Schizophrenia
Conditions
Keywords
Schizophrenia
Brief summary
The study hypothesis is that 3-2,4 dimethoxybenzylidene anabaseine (DMXB-A), an orally administered nicotinic cholinergic agonist, will improve attention and other neuropsychological dysfunctions in schizophrenia, leading to improved psychosocial outcome.
Detailed description
The objective of the trial is to determine if dosing 3-(2,4 dimethoxybenzylidene anabaseine) twice daily for 4 weeks will improve cognition and be safe. Secondary goals are to determine if these neurocognitive effects also have effects on neurobiological paradigms previously shown to be responsive to nicotinic receptor stimulation: suppression of P50 auditory evoked response, saccadic intrusions during smooth pursuit eye movements, and hemodynamic activity in the hippocampus during smooth pursuit eye movements as measured by functional magnetic resonance imaging. The purpose of these neurobiological measures is to assess whether the response to 3-(2,4 dimethoxybenzylidene anabaseine) is consistent with activation of nicotinic receptors. In addition, the investigators will assess clinical response using a battery of clinical assessment scales and assessments of daily living functions. The purpose of these assessments is to address the FDA requirement of a clinical effect beyond change in laboratory neuropsychological performance. This study and the subsequent two studies will also include assessments of the safety of 3-(2,4 dimethoxybenzylidene anabaseine) and related compounds. The purpose of the trial is to lay the groundwork for Phase III investigation. If this trial finds that 3-(2,4 dimethoxybenzylidene anabaseine) has effects at a safe dose, without tachyphylaxis, then the investigators intend to proceed to a Phase III trial, where the clinical importance of this effect can be measured. The trial will be a double blind trial with placebo control. The order of doses and placebo will be randomized. The Phase 1 study was completed in January, 2005, with 12 non-smoking schizophrenics subjects. The subjects were concurrently treated with neuroleptics throughout the study. They received 3 treatments, each for 1 day, in a double-blind crossover design. The treatments were 3-(2,4 dimethoxybenzylidene anabaseine) (150 mg + 75 mg 2 hours later), 3-(2,4 dimethoxybenzylidene anabaseine)(75 mg + 37.5 mg 2 hours later), and placebo. A significant effect on neurocognition, as measured by the Repeatable Battery for Assessment of Neuropsychological Status, and on sensory gating, as measured by P50 auditory evoked potentials was observed. Subjects reported no significant symptoms. One subject's white blood cell count decreased from just above normal limits on placebo to just below normal levels on 3-(2,4 dimethoxybenzylidene anabaseine)(150 + 75 mg 2 hours later). He did not receive further exposure to drug and his white blood cell count returned to normal at the next testing, 2 days later.
Interventions
DRUGPlacebo
Placebo by mouth twice a day for 4 weeks
DRUG3-(2,4 dimethoxybenzylidene anabaseine) 150 mg
3-(2,4 dimethoxybenzylidene) 150 mg by mouth twice a day for 4 weeks
DRUG3-(2,4 dimethoxybenzylidene anabaseine) 75 mg
3-(2,4 dimethoxybenzylidene) 75 mg by mouth twice a day for 4 weeks
Sponsors
VA Office of Research and Development
University of Colorado, Denver
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Schizophrenia * Currently treated with neuroleptic drugs
Exclusion criteria
* Treatment with clozapine; * Head injury or neurological condition; * Cardiovascular disease; * Substance abuse or dependence, including nicotine
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Neurocognitive Performance | 1 month | The measurement of neurocognitive performance on 6 domains, speed of processing, attention/vigilance, working memory, verbal learning, visual learning and reasoning/problem solving. Each domain is compared to a normative sample of schizophrenia subjects and the performance is determined and compared by a T-Test to the subjects baseline performance to determine the effect of drug or placebo. The scale is the National Institute of Mental Health Measurement and Treatment Research to Improve Cognition in Schizophrenia Neurocognitive Consensus Combined Battery, range 0-100. A higher score indicates better performance. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Scale for the Assessment of Negative Symptoms (SANS) | 1 month | The Scale for the Assessment of Negative Symptoms measures the measure negative symptoms in schizophrenia by measuring the domains of anhedonia, alogia, avolition and anhedonia in schizophrenia on a scale from 1 to 20 that sums the global scores of all 4 domains, each of which are rated on a scale of 1-5. Higher scores indicate greater severity of negative symptoms |
Countries
United States
Participant flow
Recruitment details
Thirty-four subjects were screened. Two were excluded because of abnormal laboratory values and one was excluded for a recent hospitalization. Thirty-one subjects were enrolled at two sites: The University of Colorado, Denver/Denver VA Medical Center (25 subjects) and The Maryland Psychiatric Research Center 6 subjects.
