Pharmacogenetics, Emotional Reactivity and Smoking

• Sponsor: M.D. Anderson Cancer Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT00507728
• Collaborator: National Institutes of Health (NIH) (NIH), National Institute on Drug Abuse (NIDA) (NIH)
• Enrollment: 646
• Location: 1
• Arms: 3
• Actual Duration (Months): 168.3
• Patients Per Site Per Month: 3.8

Study Details

Study Description

Brief Summary

The goals of this placebo-controlled randomized clinical trial were to evaluate the differences in emotional reactivity (peak startle response to affective stimuli) during a cessation attempt among smokers treated with bupropion, varenicline, or placebo, and to determine if these differences were moderated by genotype.

Condition or Disease	Intervention/Treatment	Phase
Tobacco Use Disorder; Smoking Cessation	Drug: Bupropion; Drug: Varenicline; Drug: Placebo; Behavioral: Smoking Cessation Counseling	Phase 2/Phase 3

Detailed Description

Bupropion and Varenicline are smoking cessation aids that may help people to quit smoking.

During the orientation visit, the study will be explained to you and you will be given an opportunity to ask, and have answered, any questions you may have. You will also be asked to give a buccal (cheek cell) sample for genetic analysis. This session will last about 1.5 hours.

During the screening visit, you will be asked questions about your health, medication use, smoking history, and tobacco use. You will be asked about any current or past feelings of depression. Also, a small blood sample will be drawn (about 2 tablespoons) from your upper arm for a liver and kidney function test and a saliva sample will be collected to measure whether you are smoking. Women who are able to have children must have a negative urine pregnancy test. This session will last about 2.5 hours.

If you are eligible to take part in the study, you will be randomly assigned (as in the toss of a coin) to one of three treatment groups. Participants in the first group will receive Bupropion. Participants in the second group will receive Varenicline. Participants in the third group will receive a placebo. A placebo is a substance that looks like the study drug but which has no active ingredients. You will have an equal chance of being assigned to the Bupropion, Varenicline, or placebo treatment group. Neither you nor your counselor will know to which group you were assigned.

All participants will take study pills (either Bupropion, Varenicline, or placebo) by mouth for 12 weeks. The dose of study medication may or may not change during the study. You will be responsible for returning any unused, used, or partly used study medication bottles to a study staff member.

All participants will receive smoking cessation counseling to help them quit smoking, in the form of both in-person and telephone counseling sessions. Some of the counseling sessions may be videotaped or audio-taped. The videotapes will be used to help the investigators make sure that the counselors are following the correct procedures and will be erased within one year following your completion of the study. No one but the study investigators or those delegated by the study investigators will be allowed to view the tapes and the identity of the participants will be kept strictly confidential. Staff that may be given permission to view the tapes include project staff, consultants that review and rate how well the study counselors follow guidelines, and/or consultants that review how well the assessments are given.

You will need to come to the Behavioral Science Research Clinic at M. D. Anderson for 9 clinic visits over an 8-month period. You will receive 5 telephone calls from the study staff (while in treatment and during follow-up) to check on your progress in quitting smoking.

You will complete your first lab evaluation session (baseline) before any treatment begins (while you are still smoking). Immediately after the baseline lab session (on the same day), you will begin to receive counseling to quit smoking. You will begin taking one of the 3 study medications (Bupropion, Varenicline, or placebo) the next morning.

There will be 3 lab sessions, during which you will be asked to complete questionnaires about your mood and feelings (about 30 minutes total). Also, you will give a breath sample by blowing air into a small tube. This sample shows how much you have smoked. In each session you will be asked to watch slides and listen to a series of tones through earphones. The slides will include pictures of people, nature scenes, and artwork. Slides showing victims of car crashes, medical procedures, and nude people will also be shown. You will be shown examples of these slides before beginning the procedure and given the opportunity to withdraw from the study. During the lab sessions, your heart rate, brain electrical activity (EEG), skin sweating, and muscle tension will be monitored. To do this, small sensors will be placed on the fingers, arms, scalp and face. You should not drink more than 2 cups of coffee or other caffeine drinks at least 2.5 hours before each session.

During the first counseling visit, you will set a quit date for stopping smoking about 2 weeks after starting your study medication. You are asked not to quit smoking before the set quit date. After your quit date, you are asked to stay smoke free. You are asked to attend all your sessions whether you are smoking or not. All participants will receive smoking cessation counseling in the form of both in-person and telephone counseling sessions. The purpose of these visits will be to prepare you for quitting and to check the effects of the study medication on your attempt to stop smoking.

At each of your clinic visits, your blood pressure will be taken and you will be asked to blow air through a carbon monoxide (CO) measuring device. CO is a gas that is found in higher levels among cigarette smokers. At several visits you will be asked to provide a saliva sample to check for cotinine, a chemical produced by the breakdown of nicotine during smoking. You will be asked to give a saliva sample in a collection tube. Like the CO test, this test will help researchers measure how much you are smoking.

At your visits you will be asked questions about your smoking behavior. You will also be asked questions about your health and medical condition, and about any medications you are taking. You will be asked to complete a daily diary on cigarette smoking and drug dosing.

You will also be asked to mail saliva samples back to the clinic at least two times after stopping the medication. This will allow researchers to check on your smoking status.

Your total participation in this study will last about 8 months. This will include a 3-month and 6-month follow-up visit after your scheduled quit date. If the study staff is not able to reach you by phone, mail, or the information provided by your contacts, they may try to locate you through telephone directory assistance (411) or internet search sources (for example, Google or Yahoo!), which use information from the public domain (meaning everyone has access to it). If the study staff is still unable to find you, they may use a locator service such as Transunion or the National Change of Address (NCOA) database maintained by the United States Postal Service, as a last resort. Transunion uses magazine subscriptions and credit applications to find new addresses, and the NCOA uses the Change of Address cards filed with the post office when a person moves and requests their mail be forwarded to a new address. If the study staff has to use either of these services, they would only disclose your name and last known address.

At the end of the study, you will be able to ask additional questions about the results of the study and about procedures you have experienced during the study. Additionally, you will be able to sign up to receive a copy of the paper that will be written at the completion of the study.

This is an investigational study. Up to 375 smokers will take part in this study. All will be enrolled at MD Anderson.

Study Design

• Study Type: Interventional
• Actual Enrollment: 646 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: Pharmacogenetics, Emotional Reactivity and Smoking
• Actual Study Start Date: Dec 8, 2005
• Actual Primary Completion Date: Dec 18, 2019
• Actual Study Completion Date: Dec 18, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Bupropion Bupropion starting dose 150 mg by mouth daily (150 mg every morning for three days; 150 mg twice a day thereafter).	Drug: Bupropion; Starting dose 150 mg by mouth daily (150 mg every morning for three days; 150 mg twice a day thereafter); Other Names: Wellbutrin Wellbutrin SR Zyban ; Behavioral: Smoking Cessation Counseling; Counseling over 8 months and telephone support calls.
Experimental: Varenicline Varenicline starting dose 0.5 mg by mouth daily (0.5 mg every morning for days 1 - 3, then 0.5 mg twice a day for days 4 - 7, then 1 mg twice a day thereafter).	Drug: Varenicline; Starting dose 0.5 mg by mouth daily (0.5 mg every morning for days 1 - 3, then 0.5 mg twice a day for days 4 - 7, then 1 mg twice a day thereafter); Other Names: Chantix ; Behavioral: Smoking Cessation Counseling; Counseling over 8 months and telephone support calls.
Placebo Comparator: Placebo Placebo by mouth for 12 weeks.	Drug: Placebo; Placebo by mouth for 12 weeks.; Behavioral: Smoking Cessation Counseling; Counseling over 8 months and telephone support calls.

