Schizoaffective Disorder, Schizophrenia, Schizophreniform Disorder
Conditions
Keywords
Varenicline, Neurobiology, clinical trial, cognitive deficits, Schizophreniform Disorder
Brief summary
The principal aim of the project is to conduct an off-label adjunctive clinical trial evaluating varenicline as a treatment for core neurobiological and clinical deficits in schizophrenia, in addition to evaluating for smoking cessation in schizophrenia patients.
Detailed description
This is a double-blind, placebo controlled clinical trial in schizophrenia patients. Outcome measures include biomarkers and clinical symptoms and functions, and smoking cessation. Neurobiological and cognitive markers will be measured for short term (2 weeks) and longer-term (8 weeks). Current schizophrenia treatments are mostly ineffective against primary negative symptoms and the cognitive and information processing deficits associated with the disorder. Previous research has identified several neurophysiological deficits in schizophrenia that are enduring, frequently occurring before psychosis, and mark the disease liability. These schizophrenia endophenotypes provide important targets for novel treatment development as they represent the core deficits of the disorder. We hypothesize that sustained nicotinic and dopaminergic modulation by varenicline may ameliorate the core neurobiological deficits seen in schizophrenia patients, which would lead to subsequent clinical improvement. Neurobiological and neurocognitive markers and clinical and functional measures will be obtained to determine 1) short-term effect of varenicline on biomarkers; and 2) longer-term improvement in clinical symptoms, smoking cessation, and functions; and how biomarker changes predict these improvements.
Interventions
DRUGVarenicline
Varenicline 0.5mg po qd x 7 days then titrated to Varenicline 0.5mg po bid x 7 weeks
DRUGPlacebo
Placebo 0.5mg po qd x 7 days then titrated to Placebo 0.5mg po bid x 7 weeks
Sponsors
Stanley Medical Research Institute
University of Maryland, Baltimore
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
No
Inclusion criteria
* Age 18-60 * DSM-IV Diagnosis of schizophrenia, schizoaffective disorder, or schizophreniform disorder * Clinically stable with no change in antipsychotic medications and increase of daily dose for 4 weeks prior to enrollment * Sufficient understanding of the study and risks (ESC score 10 or above)
Exclusion criteria
* Major medical illness history including, but not limited to, history of heart attack, stroke, TIA (transient ischemic attack) * History of organic brain disorders that may affect neurophysiological measurements, including seizure disorder, brain tumor, head injury with evidence of significant cognitive deterioration * DSM-IV diagnosis of substance dependence within 6 months except nicotine and marijuana * On nicotine replacement therapy (nicotine patch, gum, or nasal spray) * Uncontrolled blood pressure (persistent systolic above 155 or diastolic above 95) * EKG of second or third degree atrioventricular (AV) block * Renal insufficiency with estimated creatinine clearance \<40 ml/min * Women who have positive urine pregnancy tests * Women who are pregnant, plan to become pregnant, or in breastfeeding
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Hamilton Depression Rating Scale (Ham-D) | Week 8 | Ham-D Total Score (range 0 to 54, higher score is worse). Definition is fully described in a peer-review journal reported at Arch Gen Psychiatry 2011 Dec;68(12):1195-206. |
| Memory Saccadic Positional Error, Degrees | Week 8 | A saccade is a quick eye movement. Spatial working memory was assessed by memory saccade. Participants were asked to focus on a target while a peripheral cue was flashed. Participants were signaled to look in the direction of the peripheral cue when the central target was removed, and the positional error was calculated as the distance between the saccadic and peripheral target positions. Definition is fully described in a peer-review journal reported at Arch Gen Psychiatry 2011 Dec;68(12):1195-206. |
