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Graphic warning labels (GWLs) on cigarette packs have been adopted by many jurisdictions worldwide. In the US, the introduction of GWLs has been delayed by claims that their high level of negative emotional arousal unnecessarily infringed on the tobacco manufacturers' free speech. This study aimed to provide experimental data on the contribution of emotional arousal to GWL efficacy.Observational study using long-term naturalistic exposure and functional magnetic resonance imaging.Research university in Philadelphia, PA, USA.168 adult smokers.For 4 weeks, participants received cigarettes in packs that carried either high-arousal or low-arousal GWLs (N=84 vs. 84). Smoking behavior, quitting-related cognitions and GWL-induced brain response were measured before and after the 4-week exposure. The amygdala and medial prefrontal cortex served as regions of interest.Compared with the high-arousal group, the low-arousal group smoked fewer cigarettes (log10-transformed, 1.076 vs. 1.019; difference=0.056, 95% confidence interval=[0.027,0.085], χHigh-arousal cigarette graphic warning labels (GWLs) appear to be less efficacious than low-arousal GWLs. The high emotional reaction that high-arousal GWLs elicit wanes over time. Baseline amygdala response negatively predicts efficacy of high-arousal GWLs and positively predicts efficacy of low-arousal GWLs. High emotional arousal may not be required for GWLs' sustained efficacy.

In a previous study, ondansetron, a serotonin 5-HTIn this 16-week, double-blind, placebo-controlled, parallel-group clinical trial, adults with AUD were randomized to receive low-dose oral ondansetron (0.33 mg twice daily) or placebo stratified by "responsive" versus "nonresponsive" genotype defined using population-specific genotypes at the three genetic loci. Generalized estimating equation regression models and a modified intent-to-treat analysis were used to compare the treatment groups on the primary outcome-DPDD-and two secondary outcomes-heavy drinking days per week [HDD] and drinks per day [DPD] across the 16 weeks of treatment.Of 296 prospective participants screened, 95 (58 EA and 37 AA) were randomized and received at least one dose of study medication. In the modified intent-to-treat analysis, the ondansetron group averaged 0.40 more DPDD (p = 0.51), 1.35 times as many HDD (p = 0.16), and 1.06 times as many DPD (p = 0.59) as the placebo group. There were no significant interactions with genotype. There were no study-related serious adverse events (AEs) and similar proportions of participants in the two treatment groups experienced AEs across organ systems.We found no evidence that low-dose oral ondansetron is beneficial in the treatment of AUD, irrespective of genotype, thus failing to confirm prior study findings. However, the study was underpowered to identify medication by genotype interactions.

Sequential, multiple assignment, randomized trials (SMARTs) compare sequences of treatment decision rules called dynamic treatment regimes (DTRs). In particular, the Adaptive Treatment for Alcohol and Cocaine Dependence (ENGAGE) SMART aimed to determine the best DTRs for patients with a substance use disorder. While many authors have focused on a single pairwise comparison, addressing the main goal involves comparisons of >2 DTRs. For complex comparisons, there is a paucity of methods for binary outcomes. We fill this gap by extending the multiple comparisons with the best (MCB) methodology to the Bayesian binary outcome setting. The set of best is constructed based on simultaneous credible intervals. A substantial challenge for power analysis is the correlation between outcome estimators for distinct DTRs embedded in SMARTs due to overlapping subjects. We address this using Robins’ G-computation formula to take a weighted average of parameter draws obtained via simulation from the parameter posteriors. We use non-informative priors and work with the exact distribution of parameters avoiding unnecessary normality assumptions and specification of the correlation matrix of DTR outcome summary statistics. We conduct simulation studies for both the construction of a set of optimal DTRs using the Bayesian MCB procedure and the sample size calculation for two common SMART designs. We illustrate our method on the ENGAGE SMART. The R package SMARTbayesR for power calculations is freely available on the Comprehensive R Archive Network (CRAN) repository. An RShiny app is available at https://wilart.shinyapps.io/shinysmartbayesr/.

In a prior study, topiramate reduced heavy drinking among individuals who sought to reduce their drinking, with the effect moderated by a single nucleotide polymorphism (SNP; rs2832407) in GRIK1, which encodes the kainate GluK1 receptor subunit (Kranzler et al. 2014). The present study sought to replicate prospectively the effect of topiramate and rs2832407 in patients with DSM-5 alcohol use disorder (AUD) who sought to reduce or stop their drinking. We stratified the randomization on genotype (rs2832407*C-allele homozygotes vs. A-allele carriers) and assigned 170 European-American participants (71.2% male) to receive 12 weeks of treatment with topiramate (N = 85), at a maximal daily dosage of 200 mg, or matching placebo (N = 85). At each of nine treatment visits participants received brief counseling to reduce drinking and increase abstinent days. We hypothesized that topiramate-treated patients with the rs2832407*CC genotype would reduce heavy drinking days (HDDs) more than the other three groups. The rate of treatment completion was 91.8% in both groups. The mean number of HDDs per week in the placebo group was 1.67 (95% CI = (1.29, 2.16), p = 0.0001) times greater than in the topiramate group, which was confirmed by the topiramate group’s significantly greater reduction in the concentration of the liver enzyme γ-glutamyltransferase and lower alcohol-related problems score. There was no significant difference in topiramate’s effect on HDDs between genotype groups. Although consistent with other studies showing a reduction in heavy drinking with topiramate treatment, the prior finding of a moderating effect of rs2832407 genotype was not replicated in this prospective trial.

Topiramate, a GABA/glutamate modulator, is efficacious in reducing alcohol consumption, though the mechanisms underlying this effect are not well characterized. This study analyzed functional magnetic resonance imaging (fMRI) data from 22 heavy drinkers enrolled in a 12-week placebo-controlled, randomized clinical trial of topiramate to examine the effects of topiramate on alcohol cue-elicited brain responses, craving, and heavy drinking in individuals with DSM-5 alcohol use disorder. Patients were randomized to receive either topiramate (maximal daily dosage of 200 mg/day) or placebo and were administered an fMRI alcohol cue-reactivity task at baseline (before starting medication) and after 6 weeks of double-blind treatment. Analyses compared the topiramate (n = 12) and placebo (n = 8) groups on (1) the change in brain responses during alcohol cue exposure (vs non-alcohol cues) within five a priori regions of interest related to reward—the bilateral and medial orbitofrontal cortex (OFC) and bilateral ventral striatum (VS) and (2) change in craving and heavy drinking days (HDDs) from baseline and scan 2. Topiramate, relative to placebo, reduced alcohol cue-elicited activation of the left VS, bilateral OFC, and medial OFC, alcohol cue-elicited craving, and HDDs between baseline and 6 weeks of treatment. The reduction in alcohol cue-elicited activation in the medial OFC correlated with reductions in craving, and reduced activation in the right VS, right OFC, and medial OFC correlated with the reduction in HDD. This preliminary study provides evidence that topiramate’s attenuation of alcohol cue-elicited brain activation and craving are key elements of the drug’s neurobiological mechanism of action in reducing heavy drinking.