Outcome Measures

Primary Outcome Measures

1. Emotional Reactivity By Pharmacotherapy [Baseline to 1 month]

   Emotional reactivity measured by the peak eye blink electromyography (EMG) of the orbicularis oculi (ORB) muscle responses to acoustic startle probe delivered during the presentation of emotionally valent stimuli (pleasant, unpleasant, neutral, and smoking-related pictures). A single value was estimated by averaging within the specific time interval.

2. Emotional Reactivity By Pharmacotherapy Moderated by DRD2 A1 Allele [Baseline to 1 month]

   The emotional reactivity (ORB EMG) of smokers during cessation will be moderated by genotype. A single value was estimated by averaging within the specific time interval. During a quit attempt, smokers were evaluated on how they react to smoking related cues. An interaction term was then formed by the reactivity to smoking stimulus and genotype.

Secondary Outcome Measures

1. Smoking Abstinence at 3 Months [Baseline to 3 months]

   Values represent change in probability of abstinence for unit change in emotional reactivity. Abstinence data collected using a timeline follow-back (TLFB) procedure. Continuous Abstinence was defined as no smoking within the last 4 weeks of treatment. It is scored as 0 if the participant smoked during the specific interval, and 1 if the participant abstained from smoking.

2. Smoking Abstinence at 3 Months by DRD2 A1 Allele [Baseline to 3 Month]

   Values represent change in probability of abstinence for unit change in emotional reactivity. Abstinence data collected using a timeline follow-back (TLFB) procedure. Continuous Abstinence was defined as no smoking within the last 4 weeks of treatment. It is scored as 0 if the participant smoked during the specific interval, and 1 if the participant abstained from smoking.

3. Smoking Abstinence at 6 Months [Abstinence at 6 Months ( the effects shown are the increase/decrease in probability of abstinence for 1 unit increase in the predictor)]

   Values represent change in probability of abstinence for unit change in emotional reactivity. Abstinence data collected using a timeline follow-back (TLFB) procedure. Continuous Abstinence was defined as no smoking within the last 4 weeks of treatment. It is scored as 0 if the participant smoked during the specific interval, and 1 if the participant abstained from smoking.

4. Abstinence at 6 Months by DRD2 A1 Allele [Baseline to 6 Month ( the effects shown are the increase/decrease in probability of abstinence for 1 unit increase in the predictor)]

   Values represent change in probability of abstinence for unit change in emotional reactivity. Abstinence data collected using a timeline follow-back (TLFB) procedure. Continuous Abstinence was defined as no smoking within the last 4 weeks of treatment. It is scored as 0 if the participant smoked during the specific interval, and 1 if the participant abstained from smoking.

5. Symptoms of Nicotine Withdrawal Using the Wisconsin Smoking Withdrawal Scale (WSWS) [Baseline to 8 months]

   Symptoms of nicotine withdrawal measured using Wisconsin Smoking Withdrawal Scale (WSWS). The Wisconsin Withdrawal Scale (WSWS) contains 7 factors: Anger, Anxiety, Sadness, Concentration, Craving, Sleep, and Hunger. WSWS consists of 28 items that are scored on a 5-point Likert type scale (0 = strongly disagree, 4 = strongly agree). A single value was estimated by averaging within the specific time interval. Higher values represent worse outcome. The average value was estimated from Baseline to 8 months

6. Symptoms of Nicotine Withdrawal and Negative Affect Using Positive and Negative Affect Scale (PANAS) [Baseline to 8 months]

   Symptoms of nicotine withdrawal and negative affect were measured using the Positive and Negative Affect Scale (PANAS). The Positive and Negative Affect Schedule (PANAS) is a self-report questionnaire to measure both positive and negative affect. Each item is rated on a 5-point scale of 1 (not at all) to 5 (very much). Scores can range from 10-50 for both the Positive and Negative Affect with the lower scores representing lower levels of Positive/Negative Affect and higher scores representing higher levels of Positive/Negative Affect. The average value was estimated from Baseline to 8 months

7. Symptoms of Depression Using the Center for Epidemiologic Studies Depression Scale (CES-D) [Baseline to 8 months]

   Symptoms of nicotine withdrawal measured using Center for Epidemiologic Studies Depression Scale (CES-D). Center of Epidemiologic Studies Depression Scale (CESD) a 20-item measure that asks caregivers to rate how often over the past week they experienced symptoms associated with depression, such as restless sleep, poor appetite, and feeling lonely. Response options range from 0 to 3 for each item (0 = Rarely or None of the Time, 1 = Some or Little of the Time, 2 = Moderately or Much of the time, 3 = Most or Almost All the Time). Scores range from 0 to 60, with high scores indicating greater depressive symptoms. The average value was estimated from Baseline to 8 months

8. Measures of Smoking Satisfaction and Psychological Reward Using the Modified Cigarette Evaluation Questionnaire (mCEQ) Subscales [Baseline to 8 months]

   Modified Cigarette Evaluation Questionnaire (mCEQ). mCEQ Smoking satisfaction: range (1-21); mCEQ Psychological Reward: range(1-35); mCEQ Aversion: range (1-14); mCEQ Enjoyment of Resp.Tract Sens: range (1-7); mCEQ Craving Reduction: range (1-7). For all scales of mCEQ higher scores indicate worse outcomes (greater intensity of smoking effect). Scores of mCEQ Smoking satisfaction, mCEQ psychological reward and mCEQ aversion were summed to create the subscales. mCEQ Enjoyment of Resp Tract Sens and mCEQ Craving Reduction were single items.

9. Skin Conductance Response [Baseline to 1 month]

   Skin conductance response (SCR) amplitude measured by placing an electrodermal response transducer on the fore and ring fingers of the participants non-dominant hand, and heart rate (HR) was collected by placing a photoelectric pulse plethysmogram transducer on the middle finger of the participants non-dominant hand, during the presentation of emotionally valent stimuli (positive, negative, neutral, and smoking-related pictures). A single value was estimated by averaging within the specific time interval.

10. Heart Rate Response [Baseline to 1 month]

    Heart Rate Response. A single value was estimated by averaging within the specific time interval. During a quit attempt, smokers were evaluated on how they react to smoking related cues. An interaction term was then formed by the reactivity to smoking stimulus and genotype.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Age: 18-65 years old

2. Smoking: >/= 5 cigarettes per day within the 2 months preceding the screening visit and expired CO greater than or equal to 6 ppm.

3. Able to follow verbal and written instructions in English and complete all aspects of the study

4. Have an address and home telephone number where they may be reached

5. Provide informed consent and agree to all assessments and study procedures

6. Be the only participant in their household

Exclusion Criteria:

1. Within the month immediately preceding the screening visit; use of any form of tobacco product other than cigarettes on 3 or more days within a week only if the individual refuses to refrain from non-cigarette tobacco use during the course of this study

2. Within the month immediately preceding the screening visit; use of marijuana in any form on 3 or more days within a week

3. Within the two weeks immediately preceding the screening visit, involvement on more than 3 days in any formal smoking cessation activities

4. Current visual or auditory problems that in the opinion of the investigator would interfere with the completion of study assessments

5. Treatment on a continuous basis within 2 weeks before the screening visit: any contraindicated medication for Varenicline or Bupropion.

6. Uncontrolled hypertension or other major contraindications for Bupropion or Varenicline.

7. Severe renal impairment (CR Clearance <30 ml/min/1.73 m2).

8. Laboratory evaluations outside normal limits and of potential clinical significance in the opinion of the investigator

9. Meet current criteria for psychiatric disorders or substance abuse as assessed by the MINI for items A, B, D, I, J, K, L, M and N, including a past manic or hypomanic episode as well as a lifetime psychotic disorder.

