Nicotinic Receptor Density in Smoking and Nonsmoking Schizophrenics
Nicotinic Receptor Density in Smoking and Nonsmoking Schizophrenics
Background:

 - Previous studies have suggested that smoking cigarettes affects the number of receptors in
 the brain for nicotine, a chemical present in cigarette smoke. The receptors play a role in
 an individual's ability to think and concentrate. Many people with schizophrenia and similar
 disorders smoke, and research suggests that smoking may temporarily improve concentration and
 focus in individuals with schizophrenia. Researchers are interested in studying both current
 smokers and nonsmokers with schizophrenia to determine whether smoking affects the number of
 nicotine receptors in the brains of people with schizophrenia.

 Objectives:

 - To study the distribution and volume of nicotine receptors in the brains of individuals
 with schizophrenia who are either nonsmokers or current smokers.

 Eligibility:

 -  Individuals between 18 and 50 years of age who have been diagnosed with schizophrenia
 and are either nonsmokers or current smokers (at least 10 cigarettes per day for the
 past year).

 -  Current smokers must be able to give up smoking for 48 hours.

 Design:

 -  This study involves an initial screening visit and up to five study visits.

 -  After the screening visit, participants will have two sessions in which they will
 complete questionnaires about thoughts, memory, and smoking habits. Smokers will also
 have nicotine blood and carbon monoxide breath levels taken during these sessions,
 before and after smoking a cigarette.

 -  Participants will have sessions with imaging studies (e.g., magnetic resonance imaging)
 to provide baseline measurements for later tests, and will also have tests to measure
 brain electrical activity.

 -  Participants will have a positron emission tomography (PET) scanning session to examine
 the nicotine receptors in the brain. Participants will need to stay overnight
 (nonsmokers) or for 2 nights (smokers) as an inpatient before the session. The PET scan
 session will take up to 6 hours, although participants will only be in the scanner for
 up to 3 hours.

 -  Participants will have a follow-up phone call with study researchers 1 week after the
 PET scanning session.
Objective:

 The objective of this study is to determine the distribution and volume of distribution (Vt)
 in vivo of Beta2* acetylcholine receptors (Beta2* nAChR) in schizophrenic smokers and
 nonsmokers and compare this to published data from normal healthy subjects who are smokers
 and nonsmokers.

 Study population:

 Participants will be volunteers with a diagnosis of schizophrenia aged 18 to 50 years. The
 proposed sample size is 10 per group: nonsmokers or ex-smokers and smokers for a total of 20
 participants.

 Design:

 One PET study lasting up to 8 hours after combination of bolus and continuous infusion
 administration of 2[(18)F] FA-85380. Smokers will be abstinent for at least 48 hrs. Subjects
 will also undergo a structural MRI scan for purposes of registration of PET scan data.

 Outcome Measures:

 Data from 20 schizophrenic patients (10 smokers and 10 nonsmokers) will be compared to
 published data from healthy controls. Total volume of distribution (VT) which is a measure of
 receptor density and distribution of Beta2 nAChR* will be determined in Schizophrenic smokers
 and nonsmokers and differences in these values will be compared to published values for the
 differences in nicotinic acetylcholine receptor density in healthy smokers and nonsmokers
 (Mukhin et al., 2008) Also, receptor distribution and VT will be correlated with levels of
 smoking and symptom profiles in the schizophrenic patients studied.
-  INCLUSION CRITERIA:

 Age: Subjects will be male and female volunteers aged 18 to 50 years.

 Contact: All subjects must have a stable point of contact and must agree to participate in
 one PET study and one MRI scan.

 Smoking group: must smoke at least 10 cigarettes per day for at least the last year. They
 should have experience with abstaining from smoking for at least 48 h.

 Nonsmoking group: Subjects in the non-smoking group must be nonsmokers or have smoked less
 than 100 cigarettes in their lifetime and have ceased smoking at least two years before the
 start of the study.

