Integrative circuit models and their implications for the pathophysiologies and treatments of the schizophrenias.

A preponderance of evidence indicates that the heterogeneous group of schizophrenias is accompanied by disturbances in neural elements distributed throughout multiple levels of interconnected cortico-striato-pallido-thalamic circuitry. These disturbances include a substantial loss of, or failure to develop, both cells and/or appropriate cellular connections in regions that include at least portions of the hippocampus, parahippocampal gyrus, entorhinal cortex, amygdala, prefrontal and anterior cingulate cortex, superior and transverse temporal gyri, and mediodorsal, anterior, and pulvinar nuclei of the thalamus; they appear to reflect failures of early brain maturation, that become codified into dysfunctional circuit properties, that in the opinion of this author cannot be "undone" or even predictably remediated in any physiological manner by existing pharmacotherapies. These circuit disturbances are variable across individuals with schizophrenia, perhaps reflecting the interaction of multiple different risk genes and multiple different epigenetic events. Evidence for these complex circuit disturbances has significant implications for many areas of schizophrenia research, and for future efforts toward developing more effective therapeutic approaches for this group of disorders. The conclusion of this chapter is that such future efforts should focus on further developing and refining medications that target nodal or convergent circuit points within the limbic-motor interface, with the goal of constraining the scope and severity of psychotic exacerbations, to be used in concert with systematic rehabilitative psychotherapies designed to engage healthy neural systems to compensate for and replace dysfunctional higher circuit elements. This strategy should be applied in both preventative and treatment settings, and disseminated for community delivery via an evidence-based manualized format. In contrast to alternative treatment strategies that range from complex polypharmacy to gene therapies to psychosurgical interventions, the use of combined medication plus targeted cognitive and behavioral psychotherapy has both common sense and time-tested documented efficacy with numerous other neuropsychiatric disorders.