10. Subject rated as moderate to high on suicidality as assessed by the MINI.

11. Psychiatric hospitalization within 1 year of screening date.

12. A positive urine pregnancy test during the screening period. Women who are two years post menopausal, one year post-tubal ligation, or who have had a partial or full hysterectomy will not be subject to a urine pregnancy test.

13. Pregnant, breast-feeding, or of childbearing potential who is not protected by a medically acceptable, effective method of birth control while enrolled in the study

14. Use of Varenicline or Bupropion within two weeks before the screening visit.

15. History of hypersensitivity or allergic reaction to Varenicline, tricyclic antidepressant, Bupropion (Wellbutrin, Zyban) or similar chemical classes or any component of these formulations.

16. Subject considered by the investigator as unsuitable candidate for receipt of an investigational drug, or unstable to be followed up throughout the entire duration of the study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Texas MD Anderson Cancer Center	Houston	Texas	United States	77030

Sponsors and Collaborators

• M.D. Anderson Cancer Center
• National Institutes of Health (NIH)
• National Institute on Drug Abuse (NIDA)

Investigators

• Principal Investigator: Paul Cinciripini, PhD, M.D. Anderson Cancer Center

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Feb 24, 2004

More Information

Additional Information:

• University of Texas MD Anderson Cancer Center Website

Publications

• Cinciripini PM, Green CE, Robinson JD, Karam-Hage M, Engelmann JM, Minnix JA, Wetter DW, Versace F. Benefits of varenicline vs. bupropion for smoking cessation: a Bayesian analysis of the interaction of reward sensitivity and treatment. Psychopharmacology (Berl). 2017 Jun;234(11):1769-1779. doi: 10.1007/s00213-017-4580-2. Epub 2017 Mar 8.
• Cui Y, Engelmann JM, Xian J, Minnix JA, Lam CY, Karam-Hage M, Cinciripini PM, Robinson JD. Pharmacological intervention and abstinence in smokers undergoing cessation treatment: A psychophysiological study. Int J Psychophysiol. 2018 Jan;123:25-34. doi: 10.1016/j.ijpsycho.2017.12.001. Epub 2017 Dec 6.
• Cui Y, Robinson JD, Engelmann JM, Lam CY, Minnix JA, Karam-Hage M, Wetter DW, Dani JA, Kosten TR, Cinciripini PM. Reinforcement sensitivity underlying treatment-seeking smokers' affect, smoking reinforcement motives, and affective responses. Psychol Addict Behav. 2015 Jun;29(2):300-311. doi: 10.1037/adb0000050. Epub 2015 Jan 26.
• Cui Y, Robinson JD, Versace F, Lam CY, Minnix JA, Karam-Hage M, Dani JA, Kosten TR, Wetter DW, Brown VL, Cinciripini PM. Differential cigarette-related startle cue reactivity among light, moderate, and heavy smokers. Addict Behav. 2012 Aug;37(8):885-9. doi: 10.1016/j.addbeh.2012.02.003. Epub 2012 Feb 15.
• Cui Y, Versace F, Engelmann JM, Minnix JA, Robinson JD, Lam CY, Karam-Hage M, Brown VL, Wetter DW, Dani JA, Kosten TR, Cinciripini PM. Alpha oscillations in response to affective and cigarette-related stimuli in smokers. Nicotine Tob Res. 2013 May;15(5):917-24. doi: 10.1093/ntr/nts209. Epub 2012 Oct 11.
• Meyer MJ, Coull BA, Versace F, Cinciripini P, Morris JS. Bayesian function-on-function regression for multilevel functional data. Biometrics. 2015 Sep;71(3):563-74. doi: 10.1111/biom.12299. Epub 2015 Mar 18.
• Minnix JA, Versace F, Robinson JD, Lam CY, Engelmann JM, Cui Y, Brown VL, Cinciripini PM. The late positive potential (LPP) in response to varying types of emotional and cigarette stimuli in smokers: a content comparison. Int J Psychophysiol. 2013 Jul;89(1):18-25. doi: 10.1016/j.ijpsycho.2013.04.019. Epub 2013 May 2.
• Robinson JD, Versace F, Lam CY, Minnix JA, Engelmann JM, Cui Y, Karam-Hage M, Shete SS, Tomlinson GE, Chen TT, Wetter DW, Green CE, Cinciripini PM. The CHRNA3 rs578776 Variant is Associated with an Intrinsic Reward Sensitivity Deficit in Smokers. Front Psychiatry. 2013 Sep 23;4:114. doi: 10.3389/fpsyt.2013.00114. eCollection 2013.
• Versace F, Engelmann JM, Robinson JD, Jackson EF, Green CE, Lam CY, Minnix JA, Karam-Hage MA, Brown VL, Wetter DW, Cinciripini PM. Prequit fMRI responses to pleasant cues and cigarette-related cues predict smoking cessation outcome. Nicotine Tob Res. 2014 Jun;16(6):697-708. doi: 10.1093/ntr/ntt214. Epub 2013 Dec 27.
• Versace F, Lam CY, Engelmann JM, Robinson JD, Minnix JA, Brown VL, Cinciripini PM. Beyond cue reactivity: blunted brain responses to pleasant stimuli predict long-term smoking abstinence. Addict Biol. 2012 Nov;17(6):991-1000. doi: 10.1111/j.1369-1600.2011.00372.x. Epub 2011 Oct 4.
• Versace F, Minnix JA, Robinson JD, Lam CY, Brown VL, Cinciripini PM. Brain reactivity to emotional, neutral and cigarette-related stimuli in smokers. Addict Biol. 2011 Apr;16(2):296-307. doi: 10.1111/j.1369-1600.2010.00273.x. Epub 2010 Dec 23.
• Zhu H, Versace F, Cinciripini PM, Rausch P, Morris JS. Robust and Gaussian spatial functional regression models for analysis of event-related potentials. Neuroimage. 2018 Nov 1;181:501-512. doi: 10.1016/j.neuroimage.2018.07.006. Epub 2018 Jul 6.

• Responsible Party: M.D. Anderson Cancer Center
• ClinicalTrials.gov Identifier: NCT00507728
• Other Study ID Numbers: 2003-1024; 1R01DA017073; NCI-2012-02108
• First Posted: Jul 26, 2007
• Last Update Posted: May 6, 2021
• Last Verified: Apr 1, 2021

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by M.D. Anderson Cancer Center: Pharmacogenetics; Emotional Reactivity; Smoking Cessation Counseling; Smoking; Bupropion; Wellbutrin; Wellbutrin SR; Zyban; Varenicline; Chantix; Placebo
• Additional relevant MeSH terms: Tobacco Use Disorder; Bupropion; Varenicline

Study Results

Participant Flow

Recruitment Details	A total of 254 subjects were randomized (varenicline: 75; bupropion: 89; placebo: 90 between December 2005 through October 2010. All subjects were residing in the Greater Houston Area and the study was completed at UT MD Anderson Cancer Center.
Pre-assignment Detail	646 participants signed consent, 392 were screen failures