Background Buprenorphine treatment is not equally effective in all patients with opioid use disorder (OUD). Two retrospective studies showed that, among African Americans (AAs), rs678849, a polymorphism in the delta-opioid receptor gene, moderated the therapeutic effect of sublingual buprenorphine. Methods We examined rs678849 as a moderator of the response to an extended-release subcutaneous buprenorphine formulation (BUP-XR) in a 24-week OUD treatment study of 127 AAs and 327 European Americans (EAs). Participants were randomly assigned to receive: (1) BUP-XR as 2 monthly injections of 300 mg followed by either 300 mg monthly or 100 mg monthly for 4 months, or (2) monthly volume-matched placebo injections. Generalized estimating equations logistic regression analyses tested, per population group, the main and interaction effects of treatment (BUP-XR vs placebo) and genotype group (rs678849*CC vs CT/TT) on weekly urine drug screens (UDS). Results Among AAs, the placebo group had higher rates of opioid-positive UDS than the BUP-XR group (log odds ratio = 1.67, 95% CI = 0.36, 2.98), but no genotype by treatment effect (P = .80). Among EAs, the placebo group also showed higher rates of opioid-positive UDS than the BUP-XR group (log odds ratio = 1.97, 95% CI = 1.14, 2.79) but a significant genotype by treatment interaction (χ 2(1) = 4.33, P = .04). Conclusion We found a moderating effect of rs678849 on the response to buprenorphine treatment of OUD in EAs, but not AAs. These findings require replication in well-powered, prospective studies of both AA and EA OUD patients treated with BUP-XR and stratified on rs678849 genotype.

In recent years, there has been increased interest in the development of adaptive interventions across various domains of health and psychological research. An adaptive intervention is a protocolized sequence of individualized treatments that seeks to address the unique and changing needs of individuals as they progress through an intervention program. The sequential, multiple assignment, randomized trial (SMART) is an experimental study design that can be used to build the empirical basis for the construction of effective adaptive interventions. A SMART involves multiple stages of randomizations; each stage of randomization is designed to address scientific questions concerning the best intervention option to employ at that point in the intervention. Several adaptive interventions are embedded in a SMART by design; many SMARTs are motivated by scientific questions that concern the comparison of these embedded adaptive interventions. Until recently, analysis methods available for the comparison of adaptive interventions were limited to end-of-study outcomes. The current article provides an accessible and comprehensive tutorial to a new methodology for using repeated outcome data from SMART studies to compare adaptive interventions. We discuss how existing methods for comparing adaptive interventions in terms of end-of-study outcome data from a SMART can be extended for use with longitudinal outcome data. We also highlight the scientific utility of using longitudinal data from a SMART to compare adaptive interventions. A SMART study aiming to develop an adaptive intervention to engage alcohol- and cocaine-dependent individuals in treatment is used to demonstrate the application of this new methodology. (PsycINFO Database Record (c) 2020 APA, all rights reserved).

Comorbidity between posttraumatic stress disorder (PTSD) and substance use disorders (SUD) is common, and both are associated with cognitive dysfunction. However, few studies examine the impact of cognitive deficits on treatment outcomes. Here, we leverage data from a randomized clinical trial of integrated versus phased psychotherapy for SUD and PTSD to examine the relation of cognitive functioning to treatment response.One-hundred and thirteen veterans with co-occurring PTSD and SUD completed Penn Computerized Neurocognitive Battery tests assessing attention, executive control, memory, and spatial processing. Linear mixed-effects models examined interactions between cognitive functioning and time in predicting primary PTSD and SUD outcomes across both treatments.Significant verbal immediate memory by time interactions were found for both PTSD symptoms (p = .01, f 2 = 0.020) and percent heavy drinking or drug use days (p = .004, f 2 = 0.020). There was a significant working memory by time interaction for percent heavy drinking or drug use days (p = .007, f 2 = 0.016). Participants with better verbal memory had greater reductions across time in PTSD symptoms and drinking/drug use, while those with better working memory had lesser reductions in their drinking/drug use across time.Individuals with lower verbal memory functioning had less robust PTSD and SUD symptom reductions in PTSD/SUD psychotherapy, with differences that were generally small in magnitude. Those with better working memory functioning had worse SUD outcomes. Together with prior literature, findings suggest that neurocognitive functioning may impact the effectiveness of PTSD and SUD treatment. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Although the benefits of exercise on Major Depressive Disorder (MDD) are well established, longitudinal studies of objectively measured activity in clinical populations are needed to establish specific guidelines for exercise by persons with moderate-to-severe depression. This study examines the association between objectively assessed daily step count and depressive symptoms over a 24-week follow- up period in outpatients receiving treatment for moderate-to-severe depression.Participants were US Veterans with MDD enrolled in the Precision Medicine in Mental Health Care study (PRIME Care), a pragmatic, multi-site, randomized, controlled trial that examines the utility of genetic testing in the context of pharmacotherapy for MDD. Participants were a subset (N = 66) enrolled in actigraphy (using GT9X ActiGraph) monitoring component of the trial. Daily steps were examined as a predictor of depressive symptoms over 4-, 8-, 12-, 18-, and 24-weeks.On average, participants took 3,460 (±1,768) steps per day. In generalized linear mixed models, an increase in 1,000 steps per day was associated with a 0.6-point decrease in depressive symptom severity at the subsequent follow-up assessment.Activity monitoring was observational and causal inferences cannot be made between daily steps and subsequent depressive symptom severity. Results may not generalize to non-treatment-seeking populations.Study findings provide an initial metric for persons with clinically significant MDD, of whom most do not get sufficient daily activity. The findings can inform future trials aimed at determining how much daily activity is needed to improve symptoms in individuals with MDD.

Adherence is a major factor in the effectiveness of the injectable extended-release naltrexone as a relapse prevention treatment in opioid use disorder. We examined the value of a variant of the Go/No-go paradigm in predicting extended-release naltrexone adherence in 27 detoxified opioid use disorder patients who were offered up to 3 monthly extended-release naltrexone injections. Before extended-release naltrexone, participants performed a Go/No-go task that comprised positively valenced Go trials and negatively valenced No-go trials during a functional magnetic resonance imaging scan. Errors of commission and neural responses to the No-go vs Go trials were independent variables. Adherence, operationalized as the completion of all 3 extended-release naltrexone injections, was the outcome variable. Fewer errors of commission and greater left accumbal response during the No-go vs Go trials predicted better adherence. These findings support the clinical potential of the behavioral and neurophysiological correlates of response inhibition in the prediction of extended-release naltrexone treatment outcomes in opioid use disorder.

