Hostname: page-component-cd9895bd7-lnqnp Total loading time: 0 Render date: 2024-12-25T18:15:24.917Z Has data issue: false hasContentIssue false
  • English
  • Français

Magnetic resonance spectroscopic measurement of cerebral gamma-aminobutyric acid concentrations in patients with bipolar disorders

Published online by Cambridge University Press:  24 June 2014

Po W. Wang ,
Napapon Sailasuta ,
Rebecca A. Chandler  and
Terence A. Ketter
Po W. Wang*
Affiliation:
Department of Psychiatry and Behavioral Sciences, Bipolar Disorders Clinic, Stanford University School of Medicine, Stanford, CA, USA
Napapon Sailasuta
Affiliation:
Department of Medicine, University of Hawaii, Honolulu, HI ,USA
Rebecca A. Chandler
Affiliation:
Department of Psychiatry, Oxford University, Oxford, UK
Terence A. Ketter
Affiliation:
Department of Psychiatry and Behavioral Sciences, Bipolar Disorders Clinic, Stanford University School of Medicine, Stanford, CA, USA
*
Po W. Wang, MD, Acting Assistant Professor, Department of Psychiatry and Behavioral Sciences, Bipolar Disorders Clinic, Stanford University School of Medicine, 401 Quarry Road, Suite 2117, Stanford, CA 94305-5723, USA. Tel: +1 650 723 2483; Fax: +1 650 723 2507; E-mail: wangp0@stanford.edu
Get access Rights & Permissions [Opens in a new window]

Abstract

Background:

Animal models of depression and psychopharmacological mechanisms of action suggest the importance of the gamma-amino butyric acid (GABA) system in the pathophysiology of mood disorders. Mood stabilizers have overlapping effects on GABAergic neurotransmission, and antidepressant use has been associated with alterations in GABAB receptor function. Magnetic resonance spectroscopy (MRS) provides an opportunity to noninvasively assess cerebral GABA concentrations in anterior paralimbic circuits that have been implicated in mood disorders.

Methods:

In bipolar disorder patients and healthy control subjects, we used MRS with a modified GABA-edited point resolved spectroscopy sequence (TE 68 ms, TR 1500 ms, 512 averages, total scan time 26 min) to assess GABA in an 18-cm3 occipital voxel. In addition, in another cohort of bipolar disorder patients and healthy control subjects, we similarly assessed GABA in a 12.5-cm3 medial prefrontal/anterior cingulate (MPF/AC) voxel. The concentration of GABA was referenced to creatine (Cr) from unedited spectra.

Results:

In bipolar patients and controls, we consistently detected 3.0 p.p.m. GABA peaks in occipital lobe and MPF/AC. In 16 bipolar (nine bipolar I and seven bipolar II) disorder patients, compared with six healthy control subjects, mean occipital GABA/Cr concentration was 61% higher. In addition, in 15 bipolar (five bipolar I, nine bipolar II, and one bipolar not otherwise specified) disorder patients, compared with six healthy control subjects, mean MPF/AC GABA/Cr concentration tended to be 41% higher.

Conclusions:

Patients with bipolar disorders may have increased cerebral GABA concentrations. Although this was more evident in the occipital lobe, MPC/AC GABA disturbance may be of greater potential interest in view the more established role of MPF/AC in affective processing. Additional studies are warranted to assess changes in GABAergic neurotransmission and the influences of diagnosis, mood state, and medication status in bipolar disorder patients.

Keywords

gamma-aminobutyric acid (GABA)mood disordersbenzodiazepinesantidepressantsmood stabilizersanticonvulsantsantipsychotics
Type
Case Report
Information
Acta Neuropsychiatrica , Volume 18 , Issue 2 , April 2006 , pp. 120 - 126
Copyright
Copyright © 2006 Blackwell Munksgaard

