People with schizophrenia are characterized by a broad range of symptoms, including negative symptomsand cognitive impairments. These two domains of psychopathology are the major causes of poor functionaloutcome. Antipsychotic efficacy for these domains is modest at best and sometimes adverse. In theMATRICS process, the field reached a consensus that these domains are the two major critical unmettherapeutic targets, and that new drug discovery for these two domains was essential. We will conduct aparallel group, placebo-controlled comparison of oxytocin and DMXB-A. The study will use a double-dummydesign, with a 4-week continued stability (lead-in) phase and a 6-week double-blind treatment phase. Therewill be 40 subjects in each treatment arm. Subjects will demonstrate a minimum level of persistent negativesymptoms, with a judgment that the negative symptoms are clinically significant despite treatment. Subjectswill be judged clinically stable and will not exceed threshold levels of positive, depressive, and/orextrapyramidal symptoms. The proposed study will address the following two primary aims: 1) to determinewhether adjunctive oxytocin is superior to placebo for the treatment of persistent negative symptoms, asmeasured by the SANS total score, in people with schizophrenia; and 2) to determine whether adjunctiveDMXB-A is superior to placebo for the treatment of cognitive impairments, as measured by improvement ona composite neurocognitive score (derived from processing speed (BAGS), episodic memory (HVLT),attention (RVIP)), in people with schizophrenia. In addition, the study will address the following secondaryaims: 1) to determine whether people with schizophrenia treated with adjunctive oxytocin, compared toplacebo, will show greater improvement on phenotypic markers of negative symptom liability including: socialaffiliation, facial affect recognition, olfactory discrimination, initiation of smooth pursuit and latency ofinternally-driven saccades; and 2) to determine whether people with schizophrenia treated with adjunctiveDMXB-A, compared to placebo, will show greater improvement on phenotypic markers of cognitiveimpairment liability including: predictive pursuit, P50 sensory gating and visuo-spatial working memory. Thestudy will also provide data for the determination of the relationship of drug effects across the pre-clinical,non-clinical human, and clinical trial models.
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