Smoking Cessation After Initial Treatment Failure With Varenicline or Nicotine Replacement: A Randomized Clinical Trial.

Importance: Most people who smoke do not quit on their initial attempt. Objective: To determine the best subsequent strategy for nonabstinence following initial treatment with varenicline or combined nicotine replacement therapy (CNRT). Design, Setting, and Participants: Using a double-blind, placebo-controlled, sequential multiple assignment randomized trial, 490 volunteers were randomized to receive 6 weeks of varenicline or CNRT. After 6 weeks, nonabstainers were rerandomized to continue, switch, or increase medication dosage for 6 additional weeks. The study was conducted from June 2015 through October 2019 in a Texas tobacco treatment clinic. Interventions: The initial treatment was 2 mg/d of varenicline or the combined replacement therapy of a 21-mg patch plus 2-mg lozenge. The rerandomized participants either continued with their initial therapies, switched between varenicline and CNRT, or increased dosages either to 3-mg or more of varenicline or to a 42-mg patch and lozenges. All received weekly brief counseling. Main Outcomes and Measures: Biochemically verified 7-day point prevalence abstinence at the end of treatment at 12 weeks. Results: The 490 randomized participants (210 female [43%], 287 non-Hispanic White [58%], mean age, 48.1 years) smoked an average of 20 cigarettes per day. After the first phase, 54 participants in the CNRT group were abstinent and continued their therapy; of the 191 who were not abstinent, 151 were rerandomized, and the 40 who did not return for rerandomization were assigned to continue their initial CNRT condition in phase 2. The end-of-treatment abstinence rate for the 191 phase 1 nonabstainers was 8% (95% credible interval [CrI], 6% to 10%) for the 90 (47%) who continued at the dosage condition, 14% (CrI, 10% to 18%) for the 50 (33%) who increased their dosage, and 14% (95% CrI, 10% to 18%) for the 51 (34%) who switched to varenicline (absolute risk difference [RD], 6%; 95% CrI, 6% to 11%) with more than 99% posterior probability that either strategy conferred benefit over continuing the initial dosage. After the first phase, 88 participants in the varenicline group were abstinent and continued their therapy; of the 157 who were not abstinent, 122 were rerandomized and 35 who did not return for rerandomization were assigned to continue with the varenicline condition. The end-of-treatment abstinence rate for the 157 phase 1 nonabstainers was 20% (95% CrI, 16% to 26%) for the 39 (32%) who increased their varenicline dosage, 0 (95% CrI, 0 to 0) for the 41 (34%) who switched CNRT, and 3% (95% CrI, 1% to 4%) for the 77 (49%) who were assigned to the continued varenicline condition (absolute RD, -3%; 95% CrI, -4% to -1%) with more than 99% posterior probability that continuing varenicline at the initial dosage was worse than switching to a higher dosage. Furthermore, increasing the varenicline dosage had an absolute RD of 18% (95% CrI, 13% to 24%) and a more than 99% posterior probability of conferring benefit. The secondary outcome of continuous abstinence at 6 months indicated that only increased dosages of the CNRT and varenicline provided benefit over continuation of the initial treatment dosages. Conclusions and Relevance: For individuals who smoked but did not achieve abstinence after treatment with varenicline, increasing the dosage enhanced abstinence vs continuing, whereas for nonabstainers initially treated with CNRT, a dosage increase or switch to varenicline enhanced abstinence and may be viable rescue strategies. Trial Registration: ClinicalTrials.gov Identifier: NCT02271919.

Distress tolerance: prospective associations with cognitive-behavioral therapy outcomes in adults with posttraumatic stress and substance use disorders.

