Threat of shock increases distractor susceptibility during the short-term maintenance of visual information.

Elevated arousal in anxiety is thought to affect attention control. To test this, we designed a visual short-term memory (VSTM) task to examine distractor suppression during periods of threat and no-threat. We hypothesized that threat would impair performance when subjects had to filter out large numbers of distractors. The VSTM task required subjects to attend to one array of squares while ignoring a separate array. The number of target and distractor squares varied systematically, with high (four squares) and low (two squares) target and distractor conditions. This study comprised two separate experiments. Experiment 1 used startle responses and white noise as to directly measure threat-induced anxiety. Experiment 2 used BOLD to measure brain responses. For Experiment 1, subjects showed significantly larger startle responses during threat compared to safe period, supporting the validity of the threat manipulation. For Experiment 2, we found that accuracy was affected by threat, such that the distractor load negatively impacted accuracy only in the threat condition. We also found threat-related differences in parietal cortex activity. Overall, these findings suggest that threat affects distractor susceptibility, impairing filtering of distracting information. This effect is possibly mediated by hyperarousal of parietal cortex during threat.

Intermittent theta-burst stimulation to the right dorsolateral prefrontal cortex may increase potentiated startle in healthy individuals.

Repetitive transcranial magnetic stimulation (rTMS) treatment protocols targeting the right dlPFC have been effective in reducing anxiety symptoms comorbid with depression. However, the mechanism behind these effects is unclear. Further, it is unclear whether these results generalize to non-depressed individuals. We conducted a series of studies aimed at understanding the link between anxiety potentiated startle and the right dlPFC, following a previous study suggesting that continuous theta burst stimulation (cTBS) to the right dlPFC can make people more anxious. Based on these results we hypothesized that intermittent TBS (iTBS), which is thought to have opposing effects on plasticity, may reduce anxiety when targeted at the same right dlPFC region. In this double-blinded, cross-over design, 28 healthy subjects underwent 12 study visits over a 4-week period. During each of their 2 stimulation weeks, they received four 600 pulse iTBS sessions (2/day), with a post-stimulation testing session occurring 24 h following the final iTBS session. One week they received active stimulation, one week they received sham. Stimulation weeks were separated by a 1-week washout period and the order of active/sham delivery was counterbalanced across subjects. During the testing session, we induced anxiety using the threat of unpredictable shock and measured anxiety potentiated startle. Contrary to our initial hypothesis, subjects showed increased startle reactivity following active compared to sham stimulation. These results replicate work from our two previous trials suggesting that TMS to the right dlPFC increases anxiety potentiated startle, independent of both the pattern of stimulation and the timing of the post stimulation measure. Although these results confirm a mechanistic link between right dlPFC excitability and startle, capitalizing upon this link for the benefit of patients will require future exploration.

Delayed effects of cigarette graphic warning labels on smoking behavior.

Graphic warning labels (GWLs) on cigarette packs are widely employed to communicate smoking-related health risks. Most GWLs elicit high emotional arousal. Our recent study showed lower efficacy of high-arousal GWLs than low-arousal ones during 4 weeks of naturalistic exposure. Here, we conducted a secondary analysis to investigate the delayed effects of GWLs on smoking severity after the end of the 4- week exposure. In 112 adult smokers (56 high-arousal, 56 low-arousal), there was a significant reduction in the number of cigarettes smoked per day (CPD) from immediately post-exposure to 4 weeks post-exposure. The high-arousal and low-arousal groups did not differ in CPD reduction. Our study suggests lasting impact of GWLs on smoking behavior. The finding may be particularly relevant to the high-arousal GWLs, whose efficacy is not as pronounced during direct and continuous exposure.

Towards shortening the Brief Addiction Monitor-Revised (BAM-R).

