Low versus high level of response to alcohol affects amygdala functional connectivity during processing of emotional stimuli.

BACKGROUND: Low levels of response (low LR) to alcohol predict heavy drinking and alcohol problems. Functional magnetic resonance imaging (fMRI) studies of emotion processing have shown that low LR individuals exhibit lower activation in task-related brain regions following both placebo and alcohol administration, but these studies did not examine functional brain networks that might contribute to the phenomena. The current study expands upon the earlier results by evaluating whether functional connectivity differences between the amygdala and other brain regions modulated by emotional face processing are associated with LR. Based on prior findings, we hypothesized that low LR is related to lower functional connectivity in fronto-amygdalar functional circuits, which underlie the processing of emotional stimuli. METHODS: Secondary analyses were conducted on data from a double-blind, placebo-controlled, within-subjects, cross-over study in 108 18-to-25-year-old low and high LR sex-matched pairs without alcohol use disorder at baseline. Participants performed modified emotional faces processing tasks after receiving placebo or approximately 0.7 ml/kg of ethanol. Psychophysiological interaction analyses examined functional connectivity between left and right amygdalae and related brain circuits using LR-by-alcohol general linear models. The data included 54 sex-matched pairs with 216 fMRI scans comprising alcohol and placebo conditions. RESULTS: Compared with individuals with high LR, low LR subjects demonstrated lower functional connectivity between the amygdala and the frontal lobes, insula, and parietal regions, while processing angry and happy faces. Interactions showed lower connectivity following alcohol in low LR and higher connectivity in high LR groups. CONCLUSIONS: Low LR individuals demonstrated lower functional connectivity in response both to placebo and a modest dose of ethanol. Attenuated connectivity among low LR individuals when processing emotional faces may contribute to an impaired ability to recognize alcohol intoxication in social situations and to appraise angry and happy emotions irrespective of whether alcohol is consumed.

Topiramate decreases the salience of motivationally relevant visual cues among smokers with alcohol use disorder.

BACKGROUND: There is preliminary evidence that the anticonvulsant topiramate increases the likelihood of both smoking and alcohol abstinence among smokers with alcohol use disorder (AUD), but its therapeutic mechanism has not been determined. We used event-related potentials (ERPs) to evaluate topiramate's effect on the salience of drug-related, emotional, and neutral pictorial cues to identify whether one of its potential therapeutic mechanisms involves reduction of the salience of motivationally relevant cues. METHODS: Participants enrolled in a multisite clinical trial treating smokers with AUD were randomly assigned to receive placebo, low-dose topiramate (up to 125 mg/day), or high-dose topiramate (up to 250 mg/day), along with brief behavioral compliance enhancement treatment. A subsample (n = 101) completed ERP assessments at baseline (1 week pre-medication) and week 5 (5 weeks on medication; 1 week pre-quit). We assessed the salience of pleasant, unpleasant, cigarette-related, alcohol-related, and neutral pictorial cues using the late positive potential (LPP) ERP component and measured self-reported substance use, reinforcement, craving, and withdrawal. RESULTS: Five weeks of high-dose topiramate treatment decreased LPP amplitudes in response to both emotional (pleasant and unpleasant) and drug-related cues (alcohol and cigarette), but not to neutral cues. However, results showed that the LPPs were not significant mediators of the relationship between topiramate dose and post-quit measures of substance use, reinforcement, craving, or withdrawal. CONCLUSIONS: These findings suggest that high-dose topiramate (up to 250 mg/day) decreases the motivational salience of both drug-related and emotional cues among smokers with AUD. However, the nonsignificant mediation analyses preclude any firm conclusions about whether this effect represents one of topiramate's therapeutic mechanisms of action.

The effects of varenicline, bupropion, nicotine patch, and placebo on smoking cessation among smokers with major depression: A randomized clinical trial.

IMPORTANCE: Improving treatment outcomes for smokers with major depressive disorder (MDD) can have significant public health implications. OBJECTIVE: To evaluate the safety and efficacy of smoking cessation pharmacotherapy among smokers with MDD. DESIGN: Secondary analysis of a randomized, double-blind, active- (nicotine patch) and placebo-controlled trial of 12 weeks of either varenicline or bupropion with a 12-week follow-up. PARTICIPANTS: Community volunteers 18-75 years of age; smoke 10+ cigarettes/day; with clinically stable MDD (N = 2635) or no psychiatric disorder (N = 4028), from 140 sites in 16 countries. INTERVENTION: Twelve weeks of pharmacotherapy (placebo [PLA], nicotine replacement therapy [NRT], bupropion [BUP], varenicline [VAR]) plus brief cessation counseling. MEASURE(S): Primary safety outcome: the occurrence of ≥1 treatment-emergent, moderate to severe neuropsychiatric adverse event (NPSAE). Primary efficacy outcome: biochemically confirmed continuous abstinence (CA) during the final 4 weeks of treatment (Weeks 9-12). RESULTS: A total of 6653 participants (56% female; 39% MDD) ~47 years old. Risk of NPSAEs did not differ by medication for MDD. MDD had higher risk (p < .0001) for NPSAEs than the NPC. Efficacy (6653; intent-to-treat): CA rates for MDD versus NPC respectively were 31.2% versus 38.0% VAR; 23.0% versus 26.1% BUP; 22.6% versus 26.4% NRT; and 13.4% versus 13.7% PLA but no differential treatment effect was noted within the cohorts. All active treatments differed from PLA but VAR showed the largest effect. CONCLUSIONS: Results suggest that for MDD smokers, inclusive of those with recurrent episode, varenicline plus counseling may be the best pharmacological option for the treatment of smoking given its greater efficacy effect size and similar risk of NPSAEs. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01456936. https://clinicaltrials.gov/ct2/show/NCT01456936.