Arm/Group Title	Varenicline	Bupropion	Placebo
Arm/Group Description	Varenicline starting dose 0.5 mg by mouth daily (0.5 mg every morning for days 1 - 3, then 0.5 mg twice a day for days 4 - 7, then 1 mg twice a day thereafter). Varenicline: Starting dose 0.5 mg by mouth daily (0.5 mg every morning for days 1 - 3, then 0.5 mg twice a day for days 4 - 7, then 1 mg twice a day thereafter)	Bupropion starting dose 150 mg by mouth daily (150 mg every morning for three days; 150 mg twice a day thereafter). Bupropion: Starting dose 150 mg by mouth daily (150 mg every morning for three days; 150 mg twice a day thereafter)	Placebo by mouth for 12 weeks. Placebo: Placebo by mouth for 12 weeks.
Period Title: Randomization to Month 3
STARTED	75	89	90
COMPLETED	60	75	70
NOT COMPLETED	15	14	20
Period Title: Randomization to Month 3
STARTED	60	75	70
COMPLETED	54	65	61
NOT COMPLETED	6	10	9

Baseline Characteristics

Arm/Group Title	Varenicline	Bupropion	Placebo	Total
Arm/Group Description	Varenicline starting dose 0.5 mg by mouth daily (0.5 mg every morning for days 1 - 3, then 0.5 mg twice a day for days 4 - 7, then 1 mg twice a day thereafter). Varenicline: Starting dose 0.5 mg by mouth daily (0.5 mg every morning for days 1 - 3, then 0.5 mg twice a day for days 4 - 7, then 1 mg twice a day thereafter)	Bupropion starting dose 150 mg by mouth daily (150 mg every morning for three days; 150 mg twice a day thereafter). Bupropion: Starting dose 150 mg by mouth daily (150 mg every morning for three days; 150 mg twice a day thereafter)	Placebo by mouth for 12 weeks. Placebo: Placebo by mouth for 12 weeks.	Total of all reporting groups
Overall Participants	75	89	90	254
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	43.5 (10.8)	44.5 (9.3)	45.7 (10.9)	44.6 (10.35)
Sex: Female, Male (Count of Participants)
Female	30 40%	34 38.2%	34 37.8%	98 38.6%
Male	45 60%	55 61.8%	56 62.2%	156 61.4%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	11 14.7%	6 6.7%	7 7.8%	24 9.4%
Not Hispanic or Latino	63 84%	82 92.1%	80 88.9%	225 88.6%
Unknown or Not Reported	1 1.3%	1 1.1%	3 3.3%	5 2%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	2 2.7%	1 1.1%	0 0%	3 1.2%
Asian	3 4%	1 1.1%	0 0%	4 1.6%
Native Hawaiian or Other Pacific Islander	1 1.3%	0 0%	0 0%	1 0.4%
Black or African American	18 24%	23 25.8%	22 24.4%	63 24.8%
White	39 52%	57 64%	60 66.7%	156 61.4%
More than one race	10 13.3%	4 4.5%	6 6.7%	20 7.9%
Unknown or Not Reported	2 2.7%	3 3.4%	2 2.2%	7 2.8%
Region of Enrollment (participants) [Number]
United States	75 100%	89 100%	90 100%	254 100%
Demographic and individual-level characteristics Wisconsin Smoking Withdrawal Scale (WSWS) (Score on a scale) [Mean (Standard Deviation) ]
WSWS Anger Subscale	3.8 (2.6)	4.2 (2.7)	4.2 (7.9)	4.1 (2.6)
WSWS Anxiety Subscale	7.3 (2.7)	7.3 (3.2)	7.9 (3.3)	7.5 (3.1)
WSWS Concentration Subscale	3.7 (1.9)	4 (2.2)	3.9 (2.2)	3.9 (2.1)
WSWS Craving Subscale	8.7 (3.1)	9.4 (2.8)	9.1 (2.6)	9.1 (2.8)
WSWS Hunger Subscale	9.6 (3.7)	9.8 (3.3)	11.2 (3.7)	10.2 (3.6)
WSWS Sadness Subscale	4.6 (2.5)	4.2 (2.4)	4.7 (2.5)	4.5 (2.8)
WSWS Sleep Subscale	7.7 (4.3)	9.3 (4.5)	8.6 (4.4)	8.6 (4.5)
Demographic and individual-level characteristics -Positive and Negative Affect Scales (PANAS) (Score on a scale) [Median (Standard Deviation) ]
PANAS Positive Affect	35.8 (7.1)	36.1 (5.7)	35.8 (6.2)	35.9 (6.3)
PANAS Negative Affect	14.8 (5.1)	15.6 (6.9)	16.4 (5.9)	15.6 (5.3)
Demographic and individual-level characteristics - (CESD) (Score on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Score on a scale]	6.7 (6.1)	6.9 (6.1)	8.1 (7.1)	7.3 (6.5)
Demographic and individual-level characteristics -Modified Cigarette Evaluation Questionnaire (mCEQ) (scores on a scale) [Median (Standard Deviation) ]
mCEQ Smoking Satisfaction	4.3 (1.1)	3.9 (1.2)	4.2 (1.2)	4.2 (1.2)
mCEQ Psychological Reward	4.1 (4.9)	3.7 (1.1)	3.6 (1.3)	3.8 (3.1)
mCEQ Aversion	1.6 (0.8)	1.6 (0.7)	1.5 (0.8)	1.5 (0.8)
mCEQ Enjoyment of Respiratory Tract Sensation	2.9 (1.5)	2.9 (1.4)	2.9 (1.4)	2.9 (1.5)
mCEQ Craving Reduction	5.1 (1.5)	5.1 (1.4)	4.9 (1.6)	5 (1.5)

Outcome Measures

1. Primary Outcome

Title	Emotional Reactivity By Pharmacotherapy
Description	Emotional reactivity measured by the peak eye blink electromyography (EMG) of the orbicularis oculi (ORB) muscle responses to acoustic startle probe delivered during the presentation of emotionally valent stimuli (pleasant, unpleasant, neutral, and smoking-related pictures). A single value was estimated by averaging within the specific time interval.
Time Frame	Baseline to 1 month

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Varenicline	Bupropion	Placebo
Arm/Group Description	Varenicline starting dose 0.5 mg by mouth daily (0.5 mg every morning for days 1 - 3, then 0.5 mg twice a day for days 4 - 7, then 1 mg twice a day thereafter). Varenicline: Starting dose 0.5 mg by mouth daily (0.5 mg every morning for days 1 - 3, then 0.5 mg twice a day for days 4 - 7, then 1 mg twice a day thereafter)	Bupropion starting dose 150 mg by mouth daily (150 mg every morning for three days; 150 mg twice a day thereafter). Bupropion: Starting dose 150 mg by mouth daily (150 mg every morning for three days; 150 mg twice a day thereafter)	Placebo by mouth for 12 weeks. Placebo: Placebo by mouth for 12 weeks.
Measure Participants	78	89	90
Emotional Reactivity (ORB) to Cigarette Stimuli	66.6	64.7	65.6
Emotional Reactivity (ORB) to Negative Stimuli	70.9	73.1	65.6
Emotional Reactivity (ORB) to Positive Stimuli	66.7	65.4	64.7
Emotional Reactivity (ORB) to Neutral Stimuli	59.6	64.9	72.5

2. Primary Outcome

Title	Emotional Reactivity By Pharmacotherapy Moderated by DRD2 A1 Allele
Description	The emotional reactivity (ORB EMG) of smokers during cessation will be moderated by genotype. A single value was estimated by averaging within the specific time interval. During a quit attempt, smokers were evaluated on how they react to smoking related cues. An interaction term was then formed by the reactivity to smoking stimulus and genotype.
Time Frame	Baseline to 1 month

Outcome Measure Data

Analysis Population Description

13 participants had missing data in DRD2 A1 and were not included in the analysis. 1 participant was from the Varenicline group, 7 from the Buproprion group and 5 from the placebo group.

