My career goal is to become an academic psychiatrist and independent investigator in the areas of schizophrenia focusing on its neurobiology and therapeutics, applying molecular mechanism-based research to prospective clinical studies. Specifically, I propose to investigate the importance of neurosteroids in schizophrenia. Neurosteroids are differentially expressed in males and females, modulate GABAA and NMDA receptors, regulate neuronal cytoarchitecture, demonstrate neuroprotective effects, play a role in neurodevelopment, and possess memory-enhancing effects. Neurosteroids are therefore logical candidates of investigation to elucidate schizophrenia pathophysiology, since they are potential modulators of schizophrenia gender differences, GABAergic and glutamatergic dysregulation, neurodevelopmental insults associated with increased schizophrenia risk, cytoarchitectural abnormalities in postmortem specimens from patients with schizophrenia, and cognitive disturbances in the disorder. The laboratory has demonstrated that neurosteroids protect embryonic cerebral cortical neurons against anoxia, a neurodevelopmental insult associated with increased schizophrenia risk. We have also demonstrated that acute olanzapine and clozapine administration alters cerebral cortical neurosteroids in rodents. The investigators hypothesize that neurosteroids are important modulators of schizophrenia pathophysiology (including the pronounced gender differences of the disorder) and antipsychotic drug action. We also propose that compounds affecting neurosteroid expression or neurosteroids themselves may be developed as novel therapeutic agents in the treatment of schizophrenia. To test this hypothesis, three investigational strategies are proposed: 1.) A preclinical study examining the effects of antipsychotics on cerebral cortical and serum neurosteroid levels in rodents, 2.) A postmortem study determining neurosteroid levels in parietal cortex and posterior cingulate specimens provided by the Stanley Foundation from patients with schizophrenia compared to control subjects, and 3.) A clinical study examining neurosteroid levels in subjects with schizophrenia from two UNC clinical trials (Dr. Lieberman, PI) to determine if serum or CSF neurosteroid alterations are correlated with antipsychotic efficacy, neurocognitive changes, and/or structural changes on MRI. Results from these preliminary investigations will inform the design of future prospective clinical studies to confirm initial findings and target neurosteroids as therapeutic agents in schizophrenia. To achieve these goals, the candidate will receive training through formal coursework in neuropharmacology, clinical trials design, drug development, and biostatistics. She will also learn highly sensitive and specific gas chromatography mass spectrometry (GC/MS) and other state-of-the-art neurosteroid detection methods. The mentorship of Drs. Jeffrey Lieberman and Leslie Morrow will be critical to the overarching goal of this proposal, the successful translation of exciting preclinical neurosteroid findings to prospective clinical studies examining neurosteroids in schizophrenia pathophysiology and therapeutics.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23MH065080-02
Application #
6539329
Study Section
Special Emphasis Panel (ZRG1-BDCN-6 (01))
Program Officer
Wynne, Debra K
Project Start
2001-07-01
Project End
2006-06-30
Budget Start
2002-07-01
Budget End
2003-06-30
Support Year
2
Fiscal Year
2002
Total Cost
$170,562
Indirect Cost
Name
Duke University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
071723621
City
Durham
State
NC
Country
United States
Zip Code
27705
Naylor, Jennifer C; Dolber, Trygve R; Strauss, Jennifer L et al. (2013) A pilot randomized controlled trial with paroxetine for subthreshold PTSD in Operation Enduring Freedom/Operation Iraqi Freedom era veterans. Psychiatry Res 206:318-20
Kilts, Jason D; Tupler, Larry A; Keefe, Francis J et al. (2010) Neurosteroids and self-reported pain in veterans who served in the U.S. Military after September 11, 2001. Pain Med 11:1469-76
Naylor, Jennifer C; Kilts, Jason D; Hulette, Christine M et al. (2010) Allopregnanolone levels are reduced in temporal cortex in patients with Alzheimer's disease compared to cognitively intact control subjects. Biochim Biophys Acta 1801:951-9
Marx, Christine E; Keefe, Richard S E; Buchanan, Robert W et al. (2009) Proof-of-concept trial with the neurosteroid pregnenolone targeting cognitive and negative symptoms in schizophrenia. Neuropsychopharmacology 34:1885-903
Naylor, Jennifer C; Hulette, Christine M; Steffens, David C et al. (2008) Cerebrospinal fluid dehydroepiandrosterone levels are correlated with brain dehydroepiandrosterone levels, elevated in Alzheimer's disease, and related to neuropathological disease stage. J Clin Endocrinol Metab 93:3173-8
Marx, Christine E; Yuan, Peixiong; Kilts, Jason D et al. (2008) Neuroactive steroids, mood stabilizers, and neuroplasticity: alterations following lithium and changes in Bcl-2 knockout mice. Int J Neuropsychopharmacol 11:547-52
Wang, Chunsheng; Marx, Christine E; Morrow, A Leslie et al. (2007) Neurosteroid modulation of GABAergic neurotransmission in the central amygdala: a role for NMDA receptors. Neurosci Lett 415:118-23
Marx, Christine E; Trost, William T; Shampine, Lawrence et al. (2006) Neuroactive steroids, negative affect, and nicotine dependence severity in male smokers. Psychopharmacology (Berl) 186:462-72
Marx, Christine E; Shampine, Lawrence J; Khisti, Rahul T et al. (2006) Olanzapine and fluoxetine administration and coadministration increase rat hippocampal pregnenolone, allopregnanolone and peripheral deoxycorticosterone: implications for therapeutic actions. Pharmacol Biochem Behav 84:609-17
Marx, Christine E; Shampine, Lawrence J; Duncan, Gary E et al. (2006) Clozapine markedly elevates pregnenolone in rat hippocampus, cerebral cortex, and serum: candidate mechanism for superior efficacy? Pharmacol Biochem Behav 84:598-608

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