Relationship between level of response to alcohol and acute tolerance.

BACKGROUND: A low level of response (low LR) to alcohol correlates with the later development of alcohol-related problems. Although some of the underpinnings of LR are understood, little is known about the potential relationship between LR and acute tolerance. The current analyses tested the hypothesis that a low LR will be explained in part by more intense acute tolerance to alcohol during a drinking session. METHODS: Data were generated through a reanalysis of data from 120 individuals who were 18- to 25-year-old, sex-matched pairs of low and high LR drinkers who at baseline did not meet criteria for an alcohol use disorder. Each subject participated in an oral alcohol challenge in which they consumed about 0.7 ml ethanol per kg and acute tolerance was measured as the differences in alcohol's effects at similar breath alcohol levels (BrACs) during the rising and falling breath alcohol concentration (BrAC) curve. Measures included aspects of the Subjective High Assessment Scale (SHAS) and body sway. RESULTS: Contrary to our hypothesis, but similar to results with other alcohol measures, acute tolerance was significantly attenuated in low LR compared with high LR individuals on most SHAS scores. Neither LR group demonstrated acute tolerance to alcohol for sleepiness or body sway. Men and women did not differ on any of these measures. CONCLUSION: These data do not support a role of acute tolerance in the low LR to alcohol as measured by subjective feelings of intoxication or body sway in these subjects, findings that were similar across males and females. In addition, consistent with the literature, the analyses demonstrated differences across measures such that acute tolerance was observed for most measures of subjective effects but not for body sway. Among the subjective effects, acute tolerance was observed for alcohol's intoxicating effect but not for feeling sleepy.

Psychiatric Comorbidity and Multimorbidity in the EAGLES Trial: Descriptive Correlates and Associations With Neuropsychiatric Adverse Events, Treatment Adherence, and Smoking Cessation.

INTRODUCTION: Psychiatric and substance use disorders represent barriers to smoking cessation. We sought to identify correlates of psychiatric comorbidity (CM; 2 diagnoses) and multimorbidity (MM; 3+ diagnoses) among smokers attempting to quit and to evaluate whether these conditions predicted neuropsychiatric adverse events (NPSAEs), treatment adherence, or cessation efficacy (CE). AIMS AND METHODS: Data were collected from November 2011 to January 2015 across sixteen countries and reflect the psychiatric cohort of the EAGLES trial. Participants were randomly assigned to receive varenicline, bupropion, nicotine replacement therapy, or placebo for 12 weeks and were followed for an additional 12 weeks posttreatment. NPSAE outcomes reflected 16 moderate-to-severe neuropsychiatric symptom categories, and CE outcomes included continuous abstinence at weeks 9-12 and 9-24. RESULTS: Of the 4103 participants included, 36.2% were diagnosed with multiple psychiatric conditions (20.9% CM, 15.3% MM). Psychiatric CM and MM were associated with several baseline factors, including male gender, nonwhite race or ethnicity, more previous quit attempts, and more severe mental health symptoms. The incidence of moderate-to-severe NPSAEs was significantly higher (p < .01) in participants with MM (11.9%) than those with CM (5.1%) or primary diagnosis only (4.6%). There were no significant (ps > .05) main effects or interactions with treatment condition for diagnostic grouping on treatment adherence or CE outcomes. CONCLUSIONS: While having multiple psychiatric diagnoses increased risk of developing moderate-to-severe NPSAEs during a quit attempt, neither CM nor MM were associated with treatment adherence or odds of quitting. These findings reassure providers to advise smokers with multiple stable psychiatric conditions to consider using Food and Drug Administration (FDA)-approved medications when trying to quit. IMPLICATIONS: Psychiatric MM may be associated with development of NPSAEs when smokers make a medication-assisted quit attempt, but it does not appear to be differentially associated with medication compliance or efficacy. Prescribing healthcare professionals are encouraged to not only promote use of FDA-approved pharmacotherapies by smokers with complex psychiatric presentations, but also to closely monitor such smokers for neuropsychiatric side effects that may be related to their mental health conditions. NCT #: NCT01456936.

Efficacy and safety of pharmacotherapies for smoking cessation in anxiety disorders: Subgroup analysis of the randomized, active- and placebo-controlled EAGLES trial.