Arm/Group Title	Varenicline w/o DRD2 A1 Allele	Varenicline With DRD2 A1 Allele	Bupropion w/o DRD2 A1 Allele	Bupropion With DRD2 A1 Allele	Placebo w/o DRD2 A1 Allele	Placebo With DRD2 A1 Allele
Arm/Group Description	Subjects in the Varenicline group not carrying the DRD2 A1 allele	Subjects in the Varenicline group carrying the DRD2 A1 allele	Subjects in the Bupropion group not carrying the DRD2 A1 allele	Subjects in the Bupropion group carrying the DRD2 A1 allele	Subjects in the Placebo group not carrying the DRD2 A1 allele	Subjects in the Bupropion group carrying the DRD2 A1 allele
Measure Participants	48	26	37	45	41	44
Emotional Reactivity (ORB) to Cigarette Stimuli	66.5	69.9	66.2	66	67.3	68.1
Emotional Reactivity (ORB) to Negative Stimuli	70.5	75.1	78.6	71.3	74	68.1
Emotional Reactivity (ORB) to Positive Stimuli	65.5	72	71.3	63.3	68.5	63.8
Emotional Reactivity (ORB) to Neutral Stimuli	55.3	67.2	73.9	61.2	79.7	67.8

3. Secondary Outcome

Title	Smoking Abstinence at 3 Months
Description	Values represent change in probability of abstinence for unit change in emotional reactivity. Abstinence data collected using a timeline follow-back (TLFB) procedure. Continuous Abstinence was defined as no smoking within the last 4 weeks of treatment. It is scored as 0 if the participant smoked during the specific interval, and 1 if the participant abstained from smoking.
Time Frame	Baseline to 3 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Varenicline	Bupropion	Placebo
Arm/Group Description	Varenicline starting dose 0.5 mg by mouth daily (0.5 mg every morning for days 1 - 3, then 0.5 mg twice a day for days 4 - 7, then 1 mg twice a day thereafter). Varenicline: Starting dose 0.5 mg by mouth daily (0.5 mg every morning for days 1 - 3, then 0.5 mg twice a day for days 4 - 7, then 1 mg twice a day thereafter)	Bupropion starting dose 150 mg by mouth daily (150 mg every morning for three days; 150 mg twice a day thereafter). Bupropion: Starting dose 150 mg by mouth daily (150 mg every morning for three days; 150 mg twice a day thereafter)	Placebo by mouth for 12 weeks. Placebo: Placebo by mouth for 12 weeks.
Measure Participants	75	89	90
Emotional Reactivity (ORB) to Cigarette Stimuli	-0.003	-0.01	-0.008
Emotional Reactivity (ORB) to Negative Stimuli	-0.004	-0.009	-0.007
Emotional Reactivity (ORB) to Positive Stimuli	-0.003	-0.01	-0.007
Emotional Reactivity (ORB) to Neutral Stimuli	-0.004	-0.008	-0.007

4. Secondary Outcome

Title	Smoking Abstinence at 3 Months by DRD2 A1 Allele
Description	Values represent change in probability of abstinence for unit change in emotional reactivity. Abstinence data collected using a timeline follow-back (TLFB) procedure. Continuous Abstinence was defined as no smoking within the last 4 weeks of treatment. It is scored as 0 if the participant smoked during the specific interval, and 1 if the participant abstained from smoking.
Time Frame	Baseline to 3 Month

Outcome Measure Data

Analysis Population Description

13 participants had missing data in DRD2 A1 and were not included in the analysis. 1 participant was from the Varenicline group, 7 from the Buproprion group and 5 from the placebo group.

Arm/Group Title	Varenicline w/o DRD2 A1 Allele	Varenicline With DRD2 A1 Allele	Bupropion w/o DRD2 A1 Allele	Bupropion With DRD2 A1 Allele	Placebo w/o DRD2 A1 Allele	Placebo With DRD2 A1 Allele
Arm/Group Description	Subjects in the Varenicline group not carrying the DRD2 A1 allele	Subjects in the Varenicline group carrying the DRD2 A1 allele	Subjects in the Bupropion group not carrying the DRD2 A1 allele	Subjects in the Bupropion group carrying the DRD2 A1 allele	Subjects in the Placebo group not carrying the DRD2 A1 allele	Subjects in the Bupropion group carrying the DRD2 A1 allele
Measure Participants	48	26	37	45	41	44
Emotional Reactivity (ORB) to Cigarette Stimuli	0.001	-0.004	0	-0.003	-0.001	-0.004
Emotional Reactivity (ORB) to Negative Stimuli	0.002	-0.005	0	-0.004	-0.001	-0.004
Emotional Reactivity (ORB) to Positive Stimuli	0.001	-0.005	0	-0.003	-0.001	-0.004
Emotional Reactivity (ORB) to Neutral Stimuli	0.001	-0.005	0.001	-0.002	-0.001	-0.003

5. Secondary Outcome

Title	Smoking Abstinence at 6 Months
Description	Values represent change in probability of abstinence for unit change in emotional reactivity. Abstinence data collected using a timeline follow-back (TLFB) procedure. Continuous Abstinence was defined as no smoking within the last 4 weeks of treatment. It is scored as 0 if the participant smoked during the specific interval, and 1 if the participant abstained from smoking.
Time Frame	Abstinence at 6 Months ( the effects shown are the increase/decrease in probability of abstinence for 1 unit increase in the predictor)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Varenicline	Bupropion	Placebo
Arm/Group Description	Varenicline starting dose 0.5 mg by mouth daily (0.5 mg every morning for days 1 - 3, then 0.5 mg twice a day for days 4 - 7, then 1 mg twice a day thereafter). Varenicline: Starting dose 0.5 mg by mouth daily (0.5 mg every morning for days 1 - 3, then 0.5 mg twice a day for days 4 - 7, then 1 mg twice a day thereafter)	Bupropion starting dose 150 mg by mouth daily (150 mg every morning for three days; 150 mg twice a day thereafter). Bupropion: Starting dose 150 mg by mouth daily (150 mg every morning for three days; 150 mg twice a day thereafter)	Placebo by mouth for 12 weeks. Placebo: Placebo by mouth for 12 weeks.
Measure Participants	75	89	90
Emotional Reactivity (ORB) to Cigaretee Stimuli	0.007	-0.002	-0.006
Emotional Reactivity (ORB) to Negative Stimuli	0.008	-0.003	-0.005
Emotional Reactivity (ORB) to Positive Stimuli	0.01	-0.003	-0.005
Emotional Reactivity (ORB) to Neutral Stimuli	0.008	-0.001	-0.005

6. Secondary Outcome

Title	Abstinence at 6 Months by DRD2 A1 Allele
Description	Values represent change in probability of abstinence for unit change in emotional reactivity. Abstinence data collected using a timeline follow-back (TLFB) procedure. Continuous Abstinence was defined as no smoking within the last 4 weeks of treatment. It is scored as 0 if the participant smoked during the specific interval, and 1 if the participant abstained from smoking.
Time Frame	Baseline to 6 Month ( the effects shown are the increase/decrease in probability of abstinence for 1 unit increase in the predictor)

Outcome Measure Data

Analysis Population Description

13 participants had missing data in DRD2 A1 and were not included in the analysis. 1 participant was from the Varenicline group, 7 from the Buproprion group and 5 from the placebo group.

