Glutamatergic Effects of Divalproex in Adolescents With Mania: A Proton Magnetic Resonance Spectroscopy Study


      This study used proton magnetic resonance spectroscopy (1H 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.


      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 1H MRS scanning at baseline (before treatment) and on days 7 and 28. Healthy comparison subjects (n = 15) also underwent 1H 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.


      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.


      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.

      Key Words

      To read this article in full you will need to make a payment


        • Bhangoo R.K.
        • Lowe C.H.
        • Myers F.S.
        • et al.
        Medication use in children and adolescents treated in the community for bipolar disorder.
        J Child Adolesc Psychopharmacol. 2003; 13: 515-522
        • Kowatch R.A.
        • Suppes T.
        • Carmody T.J.
        • et al.
        Effect size of lithium, divalproex sodium, and carbamazepine in children and adolescents with bipolar disorder.
        J Am Acad Child Adolesc Psychiatry. 2000; 39: 713-720
        • Wagner K.D.
        • Redden L.
        • Kowatch R.A.
        • et al.
        A double-blind, randomized, placebo-controlled trial of divalproex extended-release in the treatment of bipolar disorder in children and adolescents.
        J Am Acad Child Adolesc Psychiatry. 2009; 48: 519-532
        • Kowatch R.A.
        • DelBello M.P.
        The use of mood stabilizers and atypical antipsychotics in children and adolescents with bipolar disorders.
        CNS Spectrums. 2003; 8: 273-280
        • Löscher W.
        Valproate: a reappraisal of its pharmacodynamic properties and mechanisms of action.
        Prog Neurobiol. 1999; 58: 31-59
        • Martin G.
        • Durozard D.
        • Besson J.
        • Baverel G.
        Effect of the antiepileptic drug sodium valproate on glutamine and glutamate metabolism in isolated human kidney tubules.
        Biochim Biophys Acta. 1990; 1033: 261-266
        • Nilsson M.
        • Hansson E.
        • Rönnbäck L.
        Interactions between valproate, glutamate, aspartate, and GABA with respect to uptake in astroglial primary cultures.
        Neurochem Res. 1992; 17: 327-332
        • Kang T.C.
        • Kim D.S.
        • Kwak S.E.
        • et al.
        Valproic acid reduces enhanced vesicular glutamate transporter immunoreactivities in the dentate gyrus of the seizure prone gerbil.
        Neuropharmacology. 2005; 49: 912-921
        • Yüksel C.
        • Öngür D.
        Magnetic resonance spectroscopy studies of glutamate-related abnormalities in mood disorders.
        Biol Psychiatry. 2010; 68: 785-794
        • Michael N.
        • Erfurth A.
        • Ohrmann P.
        • et al.
        Acute mania is accompanied by elevated glutamate/glutamine levels within the left dorsolateral prefrontal cortex.
        Psychopharmacology (Berl). 2003; 168: 344-346
        • Dager S.R.
        • Friedman S.D.
        • Parow A.
        • et al.
        Brain metabolic alterations in medication-free patients with bipolar disorder.
        Arch Gen Psychiatry. 2004; 61: 450-458
        • Moore C.M.
        • Frazier J.A.
        • Glod C.A.
        • Breeze J.L.
        • et al.
        Glutamine and glutamate levels in children and adolescents with bipolar disorder: a 4.0-T proton magnetic resonance spectroscopy study of the anterior cingulate cortex.
        J Am Acad Child Adolesc Psychiatry. 2007; 46 (a): 524-534
        • Moore C.M.
        • Biederman J.
        • Wozniak J.
        • et al.
        Mania, glutamate/glutamine and risperidone in pediatric bipolar disorder: a proton magnetic resonance spectroscopy study of the anterior cingulate cortex.
        J Affect Disord. 2007; 99 (b): 19-25
        • Castillo M.
        • Kwock L.
        • Courvoisie H.
        • Hooper S.R.
        Proton MR spectroscopy in children with bipolar affective disorder: preliminary observations.
        Am J Neuroradiol. 2000; 21: 832-838
        • Mangia S.
        • Tkaac I.
        • Gruetter R.
        • et al.
        Sensitivity of single-voxel 1H-MRS in investigating the metabolism of the activated human visual cortex at 7 T.
        Magn Reson Imaging. 2006; 24: 343-348
        • Geller B.
