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: L Fredrik Jarskog, Zhengchao Dong, Alayar Kangarlu, Tiziano Colibazzi, Ragy R Girgis, Lawrence S Kegeles, Deanna M Barch, Robert W Buchanan, John G Csernansky, Donald C Goff, Michael P Harms, Daniel C Javitt, Richard Se Keefe, Joseph P McEvoy, Robert P McMahon, Stephen R Marder, Bradley S Peterson, Jeffrey A Lieberman
• Journal: Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology (Neuropsychopharmacology) Vol. 38 Issue 7 Pg. 1245-52 (Jun 2013) ISSN: 1740-634X [Electronic] England
• PMID: 23325325 (Publication Type: Journal Article, Randomized Controlled Trial)

Chemical References

• Antipsychotic Agents
• Oligopeptides
• Aspartic Acid
• N-acetylaspartate
• davunetide
• Creatine
• Choline

Topics

• Adolescent
• Adult
• Antipsychotic Agents (pharmacology, therapeutic use)
• Aspartic Acid (analogs & derivatives, metabolism)
• Choline (metabolism)
• Cognition (drug effects)
• Creatine (metabolism)
• Female
• Functional Neuroimaging
• Humans
• Male
• Middle Aged
• Oligopeptides (pharmacology, therapeutic use)
• Prefrontal Cortex (drug effects, metabolism)
• Schizophrenia (drug therapy, metabolism)
• Schizophrenic Psychology