The proposed study is designed to specifically evaluate: (1) the working memory impairment associated with schizotypal personality disorder (SPD), assessing components of manipulation and maintenance as delineated in Baddeley's comprehensive model in both auditory and visuospatial modes, (2) a multimodal dual task information processing task reflecting processing capacity, (3) a standard context-processing dependent working memory task , (4) performance-based measures of functional capacity and (5) a standardized battery of episodic memory and working memory tasks. These tasks will be evaluated at baseline and after 4 weeks of a double blind placebo controlled trial of guanfacine in 60 patients with SPD and 60 patients with a non-schizophrenia related personality disorder, avoidant personality disorder (AvPD). These tasks will also be evaluated at baseline in 60 healthy controls and 4 weeks later. It is hypothesized that SPD patients will demonstrate impairment in central executive functions (maintenance plus manipulation) that is disproportionate to their maintenance only performance compared to the patients with AvPD and healthy control (HC) groups, similar to previous results found in schizophrenic patients. Dual task processing (time sharing) will be markedly impaired in SPD as compared to AvPD and, similar to other central executive measures, responsive to treatment with guanfacine. It is hypothesized that guanfacine will improve working memory performance on the Cannon-Glahn tasks particularly in the realm of central executive (i.e. manipulation and context processing), but will not improve episodic memory compared to placebo. It is also hypothesized that performance-based measures of functional capacity will be impaired in SPD patients and will improve with guanfacine treatment. These studies will more specifically characterize the impairment in working memory that appears to account for much of the cognitive impairment of the schizophrenia spectrum disorders and to evaluate the effects of a pharmacologic intervention with guanfacine on working memory in SPD patients. Difficulty in holding information in memory over short periods of time is an important contributor to the occupational and social problems of individuals with the schizophrenic disorders. These studies will help to clarify the exact nature of this memory problem and investigate how it can be improved by medication treatment.
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