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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Specialized Center (P50)
Project #
5P50MH082999-05
Application #
8380307
Study Section
Special Emphasis Panel (ZMH1-ERB-L)
Project Start
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
5
Fiscal Year
2012
Total Cost
$460,129
Indirect Cost
$162,753
Name
University of Maryland Baltimore
Department
Type
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Buchanan, Robert W; Kelly, Deanna L; Weiner, Elaine et al. (2017) A Randomized Clinical Trial of Oxytocin or Galantamine for the Treatment of Negative Symptoms and Cognitive Impairments in People With Schizophrenia. J Clin Psychopharmacol 37:394-400
Cohen, Alex S; Mitchell, Kyle R; Strauss, Gregory P et al. (2017) The effects of oxytocin and galantamine on objectively-defined vocal and facial expression: Data from the CIDAR study. Schizophr Res 188:141-143
Lee, Mary R; Wehring, Heidi J; McMahon, Robert P et al. (2016) Relationship of plasma oxytocin levels to baseline symptoms and symptom changes during three weeks of daily oxytocin administration in people with schizophrenia. Schizophr Res 172:165-8
Strauss, Gregory P; Keller, William R; Koenig, James I et al. (2015) Endogenous oxytocin levels are associated with the perception of emotion in dynamic body expressions in schizophrenia. Schizophr Res 162:52-6
Strauss, Gregory P; Keller, William R; Koenig, James I et al. (2015) Plasma oxytocin levels predict olfactory identification and negative symptoms in individuals with schizophrenia. Schizophr Res 162:57-61
Strauss, Gregory P; Keller, William R; Koenig, James I et al. (2015) Plasma oxytocin levels predict social cue recognition in individuals with schizophrenia. Schizophr Res 162:47-51
Wilson, Christina A; Koenig, James I (2014) Social interaction and social withdrawal in rodents as readouts for investigating the negative symptoms of schizophrenia. Eur Neuropsychopharmacol 24:759-73
Schulz, Kalynn M; Andrud, Kristin M; Burke, Maria B et al. (2013) The effects of prenatal stress on alpha4 beta2 and alpha7 hippocampal nicotinic acetylcholine receptor levels in adult offspring. Dev Neurobiol 73:806-14
Braff, David L; Ryan, James; Rissling, Anthony J et al. (2013) Lack of use in the literature from the last 20 years supports dropping traditional schizophrenia subtypes from DSM-5 and ICD-11. Schizophr Bull 39:751-3
Taylor, S B; Taylor, A R; Koenig, J I (2013) The interaction of disrupted type II neuregulin 1 and chronic adolescent stress on adult anxiety- and fear-related behaviors. Neuroscience 249:31-42

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