        • Zimerman B.
        • Williams M.
        • et al.
        Reliability of the Washington University in St. Louis Kiddie Schedule for Affective Disorders and Schizophrenia (WASH-U-KSADS) mania and rapid cycling sections.
        J Am Acad Child Adolesc Psychiatry. 2001; 40: 450-455
        • DelBello M.P.
        • Schwiers M.L.
        • Rosenberg H.L.
        • Strakowski S.M.
        A double-blind, randomized, placebo-controlled study of quetiapine as adjunctive treatment for adolescent mania.
        J Am Acad Child Adolesc Psychiatry. 2002; 41: 1216-1223
        • Andreasen N.C.
        • Endicott J.
        • Spitzer R.L.
        • Winokur G.
        The family history method using diagnostic criteria: reliability and validity.
        Arch Gen Psychiatry. 1977; 34: 1229-1235
        • Young R.C.
        • Biggs J.T.
        • Ziegler V.E.
        • Meyer D.A.
        A rating scale for mania: reliability, validity and sensitivity.
        Br J Psychiatry. 1978; 133: 429-435
        • Poznanski E.O.
        • Grossman J.A.
        • Buchsbaum Y.
        • Banegas M.
        • Freeman L.
        • Gibbons R.
        Preliminary studies of the reliability and validity of the children's depression rating scale.
        J Am Acad Child Psychiatry. 1984; 23: 191-197
        • Lee J.-H.
        • Garwood M.
        • Menon R.
        • et al.
        High contrast and fast three-dimensional magnetic resonance imaging at high fields.
        Magn Reson Med. 1995; 34: 308-312
        • Cecil K.M.
        • DelBello M.P.
        • Morey R.
        • Strakowski S.M.
        Frontal lobe differences in bipolar disorder as determined by proton MR spectroscopy.
        Bipolar Disord. 2002; 4: 357-365
        • Cecil K.M.
        • DelBello M.P.
        • Sellars M.C.
        • Strakowski S.M.
        Proton magnetic resonance spectroscopy of the frontal lobe and cerebellar vermis in children with a mood disorder and a familial risk for bipolar disorders.
        J Child Adolesc Psychopharmacol. 2003; 13: 545-555
        • Gruetter R.
        • Boesch C.
        Fast, noniterative shimming of spatially localized signals.
        J Magn Reson. 1992; 96: 323-334
        • Tkac I.
        • Staruck Z.
        • Choi I.Y.
        • Gruetter R.
        In vivo 1H NMR spectroscopy of rat brain at 1ms echo time.
        Magn Reson Med. 1999; 41: 649-656
        • Provincher S.W.
        Estimation of metabolite concentration from localized in vivo proton NMR spectra.
        Magn Reson Med. 1993; 30: 672-679
        • Kalmar J.H.
        • Wang F.
        • Chepenik L.G.
        • Womer F.Y.
        • Jones M.M.
        • Pittman B.
        • Shah M.P.
        • Martin A.
        • Constable R.T.
        • Blumberg H.P.
        Relation between amygdala structure and function in adolescents with bipolar disorder.
        J Am Acad Child Adolesc Psychiatry. 2009; 48: 636-642
        • Correll C.U.
        • Sheridan E.M.
        • DelBello M.P.
        Antipsychotic and mood stabilizer efficacy and tolerability in pediatric and adult patients with bipolar I mania: a comparative analysis of acute, randomized, placebo-controlled trials.
        Bipolar Disord. 2010; 12: 116-141
        • Mayer D.
        • Spielman D.M.
        Detection of glutamate in the human brain at 3T using optimizing constant time point resolved spectroscopy.
        Magn Reson Med. 2005; 54: 439-442
        • Hu J.
        • Yang S.
        • Xuan Y.
        • Jian Q.
        • Yang Y.
        • Haacke E.M.
        Simultaneous detection of resolved glutamate, glutamine, and γ-aminobutyric acid at 4T.
        J Magn Reson. 2007; 185: 204-213
        • Yang S.
        • Hu J.
        • Kou Z.
        • Yang Y.
        Spectral simplification for resolved glutamate and glutamine measurement using a standard STEAM sequence with optimized timing parameters at 3, 4, 4.7, 7, and 9.4T.
        Magn Reson Med. 2008; 59: 236-244
        • Masi G.
        • Perugi G.
        • Millepiedi S.
        • et al.
        Pharmacological response in juvenile bipolar disorder subtypes: a naturalistic retrospective examination.
        Psychiatry Res. 2010; 177: 192-198
        • DelBello M.P.
        • Strakowski S.M.
        Neurochemical predictors of response to pharmacologic treatments for bipolar disorder.
        Curr Psychiatry Rep. 2004; 6: 466-472