Bupropion SR in Adolescents With Comorbid ADHD and Nicotine Dependence: A Pilot Study

Bupropion SR in Adolescents With Comorbid ADHD and Nicotine Dependence: A Pilot Study HIMANSHU P. UPADHYAYA, M.B.B.S., M.S., KATHLEEN T. BRADY, M.D., PHD.,

AND

WEI WANG, M.S.P.H.

ABSTRACT Objective: Bupropion SR has been shown to be effective for the treatment of nicotine dependence in adults. This open-label pilot study was designed to examine the feasibility and preliminary tolerability of bupropion SR in adolescents with nicotine dependence. Method: Sixteen adolescents aged 12 to 19 years were enrolled in the study. Eleven of the 16 participants also had comorbid attention-deficit/hyperactivity disorder (ADHD). Participants were titrated over 1 week to bupropion SR 150 mg b.i.d. and maintained at this dosage for 6 weeks. Participants also received two brief smoking cessation counseling sessions. Results: Nine participants received at least 4 weeks of medication. There was a significant decrease in the average number of cigarettes smoked (p < .00) and carbon monoxide levels (p = .04) over the course of treatment. Intent-to-treat analysis showed that 31.25% of the adolescents were completely abstinent (5/16) after 4 weeks of taking bupropion SR. Participants’ weight did not change significantly during the study (p = .55). There was a no significant change in ADHD symptoms during the study (p = .1). Conclusions: Bupropion SR along with brief counseling may be safe and potentially efficacious for adolescents with nicotine dependence with and without ADHD. Smoking cessation trials in adolescents need to focus on strategies to increase retention for optimal effect. J. Am. Acad. Child Adolesc. Psychiatry, 2004;43(2):199–205. Key Words: bupropion, attention-deficit/hyperactivity disorder, nicotine dependence, adolescents.

Nicotine use among adolescents is an area of considerable public health concern. About 17% of high school seniors smoke daily (Johnston et al., 2002), and more than 4 million adolescents in the United States are smokers. Sixty-six percent of adolescent smokers state they wanted to quit, and 70% would not have started smoking if they could choose again (American Health Association, 1995). Also, tobacco is often one of the first drugs tried by individuals who later use illicit drugs (Kandel et al., 1978; Kandel and Yamaguchi, 1993),

Accepted September 11, 2003. Drs. Upadhyaya and Brady are with the Department of Psychiatry and Behavioral Sciences and Ms. Wang is with the Department of Biometry and Epidemiology, Medical University of South Carolina, Charleston. Financial support for these studies was provided in part by NIDA grant DA00357-03, General Clinical Research Center USPHS grant M01RR01070, and GlaxoSmithKline. The authors acknowledge the technical help of Christine Horne and Molly Wharton as well as the valuable insights of Robert F. Woolson, Ph.D., in the preparation of this manuscript. Reprint requests to Dr. Upadhyaya, Institute of Psychiatry, Medical University of South Carolina, 2S, IOP-P–MUSC, 67 President Street, Charleston, SC 29425. 0890-8567/04/4302–0199©2004 by the American Academy of Child and Adolescent Psychiatry. DOI: 10.1097/01.chi.0000100426.25002.4f

and 80% of adult smokers become addicted to tobacco by age 18 (American Health Association, 1995). Surveys indicate that up to 70% of adolescents try cigarettes and one third of all adolescents are currently smoking (Massachusetts Medical Society, 1995). Smoking is responsible for 20% of all deaths in the United States, and 45% of smokers will die of a tobacco-induced disorder (Peto et al., 1992). Premature mortality due to cigarette smoking is estimated at a loss of 15 years (Milberger et al., 1997). Bupropion SR has been shown to be efficacious for the treatment of nicotine dependence in adults (Dale et al., 2001; Gonzales et al., 2002; Hurt et al., 1997; Jorenby et al., 1999; Lerman et al., 2002), including adult patients with comorbid psychopathology such as schizophrenia (George et al., 2002), as well as in diverse racial groups such as African Americans (Ahluwalia et al., 2002). Bupropion SR has also been shown to be efficacious for relapse prevention during chronic abstinence in adults with nicotine dependence (Hays et al., 2001). The studies in adult smokers differ in the duration of treatment with bupropion SR, as well as the duration of follow-up. The quit rate in those studies ranged from around 30.3% (Jorenby et al., 1999) to

