@article{44ae2877f6374cd4b733749e45cad2d7,
title = "Effects of davunetide on N-acetylaspartate and choline in dorsolateral prefrontal cortex in patients with schizophrenia",
abstract = "Schizophrenia is associated with extensive neurocognitive and behavioral impairments. Studies indicate that N-acetylaspartate (NAA), a marker of neuronal integrity, and choline, a marker of cell membrane turnover and white matter integrity, may be altered in schizophrenia. Davunetide is a neurotrophic peptide that can enhance cognitive function in animal models of neurodegeneration. Davunetide has recently demonstrated modest functional improvement in a study of people with schizophrenia. In a subset of these subjects, proton magnetic resonance spectroscopy (1 H-MRS) was conducted to explore the effects of davunetide on change in NAA/creatine (NAA/Cr) and choline/creatine (choline/Cr) over 12 weeks of treatment. Of 63 outpatients with schizophrenia who received randomized davunetide (5 and 30 mg/day) or placebo in the parent clinical trial, 18 successfully completed 1 H-MRS in dorsolateral prefrontal cortex (DLPFC) at baseline and at 12 weeks. Cognition was assessed using the MATRICS Consensus Cognitive Battery (MCCB). NAA/Cr was unchanged for combined high-and low-dose davunetide groups (N=11). NAA/Cr in the high-dose davunetide group (N=8) suggested a trend increase of 8.0% (P=0.072) over placebo (N=7). Choline/Cr for combined high-and low-dose davunetide groups suggested a 6.4% increase (P=0.069), while the high-dose group showed a 7.9% increase (P=0.040) over placebo. Baseline NAA/Cr correlated with the composite MCCB score (R=0.52, P=0.033), as did individual cognitive domains of attention/vigilance, verbal learning, and social cognition; however, neither metabolite correlated with functional capacity. In this exploratory study, 12 weeks of adjunctive davunetide appeared to produce modest increases in NAA/Cr and choline/Cr in DLPFC in people with schizophrenia. This is consistent with a potential neuroprotective mechanism for davunetide. The data also support use of MRS as a useful biomarker of baseline cognitive function in schizophrenia. Future clinical and preclinical studies are needed to fully define the mechanism of action and cognitive effects of davunetide in schizophrenia.",
keywords = "MRS, cognition, neuroprotective, neurotrophic, proton magnetic resonance spectroscopy",
author = "Jarskog, {L. Fredrik} and Zhengchao Dong and Alayar Kangarlu and Tiziano Colibazzi and Girgis, {Ragy R.} and Kegeles, {Lawrence S.} and Barch, {Deanna M.} and Buchanan, {Robert W.} and Csernansky, {John G.} and Goff, {Donald C.} and Harms, {Michael P.} and Javitt, {Daniel C.} and Keefe, {Richard Se} and McEvoy, {Joseph Patrick} and McMahon, {Robert P.} and Marder, {Stephen R.} and Peterson, {Bradley S.} and Lieberman, {Jeffrey A.}",
note = "Funding Information: During the past 3 years, the authors declare the following financial disclosures. Dr Jarskog has received research funding from GlaxoSmithKline, Novartis, Sunovion and Genentech and has served as a DSMB member for Janssen. Dr Girgis has received research funding from Eli Lilly. Dr Kegeles has received research funding from Pfizer and Amgen. Dr Barch has received research funding from National Institute of Mental Health, Allon and Novartis and has served as a consultant for Pfizer. Dr Buchanan has served on advisory boards for Abbott, Amgen, Astellas, Janssen Pharmaceuticals Inc., Merck, NuPathe, Pfizer, Roche, Solvay Pharmaceuticals, Inc. and Takeda; he has served as a consultant for Abbott, Amgen, AstraZeneca, Bristol-Myers Squibb, Cypress Bioscience, EnVivo, Glax-oSmithKline, Pfizer, and Takeda; he serves as a DSMB member for Pfizer, Cephalon and Otsuka. Dr