Krankenhauspsychiatrie 2002; 13(Sh1): 7-12
DOI: 10.1055/s-2002-34597
Originalarbeit
© Georg Thieme Verlag Stuttgart · New York

Pathophysiologische Erklärungsansätze bipolarer Störungen - Was kann uns der Wirkmechanismus von Stimmungsstabilisierern verraten?

Pathophysiological Explanations for Bipolar Disorders - what Can we Learn from Mood Stabilisers?H.  Grunze1 , J.  Walden2
  • 1Psychiatrische Klinik der LMU München
  • 2Abteilung für Psychiatrie und Psychotherapie der Albert-Ludwigs-Universität, Freiburg
Further Information

Publication History

Publication Date:
09 October 2002 (online)

Zusammenfassung

Spätestens seit der klassifikatorischen Erweiterung durch DSM IV und ICD 10 in Richtung eines bipolaren Spektrums kann man annehmen, dass bipolare Störungen nicht nur klinisch heterogen sind, sondern auch unterschiedliche Mechanismen der Erkrankung zugrunde liegen können. Dennoch gibt es einige übergreifende Prinzipien, die bei der Regulierung der neuronalen Erregbarkeit, aber auch bei der Überlebensfähigkeit der Neurone eine tragende Rolle spielen. Hier sind zugleich Angriffspunkte der im klinischen Alltag am häufigsten eingesetzten Stimmungsstabilisierer, wie Lithium, Carbamazepin, Valproat oder Lamotrigin. Der Wirkmechanismus dieser Substanzen lässt zumindest indirekte Schlüsse zu, welche Störungen auf zellulärer Ebene den bipolaren Störungen zugrunde liegen könnten.

Abstract

Not ever since the broadening of diagnosis towards bipolar spectrum disorder with DSM IV and ICD-10 at the latest, we should assume that bipolar disorders are not only clinically heterogeneous, but may have a diversity of underlying pathophysiological disturbances. However, there are some general principles which are of importance both for the regulation of neuronal excitability and neuronal survival. They may also constitute the main targets of clinically used mood stabilisers as lithium, carbamazepine, valproate and lamotrigine. The mechanisms of action of these substances may give us at least indirect hints for the underlying cellular disturbances in bipolar disorders.

