101 Population-based cohort studies102,103 have found that compromised general cognitive ability in late adolescence is a strong predictor of subsequent schizophrenia risk. Family studies indicate that a proportion of the unaffected first-degree relatives of index cases of schizophrenia display similar patterns of deficit in an attenuated form.104-106 The balance of evidence suggests that cognitive dysfunction meets most of the criteria of an endophenotype in schizophrenia. This is underscored by the meta-analysis by Heinrichs and Zakzanis107 of 204 studies published between

1980 and 1994 (a total of 7420 schizophrenia patients and 5865 controls), Inhibitors,research,lifescience,medical in which effect sizes (Cohen’s d) and the U statistic (degree of non-overlap) were calculated for 22 neurocognitive test variables ranging from IQ, verbal

memory, and attention to executive function and language. Although no single test or cognitive construct was capable of separating perfectly schizophrenia patients from normal controls, 7 measures achieved effect sizes greater than 1.0 (6070% Inhibitors,research,lifescience,medical non-overlap between the cases and controls): verbal memory (1.41), bilateral motor skills (1.30), performance IQ Inhibitors,research,lifescience,medical (1.26), the continuous performance task (1.16), word fluency (1.15), the Stroop task (1.11), and WAIS-R IQ (1.10). Although a Survivin inhibitor subset of ~50% of patients had nearly normal performance, significant cognitive impairment was Inhibitors,research,lifescience,medical common in schizophrenia and exceeded the deficits found in some neurological disorders, justifying the view that “schizophrenia is a neurological disorder that manifests itself in behavior.107 There is, at least, a preliminary evidence that composite cognitive endophenotypes have the capacity to identify genetically distinct subtypes of schizophrenia.108 Inhibitors,research,lifescience,medical Conclusion: the

way forward More than a century since the delineation of dementia praecox by Kraepelin, the etiology, neuropathology, and pathophysiology of schizophrenia remain elusive. Despite the availability of criteria allowing reliable diagnostic identification, schizophrenia essentially remains a broad clinical syndrome defined by reported subjective experiences (symptoms), loss of function (behavioral impairments) and variable patterns of course. Research has identified a number of putative biological markers associated SPTLC1 with the disorder, including neurocognitive dysfunction, brain dysmorphology, and neurochemical abnormalities. Yet none of these variables has to date been definitively proven to possess the sensitivity and specificity expected of a diagnostic test. Genetic linkage and association studies have targeted multiple candidate loci and genes, but failed to demonstrate that any specific gene variant, or a combination of genes, is either necessary or sufficient to cause schizophrenia. Thus, the existence of a specific brain disease underlying schizophrenia remains a hypothesis.