = 26.4 out of 32, SD = 4.5). Pre to post, total standard drinks in the prior 30 days (MPre = 142.7, MPost = 85.6), Drinks Per Drinking Day (MPre = 5.4, MPost = 4.0), and Percent Heavy Drinking Days (MPre = 35.3%, MPost = 20.1%) decreased significantly (ps < .05). Findings indicate that Peer-Supported Stand Down is highly acceptable to veteran primary care patients and may help reduce drinking in this population. A larger controlled trial of this intervention is warranted. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Ibudilast for alcohol use disorder: study protocol for a phase II randomized clinical trial

BackgroundAlcohol use disorder (AUD) is a chronic and relapsing condition for which current pharmacological treatments are only modestly effective. The development of efficacious medications for AUD remains a high research priority with recent emphasis on identifying novel molecular targets for AUD treatment and to efficiently screen new compounds aimed at those targets. Ibudilast, a phosphodiesterase inhibitor, has been advanced as a novel addiction pharmacotherapy that targets neurotrophin signaling and neuroimmune function.MethodsThis study will conduct a 12-week, double-blind, placebo controlled randomized clinical trial of ibudilast (50 mg BID) for AUD treatment. We will randomize 132 treatment-seeking men and women with current AUD. We will collect a number of alcohol consumption outcomes. Primary among these is percent heavy drinking days (PHDD); secondary drinking outcomes include drinks per day, drinks per drinking day, percent days abstinent, percent subjects with no heavy drinking days, and percent subjects abstinent, as well as measures of alcohol craving and negative mood. Additionally, participants will have the option to opt-in to a neuroimaging session in which we examine the effects of ibudilast on neural activation to psychosocial stress and alcohol cues. Finally, we will also collect plasma levels of proinflammatory markers, as well as subjective and biological (salivary cortisol) markers of stress response.DiscussionThis study will further develop ibudilast, a safe and promising novel compound with strong preclinical and clinical safety data for AUD, and will probe biological mechanisms underlying the effects of Ibudilast on stress, neuroinflammation, and alcohol cue-reactivity and craving. If ibudilast proves superior to placebo in this study, it will set the stage for a confirmatory multi-site trial leading to FDA approval of a novel AUD treatment.Trial registrationClinicalTrials.gov NCT03594435 “Ibudilast for the Treatment of Alcohol Use Disorder”. Registered on 20 July 2018.

Oxytocin attenuates neural response to emotional faces in social drinkers: an fMRI study

IntroductionOxytocin is a key mediator of emotional and social behavior that seems to be of relevance for the development and maintenance of addictive behaviors. We thus investigated the effect of oxytocin on neural response and behavior during a face-matching task in a sample of social drinkers.MethodsThirteen social drinkers underwent a randomized double-blind placebo-controlled cross-over functional magnetic resonance imaging face-matching task with and without prior intranasal application of 24 international units oxytocin. Effects of oxytocin and task condition (faces, shapes) on brain activation and individual task performance were assessed.ResultsFace-matching compared to shape-matching trials resulted in higher brain activation in the bilateral amygdala, hippocampus and parts of the occipital gyri. Oxytocin application vs. placebo reduced activation in bilateral amygdala, parts of the frontal gyri, and the parietal lobe. Region of interest analyses indicated that the oxytocin-induced attenuation of amygdala response was specific to face-stimuli and associated with lower subjective alcohol craving, and a lower percentage of heavy-drinking days (defined as ≥ 5 standard drinks/day).ConclusionFor the first time, we could show that a larger oxytocin-induced attenuation of amygdala response to fearful faces is associated with lower subjective craving for alcohol and percentage of heavy drinking days in social drinkers. Modulation of amygdala activation, induced by emotional stimuli, might represent a neurobiological substrate of oxytocin’s protective effects on drug seeking behavior.

Longitudinal Findings from a Randomized Clinical Trial of Varenicline for Alcohol Use Disorder with Comorbid Cigarette Smoking.