BACKGROUND: Smoking rates are high in adults with anxiety disorders (ADs), yet little is known about the safety and efficacy of smoking-cessation pharmacotherapies in this group. METHODS: Post hoc analyses in 712 smokers with AD (posttraumatic stress disorder [PTSD], n = 192; generalized anxiety disorder [GAD], n = 243; panic disorder [PD], n = 277) and in a nonpsychiatric cohort (NPC; n = 4,028). Participants were randomly assigned to varenicline, bupropion, nicotine-replacement therapy (NRT), or placebo plus weekly smoking-cessation counseling for 12 weeks, with 12 weeks follow-up. General linear models were used to test the effects of treatment group, cohort, and their interaction on neuropsychiatric adverse events (NPSAEs), and continuous abstinence weeks 9-12 (treatment) and 9-24 (follow-up). RESULTS: NPSAE incidence for PTSD (6.9%), GAD (5.4%), and PD (6.2%) was higher versus NPC (2.1%), regardless of treatment. Across all treatments, smokers with PTSD (odds ratio [OR] = 0.58), GAD (OR = 0.72), and PD (OR = 0.53) had lower continuous abstinence rates weeks 9-12 (CAR9-12) versus NPC. Varenicline demonstrated superior efficacy to placebo in smokers with GAD and PD, respectively (OR = 4.53; 95% confidence interval [CI] = 1.20-17.10; and OR = 8.49; 95% CI = 1.57-45.78); NRT was superior to placebo in smokers with PD (OR = 7.42; 95% CI = 1.37-40.35). While there was no statistically significant effect of any treatment on CAR9-12 for smokers with PTSD, varenicline improved 7-day point prevalence abstinence at end of treatment in this subcohort. CONCLUSION: Individuals with ADs were more likely than those without psychiatric illness to experience moderate to severe NPSAEs during smoking-cessation attempts, regardless of treatment. While the study was not powered to evaluate abstinence outcomes with these subgroups of smokers with ADs, varenicline provided significant benefit for cessation in those with GAD and PD, while NRT provided significant benefit for those with PD.

Predictors of Neuropsychiatric Adverse Events with Smoking Cessation Medications in the Randomized Controlled EAGLES Trial.

BACKGROUND: Pre-treatment factors that increase smokers' risk of experiencing neuropsychiatric adverse events (NPSAEs) when quitting smoking are unknown. OBJECTIVE: To identify baseline smoker characteristics beyond the history of mental illness that predict which participants were more likely to experience moderate to severe NPSAEs in EAGLES. DESIGN: A prospective correlational cohort study in the context of a multinational, multicenter, double-blind, randomized trial. PARTICIPANTS: Smokers without (N = 3984; NPC)/with (N = 4050; PC) histories of, or current clinically stable, psychiatric disorders including mood (N = 2882; 71%), anxiety (N = 782; 19%), and psychotic (N = 386; 10%) disorders. INTERVENTIONS: Bupropion, 150 mg twice daily, or varenicline, 1 mg twice daily, versus active control (nicotine patch, 21 mg/day with taper) and placebo for 12 weeks with 12-week non-treatment follow-up. MAIN MEASURES: Primary safety outcome was the incidence of a composite measure of moderate/severe NPSAEs. Associations among baseline demographic/clinical characteristics and the primary safety endpoint were analyzed post hoc via generalized linear regression. KEY RESULTS: The incidence of moderate to severe NPSAEs was higher among smokers in the PC (238/4050; 5.9%) than in the NPC (84/3984; 2.1%). Three baseline characteristics predicted increased risk for experiencing clinically significant NPSAEs when quitting regardless of carrying a psychiatric diagnosis: current symptoms of anxiety (for every ~ 4-unit increase in HADS anxiety score, the absolute risk of occurrence of the NPSAE endpoint increased by 1% in both PC and NPC); prior history of suicidal ideation and/or behavior (PC, 4.4% increase; P = 0.001; NPC, 4.1% increase; P = 0.02), and being of White race (versus Black: PC, 2.9% ± 0.9 [SE] increase; P = 0.002; and NPC, 3.4% ± 0.8 [SE] increase; P = 0.001). Among smokers with psychiatric disorders, younger age, female sex, history of substance use disorders, and proxy measures of nicotine dependence or psychiatric illness severity also predicted greater risk. There were no significant interactions between these characteristics and treatment. Smokers with unstable psychiatric disorders or with current, active substance abuse were excluded from the study. CONCLUSIONS: Irrespective of cessation pharmacotherapy use, smokers attempting to quit were more likely to experience moderate to severe NPSAEs if they reported current anxiety or prior suicidal ideation at baseline and were White. In smokers with a psychiatric history, female sex, younger age, and greater severity of nicotine dependence were also predictive. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01456936.

Neuropsychiatric Safety and Efficacy of Varenicline, Bupropion, and Nicotine Patch in Smokers With Psychotic, Anxiety, and Mood Disorders in the EAGLES Trial.