| Predictive Pursuit Gain | Week 8 | Pursuit gain is the averaged artifact-free eye velocity divided by target velocity. Participants are asked to track a target with their eyes. Participants may use a predictive mechanism to perform the tracking. The pursuit gain using the predictive mechanism is calculated. Further definition is fully described in a peer-review journal reported at Arch Gen Psychiatry 2011 Dec;68(12):1195-206. |
| Maintenance Pursuit Gain | Week 8 | Pursuit gain is the averaged artifact-free eye velocity divided by target velocity. Eye velocity during the regular eye-tracking period (without foveal stabilization) divided by target velocity was used to calculate the maintenance pursuit gain. Further definition is fully described in a peer-review journal reported at Arch Gen Psychiatry 2011 Dec;68(12):1195-206. |
| Digit Symbol Test | Week 0, Week 2 and Week 8 | Digit symbol test score (0 to no definite upper range, higher score is better). Definition is fully described in a peer-review journal reported at Arch Gen Psychiatry 2011 Dec;68(12):1195-206. |
| Conner's Continuous Performance Test (CPT) Detectability Score | Week 0, Week 2 and Week 8 | Conner's CPT Detectability Score (no set normal range, higher is generally better). Definition is fully described in a peer-review journal reported at Arch Gen Psychiatry 2011 Dec;68(12):1195-206. |
| Antisaccade Error Rates | Week 0, Week 2 and Week 8 | In antisaccade, participants were asked to focus on a central target. When a peripheral cue was presented, participants were asked to look in an equidistant and opposite direction of the peripheral cue. The error rate is calculated as the number of trials in which the participant looked toward the cue, rather than in the opposite direction, divided by the total number of trials. Further definition is fully described in a peer-review journal reported at Arch Gen Psychiatry 2011 Dec;68(12):1195-206. |
| P50 | Week 0, Week 2 and Week 8 | P50 response is a measure of the amplitude of the brain wave in response to a sound, where the positive going amplitude of the brain wave occurring at about 50 milliseconds after the sound. Further definition is fully described in a peer-review journal reported at Arch Gen Psychiatry 2011 Dec;68(12):1195-206. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Varenicline | 35 |
| Placebo | 34 |
| Total | 69 |
Baseline characteristics
| Characteristic | Varenicline | Placebo | Total |
|---|---|---|---|
| Age, Continuous Non-Smoker | 45.7 years STANDARD_DEVIATION 2.6 | 42.1 years STANDARD_DEVIATION 3.2 | 43.9 years STANDARD_DEVIATION 2.8 |
| Age, Continuous Smoker | 43.0 years STANDARD_DEVIATION 2.5 | 41.5 years STANDARD_DEVIATION 2.5 | 42.2 years STANDARD_DEVIATION 2.5 |
| BPRS Total Non-Smoker | 31.2 units on a scale STANDARD_DEVIATION 2 | 34.0 units on a scale STANDARD_DEVIATION 2.5 | 32.6 units on a scale STANDARD_DEVIATION 2.2 |
| BPRS Total Smoker | 36.2 units on a scale STANDARD_DEVIATION 1.9 | 35.0 units on a scale STANDARD_DEVIATION 2 | 35.6 units on a scale STANDARD_DEVIATION 1.9 |
| Ham-D Total Score Nonsmoker | 5.2 units on a scale STANDARD_DEVIATION 0.7 | 6.6 units on a scale STANDARD_DEVIATION 1 | 5.8 units on a scale STANDARD_DEVIATION 0.8 |
| Ham-D Total Score Smoker | 5.0 units on a scale STANDARD_DEVIATION 0.9 | 5.76 units on a scale STANDARD_DEVIATION 1.15 | 5.38 units on a scale STANDARD_DEVIATION 1 |
| Region of Enrollment United States | 35 participants | 34 participants | 69 participants |
| Sex: Female, Male Female | 12 Participants | 10 Participants | 22 Participants |
| Sex: Female, Male Male | 23 Participants | 24 Participants | 47 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 35 | 0 / 34 |
| serious Total, serious adverse events | 0 / 35 | 0 / 34 |
Outcome results
Primary
Antisaccade Error Rates
In antisaccade, participants were asked to focus on a central target. When a peripheral cue was presented, participants were asked to look in an equidistant and opposite direction of the peripheral cue. The error rate is calculated as the number of trials in which the participant looked toward the cue, rather than in the opposite direction, divided by the total number of trials. Further definition is fully described in a peer-review journal reported at Arch Gen Psychiatry 2011 Dec;68(12):1195-206.
