The Effects of Nicotine on Cognition in Schizophrenia

We propose to test the efficacy and safety of transdermal nicotine for attention and working
memory in outpatients with stable symptoms of schizophrenia treated with high potency
antipsychotic medications that do not smoke cigarettes or use nicotine-containing products.
This is a randomized, double-blind, placebo-controlled pilot study to determine whether
transdermal nicotine, initiated in a clinic setting and dosed for four hours is safe and
effective for improving attention and spatial working memory deficits in patients with
schizophrenia. This is an add-on study, subjects will continue with their usual medications
and treatments throughout.

Subjects are 30- non-smoking outpatients with stable treated schizophrenia and 30 normal
controls who do not have a major mental illness and who are matched for age sex and parental
education. Subjects are randomized to one of 2 groups for order of receiving active and
placebo patch, using a computer generated random number sequence. Randomization is concealed
using opaque envelopes. Assessors and subjects are blind to group allocation.

The primary outcome measure is d' measure on the CPT-IP following a 4 hour administration of
the transdermal nicotine patch. Secondary outcome measures are performance on tasks
assessing attention, numeric and visuospatial working memory, psychomotor ability, executive
functioning and motivation for reward following nicotine patch administration.

Specific Aims

1. To evaluate the effectiveness of transdermal nicotine compared with placebo for
attentional impairment in patients with schizophrenia

Hypothesis 1.1: Subjects will demonstrate greater signal detection as measured by the
d' (hits vs. false alarms) on the Continuous Performance Test Identical Pairs Version
(CPT-IP) following 4-hour nicotine administration when compared with placebo
administration.

Hypothesis 1.2: Subjects will demonstrate decreased false alarms on the CPT-IP
following 4-hour nicotine administration when compared with placebo administration.

Hypothesis 1.3: Subjects will demonstrate decreased reaction time on the CPT-IP
following 4- hour nicotine administration when compared with placebo administration.

2. To evaluate the effect of transdermal nicotine in patients with schizophrenia compared
with normal matched controls

Hypothesis 2.1: Schizophrenia subjects will demonstrate greater improvement in signal
detection as measured by the d' (hits vs. false alarms) on the Continuous Performance test
identical pairs version(CPT-IP) following 4-hour nicotine administration when compared with
normal controls.

Hypothesis 2.2: Schizophrenia subjects will demonstrate greater reduction in false alarms on
the CPT-IP following 4-hour nicotine administration when compared with normal controls.

Hypothesis 2.3: Schizophrenia subjects will demonstrate decreased reaction time on the
CPT-IP following 4- hour nicotine administration when compared with normal controls.
Performance Test Identical Pairs Version

Inclusion Criteria:

Patients:

- DSM IV diagnosis of schizophrenia,

- age 18 - 60 inclusive,

- able to provide informed consent,

- treated with antipsychotic medications at a stable dose for at least 4 weeks,

- not treated with an investigational medication in the past 30 days,

- WRAT-3 IQ raw score greater than or equal to 35,

- non smokers for more than 3 months*,

- normal or corrected to normal vision.

Non Smoking defined by:

1. Self report of not smoking a single cigarette in the past 3 months.

2. Salivary Cotinine level < 30 ng/ml at screening and on the day of testing

3. Expired air CO < 9ppm on the day of the testing

Inclusion Criteria:

Control Group:

- Age 18 - 60 inclusive,

- able to provide informed consent,

- not treated with an investigational medication in the past 30 days,

- WRAT-3 IQ raw score greater than or equal to 35,

- non smokers for more than 3 months*,

- normal or corrected to normal vision,

- Non Smoking as defined above.

Exclusion Criteria:

Patients:

- Use of any nicotine containing product in the past 3 months by self report,

- use of cholinesterase inhibitors such as galantamine in the past 3 months,

- untreated ischaemic heart disease,

- uncontrolled hypertension,

- current unstable serious medical illness (renal, neoplastic, hematological),

- allergy to patches.

- Currently or planning to be pregnant in the next 8 weeks, as verified by positive
pregnancy test, or childbearing potential and not using adequate contraception.
Those not of childbearing potential include post-menopausal, surgically sterilized,
and male participants.

- Substance abuse in the past month: self-reported, diagnosed during chart review, and
verified by a positive salivary test for cotinine, cocaine, methamphetamine,
amphetamine, ethanol, TCH, opiates or PCP at screen.

- Recent deterioration in mental state, current major depressive disorder, history of
cognitive impairment secondary to other disorders such as head injury, dementia,
general medical condition, diagnosis of mental retardation

Exclusion criteria:

Controls:

- Past or present DSM IV diagnosis of schizophrenia, schizoaffective disorder, major
depression, bipolar disorder, or mental retardation.

- First degree relative with diagnosis of schizophrenia or schizoaffective disorder,

- use of cholinesterase inhibitors such as galantamine in the past 3 months,

- untreated ischaemic heart disease,

- uncontrolled hypertension,

- current unstable serious medical illness (renal, neoplastic, hematological,)

- allergy to patches,

- currently or planning to be pregnant in the next 8 weeks, as verified by positive
pregnancy test, or childbearing potential and not using adequate contraception.
Those not of childbearing potential include post-menopausal, surgically sterilized,
and male participants.

- Substance abuse in the past month: self-reported, diagnosed during chart review, and
verified by a positive salivary test for cotinine, cocaine, methamphetamine,
amphetamine, ethanol, TCH, opiates and PCP at screen.

- History of cognitive impairment secondary to other disorders such as head injury,
dementia, general medical condition