The rational development of new treatments requires an understanding of the disease process.
In addition to their limited effectiveness, all medications currently used to treat schizophrenia and related disorders were discovered by serendipity. These problems emphasize the need for a new approach to treatment development similar to that used in other domains of medicine where drug development begins with the identification of molecular targets based on their role in the pathophysiology of an illness. Although the need for a shift in strategy is compelling, its implementation depends upon knowledge of the underlying disease process. In this view of a disease process, the etiology or cause of a brain illness unleashes pathogenic mechanisms that produce a pathological entity, a conserved set of molecular and cellular disturbances in the brain. This pathological entity so alters the brain’s normal circuitry and function that the resulting pathophysiology gives rise to the emergent properties recognized as the clinical features of the illness. Thus, rational therapeutic interventions normalize function at molecular and cellular levels in order to improve the physiological functions of the affected neural circuits so that the clinical features are ameliorated.
Understanding this disease process is, of course, complicated by the heterogeneity associated with the diagnosis of schizophrenia. Etiologically, most cases of schizophrenia appear to be the consequence of the complex interplay of a large number of genetic liabilities and environmental risk factors that alter the developmental trajectories of neural circuits. At the other end of the disease process, the broad range of clinical features found in individuals who meet DSM criteria for schizophrenia suggests that multiple brain systems are affected. Thus, the etiological and clinical heterogeneity of schizophrenia likely represents both diversity (the existence of different disease entities within the population meeting DSM criteria) and variability (variance of particular parameters within a disease entity due to genetic background and other differences). Consequently, a critical challenge in schizophrenia research is the development of an investigative strategy that is robust to etiologic and clinical diversity and sufficiently powered to account for both biological and experimental variability. Below we outline a set of research approaches (e.g., a focus on specific dimensions of symptoms, on a common pathology downstream from etiological factors and on conserved proximal pathophysiological mechanisms) that we believe will allow us to deal productively with such heterogeneity.
Silvio O. Conte Center for Translational Mental Health Research
Funded by the National Institute of Mental Health (MH103204)