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Roberts, E, Chase, TN, Tower, DB. GABA in nervous system function. New York: Raven Press, 1976. Google Scholar
Schon, FE, Iversen, LL. The use of autoradiographic techniques for the identification and mapping of transmitter-specific neurones in the brain. Life Sci 1974;15: 157–175. CrossRefGoogle ScholarPubMed
Fahn, S, Cote, LJ. Regional distribution of gamma-aminobutyric acid (GABA) in brain of the rhesus monkey. J Neurochem 1968;15 (2):209–213. CrossRefGoogle ScholarPubMed
Bowery, NG, Hudson, AL, Price, GW. GABAA and GABAB receptor site distribution in the rat central nervous system. Neuroscience 1987;20 (2):365–383. CrossRefGoogle ScholarPubMed
Borsini, F, Mancinelli, A, D'Aranno, V, Evangelista, S, Meli, A. On the role of endogenous GABA in the forced swimming test in rats. Pharmacol Biochem Behav 1988;29 (2):275–279. CrossRefGoogle ScholarPubMed
Sherman, AD, Petty, F. Neurochemical basis of the action of antidepressants on learned helplessness. Behav Neural Biol 1980;30 (2):119–134. CrossRefGoogle ScholarPubMed
Petty, F, Sherman, AD. GABAergic modulation of learned helplessness. Pharmacol Biochem Behav 1981;15 (4):567–570. CrossRefGoogle ScholarPubMed
Martin, P, Pichat, P, Massol, J, Soubrie, P, Lloyd, KG, Puech, AJ. Decreased GABA B receptors in helpless rats: reversal by tricyclic antidepressants. Neuropsychobiology 1989;22 (4):220–224. CrossRefGoogle ScholarPubMed
Lloyd, KG, Pichat, P. Decrease in GABA-B in the frontal cortex of olfactory bulbectomized rats. Br J Pharmacol 1985;87: 36P. (Abstract).Google Scholar
Joly, D, Lloyd, KG, Pichat, P, Sanger, DJ. Correlation between the behavioral effect of desipramine and GABA-B receptor regulation in the olfactory bulbectomized rat. Br J Pharmacol 1987;90: 125P. (Abstract).Google Scholar
Emrich, HM, Von Zerssen, D, Kissling, W, Moller, HJ, Windorfer, A. Effect of sodium valproate on mania. The GABA-hypothesis of affective disorders. Arch Psychiatr Nervenkr 1980;229 (1):1–16. CrossRefGoogle ScholarPubMed
Bernasconi, R. The GABA hypothesis of affective illness: influence of clinically effective antimanic drugs on GABA turnover. In: Emrich, HM, Aidenhoff, JB, Lux, HD, eds. Basic mechanisms in the action of lithium. Proceedings of a Symposium, Bavaria, 1981. Amsterdam: Elsevier Science Publishing, 1982: 183–192. Google Scholar
Bartholini, G, Lloyd, KG, Scatton, B, Zivkovic, B, Morselli, PL. The GABA hypothesis of depression and antidepressant drug action. Psychopharmacol Bull 1985;21 (3):385–388. Google ScholarPubMed
Motohashi, N, Ikawa, K, Kariya, T. GABAB receptors are up-regulated by chronic treatment with lithium or carbamazepine. GABA hypothesis of affective disorders? Eur J Pharmacol 1989;166 (1):95–99. CrossRefGoogle ScholarPubMed
Lloyd, KG, Zivkovic, B, Scatton, B, Morselli, PL, Bartholini, G. The GABAergic hypothesis of depression. Prog Neuropsychopharmacol Biol Psychiatry 1989;13 (3–4):341–351. CrossRefGoogle ScholarPubMed
Petty, F. GABA and mood disorders: a brief review and hypothesis. J Affect Disord 1995;34 (4):275–281. CrossRefGoogle ScholarPubMed
Twyman, RE, Rogers, CJ, Macdonald, RL. Differential regulation of gamma-aminobutyric acid receptor channels by diazepam and phenobarbital. Ann Neurol 1989;25 (3):213–220. CrossRefGoogle ScholarPubMed
Gray, JA, Goodwin, GM, Heal, DJ, Green, AR. Hypothermia induced by baclofen, a possible index of GABAB receptor function in mice, is enhanced by antidepressant drugs and ECS. Br J Pharmacol 1987;92 (4): 863–870. CrossRefGoogle ScholarPubMed
Gray, JA, Green, AR. Increased GABAB receptor function in mouse frontal cortex after repeated administration of antidepressant drugs or electroconvulsive shocks. Br J Pharmacol 1987;92 (2):357–362. CrossRefGoogle ScholarPubMed