IntroductionMentholated tobacco cigarettes are believed to be more addictive than non-menthol ones. Packaging of most menthol cigarette brands includes distinctive green hues, which may act as conditioned stimuli (ie, cues) and promote menthol smoking. To examine the cue properties of menthol cigarette packaging, we used a priming paradigm to assess the effect of packaging on the neural substrates of smoking cue reactivity. We hypothesised that menthol packaging will exert a specific priming effect potentiating smoking cue reactivity in menthol compared with non-menthol smokers.MethodsForty-two menthol and 33 non-menthol smokers underwent functional MRI while viewing smoking and neutral cues. The cues were preceded (ie, primed) by briefly presented images of menthol or non-menthol cigarette packages. Participants reported craving for cigarettes in response to each cue.ResultsMenthol packaging induced greater frontostriatal and occipital smoking cue reactivity in menthol smokers than in non-menthol smokers. Menthol packaging also enhanced the mediation by neural activity of the relationship between cue exposure and cigarette craving in menthol but not non-menthol smokers. Dynamic causal modelling showed stronger frontostriatal-occipital connectivity in response to menthol packaging in menthol compared with non-menthol smokers. The effects of non-menthol packaging did not differ between categories of smokers.ConclusionsOur findings demonstrate heightened motivational and perceptual salience of the green-hued menthol cigarette packaging that may exacerbate menthol smokers’ susceptibility to smoking cues. These effects could contribute to the greater addiction severity among menthol smokers and could be considered in the development of science-based regulation and legal review of tobacco product marketing practices.

BACKGROUND AND AIMS Management of alcohol use disorder (AUD) could be enhanced by effective remote treatments. Study tested whether supplementing intensive outpatient programs (IOPs) with continuing care delivered via: (1) telephone, (2) smartphone, or (3) their combination improves outcomes relative to (4) IOP only. Continuing care conditions were also compared. DESIGN Randomized controlled trial of 4 groups with 3, 6, 9, 12, and 18-month follow-ups. SETTING University research center in Philadelphia, Pennsylvania, USA. PARTICIPANTS Participants (N=262) met DSM-V criteria for AUD, were largely male (71%) and African-American (82%). INTERVENTIONS AND COMPARATOR Telephone Monitoring and Counseling (TMC; N=59), Addiction Comprehensive Health Enhancement Support System (ACHESS; N=68), and TMC+ACHESS (N=70) provided for 12 months. The control condition received IOP only (TAU; N=65). MEASUREMENT Primary outcome was percent days heavy drinking (PDHD) in months 1-12. Secondary outcomes were any drinking, any drug use, drinking consequences, and quality of life. FINDINGS Mean PDHD in months 1-12 was 10.29 in TAU, 5.41 in TMC, 6.80 in ACHESS, and 5.99 in TMC+ACHESS. PDHD was lower in TMC (d=.35, p=0.018, 95% confidence interval (CI) = [-1.42, -0.20]), ACHESS (d= .31, p= .031, 95% CI= [-1.27, -0.06]), and TMC+ACHESS (d= .36, p=0.009, 95% CI = [-1.40, -0.20]) than in TAU. Differences between TMC+ACHESS, TMC, and ACHESS were small (d< .06) and non-significant. Findings were inconclusive as to whether or not the treatment conditions differed on PDHD at 18 months. A significant effect was obtained on Any Drinking, which was higher in months 1-12 in TAU than in TMC (odds ratio (OR)= 3.02, standard error (SE)=0.43, 95% CI= [1.30, 6.99], p=0.01) and TMC+ACHESS (OR= 2.43, SE=0.39, 95% CI= [1.12, 5.27], p=0.03). No other significant effects were obtained on other secondary outcomes during or after treatment. CONCLUSIONS A telephone-delivered intervention and a smartphone-delivered intervention, alone and in combination, provided effective remote continuing care for alcohol use disorder. The combination of both interventions was not superior to either alone and effects did not persist post-treatment.

BackgroundPost-traumatic stress disorder (PTSD) is a prevalent, debilitating, and costly psychiatric disorder. Evidenced-based psychotherapies, including Cognitive Processing Therapy (CPT), are effective in treating PTSD, although a fair proportion of individuals show limited benefit from such treatments. CPT requires cognitive demands such as encoding, recalling, and implementing new information, resulting in behavioral change that may improve PTSD symptoms. Individuals with PTSD show worse cognitive functioning than those without PTSD, particularly in acquisition of verbal memory. Therefore, memory dysfunction may limit treatment gains in CPT in some individuals with PTSD.Methods and AnalysisHere, we present a protocol describing the Cognition and PsychoTherapy in PTSD (CPTPTSD) study, a prospective, observational study examining how cognitive functioning affects treatment response in CPT for PTSD (NCT# 03641924). The study aims to recruit 105 outpatient veterans with PTSD between the ages of 18 and 70 years. Prior to beginning 12 sessions of CPT, Veteran participants will have standardized assessments of mood and functioning and complete a comprehensive neurocognitive battery assessing episodic learning, attention and speed of processing, language ability, executive control, and emotional functioning. This study aims to fill gaps in the current literature by: (1) examining the specificity of memory effects on treatment response; (2) exploring how baseline cognitive functioning impacts functional outcomes; and (3) examining potential mechanisms, such as memory for treatment content, that might explain the effects of baseline memory functioning on PTSD symptom trajectory.DiscussionIf successful, this research could identify clinically relevant neurocognitive mechanisms that may impact PTSD psychotherapy and guide the development of individualized treatments for PTSD.

Background: Pharmacogenetic (PGx) testing is a potentially important, but understudied approach to precision medicine that could improve prescribing practices for antidepressants (ADs) in patients with Major Depressive Disorder (MDD). Thus, it is important to understand the scope of its potential impact and to identify patients who may benefit most from PGx-guided care. Methods: Participants were treatment-seeking US veterans (N=1149) with MDD enrolled in the Precision Medicine in Mental Health Care study, a pragmatic multi-site, randomized, controlled trial that examines the utility of PGx testing in the context of pharmacotherapy for MDD. We report the prevalence of ADs with predicted moderate and clinically significant gene-drug interaction potential based on next-intended treatment. We also examined demographic and treatment history characteristics as predictors of the gene-drug interaction potential of participants’ next-intended treatment. Results: Prevalence of the next-intended AD with moderate or clinically significant gene-drug interaction was 45.1% and19.3%. Previous treatment with an AD in the past two years was associated with a 1.59 increased likelihood of having a next-intended AD treatment with predicted clinically significant gene-drug interaction (95% CI: 1.08-2.35). Limitations: The gene-drug interaction potential of ADs is specific to the PGx test panel used in this study and may not generalize to other PGx test panels. Conclusions: PGx testing could benefit one in five patients prescribed ADs with clinically significant gene-drug interaction potential. Patients with prior AD treatment are more likely to have an AD with significant gene-drug interaction potential as their next-intended treatment and therefore may benefit most from PGx testing.

