People with schizophrenia are characterized by a broad range of symptoms, including negative symptoms and cognitive impairments. These two domains of psychopathology are the major causes of poor functional outcome. Antipsychotic efficacy for these domains is modest at best and sometimes adverse. In the MATRICS process, the field reached a consensus that these domains are the two major critical unmet therapeutic targets, and that new drug discovery for these two domains was essential. We will conduct a parallel group, placebo-controlled comparison of oxytocin and DMXB-A. The study will use a double-dummy design, with a 4-week continued stability (lead-in) phase and a 6-week double-blind treatment phase. There will be 40 subjects in each treatment arm. Subjects will demonstrate a minimum level of persistent negative symptoms, with a judgment that the negative symptoms are clinically significant despite treatment. Subjects will be judged clinically stable and will not exceed threshold levels of positive, depressive, and/or extrapyramidal symptoms. The proposed study will address the following two primary aims: 1) to determine whether adjunctive oxytocin is superior to placebo for the treatment of persistent negative symptoms, as measured by the SANS total score, in people with schizophrenia;and 2) to determine whether adjunctive DMXB-A is superior to placebo for the treatment of cognitive impairments, as measured by improvement on a 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 secondary aims: 1) to determine whether people with schizophrenia treated with adjunctive oxytocin, compared to placebo, will show greater improvement on phenotypic markers of negative symptom liability including: social affiliation, facial affect recognition, olfactory discrimination, initiation of smooth pursuit and latency of internally-driven saccades;and 2) to determine whether people with schizophrenia treated with adjunctive DMXB-A, compared to placebo, will show greater improvement on phenotypic markers of cognitive impairment liability including: predictive pursuit, P50 sensory gating and visuo-spatial working memory. The study will also provide data for the determination of the relationship of drug effects across the pre-clinical, non-clinical human, and clinical trial models.
Showing the most recent 10 out of 22 publications
