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.
authors: Department of Psychiatry, University of North Carolina-Chapel Hill School of Medicine, Chapel Hill, NC, USA.
authors: L Fredrik
authors: LF
authors: Jarskog
authors: Zhengchao
authors: Z
authors: Dong
authors: Alayar
authors: A
authors: Kangarlu
authors: Tiziano
authors: T
authors: Colibazzi
authors: Ragy R
authors: RR
authors: Girgis
authors: Lawrence S
authors: LS
authors: Kegeles
authors: Deanna M
authors: DM
authors: Barch
authors: Robert W
authors: RW
authors: Buchanan
authors: John G
authors: JG
authors: Csernansky
authors: Donald C
authors: DC
authors: Goff
authors: Michael P
authors: MP
authors: Harms
authors: Daniel C
authors: DC
authors: Javitt
authors: Richard Se
authors: RS
authors: Keefe
authors: Joseph P
authors: JP
authors: McEvoy
authors: Robert P
authors: RP
authors: McMahon
authors: Stephen R
authors: SR
authors: Marder
authors: Bradley S
authors: BS
authors: Peterson
authors: Jeffrey A
authors: JA
authors: Lieberman
mesh_terms: D000293:Adolescent; D000328:Adult; D014150:Antipsychotic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000378:metabolism; D002794:Choline / Q000378:metabolism*; D003071:Cognition / Q000187:drug effects*; D003401:Creatine / Q000378:metabolism; D005260:Female; D059907:Functional Neuroimaging; D006801:Humans; D008297:Male; D008875:Middle Aged; D009842:Oligopeptides / Q000494:pharmacology* / Q000627:therapeutic use; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism*; D012559:Schizophrenia / Q000188:drug therapy / Q000378:metabolism*; D012565:Schizophrenic Psychology
chemical_list: D014150:Antipsychotic Agents; D009842:Oligopeptides; D001224:Aspartic Acid; C000179:N-acetylaspartate; C425904:davunetide; D003401:Creatine; D002794:Choline