Glutamatergic effects of divalproex in adolescents with mania: a proton magnetic resonance spectroscopy study.
OBJECTIVE
This study used proton magnetic resonance spectroscopy ((1)H MRS) to evaluate the in vivo effects of extended-release divalproex sodium on the glutamatergic system in adolescents with bipolar disorder, and to identify baseline neurochemical predictors of clinical remission.


METHODS
Adolescents with bipolar disorder who were experiencing a manic or mixed episode (N = 25) were treated with open-label, extended-release divalproex (serum levels 85-125 μg/mL) and underwent (1)H MRS scanning at baseline (before treatment) and on days 7 and 28. Healthy comparison subjects (n = 15) also underwent (1)H MRS scanning at the same time points. Glutamate (Glu) and glutamate+glutamine (Glx) concentrations were measured in three voxels: anterior cingulate cortex (ACC), left ventrolateral prefrontal cortex (LVLPFC), and right ventrolateral prefrontal cortex (RVLPFC), and were compared between bipolar and healthy subjects. Within the bipolar subjects, Glu and Glx concentrations at baseline and each time point were also compared between remitters and nonremitters after divalproex treatment.


RESULTS
At baseline, no differences in Glu or Glx concentrations between bipolar and healthy subjects were observed. Group (HC vs. BP) by time effects revealed an interaction for Glu in the ACC, and change over time effects for Glx were noted in the ACC in patients with bipolar disorder (increase from day 0 to day 7 and then a decrease from day 7 to day 28) but not in HC. Remitters had significantly lower baseline Glx concentrations in LVLPFC, and in remitters the change in LVLPFC Glu correlated with the change in YMRS score.


CONCLUSIONS
Successful treatment of mania with divalproex may be predicted by lower baseline concentrations of Glx in the LVLPFC. In addition, in remitters, the degree of symptomatic improvement is related to the change in Glu concentrations in this region, suggesting that divalproex may work via modulation of the prefrontal glutamatergic system in youth with bipolar disorder.
University of Cincinnati, College of Medicine, Cincinnati, OH 45267, USA.
Jeffrey R
JR
Strawn
Nick C
NC
Patel
Wen-Jang
WJ
Chu
Jing-Huei
JH
Lee
Caleb M
CM
Adler
Mi Jung
MJ
Kim
Holly S
HS
Bryan
David C
DC
Alfieri
Jeffrey A
JA
Welge
Thomas J
TJ
Blom
Jayasree J
JJ
Nandagopal
Stephen M
SM
Strakowski
Melissa P
MP
DelBello
D000293:Adolescent; D018692:Antimanic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001714:Bipolar Disorder / Q000175:diagnosis / Q000188:drug therapy / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D008297:Male; D018377:Neurotransmitter Agents / Q000378:metabolism; D011569:Psychiatric Status Rating Scales; D012074:Remission Induction; D016896:Treatment Outcome; D014635:Valproic Acid / Q000494:pharmacology / Q000627:therapeutic use
D018692:Antimanic Agents; D018377:Neurotransmitter Agents; D018698:Glutamic Acid; D014635:Valproic Acid