***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: IMPORTANCE Cigarette smoking leads to upregulation of nicotinic acetylcholine receptors ( nAChRs ) in the human brain , including the common α4β2 * nAChR subtype . While subjective aspects of tobacco dependence have been extensively examined as predictors of quitting smoking with treatment , no studies to our knowledge have yet reported the relationship between the extent of pretreatment upregulation of nAChRs and smoking cessation . OBJECTIVE To determine whether the degree of nAChR upregulation in smokers predicts quitting with a st and ard course of treatment . DESIGN , SETTING , AND PARTICIPANTS Eighty-one tobacco-dependent cigarette smokers ( volunteer sample ) underwent positron emission tomographic ( PET ) scanning of the brain with the radiotracer 2-FA followed by 10 weeks of double-blind , placebo-controlled treatment with nicotine patch ( r and om assignment ) . Pretreatment specific binding volume of distribution ( VS/fP ) on PET images ( a value that is proportional to α4β2 * nAChR availability ) was determined for 8 brain regions of interest , and participant-reported ratings of nicotine dependence , craving , and self-efficacy were collected . Relationships between these pretreatment measures , treatment type , and outcome were then determined . The study took place at academic PET and clinical research centers . MAIN OUTCOMES AND MEASURES Posttreatment quit status after treatment , defined as a participant report of 7 or more days of continuous abstinence and an exhaled carbon monoxide level of 3 ppm or less . RESULTS Smokers with lower pretreatment VS/fP values ( a potential marker of less severe nAChR upregulation ) across all brain regions studied were more likely to quit smoking ( multivariate analysis of covariance , F8,69 = 4.5 ; P < .001 ) , regardless of treatment group assignment . Furthermore , pretreatment average VS/fP values provided additional predictive power for likelihood of quitting beyond the self-report measures ( stepwise binary logistic regression , likelihood ratio χ21 = 19.8 ; P < .001 ) . CONCLUSIONS AND RELEVANCE Smokers with less upregulation of available α4β2 * nAChRs have a greater likelihood of quitting with treatment than smokers with more upregulation . In addition , the biological marker studied here provided additional predictive power beyond subjectively rated measures known to be associated with smoking cessation outcome . While the costly , time-consuming PET procedure used here is not likely to be used clinical ly , simpler methods for examining α4β2 * nAChR upregulation could be tested and applied in the future to help determine which smokers need more intensive and /or lengthier treatment . TRIAL REGISTRATION clinical trials.gov Identifier : NCT01526005 INTRODUCTION Ex vivo storage phosphor imaging rat studies reported increased brain dopamine D2/3 receptor ( DRD2/3 ) availability following treatment with varenicline  , a nicotinergic drug . However , ex vivo studies can only be performed using cross-sectional design s. Small-animal imaging offers the opportunity to perform serial assessment s. We evaluated whether high-resolution pinhole single photon emission computed tomography ( SPECT ) imaging in rats was able to reproduce previous ex vivo findings . METHODS Rats were imaged for baseline striatal DRD2/3 availability using ultra-high-resolution pinhole SPECT ( U-SPECT-II ) and [123I]IBZM as a radiotracer , and r and omized to varenicline ( n=7 ; 2 mg/kg ) or  saline ( n=7 ) . Following 2 weeks of treatment , a second scan was acquired . RESULTS Significantly increased striatal DRD2/3 availability was found following varenicline treatment compared to saline ( time⁎treatment effect ) : posttreatment difference in binding potential between groups corrected for initial baseline differences was 2.039 ( P=.022 ) , indicating a large effect size ( d=1.48 ) . CONCLUSIONS Ultra-high-resolution pinhole SPECT can be used to assess varenicline-induced changes in DRD2/3 availability in small laboratory animals over time . Future small-animal studies should include imaging techniques to enable repeated within-subjects measurements and reduce the amount of animals While the combination