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 were discovered by serendipity. These problems emphasize the need for a new approach to treatment development in schizophrenia 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 (Fig 1). According to this view of a disease process, the etiology or cause of a brain illness unleashes pathogenetic 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. As illustrated here, a rational therapeutic intervention normalizes the physiology of the affected neural circuits so that the clinical features are ameliorated.
Understanding this disease process is, of course, complicated by the apparent heterogeneity associated with the diagnosis of schizophrenia. Etiologically, most cases of schizophrenia are thought to be the consequence of the complex interplay of an unknown 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 diagnostic criteria for schizophrenia suggests that multiple brain systems are affected in this disorder. Thus, the etiological and clinical heterogeneity of schizophrenia likely represents both diversity (the existence of different disease entities within the population meeting diagnostic criteria) and variability (variance of particular parameters within a disease entity due to differences in genetic background and other factors). 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.
Given the number of different genetic liabilities and environmental exposures associated with an increased risk of schizophrenia, different combinations of these causal factors probably induce distinct sets of molecular alterations that are distal from the pathophysiology of a given clinical feature and that differ across affected individuals. However, these alterations are likely to converge upon a more limited set of proximal molecular and cellular changes that directly give rise to the pathophysiology underlying a given clinical feature, and thus would be expected to be conserved across individuals who share that clinical feature. Consequently, in our studies we have elected to focus on the clinical features and pathological markers that appear to be relatively common across individuals diagnosed with schizophrenia. At the clinical level, we begin with a focus on a well-established information processing deficit in schizophrenia--the impairments in cognitive processes dependent upon the circuitry of the dorsolateral prefrontal cortex (DLPFC). At the pathological level, we focus on the alterations in markers of GABA neurotransmission in the DLPFC, perhaps the most widely replicated finding in postmortem schizophrenia research. The proposed studies are designed to test the hypothesis that these abnormalities are linked by the pathophysiology of altered DLPFC gamma frequency oscillations. Thus, the Center is organized to provide a proof-of-concept test of this model. However, we recognize that disturbances in other domains of information processing, in other frequencies of neural network oscillations and in other cortical regions are present in the illness. Hence, we also seek to extend the testing of this strategic model to these other phenomena (see Figure 2).The rationale for this strategy is based upon our two-fold goal of 1) identifying novel pathophysiologically-based treatment targets that can be used to guide drug development, and 2) developing novel pathophysiologically-based biomarkers that can be used in clinical trials to assess the extent to which a drug normalizes the pathophysiology. Achieving the first goal requires recognizing that molecular alterations observed in association with the disease state could represent any of the following four “C’s”: 1) Cause, an upstream factor related to the disease pathogenesis; 2) Consequence, a deleterious effect of a cause; 3) Compensation, a response to either cause or consequence that helps restore homeostasis; or 4) Confound, a product of factors frequently associated with, but not a part of, the disease process, or an artifact of the approach used to obtain the measure of interest. The molecular alterations most likely to be useful as drug targets are the downstream consequences (or compensations) that are closely tied to, and the direct and powerful determinants of, the disturbed brain physiology that mediates the clinical feature of interest. Thus, three of the research projects comprising the Center focus on an integration of postmortem human investigations and in vitro and in vivo studies in non-human primates to provide pathological and physiological bases for identifying and validating potential novel drug targets. In parallel, the remaining two projects use an integration of electrophysiological and multi-modal imaging measures in the context of specific information processing tasks in humans to assess potential biomarkers that reflect the underlying pathophysiology of the clinical features of interest.
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Corrie Long