74Distress tolerance (DT; perceived or actual ability to tolerate aversive physical or emotional states) is related to both posttraumatic stress disorder (PTSD) symptoms and substance use disorders (SUD). This investigation evaluates self-report and behavioral measures of DT as potential predictors of PTSD and SUD cognitive-behavioral therapy outcomes. Participants included 41 treatment-seeking adults (53.7% women; 73.2% African American; Mage = 44.90, SD = 9.68) who met at least four symptoms of DSM-5 PTSD and DSM-IV substance dependence, assessed via structured interviews. At baseline (pre-treatment), participants completed the Distress Tolerance Scale (DTS), Mirror-Tracing Persistence Task (MTPT), Breath Holding task, and Paced Auditory Serial Addition Task. The Clinician-Administered PTSD Scale for DSM-5 severity scores and percent days of primary substance use, measured via Timeline Follow-back, were used as indicators of PTSD symptoms and substance use, respectively. Covariates included treatment condition, baseline PTSD symptom severity, and baseline substance use. Lower perceived DT at baseline (DTS total score) was associated with higher PTSD symptom severity at end-of-treatment. Lower behavioral DT at baseline (MTPT duration) was associated with higher substance use at the conclusion of treatment (i.e. proportion of number of use days to total number of days between two final treatment sessions).

Neurophysiological and clinical effects of the NMDA receptor antagonist lanicemine (BHV-5500) in PTSD: A randomized, double-blind, placebo-controlled trial.

BACKGROUND: Posttraumatic stress disorder (PTSD) is associated with hyperarousal and stress reactivity, features consistent with behavioral sensitization. In this Phase 1b, parallel-arm, randomized, double-blind, placebo-controlled trial, we tested whether the selective low-trapping N-methyl-D-aspartate receptor (NMDAR) antagonist [Lanicemine (BHV-5500)] blocks expression of behavioral sensitization. METHODS: Twenty-four participants with elevated anxiety potentiated startle (APS) and moderate-to-severe PTSD symptoms received three infusions of lanicemine 1.0 mg/ml (100 mg) or matching placebo (0.9% saline) (1:1 ratio), over a 5-day period. The primary outcome was change in APS from baseline to end of third infusion. We also examined changes in EEG gamma-band oscillatory activity as measures of NMDAR target engagement and explored Clinician-Administered PTSD Scale (CAPS-5) hyperarousal scores. RESULTS: Lanicemine was safe and well-tolerated with no serious adverse events. Using Bayesian statistical inference, the posterior probability that lanicemine outperformed placebo on APS T-score after three infusions was 38%. However, after the first infusion, there was a 90% chance that lanicemine outperformed placebo in attenuating APS T-score by a standardized effect size more than 0.4. CONCLUSION: We demonstrated successful occupancy of lanicemine on NMDAR using gamma-band EEG and effects on hyperarousal symptoms (Cohen's d = 0.75). While lanicemine strongly attenuated APS following a single infusion, differential changes from placebo after three infusions was likely obscured by habituation effects. To our knowledge, this is the first use of APS in the context of an experimental medicine trial of a NMDAR antagonist in PTSD. These findings support selective NMDAR antagonism as a viable pharmacological strategy for salient aspects of PTSD.

Exenatide Adjunct to Nicotine Patch Facilitates Smoking Cessation and May Reduce Post-Cessation Weight Gain: A Pilot Randomized Controlled Trial.