Background Usual treatment for persons with opioid use disorders who are in prison is detoxification with referral to treatment after release but failure to engage in treatment and relapse is common. Starting medication treatment before release might improve outcomes. Objectives Determine if administering extended-release injectable naltrexone (XR-NTX) before release (BR) from prison results in less relapse within the first three months after release than when offered by referral after release (AR). Methods The study randomized 1:1 persons who had an OUD, expressed interest in XR-NTX, and met study admission criteria to receive XR-NTX BR or at a local program AR, with continued medication and counseling available at that program. Results Four-hundred and two persons expressed interest in the study, 222 consented, and the study randomized 146. Uncertainty about release dates resulted in a time lag between randomization and final disposition during which 60 of the randomized patients were sentenced to other facilities, withdrew consent, or became otherwise unavailable for study treatment, leaving 86 for outcome analyses (38, BR; 48 AR). Missed follow-up appointments on the remaining 86 led to development of a phone-based questionnaire to determine presence/absence of relapse. Using it to supplement other data, we were able to confirm relapse or nonrelapse for 63 of the 86 (73%). All BR and a third of the AR patients received their first XR-NTX dose, however dropout was high and nonrelapse by month three was not significantly different between BR (39.5%) and AR (25%) (Chisq (2) = 3.23, p = 0.20). Conclusions BR patients were much more likely to receive medication and its extended relapse and overdose protection effects in the first weeks after release. Dropout was high and the study detected no significant difference in relapse by month 3; however, the less-than-planned number of patients and missing data make this finding inconclusive.

Genomic testing has the potential to improve patient outcomes and reduce patient care costs by personalizing medication selection. Commercial pharmacogenetic (PGx) testing for psychotropic and other medications is widely available and promoted as a means to implement "precision medicine." Despite evidence that genetic variation affects the metabolism of psychotropic medications, the clinical utility of these test results has not been established. Moreover, implementing such testing in routine clinical care is complex, requiring informatics support and a systematic approach to patient and provider education. The PRIME Care program is designed to bridge this gap, applying both clinical trials and implementation science methods to conduct a program of research. It is centered on a large, pragmatic randomized clinical trial (RCT) in which 2000 Veterans with a major depressive disorder (MDD) and their health care providers are randomized together to receive PGx test results at the beginning of an episode of care or 6 months later. We hypothesize that providers who receive the PGx test results will prescribe an antidepressant guided by the PGx findings and Veterans whose care is guided by PGx testing will experience higher rates of remission from MDD. If the results of the trial replicate those of prior PGx studies, which provided preliminary evidence of the utility of PGx guided prescribing, it would strongly support using a precision medicine approach to treat MDD. This program of research is also evaluating dissemination influencers, other biomarkers (e.g., genetic variation associated with depression response), and the health care cost implications of PGx testing. ClinicalTrials.gov Identifier: NCT03170362.

We tested the predictive validity of the Progress Assessment (PA), a brief counselor administered tool for use in measurement-based care for substance use disorders. The PA includes 5 items assessing relapse risk and 5 items assessing factors protective against relapse. Data were drawn from a completed study of continuing care for cocaine dependence (McKay et al., 2013) and includes 12 months of follow-up on158 participants (76% male) who received brief telephone or face-to-face sessions. Each session began with the administration of the PA, followed by cognitive-behavioral counseling tied to the results of the PA and anticipated risky situations. Outcome was assessed via urine toxicology every 3 months. As administered in an effectiveness trial, average PA risk and protective scales within each 3-month segment of the study predicted urine toxicology results at the end of that period, with higher risk scores and lower protective scores predicting greater rates of cocaine positive urine drug screens. PA scores did not predict dropout from continuing care participation. The 10-item PA shows promise as a pragmatic clinical tool for ongoing monitoring during continuing care for substance dependence.

Chronic pain and opioid use are associated with increased risk for suicidal ideation and behaviors (SIB) in cross-sectional studies, particularly among individuals who catastrophize about their pain. This study examined the longitudinal association between two styles of pain coping, catastrophizing and hoping/praying, as predictors of subsequent SIB, as well as possible mediators of this association among patients with chronic pain receiving long-term opioid therapy. Participants (n = 496) were adults with chronic nonmalignant pain on long-term opioid therapy who did not develop an opioid use disorder. Participants were assessed for pain coping, suicidal ideation, depression, social support and pain interference at baseline, and were reassessed for SI, depression, and pain interference at 6- and 12-month follow-ups. Catastrophizing was a significant predictor of increased subsequent SIB, whereas hoping/praying did not protect against future SIB. The relationship between catastrophizing and future SIB was mediated by depression, but not social support or pain interference. In conclusion, catastrophizing was an important predictor of subsequent SIB due to its effect on increasing depression among patients with chronic nonmalignant pain receiving long-term opioid therapy. Future research should explore the extent to which targeting catastrophizing reduces subsequent depression and suicide risk.

Introduction Pregnant women exposed chronically to opioids smoked more cigarettes per day (CPD) and had a higher nicotine metabolite ratio (NMR), 3-hydroxycotinine/cotinine, a biomarker of nicotine metabolism and clearance, than those not receiving opioids. We examined CPD and NMR in a group of pregnant smokers, a quarter of whom were receiving opioid agonist therapy (OAT). Aims and Methods Pregnant smokers recruited to participate in a placebo-controlled trial of bupropion for smoking cessation provided a blood sample for measurement of NMR. Results Half (52.4%) of the 124 women with NMR data were African American. OAT-treated women (n = 34, 27.4%; 27 receiving methadone and 7 buprenorphine) were more likely to be white (79% vs. 30%, p < .001) and to have a lower mean PHQ-9 total score (2.91 [SD = 2.83] vs. 4.83 [SD = 3.82], p = .007). OAT-treated women reported smoking more CPD (9.50 [SD = 5.26] vs. 7.20 [SD = 3.65], p = .005) and had higher NMR (0.78 [SD = 0.36] vs. 0.56 [SD = 0.25], p = .001) than the non-OAT-treated group. In a linear regression analysis adjusting for race, depression severity, and CPD, NMR was greater in the OAT group (p = .025), among whom the daily methadone-equivalent dosage correlated with NMR (Spearman’s ρ = 0.49, p = .003). Conclusions Consistent with the findings of Oncken et al. (2019), we found that OAT smokers smoked more and had higher NMR than non-OAT smokers. As higher NMR is associated with a reduced likelihood of smoking cessation, the effects on NMR of both pregnancy and OAT could contribute to a lower smoking cessation rate in pregnant smokers receiving chronic opioid therapy. Implications We replicated the finding that the NMR is significantly greater among pregnant smokers receiving OAT than those not receiving this treatment for opioid use disorder. Furthermore, we found that the dosage of the OAT was significantly associated with the NMR level. These findings may contribute to a poorer response to smoking cessation treatment in pregnant women treated with OAT, particularly those receiving high-dose therapy, and raise the question of whether novel approaches are needed to treat smoking in this subgroup of pregnant smokers.

