The Effects of Nicotine Withdrawal on Reward Responsivity in Schizophrenia
Condition: Schizophrenia; Schizoaffective Disorder
MeSH terms: Schizophrenia; Psychotic Disorders
Study type: Interventional
Phase: Phase 4

Summary: 
      It has been suggested that patients with schizophrenia smoke in order to produce amelioration
      of dysfunctional dopaminergic pathways allowing them to experience pleasure and satisfaction
      and overcome anhedonia. No studies have assessed the effects of nicotine withdrawal on reward
      responsivity in patients with schizophrenia. The investigators believe that an understanding
      of this is crucial if improved treatments for nicotine dependence are to be developed for
      this patient population. If this group already has deficits in reward responsivity as a
      symptom of the disease then they may be particularly prone to the effects of nicotine
      withdrawal on reward systems. Smoking cessation may lead to a further decrease in their
      responsivity to pleasurable stimuli and worsening anhedonia. Treatments for smoking cessation
      may need to ameliorate any increased deficits if they are likely to be effective in patients
      with schizophrenia.
    

Detailed description: 
      Heavy smoking continues to represent a significant public health problem for people in the
      general population and for people with major mental illness. Twenty-four percent of adults in
      the general population smoke and it has been estimated that 74-92% of people with
      schizophrenia smoke. While effective treatments for smoking cessation have been developed,
      response rates are modest and relapse rates are high. Approximately 70% of people who quit
      smoking with effective treatments relapse to smoking within one year. A syndrome of negative
      affect and anhedonia has been described as an important component in maintenance of
      dependence on nicotine. It has also been suggested that preventing the syndrome of anhedonia
      and negative affect during early abstinence may reduce relapse rates. If the syndrome of
      anhedonia can be measured objectively and quantitatively, we will be better able to test
      treatments for this withdrawal syndrome. It is our hypothesis that the syndrome of anhedonia
      during early abstinence from nicotine is quantifiable as a deficit in reward responsivity.

      Animal studies suggest that nicotine withdrawal is associated with an alteration in reward
      responsivity. Brain stimulation reward thresholds have been used to measure anhedonia and
      responsivity to reward in animal models. Nicotine withdrawal has been associated with a
      significant decrease in brain reward function as measured by elevations in brain reward
      thresholds that persist for 4 days. Nicotine withdrawal has also been associated with failure
      of conditioning to an environment paired with novel stimuli, possibly due to a decrease in
      reward associated with novel stimuli. Drug withdrawal states have also been associated with
      inhibition of mesolimbic release in murine models.

      We propose a randomized placebo controlled trial to investigate the effects of nicotine
      abstinence on reward responsivity in patients with no major mental illness and in patients
      with schizophrenia.

      Principal Aims:

      Aim 1: To evaluate the effects of nicotine withdrawal on a measure of reward responsivity
      Hypothesis 1a: Normal controls and subjects with schizophrenia will demonstrate deterioration
      on a measure of reward responsivity during abstinence (placebo condition) compared to
      baseline. (Primary Outcome Measure)

      Aim 2: To evaluate the effects of transdermal nicotine on reward responsivity during
      abstinence.

      Hypothesis 2a: Normal controls and subjects with schizophrenia will demonstrate greater
      response bias toward a rewarded condition following transdermal nicotine administration
      relative to placebo patch during a 3 day period of abstinence.

      Aim 3: To evaluate the effects of smoking abstinence and transdermal nicotine on a measure of
      reward responsivity in patients with schizophrenia who smoke relative to normal control
      smokers.

      Hypothesis 3a: Subjects with schizophrenia will demonstrate decreased reward responsivity
      during all conditions (baseline, nicotine replacement therapy condition and placebo
      condition) relative to normal controls.

      Secondary aims:

      Aim 4: To evaluate the effects of nicotine withdrawal on cognitive function in smokers
      Hypothesis 4a: Normal controls and subjects with schizophrenia will demonstrate poorer
      performance on tests of cognition following placebo administration compared with baseline and
      nicotine conditions.

      We propose to test the effects of smoking abstinence and nicotine replacement therapy, using
      nicotine transdermal patch on a measure of reward responsivity in patients who smoke. We
      propose a randomized placebo controlled crossover trial with the primary outcome measure
      being Response bias using a signal detection task.

      Subjects are 70 patients with schizophrenia who smoke and 70 normal control smokers who do
      not have a major mental illness and who are matched for age, sex and nicotine dependence.
      Though we expect to consent 70 subjects in each group, we expect only 20 subjects in each
      group to complete the study
    

Intervention name(s): transdermal nicotine patch
Intervention type(s): Drug
Intervention MeSH terms: Nicotine
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double
Primary purpose: Treatment
Keywords: nicotine; schizophrenia; reward; withdrawal