INTRODUCTION: Approved pharmacological treatments for smoking cessation are modestly effective, underscoring the need for improved pharmacotherapies. Glucagon-like peptide-1 receptor (GLP-1R) agonists attenuate the rewarding effects of nicotine in preclinical studies. We examined the efficacy of extended-release exenatide, a GLP-1R agonist, combined with nicotine replacement therapy (NRT, patch) for smoking cessation, craving, and withdrawal symptoms, with post-cessation body weight as a secondary outcome. METHODS: Eighty-four prediabetic and/or overweight smokers were randomized (1 : 1) to once-weekly placebo or exenatide, 2 mg, subcutaneously. All participants received NRT (21 mg) and brief smoking cessation counseling. Seven-day point prevalence abstinence (expired CO level ≤5 ppm), craving, withdrawal, and post-cessation body weight were assessed following 6 weeks of treatment. A Bayesian approach for analyzing generalized linear models yielded posterior probabilities (PP) to quantify the evidence favoring hypothesized effects of treatment on the study outcomes. RESULTS: Exenatide increased the risk for smoking abstinence compared to placebo (46.3% and 26.8%, respectively), (risk ratio [RR] = 1.70; 95% credible interval = [0.96, 3.27]; PP = 96.5%). Exenatide reduced end-of-treatment craving in the overall sample and withdrawal among abstainers. Post-cessation body weight was 5.6 pounds lower in the exenatide group compared to placebo (PP = 97.4%). Adverse events were reported in 9.5% and 2.3% of participants in the exenatide and placebo groups, respectively. CONCLUSIONS: Exenatide, in combination with the NRT improved smoking abstinence, reduced craving and withdrawal symptoms, and decreased weight gain among abstainers. Findings suggest that the GLP-1R agonist strategy is worthy of further research in larger, longer duration studies. IMPLICATIONS: Despite considerable progress in tobacco control, cigarette smoking remains the leading cause of preventable disease, disability, and death. In this pilot study, we showed that extended-release exenatide, a glucagon-like peptide-1 receptor agonist, added to the nicotine patch, improved abstinence and mitigated post-cessation body weight gain compared to patch alone. Further research is needed to confirm these initial positive results.

Socioecological indicators of senior financial exploitation: an application of data science to 8,800 substantiated mistreatment cases.

Senior financial exploitation (FE) is prevalent and harmful. Its often insidious nature and co-occurrence with other forms of mistreatment make detection and substantiation challenging. A secondary data analysis of N = 8,800 Adult Protective Services substantiated senior mistreatment cases, using machine learning algorithms, was conducted to determine when pure FE versus hybrid FE was occurring. FE represented N = 2514 (29%) of the cases with 78% being pure FE. Victim suicidal ideation and threatening behaviors, injuries, drug paraphernalia, contentious relationships, caregiver stress, and burnout and victims needing assistance were most important for differentiating FE vs non-FE-related mistreatment. The inability to afford housing, medications, food, and medical care as well as victims suffering from intellectual disability disorder(s) predicted hybrid FE. This study distinguishes socioecological factors strongly associated with the presence of FE during protective service investigations. These findings support existing and new indicators of FE and could inform protective service investigation practices.

Brain Responses to Cigarette-Related and Emotional Images in Smokers During Smoking Cessation: No Effect of Varenicline or Bupropion on the Late Positive Potential.

Introduction: Varenicline and bupropion are two effective smoking cessation pharmacotherapies. Researchers have hypothesized that they might be effective, in part, because they reduce cue reactivity and cue-induced cravings. Here, we used event-related potentials (ERPs) to directly measure brain responses to cigarette-related and other motivationally relevant images during a pharmacologically aided quit attempt. Methods: Smokers involved in a 12-week placebo-controlled double-blind clinical trial of smoking cessation medications (varenicline, bupropion, placebo) took part in the study. We assessed participants at two time points: 24 h (n = 140) and 4 weeks (n = 176) after the quit date. At both sessions, we measured the amplitude of the late positive potential (LPP), an ERP component reliably associated with motivational relevance, and self-reported tonic craving using the brief version of the Questionnaire of Smoking Urges (QSU-Brief). Results: At both sessions, emotional and cigarette-related images evoked significantly larger LPPs than neutral images. Neither drug type nor smoking abstinence altered this effect at either session. At both sessions, varenicline and bupropion significantly reduced self-reported tonic craving relative to the placebo condition. Conclusions: While both varenicline and bupropion reduced self-reported tonic craving, neither medication altered the amplitude of the LPP to cigarette-related or emotional pictures in smokers attempting to quit. These medications may influence abstinence by means other than by reducing neuroaffective responses to cigarette-related cues. Smokers should be prepared for the likelihood that even after several weeks of successful abstinence, once treatment ends, cigarette-related cues may remain motivationally relevant and trigger cravings that might lead to relapse. Implications: Bupropion and varenicline do not alter electrophysiological responses, as measured by the LPP, to cigarette-related and emotional images. These findings help explain why cigarette-related cues can trigger relapse when smoking cessation medication treatments end.

