Schizophrenia
Conditions
Keywords
cognition, nicotine, schizophrenia
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
Interventions
DRUGtransdermal nicotine patch
14mg transdermal nicotine application
DRUGTransdermal Nicotine Patch
14mg transdermal nicotine application
Sponsors
Stanley Medical Research Institute
North Suffolk Mental Health Association
Massachusetts General Hospital
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 | Visit 1 and visit 2 (separated by an interval of 7-10 days) | The primary outcome measure was attention as measured by the Continuous Performance Test Identical Pairs (CPT-IP) Version 4.0 (Biobehavioral Technologies, New York, USA), developed for use in patients with schizophrenia and normal controls. In this task, participants were asked to respond when two identical pairs of numbers were presented in sequence by pressing a mouse key as quickly as possible using the dominant hand.The stimuli were presented with increasing cognitive load in successive blocks: two-,three- and four-digit target in the first, second and third block, respectively. Hit reaction time, a standard outcome variables on the CPTIP, is presented here. It was measured 3 hrs after application of the patch |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | Visit 1 and visit 2 (separated by an interval of 7-10 days) | This standard test of visual attention, processing speed and cognitive interference was performed, in which three cards (Stoelting Co., Wood Dale, IL, USA) were presented in order: the first card with color names, the second with colored patches of ink and the third with color namesprinted in incongruously colored ink. Participants were asked to read or name as many colors as possible in 45 s for each condition. The raw interference score was calculated by subtracting the predicted color-word score (calculated using raw word and color scores) from the observed raw color-word score. This value was converted to an interference T score by referring to a standardized table. A higher interference T score indicates better task performance with less interference. It was measured 3 hrs after application of the patch, after CPT |
| Effects of Nicotine Patch Compared With Placebo in Non- Smokers With Schizophrenia and Control Groups on Letter Number Sequencing | Visit 1 and visit 2 (separated by an interval of 7-10 days) | This measure of working memory and auditory attention was performed under two conditions. In the first condition, participants were read progressively longer lists of letters and numbers and instructed to repeat these exactly as given, without reordering. In the second condition, participants were read progressively longer lists of numbers and letters and instructed to re-order the list and give the numbers first in ascending order and then the letters in alphabetical order (WMS-III). The sum of the trial scores provided the item score and the sum of the item scores provided the total score.It was measured 3 hrs after application of the patch, after CPT and Stroop. The total score ranges from 0 to 21.Higher scores of Letter number sequencing means better working memory and auditory attention |
| Effects of Nicotine Patch Compared With Placebo in Non- Smokers With Schizophrenia and Control Groups on Lateralized Psychomotor Speed Measured by the Grooved Pegboard | Visit 1 and visit 2 (separated by an interval of 7-10 days) | The Grooved Pegboard (model 32025 Lafayette Instrument Company, Lafayette, IN, USA). In this test of lateralized psychomotor speed, participants had 45 s to place as many pegs as possible into grooves on a board using their dominant hand. The number of correctly placed pegs were recorded for each of the two trials.It was measured 3 hrs after application of the patch after CPT, Stroop and Letter number sequencing |
Countries
United States
Participant flow
Recruitment details
Non-smoking adults with a DSM IV diagnosis of schizophrenia or schizoaffective disorder, depressed type, were recruited from an urban community mental health clinic. Non-smoking adults without psychiatric illness were recruited using advertising in local press and internet sites. All study procedures took place between January 2005 and July 2006.