BACKGROUND: Neuropsychiatric safety and relative efficacy of varenicline, bupropion, and transdermal nicotine patch (NRT) in those with psychiatric disorders are of interest. METHODS: We performed secondary analyses of safety and efficacy outcomes by psychiatric diagnosis in EAGLES (Evaluating Adverse Events in a Global Smoking Cessation Study), a 12-week, randomized, double-blind, triple-dummy, placebo- and active (NRT)-controlled trial of varenicline and bupropion with 12-week follow-up, in a subset population, n = 4092, with a primary psychotic (n = 390), anxiety (n = 792), or mood (n = 2910) disorder. Primary end-point parameters were incidence of prespecified moderate and severe neuropsychiatric adverse events (NPSAEs) and weeks 9 to 12 continuous abstinence rates (9-12CAR). RESULTS: The observed NPSAE incidence across treatments was 5.1% to 6.3% in those with a psychotic disorder, 4.6% to 8.0% in those with an anxiety disorder, and 4.6% to 6.8% in those with a mood disorder. Neither varenicline nor bupropion was associated with significantly increased NPSAEs relative to NRT or placebo in the psychiatric cohort or any psychiatric diagnostic subcohort. There was a significant effect of treatment on 9-12CAR (P < 0.0001) and no significant treatment-by-diagnostic subcohort interaction (P = 0.24). Abstinence rates with varenicline were superior to bupropion, NRT, and placebo, and abstinence with bupropion and NRT was superior to placebo. Within-diagnostic subcohort comparisons of treatment efficacy yielded estimated odds ratios for 9-12CAR versus placebo of greater than 3.00 for varenicline, greater than 1.90 for bupropion, and greater than 1.80 for NRT for all diagnostic groups. CONCLUSIONS: Varenicline, bupropion, and nicotine patch are well tolerated and effective in adults with psychotic, anxiety, and mood disorders. The relative effectiveness of varenicline, bupropion, and NRT versus placebo did not vary across psychiatric diagnoses.

Effects of Varenicline, Depressive Symptoms, and Region of Enrollment on Smoking Cessation in Depressed Smokers.

Introduction: Despite effective treatments, relapse to smoking remains a vexing global health problem. One predictor of relapse is depressive symptoms. Medications such as varenicline reduce withdrawal-related symptoms of depression, reducing relapse. This study examined whether varenicline moderated the effect of depressive symptoms on relapse, and whether this varied by region of enrollment. Methods: Adult smokers (n = 525; 37% male) with past or current, stable major depressive disorder recruited from United States (n = 255), and European (n = 270) sites participated in a randomized, double-blind cessation treatment trial including 12 weeks of varenicline or placebo, with 40-week nontreatment follow-up. Results: Longitudinal and binary logistic regressions were used to model the probability of sustained abstinence by end of treatment and point-prevalence abstinence in follow-up. The association between depression symptoms and abstinence was moderated by intervention group at end of treatment, and by region during follow-up: more severe symptoms were associated with end-of-treatment relapse for placebo (odds ratio [OR] = 0.91, p = .003), but not varenicline (OR = 0.99, p = .568). During follow-up, increased symptoms of depression predicted greater likelihood of smoking for European (p = .009) but not US participants. Europeans were more likely to be abstinent for both outcomes (p < .01). Conclusions: These results extend studies demonstrating varenicline is associated with less withdrawal-related depression, and suggest it aids cessation even in smokers with depressive symptoms. Findings also suggest regional differences in the relationship between depressive symptoms and cessation that may be related to differences in prevalence. Implications: This study indicates varenicline may aid cessation partially by reducing withdrawal-related symptoms of depression. It also suggests that the impact of depressive symptoms on cessation varies regionally, and that this variation may be related to differences in smoking prevalence.

Pooled analysis of three randomized, double-blind, placebo controlled trials with rimonabant for smoking cessation.

Despite the withdrawal of CB1 antagonists, such as rimonabant, from the market and from active clinical development because of concerns about their side effect profiles, research suggests that the endocannabinoid system may play an important role in modulating nicotine's effects. We report the combined results, using a pooled analysis, of three previously unpublished trials assessing rimonabant as a smoking cessation pharmacotherapy conducted between 2002 and 2004. Smokers (n = 2097) motivated to quit were enrolled in three randomized, double-blind, placebo-controlled trials, STRATUS EU, US, and META, which consisted of a 10-week treatment period with either rimonabant 20 mg (n = 789), 5 mg (n = 518; used in only two of the three studies), or placebo (n = 790), in conjunction with brief counseling. The impact of drug on prolonged abstinence and adverse events was examined at 8 weeks (end-of-treatment) and at 48 weeks (available for STRATUS EU and US) after the targeted quit date. Rimonabant 20 mg resulted in significantly higher abstinence at end-of-treatment and at 48 weeks post-targeted quit date compared with placebo, while rimonabant 5 mg and placebo did not differ. Serious AEs did not differ by drug group. The 20 mg rimonabant dose, compared with placebo, produced increased nausea, diarrhea, anxiety symptoms, hyporexia, and vomiting, and decreased headache, constipation, and cough. These results support rimonabant 20 mg as a modestly effective aid for smoking cessation. Although work on CB1 antagonists such as rimonabant has mostly been stopped because of unacceptable adverse events, these results may inform and spur the development of other endocannabinoids for smoking cessation.

"I Smoke Like This to Suppress These Issues That Are Flaws of My Character": Challenges and Facilitators of Cessation Among Smokers With Bipolar Disorder.

