Smoking Relapse Prevention in Schizophrenia
Condition: Schizophrenia; Schizoaffective Disorder; Smokers
MeSH terms: Recurrence; Schizophrenia; Psychotic Disorders
Study type: Interventional
Phase: Phase 4

Summary: 
      This study seeks to determine if continued treatment with bupropion and nicotine replacement
      therapy (NRT) can reduce the smoking relapse rate in patients with schizophrenia.
    

Detailed description: 
      Background and Preliminary Data:

      Between 72% and 90% of patients with schizophrenia smoke cigarettes, and schizophrenia
      patients are more likely than the general population to smoke and to smoke heavily (1-6).
      Compared with the general population, patients with schizophrenia have low smoking cessation
      rates, even through they can be both highly motivated and persistent in their attempts to
      quit smoking (7-10) and can tolerate short-term tobacco abstinence without significant
      exacerbation in clinical or cognitive symptoms (11, 12). Nicotine replacement therapy (NRT)
      and bupropion are each well tolerated by patients with schizophrenia, and bupropion is
      superior to placebo for smoking cessation in this population when added to CBT (13-20).
      However, abstinence rates have been low (4-19%) at 3-6 month follow up, whereas placebo plus
      CBT has produced cessation rates of 0-6%.

      It has been estimated that 45% of cigarettes sold in the US are sold to people with a mental
      illness (21) and that in the UK and Ireland, patients with schizophrenia spend approximately
      one third of their weekly income on cigarettes (22, 23). Age-adjusted mortality from
      smoking-related diseases such as pulmonary and cardiovascular disease are two to six times
      higher among people with schizophrenia compared to age matched samples (24-27). More
      effective pharmacologic treatments for smoking cessation in patients with schizophrenia are
      thus urgently needed.

      Combination treatment with bupropion and NRT has shown promise. In a large study in a
      non-psychiatric population, a combination of bupropion SR and NRT was superior to placebo and
      to NRT alone but not to bupropion alone for smoking cessation (28). In an open,
      non-randomized smoking cessation study in 115 nicotine dependent patients with co-morbid
      psychiatric and substance use disorders, patients treated with bupropion SR plus NRT and
      weekly CBT had significantly greater reduction in smoking than those on bupropion SR plus
      CBT, NRT plus CBT or CBT alone (29). Subjects on a combination of bupropion SR plus NRT also
      had significantly greater retention in the smoking cessation program and tolerated the
      combination treatment well.

      These findings were extended to patients with schizophrenia in a 12-week, randomized,
      double-blind trial of bupropion or placebo added to NRT + CBT (30). In this trial, bupropion
      300 mg/d or identical placebo was added to NRT and CBT for 12 weeks. NRT was given, starting
      on the quit date at week 4, as nicotine patch 21 mg/d for 4 weeks, 14 mg/d for 2 weeks and 7
      mg/d for 2 weeks combined with nicotine gum up to 18 mg per day prn. Combination treatment
      with bupropion and NRT was well tolerated and more beneficial than NRT alone for significant
      smoking reduction in patients with schizophrenia (Table 1 & Figure 1). The combination
      treatment was also superior for continuous abstinence until week 8 when the dose of NRT was
      reduced. When subjects were taking bupropion 300 mg per day, nicotine patch 21 mg per day and
      prn nicotine gum up to 18 mg per day, they had a cessation rate of 52%. See Table 1. Patients
      began to relapse to smoking after the dose of nicotine patch was reduced to 14 mg per day and
      continued to relapse through the 12 month follow up.