Introduction: The Brief Addiction Monitor-Revised (BAM-R) is a widely used, 17-item assessment of substance use, risk, and protective factors associated with recovery from substance use disorders. Despite wide adoption in the U.S. Department of Veterans Affairs (VA) and recommendations for use in measurement-based care (MBC), administration may not be feasible in many MBC settings due to time constraints. The purpose of this study was to derive a shortened version of the BAM-R for use in fast-paced healthcare settings. Methods: BAM-R data from 32,002 Veterans were obtained through the VA's Corporate Data Warehouse. We used logistic regression models to identify items for removal based on prediction of two clinical outcomes (90-day substance use disorder (SUD) treatment retention and 12-month mortality) and item-level sensitivity to change during substance use treatment. Results: Although no intake BAM-R items predicted SUD treatment retention or mortality, effect sizes for item-level sensitivity to change during substance use treatment varied from small to large. Seven items were judged as relevant for MBC of SUD. Among all BAM-R items, Heavy Alcohol Use, Self-Help, Drug Use, Craving, and Mood items demonstrated the greatest magnitude of sensitivity to change. Conclusions: Although additional research is recommended before a shortened BAM-R can be implemented in non-specialty MBC settings, we identified 5 BAM-R items with perceived clinical utility and scores that demonstrated evidence of sensitivity to change. Shortening the BAM-R increases feasibility of use, though more work is needed to optimize measurement for SUD MBC.

Association between body mass index and treatment completion in extended-release naltrexone-treated patients with opioid dependence.

Background: Excessive consumption of opioids is associated with impaired metabolic function including increased body mass index (BMI). Opioid antagonist naltrexone (NTX) is an effective treatment for opioid use disorder (OUD) that has the potential to mitigate such metabolic disturbances. Understanding the relationship between treatment adherence and BMI in NTX-treated OUD patients may provide valuable insights into optimizing clinical outcomes. Methods: Patients with opioid dependence were offered up to three monthly injections of extended-release (XR) NTX. Treatment completers (n = 41) were defined as those who had received all three XR-NTX injections, and non-completers (n = 20) as those missing at least one injection. Logistic regression was performed to examine the association between pre-treatment BMI and treatment completion. Results: BMI was positively associated with treatment completion. This association remained significant after adjusting for potentially confounding variables. Conclusion: Our findings suggest that baseline BMI may serve as a potential predictor of XR-NTX treatment adherence in patients with OUD and could help healthcare providers and policy makers alike in developing strategies to improve retention and tailor interventions for specific patient subgroups.

Nonparametric Bayesian Q-learning for optimization of dynamic treatment regimes in the presence of partial compliance.

Existing methods for estimation of dynamic treatment regimes are mostly limited to intention-to-treat analyses-which estimate the effect of randomization to a particular treatment regime without considering the compliance behavior of patients. In this article, we propose a novel nonparametric Bayesian Q-learning approach to construct optimal sequential treatment regimes that adjust for partial compliance. We consider the popular potential compliance framework, where some potential compliances are latent and need to be imputed. The key challenge is learning the joint distribution of the potential compliances, which we accomplish using a Dirichlet process mixture model. Our approach provides two kinds of treatment regimes: (1) conditional regimes that depend on the potential compliance values; and (2) marginal regimes where the potential compliances are marginalized. Extensive simulation studies highlight the usefulness of our method compared to intention-to-treat analyses. We apply our method to the Adaptive Treatment for Alcohol and Cocaine Dependence (ENGAGE) study , where the goal is to construct optimal treatment regimes to engage patients in therapy.

A non-parametric Bayesian approach for adjusting partial compliance in sequential decision making.

Existing methods for estimating the mean outcome under a given sequential treatment rule often rely on intention-to-treat analyses, which estimate the effect of following a certain treatment rule regardless of compliance behavior of patients. There are two major concerns with intention-to-treat analyses: (1) the estimated effects are often biased toward the null effect; (2) the results are not generalizable and reproducible due to the potentially differential compliance behavior. These are particularly problematic in settings with a high level of non-compliance, such as substance use disorder studies. Our work is motivated by the Adaptive Treatment for Alcohol and Cocaine Dependence study (ENGAGE), which is a multi-stage trial that aimed to construct optimal treatment strategies to engage patients in therapy. Due to the relatively low level of compliance in this trial, intention-to-treat analyses essentially estimate the effect of being randomized to a certain treatment, instead of the actual effect of the treatment. We obviate this challenge by defining the target parameter as the mean outcome under a dynamic treatment regime conditional on a potential compliance stratum. We propose a flexible non-parametric Bayesian approach based on principal stratification, which consists of a Gaussian copula model for the joint distribution of the potential compliances, and a Dirichlet process mixture model for the treatment sequence specific outcomes. We conduct extensive simulation studies which highlight the utility of our approach in the context of multi-stage randomized trials. We show robustness of our estimator to non-linear and non-Gaussian settings as well.

