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

• N-back Task - Reaction Time [ Time Frame: Week 4 ] [ Designated as safety issue: No ]
  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.
• N-back Task - Error Rate [ Time Frame: Week 4 ] [ Designated as safety issue: No ]
  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.
• AX Continuous Performance Test Task D-prime [ Time Frame: Week 4 ] [ Designated as safety issue: No ]
  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.
• Preparing to Overcome Prepotency (POP) Task - Reaction Time [ Time Frame: Week 4 ] [ Designated as safety issue: No ]
  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.
• Preparing to Overcome Prepotency Task - Error Rate [ Time Frame: Week 4 ] [ Designated as safety issue: No ]
  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.

• Brief Psychiatric Rating Scale Total Score [ Time Frame: Week 4 ] [ Designated as safety issue: No ]
  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).
• Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Total Score [ Time Frame: Week 4 ] [ Designated as safety issue: No ]
  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).
• Repeatable Battery for the Assessment of Neuropsychological Status - Delayed Memory Subindex [ Time Frame: Week 4 ] [ Designated as safety issue: No ]
  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).

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.

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.

• 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 Name: MK-0777
• 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
  Intervention: Drug: Merck L-830982
• Placebo Comparator: Sugar pill
  Intervention: Drug: Placebo

• 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. Epub 2008 Oct 15.
• Lewis DA, Hashimoto T, Volk DW. Cortical inhibitory neurons and schizophrenia. Nat Rev Neurosci. 2005 Apr;6(4):312-24. Review.
• 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. Epub 2003 Dec 9. Review.

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