therapy of varenicline and sustained release bupropion ( bupropion SR ) for cigarette smoking cessation can increase smoking abstinence rates , it has also been associated with increases in self-reported depressive symptoms . We conducted an analysis of the Beck Depression Inventory , second edition ( BDI-II ) , data completed by 505 patients from a large r and omized clinical trial , evaluating the efficacy of 12 weeks of combination therapy ( varenicline+bupropion SR ) compared to varenicline alone . At medication treatment week 2 ( 1 week after target quit date [ TQD ] ) , increased depressive symptoms were observed in patients receiving combination therapy ( effect estimate=0.61 , 95 % CI [ 0.03 , 1.19 ] , P=.039 ) and those with a history of depression ( effect estimate=0.82 , 95 % CI [ 0.07 , 1.57 ] , P=.033 ) . For treatment weeks 2 to 4 , smokers with a history of depression on combination therapy had a greater decline in depressive symptoms compared to those on varenicline alone ( effect estimate=-1.99 , 95 % CI [ -3.99 , 0.00 ] , P=.050 ) . After treatment week 4 , no significant effects of treatment or depression history on BDI-II scores were observed . A history of depression did not moderate the efficacy of combination therapy for smoking abstinence . Our study suggests that for combination therapy with varenicline and bupropion SR , an increase in depressive symptoms over the first 2 weeks may be observed ; however , the effects on depressive symptoms do not last beyond 4 weeks . We conclude that among smokers without active moderate or severe depression , the decision to use this combination treatment approach should not be based upon a self-reported history of depression IMPORTANCE Combining pharmacotherapies for tobacco-dependence treatment may increase smoking abstinence . OBJECTIVE To determine efficacy and safety of varenicline and bupropion sustained-release ( SR ; combination therapy ) compared with varenicline ( monotherapy ) in cigarette smokers . DESIGN , SETTING , AND PARTICIPANTS R and omized , blinded , placebo-controlled multicenter clinical trial with a 12-week treatment period and follow-up through week 52 conducted between October 2009 and April 2013 at 3 midwestern clinical research sites . Five hundred six adult ( ≥18 years ) cigarette smokers were r and omly assigned and 315 ( 62 % ) completed the study . INTERVENTIONS Twelve weeks of varenicline and bupropion SR or varenicline and placebo . MAIN OUTCOMES AND MEASURES Primary outcome was abstinence rates at week 12 , defined as prolonged ( no smoking from 2 weeks after the target quit date ) abstinence and 7-day point-prevalence ( no smoking past 7 days ) abstinence . Secondary outcomes were prolonged and point-prevalence smoking abstinence rates at weeks 26 and 52 . Outcomes were biochemically confirmed . RESULTS At 12 weeks , 53.0 % of the combination therapy group achieved prolonged smoking abstinence and 56.2 % achieved 7-day point-prevalence smoking abstinence compared with 43.2 % and 48.6 % in varenicline monotherapy ( odds ratio [ OR ] , 1.49 ; 95 % CI , 1.05 - 2.12 ; P = .03 and OR , 1.36 ; 95 % CI , 0.95 - 1.93 ; P = .09 , respectively ) . At 26 weeks , 36.6 % of the combination therapy group achieved prolonged and 38.2 % achieved 7-day point-prevalence smoking abstinence compared with 27.6 % and 31.9 % in varenicline monotherapy ( OR , 1.52 ; 95 % CI , 1.04 - 2.22 ; P = .03 and OR , 1.32 ; 95 % CI , 0.91 - 1.91 ; P = .14 , respectively ) . At 52 weeks , 30.9 % of the combination therapy group achieved prolonged and 36.6 % achieved 7-day point-prevalence smoking abstinence compared with 24.5 % and 29.2 % in varenicline monotherapy ( OR , 1.39 ; 95 % CI , 0.93 - 2.07 ; P = .11 and OR , 1.40 ; 95 % CI , 0.96 - 2.05 ; P = .08 , respectively ) . Participants receiving combination therapy reported more anxiety ( 7.2 % vs 3.1 % ; P = .04 ) and depressive symptoms ( 3.6 % vs 0.8 % ; P = .03 ) . CONCLUSIONS AND RELEVANCE Among cigarette smokers , combined use of varenicline and bupropion , compared with varenicline alone , increased prolonged abstinence but not 7-day point prevalence at 12 and 26 weeks . Neither outcome was significantly different at 52 weeks . Further research is required to determine the