BACKGROUND AND AIMS Longitudinal electronic health record (EHR) data offer a large-scale, untapped source of phenotypical information on harmful alcohol use. Using established, alcohol-associated variants in the gene that encodes the enzyme alcohol dehydrogenase 1B (ADH1B) as criterion standards, we compared the individual and combined validity of three longitudinal EHR-based phenotypes of harmful alcohol use: Alcohol Use Disorders Identification Test-Consumption (AUDIT-C) trajectories; mean age-adjusted AUDIT-C; and diagnoses of alcohol use disorder (AUD). DESIGN With longitudinal EHR data from the Million Veteran Program (MVP) linked to genetic data, we used two population-specific polymorphisms in ADH1B that are associated strongly with AUD in African Americans (AAs) and European Americans (EAs): rs2066702 (Arg369Cys, AAs) and rs1229984 (Arg48His, EAs) as criterion measures. SETTING United States Department of Veterans Affairs Healthcare System. PARTICIPANTS A total of 167 721 veterans (57 677 AAs and 110 044 EAs; 92% male, mean age = 63 years) took part in this study. Data were collected from 1 October 2007 to 1 May 2017. MEASUREMENTS Using all AUDIT-C scores and AUD diagnostic codes recorded in the EHR, we calculated age-adjusted mean AUDIT-C values, longitudinal statistical trajectories of AUDIT-C scores and ICD-9/10 diagnostic groupings for AUD. FINDINGS A total of 19 793 AAs (34.3%) had one or two minor alleles at rs2066702 [minor allele frequency (MAF) = 0.190] and 6933 EAs (6.3%) had one or two minor alleles at rs1229984 (MAF = 0.032). In both populations, trajectories and age-adjusted mean AUDIT-C were correlated (r = 0.90) but, when considered separately, highest score (8+ versus 0) of age-adjusted mean AUDIT-C demonstrated a stronger association with the ADH1B variants [adjusted odds ratio (aOR) 0.54 in AAs and 0.37 in AAs] than did the highest trajectory (aOR 0.71 in AAs and 0.53 in EAs); combining AUDIT-C metrics did not improve discrimination. When age-adjusted mean AUDIT-C score and AUD diagnoses were considered together, age-adjusted mean AUDIT-C (8+ versus 0) was associated with lower odds of having the ADH1B minor allele than were AUD diagnostic codes: aOR = 0.59 versus 0.86 in AAs and 0.48 versus 0.68 in EAs. These independent associations combine to yield an even lower aOR of 0.51 for AAs and 0.33 for EAs. CONCLUSIONS The age-adjusted mean AUDIT-C score is associated more strongly with genetic polymorphisms of known risk for alcohol use disorder than are longitudinal trajectories of AUDIT-C or AUD diagnostic codes. AUD diagnostic codes modestly enhance this association.

Background New smartphone communication technology provides a novel way to provide personalized continuing care support following alcohol treatment. One such system is the Addiction version of the Comprehensive Health Enhancement Support System (A-CHESS), which provides a range of automated functions that support patients. A-CHESS improved drinking outcomes over standard continuing care when provided to patients leaving inpatient treatment. Effective continuing care can also be delivered via telephone calls with a counselor. Telephone Monitoring and Counseling (TMC) has demonstrated efficacy in two randomized trials with alcohol-dependent patients. A-CHESS and TMC have complementary strengths. A-CHESS provides automated 24/7 recovery support services and frequent assessment of symptoms and status, but does not involve regular contact with a counselor. TMC provides regular and sustained contact with the same counselor, but no ongoing support between calls. The future of continuing care for alcohol use disorders is likely to involve automated mobile technology and counselor contact, but little is known about how best to integrate these services. Methods/Design To address this question, the study will feature a 2 × 2 design (A-CHESS for 12 months [yes/no] × TMC for 12 months [yes/no]), in which 280 alcohol-dependent patients in intensive outpatient programs (IOPs) will be randomized to one of the four conditions and followed for 18 months. We will determine whether adding TMC to A-CHESS produces fewer heavy drinking days than TMC or A-CHESS alone and test for TMC and A-CHESS main effects. We will determine the costs of each of the four conditions and the incremental cost-effectiveness of the three active conditions. Analyses will also examine secondary outcomes, including a biological measure of alcohol use, and hypothesized moderation and mediation effects. Discussion The results of the study will yield important information on improving patient alcohol use outcomes by integrating mobile automated recovery support and counselor contact. Trial registration ClinicalTrials.gov, NCT02681406. Registered on 2 September 2016. Electronic supplementary material The online version of this article (10.1186/s13063-018-2466-1) contains supplementary material, which is available to authorized users.

OBJECTIVE: Recent clinical practice guidelines recommend the delivery of evidence-based psychotherapies for both substance use disorder (SUD) and posttraumatic stress disorder (PTSD) within the same treatment episode for patients with SUD/PTSD comorbidity. This randomized clinical trial evaluated the comparative effectiveness of integrating versus phasing evidence-based psychotherapies for SUD and PTSD among veterans with co-occurring SUD/PTSD. METHOD: 183 veterans with DSM-IV PTSD and SUD at two VA Medical Centers were randomized to one of two psychotherapies during which Motivational Enhancement Therapy [MET] for SUD and Prolonged Exposure [PE] for PTSD were either phased or integrated throughout treatment. Primary outcomes as evaluated by blinded assessors were percent days with drug use or heavy drinking and PTSD symptomology. We hypothesized integrated MET/PE (n = 95) would yield better SUD and PTSD-related outcomes at posttreatment than phased MET/PE (n = 88). RESULTS: In intent-to-treat analyses (n=183), both treatment groups achieved clinically (d=0.46 – 1.06) and statistically significant reductions in SUD (p < 0.01) and PTSD (p < 0.01) symptomology; the time by treatment interactions were not significant. Post-hoc analyses could not confirm statistical non-inferiority; between-group effect sizes suggest a lack of clinically-meaningful differences between the two treatment approaches (d=0.08 – 0.27). CONCLUSIONS: Our hypothesis that integrated MET/PE would result in better outcomes than phased MET/PE across a range of PTSD and SUD measures was not supported; both strategies for combining two single-disorder treatments for co-occurring SUD/PTSD yielded significant symptom reduction.

Sequential multiple assignment randomized trials (SMARTs) are a useful and increasingly popular approach for gathering information to inform the construction of adaptive interventions to treat psychological and behavioral health conditions. Until recently, analysis methods for data from SMART designs considered only a single measurement of the outcome of interest when comparing the efficacy of adaptive interventions. Lu and co-workers (2016) proposed a method for considering repeated outcome measurements to incorporate information about the longitudinal trajectory of change. While their proposed method can be applied to many kinds of outcome variables, they focused mainly on linear models for normally distributed outcomes. Practical guidelines and extensions are required to implement this methodology with other types of repeated outcome measures common in behavioral research. In this paper we discuss implementation of this method with repeated binary outcomes. We explain how to compare adaptive interventions in terms of various summaries of repeated binary outcome measures, including average outcome (area under the curve) and delayed effects. The method is illustrated using an empirical example from a SMART study to develop an adaptive intervention for engaging alcohol- and cocaine-dependent patients in treatment. Monte Carlo simulations are provided to demonstrate the good performance of the proposed technique.