Change in physical activity and quality of life in endometrial cancer survivors receiving a physical activity intervention.

BACKGROUND: Endometrial cancer survivors are at an increased risk of poor quality of life outcomes. Physical activity is positively associated with general quality of life in this population, however, little is known about how changes in physical activity may be associated with changes in specific aspects of quality of life. The aim of this secondary data analysis was to explore the relationships between change in physical activity and change in physical, mental, social, and other aspects of quality of life in endometrial cancer survivors receiving a physical activity intervention. METHODS: Endometrial cancer survivors (N = 100) participated in a telephone-based physical activity intervention for six months. At baseline and post-intervention we measured physical activity via accelerometry and ecological momentary assessment, and quality of life via the Short Form Health Survey (SF-36), the Quality of Life of Adult Cancer Survivors instrument, the Brief Symptom Inventory, the Pittsburgh Sleep Quality Index, and the Perceived Stress Scale. We conducted structural equation modeling path analyses to investigate how physical activity post-intervention was associated with the quality of life measures' subscales post-intervention, adjusting for baseline levels and potentially confounding covariates. RESULTS: Increasing physical activity was positively associated with improvements in general health (p = .044), role limitation due to physical health (p = .005), pain (p = .041), and somatic distress (p = .023). There was no evidence to indicate that change in physical activity was associated with change in other aspects of quality of life. CONCLUSIONS: Endometrial cancer survivors are at higher risk for suffering from challenges to physical quality of life, and findings from this study suggest that increasing physical activity may alleviate some of these problems. Further research is needed to determine whether other aspects of quality of life are linked to change in physical activity. TRIAL REGISTRATION: Trial registration number: NCT00501761 Name of registry: clinicaltrials.gov Date of registration: July 16, 2007. Date of enrollment: June 16, 2005.

Resting Heart Rate Variability: Exploring Associations With Symptom Severity in Adults With Substance Use Disorders and Posttraumatic Stress.

Objective: Substance use disorders and posttraumatic stress symptoms are commonly comorbid. Previous studies have established that those with substance use disorders or posttraumatic stress disorder (PTSD) have lower high frequency-heart rate variability (HF-HRV) compared to controls, suggesting that low HF-HRV may be a biomarker of a common physiological mechanism underlying both disorders. We evaluated HF-HRV as a potential biomarker of a common underlying process by testing whether lower HF-HRV related to greater severity of substance use and PTSD symptoms in individuals with both substance use disorders and at least four symptoms of PTSD. Methods: HF-HRV was measured in 49 adults with substance use disorders and at least four symptoms of PTSD. We performed a series of regressions controlling for age to test whether low HF-HRV was associated with greater substance use disorder and PTSD symptom severity. Substance use disorder symptoms were measured by the Addiction Severity Index and PTSD symptoms were measured by the Clinician-Administered PTSD Scale and the PTSD Checklist. Results: After controlling for age, low resting HF-HRV was significantly associated with drug and alcohol symptom severity but not PTSD symptom severity. Conclusions: HF-HRV may be more sensitive to the severity of drug and alcohol use rather than PTSD. Findings may suggest that in PTSD populations, HF-HRV may primarily index comorbid substance use disorder symptoms. HF-HRV could serve as an objective measure of substance use severity and should be further investigated as a predictor of outcomes in treatment for substance use disorders.

Improvement of Smoking Abstinence Rates With Increased Varenicline Dosage: A Propensity Score-Matched Analysis.

