A Comparison of Bupropion SR and Placebo for Smoking Cessation
Condition: Tobacco Use Disorder
MeSH terms: Tobacco Use Disorder
Study type: Interventional
Phase: Phase 4

Summary: 
      The purpose of this study is to examine whether the adjunctive use of bupropion SR in the
      context of a psychoeducational program modified for people with schizophrenia might improve
      the likelihood of successful abstinence in this population. If bupropion SR is effective for
      reducing cigarette smoking, then it will be important to determine if decreased nicotine
      intake is associated with a worsening of psychotic, anxiety or depressive symptoms. In
      addition, it would be important to determine the effect that a reduction in nicotine
      stimulation would have on patient's cognitive functioning, as nicotinic receptors have been
      shown to regulate attention and memory function, and it is hypothesized that these functions
      are normalized by acute nicotine administration in people with schizophrenia
    

Detailed description: 
      After obtaining consent, patients will enter a two week stabilization phase followed by a 14
      week treatment phase. The treatment phase begins with a 9 session group therapy led by clinic
      nurses trained in the educational model of the American Cancer Association. Subjects will
      begin the double-blind, randomized, placebo controlled medication phase of treatment
      following the third group session, which is two weeks prior to the established quit day.
      Patients will receive either bupropion SR 150mg twice a day (starting with 150mg once a day
      for three days) or placebo in addition to their usual medication regimen. Patients will be
      offered the use of nicotine replacement in the form of Nicorette gum from quit day through
      week 8, the end of the group therapy course. Correct use of the gum will be reviewed in
      group. Following completion of the group therapy course, patients will continue in their
      assigned medication group until study completion.

      Prior to starting the study, subjects will receive a physical exam and ECG, if they have not
      had one in the last calendar year. All women will have a pregnancy test, and pregnant women
      will be excluded from the study. If not already completed, the following Index Assessments
      will be completed: Demographic forms 1 and 2, SCID, Schedule for the Deficit Syndrome,
      Patient Psychiatric and Medical History Form. The Fagerstrom Test for Nicotine Dependence,
      symptom/ functional ratings (BPRS, SANS), Extrapyramidal Rating Scale, body weight, and
      urinary cotinine levels will be obtained during stabilization and at treatment weeks 2, 4, 8,
      and 14. The MPRC Side-effect Check List will be obtained week 2 (the start of study
      medication) and biweekly thereafter throughout the end of the treatment phase. Expired carbon
      monoxide levels will be measured weekly during the study.

      Patients will receive a 60 minute neuropsychological test battery during stabilization and at
      the end of the study. The test battery will consist of the Rey Auditory Verbal Learning Test,
      Brief Visuospatial Memory Test, Symbol Digit, Letter Number Sequencing, and Distractibility
      CPT. Similarly, at stabilization, treatment week 8, and study completion (treatment week 14),
      subjects will meet with a MIRECC rater to complete a Smoking History (on stabilization only),
      the Change Assessment Scale, Temptation to Smoke Scale, Decisional Balance Scale, and Smoking
      Abstinence Self-Efficacy Scale. At these time points they will also have antipsychotic blood
      levels drawn. Patients will be seen for follow-up assessments at 6 months and one-year. Urine
      cotinine levels, expired CO levels, and Fagerstrom Test for Nicotine Dependence will be
      obtained at this time.

      A total of fifty subjects will be recruited from the Maryland Psychiatric Research Center,
      Outpatient Research Program (MPRC ORP), Key Point Southwest Mental Health Center, Revisions,
      Inc., and The Baltimore, VA. The sample will consist of 50 patients who meet the following
      inclusion and exclusion criteria:

      Inclusion Criteria are:

        1. DSM-IV diagnosis of Schizophrenia or schizoaffective disorder

        2. Age: 18-64

        3. Regular half pack a day smokers

        4. Score of at least 4 on the Nicotine Dependency Test

      Exclusion Criteria are:

        1. Seizure disorders, other Neurologic illnesses, or a family history of seizures

        2. A medical condition that could manifest psychiatrically

        3. Currently experiencing a depressive episode

        4. Active substance abuse

        5. Currently receiving bupropion

        6. Pregnant women

        7. Children (<18 years of age)

        8. Two consecutive sodium levels of 130 mmol/L or less

      Patients will be paid for their time and any inconvenience they may experience through their
      participation.

      An educational informed consent process will be utilized, and only patients able to give
      informed and voluntary written consent will be able to participate in the study. Before
      patients are accepted into the study, they must:

        1. give oral and written consent;

        2. pass the MPRC evaluation of signed consent test which documents factual understanding of
           research participation (see Appendix);

        3. be aware of alternative treatments, and that alternative clinical care is available;

        4. be aware of the right to withdraw, and be aware of the appropriate contact person if
           they wish to withdraw; and

        5. be aware that they may have family members or significant friends involved in the
           informed consent procedures.