Arm/Group Title	Varenicline w/o DRD2 A1 Allele	Varenicline With DRD2 A1 Allele	Bupropion w/o DRD2 A1 Allele	Bupropion With DRD2 A1 Allele	Placebo w/o DRD2 A1 Allele	Placebo With DRD2 A1 Allele
Arm/Group Description	Subjects in the Varenicline group not carrying the DRD2 A1 allele	Subjects in the Varenicline group carrying the DRD2 A1 allele	Subjects in the Bupropion group not carrying the DRD2 A1 allele	Subjects in the Bupropion group carrying the DRD2 A1 allele	Subjects in the Placebo group not carrying the DRD2 A1 allele	Subjects in the Bupropion group carrying the DRD2 A1 allele
Measure Participants	48	26	37	45	41	44
Emotional Reactivity (ORB) to Cigarette Stimuli	0.003	-0.001	0.001	-0.001	0	-0.005
Emotional Reactivity (ORB) to Negative Stimuli	0.003	-0.001	0.001	-0.002	0	-0.004
Emotional Reactivity (ORB) to Positive Stimuli	0.003	0	0	-0.001	0	-0.004
Emotional Reactivity (ORB) to Neutral Stimuli	0.003	-0.001	0.001	-0.001	0	-0.004

7. Secondary Outcome

Title	Symptoms of Nicotine Withdrawal Using the Wisconsin Smoking Withdrawal Scale (WSWS)
Description	Symptoms of nicotine withdrawal measured using Wisconsin Smoking Withdrawal Scale (WSWS). The Wisconsin Withdrawal Scale (WSWS) contains 7 factors: Anger, Anxiety, Sadness, Concentration, Craving, Sleep, and Hunger. WSWS consists of 28 items that are scored on a 5-point Likert type scale (0 = strongly disagree, 4 = strongly agree). A single value was estimated by averaging within the specific time interval. Higher values represent worse outcome. The average value was estimated from Baseline to 8 months
Time Frame	Baseline to 8 months

Outcome Measure Data

Analysis Population Description

13 participants had missing data in DRD2 A1 and were not included in the analysis. 1 participant was from the Varenicline group, 7 from the Buproprion group and 5 from the placebo group.

Arm/Group Title	Varenicline w/o DRD2 A1 Allele	Varenicline With DRD2 A1 Allele	Bupropion w/o DRD2 A1 Allele	Bupropion With DRD2 A1 Allele	Placebo w/o DRD2 A1 Allele	Placebo With DRD2 A1 Allele
Arm/Group Description	Subjects in the Varenicline group not carrying the DRD2 A1 allele	Subjects in the Varenicline group carrying the DRD2 A1 allele	Subjects in the Bupropion group not carrying the DRD2 A1 allele	Subjects in the Bupropion group carrying the DRD2 A1 allele	Subjects in the Placebo group not carrying the DRD2 A1 allele	Subjects in the Bupropion group carrying the DRD2 A1 allele
Measure Participants	48	26	37	45	41	44
Anger	4.394	4.222	4.28	4.41	5.584	5.752
Anxiety	6.218	5.873	6.587	6.587	7.785	7.915
Concentration	3.743	3.407	4.238	3.935	4.764	4.951
Craving	6.646	6.252	6.814	6.78	9.024	8.696
Hunger	11.016	10.707	9.79	11.082	11.207	11.044
Sadness	4.246	3.738	4.005	4.338	5.293	5.865
Sleep	7.721	8.153	9.672	9.528	9.078	8.629

8. Secondary Outcome

Title	Symptoms of Nicotine Withdrawal and Negative Affect Using Positive and Negative Affect Scale (PANAS)
Description	Symptoms of nicotine withdrawal and negative affect were measured using the Positive and Negative Affect Scale (PANAS). The Positive and Negative Affect Schedule (PANAS) is a self-report questionnaire to measure both positive and negative affect. Each item is rated on a 5-point scale of 1 (not at all) to 5 (very much). Scores can range from 10-50 for both the Positive and Negative Affect with the lower scores representing lower levels of Positive/Negative Affect and higher scores representing higher levels of Positive/Negative Affect. The average value was estimated from Baseline to 8 months
Time Frame	Baseline to 8 months

Outcome Measure Data

Analysis Population Description

13 participants had missing data in DRD2 A1 and were not included in the analysis. 1 participant was from the Varenicline group, 7 from the Buproprion group and 5 from the placebo group.

Arm/Group Title	Varenicline w/o DRD2 A1 Allele	Varenicline With DRD2 A1 Allele	Bupropion w/o DRD2 A1 Allele	Bupropion With DRD2 A1 Allele	Placebo w/o DRD2 A1 Allele	Placebo With DRD2 A1 Allele
Arm/Group Description	Subjects in the Varenicline group not carrying the DRD2 A1 allele	Subjects in the Varenicline group carrying the DRD2 A1 allele	Subjects in the Bupropion group not carrying the DRD2 A1 allele	Subjects in the Bupropion group carrying the DRD2 A1 allele	Subjects in the Placebo group not carrying the DRD2 A1 allele	Subjects in the Bupropion group carrying the DRD2 A1 allele
Measure Participants	48	26	37	45	41	44
Positive Affect	35.507	37.315	36.429	35.281	33.672	33.984
Negative Affect	15.93	14.98	15.782	16.385	18.017	18.902

9. Secondary Outcome

Title	Symptoms of Depression Using the Center for Epidemiologic Studies Depression Scale (CES-D)
Description	Symptoms of nicotine withdrawal measured using Center for Epidemiologic Studies Depression Scale (CES-D). Center of Epidemiologic Studies Depression Scale (CESD) a 20-item measure that asks caregivers to rate how often over the past week they experienced symptoms associated with depression, such as restless sleep, poor appetite, and feeling lonely. Response options range from 0 to 3 for each item (0 = Rarely or None of the Time, 1 = Some or Little of the Time, 2 = Moderately or Much of the time, 3 = Most or Almost All the Time). Scores range from 0 to 60, with high scores indicating greater depressive symptoms. The average value was estimated from Baseline to 8 months
Time Frame	Baseline to 8 months

Outcome Measure Data

Analysis Population Description

13 participants had missing data in DRD2 A1 and were not included in the analysis. 1 participant was from the Varenicline group, 7 from the Buproprion group and 5 from the placebo group.

Arm/Group Title	Varenicline w/o DRD2 A1 Allele	Varenicline With DRD2 A1 Allele	Bupropion w/o DRD2 A1 Allele	Bupropion With DRD2 A1 Allele	Placebo w/o DRD2 A1 Allele	Placebo With DRD2 A1 Allele
Arm/Group Description	Subjects in the Varenicline group not carrying the DRD2 A1 allele	Subjects in the Varenicline group carrying the DRD2 A1 allele	Subjects in the Bupropion group not carrying the DRD2 A1 allele	Subjects in the Bupropion group carrying the DRD2 A1 allele	Subjects in the Placebo group not carrying the DRD2 A1 allele	Subjects in the Bupropion group carrying the DRD2 A1 allele
Measure Participants	48	26	37	45	41	44
Least Squares Mean (95% Confidence Interval) [score on a scale]	8.084	6.847	7.588	8.362	8.65	10.799

10. Secondary Outcome

Title	Measures of Smoking Satisfaction and Psychological Reward Using the Modified Cigarette Evaluation Questionnaire (mCEQ) Subscales
Description	Modified Cigarette Evaluation Questionnaire (mCEQ). mCEQ Smoking satisfaction: range (1-21); mCEQ Psychological Reward: range(1-35); mCEQ Aversion: range (1-14); mCEQ Enjoyment of Resp.Tract Sens: range (1-7); mCEQ Craving Reduction: range (1-7). For all scales of mCEQ higher scores indicate worse outcomes (greater intensity of smoking effect). Scores of mCEQ Smoking satisfaction, mCEQ psychological reward and mCEQ aversion were summed to create the subscales. mCEQ Enjoyment of Resp Tract Sens and mCEQ Craving Reduction were single items.
Time Frame	Baseline to 8 months

Outcome Measure Data

Analysis Population Description

13 participants had missing data in DRD2 A1 and were not included in the analysis. 1 participant was from the Varenicline group, 7 from the Buproprion group and 5 from the placebo group.