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55.1% (Hays et al., 2001). Although bupropion SR has demonstrated efficacy for smoking cessation in adults, to our knowledge there are no published studies of bupropion treatment for adolescent smokers. Bupropion has also been shown to be effective in placebocontrolled, double-blind, randomized trials for the treatment of attention-deficit/hyperactivity disorder (ADHD) in adults (Wilens et al., 2001), as well as in children and adolescents (Barrickman et al., 1995; Conners et al., 1996). To our knowledge, there are no reports of treatment in comorbid ADHD and nicotine dependence with adolescents. Evidence suggests that patients with ADHD initiate smoking at an earlier age (Milberger et al., 1997) and experience more difficulty with quitting (Pomerleau et al., 1995). There is also evidence that nicotine may improve symptoms of ADHD in adults (Conners et al., 1996; Levin et al., 1996). Hence, the objective of this pilot study was to evaluate the safety, tolerability, and preliminary efficacy of brief counseling and bupropion SR for smoking cessation in adolescents with and without ADHD. There is evidence in adult smokers that the combination of nicotine replacement therapy and behavior therapy works better for smoking cessation than either therapy alone (e.g., Fiore et al., 1994; Schneider et al., 1983). Hence, we believed that it would be unethical in this preliminary open-label study not to provide some brief smoking cessation counseling in addition to medication. Therefore, we provided two brief smoking cessation counseling sessions (psychoeducation based on American Cancer Society brochures) over two sessions; each session was no longer than 30 minutes. METHOD Subjects Sixteen adolescents (aged 12–19 years) with nicotine dependence were recruited from the community by advertisements and word of mouth. The study was approved by the Medical University of South Carolina institutional review board. For minors, informed consent of the parents and assent of the participants was obtained. For participants 18 and older, informed consent of the participant was obtained. Subsequently, adolescents were screened for inclusion and exclusion criteria. Inclusion criteria were current daily smokers, smoking at least five cigarettes per day, age range of 12 to 19. Exclusion criteria were active substance abuse/dependence (other than nicotine) within 4 weeks prior to participating in the study; current DSM-IV (American Psychiatric Association, 1994) Axis I disorder other than oppositional defiant disorder and ADHD; pregnancy; positive urine drug screen at baseline; history of seizure disorder or predisposition to seizures (e.g., history of significant head trauma, currently taking medications that lower seizure

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threshold); history of significant medical problems; hypersensitivity to bupropion; patients currently treated with any other medication containing bupropion; current or past history of bulimia or anorexia; being treated with monoamine oxidase inhibitors currently or within 2 weeks of starting the study. Twenty-four participants were screened for the study and 16 met the criteria for the study. All 16 participants were enrolled into the study; no potential participant refused to participate in the study. Variables Primary outcome measures were self-report of cigarettes smoked per day (by smoking diary) and carbon monoxide (CO) levels. CO level, measured as parts per million (ppm) in expired air, has been used in several smoking cessation studies as a biomarker of recent cigarette smoking (e.g., Corby et al., 2000). Secondary outcome measures were cigarette craving, ADHD symptoms, and change in weight. Although we did not enroll any subjects with current depressive disorders in the study, change in symptoms of depression were measured. Instruments The Schedule for Affective Disorders and Schizophrenia for School-Age Children (K-SADS) (Kaufman et al., 1997) is a semistructured instrument for DSM-IV psychiatric diagnosis that has been validated for use with adolescents. The ADHD Rating ScaleIV (DuPaul et al., 1998) is an 18-item scale based on DSM-IV symptoms of ADHD and has been validated in adolescents. Questionnaire for Smoking Urges-Brief (QSU-B) (Drobes and Tiffany, 1997) is a 10-item questionnaire that measures craving for cigarettes at a particular moment. The Modified Fagerstrom Tolerance Questionnaire (mFTQ) is an adolescent version of the adult Fagerstrom Tolerance Questionnaire (Prokhorov et al., 1996). The mFTQ is a validated seven-item instrument that measures the severity of addiction to nicotine. The Kutcher Adolescent Depression Scale (KADS) (LeBlanc et al., 2002) is a self-report instrument for symptoms of depression validated for use in adolescents. The Reasons to Smoke questionnaire is a 17-item questionnaire that assesses participants’ self-reported reasons for smoking. The participants make a checkmark on an analog scale from 0 to 10. The questionnaire was compiled using items from standard questionnaires, such as those used by Ikard and Tomkins (1973). We added adolescentspecific questions to address family and peer factors. K-SADS, ADHD Rating Scale-IV, smoking diary, mFTQ, KADS, QSU-B, and side effects questionnaire were administered at the baseline assessment. KADS, smoking diary, Reason to Smoke questionnaire, ADHD Rating Scale-IV, side effects questionnaire, and QSU-B were administered at follow-up visits. Design Participants were assessed by a board-certified child and adolescent psychiatrist. During the initial assessment, the K-SADS was administered and a physical examination and several laboratory tests were done. Laboratory tests included urine drug screen, exhaled CO level, complete blood count (CBC), serum metabolic panel, liver function test, urine analysis, urine toxicology screen, and a urine pregnancy test (females). Participants received openlabel fixed-dose 150 mg of bupropion SR by mouth in the morning for 3 days. Participants weighing less than 90 lb were maintained on this dose. For other participants, bupropion was increased to 150 mg twice a day on day 4. Participants were asked to select a “quit date” between the second and third visit (1–2 weeks on medication). Participants started medication within 1 to 3 days of the