This study is the first to examine longitudinal posttreatment outcomes of a placebo-controlled trial of varenicline for alcohol use disorder (AUD) with comorbid cigarette smoking. Participants were 131 adults (n=39 female) seeking alcohol treatment in a randomized, double-blind, parallel group, placebo-controlled, 16-week multisite trial of varenicline combined with medical management (MM). Timeline follow-back assessments of alcohol and smoking behavior were conducted at the end of treatment (4months), with follow-ups at 6, 9, and 12months. Outcomes were percentage of heavy drinking days (PHDD), percent of participants with no heavy drinking days (NHDD), cotinine-confirmed prolonged smoking abstinence (PA), and good clinical outcome on either NHDD or PA. Treatment improvements were maintained posttreatment. For the sample overall, PHDD or NHDD did not differ significantly by treatment condition (ps>0.13), but varenicline produced higher rates of PA versus placebo at 4, 9, and 12months (p<0.05). Significant differences were observed by sex: Males had higher rates of NHDD with varenicline (28.9%) versus placebo (6.4%) at the end of treatment (p=0.004), and these effects were maintained at 12months (varenicline: 40.0% vs. placebo: 19.2%, p=0.03). Higher rates of PA were seen for varenicline in both males (8.9%) and females (21.1%) versus placebo (males/females: 0%) at the end of treatment (p=0.05), and this effect was maintained at 12months for females (varenicline: 21.1% vs. placebo, 0.0%, p=0.05). Varenicline treatment combined with MM appears to have enduring benefits for patients with co-occurring AUD and cigarette smoking, and these effects may differ by sex.

Consumption outcomes in clinical trials of alcohol use disorder treatment: Consideration of standard drink misestimation

ABSTRACTBackground. The Food and Drug Administration recently added a new clinical endpoint for evaluating the efficacy of alcohol use disorder (AUD) treatment that is more inclusive of treatment goals besides abstinence: no heavy drinking days (NHDD). However, numerous critiques have been noted for such binary models of treatment outcome. Further, there is mounting evidence that participants inaccurately estimate the quantities of alcohol they consume during drinking episodes (i.e., drink size misestimation), which may be particularly problematic when using a binary criterion (NHDD) compared to a similar, continuous alternative outcome variable: percent heavy drinking days (PHDD). Yet, the impact of drinking misestimation on binary (e.g., NHDD) versus continuous outcome variables (e.g., PHDD) has not been studied.Objectives. Using simulation methods, the present study examined the potential impact of drink size misestimation on NHDD and PHDD.Methods. Data simulations were based on previously published findings of the amount of error in how much alcohol is actually poured when estimating standard drinks. We started with self-reported daily drinking data from COMBINE study participants with complete data (N = 888; 68.1% male), then simulated inaccuracy in those estimations based on literature on standard drink size misestimation.Results. Clinical trial effect sizes were consistently lower for NHDD than for PHDD. Drink size misestimation further lowered effect sizes for NHDD and PHDD.Conclusions. Drink size misestimation may lead to inaccurate conclusions about drinking outcomes and the comparative effectiveness of AUD treatments, including inflated type-II error rates, particularly when treatment “success” is defined by binary outcomes such as NHDD.

Elucidating the Effect of a Brief Drinking Intervention Using Neuroimaging: A Preliminary Study.

Brief interventions have empirical support for acutely reducing alcohol use among non-treatment-seeking heavy drinkers. Neuroimaging techniques allow for the examination of the neurobiological effect of behavioral interventions, probing brain systems putatively involved in clinical response to treatment. Few studies have prospectively evaluated whether psychosocial interventions attenuate neural cue reactivity that in turn reduces drinking in the same population. This study aimed to examine the effect of a brief intervention on drinking outcomes, neural alcohol cue reactivity, and the ability of neural alcohol cue reactivity to prospectively predict drinking outcomes. Non-treatment-seeking heavy drinking participants were randomized to receive a brief interview intervention (n=22) or an attention-matched control (n=24). Immediately following the intervention or control, participants underwent a functional magnetic resonance imaging scan comprised of the alcohol taste cues paradigm. Four weeks after the intervention (or control), participants completed a follow-up visit to report on their past-month drinking. Baseline and follow-up percent heavy drinking days (PHDD) were calculated for each participant. There was no significant effect of the brief intervention on PHDD at follow-up or on modulating neural activation to alcohol relative to water taste cues. There was a significant association between neural response to alcohol taste cues and PHDD across groups (Z>2.3, p<0.05), such that individuals who had greater neural reactivity to alcohol taste cues in the precuneus and prefrontal cortex (PFC) had fewer PHDD at follow-up. This study did not find an effect of the brief intervention on alcohol use in this sample, and the intervention was not associated with differential neural alcohol cue reactivity. Nevertheless, greater activation of the precuneus and PFC during alcohol cue exposure predicted less alcohol use prospectively suggesting that these neural substrates subserve the effects of alcohol cues on drinking behavior.

