Major Depressive Disorder, Nicotine Dependence
Conditions
Keywords
Smoking Cessation, Major Depressive Disorder, Nicotine Dependence, Varenicline, Behavioral Activation Therapy, Cigarette Smoking
Brief summary
Persons who struggle with depression smoke at high rates and experience low quit rates in treatment. The best way to improve cessation treatment for this underserved population remains unknown. The proposed trial tests whether the combination of varenicline and behavioral mood management treatment enhances long-term abstinence for depressed smokers and, if so, whether this treatment achieves its effects through addressing the unique psychological factors that appear to maintain tobacco dependence for these smokers.
Detailed description
Upwards of 43% of persons with major depressive disorder (MDD) are daily smokers who are more likely to smoke heavily, show greater tobacco dependence, suffer more severe withdrawal, and experience lower quit rates than smokers without MDD. Little is known about treatment strategies that might optimize smoking cessation for smokers with MDD because almost all randomized clinical trials have excluded these smokers. This project answers many prominent but largely unanswered calls over the last decade to address tobacco dependence in persons with mental health disorders, especially major depressive disorder (MDD). Using a double-blind, placebo-controlled, randomized design, the investigators will evaluate the efficacy of behavioral activation for smoking cessation (BASC) plus varenicline for treating tobacco dependence in smokers with current or lifetime MDD. Three hundred and thirty daily (≥1 cigarettes/day) smokers will be randomized to receive 12 weeks of one of four treatments: 1) Standard behavioral cessation treatment (ST) + placebo; 2) Behavioral activation integrated with ST (BASC) + placebo; 3) ST + varenicline; or 4) BASC + varenicline. Both BASC and ST will be administered in eight 45 minute sessions, occurring weekly for the first four weeks and biweekly for the final eight weeks. Randomization will be stratified on clinical site (Northwestern, University of Pennsylvania), gender, and severity of depressive symptoms (minimal/mild vs. moderate/severe). The primary outcomes will be carbon monoxide (CO) verified 7-day point prevalence abstinence at 24-weeks post-quit. Additional aims include assessing adverse event rates between varenicline and placebo arms, and testing for mediation of treatment effects by anhedonia, cognitive function (attention and memory), cigarette reward value, and craving and withdrawal. This randomized controlled trial will be the first adequately powered trial of BASC in this population; the first trial to evaluate varenicline among a community sample of smokers with MDD; and the first trial to assess the main and combined effects of these two treatments.
Interventions
DRUGVarenicline
Participants will be randomly assigned to 12 weeks of either placebo or varenicline medication (1mg twice daily). Participants and research personnel will be blind to treatment assignment.
BEHAVIORALBASC
The goal of behavioral activation therapy is to increase engagement in rewarding activities, a problem for smokers with depression who find smoking especially rewarding and prefer it over many other traditionally rewarding activities, by reducing patterns of behavioral avoidance, withdrawal, and inactivity. In this study, behavioral activation will be integrated with standard behavioral smoking cessation treatment. Treatment will be delivered in eight 45-minute sessions over 12 weeks occurring weekly for the first four sessions and biweekly for the final four sessions.
BEHAVIORALStandard treatment
Standard behavioral smoking cessation treatment is an effective treatment for nicotine dependence. Treatment focuses on self-monitoring of smoking behavior, identifying smoking triggers and alternative trigger management strategies, relaxation, social support for non-smoking, and relapse prevention. Treatment will be delivered in eight 45-minute sessions over 12 weeks occurring weekly for the first four sessions and biweekly for the final four sessions.
Sponsors
National Cancer Institute (NCI)
Northwestern University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. adult (18 years of age or older) daily cigarette smokers (1+ cigarettes per day) 2. meet criteria for current or lifetime MDD without psychotic features 3. have or are willing to acquire a personal email address and access to a camera phone or other method for submission of therapy practice assignments 4. speak, read, and write fluently in English 5. able to provide written informed consent 6. intend to reside in the geographic area for \>8 months 7. women of childbearing potential must agree to use a medically acceptable method of birth control or abstain from sexual intercourse during the time they are taking study medication and for at least one month after the medication period ends. 8. The candidate had to answer yes to the question: Are you interested in quitting smoking?