      It is our hypothesis that the 8-12 week treatment model that has been traditionally used for
      smoking cessation treatment is not of adequate duration for patients with schizophrenia. In
      our trial of bupropion combined with NRT, subjects experienced a 30% relapse rate during the
      taper of NRT patch from 21 mg/day to 7 mg/day while still on bupropion. In patients who are
      able to achieve abstinence with short-term treatment, a trial of longer duration treatment
      with bupropion + combination NRT at the dose used to quit smoking is warranted. It is our
      hypothesis that the rate of relapse to smoking will be lower with longer duration of the
      pharmacologic treatment used to quit smoking. Longer duration treatment can be justified in
      patients with schizophrenia for several reasons. First, schizophrenia patients have known
      abnormalities in nicotinic receptor expression and function and may benefit more than the
      general population from continued pharmacotherapy for maintenance of abstinence (32-34).
      Nicotinic receptors are reduced in number in patients with schizophrenia (32, 35) and heavy
      smoking in schizophrenia may be attributable to attempts to overcome a deficit in nicotinic
      activity. Benefits of nicotine to patients with schizophrenia include reversal of some of the
      specific cognitive deficits associated with schizophrenia and antipsychotic medications
      (36-40). Nicotine has been shown to improve learning, visual and spatial working memory,
      attention, auditory sensory gating smooth pursuit eye movements and reaction time (41, 42).
      The positive effects of chronic nicotine treatment appear to persist over time, and in some
      studies, improvements in cognition with chronic nicotine treatment become more robust over
      time (43). Secondly, the burden of morbidity and mortality of smoking related illness is high
      in schizophrenia such that it warrants a harm reduction approach. Continued NRT may be
      considered a harm reduction approach if it is associated with long term tobacco abstinence.
      For schizophrenia patients who are heavily addicted to tobacco products and would like to try
      to quit smoking, it may be appropriate to test whether higher abstinence rates can be
      sustained with longer-term treatment with bupropion and NRT, combined with a behavioral
      intervention. This study seeks to determine if continued treatment with bupropion and NRT can
      reduce the relapse rate in patients with schizophrenia.

      Study Design:

      We propose a study that will determine if continued treatment with bupropion and NRT can
      reduce smoking relapse rates in schizophrenia. This study has been designed with 3 phases: an
      initial open, 8 week smoking cessation phase, followed by a 44 week, randomized, placebo
      controlled, relapse prevention phase and then a 3 month follow-up phase.

      One hundred and thirty adults with a diagnosis of schizophrenia or schizoaffective disorder
      will be entered into an 8-week open smoking cessation trial. Subjects will receive weekly
      cognitive behavioral therapy (CBT), bupropion 300 mg/d nicotine patch 21mg/day and up to 20
      mg/day of either nicotine gum or lozenge for prn use. Those who attain abstinence and agree
      to participate in the relapse prevention phase(n=60-70), will be randomized, according to a
      double-blind, parallel group design, to receive continued treatment with a 21 mg nicotine
      patch and bupropion SR 300 mg or placebo added to CBT for 44 weeks. Adverse events will be
      documented at each visit. Study medication will be distributed bi-weekly during the double
      blind phase.

      Study Procedures:

      Baseline Measures and Screening:

        1. Review of medical chart to confirm DSMIV diagnosis of schizophrenia/schizoaffective
           disorder and medication

        2. Demographic Questionnaire

        3. Clinical Rating Scales: SANS (Schedule for assessment of Negative symptoms), BPRS (Brief
           Psychiatric Rating Scale), Hamilton Calgary depression scale, AIMS (Abnormal Involuntary
           Movement Scale), SAS (Simpson Angus Scale), BAS (Barnes Akathisia Scale), Tiffany
           Questionnaire of Smoking Urges, State-Trait Anxiety Inventory, Snaith Hamilton Anhedonia
           scale, Barrett Impulsiveness Scale, SF-12 smoking Self Efficacy Questionnaire and the
           Wisconsin Smoking Withdrawal Scale.

