Beyond the facts in schizophrenia: closing the gaps in diagnosis, pathophysiology, and treatment.

BACKGROUND: Although schizophrenia has been considered a distinct disease entity for the past century, its precise definition and etio-pathophysiology remain obscure and its treatment remains unsatisfactory. In this review, we summarize our state of knowledge about the etiology, pathophysiology, clinical features, and treatment of schizophrenia. METHODOLOGICAL ISSUES: The inadequacy of the major conceptual models of schizophrenia is a major roadblock in providing a coherent explanation for the known facts of this illness, despite these limitations and its changing definitions, the construct of schizophrenia does convey useful information: (i) patients diagnosed as having schizophrenia do have a real disease--they experience both suffering and disability; (ii) a diagnosis of schizophrenia does suggest a distinctive clinical profile--a characteristic long-term course; an admixture of positive, negative, and cognitive symptoms; (iii) a diagnosis of schizophrenia has clear treatment and prognostic implications--likelihood of benefit from antipsychotic treatment and likelihood of incomplete recovery; and (iv) schizophrenia satisfies criteria for a valid diagnostic entity better than almost any other psychiatric diagnosis. DISCUSSION: On the other hand, the concept of schizophrenia has serious shortcomings. First, it is not a single disease entity--it has multiple etiological factors and pathophysiological mechanisms but common phenotypic features. Second, its clinical manifestations are so diverse that its extreme variability has been considered by some to be a core feature. Third, its boundaries remain ill defined and not clearly demarcated from other clinical entities.
CONCLUSIONS: A necessary next step is to deconstruct schizophrenia as an entity into component dimensions--endophenotypes linked to unique etiological and pathophysiological processes that may yield unique treatment targets. Innovative approaches are needed to elucidate the biological substrates of these entities because such clarity is vital for replicable research. We conclude by identifying the critical gaps in our knowledge, and unmet needs in our approaches to care, and outline steps that can move the field forward.