Time frame: Week 0, Week 2 and Week 8
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Varenicline | Antisaccade Error Rates | Week 0 | 0.61 percentage errors | Standard Deviation 0.27 |
| Varenicline | Antisaccade Error Rates | Week 2 | 0.49 percentage errors | Standard Deviation 0.27 |
| Varenicline | Antisaccade Error Rates | Week 8 | 0.45 percentage errors | Standard Deviation 0.26 |
| Placebo | Antisaccade Error Rates | Week 0 | 0.54 percentage errors | Standard Deviation 0.27 |
| Placebo | Antisaccade Error Rates | Week 2 | 0.54 percentage errors | Standard Deviation 0.26 |
| Placebo | Antisaccade Error Rates | Week 8 | 0.53 percentage errors | Standard Deviation 0.28 |
Comparison: Mixed model ANCOVA in which baseline Antisaccade Errors served as the covariate and Smoking status and measurement occasions were between and within-groups factors, respectively.p-value: <0.05ANCOVA
Primary
Conner's Continuous Performance Test (CPT) Detectability Score
Conner's CPT Detectability Score (no set normal range, higher is generally better). Definition is fully described in a peer-review journal reported at Arch Gen Psychiatry 2011 Dec;68(12):1195-206.
Time frame: Week 0, Week 2 and Week 8
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Varenicline | Conner's Continuous Performance Test (CPT) Detectability Score | Week 0 | 0.87 units on a scale | Standard Deviation 0.38 |
| Varenicline | Conner's Continuous Performance Test (CPT) Detectability Score | Week 2 | 0.89 units on a scale | Standard Deviation 0.42 |
| Varenicline | Conner's Continuous Performance Test (CPT) Detectability Score | Week 8 | 0.95 units on a scale | Standard Deviation 0.48 |
| Placebo | Conner's Continuous Performance Test (CPT) Detectability Score | Week 0 | 0.87 units on a scale | Standard Deviation 0.5 |
| Placebo | Conner's Continuous Performance Test (CPT) Detectability Score | Week 2 | 0.97 units on a scale | Standard Deviation 0.54 |
| Placebo | Conner's Continuous Performance Test (CPT) Detectability Score | Week 8 | 0.97 units on a scale | Standard Deviation 0.53 |
Comparison: Mixed model ANCOVA in which baseline CPT Detectability served as the covariate and Smoking status and measurement occasions were between and within-groups factors, respectively.p-value: >0.05ANCOVA
Primary
Digit Symbol Test
Digit symbol test score (0 to no definite upper range, higher score is better). Definition is fully described in a peer-review journal reported at Arch Gen Psychiatry 2011 Dec;68(12):1195-206.
Time frame: Week 0, Week 2 and Week 8
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Varenicline | Digit Symbol Test | Week 0 | 53.9 units on a scale | Standard Deviation 19.3 |
| Varenicline | Digit Symbol Test | Week 2 | 55.9 units on a scale | Standard Deviation 19 |
| Varenicline | Digit Symbol Test | Week 8 | 54.2 units on a scale | Standard Deviation 20.3 |
| Placebo | Digit Symbol Test | Week 0 | 53.2 units on a scale | Standard Deviation 19.1 |
| Placebo | Digit Symbol Test | Week 2 | 53.8 units on a scale | Standard Deviation 20.6 |
| Placebo | Digit Symbol Test | Week 8 | 54.3 units on a scale | Standard Deviation 21.7 |
Comparison: Mixed model ANCOVA in which baseline served as the covariate and Smoking status and measurement occasions were between and within-groups factors, respectively.p-value: <0.05ANCOVA
Primary
Hamilton Depression Rating Scale (Ham-D)
Ham-D Total Score (range 0 to 54, higher score is worse). Definition is fully described in a peer-review journal reported at Arch Gen Psychiatry 2011 Dec;68(12):1195-206.