PURPOSE/BACKGROUND: It is unclear whether increasing the dose of varenicline beyond the standard dose of 2 mg/d would improve smoking abstinence. METHODS: We examined the effect of 3 mg/d of varenicline on smoking abstinence among smokers who had reduced their smoking by 50% or more in response to 2 mg/d for at least 6 weeks but had not quit smoking. Of 2833 patients treated with varenicline, dosage of a subset of 73 smokers was increased to 3 mg/d after 6 weeks. We used a propensity score analysis involving multiple baseline covariates to create a comparative sample of 356 smokers who remained on 2 mg/d. All smokers received concurrent and similar smoking-cessation counseling. RESULTS: At 3 months, we found higher 7-day point prevalence smoking-abstinence rate in the 3-mg group (26%) than in the 2-mg group (11.5%, χ = 10.60, P < 0.001; risk ratio [RR], 2.3; 95% confidence interval [CI], 1.4-3.6). The difference in abstinence rates remained significant at the 6-month (P < 0.001; RR, 2.6; 95% CI, 1.6-3.9) and 9-month follow-up (P < 0.001; RR, 2.2; 95% CI, 1.4-3.3). CONCLUSIONS: A relatively small increase in the daily dose of varenicline seems to offer a benefit for those who are not able to achieve total abstinence after approximately 6 weeks of 2 mg/d.

Patterns of Tobacco Product Use and Correlates Among Adults in the Population Assessment of Tobacco and Health (PATH) Study: A Latent Class Analysis.

Introduction: As the tobacco industry and market evolves, there is a growing need to understand the patterns of use of tobacco products and how they relate to demographics, dependency, withdrawal, and quit behavior. Methods: We analyzed data from wave 1 of the PATH Study consisting of 14856 individuals. Current users were defined as consuming at least 1 of 10 tobacco products. We performed a latent class analysis (LCA) to identify patterns of tobacco use. We used multinomial regression analysis to explore the association between these patterns with covariates representing socioeconomic status dependence/addiction, past quit attempts, and withdrawal severity. Results: We identified four groups of current tobacco users with distinct profiles: (1) 61% of the sample were identified as cigarette-only users; (2) 9% were smokeless tobacco users; (3) 17% of the sample were characterized by being current users of all types of combustible tobacco including cigars, cigarillos, filtered cigars, and smoking a pipe (4) finally, 13% were e-cig and hookah users. All classes also shared a varying frequency of cigarette use. Exclusive cigarette users were more likely to be older and female, and experienced higher dependency and withdrawal. Users of e-cigs and hookah were the younger, most educated of all four subgroups, and presented the lowest dependency and withdrawal among the four groups. Conclusions: FDA policy makers may want to discourage the use of tobacco products associated with higher tobacco dependency, and products that may contribute to experiencing higher levels of withdrawal symptoms by the user when trying to quit. Implications: We identified four patterns of tobacco product use that are significantly related to demographic characteristics, dependency, and withdrawal. Policies should target users more likely to use tobacco products that increase dependency and withdrawal, making quitting more difficult.

Cigarette Nicotine Content as a Moderator of the Relationship Between Negative Affect and Smoking.

INTRODUCTION: Research suggests a strong association between negative affect (NA) and smoking. However, little is known about the association between NA and smoking among individuals who switch to reduced-nicotine cigarettes. The goal of this study was to examine the extent to which cigarette nicotine content moderates the relationship between NA and smoking over time. METHODS: Seven hundred and seventeen participants, 237 in the normal nicotine content (NNC; 15.8 mg/g and usual brand) cigarette group and 480 in the very low nicotine content (VLNC; 2.4 mg/g nicotine or less) cigarette group, participated in a randomized trial that examined the effects of cigarette nicotine content on smoking behavior over 6 weeks. We used parallel process latent growth curve modeling to estimate the relationship between changes in NA and changes in the numbers of cigarettes smoked per day (CPD), from baseline to 6 weeks, as a function of cigarette nicotine content. RESULTS: The relationship between NA and investigational CPD reduced over time for those in the VLNC group, but not for those in the NNC group. There was no significant relationship between change in PA and CPD over time for either cigarette group. CONCLUSIONS: Smoking VLNC cigarettes disrupts the relationship between smoking and negative affect, which may help reduce nicotine dependence. IMPLICATIONS: This study suggests that the association between NA and smoking behavior is reduced over time among those that smoked reduced-nicotine content cigarettes. This provides additional evidence that smoking reduced-nicotine content cigarettes may help reduce nicotine dependence.