Exclusion criteria
1. current enrollment or plan to enroll in another smoking cessation program in the next 8 months 2. regular (daily) use of e-cigarettes, chewing tobacco, snuff, snus, or other tobacco products 3. current use or plan to use nicotine replacement therapy or other smoking cessation medication within the next 8 months 4. medications indicated for bipolar or psychotic disorder if prescribed for bipolar or psychotic disorder 5. pregnant or planning to become pregnant within the next 8 months, or breast feeding 6. history of seizures or current seizure disorder without medication 7. history of severe (stage IV or V) chronic kidney disease including current or prior end stage renal disease on either hemodialysis or peritoneal dialysis or prior renal transplant 8. any prior solid organ transplant or prior hematopoietic stem cell transplant 9. alcohol consumption exceeding 28 drinks per week 10. cirrhosis or end-stage liver disease 11. systolic blood pressure \>185 mmHg or diastolic blood pressure \>110 mmHg after two readings or symptomatic uncontrolled stage II hypertension 12. unstable cardiovascular disease within 3 months prior to baseline or other cardiovascular disease requiring hospitalization 13. prior hospitalization for heart failure 14. previous allergic reaction to varenicline 15. high suicide risk based on the Columbia Suicide Severity Rating Scale 16. lifetime bipolar or psychotic disorder as determined by either self-report or clinical interview
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Bioverified Point-prevalence Abstinence at 27 Weeks | 27 weeks (24-weeks post-target quit date) | Participants were classified as abstinent if they reported abstinence, not even a puff of a cigarette, for \>7 days prior to week 27 (24 weeks post-target quit date) and had an expired carbon monoxide reading of ≤ 6 parts per million at week 27. |
| Adverse Event and Serious Adverse Event Rates | Weeks 1 (1-week before starting medication), 6, and 14 (end of medication) | Adverse event and serious adverse event rates between varenicline and placebo arms. A previously developed algorithm was used to classify side effect reports as adverse events (AEs) or serious adverse events (SAEs) (Schnoll et al. 2019). Reference: Schnoll, R., Leone, F., Weisbrot, J., Veluz-Wilkins, A., Miele, A., Hole, A., Jao, N.C., Wileyto, E.P., Carroll, A.J., Kalhan, R., Patel, J., Langer, C., & Hitsman, B. (2019). A randomized controlled trial of 24-weeks of varenicline for tobacco use among cancer patients: Efficacy, safety, and adherence. Psycho-Oncology, 28, 561-569. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Bioverified Point-prevalence Abstinence at 14 Weeks (End of Treatment) | 14 weeks (11-weeks post-target quit date) | Participants were classified as abstinent if they reported abstinence, not even a puff of a cigarette, for \>7 days prior to week 14 (11-weeks post-target quit date) and had an expired carbon monoxide reading of ≤ 6 parts per million at week 14. |
| Prolonged Abstinence | 27 weeks (24 weeks post target quit date) | \<7 consecutive days of self-reported smoking after a 2-week grace period |
| Continuous Abstinence | 27 weeks (24 weeks post target quit date) | No smoking between target quit date (week 3) and week 27 |
| Time to 7-day Relapse | 27 weeks (24 weeks post target quit date) | Time to relapse as defined by 7 or more consecutive days of self-reported smoking (no grace period) |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Standard Treatment + Placebo Varenicline Standard behavioral smoking cessation treatment plus placebo varenicline
Standard treatment: Standard behavioral smoking cessation treatment is an effective treatment for nicotine dependence. Treatment focuses on self-monitoring of smoking behavior, identifying smoking triggers and alternative trigger management strategies, relaxation, social support for non-smoking, and relapse prevention. Treatment will be delivered in eight 45-minute sessions over 12 weeks occurring weekly for the first four sessions and biweekly for the final four sessions. | 68 |
| BASC + Placebo Varenicline Behavioral activation for smoking cessation plus placebo varenicline
BASC: The goal of behavioral activation therapy is to increase engagement in rewarding activities, a problem for smokers with depression who find smoking especially rewarding and prefer it over many other traditionally rewarding activities, by reducing patterns of behavioral avoidance, withdrawal, and inactivity. In this study, behavioral activation will be integrated with standard behavioral smoking cessation treatment.
Treatment will be delivered in eight 45-minute sessions over 12 weeks occurring weekly for the first four sessions and biweekly for the final four sessions. | 68 |
| Standard Treatment + Active Varenicline Standard behavioral smoking cessation treatment plus active varenicline
Varenicline: Participants will be randomly assigned to 12 weeks of either placebo or varenicline medication (1mg twice daily). Participants and research personnel will be blind to treatment assignment.
Standard treatment: Standard behavioral smoking cessation treatment is an effective treatment for nicotine dependence. Treatment focuses on self-monitoring of smoking behavior, identifying smoking triggers and alternative trigger management strategies, relaxation, social support for non-smoking, and relapse prevention. Treatment will be delivered in eight 45-minute sessions over 12 weeks occurring weekly for the first four sessions and biweekly for the final four sessions. | 81 |
| BASC + Active Varenicline Behavioral activation for smoking cessation plus active varenicline
Varenicline: Participants will be randomly assigned to 12 weeks of either placebo or varenicline medication (1mg twice daily). Participants and research personnel will be blind to treatment assignment.
