Gamma-Amino Butyric Acid (GABA)-A Alpha2/3 Study

Study Overview
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Brief Summary
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The purpose of this research study is to determine whether a short-term administration of an investigational study drug may provide evidence of improvement in cognitive functioning in a group of stable male subjects with schizophrenia.

Detailed Description
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The goal of this study is to determine whether the short-term (4 week), double-blind administration of Merck L-830982 provides evidence of improvement in cognitive functioning in stable male subjects with schizophrenia. This initial, small sample size study (n=9 on L-830982 and n=6 on placebo) is restricted to males in order to reduce the variance that might be attributable to the well-documented sex differences in the clinical features of schizophrenia.

Official Title
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Treatment of Cognitive Disability in Schizophrenia With a GABA-A Alpha2/3 Receptor Agonist

Conditions
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Schizophrenia

Intervention / Treatment
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* Drug: Merck L-830982
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male participants Between the ages of 18 and 50 Meet diagnostic criteria for schizophrenia or schizoaffective disorder Are clinically stable for a minimum of 3 months on current dose of medication Are unemployed (i.e., work less than 20 hours per week at competitive employment) Exclusion Criteria: Psychoactive substance dependence within the past 6 months or substance abuse within the past month History of head trauma or other neurological disorder Medical illness or medications, such as benzodiazepine treatment or HIV medications, that may be affected by study participation (the study doctor will discuss this with potential subjects) Mental retardation Seizure disorder History of a heart attack, arrhythmia, or other heart disease

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Merck L-830982<br> | Drug: Merck L-830982<br>* The initial dose of L-830982 was 3.0 mg twice daily (b.i.d.) the dosage increased to 5.0 mg b.i.d. at the end of week 1 and 8.0 mg b.i.d. at the end of week 2, which was continued for the remaining 2 weeks of the trial. Medications were dispensed weekly in blister packs by the hospital pharmacy.<br>* Other names: MK-0777;|
| Placebo Comparator: Sugar pill<br> | Drug: Placebo<br>* Medications were dispensed weekly in blister packs by the hospital pharmacy, using the same number of pills as those on active drug.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| N-back Task - Reaction Time | The N-back task is a sequential-letter memory task for which working memory load is varied, as the respondent must indicate when the current stimulus matches the one from 'n' steps earlier in the sequence. The dependent measure for the N-back task was performance in the 2-back condition, which provides the best index of performance and dorsolateral prefrontal cortex disturbances in subjects with schizophrenia. | Week 4 | 
| N-back Task - Error Rate | The N-back task is a sequential-letter memory task for which working memory load is varied, as the respondent must indicate when the current stimulus matches the one from 'n' steps earlier in the sequence. The dependent measure for the N-back task was performance in the 2-back condition, which provides the best index of performance and dorsolateral prefrontal cortex disturbances in subjects with schizophrenia. | Week 4 | 
| AX Continuous Performance Test Task D-prime | For the AX Continuous Performance Test, subjects are required to maintain an attentional set across a delay interval in order to overcome a prepotent response tendency (target responses are required when an X is presented but only in the context of a preceding A; non-target conditions are AY, BX and BY). The dependent measure was d-prime at the long delay (calculated as AX hits minus BX false alarms, which is particularly sensitive to context processing impairments in individuals with schizophrenia. | Week 4 | 
| Preparing to Overcome Prepotency (POP) Task - Reaction Time | The POP task is a cued stimulus-response reversal paradigm that, similar to the AX Continuous Performance Test, requires increases in cognitive control through the maintenance and use of context information to overcome prepotent response tendencies. | Week 4 | 
| Preparing to Overcome Prepotency Task - Error Rate | The POP task is a cued stimulus-response reversal paradigm that, similar to the AX Continuous Performance Test, requires increases in cognitive control through the maintenance and use of context information to overcome prepotent response tendencies. | Week 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Brief Psychiatric Rating Scale Total Score | The Brief Psychiatric Rating Scale-anchored (BPRS; Overall and Gorham, 1962; Woerner, Mannuzza, Kane, 1988) is an 18-item scale that is among the most widely used measure of psychopathology. Scores range from 1-7, with higher scores reflecting greater pathology. A total score is derived from the sum of all 18 items (possible scores range from 18-126). It relies on clinical judgment in the assessment of key areas of psychopathology (depression, anxiety, psychosis). | Week 4 | 
| Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Total Score | Five index scores are computed from the RBANS (immediate memory, language, visuospatial, attention, delayed memory) that are combined to provide the Total Score. The Total Score is expressed as a standardized score normalized to a population mean of 100, with a standard deviation of 15 (possible scores 40-135). Higher scores reflect better performance. All subjects received the A form at baseline and the wk-4 visit and the B form at the wk-2 visit (the A/B forms are equivalent alternate forms, which allow for retesting patients without the confound of practice effects). | Week 4 | 
| Repeatable Battery for the Assessment of Neuropsychological Status - Delayed Memory Subindex | The Delayed Memory Index consists of verbal and nonverbal recall tasks (words, drawings) that the subject views early in the evaluation and without warning, is asked to recall  1/2 hr later. Scores are expressed as standardized scores normalized to a population mean of 100, with a standard deviation of 15 (possible scores between 40-135). Higher scores reflect better performance. Subjects received the A form at baseline and wk-4 visit and the B form at the wk-2 visit (A/B forms are equivalent alternate forms, which allow for retesting patients without the confound of practice effects). | Week 4 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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schizophrenia