role of combination therapy in smoking cessation . TRIAL REGISTRATION clinical trials.gov Identifier : http:// clinical trials.gov/show/NCT00935818 BACKGROUND Sex differences in addictive disorders have been described . Pre clinical studies have implicated the striatal dopamine system in these differences , but human studies have yet to substantiate these findings . METHODS Using positron emission tomography ( PET ) scans with high-specific-activity [ 11C ] raclopride and a reference tissue approach , we compared baseline striatal dopamine binding potential ( BP ) and dopamine release in men and women following amphetamine and placebo challenges .  Subjective drug effects and plasma cortisol and growth hormone responses were also examined . RESULTS Although there was no sex difference in baseline BP , men had markedly greater dopamine release than women in the ventral striatum . Secondary analyses indicated that men also had greater dopamine release in three of four additional striatal regions . Paralleling the PET findings , men 's ratings of the positive effects of amphetamine were greater than women 's . We found no sex difference in neuroendocrine hormone responses . CONCLUSIONS We report for the first time a sex difference in dopamine release in humans . The robust dopamine release in men could account for increased vulnerability to stimulant use disorders and methamphetamine toxicity . Our findings indicate that future studies should control for sex and may have implication s for the interpretation of sex differences in other illnesses involving the striatum OBJECTIVE The authors assessed the efficacy and safety of combination treatment with varenicline and sustained-release bupropion for smokers who , based on an assessment of initial smoking reduction prior to the quit date , were deemed unlikely to achieve abstinence using nicotine patch treatment . METHOD In a r and omized , double-blind , parallel-group adaptive treatment trial , the authors identified 222 cigarette smokers who failed to show a reduction of more than 50 % in smoking after 1 week of nicotine patch treatment .  Smokers were r and omly assigned to receive 12 weeks of varenicline plus bupropion or varenicline plus placebo . The primary outcome measure was continuous smoking abstinence at weeks 8 - 11 after the target quit date . RESULTS Both treatments were well tolerated . Participants who received the combination treatment had a significantly higher abstinence rate than those who received varenicline plus placebo ( 39.8 % compared with 25.9 % ; odds ratio=1.89 ; 95 % CI=1.07 , 3.35 ) . Combination treatment had a significantly greater effect on abstinence rate in male smokers ( odds ratio=4.26 ; 95 % CI=1.73 , 10.49 ) than in female smokers ( odds ratio=0.94 ; 95 % CI=0.43 , 2.05 ) . It also had a significantly greater effect in highly nicotine-dependent smokers ( odds ratio=3.51 , 95 % CI=1.64 , 7.51 ) than in smokers with lower levels of dependence ( odds ratio=0.71 , 95 % CI=0.28 , 1.80 ) . CONCLUSIONS Among smokers who did not show a sufficient initial response to prequit nicotine patch treatment , combination treatment with varenicline and bupropion proved more efficacious than varenicline alone for male smokers and for smokers with a high degree of nicotine dependence INTRODUCTION Varenicline and bupropion sustained release ( SR ) are both safe and effective for the treatment of tobacco dependence and have different mechanisms of action . Combination pharmacotherapy with these agents may increase long-term smoking abstinence rates above what is observed with single-agent therapy . METHODS We enrolled cigarettes smokers in an open-label , one-arm , Phase II clinical trial to obtain preliminary data on the potential effectiveness and safety of combination therapy with varenicline and bupropion SR for the treatment of tobacco dependence . Eligible subjects received varenicline titrated to 1 
    Output:
    
Subgroup analyses suggest that this combination may be more beneficial in males and patients with higher baseline nicotine dependence .
CONCLUSION To the authors ' knowledge , this is the first review conducted to compile current literature on this novel pharmacotherapy combination for smoking cessation .