Background Adaptive interventions, sometimes referred to as “stepped care”, are those interventions in which the type or dosage of treatment offered to patients is tailored to baseline clinical presentation and then adjusted over time in response to patient progress or lack thereof. Currently, no adaptive brief interventions exist specifically for alcohol use disorder (AUD). Method This study used a sequential multiple assignment randomized trial design with 160 individuals with AUD recruited both locally and nationally who had a goal to reduce or abstain from drinking. Participants received brief advice (BA) and then the study reassessed them three weeks later; the study randomized those who did not respond to BA, defined as reducing their drinking to low-risk guidelines, to two session of motivational interviewing (MI) or more BA. The study then reassessed participants at week 8. The study re-randomized nonresponders to receive either MI alone or MI plus behavioral self-control therapy (BSCT), also referred to as coping skills therapy, and evaluated participants at week 13. Results Overall, participants receiving any BSCT made the greatest reductions in drinking. Participants who received MI at week 4 and BSCT at week 8 outperformed all other groups. Conclusion Findings reveal that prolonged treatment, more sessions, and/or a specific combination of MI and BSCT provided optimal outcomes. Future research should determine whether such an algorithm holds across heterogenous groups of individuals with AUD.

Background People with opioid use disorder (OUD) often have a co-occurring psychiatric disorder, which elevates the risk of morbidity and mortality. Promising evidence supports the use of collaborative care for treating people with OUD in primary care. Whether collaborative care interventions that treat both OUD and psychiatric disorders will result in better outcomes is presently unknown. Methods The Whole Health Study is a 3-arm randomized controlled trial designed to test collaborative care treatment for OUD and the psychiatric disorders that commonly accompany OUD. Approximately 1200 primary care patients aged ≥18 years with OUD and depression, anxiety, or PTSD will be randomized to one of three conditions: (1) Augmented Usual Care, which consists of a primary care physician (PCP) waivered to prescribe buprenorphine and an addiction psychiatrist to consult on medication-assisted treatment; (2) Collaborative Care, which consists of a waivered PCP, a mental health care manager trained in psychosocial treatments for OUD and psychiatric disorders, and an addiction psychiatrist who provides consultation for OUD and mental health; or (3) Collaborative Care Plus, which consists of all the elements of the Collaborative Care arm plus a Certified Recovery Specialist to help with treatment engagement and retention. Primary outcomes are six-month rates of opioid use and six-month rates of remission of co-occurring psychiatric disorders. Discussion The Whole Health Study will investigate whether collaborative care models that address OUD and co-occurring depression, anxiety, or PTSD will result in better patient outcomes. The results will inform clinical care delivery during the current opioid crisis. Clinical Trials Registration www.clinicaltrials.gov registration: NCT04245423

A dynamic treatment regime (DTR) is a sequence of decision rules, each of which recommends a treatment based on a patient's past and current health status. Sequential, multiple assignment, randomized trials (SMARTs) are multi-stage trial designs that yield data specifically for building effective DTRs. Modeling the marginal mean trajectories of a repeated-measures outcome arising from a SMART presents challenges, because traditional longitudinal models used for randomized clinical trials do not take into account the unique design features of SMART. We discuss modeling considerations for various forms of SMART designs, emphasizing the importance of considering the timing of repeated measures in relation to the treatment stages in a SMART. For illustration, we use data from three SMART case studies with increasing level of complexity, in autism, child attention deficit hyperactivity disorder, and adult alcoholism. In all three SMARTs, we illustrate how to accommodate the design features along with the timing of the repeated measures when comparing DTRs based on mean trajectories of the repeated-measures outcome.

Mechanisms of behavior change (MOBC) within Motivational Interviewing (MI) are thought to operate via both relational and technical elements. These elements are hypothesized to increase client motivation and self-efficacy for change and subsequently decrease drinking. Only partial support for this causal chain exists, particularly when using within-session change talk as the primary intervening variable. This study explored whether commitment to moderate or abstain from drinking and confidence to moderate drinking in the next day measured via ecological momentary assessment (EMA) provided alternative support for the theory. Data were from a pilot randomized controlled trial testing active ingredients of MI. Problem drinkers (N = 89) seeking to moderate their drinking were randomly assigned to one of the three conditions: 1) MI; 2) Spirit only MI (SOMI), consisting of non-directive elements of MI, e.g., reflective listening; and 3) a non-therapy control. Participants completed daily EMA that measured confidence, both types of commitment, and drinks per day for a week prior to and during seven weeks of treatment. Hypotheses were not supported, and results were unexpected. Participants in SOMI were more likely to have higher daily confidence than those in MI; there were no condition differences for either type of commitment. All daily measures significantly predicted drinking; however, the MI group did not demonstrate a stronger relationship between the intervening variables and drinking, as hypothesized. Instead, participants in SOMI yielded the strongest relationship between daily commitment to abstain and drinking compared to the other two conditions. Multiple possible explanations for the unexpected findings are discussed.

Introduction Alcohol Care Management (ACM) is a manualized treatment provided by behavioral health providers working in a primary care team aimed at increasing patients’ treatment engagement and decreasing their alcohol use. Research has shown that ACM is effective in reducing alcohol consumption; however, the mechanisms of ACM are unknown. Therefore, the purpose of this study is to examine the mechanisms of change in ACM in the context of a randomized clinical trial evaluating the effectiveness of ACM. Materials and Methods This study performed secondary data analysis of existing data from a larger study that involved a sample of U.S. veterans (N = 163) who met criteria for current alcohol dependence. Upon enrollment into the study, participants were randomized to receive either ACM or standard care. ACM was delivered in-person or by telephone within the primary care clinic and focused on the use of oral naltrexone and manualized psychosocial support. According to theory, we hypothesized several ACM treatment components that would mediate alcohol consumption outcomes: engagement in addiction treatment, reduced craving, and increased readiness to change. Parallel mediation models were performed by the PROCESS macro Model 4 in SPSS to test study hypotheses. The institutional review boards at each of the participating facilities approved all study procedures before data collection. Results As hypothesized, results showed that treatment engagement mediated the relation between treatment and both measures of alcohol consumption outcomes, the percentage of alcohol abstinent days, and the percentage of heavy drinking days. Neither craving nor readiness to change mediated the treatment effect on either alcohol consumption outcome. Conclusions Findings suggest that ACM may be effective in changing drinking patterns partially due to an increase in treatment engagement. Future research may benefit from evaluating the specific factors that underlie increased treatment engagement. The current study provides evidence that alcohol use disorder interventions should aim to increase treatment engagement and reduce barriers to care.

