Proof-of-concept studies are planned in Project #2 that will examine the effects of novel drug probes on the biomarkers associated with schizophrenia cognitive phenotype and negative symptom phenotype. Participants will be relatives of schizophrenia probands who show evidence of schizophrenia liability as suggested by the presence of schizophrenia spectrum personality traits and poor visuo-spatial working memory. These studies provide a means of ascertaining an early human signal of potential efficacy of a compound for schizophrenia cognition and/or negative symptoms. There are several advantages to the proposed study design that recruits participants who are positive for biomarkers without having the full-blown schizophrenia. These studies will allow evaluation of the effects of the novel pharmacological agents on the physiological deficit in isolation, absent the effects of current or past antipsychotic drugs, overt psychosis, and generalized cognitive deficits that may cloud or modulate the treatment related cognitive """"""""signal"""""""". Two studies are proposed that will examine the effects of oxytocin and a nicotinic agonist, DMXB-A, on a battery of biomarkers. We will test the hypothesis that oxytocin will benefit negative symptom phenotype confirmed by significant improvements in measures of social drive, olfaction, facial affect recognition, smooth pursuit eye movement initiation and latency of internally-driven saccades. DMXB-A will benefit cognition as confirmed by significant improvements in visuo-spatial working memory, processing speed, verbal episodic memory, P50 sensory gating, and predictive pursuit eye movement gain.
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