title: The FDA-NIMH-MATRICS guidelines for clinical trial design of cognitive-enhancing drugs: what do we know 5 years later?
abstract: The Food and Drug Administration (FDA)-National Institute of Mental Health (NIMH)-Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) clinical trial guidelines for cognitive-enhancing drugs in schizophrenia and the MATRICS Consensus Cognitive Battery (MCCB) were designed to facilitate novel compound development in the treatment of cognitive impairments. Several studies have recently utilized the FDA-NIMH-MATRICS guidelines and MCCB and allow an evaluation of the feasibility of guideline implementation and MCCB performance. In light of the study results, we would recommend the following inclusion criteria revisions-(1) clinical status and symptom inclusion criteria: maximum allowed score for hallucinations and delusions should be increased from moderate to moderately severe and the negative symptom criterion should be dropped in phase 2 studies; (2) antipsychotic medication inclusion criteria: first-generation antipsychotics should be allowed, but only in the context of no concomitant anticholinergic agents and minimal extrapyramidal symptoms, and antipsychotic polypharmacy should be allowed in the absence of pertinent pharmacokinetic or pharmacodynamic considerations; and (3) people who use illicit substances should not be allowed in phase 1B or 2A proof-of-concept studies but may be included in phase 2B and 3 studies in which proof of effectiveness and generalizability of results become more important goals. These revisions are recommended to enhance recruitment while maintaining sufficient methodological rigor to ensure the validity of study results. The MCCB has been shown to have excellent psychometric characteristics, including reliability for multisite clinical trials, clinical relevance for real-world functioning, and possible sensitivity to behavioral treatment, and should continue to serve as the standard outcome measure for cognitive enhancement studies in schizophrenia.
authors.affiliation: Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, 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: Daniel
authors.initials: D
authors.lastname: Umbricht
authors.forename: Michael F
authors.initials: MF
authors.lastname: Green
authors.forename: Thomas
authors.initials: T
authors.lastname: Laughren
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Marder
mesh_terms: D000328:Adult; D014150:Antipsychotic Agents / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D003071:Cognition / Q000187:drug effects*; D017408:Guidelines as Topic; D006801:Humans; D009315:National Institute of Mental Health (U.S.); D009483:Neuropsychological Tests; D018697:Nootropic Agents / Q000627:therapeutic use*; D012107:Research Design; D012559:Schizophrenia / Q000188:drug therapy*; D012565:Schizophrenic Psychology; D014481:United States; D014486:United States Food and Drug Administration
chemical_list: D014150:Antipsychotic Agents; D018697:Nootropic Agents
references.citation: Am J Psychiatry. 2009 Sep;166(9):1055-62
references.pmid: 19570929
references.citation: Biol Psychiatry. 2004 May 15;55(10):1013-22
references.pmid: 15121486
references.citation: Schizophr Bull. 2007 Nov;33(6):1364-72
references.pmid: 17341468
references.citation: Schizophr Bull. 2006 Apr;32(2):220-2
references.pmid: 16079389
references.citation: Psychiatry Res. 2007 May 30;151(1-2):55-66
references.pmid: 17379319
references.citation: Biol Psychiatry. 2002 Jun 15;51(12):972-8
references.pmid: 12062881
references.citation: Am J Psychiatry. 2005 Oct;162(10):1888-95
references.pmid: 16199835
references.citation: Neuropsychopharmacology. 2009 Jul;34(8):1885-903
references.pmid: 19339966
references.citation: Arch Gen Psychiatry. 2001 Feb;58(2):165-71
references.pmid: 11177118
references.citation: Schizophr Bull. 2007 Sep;33(5):1201-12
references.pmid: 17159230
references.citation: Biol Psychiatry. 2004 Sep 1;56(5):301-7
references.pmid: 15336511
references.citation: Am J Psychiatry. 2006 Mar;163(3):426-32
references.pmid: 16513863
references.citation: Schizophr Res. 2008 Nov;106(1):59-69
references.pmid: 17900866
references.citation: Pharmacoepidemiol Drug Saf. 2003 Jan-Feb;12(1):41-8
references.pmid: 12616846
references.citation: Psychiatr Serv. 2006 Aug;57(8):1094-101
references.pmid: 16870959
references.citation: Schizophr Bull. 2007 Sep;33(5):1093-9
references.pmid: 17673495
references.citation: Am J Psychiatry. 2005 Mar;162(3):495-506
references.pmid: 15741466
references.citation: Arch Gen Psychiatry. 2007 Jun;64(6):633-47
references.pmid: 17548746
references.citation: Schizophr Res. 2004 Dec 15;72(1):41-51
references.pmid: 15531406
references.citation: Am J Psychiatry. 2008 Feb;165(2):214-20
references.pmid: 18172018
references.citation: Am J Psychiatry. 2009 Jul;166(7):805-11
references.pmid: 19448187
references.citation: Arch Gen Psychiatry. 2007 Oct;64(10):1115-22
references.pmid: 17909123
references.citation: Schizophr Res. 2006 May;84(1):90-9
references.pmid: 16631354
references.citation: J Abnorm Psychol. 1994 May;103(2):371-8
references.pmid: 8040506
references.citation: Am J Psychiatry. 2007 Jul;164(7):1050-60
references.pmid: 17606657
references.citation: J Clin Psychiatry. 2004 Oct;65(10):1377-88
references.pmid: 15491242
references.citation: Lancet. 2008 Mar 29;371(9618):1085-97
references.pmid: 18374841
references.citation: Am J Psychiatry. 1996 Mar;153(3):321-30
references.pmid: 8610818
references.citation: Am J Psychiatry. 2004 Jun;161(6):985-95
references.pmid: 15169686
references.citation: Am J Psychiatry. 2009 Jun;166(6):675-82
references.pmid: 19369319
references.citation: Schizophr Bull. 2001;27(2):235-45
references.pmid: 11354591
references.citation: Am J Psychiatry. 2008 Feb;165(2):203-13
references.pmid: 18172019
references.citation: Schizophr Res. 2004 Dec 15;72(1):53-67
references.pmid: 15531407
references.citation: Am J Psychiatry. 2008 Jan;165(1):82-9
references.pmid: 17986678
references.citation: Am J Psychiatry. 2008 Aug;165(8):1040-7
references.pmid: 18381905
references.citation: Schizophr Bull. 2005 Jan;31(1):5-19
references.pmid: 15888422
references.citation: Am J Psychiatry. 2008 Feb;165(2):221-8
references.pmid: 18172017