Treatment policies, also known as dynamic treatment regimes, are sequences of decision rules that link the observed patient history with treatment recommendations. Multiple, plausible, treatment policies are frequently constructed by researchers using expert opinion, theories, and reviews of the literature. Often these different policies represent competing approaches to managing an illness. Here, we develop an "assisted estimator" that can be used to compare the mean outcome of competing treatment policies. The term "assisted" refers to the fact estimators from the Structural Nested Mean Model, a parametric model for the causal effect of treatment at each time point, are used in the process of estimating the mean outcome. This work is motivated by our work on comparing the mean outcome of two competing treatment policies using data from the ExTENd study in alcohol dependence.

Although alcohol dependence (AD) is approximately 50% heritable, little is known about how specific genetic loci affect AD risk. In a genome-wide association study (GWAS), we identified highly significant associations between two population-specific functional variants in the alcohol dehydrogenase 1B gene (ADH1B) and AD in African-Americans (AAs; rs2066702) and European-Americans (EAs; rs1229984). In the current study, we determined which specific diagnostic criteria contributed to the observed associations of ADH1B SNPs with AD. Our analysis included both the DSM-IV and DSM-5 diagnostic systems. We also investigated the relationship of ADH1B variants to the maximum number of drinks consumed in a 24-hour period (MaxDrinks), a presumed intermediate phenotype of AD. We found that, although all criteria made strong individual contributions to the associations, the largest contributions came from those reflecting neuroadaptation: tolerance (rs2066702) and withdrawal (rs1229984). Overall, evidence for association with DSM-5 criteria was slightly stronger than for DSM-IV criteria. For rs2066702, results were similar for DSM-IV and DSM-5 criteria. However, the most significant DSM-5 criterion associated with rs1229984 was alcohol-related social/interpersonal problems. Both ADH1B variants were associated with MaxDrinks, a measure of innate tolerance, and MaxDrinks mediated the associations between ADH1B and alcohol outcomes. We replicated the findings for rs2066702 and tolerance in an independent sample of AAs. Taken together, these results suggest that variation in ADH1B affects the adaptation to heavy drinking, highlighting population-specific differences in genetic risk for AUD. They also suggest that the revisions reflected in DSM-5 AUD may enhance the utility of that diagnosis for gene finding.

Soldier deployment can create a stressful environment for U.S. Army families with young children. Prior research has identified elevated rates of child maltreatment in the 6 months immediately following a soldier's return home from deployment. In this study, we longitudinally examine how other child- and family-level characteristics influence the relationship of deployment to risk for maltreatment of dependent children of U.S. Army soldiers.We conducted a person-time analysis of substantiated reports and medical diagnoses of maltreatment among the 73,404 children of 56,087 U.S. Army soldiers with a single deployment between 2001 and 2007. Cox proportional hazard models estimated hazard rates of maltreatment across deployment periods and simultaneously considered main effects for other child- and family-level characteristics across periods.In adjusted models, maltreatment hazard was highest in the 6 months following deployment (hazard ratio [HR] = 1.63, p0.001). Children born prematurely or with early special needs independently had an increased risk for maltreatment across all periods (HR = 2.02, p0.001), as well as those children whose soldier-parent had been previously diagnosed with a mental illness (HR = 1.68, p0.001). In models testing for effect modification, during the 6 months before deployment, children of female soldiers (HR = 2.22, p = 0.006) as well as children of soldiers with a mental health diagnosis (HR = 2.78, p = 0.001) were more likely to experience maltreatment, exceeding the risk at all other periods.Infants and children are at increased risk for maltreatment in the 6 months following a parent's deployment, even after accounting for other known family- and child-level risk factors. However, the risk does not appear to be the same for all soldiers and their families in relation to deployment, particularly for female soldiers and those who had previously diagnosed mental health issues, for whom the risk appears most elevated before deployment. Accounting for the unique needs of high-risk families at different stages of a soldier's deployment cycle may allow the U.S. Army to better direct resources that prevent and address child maltreatment.

Background There is a high co-occurrence of cocaine and alcohol use disorders, and patients with both of these problems are difficult to treat. There is a reasonable rationale and some empirical data to justify a pilot trial of an injectable, extended-release formulation of naltrexone for treating co-occurring cocaine and alcohol addiction. Methods Eighty cocaine (n = 80) and alcohol dependent, treatment-seeking subjects were randomly assigned to receive either two monthly extended-release injections of naltrexone or two matching placebo injections in an 8-week clinical trial, with weekly medical management plus cognitive behavioral therapy visits. Results No differences in reduction in cocaine or alcohol use were observed between the injectable naltrexone and placebo groups during the 8-week trial. Conclusions Injectable extended-release naltrexone, while an ideal method for ensuring medication adherence in these traditionally hard-to-treat patients, did not result in any measurable reduction in cocaine or alcohol use over the course of 8 weeks of treatment. (Am J Addict 2014;23:591–597)

Objective Systematically identifying reasons that clients enter substance abuse treatment may allow clinicians to immediately focus on issues of greatest relevance to the individual and enhance treatment engagement. We developed the Survey of Treatment Entry Pressures (STEP) to identify the specific factors that precipitated an individual's treatment entry. The instrument contains 121 items from 6 psychosocial domains (i.e., family, financial, social, medical, psychiatric, legal). The current study examined the STEP's psychometric properties. Method A total of 761 participants from various treatment settings and modalities completed the STEP prior to treatment admission and 4–7 days later. Analyses were performed to examine the instrument's psychometric properties including item response rates, test–retest reliability, internal consistency, and factor structure. Results The items displayed adequate test–retest reliability and internal consistency within each psychosocial domain. Generally, results from exploratory and confirmatory factor analyses support a 2-factor structure reflecting type of reinforcement schedule. Conclusion The study provides preliminary support for the psychometric properties of the STEP. The STEP may provide a reliable way for clinicians to characterize and capitalize on a client's treatment motivation early on which may serve to improve treatment retention and therapeutic outcomes.

The goal of this study was to determine which cocaine dependent patients engaged in an intensive outpatient program (IOP) were most likely to benefit from extended continuing care (24 months). Participants (N=321) were randomized to: IOP treatment as usual (TAU), TAU plus Telephone Monitoring and Counseling (TMC), or TAU plus TMC plus incentives for session attendance (TMC+). Potential moderators examined were gender, stay in a controlled environment prior to IOP, number of prior drug treatments, and seven measures of progress toward IOP goals. Outcomes were: (1) abstinence from all drugs and heavy alcohol use, and (2) cocaine urine toxicology. Follow-ups were conducted at 3, 6, 9, 12, 18, and 24 months post-baseline. Results indicated that there were significant effects favoring TMC+ over TAU on the cocaine urine toxicology outcome for participants in a controlled environment prior to IOP and for those with no days of depression early in IOP. Trends were obtained favoring TMC over TAU for those in a controlled environment (cocaine urine toxicology outcome) or with high family/social problem severity (abstinence composite outcome), and TMC+ over TAU for those with high family/social problem severity or high self-efficacy (cocaine urine toxicology outcome). None of the other potential moderator effects examined reached the level of a trend. These results generally do not suggest that patients with greater problem severity or poorer performance early in treatment on the measures considered in this report will benefit to a greater degree from extended continuing care.