OBJECTIVE: Smokers with bipolar disorder (BD) have low rates of successful quitting, yet no prior studies have evaluated the process of quitting among these smokers in the context of a current quit attempt. To facilitate development of more effective interventions, we conducted a qualitative exploration of challenges and facilitators of quitting in an intervention study for smokers with BD. METHODS: Participants were adult daily smokers with BD (n = 10) who completed a 10-week smoking cessation intervention consisting of Acceptance and Commitment Therapy (ACT) and nicotine patch. We administered semistructured interviews focused on the quitting process at the end of treatment and used inductive content analysis to extract themes. RESULTS: Emergent themes representing challenges of quitting included social impediments, lack of awareness, avoidance, maladaptive beliefs, ambivalence, benefits of smoking, and difficulties with nicotine replacement. Themes representing change facilitators included positive treatment effects (ACT-specific, nonspecific, and nicotine patch-related), coping behaviors, reasons to quit, changes in self-perception, and social benefits. CONCLUSIONS: Results suggest a need for assistance with obtaining social support and handling social impediments, interrupting the automaticity of smoking, expanding the behavioral repertoire to handle aversive internal states that tend to be avoided by smoking, preventing maladaptive beliefs from interfering with quitting, taking meaningful action toward change while experiencing ambivalence, either replacing the benefits of smoking or accepting their loss, and troubleshooting difficulties with nicotine replacement. Findings regarding facilitators of quitting supported previous quantitative findings that the ACT intervention impacted theory-based targets and highlighted the importance of the counseling relationship.

Neuropsychiatric safety and efficacy of varenicline, bupropion, and nicotine patch in smokers with and without psychiatric disorders (EAGLES): a double-blind, randomised, placebo-controlled clinical trial.

BACKGROUND: Substantial concerns have been raised about the neuropsychiatric safety of the smoking cessation medications varenicline and bupropion. Their efficacy relative to nicotine patch largely relies on indirect comparisons, and there is limited information on safety and efficacy in smokers with psychiatric disorders. We compared the relative neuropsychiatric safety risk and efficacy of varenicline and bupropion with nicotine patch and placebo in smokers with and without psychiatric disorders. METHODS: We did a randomised, double-blind, triple-dummy, placebo-controlled and active-controlled (nicotine patch; 21 mg per day with taper) trial of varenicline (1 mg twice a day) and bupropion (150 mg twice a day) for 12 weeks with 12-week non-treatment follow-up done at 140 centres (clinical trial centres, academic centres, and outpatient clinics) in 16 countries between Nov 30, 2011, and Jan 13, 2015. Participants were motivated-to-quit smokers with and without psychiatric disorders who received brief cessation counselling at each visit. Randomisation was computer generated (1:1:1:1 ratio). Participants, investigators, and research personnel were masked to treatment assignments. The primary endpoint was the incidence of a composite measure of moderate and severe neuropsychiatric adverse events. The main efficacy endpoint was biochemically confirmed continuous abstinence for weeks 9-12. All participants randomly assigned were included in the efficacy analysis and those who received treatment were included in the safety analysis. The trial is registered at ClinicalTrials.gov (number NCT01456936) and is now closed. FINDINGS: 8144 participants were randomly assigned, 4116 to the psychiatric cohort (4074 included in the safety analysis) and 4028 to the non-psychiatric cohort (3984 included in the safety analysis). In the non-psychiatric cohort, 13 (1·3%) of 990 participants reported moderate and severe neuropsychiatric adverse events in the varenicline group, 22 (2·2%) of 989 in the bupropion group, 25 (2·5%) of 1006 in the nicotine patch group, and 24 (2·4%) of 999 in the placebo group. The varenicline-placebo and bupropion-placebo risk differences (RDs) for moderate and severe neuropsychiatric adverse events were -1·28 (95% CI -2·40 to -0·15) and -0·08 (-1·37 to 1·21), respectively; the RDs for comparisons with nicotine patch were -1·07 (-2·21 to 0·08) and 0·13 (-1·19 to 1·45), respectively. In the psychiatric cohort, moderate and severe neuropsychiatric adverse events were reported in 67 (6·5%) of 1026 participants in the varenicline group, 68 (6·7%) of 1017 in the bupropion group, 53 (5·2%) of 1016 in the nicotine patch group, and 50 (4·9%) of 1015 in the placebo group. The varenicline-placebo and bupropion-placebo RDs were 1·59 (95% CI -0·42 to 3·59) and 1·78 (-0·24 to 3·81), respectively; the RDs versus nicotine patch were 1·22 (-0·81 to 3·25) and 1·42 (-0·63 to 3·46), respectively. Varenicline-treated participants achieved higher abstinence rates than those on placebo (odds ratio [OR] 3·61, 95% CI 3·07 to 4·24), nicotine patch (1·68, 1·46 to 1·93), and bupropion (1·75, 1·52 to 2·01). Those on bupropion and nicotine patch achieved higher abstinence rates than those on placebo (OR 2·07 [1·75 to 2·45] and 2·15 [1·82 to 2·54], respectively). Across cohorts, the most frequent adverse events by treatment group were nausea (varenicline, 25% [511 of 2016 participants]), insomnia (bupropion, 12% [245 of 2006 participants]), abnormal dreams (nicotine patch, 12% [251 of 2022 participants]), and headache (placebo, 10% [199 of 2014 participants]). Efficacy treatment comparison did not differ by cohort. INTERPRETATION: The study did not show a significant increase in neuropsychiatric adverse events attributable to varenicline or bupropion relative to nicotine patch or placebo. Varenicline was more effective than placebo, nicotine patch, and bupropion in helping smokers achieve abstinence, whereas bupropion and nicotine patch were more effective than placebo. FUNDING: Pfizer and GlaxoSmithKline.