Beyond Cue Reactivity: Non-Drug-Related Motivationally Relevant Stimuli Are Necessary to Understand Reactivity to Drug-Related Cues.

Neurobiological models of addiction posit that drug use can alter reward processes in two ways: (1) by increasing the motivational relevance of drugs and drug-related cues and (2) by reducing the motivational relevance of non-drug-related rewards. Here, we discuss the results from a series of neuroimaging studies in which we assessed the extent to which these hypotheses apply to nicotine dependence. In these studies, we recorded smokers' and nonsmokers' brain responses to a wide array of motivationally relevant visual stimuli that included pleasant, unpleasant, cigarette-related, and neutral images. Based on these findings, we highlight the flaws of the traditional cue reactivity paradigm and we conclude that responses to non-drug-related motivationally relevant stimuli should be used to appropriately gauge the motivational relevance of cigarette-related cues and to identify smokers attributing higher motivational relevance to drug-related cues than to non-drug-related rewards. Identifying these individuals is clinically relevant as they achieve lower rates of long-term smoking abstinence when attempting to quit. Finally, we show how this approach may be extended beyond nicotine dependence to inform theoretical and clinical research in the study of obesity. Implications: The cue reactivity paradigm (ie, comparing responses evoked by drug-related cues to those evoked by neutral cues) cannot provide conclusive information about the motivational relevance of drug-related cues. Responses to non-drug-related motivationally relevant stimuli should be used to appropriately gauge the level of motivational relevance that substance-dependent individuals attribute to drug-related cues.

Effects of oxytocin on aggressive responding in healthy adult men.

This study investigated the acute effects of oxytocin (OT) on human aggression using a well-established laboratory measure of state (reactive) aggression to test the hypothesis that OT would decrease the frequency of aggressive responding. In a within-subject design, 17 healthy male volunteers received placebo or 24 IU of intranasal OT. Aggression was measured using the Point Subtraction Aggression Paradigm at 30 min before and 30, 60, and 90 min after dose. Acute OT did not produce a significant main effect on aggressive behavior. OT attenuated the expected rise in diastolic blood pressure from morning to early afternoon observed under placebo, providing a possible indication of biological activity. Examination of individual differences showed that aggressive responding following OT dosing (but not placebo) was positively correlated with psychometric measures of interpersonal manipulation and anger (Pearson's r=0.57), indicating that higher scores on these antisocial personality traits were related to increased aggressive behavior following OT administration. These preliminary results stand in contrast to previous work on the prosocial effects of OT and highlight the need for further understanding of individual differences in aggression following OT administration. Such individual differences may have implications for the therapeutic use of OT in individuals with psychiatric disorders and dysfunctional social behavior.

Demographic and psychological factors associated with lifetime cocaine use: An exploratory factor analysis of baseline questionnaires.