Csernansky has served as a DSMB member for Eli Lilly and Sanofi-Aventis. Dr Goff has received research funding from Janssen, Pfizer, GlaxoSmithKline, PamLab and Novartis; he has served as a consultant to Eli Lilly, Bristol-Myers Squibb, Roche, Endo Pharmaceuticals, Genentech, Cypress Bioscience, Dainippon Sumitomo, Solvay, Biovail, and Takeda Pharmaceuticals; he has served as a DSMB member for Otsuka; he has applied for patents regarding genetic predictors of response to glutamatergic agents and folate. Dr Javitt has received research funding from Jazz, Pfizer, Roche; he has served as a consultant for NPS, Solvay, Sepracor, AstraZeneca, Pfizer, Cypress, Merck, Sunovion, Bristol-Myers Squibb, Eli Lilly, and Takeda; he has served on advisory boards for Promentis; he has equity in Glytech and AASI. Dr Keefe has received research funding from the Department of Veterans Affairs, GlaxoSmithKline, National Institute of Mental Health, Novartis, Psychogenics, Research Foundation for Mental Hygiene, Inc., and the Singapore National Medical Research Council; he has received honoraria, served as a consultant, or advisory board member for Abbott, Amgen, Astellas, Asubio, BiolineRx, Boehringer-Ingelheim, BrainCells, Bristol-Myers Squibb, Eli Lilly, EnVivo, Helicon, Lundbeck, Merck, Mitsubishi, Novartis, Otsuka, Pfizer, Roche, Sanofi-Aventis, Shire, Solvay, Sunovion, Takeda, Targacept and Wyeth; he receives royalties from the BACS testing battery and the MATRICS Battery (BACS Symbol Coding); he is a shareholder in NeuroCog Trials, Inc.; Duke University holds the copyright for the SCoRS, and licenses are issued by NeuroCog Trials, Inc., however, there is currently no license fee to use the SCoRS. Dr McEvoy has received research grants from Roche/Genentech, Psychogenics, Merck and has received honoraria for speaking from Eli Lilly, Merck and Sunovion. Dr McMahon has served as a consultant for Amgen. Dr Marder has received research funding from Allon, GlaxoSmithKline, Novartis, Sunovion, and Psycho-genics; he has served as a consultant for Amgen, Abbott, Astellas, Otsuka, Pfizer, Roche, Genentech, Lundbeck, Shire and Targacept. Dr Lieberman does not receive direct financial compensation or salary support for participation in research, consulting, or advisory board activities. He serves or has served on advisory boards for Alkermes, Bioline, Intracellular Therapies, Pierre Fabre and Psycho-Genics. He receives grant support from Allon, F. Hoffman-La Roche LTD, GlaxoSmithKline, Eli Lilly, Merck, Novartis, Pfizer, Psychogenics, Sunovion and Targacept; and he holds a patent from Repligen. Drs Peterson, Kangarlu, Dong, Colibazzi and Harms declare no conflict of interest. Funding Information: This study was funded by a NARSAD Distinguished Investigator Award (Lieberman), National Institute of Mental Health contract HHSN278200441003C (Marder), and Allon Therapeutics, Inc. Double-blind medications were provided by Allon Therapeutics, Inc. The sponsors had no role in study design, data collection, and data analysis, or in manuscript preparation, revision, and final approval. The authors wish to acknowledge Dr Dikoma Shungu (Weill Cornell Medical College, NY, NY) for his assistance with the protocol for voxel placement. This work was presented in part at the 13th International Congress on Schizophrenia Research, Colorado Springs, CO 04/04/2011. Clinicaltrials.-gov registry no. NCT00505765. The trial was conducted under a FDA IND and oversight provided by a NIMH Drug Safety and Monitoring Board.",
year = "2013",
month = jun,
doi = "10.1038/npp.2013.23",
language = "English (US)",
volume = "38",
pages = "1245--1252",
journal = "Neuropsychopharmacology",
issn = "0893-133X",
publisher = "Nature Publishing Group",
number = "7",
}