Nicotine-Use/Smoking Is Associated with the Efficacy of Naltrexone in the Treatment of Alcohol Dependence.

The opioid antagonist naltrexone is not efficacious for every alcohol treatment seeker. However, various individual factors, such as genetic differences and nicotine-use/smoking status, have been suggested as predictors of naltrexone response. In a randomized clinical trial, we previously reported that nicotine-use/smoking status might be a stronger predictor of naltrexone efficacy than OPRM1 A118G single nucleotide polymorphism (SNP) genotype. In this report, we further characterize the nicotine-users in that trial, examine other drinking outcomes, examine the influence of smoking change on naltrexone effects on drinking, and validate the result in smokers with disialo carbohydrate-deficient transferrin (%dCDT) change as an independent biomarker of response. Individuals (n=146) meeting DSM-IV criteria for alcohol dependence who were genotyped for the OPRM1 A118G SNP and who did, or did not, use nicotine/cigarettes were randomized, in a balanced fashion, to naltrexone (50mg/d) or placebo and provided medical management (MM) over a 16-week clinical trial. Alcohol use and smoking during the trial were assessed and analyzed. Nicotine-use/smoking status significantly interacted with medication in reducing percent heavy drinking days (PHDD) during the trial (p=0.003), such that nicotine-users/smokers showed significantly lower PHDD on naltrexone versus placebo (p=0.0001, Cohen's d=0.89), while nonusers showed no significant difference between naltrexone and placebo (p=0.95, Cohen's d=0.02). Similar effects were shown for drinks per day and percent days drinking. The superiority of naltrexone over placebo on PHDD reduction in nicotine-users/smokers was confirmed with %dCDT (Cohen's d range 0.3 to 0.9 over the study). Naltrexone did not significantly change cigarette use in smokers, and change in use did not influence naltrexone's effect on PHDD. These data confirm past findings that naltrexone is more efficacious in those who use nicotine/cigarettes. Compared to previous work on the OPRM1 A118G SNP, it appears that nicotine-use might be a more salient predictor of naltrexone treatment response. While naltrexone did not change cigarette use during the study, and smoking change was not related to alcohol reduction, it should be noted that participants were not seeking smoking cessation and MM did not address this issue.

Automatic avoidance tendencies for alcohol cues predict drinking after detoxification treatment in alcohol dependence.

Alcohol dependence is characterized by conflict between approach and avoidance motivational orientations for alcohol that operate in automatic and controlled processes. This article describes the first study to investigate the predictive validity of these motivational orientations for relapse to drinking after discharge from alcohol detoxification treatment in alcohol-dependent patients. One hundred twenty alcohol-dependent patients who were nearing the end of inpatient detoxification treatment completed measures of self-reported (Approach and Avoidance of Alcohol Questionnaire; AAAQ) and automatic (modified Stimulus-Response Compatibility task) approach and avoidance motivational orientations for alcohol. Their drinking behavior was assessed via telephone follow-ups at 2, 4, and 6 months after discharge from treatment. Results indicated that, after controlling for the severity of alcohol dependence, strong automatic avoidance tendencies for alcohol cues were predictive of higher percentage of heavy drinking days (PHDD) at 4-month (β = 0.22, 95% CI [0.07, 0.43]) and 6-month (β = 0.22, 95% CI [0.01, 0.42]) follow-ups. We failed to replicate previous demonstrations of the predictive validity of approach subscales of the AAAQ for relapse to drinking, and there were no significant predictors of PHDD at 2-month follow-up. In conclusion, strong automatic avoidance tendencies predicted relapse to drinking after inpatient detoxification treatment, but automatic approach tendencies and self-reported approach and avoidance tendencies were not predictive in this study. Our results extend previous findings and help to resolve ambiguities with earlier studies that investigated the roles of automatic and controlled cognitive processes in recovery from alcohol dependence.