Time frame: Week 8
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Varenicline | Hamilton Depression Rating Scale (Ham-D) | Smoker | 22.9 units on a scale | Standard Error 3.2 |
| Varenicline | Hamilton Depression Rating Scale (Ham-D) | Nonsmoker | 19.4 units on a scale | Standard Error 3.2 |
| Placebo | Hamilton Depression Rating Scale (Ham-D) | Smoker | 20.6 units on a scale | Standard Error 3.4 |
| Placebo | Hamilton Depression Rating Scale (Ham-D) | Nonsmoker | 18.6 units on a scale | Standard Error 2.2 |
Primary
Maintenance Pursuit Gain
Pursuit gain is the averaged artifact-free eye velocity divided by target velocity. Eye velocity during the regular eye-tracking period (without foveal stabilization) divided by target velocity was used to calculate the maintenance pursuit gain. Further definition is fully described in a peer-review journal reported at Arch Gen Psychiatry 2011 Dec;68(12):1195-206.
Time frame: Week 8
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Varenicline | Maintenance Pursuit Gain | Smoker | 0.8 velocity ratio | Standard Error 0.1 |
| Varenicline | Maintenance Pursuit Gain | Nonsmoker | 0.8 velocity ratio | Standard Error 0.1 |
| Placebo | Maintenance Pursuit Gain | Smoker | 0.8 velocity ratio | Standard Error 0.04 |
| Placebo | Maintenance Pursuit Gain | Nonsmoker | 0.8 velocity ratio | Standard Error 0.1 |
Primary
Memory Saccadic Positional Error, Degrees
A saccade is a quick eye movement. Spatial working memory was assessed by memory saccade. Participants were asked to focus on a target while a peripheral cue was flashed. Participants were signaled to look in the direction of the peripheral cue when the central target was removed, and the positional error was calculated as the distance between the saccadic and peripheral target positions. Definition is fully described in a peer-review journal reported at Arch Gen Psychiatry 2011 Dec;68(12):1195-206.
Time frame: Week 8
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Varenicline | Memory Saccadic Positional Error, Degrees | Smoker | 1.6 degrees | Standard Error 0.2 |
| Varenicline | Memory Saccadic Positional Error, Degrees | Nonsmoker | 1.7 degrees | Standard Error 0.1 |
| Placebo | Memory Saccadic Positional Error, Degrees | Smoker | 1.7 degrees | Standard Error 0.2 |
| Placebo | Memory Saccadic Positional Error, Degrees | Nonsmoker | 1.8 degrees | Standard Error 0.2 |
Primary
P50
P50 response is a measure of the amplitude of the brain wave in response to a sound, where the positive going amplitude of the brain wave occurring at about 50 milliseconds after the sound. Further definition is fully described in a peer-review journal reported at Arch Gen Psychiatry 2011 Dec;68(12):1195-206.
Time frame: Week 0, Week 2 and Week 8
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Varenicline | P50 | Week 0 | 3.2 microvolts | Standard Error 0.73 |
| Varenicline | P50 | Week 2 | 3.2 microvolts | Standard Error 0.75 |
| Varenicline | P50 | Week 8 | 3.2 microvolts | Standard Error 0.6 |
| Placebo | P50 | Week 0 | 3.1 microvolts | Standard Error 0.71 |
| Placebo | P50 | Week 2 | 3.0 microvolts | Standard Error 0.72 |
| Placebo | P50 | Week 8 | 2.5 microvolts | Standard Error 0.77 |
Primary
Predictive Pursuit Gain
Pursuit gain is the averaged artifact-free eye velocity divided by target velocity. Participants are asked to track a target with their eyes. Participants may use a predictive mechanism to perform the tracking. The pursuit gain using the predictive mechanism is calculated. Further definition is fully described in a peer-review journal reported at Arch Gen Psychiatry 2011 Dec;68(12):1195-206.
Time frame: Week 8
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Varenicline | Predictive Pursuit Gain | Smoker | 0.31 velocity ratio | Standard Error 0.03 |
| Varenicline | Predictive Pursuit Gain | Nonsmoker | 0.24 velocity ratio | Standard Error 0.04 |
| Placebo | Predictive Pursuit Gain | Smoker | 0.34 velocity ratio | Standard Error 0.04 |
| Placebo | Predictive Pursuit Gain | Nonsmoker | 0.31 velocity ratio | Standard Error 0.04 |