Are we studying and treating schizophrenia correctly?

Abstract

New findings are rapidly revealing an increasingly detailed image of neural- and molecular-level dysfunction in schizophrenia, distributed throughout interconnected cortico-striato-pallido-thalamic circuitry. Some disturbances appear to reflect failures of early brain maturation, that become codified into dysfunctional circuit properties, resulting in a substantial loss of, or failure to develop, both cells and/or appropriate connectivity across widely dispersed brain regions. These circuit disturbances are variable across individuals with schizophrenia, perhaps reflecting the interaction of multiple different risk genes and epigenetic events. Given these complex and variable hard-wired circuit disturbances, it is worth considering how new and emerging findings can be integrated into actionable treatment models. This paper suggests that future efforts towards developing more effective therapeutic approaches for the schizophrenias should diverge from prevailing models in genetics and molecular neuroscience, and focus instead on a more practical three-part treatment strategy: 1) systematic rehabilitative psychotherapies designed to engage healthy neural systems to compensate for and replace dysfunctional higher circuit elements, used in concert with 2) medications that specifically target cognitive mechanisms engaged by these rehabilitative psychotherapies, and 3) antipsychotic medications that target nodal or convergent circuit points within the limbic-motor interface, to constrain the scope and severity of psychotic exacerbations and thereby facilitate engagement in cognitive rehabilitation. The use of targeted cognitive rehabilitative psychotherapy plus synergistic medication has both common sense and time-tested efficacy with numerous other neuropsychiatric disorders.

Copyright © 2011 Elsevier B.V. All rights reserved.

Figures

Figure 1

Schematic overview of one proposed clinical strategy for identifying drug candidates for enhancing the effectiveness of CT in schizophrenia (parallel research activities are shown in parentheses). As discussed in the text, biomarkers are identified in a patient that predict an increased sensitivity to the ability of a drug to augment a CSPT-regulated laboratory measure that is: 1) deficient in schizophrenia, and 2) associated with neurocognitive processes that might enhance CT. This biomarker profile would inform the choice of drug and predictive measure; for example, high levels of DRD3 expression are associated with WM-enhancing effects of the D3 agonist, pramipexole (Ersche et al. 2011), while individuals carrying the Val/Val alleles of the Val158Met COMT polymorphism exhibit greater sensitivity to the ability of tolcapone (Roussos et al. 2009) to enhance sensorimotor gating, and individuals with low basal levels of PPI are most sensitive to the PPI-enhancing effects of memantine (Swerdlow et al. 2009b). A patient would then be tested in a within-subject “challenge dose” design (placebo vs. active dose), and findings of drug-enhanced performance in one or more predictive measure would suggest that the requisite neural circuitry for such an effect is “spared” and could be drug-activated in the service of CT. The patient might then be entered in a structured CT program (e.g. for 12 weeks), with daily drug augmentation. Conceivably, some forms of CT might benefit most from enhanced performance in specific neurocognitive or neurophysiological processes, and might be matched according to such drug effects identified in any given patient. Parallel translational research activities might identify the neural mechanisms for drug effects on specific neurophysiological processes; large, prospective trials would identify strongest biomarker- and laboratory measure-predictors of positive drug effects on specific forms of CT.