Cannabis use during treatment for alcohol use disorders predicts alcohol treatment outcomes.

To compare post-treatment alcohol use between those who use cannabis and those who abstain during treatment for alcohol use disorders (AUD); and to examine potential cannabis use thresholds by comparing post-treatment alcohol use between four frequency groups of cannabis users relative to abstainers. Secondary analyses of the Combined Pharmacotherapies and Behavioral Interventions (COMBINE) Study, a randomized control trial of AUD treatments. The current study compares longitudinal drinking data between those who used cannabis versus those who abstained during COMBINE treatment. The COMBINE Study treatments were delivered on an out-patient basis for 16weeks. The current analyses include 206 cannabis users and 999 cannabis abstainers. All participants met diagnosis of primary alcohol dependence (n=1383). Primary exposures were any cannabis use and quartiles of cannabis use (Q1: 1-4 use days during treatment, Q2: 5-9days, Q3: 10-44days, Q4: 45-112days). Outcomes were percentage of days abstinent from alcohol (PDA), drinks per drinking day (DPDD) and percentage of heavy drinking days (PHD), all measured at treatment end and 1year post-treatment. Compared with no cannabis use, any cannabis use during treatment was associated with 4.35% [95% confidence interval (CI)=-8.68, -0.02], or approximately 4 fewer alcohol abstinent days at the end of treatment. This association weakened by 1 year post-treatment (95% CI=-9.78, 0.54). Compared with no cannabis use, only those in the second quartile of cannabis use (those who used once or twice per month during treatment) had 8.81% (95% CI=-17.00, -0.63), or approximately 10 fewer days alcohol abstinent at end of treatment, and 11.82% (95% CI=-21.56, -2.07), or approximately 13 fewer alcohol abstinent days 1 year post-treatment. Neither any cannabis use nor quartiles were associated with DPDD or PHD at either time-point. Among individuals in alcohol treatment, any cannabis use (compared with none) is related to a significantly lower percentage of days abstinent from alcohol post-treatment, although only among those who used cannabis once or twice per month.

Subgroup Identification in Personalized Treatment of Alcohol Dependence.

Identification of patient subgroups to enhance treatment effects is an important topic in personalized (or tailored) alcohol treatment. Recently, several recursive partitioning methods have been proposed to identify subgroups benefiting from treatment. These novel data mining methods help to address the limitations of traditional regression-based methods that focus on interactions. We propose an exploratory approach, using recursive partitioning methods, for example, interaction trees (IT) and virtual twins (VT), to flexibly identify subgroups in which the treatment effect is likely to be large. We apply these tree-based methods to a pharmacogenetic trial of ondansetron. Our methods identified several subgroups based on patients' genetic and other prognostic covariates. Among the 251 subjects with complete genotype information, the IT method identified 118 with specific genetic and other prognostic factors, resulting in a 17.2% decrease in the percentage of heavy drinking days (PHDD). The VT method identified 88 subjects with a 21.8% decrease in PHDD. Overall, the VT subgroup achieved a good balance between the treatment effect and the group size. A data mining approach is proposed as a valid exploratory method to identify a sufficiently large subgroup of subjects that is likely to receive benefit from treatment in an alcohol dependence pharmacotherapy trial. Our results provide new insights into the heterogeneous nature of alcohol dependence and could help clinicians to tailor treatment to the biological profile of individual patients, thereby achieving better treatment outcomes.

Posttreatment effects of topiramate treatment for heavy drinking.

