Vol 8, No 1 Diagnosis and Management of Schizophrenic Disorders
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or the past half-century or so, the US Food and Drug Administration (FDA) has licensed drugs for use in schizophrenia only if they reduced the positive symp- toms of psychosis. This limitation was identified as a bottleneck preventing the identification and develop- ment of novel treatments for the problems experienced by schizophrenia patients.1,2 Implicitly, the FDA oper- ated from the assumption that one must treat the entire disorder with one compound, rather than treat specific clinical  problems  with  specific  compounds. It  has become  widely  accepted  that  a  cluster  of  cognitive deficits—which  have  been  long  recognized  as  being important aspects of schizophrenia—are not treated adequately, if  at  all, by  existing  antipsychotic  treat- ments.2,3 Furthermore, evidence has accumulated that these cognitive deficits are largely responsible for the disappointingly poor functional outcome demonstrated 9 B a s i c  r e s e a r c h F Copyright © 2006 LLS SAS.  All rights reserved www.dialogues-cns.org Are cross-species measures of sensorimotor gating useful for the discovery of procognitive cotreatments for schizophrenia? Mark A. Geyer, PhD Keywords: schizophrenia; prepulse inhibition; sensorimotor gating;
cognitive deficit; antipsychotic; animal model Author  affiliations: Department  of  Psychiatry,  University  
of California,  San Diego, La Jolla, Calif, USA Address for correspondence: Mark A. Geyer, PhD, University of
California San Diego, 9500 Gilman Drive 0804, La Jolla, CA 92093-0804,
USA (e-mail: mgeyer@ucsd.edu) Prepulse inhibition of startle (PPI), a measure of sensorimotor gating used to identify antipsychotics, is reduced in schiz- ophrenia patients and in rodents treated with dopamine agonists or glutamate antagonists. The National Institute of Mental Health (NIMH)–funded Measurement And Treatment Research to Improve Cognition in Schizophrenia (MATRICS) program has initiated a new era in the development of procognitive cotreatments in schizophrenia, independently of treating positive symptoms. Although PPI is not a cognitive process per se, such abnormalities in attention may be pre- dictive of or lead to cognitive deficits. Since first-generation antipsychotics block PPI deficits induced by dopamine ago- nists, this model cannot identify cognitive enhancers for use as cotreatments with antipsychotics. PPI deficits caused by glutamate antagonists, like the exacerbation of symptoms they produce in patients, are insensitive to dopamine antag- onists, but reduced by clozapine. Similarly, both PPI and cognitive deficits in schizophrenia patients are insensitive to first- generation antipsychotics, but attenuated by clozapine. Hence, treatment-induced reversals of glutamate antagonist effects on PPI may provide animal and human models to identify treatments of cognitive deficits in patients already treated with existing antipsychotics.   © 2006, LLS SAS Dialogues Clin Neurosci. 2006;8:9-16.