 Diagnosis: Each volunteer will have a diagnosis of schizophrenia using DSMIV criteria. Each
 subject will have the following information available for diagnostic consideration:
 Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I), a general psychiatric
 interview for past illness characteristics and family history, information from 2-3 months
 of independent clinician observation including current detailed mental status evaluations
 using the Brief Psychiatric Rating Scale (BPRS), Schedule for the Assessment of Positive
 and Negative Symptoms (SAPS/SANS), and Schedule for Deficit Syndrome (SDS). An assessment
 of impulsivity will also be done (Patton, 1995).

 Comorbidity: No subject with a current axis I diagnosis other than schizophrenia will be
 allowed. No subject with known claustrophobia will be allowed.

 Medications: Study participants will continue to take their antipsychotic medications that
 they have been taking for at least 3 months prior to the study. Haldol, risperidone and
 olanzapine will be allowed because of their lack of significant effect on the density of
 beta2* nACh receptors after prolonged administration to rats (Haldol; Breese et al., 2000;
 risperidone and olanzapine; personal communication, Mukhin, also SFN abstract).

 EXCLUSION CRITERIA:

 Weight: Anyone weighing more than 300 lbs is excluded from the study. The purpose of this
 exclusion is the weight limit of the PET scanner.

 History of Drug Abuse: Participants reporting current or having a significant history of
 illicit drug abuse will be excluded from the study. Subjects may use moderate amounts of
 alcohol and caffeine and smoke an occasional marijuana cigarette, but must not be dependent
 on alcohol, caffeine or marijuana. No alcohol or marijuana for at least 72 hours prior to
 scanning. No smoking for 48 hrs before the PET scan.

 Current Medication Use: Participants will continue to use their prescription medications.
 The following hypertension medications will be exclusionary: Indapamide, spironolactone,
 clonidine, guanfacine, methyldopa, propranolol. Over the counter medications are not
 exclusionary, however, subjects will not be allowed to use over the counter medications in
 the week prior to their PET scan.

 CNS disease: History of known structural brain abnormalities (e.g., neoplasm, subarachnoid
 cysts), cerebrovascular disease, infectious disease (e.g., abscess), history of head trauma
 (defined as documented loss of consciousness for 5 min or greater), history of seizures as
 an adult, sleep apnea.

 Cardiovascular, pulmonary, or systemic disease: Untreated hypertension known arrhythmia,
 symptomatic or known coronary artery disease; history of endocarditis, cerebral embolism,
 obstructive pulmonary disease, asthma, active tuberculosis, known endocrine disease
 (derangements in adrenal, thyroid, bone or reproductive function) known chronic renal or
 hepatic dysfunction, known HIV seropositive, known current autoimmune disease involving the
 CNS, type I diabetes mellitus. Subjects with type II diabetes mellitus will be allowed if
 their Hb A1C is less than 7.

 Special considerations for female subjects. Female participants who are planning to become
 pregnant, currently pregnant or nursing will not be allowed to participate in this study
 because of potential damage to the fetus or baby from the radiation. In addition, women of
 child bearing age who are sexually active are required to use an effective form of birth
 control for the duration of the study. Effective forms of birth control include:

 1. hormonal contraceptives (birth control pills, injectable hormones, vaginal ring
 hormones),

 2. surgical sterility (tubal ligation or hysterectomy)

 3. IUD

 4. Diaphragm with spermicide

 5. Condom with spermicide

 Female subjects will be given a serum pregnancy test (quantitative beta HCG) within 24
 hours of the PET study. Menstrual cycle phase or sex has not been shown to affect receptor
 availability (Cosgrove et al., 2007).

 Radiation exposure: Any subject who has participated in any research studies in which
 he/she received a radiation exposure that would result in combination with the present
 study, in a total effective radiation exposure (from research studies) exceeding 5.0 rem in
 a year.

 Children under the age of 18 will be excluded to avoid unnecessary exposure to radiation to
 these populations.

 Presence in body of metallic implants or materials that could be moved by the magnet of the
 MRI scanner: pacemakers, surgical implants, aneurysm clips, dental braces, bullet(s) or
 other metallic materials.