We examined whether the effects of topiramate and a single nucleotide polymorphism (rs2832407) in GRIK1, which encodes a kainate receptor subunit, persisted following a 12-week, placebo-controlled trial in 138 heavy drinkers with a treatment goal of reduced drinking. During treatment, topiramate 200mg/d significantly reduced heavy drinking days and increased the frequency of abstinent days (Am J Psychiatry, 2014, 171:445). In the European-American (EA) subsample (n=122), rs2832407 moderated the treatment effect on heavy drinking. Patients were re-interviewed 3 and 6months after the end of treatment. During treatment, we obtained 92.4% of drinking data, with 89.1 and 85.5% complete data at the 3- and 6-month follow-up visits, respectively. We examined 4 outcomes over time in the overall sample and the EA subsample: percent heavy drinking days (PHDD), percent days abstinent (PDA), serum γ-glutamyl transpeptidase (GGTP) concentration, and a measure of alcohol-related problems. In the full sample, the lower PHDD and higher PDA seen with topiramate treatment were no longer significant during follow-up. Nonetheless, the topiramate-treated patients had lower alcohol-related problem scores during treatment and both follow-up periods. Further, in the EA subsample, the greater reduction in PHDD seen with topiramate treatment in rs2832407*C-allele homozygotes persisted throughout follow-up, with no significant effects in A-allele carriers. A reduction in GGTP concentration was consistent with the reduction in heavy drinking, but did not reach statistical significance. There are persistent therapeutic effects of topiramate in heavy drinkers, principally in rs2832407*C-allele homozygotes.

Web intervention for OEF/OIF veterans with problem drinking and PTSD symptoms: A randomized clinical trial.

Veterans who served in Operation Enduring Freedom (OEF) and Operation Iraqi Freedom (OIF) commonly experience alcohol misuse and symptoms of posttraumatic stress disorder (PTSD) following their return from deployment to a war zone. We conducted a randomized clinical trial to evaluate the efficacy of a newly developed, 8-module, self-management web intervention (VetChange) based on motivational and cognitive-behavioral principles to reduce alcohol consumption, alcohol-related problems, and PTSD symptoms in returning combat veterans. Six hundred participants, recruited through targeted Facebook ads, were randomized to either an Initial Intervention Group (IIG; n = 404) or a Delayed Intervention Group (DIG; n = 196) that waited 8 weeks for access to VetChange. Primary outcome measures were Drinks per Drinking Day, Average Weekly Drinks, Percent Heavy Drinking Days, and PTSD symptoms. Intent-to-treat analyses compared changes in outcome measures over time between IIG and DIG as well as within-group changes. IIG participants demonstrated greater reductions in drinking (p < .001 for each measure) and PTSD symptoms (p = .009) between baseline and end-of-intervention than did DIG participants between baseline and the end of the waiting period. DIG participants showed similar improvements to those in IIG following participation in VetChange. Alcohol problems were also reduced within each group between baseline and 3-month follow-up. Results indicate that VetChange is effective in reducing drinking and PTSD symptoms in OIF/OEF veterans. Further studies of VetChange are needed to assess web-based recruitment and retention methods and to determine VetChange's effectiveness in demographic and clinical sub-populations of returning veterans.

Ethnicity as a moderator of motivational interviewing for incarcerated adolescents after release

Motivational interviewing (MI) has been found to be an effective treatment for substance using populations, including incarcerated adolescents. Although some studies suggest MI is more successful with individuals from minority backgrounds, the research remains mixed. The current study investigated the impact of ethnicity on treatment in reducing alcohol and marijuana use among incarcerated adolescents. Adolescents (14–19years of age) were recruited from a state juvenile correctional facility and randomly assigned to receive MI or relaxation therapy (RT) (N=147; 48 White, 51 Hispanic, and 48 African American; 126 male; 21 female). Interviews were conducted at admission to the facility and 3months after release. Results suggest that the effects of MI on treatment outcomes are moderated by ethnicity. Hispanic adolescents who received MI significantly decreased total number of drinks on heavy drinking days (NDHD) and percentage of heavy drinking days (PHDD) as compared to Hispanic adolescents who received RT. These findings suggest that MI is an efficacious treatment for an ethnic minority juvenile justice-involved population in need of evidence-based treatments.