Effects of current smoking severity on brain gray matter volume in opioid use disorder - a voxel-based morphometry study.

Background: Cigarette smoking (CS) and opioid use disorder (OUD) significantly alter brain structure. Although OUD and cigarette smoking are highly comorbid, most prior neuroimaging research in OUD did not control for smoking severity. Specifically, the combined effect of smoking and OUD on the brain gray matter volume (GMV) remains unknown.Objectives: We used structural magnetic resonance imaging (sMRI) to examine: (1) the GMV differences between OUD and non-OUD individuals with comparable smoking severity; and (2) the differential effect of smoking severity on the brain GMV between individuals with and without OUD.Methods: We performed a secondary analysis of existing sMRI datasets of 116 individuals who smoked cigarettes daily, among whom 60 had OUD (CS-OUD; 37 male, 23 female) and 56 did not (CS; 31 male, 25 female). Brain GMV was estimated by voxel-based morphometry analysis.Results: Compared to the CS group, the CS-OUD group had a higher GMV in the occipital cortex and lower GMV in the prefrontal and temporal cortex, striatum, and pre/postcentral gyrus (whole-brain corrected-p < .05). There was a significant interaction between group and smoking severity on GMV in the medial orbitofrontal cortex (whole-brain corrected-p < .05), such that heavier smoking was associated with lower medial orbitofrontal GMV in the CS-OUD but not CS participants (r=-0.32 vs. 0.12).Conclusions: Our findings suggest a combination of independent and interactive effects of cigarette smoking and OUD on the brain gray matter. Elucidating the neuroanatomical correlates of comorbid opioid and tobacco use may shed the light on the development of novel interventions for affected individuals.

Baseline platelet serotonin in a multi-site treatment study of depression in veterans administration patients: Distribution and effects of demographic variables and serotonin reuptake inhibitors.

BACKGROUND: The objectives of the study were: (1) to examine the overall distribution of baseline platelet serotonin (5-hydroxytryptamine, 5-HT) values in patients seeking treatment for depression and to define subgroups based on the apparent presence or absence of drug exposure; (2) to assess the bioeffect of 5-HT reuptake inhibitors (SRIs) at the platelet 5-HT transporter; and (3) to examine the relationships of demographic variables including population (ancestry), sex, age, and season of sampling to platelet 5-HT concentration. METHODS: Platelet 5-HT levels were measured in a cross-sectional study of 1433 Veterans Administration (VA) patients participating in a pragmatic multi-site pharmacogenomic treatment study of depression. Patients were characterized medically and demographically using VA health records and self-report. RESULTS: A clearly bimodal distribution was observed for platelet 5-HT levels with the lower mode associated with patients exposed to SRIs at baseline. Median transporter blockade bioeffects were similar across the various selective 5-HT reuptake inhibitors (SSRIs) and 5-HT/norepinephrine reuptake inhibitors (SNRIs). In a subset of patients apparently not exposed to an SRI, significant effects of population and sex were observed with group mean platelet 5-HT levels being 25 % greater (p < 0.001) in African-American (AA) individuals compared to European-Americans (EAs). The female group mean was 14 % (p < 0.001) greater than male group mean. An effect of age was observed (r = -0.11, p < 0.001) and no effect of season or month of sampling was seen. CONCLUSIONS: Further research is warranted to understand the bases and clinical implications of the population and sex differences. The apparent similarity in bioeffect at the 5-HT transporter across SSRIs and when comparing SSRIs and SNRIs informs discussions about initiating, dose adjustment and switching of 5-HT reuptake inhibitors.

Addicted to green: priming effect of menthol cigarette packaging on brain response to smoking cues.

INTRODUCTION: Mentholated 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. METHODS: Forty-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. RESULTS: Menthol 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. CONCLUSIONS: Our 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.

Effects of emotional arousal on the neural impact and behavioral efficacy of cigarette graphic warning labels.