Arm/Group Title	Varenicline w/o DRD2 A1 Allele	Varenicline With DRD2 A1 Allele	Bupropion w/o DRD2 A1 Allele	Bupropion With DRD2 A1 Allele	Placebo w/o DRD2 A1 Allele	Placebo With DRD2 A1 Allele
Arm/Group Description	Subjects in the Varenicline group not carrying the DRD2 A1 allele	Subjects in the Varenicline group carrying the DRD2 A1 allele	Subjects in the Bupropion group not carrying the DRD2 A1 allele	Subjects in the Bupropion group carrying the DRD2 A1 allele	Subjects in the Placebo group not carrying the DRD2 A1 allele	Subjects in the Bupropion group carrying the DRD2 A1 allele
Measure Participants	48	26	37	45	41	44
Smoking Satisfaction	2.895	2.591	4.064	3.369	3.025	3.515
Psychological Reward	2.819	2.155	2.519	2.723	3.575	3.246
Aversion	1.612	1.694	1.988	1.79	1.808	1.69
Enjoyment of Respiratory Tract Sensation	1.912	1.703	4.096	1.955	3.711	2.783
Craving Reduction	4.531	3.952	4.564	6.628	4.486	4.673

11. Secondary Outcome

Title	Skin Conductance Response
Description	Skin conductance response (SCR) amplitude measured by placing an electrodermal response transducer on the fore and ring fingers of the participants non-dominant hand, and heart rate (HR) was collected by placing a photoelectric pulse plethysmogram transducer on the middle finger of the participants non-dominant hand, during the presentation of emotionally valent stimuli (positive, negative, neutral, and smoking-related pictures). A single value was estimated by averaging within the specific time interval.
Time Frame	Baseline to 1 month

Outcome Measure Data

Analysis Population Description

13 participants had missing data in DRD2 A1 and were not included in the analysis. 1 participant was from the Varenicline group, 7 from the Buproprion group and 5 from the placebo group.

Arm/Group Title	Varenicline w/o DRD2 A1 Allele	Varenicline With DRD2 A1 Allele	Bupropion w/o DRD2 A1 Allele	Bupropion With DRD2 A1 Allele	Placebo w/o DRD2 A1 Allele	Placebo With DRD2 A1 Allele
Arm/Group Description	Subjects in the Varenicline group not carrying the DRD2 A1 allele	Subjects in the Varenicline group carrying the DRD2 A1 allele	Subjects in the Bupropion group not carrying the DRD2 A1 allele	Subjects in the Bupropion group carrying the DRD2 A1 allele	Subjects in the Placebo group not carrying the DRD2 A1 allele	Subjects in the Bupropion group carrying the DRD2 A1 allele
Measure Participants	48	26	37	45	41	44
Skin conductance to Cigarette Stimuli	2.301	2.016	2.275	1.797	2.272	2.443
Skin conductance to Negative Stimuli	2.295	1.969	2.31	1.695	2.355	2.485
Skin conductance to Positive Stimuli	2.256	1.984	2.299	1.7	2.296	2.565
Skin conductance to Neutral Stimuli	2.261	2.017	2.369	1.699	2.362	2.559

12. Secondary Outcome

Title	Heart Rate Response
Description	Heart Rate Response. A single value was estimated by averaging within the specific time interval. During a quit attempt, smokers were evaluated on how they react to smoking related cues. An interaction term was then formed by the reactivity to smoking stimulus and genotype.
Time Frame	Baseline to 1 month

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Varenicline w/o DRD2 A1 Allele	Varenicline With DRD2 A1 Allele	Bupropion w/o DRD2 A1 Allele	Bupropion With DRD2 A1 Allele	Placebo w/o DRD2 A1 Allele	Placebo With DRD2 A1 Allele
Arm/Group Description	Subjects in the Varenicline group not carrying the DRD2 A1 allele	Subjects in the Varenicline group carrying the DRD2 A1 allele	Subjects in the Bupropion group not carrying the DRD2 A1 allele	Subjects in the Bupropion group carrying the DRD2 A1 allele	Subjects in the Placebo group not carrying the DRD2 A1 allele	Subjects in the Bupropion group carrying the DRD2 A1 allele
Measure Participants	48	26	37	45	41	44
Heart Rate response to Cigarette Stimuli	69.731	68.652	71.427	69.836	65.966	65.276
Heart Rate response to Negative Stimuli	69.562	68.078	71.077	69.595	65.768	65.569
Heart Rate response to Positive Stimuli	69.151	68.711	71.518	70.404	65.787	65.927
Heart Rate response to Neutral Stimuli	69.621	68.969	71.706	70.234	65.237	66.04

