Effects of davunetide on N-acetylaspartate and choline in dorsolateral prefrontal cortex in patients with schizophrenia

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 Patrick McEvoy, Robert P. McMahon, Stephen R. Marder, Bradley S. Peterson, Jeffrey A. Lieberman

Research output: Contribution to journalArticle

43 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1245-1252
Number of pages8
JournalNeuropsychopharmacology
Volume38
Issue number7
DOIs
StatePublished - Jun 1 2013

Fingerprint

Choline
Prefrontal Cortex
Schizophrenia
Cognition
Creatine
Placebos
Consensus
davunetide
N-acetylaspartate
Verbal Learning
Outpatients
Animal Models
Biomarkers
Cell Membrane
Clinical Trials
Peptides

Keywords

  • MRS
  • cognition
  • neuroprotective
  • neurotrophic
  • proton magnetic resonance spectroscopy

ASJC Scopus subject areas

  • Pharmacology
  • Psychiatry and Mental health

Cite this

Jarskog, L. F., Dong, Z., Kangarlu, A., Colibazzi, T., Girgis, R. R., Kegeles, L. S., ... Lieberman, J. A. (2013). Effects of davunetide on N-acetylaspartate and choline in dorsolateral prefrontal cortex in patients with schizophrenia. Neuropsychopharmacology, 38(7), 1245-1252. https://doi.org/10.1038/npp.2013.23

Effects of davunetide on N-acetylaspartate and choline in dorsolateral prefrontal cortex in patients with schizophrenia. / Jarskog, L. Fredrik; Dong, Zhengchao; Kangarlu, Alayar; Colibazzi, Tiziano; Girgis, Ragy R.; Kegeles, Lawrence S.; Barch, Deanna M.; Buchanan, Robert W.; Csernansky, John G.; Goff, Donald C.; Harms, Michael P.; Javitt, Daniel C.; Keefe, Richard Se; McEvoy, Joseph Patrick; McMahon, Robert P.; Marder, Stephen R.; Peterson, Bradley S.; Lieberman, Jeffrey A.

In: Neuropsychopharmacology, Vol. 38, No. 7, 01.06.2013, p. 1245-1252.

Research output: Contribution to journalArticle

Jarskog, LF, Dong, Z, Kangarlu, A, Colibazzi, T, Girgis, RR, Kegeles, LS, Barch, DM, Buchanan, RW, Csernansky, JG, Goff, DC, Harms, MP, Javitt, DC, Keefe, RS, McEvoy, JP, McMahon, RP, Marder, SR, Peterson, BS & Lieberman, JA 2013, 'Effects of davunetide on N-acetylaspartate and choline in dorsolateral prefrontal cortex in patients with schizophrenia', Neuropsychopharmacology, vol. 38, no. 7, pp. 1245-1252. https://doi.org/10.1038/npp.2013.23
Jarskog, L. Fredrik ; Dong, Zhengchao ; Kangarlu, Alayar ; Colibazzi, Tiziano ; Girgis, Ragy R. ; Kegeles, Lawrence S. ; Barch, Deanna M. ; Buchanan, Robert W. ; Csernansky, John G. ; Goff, Donald C. ; Harms, Michael P. ; Javitt, Daniel C. ; Keefe, Richard Se ; McEvoy, Joseph Patrick ; McMahon, Robert P. ; Marder, Stephen R. ; Peterson, Bradley S. ; Lieberman, Jeffrey A. / Effects of davunetide on N-acetylaspartate and choline in dorsolateral prefrontal cortex in patients with schizophrenia. In: Neuropsychopharmacology. 2013 ; Vol. 38, No. 7. pp. 1245-1252.
@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.}",
year = "2013",
month = "6",
day = "1",
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",

}

TY - JOUR

T1 - Effects of davunetide on N-acetylaspartate and choline in dorsolateral prefrontal cortex in patients with schizophrenia

AU - Jarskog, L. Fredrik

AU - Dong, Zhengchao

AU - Kangarlu, Alayar

AU - Colibazzi, Tiziano

AU - Girgis, Ragy R.

AU - Kegeles, Lawrence S.

AU - Barch, Deanna M.

AU - Buchanan, Robert W.

AU - Csernansky, John G.

AU - Goff, Donald C.

AU - Harms, Michael P.

AU - Javitt, Daniel C.

AU - Keefe, Richard Se

AU - McEvoy, Joseph Patrick

AU - McMahon, Robert P.

AU - Marder, Stephen R.

AU - Peterson, Bradley S.

AU - Lieberman, Jeffrey A.

PY - 2013/6/1

Y1 - 2013/6/1

N2 - 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.

AB - 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.

KW - MRS

KW - cognition

KW - neuroprotective

KW - neurotrophic

KW - proton magnetic resonance spectroscopy

UR - http://www.scopus.com/inward/record.url?scp=84878556531&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84878556531&partnerID=8YFLogxK

U2 - 10.1038/npp.2013.23

DO - 10.1038/npp.2013.23

M3 - Article

C2 - 23325325

AN - SCOPUS:84878556531

VL - 38

SP - 1245

EP - 1252

JO - Neuropsychopharmacology

JF - Neuropsychopharmacology

SN - 0893-133X

IS - 7

ER -