BASC: The goal of behavioral activation therapy is to increase engagement in rewarding activities, a problem for smokers with depression who find smoking especially rewarding and prefer it over many other traditionally rewarding activities, by reducing patterns of behavioral avoidance, withdrawal, and inactivity. In this study, behavioral activation will be integrated with standard behavioral smoking cessation treatment.
Treatment will be delivered in eight 45-minute sessions over 12 weeks occurring weekly for the first four sessions and biweekly for the final four sessions. | 83 |
| Total | 300 |
Baseline characteristics
| Characteristic | Standard Treatment + Placebo Varenicline | Standard Treatment + Active Varenicline | BASC + Active Varenicline | BASC + Placebo Varenicline | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 5 Participants | 7 Participants | 8 Participants | 10 Participants | 30 Participants |
| Age, Categorical Between 18 and 65 years | 63 Participants | 74 Participants | 75 Participants | 58 Participants | 270 Participants |
| Age, Continuous | 50.3 years STANDARD_DEVIATION 10.8 | 48.7 years STANDARD_DEVIATION 12.7 | 50.3 years STANDARD_DEVIATION 13.2 | 50.7 years STANDARD_DEVIATION 13.5 | 50.0 years STANDARD_DEVIATION 12.6 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 3 Participants | 0 Participants | 1 Participants | 4 Participants |
| Race (NIH/OMB) Black or African American | 40 Participants | 43 Participants | 37 Participants | 37 Participants | 157 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 4 Participants | 8 Participants | 3 Participants | 16 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 2 Participants | 1 Participants | 0 Participants | 5 Participants |
| Race (NIH/OMB) White | 25 Participants | 28 Participants | 36 Participants | 27 Participants | 116 Participants |
| Region of Enrollment United States | 68 participants | 81 participants | 83 participants | 68 participants | 300 participants |
| Sex: Female, Male Female | 39 Participants | 44 Participants | 44 Participants | 38 Participants | 165 Participants |
| Sex: Female, Male Male | 29 Participants | 37 Participants | 39 Participants | 30 Participants | 135 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk | EG012 affected / at risk | EG013 affected / at risk | EG014 affected / at risk | EG015 affected / at risk | EG016 affected / at risk | EG017 affected / at risk | EG018 affected / at risk | EG019 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 136 | 0 / 164 | 0 / 114 | 0 / 137 | 0 / 100 | 0 / 120 | 0 / 91 | 0 / 121 | 0 / 85 | 0 / 119 | 0 / 80 | 0 / 115 | 0 / 79 | 0 / 113 | 0 / 79 | 0 / 109 | 0 / 74 | 0 / 104 | 0 / 68 | 0 / 102 |
| other Total, other adverse events | 104 / 136 | 136 / 164 | 90 / 114 | 103 / 137 | 80 / 100 | 93 / 120 | 68 / 91 | 81 / 121 | 65 / 85 | 77 / 119 | 57 / 80 | 71 / 115 | 51 / 79 | 71 / 113 | 52 / 79 | 63 / 109 | 50 / 74 | 60 / 104 | 37 / 68 | 55 / 102 |
| serious Total, serious adverse events | 28 / 136 | 34 / 164 | 24 / 114 | 29 / 137 | 21 / 100 | 19 / 120 | 26 / 91 | 22 / 121 | 18 / 85 | 18 / 119 | 15 / 80 | 14 / 115 | 15 / 79 | 18 / 113 | 12 / 79 | 12 / 109 | 9 / 74 | 8 / 104 | 10 / 68 | 12 / 102 |
Outcome results
Primary
Adverse Event and Serious Adverse Event Rates
Adverse event and serious adverse event rates between varenicline and placebo arms. A previously developed algorithm was used to classify side effect reports as adverse events (AEs) or serious adverse events (SAEs) (Schnoll et al. 2019). Reference: Schnoll, R., Leone, F., Weisbrot, J., Veluz-Wilkins, A., Miele, A., Hole, A., Jao, N.C., Wileyto, E.P., Carroll, A.J., Kalhan, R., Patel, J., Langer, C., & Hitsman, B. (2019). A randomized controlled trial of 24-weeks of varenicline for tobacco use among cancer patients: Efficacy, safety, and adherence. Psycho-Oncology, 28, 561-569.
