Schizophrenia is a major public health problem affecting almost 1% of the population with youthful onset of psychosis and poor functional outcomes. Personal, family, and societal impact is substantial. Two psychopathological domains, negative symptoms and cognitive impairments, typically preceed psychosis, and are robustly associated with poor functional outcome. No treatment has documented efficacy for these two domains. The purpose of the proposed studies is to advance drug discovery for these two domains using innovative evaluation platforms and testing drugs with novel molecular targets.
Specific aims i nvolve establishing innovative evaluation techniques and to determine the effect of a compound hypothesized to have efficacy for negative symptoms and a compound hypothesized to have efficacy for cognitive impairments.
A second aim i s to determine whether these two domains represent similar or separate developmental pathways for drug discovery.
These aims will be accomplished by establishing three evaluation platforms: a] a pre-natal stress rat model which manifests phenotypes of both psychopathological domains;b] subjects selected from the biological relatives of schizophrenia probands who manifest phenotypes for both psychopathologies;and c] a clinical trials platform with schizophrenia subjects selected with phenotypic manifestations of the two psychopathologies. The two compounds chosen for testing are oxytocin for negative symptoms and 3-[(2,4-dimethoxy) benzylidene]anabaseine (DXMB-A), an alpha-7 nicotinic receptor partial agonist, for cognitive impairments. We will determine: a] the effect of each compound on both negative and cognitive phenotypes in each evaluation platform;b] whether effects in the pre-clinical and non-schizophrenia human models predicts effects in the clinical model;c] whether efficacy is observed in the clinical trial;and d] whether effects of each compound are specific for the hypothesized psychopathological domain. This project addresses the unmet therapeutic needs for schizophrenia by testing novel compounds for negative symptoms and cognitive impairments. Testing is performed on novel animal and human evaluation platforms in order to develop new approaches to early drug evaluation. Efficacy is determined in a clinical trial where patient subjects are selected according negative symptom and cognitive phenotypes.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Specialized Center (P50)
Project #
Application #
Study Section
Special Emphasis Panel (ZMH1-ERB-L (01))
Program Officer
Hillefors, MI
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Maryland Baltimore
Schools of Medicine
United States
Zip Code
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
Markham, Julie A; Mullins, Sylvina E; Koenig, James I (2013) Periadolescent maturation of the prefrontal cortex is sex-specific and is disrupted by prenatal stress. J Comp Neurol 521:1828-43
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
Markham, Julie A; Koenig, James I (2011) Prenatal stress: role in psychotic and depressive diseases. Psychopharmacology (Berl) 214:89-106
Taylor, Sara B; Markham, Julie A; Taylor, Adam R et al. (2011) Sex-specific neuroendocrine and behavioral phenotypes in hypomorphic Type II Neuregulin 1 rats. Behav Brain Res 224:223-32
Taylor, S B; Taylor, A R; Markham, J A et al. (2011) Disruption of the neuregulin 1 gene in the rat alters HPA axis activity and behavioral responses to environmental stimuli. Physiol Behav 104:205-14
Neeley, E W; Berger, R; Koenig, J I et al. (2011) Prenatal stress differentially alters brain-derived neurotrophic factor expression and signaling across rat strains. Neuroscience 187:24-35
Koenig, James I (2009) Corticotropin-releasing factor, serotonin, and sex: keys to the castle of depressive illness. Endocrinology 150:3440-2
Fischer, Bernard A; Carpenter Jr, William T (2009) Will the Kraepelinian dichotomy survive DSM-V? Neuropsychopharmacology 34:2081-7
Carpenter, William T; Koenig, James I (2008) The evolution of drug development in schizophrenia: past issues and future opportunities. Neuropsychopharmacology 33:2061-79