Schizophrenia, "Just the Facts" 6. Moving ahead with the schizophrenia concept: from the elephant to the mouse.

The current construct of schizophrenia as a unitary disease is far from satisfactory, and is in need of reconceptualization. The first five papers in our "facts" series reviewed what is known about schizophrenia to date, and a limited number of key facts appear to stand out. Schizophrenia is characterized by persistent cognitive deficits, positive and negative symptoms typically beginning in youth, substantive heritability, and brain structural, functional and neurochemical alterations including dopaminergic dysregulation. Several pathophysiological models have been proposed with differing interpretations of the illness, like the fabled six blind Indian men groping different parts of an elephant coming up with different conclusions. However, accumulating knowledge is integrating the several extant models of schizophrenia etiopathogenesis into unifying constructs; we discuss an example, involving a neurodevelopmental imbalance in excitatory/inhibitory neural systems leading to impaired neural plasticity. This imbalance, which may be proximal to clinical manifestations, could result from a variety of genetic, epigenetic and environmental causes, as well as pathophysiological processes such as inflammation and oxidative stress. Such efforts to "connect the dots" (and visualizing the elephant) are still limited by the substantial clinical, pathological, and etiological heterogeneity of schizophrenia and its blurred boundaries with several other psychiatric disorders leading to a "fuzzy cluster" of overlapping syndromes, thereby reducing the content, discriminant and predictive validity of a unitary construct of this illness. The way ahead involves several key directions: a) choosing valid phenotype definitions increasingly derived from translational neuroscience; b) addressing clinical heterogeneity by a cross-diagnostic dimensional and a staging approach to psychopathology; c) addressing pathophysiological heterogeneity by elucidating independent families of "extended" intermediate phenotypes and pathophysiological processes (e.g. altered excitatory/inhibitory, salience or executive circuitries, oxidative stress systems) that traverse structural, functional, neurochemical and molecular domains; d) resolving etiologic heterogeneity by mapping genomic and environmental factors and their interactions to syndromal and specific pathophysiological signatures; e) separating causal factors from consequences and compensatory phenomena; and f) formulating or reformulating hypotheses that can be refuted/tested, perhaps in the mouse or other experimental models. These steps will likely lead to the current entity of schizophrenia being usefully deconstructed and reconfigured into phenotypically overlapping, but etiopathologically unique and empirically testable component entities (similar to mental retardation, epilepsy or cancer syndromes). The mouse may be the way to rescue the trapped elephant!