        4. Drug, alcohol and smoking history including Fagerstrom Test for Nicotine Dependence.

        5. Cognitive tests including AX-Continuous Performance Test, WMS-III spatial span, Brief
           visuospatial memory test, Emotional Stroop, finger tapping, signal detection (reward
           responsivity) and WTAR IQ.6. Measure of reward responsivity using a signal detection
           test7. Expired air CO, Salivary Cotinine

      8. Weight, height, pulse, blood pressure, and the UKU self-report of adverse events form.

      9. Salivary Drug test to exclude current abuse of PCP, cannabis, alcohol, cocaine,
      methamphetamine and opiates.

      10. Phlebotomy to measure metabolic health, cotinine, bupropion medication levels, genes for
      nicotine metabolism, and genes associated with smoking cessation and nicotine dependence.
      Additional serum will be stored. If there is a significant effect of continued treatment on
      smoking relapse, this serum will be tested for comparison of lipids and inflammatory
      biomarkers between groups.

        1. Open Phase:

           All enrolled subjects will receive weekly CBT group sessions, bupropion 300 mg/ daily,
           nicotine patch 21 mg/day, and up to 20 mg/day of nicotine gum, lozenge, or nasal spray
           for prn use. Subjects will set a quit date between group sessions 3 and 4. The open
           phase groups will consist of 8 weekly CBT meetings with up to 10 participants. Subjects
           who achieve 2 weeks continuous abstinence at the end of the open intervention will be
           eligible for the double blind, relapse prevention trial.

        2. Relapse Prevention Phase:

           Subjects will be randomized to receive either nicotine patch and bupropion or placebo
           patch and pill added to CBT for 44 weeks. Randomization will take place using a
           computer-generated table of random numbers.

           Visits will then take place bi-weekly for the first 4 visits then monthly throughout the
           relapse prevention phase for CBT group treatment. Study medication will be distributed
           at each visit. Smoking status will be determined at each visit with self-report and
           expired air CO. Medication side effects will also be recorded at each visit.

        3. Follow- up Phase:

      During medication taper and after medication is discontinued, subjects will attend 4 follow
      up visits over the next 3 months.

      Clinical status using rating scales will be evaluated at visits 1, 11, 17, 20, 30 and 34.
      Serum levels of psychiatric medications and metabolic markers will also be monitored.

      Subjects will be paid $5 for each of the group meetings during the open and relapse
      prevention phases. Subjects will also be paid an additional $5 for each follow-up visit they
      attend for self-report and $20 for clinical and cognitive assessments. Subjects who complete
      visits 30 and 34 at the end of the study will receive an additional $50 bonus.

      Subject Selection and Recruitment:

      Subjects are 130 adult outpatients with schizophrenia or schizoaffective disorder who smoke
      more than 10 cigarettes per day and wish to stop smoking. Subjects will be recruited by
      referral from treatment staff at Freedom Trail Clinic in Boston and by self-referral by
      responding to posted fliers in clinic waiting rooms. The Freedom Trail Clinic has established
      procedures for identifying and recruiting subjects for research. Clinicians and members of
      research teams meet each week to discuss current projects. Using this information clinicians
      approach their patients if they are likely to be suitable and interested in the study. Those
      who contact research staff about the study will be given information by a research assistant.
      Those who remain interested and express a desire to quit smoking will meet with a research
      psychiatrist. At this meeting subjects will be given further information about the study
      including risks and benefits and screening for eligibility criteria.

      Case managers, primary care physicians and residential treatment staff within the Boston Area
      will also refer subjects. Research staff will meet with local case managers, residential
      staff and primary care physicians to inform them of the study, eligibility criteria and means
      of referral. Fliers will also be placed in local mental health facilities.
    

Intervention name(s): bupropion + nicotine patch + nicotine gum or lozenges; Placebo pill + placebo patch
Intervention type(s): Drug; Drug
Intervention description(s): Subjects eligible for bupropion were randomized to receive either nicotine patch and bupropion or placebo patch and pill added to CBT for 44 weeks.; Subjects eligible for bupropion were randomized to receive either nicotine patch and bupropion or placebo patch and pill added to CBT for 44 weeks.
Intervention MeSH terms: Bupropion; Nicotine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: schizophrenia; smoking cessation; relapse prevention; nicotine; bupropion; cognitive behavioral therapy; nicotine replacement therapy