Literatur

  • 1 Mukherjee S, Sackeim H A, Schnur D B. Electroconvulsive therapy of acute manic episodes: a review of 50 years' experience.  Am J Psychiatry. 1994;  151(2) 169-176
  • 2 Mukherjee S. Mechanisms of antimanic effect of electroconvulsive therapy.  Convulsive Therapy. 1989;  5 227-243
  • 3 Granger P, Biton B, Faure C, Vige X, Depoortere H, Graham D, Langer S Z, Scatton B, Avenet P. Modulation of the gamma-aminobutyric acid type A receptor by the antiepileptic drugs carbamazepine and phenytoin.  Mol Pharmacol. 1995;  47(6) 1189-1196
  • 4 Emrich H M, Wolf R. Valproate treatment of mania.  Prog Neuropsychopharmacol Biol Psychiatry. 1992;  16(5) 691-701
  • 5 Shank R P, Gardocki J F, Streeter A J, Maryanoff B E. An overview of the preclinical aspects of topiramate: pharmacology, pharmacokinetics, and mechanism of action.  Epilepsia. 2000;  41 Suppl 1 S3-S9
  • 6 Grunze H, Erfurth A, Marcuse A, Amann B, Normann C, Walden J. Tiagabine appears not to be efficacious in the treatment of acute mania.  J Clin Psychiatry. 1999;  60(11) 759-762
  • 7 Lampe H, Bigalke H. Carbamazepine blocks NMDA-activated currents in cultured spinal cord neurons.  Neuroreport. 1990;  1(1) 26-28
  • 8 Löscher W. Effects of the antiepileptic drug valproate on metabolism and function of inhibitory and excitatory amino acids in the brain.  Neurochem Res. 1993;  18(4) 485-502
  • 9 Teoh H, Fowler L J, Bowery N G. Effect of lamotrigine on the electrically-evoked release of endogenous amino acids from slices of dorsal horn of the rat spinal cord.  Neuropharmacology. 1995;  34(10) 1273-1278
  • 10 Waldmeier P C, Baumann P A, Wicki P, Feldtrauer J J, Stierlin C, Schmutz M. Similar potency of carbamazepine, oxcarbazepine, and lamotrigine in inhibiting the release of glutamate and other neurotransmitters.  Neurology. 1995;  45(10) 1907-1913
  • 11 Smith L, Price-Jones M, Hughes K, Egebjerg J, Poulsen F, Wiberg F C, Shank R P. Effects of topiramate on kainate- and domoate-activated [14C]guanidinium ion flux through GluR6 channels in transfected BHK cells using Cytostar-T scintillating microplates.  Epilepsia. 2000;  41 Suppl 1 S48-S51
  • 12 Buki V M, Goodnick P. Catecholamines. In: Goodnick P, editor. Mania. Clinical and Research perspectives Washington DC: APA Press 1998: 119-134
  • 13 Löscher W, Hönack D. Valproate and its major metabolite E-2-en-valproate induce different effects on behaviour and brain monoamine metabolism in rats.  Eur J Pharmacol. 1996;  299 (1 - 3) 61-67
  • 14 Sokomba E N, Patsalos P N, Lolin Y I, Curzon G. Concurrent monitoring of central carbamazepine and transmitter amine metabolism and motor activity in individual unrestrained rats using repetitive withdrawal of cerebrospinal fluid.  Neuropharmacology. 1988;  27 (4) 409-415
  • 15 Yatham L N, Liddle P F, Shia I, Lam R W, Ngan E. Presynaptic dopamine function in first episode neuroleptic and mood stabilizer naive non-psychotic mania and effects of treatment with divalproex sodium. a PET study.  Bipolar Disord. 2001;  3 [Suppl. 1] 62
  • 16 Diehl D J, Gershon S. The role of dopamine in mood disorders.  Compr Psychiatry. 1992;  33 (2) 115-120
  • 17 Wong W F, Pearlson G D, Tune L E, Young L T, Meltzer C C, Dannals R F, Ravert H T, Reith J, Kuhar M J, Gjedde A. Quantification of neuroreceptors in the living human brain: IV. Effect of aging and elevations of D2-like receptors in schizophrenia and bipolar illness.  J Cereb Blood Flow Metab. 1997;  17 (3) 331-342
  • 18 Manki H, Kanba S, Muramatsu T, Higuchi S, Suzuki E, Matsushita S, Ono Y, Chiba H, Shintani F, Nakamura M, Yagi G, Asai M. Dopamine D2, D3 and D4 receptor and transporter gene polymorphisms and mood disorders.  J Affect Disord. 1996;  40 (1 - 2) 7-13
  • 19 Kelsoe J R, Sadovnick A D, Kristbjarnarson H, Bergesch P, Mroczkowski-Parker Z, Drennan M, Rapaport M H, Flodman P, Spence M A, Remick R A. Possible locus for bipolar disorder near the dopamine transporter on chromosome 5.  Am J Med Genet. 1996;  67 (6) 533-540
  • 20 Waldman I D, Robinson B F, Feigon S A. Linkage disequilibrium between the dopamine transporter gene (DAT1) and bipolar disorder: extending the transmission disequilibrium test (TDT) to examine genetic heterogeneity.  Genet Epidemiol. 1997;  14 (6) 699-704