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screening visit. Participants were maintained on 150 mg twice a day for 6 weeks, but the dosage could be decreased based on medication tolerability. Participants were seen for weekly outpatient visits and received two 30-minute individual sessions of smoking cessation counseling based on American Cancer Society brochures involving psychoeducation, coping with craving, and identifying the triggers for smoking and how to avoid them. The individual counseling sessions were administered during the first and second sessions by a child and adolescent psychiatrist (H.U.). The first session addressed common questions regarding smoking cessation, such as what withdrawal symptoms to expect. The second session involves tips on how to be successful at smoking cessation, such as how to cope with craving. Two 30-minute sessions were required to address the salient points in the American Cancer Society brochures. Participants completed smoking questionnaires, ADHD Rating Scale-IV, KADS, and side effects questionnaire and the expired air CO level was measured during each visit. Participants received riboflavin (vitamin B2) 100 mg along with bupropion for monitoring medication adherence. The number of tablets dispensed during each visit was recorded and participants were instructed to return all unused tablets at next visit. At the subsequent visit, the tablets returned were counted (“pill count”) as a measure of medication adherence. Participants received monetary compensation for participation in the study. Data Analysis Because the sample size was relatively small, a nonparametric paired-sample analysis (Sign test) (Zar, 1999) was used to examine the difference between premedication (baseline) and postmedication (at least 4-week trial) average number of cigarettes smoked, CO level, and weight. An intent-to-treat approach was used with subjects who took at least one dose of medication during the study. Both the Sign test and intent-to-treat analysis are more conservative approaches of data analysis. Craving and depression were also analyzed in the same fashion. Each outcome variable was analyzed independently. Four weeks of medication with bupropion SR was chosen as an adequate trial based on efficacy data from clinical trials using bupropion SR with adult smokers (Dale et al., 2001; Gonzales et al., 2002; Hurt et al., 1997; Jorenby et al., 1999; Lerman et al., 2002). Those trials demonstrate that this time period is adequate to show the efficacy of bupropion SR. In those studies, although the duration of bupropion SR treatment was varied, statistically significant results were obtained within 4 weeks. One subject dropped out after the initial visit and was deleted completely from any analysis. Four participants had only baseline weight data and hence were excluded from weight change analysis. The type I error rate for each test was set at 0.05. The Mann-Whitney test was used to test if the outcomes (number of cigarettes, CO level, and weight) were different between participants with and without history of Axis I disorders (e.g., major depression). The type I error rate for each test was set at 0.05. RESULTS Sample

Table 1 describes the sample. Fifty percent (8/16) of the participants lived in a house where someone else smoked. Most adolescents had tried to quit between zero and five times prior to study participation; one adolescent had 25 prior quit attempts. All participants received the two counseling sessions.

TABLE 1 Sample Description (n = 16) n Gender Male Female Race Caucasian African American ADHD Yes No

Cigarettes/day Duration of smoking (yr) Previous quit attempts

Age (yr) mFTQ

%

10 6

62.5 37.5

14 2

87.5 12.5

11 5

68.8 31.2

Mean

(Range)

18.06 4.58 3.56

(6–40) (2–8) (0–25)

Mean

(SD)

18 5.6

(1.3) (2.03)

Note: ADHD = attention-deficit/hyperactivity disorder; mFTQ = modified Fagerstrom Tolerance Questionnaire.

Dropouts

Two participants were withdrawn from the study as a result of pregnancy, three participants withdrew due to medication side effects, one participant was withdrawn after taking an overdose of study medication, and four participants were lost to follow-up. Nine participants competed at least 4 weeks of the study. Medication Dosage

Most participants received the 300-mg/day target dosage. Only one participant had the dosage reduced to 150 mg once a day due to gastrointestinal side effects. Reasons for Smoking

Table 2 describes the average analog self-report scores of each item on the Reasons to Smoke questionnaire. The top five reasons to smoke were (1) helps me relax; (2) helps me calm down; (3) something to do with my hands; (4) my friends smoke; (5) helps me focus. Medication Adherence

We estimated medication compliance (number of medication doses missed) at each study week by counting the number of returned tablets (“pill count”). As

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TABLE 2 Reasons to Smoke (n = 16) Reason

Mean Scores (±SD)

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17.