Lloyd, KG, Thuret, F, Pilc, A. Upregulation of gamma-aminobutyric acid (GABA) B binding sites in rat frontal cortex: a common action of repeated administration of different classes of antidepressants and electroshock. J Pharmacol Exp Ther 1985;235 (1):191–199. Google ScholarPubMed
Lloyd, KG, Thuret, F, Pilc, A. GABA and the mechanism of action of antidepressant drugs. In: Bartholini, G, Lloyd, KG, Morselli, PL, eds. GABA and mood disorders: experimental and clinical research. (L.E.R.S. Monograph Series, Vol. IV). New York: Raven Press, 1986: 33–42. Google Scholar
Pratt, GD, Bowery, NG. Repeated administration of desipramine and a GABAB receptor antagonist, CGP 36742, discretely up-regulates GABAB receptor binding sites in rat frontal cortex. Br J Pharmacol 1993;110 (2): 724–735. CrossRefGoogle Scholar
Uzunov, DP, Cooper, TB, Costa, E, Guidotti, A. Fluoxetine-elicited changes in brain neurosteroid content measured by negative ion mass fragmentography. Proc Natl Acad Sci USA 1996;93 (22):12599–12604. CrossRefGoogle ScholarPubMed
Uzunova, V, Sheline, Y, Davis, JMet al. Increase in the cerebrospinal fluid content of neurosteroids in patients with unipolar major depression who are receiving fluoxetine or fluvoxamine. Proc Natl Acad Sci USA 1998;95 (6):3239–3244. CrossRefGoogle ScholarPubMed
Bernasconi, R, Martin, P. Effects of antiepiletic drugs on the GABA turnover rate. Naunyn Schmiedebergs Arch Pharmacol 1979;307: R63. (Abstract 251).Google Scholar
Bernasconi, R, Hauser, K, Martin, P, Shcmutz, M. Biochemical aspects of the mechanism of action of valproate. In: Emrich, HM, Okuma, T, Müller, AA, eds. Anticonvulsants in affective disorders. Amsterdam: Elsevier Science Publishers B.V., 1984: 14–32. Google Scholar
Schwark, WS, Löscher, W. Comparison of the anticonvulsant effects of two novel GABA uptake inhibitors and diazepam in amygdaloid kindled rats. Naunyn Schmiedebergs Arch Pharmacol 1985;329 (4):367–371. CrossRefGoogle ScholarPubMed
Motohashi, N. GABA receptor alterations after chronic lithium administration. Comparison with carbamazepine and sodium valproate. Prog Neuropsychopharmacol Biol Psychiatry 1992;16 (4):571–579. Google ScholarPubMed
Gottesfeld, Z, Ebstein, BS, Samuel, D. Effect of lithium on concentrations of glutamate and GABA levels in amygdala and hypothalamus of rat. Nat New Biol 1971;234 (47):124–125. CrossRefGoogle ScholarPubMed
Ahluwalia, P, Grewaal, DS, Singhal, RL. Brain GABAergic and dopaminergic systems following lithium treatment and withdrawal. Prog Neuropsychopharmacol 1981;5 (5–6):527–530. CrossRefGoogle ScholarPubMed
Marcus, SR, Nadiger, HA, Chandrakala, MV, Rao, TI, Sadasivudu, B. Acute and short-term effects of lithium on glutamate metabolism in rat brain. Biochem Pharmacol 1986;35 (3):365–369. CrossRefGoogle ScholarPubMed
Rubio, MC, Otero Losada, ME. GABAergic responses to lithium chloride: dependence on dose, treatment length and experimental condition. Adv Biochem Psychopharmacol 1986;42: 69–77. Google ScholarPubMed
Higuchi, T, Yamazaki, O, Takazawa, Aet al. Effects of carbamazepine and valproic acid on brain immunoreactive somatostatin and gamma-aminobutyric acid in amygdaloid-kindled rats. Eur J Pharmacol 1986;125 (2): 169–175. CrossRefGoogle ScholarPubMed
Mitsushio, H, Takashima, M, Mataga, N, Toru, M. Effects of chronic treatment with trihexyphenidyl and carbamazepine alone or in combination with haloperidol on substance P content in rat brain: a possible implication of substance P in affective disorders. J Pharmacol Exp Ther 1988;245 (3):982–989. Google ScholarPubMed
Nagaki, S, Kato, N, Minatogawa, Y, Higuchi, T. Effects of anticonvulsants and gamma-aminobutyric acid (GABA)-mimetic drugs on immunoreactive somatostatin and GABA contents in the rat brain. Life Sci 1990;46 (22):1587–1595. CrossRefGoogle ScholarPubMed
Patsalos, PN, Lascelles, PT. Changes in regional brain levels of amino acid putative neurotransmitters after prolonged treatment with the anticonvulsant drugs diphenylhydantoin, phenobarbitone, sodium valproate, ethosuximide, and sulthiame in the rat. J Neurochem 1981;36 (2):688–695. CrossRefGoogle ScholarPubMed