  • 21 Maes M, Calabrese J, Jayathilake K, Meltzer H Y. Effects of subchronic treatment with valproate on L-5-HTP-induced cortisol responses in mania: evidence for increased central serotonergic neurotransmission.  Psychiatry Res. 1997;  71 (2) 67-76
  • 22 Normann C. Towards a new model for cellular pathophysiology in affective disorder.  Acta Neuropsychiatrica. 2000;  12 (3) 77-80
  • 23 Mühlbauer H D, Müller-Oerlinghausen B. Fenfluramine stimulation of serum cortisol in patients with major affective disorders and healthy controls: further evidence for a central serotonergic action of lithium in man.  J Neural Transm. 1985;  61 (1 - 2) 81-94
  • 24 Hegerl U, Wulff H, Müller-Oerlinghausen B. Intensity dependence of auditory evoked potentials and clinical response to prophylactic lithium medication: a replication study.  Psychiatry Res. 1992;  44 (3) 181-190
  • 25 Whitton P S, Oreskovic D, Jernej B, Bulat M. Effect of valproic acid on 5-hydroxytryptamine turnover in mouse brain.  J Pharm Pharmacol. 1985;  37 (3) 199-200
  • 26 Dailey J W, Reith M E, Yan Q S, Li M Y, Jobe P C. Carbamazepine increases extracellular serotonin concentration: lack of antagonism by tetrodotoxin or zero Ca2+.  Eur J Pharmacol. 1997;  328 (2 - 3) 153-162
  • 27 Southam E, Kirby D, Higgins G A, Hagan R M. Lamotrigine inhibits monoamine uptake in vitro and modulates 5-hydroxytryptamine uptake in rats.  Eur J Pharmacol. 1998;  358 19-24
  • 28 von Wegerer J, Berger M, Walden J. Changes of serotonin-induced field potentials by lamotrigine.  Epilepsia. 1997;  38 [Suppl. 3] 175-176
  • 29 Macdonald R L, Kelly K M. Antiepileptic drug mechanisms of action.  Epilepsia. 1995;  36 Suppl 2 S2-12
  • 30 Mishory A, Yaroslavsky Y, Bersudsky Y, Belmaker R H. Phenytoin as an antimanic anticonvulsant: a controlled study.  Am J Psychiatry. 2000;  157 (3) 463-465
  • 31 Grunze H, Kammerer C, Ackenheil M. The neurobiology of bipolar disorder.  Journal of Bipolar Disorder. 1997;  1 (1) 2-12
  • 32 Hough C, Lu S J, Davis C L, Chuang D M, Post R M. Elevated basal and thapsigargin-stimulated intracellular calcium of platelets and lymphocytes from bipolar affective disorder patients measured by a fluorometric microassay.  Biol Psychiatry. 1999;  46 (2) 247-255
  • 33 el Mallakh R S, Wyatt R J. The Na,K-ATPase hypothesis for bipolar illness.  Biol Psychiatry. 1995;  37 (4) 235-244
  • 34 Wood A J, Elphick M, Aronson J K, Grahame-Smith D G. The effect of lithium on cation transport measured in vivo in patients suffering from bipolar affective illness.  Br J Psychiatry. 1989;  155 504-510
  • 35 Moscovich D G, Belmaker R H, Agam G, Livne A. Inositol-1-phosphatase in red blood cells of manic-depressive patients before and during treatment with lithium.  Biol Psychiatry. 1990;  27 (5) 552-555
  • 36 Berridge M J, Irvine R F. Inositol phosphates and cell signalling.  Nature. 1989;  341 (6239) 197-205
  • 37 Vaden D L, Ding D, Peterson B, Greenberg M L. Lithium and valproate decrease inositol mass and increase expression of the yeast ino1 and ino2 genes for inositol biosynthesis.  J Biol Chem. 2001;  276 15 466-15 471
  • 38 Lisman J. The CaM kinase II hypothesis for the storage of synaptic memory.  Trends Neurosci. 1994;  17 (10) 406-412
  • 39 Lenox R H, Watson D G. Lithium and the brain: a psychopharmacological strategy to a molecular basis for manic depressive illness.  Clin Chem. 1994;  40 (2) 309-314
  • 40 Walden J, Grunze H, Bingmann D, Liu Z, Dusing R. Calcium antagonistic effects of carbamazepine as a mechanism of action in neuropsychiatric disorders: studies in calcium dependent model epilepsies.  Eur Neuropsychopharmacol. 1992;  2 (4) 455-462
  • 41 Altrup U, Gerlach G, Reith H, Said M N, Speckmann E J. Effects of valproate in a model nervous system (buccal ganglia of Helix pomatia): I. Antiepileptic actions.  Epilepsia. 1992;  33 (4) 743-752
  • 42 Wegerer J V, Hesslinger B, Berger M, Walden J. A calcium antagonistic effect of the new antiepileptic drug lamotrigine.  Eur Neuropsychopharmacol. 1997;  7 77-81
  • 43 Xie X, Hagan R M. Cellular and molecular actions of lamotrigine: Possible mechanisms of efficacy in bipolar disorder.  Neuropsychobiology. 1998;  38 119-130
  • 44 Hollister L E, Trevino E S. Calcium channel blockers in psychiatric disorders: a review of the literature.  Can J Psychiatry. 1999;  44 (7) 658-664