OBJECTIVES: Underlying heterogeneity among individuals with cocaine dependence is widely postulated in the literature, however, identification of a group of factors that explain risk of cocaine use severity has yet to be confirmed. METHODS: Latent mixture modeling evaluated 338 cocaine-dependent individuals recruited from the community to assess the evidence for the presence of distinct subgroups. Variables included 5 baseline questionnaires measuring cognitive function (Shipley), impulsivity (BIS), mood (BDI), affective lability (ALS), and addiction severity (ASI). Results failed to suggest multiple subgroups. Given a lack of evidence for discrete latent classes, an exploratory factor analysis (EFA) followed by exploratory structural equation modeling (ESEM) was implemented to identify functional dimensions to enhance interpretation of these variables. RESULTS: Findings from the EFA indicated a 3-factor model as the best fit, and the subsequent ESEM solution resulted in associations with lifetime cocaine use. Factor 1, best characterized by demographic factors (gender, age), is associated with less lifetime cocaine use. Psychological problems best characterize factor 2, which is associated with higher lifetime cocaine use. Finally, factor 3 is characterized by other substance use (alcohol and marijuana). Although this factor did not demonstrate a statistically reliable relation with self-reported, lifetime cocaine use, it did indicate a potentially meaningful positive association. CONCLUSIONS: These 3 factors delineate dimensions of functioning that likewise help characterize the variability found in previously established associations with self-reported cocaine use.

The influence of dopamine ß-hydroxylase gene polymorphism rs1611115 on levodopa/carbidopa treatment for cocaine dependence: a preliminary study.

Recent studies have suggested that heterogeneity in the level of dopamine activity and function might be useful for identifying a subgroup of cocaine-dependent patients responding better to dopamine-enhancement pharmacotherapy. Here we hypothesized that response to levodopa/carbidopa treatment would be greater in patients with genetically determined low levels of the dopamine metabolizing enzyme dopamine ß-hydroxylase (DßH). Seventy-one cocaine-dependent patients who participated in a 12-week randomized double-blind placebo-controlled trial of levodopa/carbidopa were genotyped for the DßH gene (DBH) polymorphism rs1611115. Our results showed that for patients with the low DßH activity genotypes (CT/TT) who received levodopa, the odds of having cocaine-positive urine decreased significantly over treatment compared with placebo-treated patients with the CT/TT genotypes (P=0.004). Individuals with the normal DßH activity genotype (CC) showed no differential response to levodopa. These preliminary results need to be confirmed in a larger sample focusing on the DBH polymorphism.

Prequit fMRI responses to pleasant cues and cigarette-related cues predict smoking cessation outcome.

INTRODUCTION: The reasons that some smokers find it harder to quit than others are unclear. Understanding how individual differences predict smoking cessation outcomes may allow the development of more successful personalized treatments for nicotine dependence. Theoretical models suggest that drug users might be characterized by increased sensitivity to drug cues and by reduced sensitivity to nondrug-related natural rewards. We hypothesized that baseline differences in brain sensitivity to natural rewards and cigarette-related cues would predict the outcome of a smoking cessation attempt. METHODS: Using functional magnetic resonance imaging, we recorded prequit brain responses to neutral, emotional (pleasant and unpleasant), and cigarette-related cues from 55 smokers interested in quitting. We then assessed smoking abstinence, mood, and nicotine withdrawal symptoms during the course of a smoking cessation attempt. RESULTS: Using cluster analysis, we identified 2 groups of smokers who differed in their baseline responses to pleasant cues and cigarette-related cues in the posterior visual association areas, the dorsal striatum, and the medial and dorsolateral prefrontal cortex. Smokers who showed lower prequit levels of brain reactivity to pleasant stimuli than to cigarette-related cues were less likely to be abstinent 6 months after their quit attempt, and they had higher levels of negative affect during the course of the quit attempt. CONCLUSIONS: Smokers with blunted brain responses to pleasant stimuli, relative to cigarette-related stimuli, had more difficulty quitting smoking. For these individuals, the lack of alternative forms of reinforcement when nicotine deprived might be an important factor underlying relapse. Normalizing these pathological neuroadaptations may help them achieve abstinence.

Opioid Risk Tool, in-hospital opioid exposure, and opioid demand predict pain outcomes following traumatic injury.