Pre-assignment details
Subjects were administered 1 week of placebo to assess their ability to comply with BID dosing prior to administration of drug or placebo. There was a 1 week washout period between arms.
Participants by arm
| Arm | Count |
|---|---|
| DMXB-A 75, Then DMXB- 150, Then Placebo Overall number of baseline participants 10
Age, continuous | 10 |
| Placebo, Then DMXB-A 75, Then DMXB-A 150 Overall number of baseline participants 10
Age , continuous | 10 |
| DMXB-A 150, Then Placebo, Then DMXB-A 75 Overall number of baseline participants 9
Age, continuous | 9 |
| Total | 29 |
Baseline characteristics
| Characteristic | DMXB-A 75, Then DMXB- 150, Then Placebo | Placebo, Then DMXB-A 75, Then DMXB-A 150 | DMXB-A 150, Then Placebo, Then DMXB-A 75 | Total |
|---|---|---|---|---|
| Age, Continuous | 42.1 years STANDARD_DEVIATION 10.3 | 40.5 years STANDARD_DEVIATION 9.8 | 43.2 years STANDARD_DEVIATION 10.4 | 41.6 years STANDARD_DEVIATION 10.1 |
| Region of Enrollment United States | 10 participants | 10 participants | 9 participants | 29 participants |
| Sex: Female, Male Female | 7 Participants | 7 Participants | 7 Participants | 21 Participants |
| Sex: Female, Male Male | 3 Participants | 3 Participants | 2 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 29 | 0 / 29 | 0 / 29 |
| serious Total, serious adverse events | 29 / 29 | 29 / 29 | 29 / 29 |
Outcome results
Primary
Neurocognitive Performance
The measurement of neurocognitive performance on 6 domains, speed of processing, attention/vigilance, working memory, verbal learning, visual learning and reasoning/problem solving. Each domain is compared to a normative sample of schizophrenia subjects and the performance is determined and compared by a T-Test to the subjects baseline performance to determine the effect of drug or placebo. The scale is the National Institute of Mental Health Measurement and Treatment Research to Improve Cognition in Schizophrenia Neurocognitive Consensus Combined Battery, range 0-100. A higher score indicates better performance.
Time frame: 1 month
Population: change from baseline in cognitive performance as measured by a t-test at 4 weeks after taking the drug or placebo
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Neurocognitive Performance | 4.5 t-score change from baseline | Standard Deviation 7.3 |
| 3-(2,4-dimethoxybenzylidene) Anabaseine 75 mg | Neurocognitive Performance | 6.1 t-score change from baseline | Standard Deviation 9.4 |
| 3-(2,4-dimethoxybenzylidene) Anabaseine 150 mg | Neurocognitive Performance | 7.6 t-score change from baseline | Standard Deviation 10.6 |
Secondary
Scale for the Assessment of Negative Symptoms (SANS)
The Scale for the Assessment of Negative Symptoms measures the measure negative symptoms in schizophrenia by measuring the domains of anhedonia, alogia, avolition and anhedonia in schizophrenia on a scale from 1 to 20 that sums the global scores of all 4 domains, each of which are rated on a scale of 1-5. Higher scores indicate greater severity of negative symptoms
Time frame: 1 month
Population: change in the total scale score from baseline measure with administration of either drug or placebo
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Scale for the Assessment of Negative Symptoms (SANS) | 6.1 units on a scale change from baseline | Standard Deviation 9.4 |
| 3-(2,4-dimethoxybenzylidene) Anabaseine 75 mg | Scale for the Assessment of Negative Symptoms (SANS) | 7.6 units on a scale change from baseline | Standard Deviation 10.6 |
| 3-(2,4-dimethoxybenzylidene) Anabaseine 150 mg | Scale for the Assessment of Negative Symptoms (SANS) | 4.6 units on a scale change from baseline | Standard Deviation 6.5 |