Time frame: Weeks 1 (1-week before starting medication), 6, and 14 (end of medication)
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Standard Treatment + Placebo Varenicline | Adverse Event and Serious Adverse Event Rates | Any adverse event | 104 Participants |
| Standard Treatment + Placebo Varenicline | Adverse Event and Serious Adverse Event Rates | Any serious adverse event | 28 Participants |
| BASC + Placebo Varenicline | Adverse Event and Serious Adverse Event Rates | Any adverse event | 136 Participants |
| BASC + Placebo Varenicline | Adverse Event and Serious Adverse Event Rates | Any serious adverse event | 34 Participants |
| Standard Treatment + Active Varenicline | Adverse Event and Serious Adverse Event Rates | Any adverse event | 68 Participants |
| Standard Treatment + Active Varenicline | Adverse Event and Serious Adverse Event Rates | Any serious adverse event | 26 Participants |
| BASC + Active Varenicline | Adverse Event and Serious Adverse Event Rates | Any serious adverse event | 22 Participants |
| BASC + Active Varenicline | Adverse Event and Serious Adverse Event Rates | Any adverse event | 81 Participants |
| Placebo - Week 14 | Adverse Event and Serious Adverse Event Rates | Any serious adverse event | 9 Participants |
| Placebo - Week 14 | Adverse Event and Serious Adverse Event Rates | Any adverse event | 50 Participants |
| Varenicline - Week 14 | Adverse Event and Serious Adverse Event Rates | Any serious adverse event | 8 Participants |
| Varenicline - Week 14 | Adverse Event and Serious Adverse Event Rates | Any adverse event | 60 Participants |
Primary
Bioverified Point-prevalence Abstinence at 27 Weeks
Participants were classified as abstinent if they reported abstinence, not even a puff of a cigarette, for \>7 days prior to week 27 (24 weeks post-target quit date) and had an expired carbon monoxide reading of ≤ 6 parts per million at week 27.
Time frame: 27 weeks (24-weeks post-target quit date)
Population: All participants enrolled in the trial (intent-to-treat sample)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Standard Treatment + Placebo Varenicline | Bioverified Point-prevalence Abstinence at 27 Weeks | 6 Participants |
| BASC + Placebo Varenicline | Bioverified Point-prevalence Abstinence at 27 Weeks | 3 Participants |
| Standard Treatment + Active Varenicline | Bioverified Point-prevalence Abstinence at 27 Weeks | 13 Participants |
| BASC + Active Varenicline | Bioverified Point-prevalence Abstinence at 27 Weeks | 13 Participants |
Secondary
Bioverified Point-prevalence Abstinence at 14 Weeks (End of Treatment)
Participants were classified as abstinent if they reported abstinence, not even a puff of a cigarette, for \>7 days prior to week 14 (11-weeks post-target quit date) and had an expired carbon monoxide reading of ≤ 6 parts per million at week 14.
Time frame: 14 weeks (11-weeks post-target quit date)
Population: All participants enrolled in the trial (intent-to-treat sample)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Standard Treatment + Placebo Varenicline | Bioverified Point-prevalence Abstinence at 14 Weeks (End of Treatment) | 8 Participants |
| BASC + Placebo Varenicline | Bioverified Point-prevalence Abstinence at 14 Weeks (End of Treatment) | 4 Participants |
| Standard Treatment + Active Varenicline | Bioverified Point-prevalence Abstinence at 14 Weeks (End of Treatment) | 26 Participants |
| BASC + Active Varenicline | Bioverified Point-prevalence Abstinence at 14 Weeks (End of Treatment) | 26 Participants |
Secondary
Continuous Abstinence
No smoking between target quit date (week 3) and week 27
Time frame: 27 weeks (24 weeks post target quit date)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Standard Treatment + Placebo Varenicline | Continuous Abstinence | 3 Participants |
| BASC + Placebo Varenicline | Continuous Abstinence | 2 Participants |
| Standard Treatment + Active Varenicline | Continuous Abstinence | 6 Participants |
| BASC + Active Varenicline | Continuous Abstinence | 2 Participants |
Secondary
Prolonged Abstinence
\<7 consecutive days of self-reported smoking after a 2-week grace period
Time frame: 27 weeks (24 weeks post target quit date)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Standard Treatment + Placebo Varenicline | Prolonged Abstinence | 13 Participants |
| BASC + Placebo Varenicline | Prolonged Abstinence | 11 Participants |
| Standard Treatment + Active Varenicline | Prolonged Abstinence | 26 Participants |
| BASC + Active Varenicline | Prolonged Abstinence | 26 Participants |
Secondary
Time to 7-day Relapse
Time to relapse as defined by 7 or more consecutive days of self-reported smoking (no grace period)
Time frame: 27 weeks (24 weeks post target quit date)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Standard Treatment + Placebo Varenicline | Time to 7-day Relapse | 15 median days to relapse |
| BASC + Placebo Varenicline | Time to 7-day Relapse | 15 median days to relapse |
| Standard Treatment + Active Varenicline | Time to 7-day Relapse | 57 median days to relapse |
| BASC + Active Varenicline | Time to 7-day Relapse | 24 median days to relapse |