Temporal patterns of adherence to medications and behavioral treatment and their relationship to patient characteristics and treatment response

BackgroundThe primary analyses of the COMBINE Study revealed significant naltrexone and Combined Behavioral Intervention (CBI) main effects on drinking outcomes but failed to find additional benefits of the combination of treatments. Investigating differences in patterns of adherence over time may shed light on the treatment effects in COMBINE. The goals of the study were to identify trajectories of medication adherence and participation in CBI, to estimate predictive and moderating effects of adherence trajectories on drinking outcomes and to characterize subjects in adherence trajectories. The results of these analyses may suggest approaches to improving adherence in order to ultimately improve treatment outcome. MethodsWe used a trajectory-based approach to identify patterns of treatment adherence separately for naltrexone, acamprosate and CBI adherence. Logistic regression and general linear models assessed associations among adherence trajectories, drinking outcomes and patient characteristics. ResultsThree trajectories of adherence were identified for each treatment: “excellent adherers”, “late non-adherers” and “early non-adherers” and there was good agreement among adherence trajectories with different treatments. “Excellent adherers” had significantly higher percent days abstinent (PDA) and lower percent heavy drinking days (PHDD). CBI significantly decreased PHDD for subjects on acamprosate in the “early non-adherers with medication” trajectory (p=0.01). Either naltrexone or acamprosate was associated with lower PHDD than placebo for “early non-adherers with CBI” (p<0.01). Receiving active medication decreased the likelihood to be in the excellent medication adherence trajectory. Younger age, greater drinking severity, dissatisfaction with the medicine and session frequency, adverse events and lack of benefit were related to less favorable medication adherence trajectories. “Excellent adherers with CBI” were significantly more satisfied with the CBI counselor. ConclusionsPatterns of treatment adherence appear to be a participant characteristic. Individuals who fail to adhere early in treatment have worse outcomes regardless of treatment. However, treatment outcomes of participants who exhibit early problems with adherence to one treatment modality could potentially be improved by offering an alternative behavioral or pharmacologic treatment.

Simultaneous Modeling of the Impact of Treatments on Alcohol Consumption and Quality of Life in the COMBINE Study: A Coupled Hidden Markov Analysis

Clinical trials for alcoholism have historically regarded alcohol consumption as the primary outcome. In a subset of trials, quality of life (QOL) has been considered as a secondary outcome. Joint latent-variable modeling techniques may provide a more accurate and powerful simultaneous analysis of primary and secondary outcomes in clinical trials. The goal of this study was to evaluate longitudinal associations between treatment status, alcohol consumption, and QOL in the Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence (COMBINE) study. A total of 1,383 alcohol-dependent patients were randomized to 9 treatment groups. Percent heavy drinking days (PHDD) and health-related QOL from the 30days preceding baseline, week 16, and week 52 were calculated using the Form 90 and the Medical Outcomes Study Health Survey Short Form-12 (SF-12), respectively. Latent profile analysis (LPA) was conducted to determine an appropriate number of latent states to represent PHDD and QOL. Subsequently, univariate and coupled hidden Markov models (for PHDD and SF-12 mental health, and PHDD and SF-12 physical) were fit to the data. LPA suggested that PHDD should be represented by 3 latent states and that each SF-12 scale should be represented by 2 states. Joint modeling results suggested that (i) naltrexone significantly predicted decreased PHDD (p<0.05), and marginally predicted improved mental health QOL via decreased PHDD (p<0.10), and (ii) that the combinations of naltrexone and combined behavioral intervention (CBI), and acamprosate and CBI, each predicted significantly improved physical QOL (p<0.05), and marginally predicted decreased PHDD via improved physical QOL (p<0.10). This study illustrates a powerful and novel statistical approach for simultaneously evaluating the impact of treatments on primary and secondary outcomes in clinical trials. This study also suggests that behavioral interventions may impact drinking behavior through their ameliorative effects on QOL.