Nicotine Replacement Therapy for Smoking Cessation in Schizophrenia
Condition: Schizophrenia; Schizoaffective Disorder
MeSH terms: Schizophrenia; Psychotic Disorders
Study type: Interventional
Phase: Phase 4

Summary: 
      This proposal seeks to evaluate a pilot smoking cessation treatment program that will combine
      nicotine replacement therapy with or without bupropion sustained-release (SR) with cognitive
      behavioral therapy for smoking cessation in patients with major mental illness.
    

Detailed description: 
      Background:

      Seventy-four to 92% of patients with schizophrenia smoke cigarettes compared to 24% of the
      adult US population and 18% of adults in Massachusetts (1-3). Patients with schizophrenia
      also smoke more cigarettes on average per day (4) and attain higher serum levels of cotinine,
      the primary metabolite of nicotine, a finding attributed to deeper smoke inhalation (5).
      Cigarette smoking has been identified as the single most important source of preventable
      morbidity and premature mortality in the general U.S. population for the last 29 years (6,
      7). Compounded by the problem that patients with schizophrenia live a less healthy lifestyle
      (8) and may be less likely to receive adequate routine and preventative medical care (9-12),
      heavy smoking represents a significant and neglected public health problem for people with
      schizophrenia. Patients with schizophrenia clearly have greater morbidity and early mortality
      from 'natural causes' than people without schizophrenia (13-22) and are more likely to die
      prematurely from cardiovascular or pulmonary disease (14, 19, 23-26). Women with
      schizophrenia have been shown to have increased risk of premature death from cancer (24) and
      previous studies showing lower mortality from cancer in patients with schizophrenia compared
      to the general population have not been confirmed (14, 27, 28). Successful smoking cessation
      programs for patients with schizophrenia could reduce this increased medical morbidity and
      mortality. A recent report of patterns of nicotine use in a cohort of 50 patients with
      schizophrenia or schizoaffective disorder underscores this point: the cohort had a mean age
      of 47 years and mean age at onset of daily smoking of 20 years; 45.8% reported they currently
      have a smoking related health problem; 95.8% had tried unsuccessfully to cut down on their
      smoking; 70% had made a serious attempt to quit smoking (29). Smoking cessation programs for
      patients with schizophrenia have reported compliance rates as high as 80% (30).

      Nicotinic receptors have been shown to be reduced in number in patients with schizophrenia
      (31, 32) and heavy smoking in schizophrenia may be attributable to attempts to overcome this
      deficit. Benefits of nicotine to patients with schizophrenia include reversal of some of the
      specific cognitive deficits associated with schizophrenia and antipsychotic treatment
      [(33-37). Nicotine has been shown to improve learning, visual and spatial working memory,
      attention, auditory sensory gating smooth pursuit eye movements and reaction time (38, 39).
      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 (40). Smoking cessation in patients with schizophrenia is associated with increase in
      positive symptoms (30). Treatment with atypical antipsychotics may enhance the effectiveness
      of smoking cessation treatment (41-43). The mechanism of this effect is not known but may be
      due to decreased extrapyramidal side effects, improved efficacy for negative symptoms or
      effects on glutamatergic systems. Combination of NRT and antidepressant medication has been
      shown to increase cessation rates over monotherapy with NRT (44) but not over antidepressant
      medication alone (45).

      Nicotine replacement therapy (NRT) is a powerful aid to smoking cessation with well
      established efficacy (46-49) in non-psychiatric patients and has been proposed as a potential
      tool in increasing smoking harm reduction in persons unable to achieve smoking abstinence
      (50). Smoking cessation outcomes in patients with schizophrenia using NRT have been extremely
      variable. Ziedonis and colleagues used a range of doses of NRT administered by patch, gum or
      combination in addition to CBT for up to 10 weeks in 24 patients with schizophrenia (51).
      Twelve subjects completed the trial. The cessation rate was 13% at 6 months (51). In one
      study, atypical antipsychotic agents, in combination with the nicotine transdermal patch,
      have been shown to significantly enhance the rate of smoking cessation (55.6% in the atypical
      agent group versus 22.2% in the typical group) (41). In this study the overall end of
      treatment point prevalence smoking cessation rate in 45 patients with schizophrenia was 35%.
      In another study of the acute effects of transdermal nicotine patch in psychiatric patients,
      however, no patients quit smoking acutely, and only heavy smokers reduced their cigarette
      consumption (52).

      Safety of NRT in patients with schizophrenia has only been evaluated on a very small scale.
      One important trial examined the effects of a 21 mg nicotine patch on smoking behavior,
      nicotine levels in blood and signs of toxicity in patients with schizophrenia (53). In this
      crossover trial, 10 male veterans were monitored while wearing nicotine vs placebo patches.
      The nicotine patch condition was associated with increased nicotine levels without signs of
      toxicity and decreased CO levels in 80% of patients. No trials have reported worsening of
      psychiatric symptoms with NRT. Larger studies in which NRT is combined with behavioral
      support are needed to evaluate the efficacy and safety of NRT in schizophrenia.