Pre-assignment details
Once enrolled, participants attended a baseline visit followed by 2 study days. At the first visit, subjects underwent a training session in the Cognitive Drug Research battery and subjects with schizophrenia completed baseline clinical scales including the Scale for Assessment of Negative Symptoms (SANS) and Positive and Negative Syndrome Scale
Participants by arm
| Arm | Count |
|---|---|
| Non Smokers With Schizophrenia | 28 |
| Controls | 32 |
| Total | 60 |
Baseline characteristics
| Characteristic | Non Smokers With Schizophrenia | Controls | Total |
|---|---|---|---|
| Age, Continuous | 47 years STANDARD_DEVIATION 8 | 40 years STANDARD_DEVIATION 11 | 43 years STANDARD_DEVIATION 9 |
| Sex: Female, Male Female | 12 Participants | 15 Participants | 27 Participants |
| Sex: Female, Male Male | 16 Participants | 17 Participants | 33 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 3 / 28 | 6 / 32 |
| serious Total, serious adverse events | 2 / 28 | 0 / 32 |
Outcome results
Primary
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
The primary outcome measure was attention as measured by the Continuous Performance Test Identical Pairs (CPT-IP) Version 4.0 (Biobehavioral Technologies, New York, USA), developed for use in patients with schizophrenia and normal controls. In this task, participants were asked to respond when two identical pairs of numbers were presented in sequence by pressing a mouse key as quickly as possible using the dominant hand.The stimuli were presented with increasing cognitive load in successive blocks: two-,three- and four-digit target in the first, second and third block, respectively. Hit reaction time, a standard outcome variables on the CPTIP, is presented here. It was measured 3 hrs after application of the patch
Time frame: Visit 1 and visit 2 (separated by an interval of 7-10 days)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Non Smokers With Schizophrenia + Nicotine Patch | 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 | 2.2 milliseconds | Standard Deviation 0.8 |
| Non Smokers With Schizophrenia + Placebo Nicotine Patch | 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 | 2.1 milliseconds | Standard Deviation 0.8 |
| Control + Nicotine Patch | 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 | 3.4 milliseconds | Standard Deviation 0.6 |
| Controls + Placebo Nicotine Patch | 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 | 3.2 milliseconds | Standard Deviation 0.6 |
Secondary
Effects of Nicotine Patch Compared With Placebo in Non- Smokers With Schizophrenia and Control Groups on Lateralized Psychomotor Speed Measured by the Grooved Pegboard
The Grooved Pegboard (model 32025 Lafayette Instrument Company, Lafayette, IN, USA). In this test of lateralized psychomotor speed, participants had 45 s to place as many pegs as possible into grooves on a board using their dominant hand. The number of correctly placed pegs were recorded for each of the two trials.It was measured 3 hrs after application of the patch after CPT, Stroop and Letter number sequencing
Time frame: Visit 1 and visit 2 (separated by an interval of 7-10 days)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Non Smokers With Schizophrenia + Nicotine Patch | Effects of Nicotine Patch Compared With Placebo in Non- Smokers With Schizophrenia and Control Groups on Lateralized Psychomotor Speed Measured by the Grooved Pegboard | 14.4 number of pegs into grooves | Standard Deviation 3.6 |
| Non Smokers With Schizophrenia + Placebo Nicotine Patch | Effects of Nicotine Patch Compared With Placebo in Non- Smokers With Schizophrenia and Control Groups on Lateralized Psychomotor Speed Measured by the Grooved Pegboard | 14.5 number of pegs into grooves | Standard Deviation 3.2 |
| Control + Nicotine Patch | Effects of Nicotine Patch Compared With Placebo in Non- Smokers With Schizophrenia and Control Groups on Lateralized Psychomotor Speed Measured by the Grooved Pegboard | 19.1 number of pegs into grooves | Standard Deviation 3.2 |
| Controls + Placebo Nicotine Patch | Effects of Nicotine Patch Compared With Placebo in Non- Smokers With Schizophrenia and Control Groups on Lateralized Psychomotor Speed Measured by the Grooved Pegboard | 18.6 number of pegs into grooves | Standard Deviation 2.7 |
Secondary
Effects of Nicotine Patch Compared With Placebo in Non- Smokers With Schizophrenia and Control Groups on Letter Number Sequencing
