Clinical trial NCT00383747: The Effects of Nicotine on Cognition in Schizophrenia
Official title: A Double Blind Placebo Controlled Trial of the Effects of Transdermal Nicotine on Cognitive Function in Non-Smokers With and Without Schizophrenia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Schizophrenia
Keywords: cognition
nicotine
schizophrenia
Lead sponsor: Massachusetts General Hospital
Sponsor class: OTHER
Collaborators: name: Stanley Medical Research Institute
name: North Suffolk Mental Health Association
First posted: 2006-10-03
Enrollment: 60
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: Patients with schizophrenia have a variety cognitive deficits and nicotine has been shown to normalize some of these deficits. The purpose of this study is to investigate the effects of nicotine on cognition in schizophrenia.We will evaluate the effects of transdermal nicotine compared with placebo for attentional impairments in non-smokers with schizophrenia and controls.

Detailed description: 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

Eligibility criteria: 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

Primary outcomes:
measure: Effects of Nicotine Patch Compared With Placebo in Non- Smokers With Schizophrenia and Control Groups on Attention Measured by the Continuous Performance Test Identical Pairs Version
timeFrame: Visit 1 and visit 2 (separated by an interval of 7-10 days)
Secondary outcomes:
measure: Effects of Nicotine Patch Compared With Placebo in Non- Smokers With Schizophrenia and Control Groups on Visual Attention and Cognitive Interference as Measured by Three Card Stroop
timeFrame: Visit 1 and visit 2 (separated by an interval of 7-10 days)
measure: Effects of Nicotine Patch Compared With Placebo in Non- Smokers With Schizophrenia and Control Groups on Letter Number Sequencing
timeFrame: Visit 1 and visit 2 (separated by an interval of 7-10 days)
measure: Effects of Nicotine Patch Compared With Placebo in Non- Smokers With Schizophrenia and Control Groups on Lateralized Psychomotor Speed Measured by the Grooved Pegboard
timeFrame: Visit 1 and visit 2 (separated by an interval of 7-10 days)
Other outcomes:
Locations:
city: Boston
country: United States
facility: Massachusetts General Hospital Schizophrenia Research Program
state: Massachusetts
Study officials:
affiliation: Massachusetts General Hosptal
name: A E EVINS, MD MPH
role: PRINCIPAL_INVESTIGATOR
References:
citation: Barr RS, Culhane MA, Jubelt LE, Mufti RS, Dyer MA, Weiss AP, Deckersbach T, Kelly JF, Freudenreich O, Goff DC, Evins AE. The effects of transdermal nicotine on cognition in nonsmokers with schizophrenia and nonpsychiatric controls. Neuropsychopharmacology. 2008 Feb;33(3):480-90. doi: 10.1038/sj.npp.1301423. Epub 2007 Apr 18.
citation: Barr RS, Pizzagalli DA, Culhane MA, Goff DC, Evins AE. A single dose of nicotine enhances reward responsiveness in nonsmokers: implications for development of dependence. Biol Psychiatry. 2008 Jun 1;63(11):1061-5. doi: 10.1016/j.biopsych.2007.09.015. Epub 2007 Nov 5.
citation: Jubelt LE, Barr RS, Goff DC, Logvinenko T, Weiss AP, Evins AE. Effects of transdermal nicotine on episodic memory in non-smokers with and without schizophrenia. Psychopharmacology (Berl). 2008 Jul;199(1):89-98. doi: 10.1007/s00213-008-1133-8. Epub 2008 Jun 12.