A Randomized Trial Evaluating Whether Topiramate Aids Smoking Cessation and Prevents Alcohol Relapse in Recovering Alcohol-Dependent Men.

BACKGROUND: Alcohol and nicotine dependence frequently co-occur, and quitting smoking might enhance long-term alcohol abstinence. Topiramate appears to help non-alcohol-dependent individuals quit smoking, and our pilot work suggested efficacy only in men. It also prevents relapse to alcohol in recently detoxified alcoholics. We evaluated topiramate in abstinent alcohol-dependent men to assess whether this medication (i) promotes smoking cessation and (ii) prevents alcohol and other drug relapse in the context of smoking cessation treatment. METHODS: One hundred and twenty-nine alcohol-abstinent (mean ~6 months) alcohol-dependent male smokers (80% with other substance use disorders) participated in this 12-week randomized, double blind, parallel group comparison of topiramate (up to 200 mg/d) and placebo with a 24-week nontreatment follow-up period. The study was carried out sequentially at 2 academic centers in the Midwest and Southern California between March 23, 2009 and November 20, 2014. All participants received manual-guided smoking cessation counseling combined with medication-focused compliance enhancement therapy. Randomization was block designed by the research pharmacist in a 1:1 ratio. Participants, investigators, and research personnel were masked to treatment assignment. The primary smoking end point was biochemically confirmed 4-week continuous abstinence from smoking during weeks 9 to 12, while the secondary end point was relapse to any drinking or drug use during the entire 36-week evaluation period. Logistic regression was used to determine the effects of topiramate on quitting smoking and alcohol relapse, controlling for relevant covariates. The trial is registered at ClinicalTrials.gov (number NCT00802412) and is now closed. RESULTS: Only a small proportion (7.9%) of topiramate-treated participants were able to quit smoking, and this cessation rate was similar to placebo (10.6%; odds ratio = 1.60; 95% confidence interval 0.4, 6.5; p = 0.51). Roughly 30% of the sample had a documented relapse to drinking or drug use during the study, and these rates were similar in the topiramate (20/63; 31.8%) and placebo groups (18/66; 27.3%; p = 0.58). Results of a longitudinal logistic regression model examining time to any alcohol relapse revealed no medication effect. CONCLUSIONS: Topiramate at a daily dosage of up to 200 mg per day, combined with smoking cessation and medication adherence counseling, had no effects on smoking cessation or the prevention of alcohol or drug relapse in male smokers who were in early or sustained full remission from alcohol and motivated to make a quit attempt. Alternative approaches for treating this high-risk, dually dependent population are needed.

Acceptance and Commitment Therapy and nicotine patch for smokers with bipolar disorder: preliminary evaluation of in-person and telephone-delivered treatment.

OBJECTIVES: People with bipolar disorder are two to three times more likely to smoke and 50% less likely to quit than the general population. New treatments are needed to improve smoking cessation outcomes in this group. The study aim was to develop and pilot test a novel cessation intervention for smokers with bipolar disorder using Acceptance and Commitment Therapy (ACT) combined with nicotine patches. METHODS: The ten-session ACT intervention was initially evaluated as in-person, individual counseling (n = 10), then as telephone-delivered counseling (n = 6). Participants were adult smokers with no more than mild current symptoms of bipolar disorder. RESULTS: For the in-person protocol, end-of-treatment outcomes were: 80% retention, 40% of participants with carbon monoxide (CO)-verified seven-day point prevalence abstinence (PPA), 90% satisfied with treatment, 8.3 of ten sessions attended, and 54% increase in acceptance of cravings to smoke (i.e., ACT's theory-based change process) from baseline. The seven-day PPA at one-month follow-up was 30%. For the telephone protocol, end-of-treatment outcomes were: 67% retention, 33% reporting seven-day PPA, 100% satisfied with treatment, 6.7 of ten treatment calls completed, and 55% increase in acceptance from baseline. At one-month follow-up, seven-day PPA was 17%. The proportion of treatment completers who used at least 80% of the nicotine patches was 62.5% for the in-person protocol and 0% for the telephone protocol. CONCLUSIONS: Both in-person and telephone-delivered ACT were feasible. Despite low adherence to nicotine patches, the intervention showed preliminary evidence of facilitating quitting and impacting ACT's change mechanism. A randomized, controlled trial of this targeted ACT intervention is now needed.

Gender effects in alcohol dependence: an fMRI pilot study examining affective processing.