      Treatment Component:

      Subjects will be outpatients who are clinically stable and currently in treatment for
      schizophrenia or schizoaffective disorder. Subjects will be recruited through referral from
      case managers, residential treatment settings and outpatient treaters. Subjects must smoke
      =1/2 pack per day of cigarettes and wish to quit smoking.

      Subjects will be randomly assigned to receive cognitive behavioral smoking cessation therapy
      CBT) with nicotine patch (NRT) plus placebo or nicotine patch combined with bupropion SR.
      Subjects who are unable to tolerate or who have a contraindication to treatment with zyban
      may be enrolled to receive CBT and open label NRT alone. All subjects will receive a 12
      session group cognitive behavioral therapy (CBT) program designed for smoking cessation
      treatment in patients with schizophrenia in addition to pharmacologic treatment.

      Evaluation Component:

      The evaluation component of this protocol involves monitoring patients for stability of
      psychiatric symptoms, serum levels of psychiatric medications, and medication side effects at
      baseline and weeks 4, 8, 12 and 14 and degree of smoking reduction or cessation weekly during
      the treatment intervention and at 6, 12 and 24 months.

      At baseline, subjects will complete a demographic questionnaire. Prior to beginning
      treatment, subjects will be evaluated for symptoms of psychosis, depression, anxiety, and
      medication side effects with standard clinical rating scales that include the schedule for
      assessment of negative symptoms (SANS), positive and negative symptom scale (PANSS), Hamilton
      depression scale (HamD), Hamilton anxiety scale (HamA), abnormal involuntary movement scale
      (AIMS), Simpson Angus Scale, and SAFTEE. A brief cognitive battery will include tests of
      response inhibition (the single trial Stroop), vigilance (continuous performance test),
      verbal fluency (FAS), verbal memory (California Verbal Learning Test), working memory (letter
      number span), non-verbal memory (Benton visual retention test), psychomotor ability (grooved
      peg board task), and executive functioning (trail making or tower of London). Baseline carbon
      monoxide (CO) measurements will be used with self report to verify number of cigarettes
      smoked per day. Serum will be drawn for cotinine and antipsychotic levels at baseline. Weight
      will be checked at baseline, 12 and 24 weeks.

      Subjects will set a quit date between weeks 3 and 4. The evaluation battery will be repeated
      at week 4 just following the quit date. It will also be repeated at week 12 when patients
      discontinue the group and medication treatment. An evaluation that includes the clinical
      battery and CO measurement will be performed at week 14, two weeks following termination of
      smoking cessation treatment and at week 24. Subjects will also be contacted at 1 and 2 years
      for follow up self report of tobacco use and CO measurement.

      Specific Aims: Treatment

        1. Increase availability of nicotine replacement therapy, which is not currently available
           by prescription, to patients with major mental illness.

        2. Train staff members with expertise in treating patients with major mental illness to be
           Tobacco Treatment Specialists using the training protocol developed by University of
           Massachusetts Medical School in collaboration with the Massachusetts Department of
           Public Health.

        3. Establish a network of centers able to deliver tobacco treatment to patients with major
           mental illness.

      Specific Aims: Evaluation

        1. Evaluate smoking cessation rates, smoking reduction rates and stability of psychiatric
           symptoms in patients with schizophrenia and schizoaffective disorder during a smoking
           cessation attempt using cognitive behavioral therapy combined with NRT plus placebo and
           NRT + bupropion SR.

        2. Evaluate safety of nicotine replacement therapy in patients with schizophrenia and
           schizoaffective disorder when combined with antipsychotic medications.

        3. Evaluate safety of nicotine replacement therapy in patients with schizophrenia and
           schizoaffective disorder when combined with bupropion SR and antipsychotic medications.

      Hypotheses:

        1. Nicotine replacement therapy combined with bupropion SR and cognitive behavioral therapy
           will be associated with improvement in smoking cessation and smoking reduction rates
           when compared to NRT alone added to CBT in patients with schizophrenia and
           schizoaffective disorder.

        2. Nicotine replacement therapy combined with bupropion SR will be associated with
           improvement in negative symptoms, depression and impulsivity when compared to NRT alone
           in patients with schizophrenia and schizoaffective disorder who quit smoking.

        3. Concurrent treatment with atypical antipsychotic medications will further enhance the
           effectiveness of NRT combined with bupropion SR and NRT plus placebo for smoking
           cessation and reduction in patients with schizophrenia and schizoaffective disorder
           compared to concurrent treatment with conventional antipsychotics.

        4. Patients with low baseline cotinine = 250 ng/ml will have higher cessation rates than
           patients with high baseline cotinine >250 ng/ml.
    

Intervention name(s): bupropion, transdermal nicotine patch
Intervention type(s): Drug
Intervention MeSH terms: Bupropion; Nicotine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double
Primary purpose: Treatment
Keywords: schizophrenia; smoking cessation; nicotine; patch; bupropion; nicotine replacement therapy; cognitive behavioral therapy