This measure of working memory and auditory attention was performed under two conditions. In the first condition, participants were read progressively longer lists of letters and numbers and instructed to repeat these exactly as given, without reordering. In the second condition, participants were read progressively longer lists of numbers and letters and instructed to re-order the list and give the numbers first in ascending order and then the letters in alphabetical order (WMS-III). The sum of the trial scores provided the item score and the sum of the item scores provided the total score.It was measured 3 hrs after application of the patch, after CPT and Stroop. The total score ranges from 0 to 21.Higher scores of Letter number sequencing means better working memory and auditory attention
Time frame: Visit 1 and visit 2 (separated by an interval of 7-10 days)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Non Smokers With Schizophrenia + Nicotine Patch | Effects of Nicotine Patch Compared With Placebo in Non- Smokers With Schizophrenia and Control Groups on Letter Number Sequencing | without reorder | 12.6 units on a scale | Standard Deviation 3.3 |
| Non Smokers With Schizophrenia + Nicotine Patch | Effects of Nicotine Patch Compared With Placebo in Non- Smokers With Schizophrenia and Control Groups on Letter Number Sequencing | with reorder | 8.8 units on a scale | Standard Deviation 3.1 |
| Non Smokers With Schizophrenia + Placebo Nicotine Patch | Effects of Nicotine Patch Compared With Placebo in Non- Smokers With Schizophrenia and Control Groups on Letter Number Sequencing | with reorder | 9.0 units on a scale | Standard Deviation 2.6 |
| Non Smokers With Schizophrenia + Placebo Nicotine Patch | Effects of Nicotine Patch Compared With Placebo in Non- Smokers With Schizophrenia and Control Groups on Letter Number Sequencing | without reorder | 12.5 units on a scale | Standard Deviation 3.4 |
| Control + Nicotine Patch | Effects of Nicotine Patch Compared With Placebo in Non- Smokers With Schizophrenia and Control Groups on Letter Number Sequencing | without reorder | 15.5 units on a scale | Standard Deviation 3.3 |
| Control + Nicotine Patch | Effects of Nicotine Patch Compared With Placebo in Non- Smokers With Schizophrenia and Control Groups on Letter Number Sequencing | with reorder | 12.2 units on a scale | Standard Deviation 3.4 |
| Controls + Placebo Nicotine Patch | Effects of Nicotine Patch Compared With Placebo in Non- Smokers With Schizophrenia and Control Groups on Letter Number Sequencing | without reorder | 15.9 units on a scale | Standard Deviation 3.4 |
| Controls + Placebo Nicotine Patch | Effects of Nicotine Patch Compared With Placebo in Non- Smokers With Schizophrenia and Control Groups on Letter Number Sequencing | with reorder | 12.6 units on a scale | Standard Deviation 3.1 |
Secondary
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
This standard test of visual attention, processing speed and cognitive interference was performed, in which three cards (Stoelting Co., Wood Dale, IL, USA) were presented in order: the first card with color names, the second with colored patches of ink and the third with color namesprinted in incongruously colored ink. Participants were asked to read or name as many colors as possible in 45 s for each condition. The raw interference score was calculated by subtracting the predicted color-word score (calculated using raw word and color scores) from the observed raw color-word score. This value was converted to an interference T score by referring to a standardized table. A higher interference T score indicates better task performance with less interference. It was measured 3 hrs after application of the patch, after CPT
Time frame: Visit 1 and visit 2 (separated by an interval of 7-10 days)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Non Smokers With Schizophrenia + Nicotine Patch | 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 | 50.4 score | Standard Deviation 5.8 |
| Non Smokers With Schizophrenia + Placebo Nicotine Patch | 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 | 49.0 score | Standard Deviation 4.6 |
| Control + Nicotine Patch | 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 | 56.8 score | Standard Deviation 10.3 |
| Controls + Placebo Nicotine Patch | 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 | 58.8 score | Standard Deviation 10 |