Neural Inhibition as a Mechanism of Nicotine Dependence Among Persons With Schizophrenia
Condition: Smoking; Nicotine Dependence; Schizophrenia; Schizophreniform Disorders; Schizoaffective Disorder; Psychosis
MeSH terms: Tobacco Use Disorder; Schizophrenia; Psychotic Disorders; Mental Disorders
Study type: Interventional

Summary: 
      Cigarette smoking decreases life expectancy, causes devastating health complications, and
      costs society billions of dollars each year. These untoward consequences are especially
      pronounced among persons with schizophrenia (SCZ) because approximately 80% to 95% of this
      group smokes cigarettes. These high prevalence rates underscore the need for research
      investigating the determinants of smoking in patients with SCZ. Several researchers have
      observed that nicotine improves specific symptoms of SCZ including negative symptoms,
      negative affect, and cognitive deficits. This has led to the hypothesis that patients with
      SCZ smoke in an attempt to self-medicate. However, the mechanism(s) by which nicotine has its
      positive effect on symptoms remains unclear. The current proposal posits that neural
      inhibition (NI) is a physiological mechanism of this effect, while variation in the
      alpha-7-nicotinic receptor subunit gene (CHRNA7) represents the genetic underpinnings of
      these processes. The proposed study will assess NI and symptom improvement after acute
      administration of nicotine to both smokers and nonsmokers with SCZ. In addition, NI and
      CHRNA7 variation will be tested as predictors of patients' ability to reduce/quit smoking
      following smoking treatment. These data may lead to the development of new pharmacological
      strategies for treating the symptoms of SCZ and new methods for assisting these patients to
      quit smoking.
    

Detailed description: 
      The prevalence of smoking is unusually high among patients with SCZ. In light of the negative
      health, economic, and social consequences of smoking, treatment efforts in this area are
      imperative. Such efforts rest, in part, on an improved understanding of the underlying causes
      of smoking within this unique population. For example, several lines of research have
      indicated that smoking improves specific SCZ-related symptoms (i.e., negative psychotic
      symptoms, negative affect, cognitive deficits) and that patients may smoke to self-medicate
      with nicotine. However, the mechanism(s) underlying this effect are unknown. The current
      proposal posits that improved NI may be one such mechanism. More specifically, NI is
      conceived as a mediator of the relationship between smoking and symptom improvement. Also,
      given its proposed mechanistic nature, we believe that nicotine-related changes in NI may
      predict quit/reduction and/or relapse rates following a smoking cessation program.
      Additionally, variants of CHRNA7 likely represent the genetic underpinnings of decreased NI,
      vulnerability to smoking, and smoking treatment resistance among patients with SCZ. These
      hypotheses are supported by previous experiments that suggest: (1) patients with SCZ have
      decreased NI (Adler et al., 1998); (2) nicotine administration (via its effects on the
      alpha-7-nicotinic receptor, which, in turn activates GABAergic interneurons) enhances NI in
      these patients (Adler et al., 1998); (3) genetic variation in the alpha-7-nicotinic receptor
      increases risk for smoking among patients with SCZ (Leonard et al., 1996); and, (4) higher
      levels of NI are associated with fewer negative symptoms, less negative affect, and better
      cognition (Yee et al., 1998). However, these studies have been hampered by several
      methodological and conceptual shortcomings including small sample sizes, the presence of
      confounding variables (e.g., the effects of nicotine withdrawal), and limited testing of
      relevant symptom domains. Furthermore, previous studies have examined only isolated aspects
      of the proposed model, leaving many of the central relationships between variables untested
      and speculative. The current proposal seeks to rectify these methodological issues within the
      context of a multidisciplinary scientific team. Globally, its objectives are twofold. First,
      to replicate and extend previous findings that nicotine causes symptom attenuation. Second to
      investigate the underlying neurophysiological and genetic mechanisms of these effects. The
      specific objectives and hypotheses addressed in this study are as follows:

        1. To acutely administer nicotine versus placebo to smokers with SCZ following transient
           abstinence from cigarettes, in order to investigate the effect of nicotine on the SCZ
           symptoms. This objective extends previous research by employing an adequately large
           sample and simultaneously testing several relevant domains of symptom improvement.
           Hypothesis: Significantly greater improvements across the domains of negative symptoms,
           negative affect, and cognitive deficits will be evident among those patients receiving
           nicotine versus placebo.

        2. To acutely administer nicotine versus placebo to nonsmokers with SCZ in order to
           investigate the effects of nicotine on the symptoms of SCZ, independent of withdrawal.
           This objective allows for the methodological disambiguation of the direct neural effects
           of nicotine from the effects of termination of withdrawal symptoms. Additionally, this
           will provide seminal data regarding the acute treatment benefits of nicotine as a
           therapeutic agent, delivered without the health risks associated with smoking.
           Hypothesis: Significantly greater improvements across all symptoms domains will be
           evident among those patients receiving nicotine versus placebo.

        3. To ascertain (using statistical techniques outlined by Kenny and others) (Baron & Kenny,
           1986; Judd &Kenny, 1981) whether the relationship between acute nicotine administration
           and symptom reductions is mediated by increased NI (as measured via ERP and TMS
           paradigms). Hypothesis: NI will meet the statistical criteria for mediating the
           relationship between nicotine administration and symptom reductions.

        4. To ascertain whether nicotine-related changes in NI predict patients' ability to reduce
           smoking, the amount of nicotine replacement therapy (NRT) required, and rates of
           quitting and smoking relapse following completion of a smoking cessation program.
           Hypothesis: NI will operate as a significant and unique predictor of the amount of
           smoking reduction and NRT use, as well as quit and relapse rates, over and above
           conventional predictors of smoking reduction from the general population (i.e., age,
           marital status, coping resources, socioeconomic status, smoking related health problems,
           the number of cigarettes smoked per day, concomitant alcohol and coffee consumption,
           treatment compliance, and stage of change) (Matheny & Weatherman, 1998; Ockene et al.,
           2000; Oritz et al., 2003).

        5. To investigate whether polymorphisms in CHRNA7 are associated with the magnitude of NI
           deficits, symptom reductions following acute nicotine administration, rates of smoking
           among patients with SCZ, and/or quit/reduction or relapse rates following smoking
           cessation treatment. Hypothesis: Significant genetic association will be demonstrated
           between CHRNA7 polymorphisms and each of the above-listed clinical variables.
    

Intervention name(s): Nicotine patch; placebo; smoking cessation group therapy
Intervention type(s): Drug; Other; Behavioral
Intervention description(s): 21 mg of nicotine via a dermal patch; placebo via a dermal patch; a 9-week group based on the "Freedom From Smoking" program designed by the American Lung Association. The treatment was manualized and modified to meet the functional and cognitive capabilities of patients with psychotic disorders
Intervention MeSH terms: Nicotine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Basic Science
Keywords: nicotine dependence; smoking; nicotine patch; double-blind; randomized; placebo; psychosis; schizophrenia; schizophreniform; schizoaffective disorder