Galantamine for Cognitive Deficits in Schizophrenia
Condition: Schizophrenia
MeSH terms: Schizophrenia; Cognition Disorders; Cognitive Dysfunction
Study type: Interventional
Phase: Phase 2/Phase 3

Summary: 
      The purpose of this study is to determine the acute effects of the nicotinic receptor
      allosteric modulator galantamine (0, 4 and 8 mg) on neurocognitive function in schizophrenic
      smokers (n=20) versus schizophrenic nonsmokers (n=10) in an outpatient human laboratory
      setting.
    

Detailed description: 
      The proposed study will entail a comprehensive evaluation of the effects of acute doses of
      the nAChR allosteric modulator galantamine hydrochloride (0, 4 and 8 mg) on neurocognitive
      measures in schizophrenic smokers (n=20) and schizophrenic non-smokers (n=10) in a human
      laboratory paradigm. After training on a battery of neurocognitive assessments, all subjects
      will be studied during three separate test weeks where they will complete the neurocognitive
      batter at baseline, and then again after acute administration of the three doses of
      galantamine in a counterbalanced order across subjects in each experimental group.
      Specifically, smokers would be randomized into one of two groups: 1) those who undergo
      overnight smoking abstinence prior to the study cognitive sessions in order to determine
      galantamine's effects on abstinence-induced cognitive impairment, and 2) those who may smoke
      as usual prior to the study cognitive sessions. The inclusion of nonsmokers will allow for
      the assessment of galantamine's effects on cognitive deficits in schizophrenia independent of
      cigarette smoking. Finally, genetic variations in key metabolic genes involved in
      catecholamine metabolism (COMT and DBH) would be evaluated as determinants of
      galantamine-related improvements in cognitive performance in schizophrenic smokers and
      nonsmokers.

      We predict that galantamine will dose-dependently improve selected cognitive deficits
      associated with schizophrenia (e.g., spatial working memory, sustained attention and prepulse
      inhibition) which we have previously shown are selectively improved by cigarette smoking in
      smokers with schizophrenia [18], and that this effect would be more pronounced in nonsmokers
      with schizophrenia. If our results are positive, they would support the rationale for
      controlled clinical trials using nAChR agonists like galantamine to treat selected domains of
      cognitive dysfunction in this disorder.

      Study Design:

      The following experimental groups will be studied:

        1. Schizophrenic Smokers under abstinence conditions (n=10)

        2. Schizophrenic Smokers in the smoking condition. (n=10)

        3. Schizophrenic Nonsmokers (n=10)

      Three acute doses of galantamine (GAL) will be tested (0, 4 and 8 mg) in all subjects during
      three separate test sessions separated by at least 3 days, with study medication doses across
      sequential subjects given in a randomized, counterbalanced manner.

      Smokers (n=20) and nonsmokers (n=10) with schizophrenia will be recruited from the outpatient
      division of The Connecticut Mental Health Center (CMHC) in New Haven, CT, and it's affiliated
      satellite centers (Hispanic Clinic, West Haven Mental Health Center, and Yale Behavioral
      Mental Health Center).

      Screening Procedures:

      All potential subjects would meet with study staff over 2-3 intake and evaluation sessions to
      determine study eligibility, which would typically take place within 4 weeks of study
      enrollment. A description of the evaluation measures is given below:

      The screening evaluation will include completion of informed consent forms, a urine
      toxicology screen to screen for recent use of illegal substances, a urine pregnancy test for
      female subjects, a psychiatric evaluation using the SCID for DSM-IV disorders, PANSS, AIMS,
      Webster, Barnes, BDI, Tiffany Questionnaire for Smoking Urges (T-QSU), Minnesota Nicotine
      Withdrawal Scale (M-NWS), Shipley Full Scale Intelligence Quotient (IQ), a blood draw for
      plasma nicotine, plasma cotinine, as well as CBC and LFT's, and a physical examination
      conducted by Dr. George. Subjects will be separately consented for the genetics portion of
      the study and blood will be taken for genotyping purposes. Finally, a pre-study
      neuropsychological testing session would be performed in order to orient and train
      participants on the laboratory procedures. Subjects who are pregnant or planning on becoming
      pregnant will not be eligible to participate.

      We will compensate all subjects who complete the screening and evaluation process ($25.00)
      and the neurocognitive training session ($25.00) for a total of $50.00. In addition, subjects
      would be paid $25.00 for donating a blood sample for genotyping.

      Blood for genotyping will be obtained for COMT and DBH polymorphisms in smokers and
      nonsmokers in schizophrenia participating in this study. The genotyping for these studies
      will be done in collaboration with the Psychiatric Genetics laboratory of Joseph F. Cubells,
      M.D., Ph.D. at Emory University.

      Experimental Procedures: Smokers will be tested on the cognitive battery at baseline (Day 1,
      with periodic smoking breaks to minimize nicotine withdrawal), and then again 24 hours later
      after overnight smoking abstinence (Day 2). Non-smokers will be tested at baseline (Day 1)
      and again 24 hours later (Day 2). Study medications will be given as a single dose before the
      Day 2 session which will produce ascending plasma drug levels (t= ½ 5/7 h) during the two
      hour testing session, in a counterbalanced dosing schedule of galantamine hydrobromide (0, 4,
      and 8 mg) within each test group. If systolic blood pressure is below 90 mm Hg, the
      galantamine study medication will be held. Before and after each session (Day 1 and Day 2),
      clinical ratings using the PANSS, HDRS, extrapyramidal ratings, and adverse event ratings
      would be completed. For smokers, pre-session tobacco craving and withdrawal ratings, expired
      breath carbon monoxide, and plasma cotinine and nicotine levels would be obtained. Smokers
      randomized to the abstinence condition would receive $150.00 for successful completion of
      each of the subsequent three test session procedures requiring overnight abstinence ($50.00
      for successful abstinence, and $100.00 for subsequent testing session completion). Smokers
      randomized to the non-abstinence condition would be also receiving $150.00 for successful
      completion of each of the three test session procedures in order to maintain consistency.
      Nonsmokers would receive $100.00 for completion of each of the three test sessions beyond the
      training session. In addition, a completion bonus of $50.00 will be paid to all subjects who
      complete all study procedures. Thus, smokers with schizophrenia could earn $575.00, and
      nonsmokers $425.00 for their completion of the entire study. The proposed single subject
      timeline is given below:
    

Intervention name(s): Galantamine
Intervention type(s): Drug
Intervention MeSH terms: Galantamine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double
Primary purpose: Treatment
Keywords: Schizophrenia; Cognition; Smoking; Galantamine; Nicotine; Cognitive Deficits