Alcohol use, abuse and dependence remain a pressing public health problem. Based on its mechanism of action, varenicline seemed to be a likely candidate for treating alcohol dependence.Alcohol dependent subjects (n=40) were enrolled in a 13-week double-blind placebo controlled clinical trial. Subject visits were once per week. At each visit, subjects were tested for breath alcohol levels, provided self-report data on alcohol and nicotine use, and on mood and craving. In addition, subjects received once a week medical management (MM).There was no difference between varenicline and placebo treated groups on any of the drinking outcomes. Compared to placebo-treated subjects, varenicline treated subjects had decreased rates of alcohol craving and cigarette smoking, as well as greater mood improvements during the later part of the study (weeks 6-13). In addition, among subjects who were cigarette smokers, those treated with varenicline were significantly less likely to report heavy drinking during the trial.Although varenicline was not significantly more effective than placebo at reducing drinking during the trial, its effects on alcohol craving and mood suggest that future investigation of the mechanism of action of varenicline, as well as additional clinical studies may be warranted. In particular, the findings regarding the influence of smoking status on heavy drinking among varenicline-treated subjects should be investigated in future studies.

Substance use disorders often have a chronic course, with afflicted individuals cycling through periods of abstinence, sporadic use, and heavy use (Hser, Longshore, & Anglin, 2007; McKay, 2009a; McLellan, Lewis, O’Brien, & Kleber, 2000). Wider use of effective continuing care has been recommended to increase rates of sustained recoveries and limit the severity and duration of relapse episodes that do occur (Dennis & Scott, 2007; Humphreys & Tucker, 2002; McKay, 2009a; Miller & Weisner, 2002). Continuing care interventions with longer durations and active efforts to deliver the intervention tend to show larger effects (McKay, 2009b; McKay et al., 2010; Scott & Dennis, 2009). Although effective, extended continuing care models for substance use disorders are labor intensive and add to the cost of treatment. It is therefore important to determine which patients are most likely to benefit from these interventions. One such group may be patients who are using drugs or alcohol immediately prior to intake, or who continue to use early in treatment. For example, prior studies shown that cocaine dependent patients who are using cocaine immediately prior to treatment have worse retention and drug use outcomes than those who have stopped using (Ahmadi et al., 2009; Alterman et al., 1997; Kampman et al., 2001). Similarly, patients who continue to use drugs or alcohol in the first few weeks of treatment are at higher risk for early dropout and poor outcomes (Higgins, Badger, & Budney, 2000; McKay et al., 1999, McKay et al., 2005; Plebani, Kampman, & Lynch, 2009; Preston et al., 1998). In a study by McKay et al. (1999), patients who continued to use cocaine or alcohol during a 4-week intensive outpatient treatment program had worse outcomes than those who remitted substance dependence during that period. However, providing coping-skills based relapse prevention continuing care to these patients produced better cocaine and alcohol use outcomes than standard care. Conversely, there were no continuing care effects in remitted patients. Alcohol use has also been reported to precipitate cocaine relapse in cocaine dependent individuals (McKay, Alterman, Rutherford, Cacciola, & McLellan, 1999). The goal of the present study was to determine whether substance use status immediately prior to intake and during the first few weeks of treatment could be used to identify patients who would most benefit from extended continuing care. Therefore, the study was designed to develop an adaptive model of treatment (McKay, 2009a; Murphy et al., 2007), in which patient progress is used to determine whether standard care needs to be augmented to achieve optimal outcomes. Participants were patients enrolled in publicly-funded intensive outpatient programs (IOPs); all were cocaine dependent and the majority were also alcohol dependent. Therefore, it was hypothesized that participants who were actively using cocaine or alcohol at intake or in the first few weeks of treatment would have worse substance use outcomes than those who had successfully achieved initial abstinence, but would benefit to a greater degree from extended continuing care. However, because patients with active use prior to or early in treatment are at greater risk to dropout, we also evaluated the impact of providing low-level incentives for continuing care session attendance. Incentivizing attendance has increased attendance rates in treatment for substance use disorders, although the magnitude of effects has been somewhat smaller than when abstinence is incentivized (Bride & Humble, 2008; Businelle et al., 2009; Lussier et al., 2006; Petry et al., 2006). A preliminary analysis of continuing care participation in the present study indicated that incentives dramatically increased the number of sessions attended in the first year of the follow-up (Van Horn, et al., 2011). The extended continuing care intervention in the study, Telephone Monitoring and Counseling, included a combination of telephone and in-person sessions. The intervention includes cognitive-behavioral therapy (CBT)-like elements, such as regular monitoring of current substance use and other risk and protective factors, identification of upcoming high-risk situations, and selection and rehearsal of coping strategies; and linkage to community supports (McKay et al., 2010). The telephone is well suited for the delivery of extended continuing care, because of added convenience for patients, reductions in barriers to attending clinic-based care, and greater flexibility in scheduling sessions (McKay, 2009b). Two prior studies have shown that this intervention produces better drug and alcohol use outcomes than standard care (McKay et al., 2005; McKay et al., 2010). In the present study, participants were cocaine dependent IOP patients (N=321) who were randomly assigned to standard care only (i.e., treatment as usual, or TAU), TAU and Telephone Monitoring and Counseling (TMC), or TAU and TMC plus incentives (TMC+), and followed for 24 months. Because many study participants were also dependent on alcohol and had a history of other drug use, the first outcome measure was abstinence from all drugs in a given follow-up period, as indicated by both urine toxicology tests and self-report, and no reported days of heavy alcohol use during the period. Cocaine urine toxicology was included as a second outcome, to provide a measure specific for cocaine use only. The following hypotheses were tested: TMC and TMC+ will produce better outcomes than TAU. Cocaine and alcohol use at intake or early in treatment will predict worse outcomes. Treatment effects favoring TMC and TMC+ over TAU will be larger in participants with cocaine or alcohol use at intake or early in treatment. Adding incentives for attendance to TMC will produce larger treatment effects.

Tom Ten Have made many contributions to causal inference and biostatistics before his untimely death. This paper reviews Tom's contributions and discusses potential related future research directions. We focus on Tom's contributions to longitudinal/repeated measures categorical data analysis and particularly his contributions to causal inference. Tom's work on causal inference was primarily in the areas of estimating the effect of receiving treatment in randomized trials with nonadherence and mediation analysis. A related area to mediation analysis he was working on at the time of his death was posttreatment effect modification with applications to designing adaptive treatment strategies.