8.63 8.32 8.26 6.71 6.22 6.17 5.37 5.01 4.65 3.73 3.43 2.63 2.40 2.39 2.23 2.02 1.30

Helps me relax Something to do with my hands Calms me down My friends smoke Helps me pay attention or focus Wakes me up when I am drowsy Miss not smoking Like the taste and smell Like to watch the smoke Like the sensations in throat or chest Helps me control my weight Gives me confidence around people Like a friend My mother smokes My father smokes Gives me a “rush” or “high” My friends will like me if I smoke

(±2.60) (±2.46) (±2.09) (±4.39) (±3.53) (±4.06) (±3.83) (±4.36) (±4.31) (±3.71) (±3.69) (±4.06) (±2.96) (±4.02) (±3.71) (±3.46) (±2.87)

can be seen in Table 3, medication adherence was satisfactory: the average number of missed doses ranged from 0.4 to 3.2 each week. We could not use the riboflavin data as several samples were stored incorrectly by the clinical laboratory and had to be discarded.

Fig. 1 Average number of cigarettes smoked and carbon monoxide (CO) levels (ppm).

cantly after 4 weeks of taking bupropion SR (mean weight 172 lb) compared to baseline (mean weight 173 lb) (p = .55). Craving and Depression

Based on the intent-to-treat approach, nine subjects were included for the craving analysis and seven for the depression analysis. The Sign test indicated that cigarette craving, as measured by QSU-B, was significantly decreased (p = .04) after 4 weeks (mean score 2.33) compared to baseline (mean score 4.35). There was no significant difference (p = 1.00) in KADS total (baseline, 6.07; week 4, 5.33) or severity scores (baseline, 4.86; week 4, 4) during the study. Adverse Events

Number of Cigarettes and Carbon Monoxide Levels

All 15 subjects were included in the analysis. The Sign test for location indicated that, on average, both number of cigarettes smoked (p = .00) and CO levels (p = .04) decreased significantly during the study (Fig. 1).

Adverse events reported by more than one participant are shown in Table 4. Each of the following symptoms was reported by 1 of the 16 subjects: vomiting, shortness of breath, “sniffing,” diarrhea, abdominal pain, “tension in stomach,” stomach cramps, increased

Weight

Data for baseline weight were incomplete for four subjects, and these subjects were not included in the analysis. Participants’ weight did not change signifiTABLE 3 Medication Doses Missed During the Study by Pill Count Week

n

1 2 3 4 5 6

12 11 11 9 5 4

Mean Doses Missed (SD) 0.4 2.2 1.7 3.2 0.4 1.8

Note: Average number of doses each week was 14.

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(1.0) (2.4) (1.8) (3.8) (0.9) (1.7)

TABLE 4 Adverse Events Reported During the Study Adverse Event Headache Insomnia Decreased appetite Cough Heartburn Dizziness Heart pounding/palpitations Migraine headache Nausea Blurred vision Tremor Bad taste Yellow urine

No. of Participants Reporting 7 6 5 3 3 2 2 2 2 2 2 2 2

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burping, nervousness, tremors, increased energy, decreased sex drive, mouth sores, hives, leg soreness, allergic reaction (rash), shoulder/neck soreness, pulled heel muscle, worsening of ADHD symptoms, forgetting words occasionally, sweating, and irritability. Two participants became pregnant during the study and one participant overdosed on the study medication after an argument with the father in an impulsive suicidal gesture (not to get “high” on the medication). ADHD

Among participants with ADHD, self-reported ADHD symptoms as measured by the ADHD Rating Scale-IV did not change significantly during the study (p = 1.00) (mean baseline score, 52.3; mean week 4 score, 36.8). History of Axis I Disorders

History of marijuana use disorder, alcohol use disorder, and depressive disorders were the predominant Axis I disorders in our sample. The outcomes (number of cigarettes, CO levels, or weight) were not statistically significantly different among participants with or without a history of marijuana use disorder, alcohol use disorder, or depressive disorders.