BACKGROUND: Alcohol dependence (AD) has global effects on brain structure and function, including frontolimbic regions regulating affective processing. Preliminary evidence suggests alcohol blunts limbic response to negative affective stimuli and increases activation to positive affective stimuli. Subtle gender differences are also evident during affective processing. METHODS: Fourteen abstinent AD individuals (8 F, 6 M) and 14 healthy controls (9 F, 5 M), ages 23 to 60, were included in this facial affective processing functional magnetic resonance imaging pilot study. Whole-brain linear regression analyses were performed, and follow-up analyses examined whether AD status significantly predicted depressive symptoms and/or coping. RESULTS: Fearful Condition-The AD group demonstrated reduced activation in the right medial frontal gyrus, compared with controls. Gender moderated the effects of AD in bilateral inferior frontal gyri. Happy Condition-AD individuals had increased activation in the right thalamus. Gender moderated the effects of AD in the left caudate, right middle frontal gyrus, left paracentral lobule, and right lingual gyrus. Interactive AD and gender effects for fearful and happy faces were such that AD men activated more than control men, but AD women activated less than control women. Enhanced coping was associated with greater activation in right medial frontal gyrus during fearful condition in AD individuals. CONCLUSIONS: Abnormal affective processing in AD may be a marker of alcoholism risk or a consequence of chronic alcoholism. Subtle gender differences were observed, and gender moderated the effects of AD on neural substrates of affective processing. AD individuals with enhanced coping had brain activation patterns more similar to controls. Results help elucidate the effects of alcohol, gender, and their interaction on affective processing.

Effects of varenicline on smoking cessation in adults with stably treated current or past major depression: a randomized trial.

UNLABELLED: Chinese translation BACKGROUND: Depression is overrepresented in smokers. OBJECTIVE: To evaluate smoking abstinence and changes in mood and anxiety levels in smokers with depression treated with varenicline versus placebo. DESIGN: Phase 4, multicenter, parallel, 1:1 allocation, double-blind, randomization trial. Randomization, stratified by antidepressant use and depression score at baseline, was blocked in sizes of 4. (ClinicalTrials.gov: NCT01078298). SETTING: 38 centers in 8 countries. PARTICIPANTS: 525 adult smokers with stably treated current or past major depression and no recent cardiovascular events. INTERVENTION: Varenicline, 1 mg twice daily, or placebo for 12 weeks, with 40-week nontreatment follow-up. MEASUREMENTS: Primary outcome was carbon monoxide-confirmed continuous abstinence rate (CAR) for weeks 9 to 12. Other outcomes included CARs assessed during nontreatment follow-up and ratings of mood, anxiety, and suicidal ideation or behavior. RESULTS: 68.4% versus 66.5% of the varenicline and placebo groups, respectively, completed the study. Varenicline-treated participants had higher CARs versus placebo at weeks 9 to 12 (35.9% vs. 15.6%; odds ratio [OR], 3.35 [95% CI, 2.16 to 5.21]; P < 0.001), 9 to 24 (25.0% vs. 12.3%; OR, 2.53 [CI, 1.56 to 4.10]; P < 0.001), and 9 to 52 (20.3% vs. 10.4%; OR, 2.36 [CI, 1.40 to 3.98]; P = 0.001). There were no clinically relevant differences between groups in suicidal ideation or behavior and no overall worsening of depression or anxiety in either group. The most frequent adverse event was nausea (varenicline, 27.0%; placebo, 10.4%). Two varenicline-group participants died during the nontreatment phase. LIMITATIONS: Some data were missing, and power to detect differences between groups was low in rare events. Smokers with untreated depression, with co-occurring psychiatric conditions, or receiving mood stabilizers and antipsychotics were not included. CONCLUSION: Varenicline increased smoking cessation in smokers with stably treated current or past depression without exacerbating depression or anxiety. PRIMARY FUNDING SOURCE: Pfizer.

Sex differences in alcohol's effects on fronto-amygdalar functional connectivity during processing of emotional stimuli.

BACKGROUND: Amygdala function underlying emotion processing has been shown to vary with an individuals' biological sex. Expanding upon functional magnetic resonance imaging (fMRI) findings reported previously where a low level of response was the focus, we examined alcohol and sex effects on functional connectivity between the amygdala and other brain regions. The central hypothesis predicted that sex would influence alcohol's effects on frontal-limbic functional circuits underlying the processing of negative and positive facial emotions. METHODS: Secondary analyses were conducted on data from a double-blind, placebo controlled, within-subjects, cross-over study in 54 sex-matched pairs (N = 108) of 18- to 25-year-old individuals without an alcohol use disorder at baseline. Participants performed an emotional faces fMRI processing task after placebo or approximately 0.7 mL/kg of ethanol. Psychophysiological interaction analyses examined functional connectivity between the amygdala with other brain regions. RESULTS: There were significant alcohol-by-sex interactions when processing negatively valenced faces. Whereas intoxicated men exhibited decreased functional connectivity between the amygdala and ventral and dorsal anterior cingulate, angular gyrus, and middle frontal gyrus connectivity was increased in intoxicated women. There was also a main sex effect where women exhibited less functional connectivity in the middle insula than men regardless of whether they received alcohol or placebo. For happy faces, main effects of both sex and alcohol were observed. Women exhibited less amygdala functional connectivity in the right inferior frontal gyrus than men. Both men and women exhibited greater functional connectivity in the superior frontal gyrus in response to alcohol than placebo. CONCLUSIONS: Alcohol's effects on amygdala functional circuits that underlying emotional processing vary by sex. Women had higher functional connectivity than men following exposure to a moderate dose of alcohol which could indicate that women are better than men at processing affectively laden stimuli when intoxicated.