BACKGROUND AND AIMS: Graphic warning labels (GWLs) on cigarette packs have been adopted by many jurisdictions world-wide. In the United States, the introduction of GWLs has been delayed by claims that their high level of negative emotional arousal unnecessarily infringed upon the tobacco manufacturers' free speech. This study aimed to provide experimental data on the contribution of emotional arousal to GWL efficacy. DESIGN: Observational study using long-term naturalistic exposure and functional magnetic resonance imaging. SETTING: Research university in Philadelphia, PA, USA. PARTICIPANTS: A total of 168 adult smokers. MEASUREMENTS: For 4 weeks, participants received cigarettes in packs that carried either high-arousal or low-arousal GWLs (n = 84 versus 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. FINDINGS: Compared with the high-arousal group, the low-arousal group smoked fewer cigarettes [log10 -transformed, 1.076 versus 1.019; difference = 0.056, 95% confidence interval (CI) = 0.027, 0.085, χ2 (1)  = 14.21, P < 0.001] and showed stronger intention to quit (2.527 versus 2.810; difference = -0.283, 95% CI = -0.468, -0.098, χ2 (1) = 8.921, P = 0.007) and endorsement of the GWLs' textual component (4.805 versus 5.503; difference = -0.698, 95% CI = -1.016, -0.380, χ2 (1) = 18.47, P < 0.001). High-arousal GWLs induced greater amygdala response than low-arousal GWLs (0.157 versus 0.052; difference = 0.105, 95% CI = 0.049, 0.161, χ2 (1) = 23.52, P < 0.001), although the response to high-arousal GWLs declined over time (slope = -0.087 versus 0.016; difference = -0.103, 95% CI = -0.198, -0.009, χ2 (1) = 6.370, P = 0.046). Greater baseline amygdala response was associated with more smoking at 4 weeks in the high-arousal group, but less smoking in the low-arousal group (slope = 0.179 versus -0.122; difference = 0.287, 95% CI = 0.076, 0.498, χ2 (1) = 7.086, P = 0.008). Medial prefrontal response did not differ significantly between groups. CONCLUSIONS: High-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 sustained GWL efficacy.

A randomized, double-blind, placebo-controlled, pharmacogenetic study of ondansetron for treating alcohol use disorder.

BACKGROUND: In a previous study, ondansetron, a serotonin 5-HT3 receptor antagonist, reduced drinking intensity (drinks/drinking day [DPDD]) among European-ancestry (EA) participants with moderate-to-severe alcohol use disorder (AUD) and variants in genes encoding the serotonin transporter (SLC6A4) and 5-HT3A (HTR3A), and 5-HT3B (HTR3B) receptors. We tested whether (1) ondansetron reduces DPDD among individuals of either European or African ancestry (AA), and (2) that reductions in DPDD are greatest among ondansetron-treated individuals with population-specific combinations of genotypes at SLC6A4, HTR3A, and HTR3B. METHODS: In 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. RESULTS: 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. CONCLUSIONS: 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.

Effect of Pharmacogenomic Testing for Drug-Gene Interactions on Medication Selection and Remission of Symptoms in Major Depressive Disorder: The PRIME Care Randomized Clinical Trial.

Importance: Selecting effective antidepressants for the treatment of major depressive disorder (MDD) is an imprecise practice, with remission rates of about 30% at the initial treatment. Objective: To determine whether pharmacogenomic testing affects antidepressant medication selection and whether such testing leads to better clinical outcomes. Design, Setting, and Participants: A pragmatic, randomized clinical trial that compared treatment guided by pharmacogenomic testing vs usual care. Participants included 676 clinicians and 1944 patients. Participants were enrolled from 22 Department of Veterans Affairs medical centers from July 2017 through February 2021, with follow-up ending November 2021. Eligible patients were those with MDD who were initiating or switching treatment with a single antidepressant. Exclusion criteria included an active substance use disorder, mania, psychosis, or concurrent treatment with a specified list of medications. Interventions: Results from a commercial pharmacogenomic test were given to clinicians in the pharmacogenomic-guided group (n = 966). The comparison group received usual care and access to pharmacogenomic results after 24 weeks (n = 978). Main Outcomes and Measures: The co-primary outcomes were the proportion of prescriptions with a predicted drug-gene interaction written in the 30 days after randomization and remission of depressive symptoms as measured by the Patient Health Questionnaire-9 (PHQ-9) (remission was defined as PHQ-9 ≤ 5). Remission was analyzed as a repeated measure across 24 weeks by blinded raters. Results: Among 1944 patients who were randomized (mean age, 48 years; 491 women [25%]), 1541 (79%) completed the 24-week assessment. The estimated risks for receiving an antidepressant with none, moderate, and substantial drug-gene interactions for the pharmacogenomic-guided group were 59.3%, 30.0%, and 10.7% compared with 25.7%, 54.6%, and 19.7% in the usual care group. The pharmacogenomic-guided group was more likely to receive a medication with a lower potential drug-gene interaction for no drug-gene vs moderate/substantial interaction (odds ratio [OR], 4.32 [95% CI, 3.47 to 5.39]; P < .001) and no/moderate vs substantial interaction (OR, 2.08 [95% CI, 1.52 to 2.84]; P = .005) (P < .001 for overall comparison). Remission rates over 24 weeks were higher among patients whose care was guided by pharmacogenomic testing than those in usual care (OR, 1.28 [95% CI, 1.05 to 1.57]; P = .02; risk difference, 2.8% [95% CI, 0.6% to 5.1%]) but were not significantly higher at week 24 when 130 patients in the pharmacogenomic-guided group and 126 patients in the usual care group were in remission (estimated risk difference, 1.5% [95% CI, -2.4% to 5.3%]; P = .45). Conclusions and Relevance: Among patients with MDD, provision of pharmacogenomic testing for drug-gene interactions reduced prescription of medications with predicted drug-gene interactions compared with usual care. Provision of test results had small nonpersistent effects on symptom remission. Trial Registration: ClinicalTrials.gov Identifier: NCT03170362.