Otero Losada, ME, Rubio, MC. Acute and chronic effects of lithium chloride on GABA-ergic function in the rat corpus striatum and frontal cerebral cortex. Naunyn Schmiedebergs Arch Pharmacol 1986;332 (2): 169–172. CrossRefGoogle ScholarPubMed
Hitchcock, E, Teixeira, M. Anticonvulsant activation of pain-suppressive systems. Appl Neurophysiol 1982;45 (6):582–593. Google ScholarPubMed
Biggs, CS, Pearce, BR, Fowler, LJ, Whitton, PS. The effect of sodium valproate on extracellular GABA and other amino acids in the rat ventral hippocampus: an in vivo microdialysis study. Brain Res 1992;594 (1):138–142. CrossRefGoogle ScholarPubMed
Loscher, W, Horstermann, D. Differential effects of vigabatrin, gamma-acetylenic GABA, aminooxyacetic acid, and valproate on levels of various amino acids in rat brain regions and plasma. Naunyn Schmiedebergs Arch Pharmacol 1994;349 (3):270–278. CrossRefGoogle ScholarPubMed
Marx, CE, Duncan, GE, Gilmore, JH, Lieberman, JA, Morrow, AL. Olanzapine increases allopregnanolone in the rat cerebral cortex. Biol Psychiatry 2000;47 (11):1000–1004. CrossRefGoogle ScholarPubMed
Farnbach-Pralong, D, Bradbury, R, Copolov, D, Dean, B. Clozapine and olanzapine treatment decreases rat cortical and limbic GABA (A) receptors. Eur J Pharmacol 1998;349 (2–3):R7–R8. CrossRefGoogle ScholarPubMed
Sakai, K, Gao, XM, Hashimoto, T, Tamminga, CA. Traditional and new antipsychotic drugs differentially alter neurotransmission markers in basal ganglia-thalamocortical neural pathways. Synapse 2001;39 (2):152–160. 3.0.CO;2-F>CrossRefGoogle ScholarPubMed
Mattson, RH, Petroff, OA, Rothman, D, Behar, K. Vigabatrin: effect on brain GABA levels measured by nuclear magnetic resonance spectroscopy. Acta Neurol Scand Suppl 1995;162: 27–30. Google ScholarPubMed
Petroff, OA, Rothman, DL, Behar, KL, Lamoureux, D, Mattson, RH. The effect of gabapentin on brain gamma-aminobutyric acid in patients with epilepsy. Ann Neurol 1996;39 (1):95–99. CrossRefGoogle ScholarPubMed
Dager, SR, Friedman, SD, Parow, Aet al. Brain metabolic alterations in medication-free patients with bipolar disorder. Arch Gen Psychiatry 2004;61 (5):450–458. CrossRefGoogle ScholarPubMed
Friedman, SD, Dager, SR, Parow, Aet al. Lithium and valproic acid treatment effects on brain chemistry in bipolar disorder. Biol Psychiatry 2004;56 (5):340–348. CrossRefGoogle ScholarPubMed
Sanacora, G, Mason, GF, Rothman, DLet al. Reduced cortical gamma-aminobutyric acid levels in depressed patients determined by proton magnetic resonance spectroscopy. Arch Gen Psychiatry 1999;56 (11):1043–1047. CrossRefGoogle ScholarPubMed
Sanacora, G, Mason, GF, Rothman, DL, Krystal, JH. Increased occipital cortex GABA concentrations in depressed patients after therapy with selective serotonin reuptake inhibitors. Am J Psychiatry 2002;159 (4):663–665. CrossRefGoogle ScholarPubMed
Hasler, G, Neumeister, A, van der Veen, JWet al. Normal prefrontal gamma-aminobutyric acid levels in remitted depressed subjects determined by proton magnetic resonance spectroscopy. Biol Psychiatry 2005;58 (12):969–973. CrossRefGoogle ScholarPubMed
Sailasuta, N, Leroux, P, Hurd, RE, Wang, PW, Sachs, N, Ketter, TA. Detection of cerebral gamma-aminobutyric acid (GABA) in bipolar disorder patients and healthy volunteers at 3T. Proc Int Soc Magn Reson Med 2001;9: 1011. Google Scholar
Shen, J, Rothman, DL, Brown, P. In vivo GABA editing using a novel doubly selective multiple quantumfilter. Magn Reson Med 2002;47: 447–454. CrossRefGoogle Scholar
Sanacora, G, Mason, GF, Rothman, DLet al. Increased cortical GABA concentrations in depressed patients receiving ECT. Am J Psychiatry 2003;160 (3):577–579. CrossRefGoogle ScholarPubMed
Ketter, TA, George, MS, Kimbrell, TA, Benson, BE, Post, RM. Functional brain imaging, limbic function, and affective disorders. Neuroscientist 1996;2 (1):55–65. CrossRefGoogle Scholar