Sex effects in predictors of smoking abstinence and neuropsychiatric adverse events in the EAGLES trial.

Significance There are sex effects in abstinence outcomes across all smoking cessation medications, but there is limited information regarding sex effects on cessation-related neuropsychiatric adverse events (NPSAEs) or interactions with psychiatric status. METHODS: Secondary analysis of data from EAGLES of 8144 adults who smoke cigarettes randomized to varenicline, bupropion, nicotine patch or placebo. Design characteristics included region (within/outside US), psychiatric cohort (absent/present), and treatment. Baseline variables included demographics, smoking history, prior use of study treatments, lifetime suicide-related history, and prior psychiatric co-morbidities and medication use. Design characteristics were forced into logistic regressions models, and then interactions among sex, design elements, and baseline characteristics were evaluated for NPSAEs and 6-month cessation outcomes. RESULTS: Findings demonstrated a significant interaction of sex and race (p < 0.02); Black women were more likely to report NPSAEs than Black men. For cessation outcomes, there were no significant interactions with psychiatric cohort and sex. Women vs men with higher baseline levels of smoking had lower odds of continuous abstinence. Women vs men who used varenicline previously had lower odds of continuous abstinence. For 6-month point prevalence, sex interacted with baseline cigarettes per day (p < 0.01) similar to the interaction for continuous abstinence. Sex interacted with medication (p < 0.03), such that women vs men had relatively greater success at achieving point prevalence abstinence on varenicline. CONCLUSIONS: Overall, results demonstrated important sex and racial differences in the incidence of NPSAEs, but psychiatric status did not interact with sex on cessation outcomes. Findings did support prior work demonstrating relative increased efficacy of varenicline for women.

Combining varenicline preloading with Acceptance and Commitment Therapy (ACT) in persons with serious mental illness who smoke: The randomized ACTSLow pilot feasibility trial.

BACKGROUND: People with serious mental illness (SMI; bipolar [BD] or schizophrenia spectrum disorders [SSD]) who smoke have 30-60% lower odds of quitting and are more prone to experience neuropsychiatric adverse events (NPSAEs) when quitting than smokers without SMI. We pilot-tested the feasibility of combining two different dosing strategies of varenicline preloading with Acceptance and Commitment Therapy (ACT) in persons with SMI in an attempt to bolster quit rates without increasing NPSAEs. METHODS: Twelve-week, single center, randomized, double-blind, pilot feasibility trial of low (0.5mg twice daily, slower titration) versus standard dose (1.0mg twice daily, standard titration) varenicline in persons with BD or SSD with a 12-week follow-up. All participants received up to 10 sessions of ACT for smoking cessation. Participants were asked to preload with varenicline while still smoking and set a flexible target quit day (TQD) by day 35. RESULTS: Recruitment was hampered by shutdowns related to COVID-19 and the worldwide varenicline recall, respectively. Retention goals were met. Treatment satisfaction was high across both dosing and diagnostic groups. Most participants (92.9%) adhered to preloading instructions and the flexible TQD. Seven-day point prevalence abstinence at week 12 was highest in BD participants (37.5%) but lowest in SSD participants (16.7%) who received the standard dose. Medication was well tolerated. CONCLUSIONS: Although recruitment was hindered by unanticipated world events, feasibility was demonstrated. Participants adhered to and were highly satisfied with the combination of pre-cessation varenicline plus ACT. Findings support testing this combined treatment approach in a fully powered trial of persons with BD who smoke.

Cigarette smoking and its relationship to mood disorder symptoms and co-occurring alcohol and cannabis use disorders following first hospitalization for bipolar disorder.

OBJECTIVES: Cigarette smoking is highly prevalent among individuals with bipolar disorder (BD) and may adversely affect symptoms of the disorder, as well as the co-occurrence of other substance use disorders. However, anecdotal reports suggesting that smoking cessation caused a worsening of mood in smokers with BD have raised concerns about quitting. In the present study, we prospectively evaluated the course of BD, alcohol use disorders, and cannabis use disorders in relation to smoking and examined the relationship between smoking abstinence and changes in mood. METHODS: Participants (N = 161) were adolescents (n=80) and adults (n = 81) with bipolar I disorder who were hospitalized for their initial mixed or manic episode. Participants were followed up to eight years post-hospitalization (median follow-up = 122 weeks) as part of a naturalistic, observational study of the longitudinal course of BD and substance use. RESULTS: The course of BD symptoms in the 12 months following index hospitalization did not differ by smoking status in either the adolescent or the adult subsample. Among adolescents, smoking was associated with an increased risk of having a cannabis or alcohol use disorder, almost all of which were new-onset disorders, in the year following first hospitalization. Neither adolescents nor adults who were abstinent from smoking for at least two months experienced significant increases in depressive or manic symptoms. CONCLUSIONS: Although cigarette smoking did not predict a worse course of BD, smoking was associated with an increased risk of developing alcohol and cannabis use disorders in adolescents with BD. Importantly, these data provide no evidence to suggest that abstinence from smoking is associated with worsening symptoms of depression or mania in the short term.