Adverse Events

Time Frame	Baseline, up to 8 months
Arm/Group Title	Varenicline		Bupropion		Placebo
Arm/Group Description	Varenicline starting dose 0.5 mg by mouth daily (0.5 mg every morning for days 1 - 3, then 0.5 mg twice a day for days 4 - 7, then 1 mg twice a day thereafter). Varenicline: Starting dose 0.5 mg by mouth daily (0.5 mg every morning for days 1 - 3, then 0.5 mg twice a day for days 4 - 7, then 1 mg twice a day thereafter)		Bupropion starting dose 150 mg by mouth daily (150 mg every morning for three days; 150 mg twice a day thereafter). Bupropion: Starting dose 150 mg by mouth daily (150 mg every morning for three days; 150 mg twice a day thereafter)		Placebo by mouth for 12 weeks. Placebo: Placebo by mouth for 12 weeks.
All Cause Mortality
	Varenicline		Bupropion		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/75 (0%)		0/89 (0%)		0/90 (0%)
Serious Adverse Events
	Varenicline		Bupropion		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/75 (2.7%)		2/89 (2.2%)		0/90 (0%)
Cardiac disorders
Chest pain - cardiac	1/75 (1.3%)		0/89 (0%)		0/90 (0%)
Nervous system disorders
Dizziness	0/75 (0%)		1/89 (1.1%)		0/90 (0%)
Renal and urinary disorders
Urinary Incontinence	0/75 (0%)		1/89 (1.1%)		0/90 (0%)
Respiratory, thoracic and mediastinal disorders
Shortness of Breath	2/75 (2.7%)		0/89 (0%)		0/90 (0%)
Increased Coughing	1/75 (1.3%)		0/89 (0%)		0/90 (0%)
Skin and subcutaneous tissue disorders
Eczema	0/75 (0%)		1/89 (1.1%)		0/90 (0%)
Other (Not Including Serious) Adverse Events
	Varenicline		Bupropion		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	63/75 (84%)		69/89 (77.5%)		66/90 (73.3%)
Cardiac disorders
Chest pain - cardiac	1/75 (1.3%)		4/89 (4.5%)		11/90 (12.2%)
Hypertension	3/75 (4%)		2/89 (2.2%)		2/90 (2.2%)
Tachycardia/Palpita..	1/75 (1.3%)		3/89 (3.4%)		0/90 (0%)
Endocrine disorders
DIABETES MELLITUS	0/75 (0%)		0/89 (0%)		1/90 (1.1%)
Glucose intolerance	0/75 (0%)		0/89 (0%)		1/90 (1.1%)
Hypothyroidism	1/75 (1.3%)		0/89 (0%)		0/90 (0%)
Eye disorders
Blurred vision	1/75 (1.3%)		4/89 (4.5%)		2/90 (2.2%)
Eye irritation	2/75 (2.7%)		1/89 (1.1%)		2/90 (2.2%)
Gastrointestinal disorders
BLOOD IN STOOL	0/75 (0%)		1/89 (1.1%)		0/90 (0%)
Constipation	6/75 (8%)		5/89 (5.6%)		3/90 (3.3%)
Diarrhea	8/75 (10.7%)		4/89 (4.5%)		12/90 (13.3%)
Dysphagia	0/75 (0%)		1/89 (1.1%)		0/90 (0%)
Flatulence	2/75 (2.7%)		4/89 (4.5%)		1/90 (1.1%)
Gastritis	6/75 (8%)		5/89 (5.6%)		4/90 (4.4%)
Hemorrhoids	0/75 (0%)		1/89 (1.1%)		1/90 (1.1%)
Nausea	21/75 (28%)		17/89 (19.1%)		8/90 (8.9%)
Vomiting	3/75 (4%)		0/89 (0%)		2/90 (2.2%)
General disorders
APPETITE DECREASED	3/75 (4%)		4/89 (4.5%)		3/90 (3.3%)
APPETITE INCREASED	8/75 (10.7%)		7/89 (7.9%)		5/90 (5.6%)
Body odor	1/75 (1.3%)		0/89 (0%)		0/90 (0%)
Dehydration	0/75 (0%)		1/89 (1.1%)		0/90 (0%)
Dizziness	4/75 (5.3%)		4/89 (4.5%)		4/90 (4.4%)
Dry mouth	1/75 (1.3%)		3/89 (3.4%)		7/90 (7.8%)
Fatigue	4/75 (5.3%)		5/89 (5.6%)		9/90 (10%)
Flushing	1/75 (1.3%)		0/89 (0%)		2/90 (2.2%)
Infection	1/75 (1.3%)		6/89 (6.7%)		3/90 (3.3%)
Influenza	6/75 (8%)		8/89 (9%)		2/90 (2.2%)
Mucositis oral	0/75 (0%)		1/89 (1.1%)		0/90 (0%)
Neck pain	1/75 (1.3%)		2/89 (2.2%)		1/90 (1.1%)
Pain	1/75 (1.3%)		2/89 (2.2%)		6/90 (6.7%)
Pelvic pain	1/75 (1.3%)		0/89 (0%)		0/90 (0%)
TASTE PERVERSION	4/75 (5.3%)		3/89 (3.4%)		6/90 (6.7%)
Toothache	3/75 (4%)		7/89 (7.9%)		3/90 (3.3%)
Weight gain	2/75 (2.7%)		2/89 (2.2%)		1/90 (1.1%)
Weight loss	0/75 (0%)		0/89 (0%)		1/90 (1.1%)
Immune system disorders
Allergic reaction	1/75 (1.3%)		0/89 (0%)		1/90 (1.1%)
Allergy, Seasonal	1/75 (1.3%)		2/89 (2.2%)		1/90 (1.1%)
Metabolism and nutrition disorders
Hypercholesterolemia	1/75 (1.3%)		0/89 (0%)		0/90 (0%)
Hypertriglyceridemia	0/75 (0%)		1/89 (1.1%)		0/90 (0%)
Hypoglycemia	0/75 (0%)		1/89 (1.1%)		0/90 (0%)
Musculoskeletal and connective tissue disorders
ACCIDENTAL INJURY	0/75 (0%)		0/89 (0%)		1/90 (1.1%)
Back pain	1/75 (1.3%)		1/89 (1.1%)		4/90 (4.4%)
Chest wall pain	1/75 (1.3%)		1/89 (1.1%)		4/90 (4.4%)
Edema	3/75 (4%)		4/89 (4.5%)		5/90 (5.6%)
Herniated Disc	1/75 (1.3%)		0/89 (0%)		0/90 (0%)
Musculoskeletal pain	10/75 (13.3%)		9/89 (10.1%)		12/90 (13.3%)
TREMOR	2/75 (2.7%)		1/89 (1.1%)		0/90 (0%)
Nervous system disorders
Cerebrospinal fluid..	1/75 (1.3%)		0/89 (0%)		0/90 (0%)
Drowsiness	3/75 (4%)		2/89 (2.2%)		5/90 (5.6%)
Headache	9/75 (12%)		13/89 (14.6%)		11/90 (12.2%)
Insomnia	16/75 (21.3%)		26/89 (29.2%)		13/90 (14.4%)
PARESTHESIA	1/75 (1.3%)		0/89 (0%)		1/90 (1.1%)
Sensory disturbance	1/75 (1.3%)		0/89 (0%)		2/90 (2.2%)
Psychiatric disorders
Abnormal Dreams	13/75 (17.3%)		6/89 (6.7%)		7/90 (7.8%)
Anxiety Symptoms	5/75 (6.7%)		5/89 (5.6%)		13/90 (14.4%)
Depression	6/75 (8%)		7/89 (7.9%)		10/90 (11.1%)
Disturbance in attention	7/75 (9.3%)		7/89 (7.9%)		12/90 (13.3%)
Elevated mood	0/75 (0%)		0/89 (0%)		1/90 (1.1%)
Emotional liability	2/75 (2.7%)		3/89 (3.4%)		4/90 (4.4%)
Irritability	11/75 (14.7%)		14/89 (15.7%)		13/90 (14.4%)
Reduced inhibition	0/75 (0%)		1/89 (1.1%)		0/90 (0%)
Restlessness	0/75 (0%)		5/89 (5.6%)		5/90 (5.6%)
Suicidal ideation	0/75 (0%)		0/89 (0%)		1/90 (1.1%)
Renal and urinary disorders
Kidney Stones	0/75 (0%)		1/89 (1.1%)		0/90 (0%)
URINARY INCONTINENCE	0/75 (0%)		1/89 (1.1%)		0/90 (0%)
Urinary frequency	1/75 (1.3%)		3/89 (3.4%)		0/90 (0%)
Urinary tract infection	0/75 (0%)		1/89 (1.1%)		1/90 (1.1%)
Urine abnormality	0/75 (0%)		2/89 (2.2%)		1/90 (1.1%)
Reproductive system and breast disorders
Libido decreased	0/75 (0%)		1/89 (1.1%)		0/90 (0%)
Respiratory, thoracic and mediastinal disorders
ASTHMA	0/75 (0%)		0/89 (0%)		1/90 (1.1%)
BRONCHITIS	0/75 (0%)		1/89 (1.1%)		1/90 (1.1%)
Increased Coughing	9/75 (12%)		7/89 (7.9%)		4/90 (4.4%)
PNEUMONIA	0/75 (0%)		1/89 (1.1%)		0/90 (0%)
Rhinitis	17/75 (22.7%)		26/89 (29.2%)		23/90 (25.6%)
Shortness of Breath	6/75 (8%)		7/89 (7.9%)		11/90 (12.2%)
Sore throat	2/75 (2.7%)		3/89 (3.4%)		9/90 (10%)
Tinnitus	0/75 (0%)		2/89 (2.2%)		0/90 (0%)
Skin and subcutaneous tissue disorders
ABSCESS	1/75 (1.3%)		2/89 (2.2%)		2/90 (2.2%)
BRUISE	0/75 (0%)		1/89 (1.1%)		0/90 (0%)
Eczema	6/75 (8%)		6/89 (6.7%)		3/90 (3.3%)
SWEATING INCREASED	0/75 (0%)		2/89 (2.2%)		2/90 (2.2%)
Surgical and medical procedures
Surgical and medical	1/75 (1.3%)		0/89 (0%)		0/90 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.