37,38 The finding becomes more intriguing when it is recalled that ~80% of individuals with schizophrenia are daily smokers.37 Additionally, there is evidence that atypical antipsychotic medications can “normalize” abnormal P50 testing.39-42 These results indicate a critical

point when considering endophenotypes: environmental see more influences must be considered, not only as sources of variance (eg, experimental error, circadian variation, Inhibitors,research,lifescience,medical influence of personal habits such as nicotine and caffeine intake), but also as clues to mechanisms that may provide pathways from gene variants to endophenotypes, or from endophenotypes to key symptom clusters or subtypes of disorders. To summarize the P50 endophenotype literature, there is substantial evidence that the P50 abnormality in schizophrenia fulfills generally accepted criteria for an endophenotype. Variation Inhibitors,research,lifescience,medical in or near the α7-nicotinic

receptor subunit gene may explain some of the genetic variance in the P50 measurement, and additional research with this endophenotype can be expected Inhibitors,research,lifescience,medical to yield new insights into this subtype of schizophrenia. Stability and heritability of an endophenotype: cognitive deficits in schizpophrenia as an example A second endophenotype that has been studied extensively in schizophrenia is working memory. This term can be defined as the holding of information in the consciousness, in preparation for complex processing. Working memory can be assessed by multiple different mental tasks, such as N back, Wisconsin Card Sort, and reverse digit Inhibitors,research,lifescience,medical span. Deficits

in working memory have been described as an endophenotype for schizophrenia (for a review, see reference 43). The fraction of individuals with schizophrenia who are designated as having abnormal working memory varies with the tests employed, Inhibitors,research,lifescience,medical the clinical population studied, and the definition of abnormal (eg, 1.5 or 2 standard deviation units below the mean for controls). If consideration is given only to studies of large numbers of cases (-100) and controls, most reports describe 25% to 50% of persons with schizophrenia as falling in the variably defined “deficit range” for working memory44-49 Several lines of evidence suggest that the working memory deficits are partly heritable. Twin studies of unaffected and discordant (for schizophrenia) no monozygotic and dizygotic twin pairs indicate that genetic influences in the schizophrenia-related working memory deficits are prominent.50-53 In addition, multiple studies suggest that a small fraction of the variance in working memory scores is explained by a functional variant in the catechol- O methyltransferase (COMT) gene,54-56 although this finding is not observed consistently57 Working memory deficits are more common among the unaffected relatives (compared with controls) of schizophrenic individuals who have deficits themselves (for a review, see reference 8).