Schizophrenia Endophenotypes as Treatment Targets

Abstract

The concept of the ``endophenotype{''} will be reviewed and its potential to elucidate genetic variations that are causally related to schizophrenia and gene-environment interactions that may be obscured with dependence on the categorical diagnosis of this disorder or reliance on symptoms and symptom clusters to detect these associations. The identification of endophenotypes that reflect genetic variations may also lead to refinement of diagnosis, especially subtyping of the disorder. Conceivable, a spectrum of schizophrenias may exist reflecting a cluster of critical endophenotypes that must be present in all individuals diagnosed with the disorder and/or discrete, nonover-lapping endophenotypes that are found in genetically-distinct groups of individuals; nonetheless, all patients that are diagnosed with the disorder using operationally-defined diagnostic criteria, such as DSM-IV-TR, share common phenotypic characteristics even though they may have different endophenotypic profiles. Moreover, because endophenotypes may reflect pathophysiological processes that contribute to the emergence of the clinical syndrome, they may serve as ``targets{''} for pharmacotherapeutic interventions that treat a fundamental pathophysiological disturbance, as opposed to ``voices.{''} Also, because endophenotypes may be detected in unaffected relatives and patients with subsyndromal disorder or spectrum disorder, these targeted interventions may prove beneficial to the functionality of these persons as well (including prevention of emergence of the clinical syndrome); presumably, subtle deficits in socialization and cognition in these seemingly unaffected or ``less-affected{''} persons may be related to the genetic variations that will be elucidated by the endophenotypic approach. Finally, a heuristic example will be given of an evolving medication strategy that addresses a presumptive endophenotype of schizophrenia that is associated with a precise genetic locus on chromosome 15, whose region contains the promoter and gene for the alpha(7) subunit of the nicotinic acetylcholine receptor. Because of the importance of the construct of the endophenotype to the elucidation of genetic variations and neurobiological mechanisms relevant to the clinical syndrome of schizophrenia, their segregation in seemingly unaffected family members and patients with schizophrenia spectrum disorders (e.g., schizotypy), utility in clarifying gene-environment interactions that can precipitate overt disorder, and potential role as targets for rationale pharmacotherapeutic strategies, the NIMH has funded a multi-site collaboration, i.e., the Consortium on the Genetics of Schizophrenia (COGS), whose goal is to examine ``the genetic architecture of quantitative endophenotypes in families with schizophrenia.{''}(1-3) Hopefully, the COGS will validate several ``candidate{''} neurocognitive and neurophysiological endophenotypes, and clarify their potential to refine our diagnosis of the disorder and its subtypes, identify persons at-risk before overt expression of the disorder, clarify environmental and other ``second-hit{''} risk factors that increase liability of expression of overt illness, and stimulate development of more effective pharmacotherapies.