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

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

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.

Study Overview

• Status: Completed
• Conditions: Schizophrenia
• Intervention / Treatment: Drug: Merck L-830982; Drug: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 16
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburgh

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: TRIPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
PLACEBO_COMPARATOR: Sugar pill	Drug: Placebo; Medications were dispensed weekly in blister packs by the hospital pharmacy, using the same number of pills as those on active drug.
EXPERIMENTAL: Merck L-830982	Drug: Merck L-830982; 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.; Other Names: MK-0777

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University of Pittsburgh
• Collaborators: Merck Sharp & Dohme LLC
• Investigators: Principal Investigator: David A Lewis, MD, University of Pittsburgh

Publications and helpful links

General Publications

• Lewis DA, Hashimoto T, Volk DW. Cortical inhibitory neurons and schizophrenia. Nat Rev Neurosci. 2005 Apr;6(4):312-24. doi: 10.1038/nrn1648.
• Lewis DA, Volk DW, Hashimoto T. Selective alterations in prefrontal cortical GABA neurotransmission in schizophrenia: a novel target for the treatment of working memory dysfunction. Psychopharmacology (Berl). 2004 Jun;174(1):143-50. doi: 10.1007/s00213-003-1673-x. Epub 2003 Dec 9.
• Lewis DA, Cho RY, Carter CS, Eklund K, Forster S, Kelly MA, Montrose D. Subunit-selective modulation of GABA type A receptor neurotransmission and cognition in schizophrenia. Am J Psychiatry. 2008 Dec;165(12):1585-93. doi: 10.1176/appi.ajp.2008.08030395. Epub 2008 Oct 15. Erratum In: Am J Psychiatry. 2009 Jan;166(1):120.

Study record dates

Study Major Dates

• Study Start: August 1, 2005
• Primary Completion (ACTUAL): January 1, 2008
• Study Completion (ACTUAL): January 1, 2008

Study Registration Dates

• First Submitted: August 10, 2005
• First Submitted That Met QC Criteria: August 10, 2005
• First Posted (ESTIMATE): August 11, 2005

Study Record Updates

• Last Update Posted (ESTIMATE): October 17, 2011
• Last Update Submitted That Met QC Criteria: October 14, 2011
• Last Verified: October 1, 2011

More Information

Terms related to this study

• Keywords: schizophrenia
• Additional Relevant MeSH Terms: Mental Disorders; Schizophrenia Spectrum and Other Psychotic Disorders; Schizophrenia
• Other Study ID Numbers: 0502027