  • 45 Garcia D A, Franke H, Pissarek M, Nieber K, Illes P. Neuroprotection by ATP-dependent potassium channels in rat neocortical brain slices during hypoxia.  Neurosci Lett. 1999;  273 (1) 13-16
  • 46 Tanaka T, Yoshida M, Yokoo H, Mizoguchi K, Tanaka M. ATP-sensitive K+ channel openers block sulpiride-induced dopamine release in the rat striatum.  Eur J Pharmacol. 1996;  297 (1 - 2) 35-41
  • 47 Zona C, Tancredi V, Palma E, Pirrone G C, Avoli M. Potassium currents in rat cortical neurons in culture are enhanced by the antiepileptic drug carbamazepine.  Can J Physiol Pharmacol. 1990;  68 (4) 545-547
  • 48 Olpe H, Kolb C N, Hausdorf A, Haas H L. 4-aminopyridine and barium chloride attenuate the anti-epileptic effect of carbamazepine in hippocampal slices.  Experientia. 1991;  47 (3) 254-257
  • 49 Georg M D, Klitgaard H. Inhibition of neuronal hypersynchrony in vitro differentiates levetiracetam from classical antiepileptic drugs.  Pharmacol Res. 2000;  42 (4) 281-285
  • 50 Walden J, Altrup U, Reith H, Speckmann E J. Effects of valproate on early and late potassium currents of single neurons.  Eur Neuropsychopharmacol. 1993;  3 (2) 137-141
  • 51 Grunze H, Greene R W, Möller H-J, Meyer T, Walden J. Lamotrigine may limit pathological excitation in the hippocampus by modulating a transient potassium outward current.  Brain Res. 1998;  791 (1 - 2) 330-334
  • 52 Chandy K G, Fantino E, Wittekindt O, Kalman K, Tong L L, Ho T H, Gutman G A, Crocq M A, Ganguli R, Nimgaonkar V, Morris-Rosendahl D J, Gargus J J. Isolation of a novel potassium channel gene hSKCa3 containing a polymorphic CAG repeat: a candidate for schizophrenia and bipolar disorder?.  Mol Psychiatry. 1998;  3 (1) 32-37
  • 53 Chang A, Li P P, Kish S, Warsh J J. Altered cAMP-dependent protein kinase subunit immunolabeling in postmortem brain from patients with bipolar affective disorder.  Bipolar Disord. 2001;  3 [Suppl. 1] 31
  • 54 Manji H K, Lenox R H. Protein kinase C signaling in the brain: molecular transduction of mood stabilization in the treatment of manic-depressive illness.  Biol Psychiatry. 1999;  46 (10) 1328-1351
  • 55 Jensen J B, Mork A. Altered protein phosphorylation in the rat brain following chronic lithium and carbamazepine treatments.  Eur Neuropsychopharmacol. 1997;  7 (3) 173-179
  • 56 Bebchuk J M, Arfken C L, Dolan M S, Murphy J, Hasanat K, Manji H K. A preliminary investigation of a protein kinase C inhibitor in the treatment of acute mania.  Arch Gen Psychiatry. 2000;  57 (1) 95-97
  • 57 Hughes P, Dragunow M. Induction of immediate-early genes and the control of neurotransmitter-regulated gene expression within the nervous system.  Pharmacol Rev. 1995;  47 (1) 133-178
  • 58 Chen G, Masana M I, Manji H K. Lithium regulates PKC-mediated intracellular cross-talk and gene expression in the CNS in vivo.  Bipolar Disord. 2000;  2 (3) 217-236
  • 59 Bonnet U, Bingmann D, Wiemann M. Intracellular pH modulates spontaneous and epileptiform bioelectric actifity of hippocampal CA3 neurones.  Eur Neuropsychopharmacol. 2000;  97 97-103
  • 60 Kato T, Murashita J, Kamiya A, Shiori T, Kato N, Inubushi T. Decreased brain intracellular pH measured by 31P-MRS in bipolar disorder: a confirmation in drug-free patients and correlation with white matter hyperintensity.  Eur Arch Psychiatry Clin Neurosci. 1998;  248 301-306
  • 61 Drevets W C, Gadde K M, Krishnan K BR. Neuroimaging studies of mood disorders. In: Charney DS, Nestler EJ, Bunney WE, editors. Neurobiology of mental illness New York: Oxford Press 1999: 394-418
  • 62 Chen G, Huang L D, Zeng W Z, Manji H K. Mood stabilizers regulate cytoprotective and mRNA-binding proteins in the brain: long-term effects on cell survival and transcript stability.  Int J Neuropsychopharmacol. 2001;  4 (1) 47-64
  • 63 Bishop A L, Hall A. Rho GTPases and their effector proteins.  Biochem J. 2000;  348 (2) 241-255
  • 64 Kaibuchi K, Kuroda S, Amano M. Regulation of the cytoskeleton and cell adhesion by the Rho family GTPases in mammalian cells.  Annu Rev Biochem. 1999;  68 459-486
  • 65 Rundfeldt C. Potassium channels and neurodegenerative diseases.  Drug News Perspect. 1999;  12 99-104

Dr. med. H. Grunze

Psychiatrische Klinik der LMU

Nußbaumstr. 7

80336 München

Email: grunze@psy.med.uni-muenchen.de