Prescribed opioids are a mainstay pain treatment after traumatic injury, but a subgroup of patients may be at risk for continued opioid use. We evaluated the predictive utility of a traditional screening tool, the Opioid Risk Tool (ORT), and two other measures: average in-hospital milligram morphine equivalents (MME) per day and an assessment of opioid demand in predicting pain outcomes. Assessments of pain-related outcomes (pain intensity, interference, injury-related stress, and need for additional pain treatment) were administered at 2 weeks and 12 months post-discharge in a sample of 34 patients hospitalized for traumatic injury. Bayesian linear models were used to evaluate changes in responses over time as a function of predictors. High-risk ORT, higher MME per day, and greater opioid demand predicted less change in outcomes over time. This report provides first evidence that malleable factors of opioid and opioid demand have utility in predicting pain outcomes following traumatic injury.

Contingency management plus acceptance and commitment therapy for initial cocaine abstinence: Results of a sequential multiple assignment randomized trial (SMART).

BACKGROUND: This study tested an adaptive intervention for optimizing abstinence outcomes over phases of treatment for cocaine use disorder using a SMART design. Phase 1 assessed whether 4 weeks of contingency management (CM) improved response with the addition of Acceptance and Commitment Therapy (ACT). Phase 2 assessed pharmacological augmentation with modafinil (MOD) vs. placebo (PLA) for individuals not achieving abstinence during Phase 1. METHOD: For Phase 1 of treatment, participants (N=118) were randomly allocated to ACT+CM or Drug Counseling (DC+CM), the comparison condition. At week 4, treatment response was defined as the submission of six consecutive cocaine-negative urine drug screens (UDS). Phase 1 non-responders were re-randomized to MOD or PLA as adjunct to their initial treatment. Phase 1 responders continued receiving their initial treatment. Primary outcomes included response rate and proportion of cocaine-negative UDS for Phase 1 and 2. Analyses used Bayesian inference with 80% pre-specified as the posterior probability (PP) threshold constituting moderate evidence that an effect exists. RESULTS: Phase 1 response was higher in the ACT+CM group (24.5%) compared to the DC+CM group (17.5%; PP = 84.5%). In Phase 2, the proportion of cocaine-negative UDS among Phase 1 responders did not differ by initial treatment (PP = 61.8%) but remained higher overall compared to Phase 1 non-responders (PPs > 99%). No evidence of an effect favoring augmentation with MOD was observed. DISCUSSION: Adding ACT to CM increased abstinence initiation. Initial responders were more likely to remain abstinent compared to initial non-responders, for whom modafinil was not an effective pharmacotherapy augmentation strategy.

Deep sequencing of candidate genes identified 14 variants associated with smoking abstinence in an ethnically diverse sample.

Despite the large public health toll of smoking, genetic studies of smoking cessation have been limited with few discoveries of risk or protective loci. We investigated common and rare variant associations with success in quitting smoking using a cohort from 8 randomized controlled trials involving 2231 participants and a total of 10,020 common and 24,147 rare variants. We identified 14 novel markers including 6 mapping to genes previously related to psychiatric and substance use disorders, 4 of which were protective (CYP2B6 (rs1175607105), HTR3B (rs1413172952; rs1204720503), rs80210037 on chr15), and 2 of which were associated with reduced cessation (PARP15 (rs2173763), SCL18A2 (rs363222)). The others mapped to areas associated with cancer including FOXP1 (rs1288980) and ZEB1 (rs7349). Network analysis identified significant canonical pathways for the serotonin receptor signaling pathway, nicotine and bupropion metabolism, and several related to tumor suppression. Two novel markers (rs6749438; rs6718083) on chr2 are flanked by genes associated with regulation of bodyweight. The identification of novel loci in this study can provide new targets of pharmacotherapy and inform efforts to develop personalized treatments based on genetic profiles.

Aggression, impulsivity, and psychopathic traits in combined antisocial personality disorder and substance use disorder.

Aggression, impulsivity, and psychopathic traits are prominent in both antisocial personality disorder (ASPD) and substance use disorders (SUD), but have rarely been examined collectively. The authors' results show that all three variables were elevated in adults with comorbid ASPD/SUD, relative to SUD-only and control subjects.