title: A randomized clinical trial of MK-0777 for the treatment of cognitive impairments in people with schizophrenia.
abstract: BACKGROUND
  In a previous pilot study, MK-0777--a γ-aminobutyric acid (GABA)(A) α2/α3 partial agonist--was reported to improve delayed memory and cognitive measures of prefrontal cortical function in people with schizophrenia. The current study was designed to further examine the efficacy and safety of MK-0777 for the treatment of cognitive impairments in schizophrenia.
  
  
  METHODS
  Sixty people with DSM-IV schizophrenia entered a 4-week, multi-center, double-blind, placebo-controlled, randomized clinical trial. Participants were randomized to: MK-0777 3 mg b.i.d. (n = 18); MK-0777 8 mg b.i.d. (n = 21); or placebo (n = 21). Participants were clinically stable. The Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery, AX-Continuous Performance Test, and N-Back were used to assess cognition. The University of California San Diego (UCSD) Performance Based Skills Assessment-2 and the Schizophrenia Cognition Rating Scale assessed functional capacity and served as functional outcome coprimary measures.
  
  
  RESULTS
  There were no significant group differences on the primary outcome measure, the MATRICS Consensus Cognitive Battery composite score. Secondary analyses suggested that participants randomized to placebo performed significantly better on visual memory and reasoning/problem-solving tests than participants assigned to either MK-0777 dose. There were no significant group differences on the AX-Continuous Performance Test or N-Back d prime scores or UCSD Performance-Based Skills Assessment-2 and Schizophrenia Cognition Rating Scale total scores. In general, MK-0777 was well-tolerated with minimal side effects.
  
  
  CONCLUSIONS
  The study results suggest that MK-0777 has little benefit for cognitive impairments in people with schizophrenia. The GABA(A) receptor remains a promising target, but a more potent partial agonist with greater intrinsic activity at the GABA(A) α2 site might be needed for cognitive enhancement in schizophrenia.
authors.affiliation: Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Maple & Locust Streets, Baltimore, MD 21228, USA. rwbuchanan@mprc.umaryland.edu
authors.forename: Robert W
authors.initials: RW
authors.lastname: Buchanan
authors.forename: Richard S E
authors.initials: RS
authors.lastname: Keefe
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Lieberman
authors.forename: Deanna M
authors.initials: DM
authors.lastname: Barch
authors.forename: John G
authors.initials: JG
authors.lastname: Csernansky
authors.forename: Donald C
authors.initials: DC
authors.lastname: Goff
authors.forename: James M
authors.initials: JM
authors.lastname: Gold
authors.forename: Michael F
authors.initials: MF
authors.lastname: Green
authors.forename: L Fredrik
authors.initials: LF
authors.lastname: Jarskog
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Javitt
authors.forename: David
authors.initials: D
authors.lastname: Kimhy
authors.forename: Michael S
authors.initials: MS
authors.lastname: Kraus
authors.forename: Joseph P
authors.initials: JP
authors.lastname: McEvoy
authors.forename: Raquelle I
authors.initials: RI
authors.lastname: Mesholam-Gately
authors.forename: Larry J
authors.initials: LJ
authors.lastname: Seidman
authors.forename: M Patricia
authors.initials: MP
authors.lastname: Ball
authors.forename: Robert P
authors.initials: RP
authors.lastname: McMahon
authors.forename: Robert S
authors.initials: RS
authors.lastname: Kern
authors.forename: James
authors.initials: J
authors.lastname: Robinson
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Marder
mesh_terms: D000293:Adolescent; D000328:Adult; D003071:Cognition / Q000187:drug effects; D003072:Cognition Disorders / Q000188:drug therapy* / Q000209:etiology*; D039721:Diagnostic and Statistical Manual of Mental Disorders; D004311:Double-Blind Method; D005260:Female; D018755:GABA Agonists / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009483:Neuropsychological Tests; D011569:Psychiatric Status Rating Scales; D011724:Pyridazines / Q000627:therapeutic use*; D011963:Receptors, GABA-A / Q000187:drug effects; D012559:Schizophrenia / Q000188:drug therapy*; D012565:Schizophrenic Psychology; D016896:Treatment Outcome; D014230:Triazoles / Q000627:therapeutic use*; D055815:Young Adult
chemical_list: C507018:7-(1,1-dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo(4,3-b)pyridazine; D018755:GABA Agonists; C484841:GABRA2 protein, human; D011724:Pyridazines; D011963:Receptors, GABA-A; D014230:Triazoles