Bayesian set of best dynamic treatment regimes: Construction and sample size calculation for SMARTs with binary outcomes.

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/.

Daily steps and depressive symptoms: A longitudinal evaluation of patients with major depressive disorder in the precision medicine in mental health care study.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. LIMITATIONS: 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. CONCLUSIONS: 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.

Efficacy and comparative effectiveness of telephone and smartphone remote continuing care interventions for alcohol use disorder: a randomized controlled trial.

BACKGROUND AND AIMS: Management of alcohol use disorder (AUD) could be enhanced by effective remote treatments. This 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 four groups with 3-, 6-, 9-, 12- and 18-month follow-ups. SETTING: University research center in Philadelphia, PA, 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: The primary outcome was percentage of 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 [Cohen's d = 0.35, P = 0.018, 95% confidence interval (CI) = (-1.42, -0.20)], ACHESS [d = 0.31, P = 0.031, 95% CI = (-1.27, -0.06)] and TMC + ACHESS [d = 0.36, P = 0.009, 95% CI = (-1.40, -0.20)] than in TAU. Differences between TMC + ACHESS, TMC and ACHESS were small (d ≤ 0.06) 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 = 0.025). 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.

Varenicline for the Treatment of Cocaine Dependence.

OBJECTIVES: Varenicline is a partial agonist at the α2ß4 and α6ß2 nAChR receptors and a full agonist at α7 receptors. Both α7 and α6ß2 receptors are implicated in the neural reward circuitry activated by cocaine use. A preliminary clinical trial suggested that varenicline treatment reduced cocaine use. This trial was intended to replicate and extend the findings of the previous trial. METHODS: This was a 12-week, double-blind, placebo-controlled clinical trial involving 156 subjects with DSM IV cocaine dependence. Subjects received up to 2 mg of varenicline or identical placebo daily along with weekly relapse prevention psychotherapy. The primary outcome measure was cocaine use measured by thrice-weekly urine drug screens. Additional outcome measures included end of study cocaine abstinence, cocaine craving, cocaine withdrawal symptom severity, cigarette use, and global improvement measure by the Clinical Global Improvement Scale. RESULTS: End of study cocaine abstinence, measured by urine drug screens during the last 3 weeks of the trial, was not different between groups (8% in the varenicline treated subjects and versus 9% in placebo-treated subjects). Generalized estimating equations analysis of urine drug screen results showed no significant difference between groups in cocaine abstinence over the 12 weeks of the trial. There were no significant differences between the 2 groups in cocaine craving or cocaine withdrawal symptom severity. Varenicline was well-tolerated. There were no medication-associated serious adverse events. CONCLUSIONS: Varenicline plus cognitive-behavioral therapy does not seem to be an efficacious treatment for cocaine dependence.

Neurocognitive predictors of treatment outcomes in psychotherapy for comorbid PTSD and substance use disorders.

OBJECTIVE: 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. METHOD: 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. RESULTS: 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. CONCLUSIONS: 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).

Extended release injectable naltrexone before vs. after release: A randomized trial of opioid addicted persons who are in prison.

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.