title: Effects of acute memantine administration on MATRICS Consensus Cognitive Battery performance in psychosis: Testing an experimental medicine strategy.
abstract: Pro-cognitive agents for chronic psychotic disorders (CPDs) might be detected via experimental medicine models, in which neural targets engaged by the drug predict sensitivity to the drug's pro-cognitive effects.
  
  
  
  This study aims to use an experimental medicine model to test the hypothesis that "target engagement" predicts pro-cognitive effects of the NMDA antagonist, memantine (MEM), in CPDs.
  
  
  
  MATRICS Consensus Cognitive Battery (MCCB) performance was assessed in CPD (n = 41) and healthy subjects (HS; n = 41) in a double-blind, randomized cross-over design of acute (single dose) MEM (placebo vs. 10 or 20 mg p.o.). Measures of prepulse inhibition (PPI) and mismatch negativity previously reported from this cohort substantiated target engagement. Biomarkers predicting MEM neurocognitive sensitivity were assessed.
  
  
  
  Testing confirmed MCCB deficits associated with CPD diagnosis, age, and anticholinergic exposure. MEM (20 mg p.o.) reduced MCCB performance in HS. To control for significant test order effects, an "order-corrected MEM effect" (OCME) was calculated. In CPD subjects, greater age, positive MEM effects on PPI, and SNP rs1337697 (within the ionotropic NMDA receptor gene, GRIN3A) predicted greater positive OCME with 20 mg MEM.
  
  
  
  An experimental medicine model to assess acute pro-cognitive drug effects in CPD subjects is feasible but not without challenges. A single MEM 20 mg dose had a negative impact on neurocognition among HS. In CPD patients, age, MEM effects on PPI, and rs1337697 predicted sensitivity to the neurocognitive effects of MEM. Any potential clinical utility of these predictive markers for pro-cognitive effects of MEM in subgroups of CPD patients cannot be inferred without a validating clinical trial.
authors.affiliation: Department of Psychiatry, UC San Diego School of Medicine, 9500 Gilman Dr., MC 0804, La Jolla, CA, 92093-0804, USA.
authors.forename: Savita G
authors.initials: SG
authors.lastname: Bhakta
authors.affiliation: Department of Psychiatry, UC San Diego School of Medicine, 9500 Gilman Dr., MC 0804, La Jolla, CA, 92093-0804, USA.
authors.forename: Hsun-Hua
authors.initials: HH
authors.lastname: Chou
authors.affiliation: Department of Psychiatry, UC San Diego School of Medicine, 9500 Gilman Dr., MC 0804, La Jolla, CA, 92093-0804, USA.
authors.forename: Brinda
authors.initials: B
authors.lastname: Rana
authors.affiliation: Department of Psychiatry, UC San Diego School of Medicine, 9500 Gilman Dr., MC 0804, La Jolla, CA, 92093-0804, USA.
authors.forename: Jo A
authors.initials: JA
authors.lastname: Talledo
authors.affiliation: Department of Psychiatry, UC San Diego School of Medicine, 9500 Gilman Dr., MC 0804, La Jolla, CA, 92093-0804, USA.
authors.forename: Bryan
authors.initials: B
authors.lastname: Balvaneda
authors.affiliation: Department of Psychiatry, UC San Diego School of Medicine, 9500 Gilman Dr., MC 0804, La Jolla, CA, 92093-0804, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Gaddis
authors.affiliation: Department of Psychiatry, UC San Diego School of Medicine, 9500 Gilman Dr., MC 0804, La Jolla, CA, 92093-0804, USA.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Light
authors.affiliation: Department of Psychiatry, UC San Diego School of Medicine, 9500 Gilman Dr., MC 0804, La Jolla, CA, 92093-0804, USA. nswerdlow@ucsd.edu.
authors.forename: Neal R
authors.initials: NR
authors.lastname: Swerdlow
mesh_terms: D000328:Adult; D035843:Biomedical Research / Q000379:methods*; D003071:Cognition / Q000187:drug effects* / Q000502:physiology; D032921:Consensus; D018592:Cross-Over Studies; D004311:Double-Blind Method; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage*; D005260:Female; D006801:Humans; D008297:Male; D008559:Memantine / Q000008:administration & dosage*; D008875:Middle Aged; D009483:Neuropsychological Tests; D011618:Psychotic Disorders / Q000175:diagnosis / Q000188:drug therapy* / Q000523:psychology
chemical_list: D018691:Excitatory Amino Acid Antagonists; D008559:Memantine
keywords: Biomarker; Experimental medicine; MATRICS; Memantine; Neurocognition; Prepulse inhibition; Schizophrenia