DISCUSSION

This is one of the first studies to report on the treatment of nicotine dependence in adolescents using bupropion SR. The results of this preliminary study indicate that bupropion SR along with brief smoking cessation counseling can be safely used in adolescents with nicotine dependence and that it may be effective for the treatment of nicotine dependence. The results are consistent with reports in adults with nicotine dependence showing that bupropion SR is efficacious for the treatment of nicotine dependence (Dale et al., 2001; Gonzales et al., 2002; Hurt et al., 1997; Jorenby et al., 1999; Lerman et al., 2002), including adults with comorbid psychopathology (e.g., schizophrenia, George et al., 2002), as well as in diverse racial groups (e.g., African Americans, Ahluwalia et al., 2002). Interestingly, the success rates reported by other studies of manualized psychosocial interventions are generally within the range of the results of our preliminary study (e.g., Colby et al., 1998; Monti et al., 1999). The average mFTQ score of the participants was 5.6

at baseline. Based on previous studies in adolescents, this indicates a significant level of nicotine dependence (e.g., Prokhorov et al., 1996; Upadhyaya et al., 2003). The participants had a significant improvement in the number of cigarettes smoked as well as CO levels at the end of the study. In a recent study of adolescent smokers, a CO level of more than 8 ppm was considered as evidence of recent smoking (Corby et al., 2000). The average CO level was close to 8 by week 4 of the current study. Hence, there was a clinically meaningful drop in CO levels. Five participants quit smoking by the fourth week of the study, with one smoking one or zero cigarettes per week. One of the important findings during the study was the lack of weight gain among participants during the smoking cessation effort. This is important because many adolescents, especially girls, are very sensitive to weight gain, which was a frequent concern expressed prior to entrance into the study. The lack of weight gain is also consistent with adult literature, in which adult smokers taking bupropion SR were followed for at least 1 year and had significantly less weight gain compared to placebo (Hays et al., 2001). Another interesting finding of the study was a lack of change in ADHD symptom scores. Bupropion has been demonstrated to be efficacious in adolescents with ADHD in placebo-controlled, double-blind randomized studies (Barrickman et al., 1995; Conners et al., 1996; Wilens et al., 2001). We speculate that symptoms of nicotine withdrawal increased the ADHD symptom score during the study and that we might have seen a difference in ADHD scores with longer follow-up periods. Alternatively, nicotine may have improved the participants’ ADHD symptoms. If so, symptoms would increase with smoking cessation and bupropion may not have offered benefit beyond those effects derived by smoking cigarettes. There is some evidence that nicotine may improve symptoms of ADHD among adult smokers and nonsmokers with a DSM-IV diagnosis of ADHD (Conners et al., 1996; Levin et al., 1996). There was a decline in the mean ADHD Rating Scale-IV scores from baseline to week 4 (52.3 to 36.8), and it is possible that if we had had a larger sample or a longer duration of study, we might have found statistical significance. Interestingly, participants without ADHD scored higher (mean 7.48 versus mean 5.59 in participants with ADHD) on the “helps me focus” question of the Reasons to Smoke questionnaire. Overall, the adverse events were similar to those ob-

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served in previous studies (e.g., Dale et al., 2001; Gonzales et al., 2002; Lerman et al., 2002). Of particular concern was one attempted overdose and two pregnancies, even after careful mental health screening and education of the participants to avoid pregnancy during the trial. Hence, future medication trials in adolescent smokers need to pay careful attention to these issues. Even with persistent effort, 4 of the 16 participants were lost to follow-up. We did not use a followup manual, which might have helped in our retention efforts. An interesting possibility is that bupropion SR might have a harm reduction effect, since some participants reduced the number of cigarettes smoked but did not quit completely. This potential aspect of bupropion SR treatment remains to be explored in adolescent smokers. Limitations

The preliminary results should be judged in light of several limitations of the study. The study was an openlabel study, and as such there was no placebo control or randomization. There was a significant dropout of participants from the study. We used CO levels as a biomarker of cigarette smoking. Recent reports suggest that salivary cotinine levels may be more suited as a biomarker for cigarette smoking in adolescents (McDonald et al., 2003). The duration of the study was short and the results with longer treatment might be different, particularly with regards to ADHD symptoms. We did not include prior quit attempts in the data analysis. In addition, all participants received two brief smoking cessation counseling sessions. Hence, those counseling sessions may have had an effect on the smoking cessation outcomes. We did not measure readiness to change, which might also have affected the smoking cessation outcomes. Clinical Implications

While this study is clearly limited, the results of our preliminary study indicate that bupropion SR might have a role in the treatment of nicotine dependence in adolescents. In light of the limited options available for the treatment of nicotine dependence in adolescents, further randomized, double-blind, placebo-controlled trials of bupropion SR are indicated to state definitively whether bupropion SR may be helpful in smoking cessation among adolescents. Future studies should also focus on increasing the retention of adolescent partici204

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