Intermittent D1 Agonist Treatment of Executive Dysfunction in Schizophrenia: A Do

Yale University, New Haven CT

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Abstract

Cognitive impairment significantly contributes to poor functional outcomes in schizophrenia. Executive function deficits in schizophrenia have been linked to prefrontal cortex (PFC) dysfunction. Current antipsychotic medications minimally benefit executive functioning. Thus, development of novel treatments for executive dysfunction in schizophrenia is imperative. Non-human primate studies show a critical role of PFC dopamine (DA) activity at D1 receptors for regulating working memory. Typical working memory tasks also require sustained and phasic attention, executive functions modulated by PFC circuits. Deficits in these functions in schizophrenia are thought to result from PFC hypodopaminergia. Event-related brain potential (ERP) studies have shown variants of the P300 ERP component to be sensitive to sustained and phasic attention and to be abnormal in schizophrenia. Although multiple neural generators contribute to P300, PFC circuitry is consistently implicated. Based on the PFC hypodopaminergia hypothesis, selective augmentation of DA activity at D1 receptors may improve executive functions and their ERP correlates in schizophrenia. In recent work from this Center, working memory deficits induced in monkeys by chronic haloperidol administration were reversed by intermittent coadministration of low dose DAS-431, a selective D1 agonist, and this improvement was sustained well beyond the active treatment phase. It is hypothesized that a similar augmentation treatment strategy could benefit cognitively impaired schizophrenic patients. Accordingly, the specific aims of the proposed project are as follows: (1) To examine whether intermittent treatment with DAS-431 can improve working memory as well as attention and its associated ERP P300 abnormalities, in schizophrenic patients taking antipsychotic medication. Patients are randomly assigned to placebo or DAS-431 at low (1mg) or ultra-low (.05mg) doses, double-blind, using an intermittent 10-week regimen comprising five 3-day treatment blocks. (2) To examine whether these improvements are sustained over a 12-week post-treatment follow-up period. (3) To examine whether significant deficits at baseline between patients and normal controls on the cognitive and ERP P300 measures are still significantfollowing DAS-431 treatment.