      MPRC booklets describing research procedures and clarifying differences between research
      clinical care and standard clinical care will be made available to potential subjects,
      referring clinicians, and interested family members. Informed consent forms are previewed by
      an ad hoc committee to assure MPRC and IRB feedback from the perspectives of family
      advocates, recipients of care, forensic psychiatry, and service system administration.

      Primary outcome measures will be:

        1. The Fagerstrom Test for Nicotine Dependence, expired CO level, and urine cotinine will
           be used to determine if bupropion SR, when used as an adjunct to antipsychotic
           medication, is superior to placebo for helping patients with schizophrenia improve their
           chances of smoking cessation.

        2. Neuropsychological testing will be used to determine the effects of smoking cessation on
           patient's attention and memory function.

      Secondary outcome measures will be:

        1. BPRS, SANS, EPRS, and body weight will be used to determine the effects of bupropion SR
           and smoking cessation on patients' positive and negative symptoms, level of functioning,
           and physical health.

        2. To determine whether responses to the Smoking Consequences Questionnaire, Change
           Assessment Scale, Temptation to Smoke Scale, Decisional Balance Scale, and Smoking
           Abstinence Self-Efficacy Scale correlate with successful smoking cessation.

      In a preliminary study, we were able to detect a 44% reduction in expired CO with bupropion
      treatment. This represents a change in 1.2 SDs, a large effect size. In order to detect the
      same effect in the proposed double-blind study, with two-sided tests at alpha=.05 and power
      of 0.80, we would need 10 subjects in each treatment group. Since open labeled study designs
      may inflate observed effects, we have decide to include 20 subjects in each group. The
      primary analytic approach will use repeated measures ANCOVA, with adjustment for baseline
      expired CO level, with treatment assignment as the between group factor and expired CO level
      as the repeated measure. Since both groups will receive group therapy, the value at the end
      of the first week of group (before starting bupropion or placebo) will be used as the
      baseline for comparing patients on bupropion versus placebo. A similar approach will be used
      to analyze the symptom and neurocognitive measures.

      The major risks of the study are the stress of and symptoms associated with nicotine
      withdrawal. Depressed mood, insomnia, irritability, anger, anxiety, difficulty concentrating,
      restlessness, decreased heart rate, and increased appetite are all common. Risks associated
      with the use of bupropion SR include allergic reactions (most commonly skin rashes and
      itching), dry mouth, insomnia, dizziness, tremor, and headaches. Of these, dry mouth and
      insomnia are most common. The risk of seizure, when using sustained -release bupropion in the
      dose range used in this study, is 0.1%, a rate similar to that of other antidepressants.
      Because bupropion is a weak dopamine agonist, it is possible that subjects may experience a
      worsening of psychosis. However, work at the MPRC ORP and other places with similar dopamine
      agonists showed there was no worsening in baseline psychotic symptoms, when patients remained
      on antipsychotics. There are studies to support the safety of combining antipsychotic
      medications with selective serotonin reuptake inhibitors and bupropion. However, there is
      always the potential for unforeseen drug interactions, with the addition of bupropion to
      existing medication regimens.

      Use of Nicorette gum has been associated with sore throat or mouth, hiccups, tired jaws,
      nausea or other gastrointestinal symptoms, and rarely mouth ulcers. Nicotine intoxication
      from overuse of the gum is unlikely, as it is released slowly from the gastrointestinal tract
      and undergoes extensive presystemic metabolism.

      The neuropsychological tests are associated with minimal risks. Some subjects may find the
      testing stressful or boring. The likelihood of this occurring is unlikely. However, frequent
      breaks in the testing will be allowed to insure that the subject does not become overwhelmed.

      To protect privacy and confidentiality, the patient's welfare will be safeguarded by
      responsible, systematically controlled procedures in the collection of information for both
      research and clinical purposes. Recorded information for research purposes will be identified
      by code number rather than by name. Information gathered will be kept in a research chart
      maintained in a locked file cabinet. Published or presented material related to the project
      will not be traceable to specific individuals.
    

Intervention name(s): Bupropion SR; Placebo Oral Tablet
Intervention type(s): Drug; Drug
Intervention description(s): 150mg twice a day (starting with 150mg once a day for three days); Comparable placebo
Intervention MeSH terms: Bupropion
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: Nicotine Dependence; Nicotine Use Disorder; Tobacco Dependence; Tobacco-Use Disorder; Smoking Cessation