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Neurobiology of antidepressant withdrawal: implications for the longitudinal outcome of depression

  • Brian H Harvey
    Correspondence
    Address reprint requests to Brian H. Harvey, Division of Pharmacology, School of Pharmacy, Potchefstroom University for Christian Higher Education, Potchefstroom, 2520, South Africa.
    Affiliations
    Division of Pharmacology (BHH), School of Pharmacy, Potchefstroom University for Christian Higher Education, Potchefstroom, South Africa
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  • Bruce S McEwen
    Affiliations
    Laboratory of Neuroendocrinology (BSM), Rockefeller University, New York, New York, USA
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  • Dan J Stein
    Affiliations
    Medical Research Council Anxiety and Stress Disorders Research Unit (DJS), Department of Psychiatry, University of Stellenbosch, Tygerberg, South Africa
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      Abstract

      Inappropriate discontinuation of drug treatment and noncompliance are a leading cause of long-term morbidity during treatment of depression. Increasing evidence supports an association between depressive illness and disturbances in brain glutamate activity, nitric oxide synthesis, and γ-amino butyric acid. Animal models also confirm that suppression of glutamate N-methyl-D-aspartate receptor activity or inhibition of the nitric oxide-cyclic guanosine monophosphate pathway, as well as increasing brain levels of γ-amino butyric acid, may be key elements in antidepressant action. Imaging studies demonstrate, for the most part, decreased hippocampal volume in patients with depression, which may worsen with recurrent depressive episodes. Preclinical models link this potentially neurodegenerative pathology to continued stress-evoked synaptic remodeling, driven primarily by the release of glucocorticoids, glutamate, and nitric oxide. These stress-induced structural changes can be reversed by antidepressant treatment. In patients with depression, antidepressant withdrawal after chronic administration is associated with a stress response as well as functional and neurochemical changes. Preclinical data also show that antidepressant withdrawal evokes a behavioral stress response that is associated with increased hippocampal N-methyl-D-aspartate receptor density, with both responses dependent on N-methyl-D-aspartate receptor activation. Drawing from both clinical and preclinical studies, this article proposes a preliminary molecular perspective and hypothesis on the neuronal implications of adherence to and discontinuation of antidepressant medication.

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      References

        • Abercrombie H.C.
        • Schaefer S.M.
        • Larson C.L.
        • Oakes T.R.
        • Lingren K.A.
        • Holden J.E.
        • et al.
        Metabolic rate in the right amygdala predicts negative affect in depressed patients.
        Neuroreport. 1998; 9: 3301-3307
        • Altamura C.
        • Maes M.
        • Dai J.
        • Meltzer H.Y.
        Plasma concentrations of excitatory amino acids, serine, glycine, taurine and histidine in major depression.
        Eur Neuropsychopharmacol. 1995; 5: 71-75
        • Altshuler L.L.
        • Bartzokis G.
        • Grieder T.
        • Curran J.
        • Mintz J.
        Amygdala enlargement in bipolar disorder and hippocampal reduction in schizophrenia.
        Arch Gen Psychiatry. 1998; 55: 663-664
        • Anderson I.M.
        Selective serotonin reuptake inhibitors versus tricyclic antidepressants.
        J Affect Disorders. 2000; 58: 19-36
        • Anthony J.P.
        • Sexton T.J.
        • Neumaier J.F.
        Antidepressant-induced regulation of 5HT1B mRNA in rat dorsal raphe nucleus reverses rapidly after drug discontinuation.
        J Neurosci Res. 2000; 61: 82-87
        • Basco M.R.
        • Rush A.J.
        Compliance of pharmacotherapy in mood disorder.
        Psychiatr Ann. 1995; 25: 269-279
        • Bell C.
        • Nutt D.J.
        Tryptophan depletion and its implications for psychiatry.
        Br J Psychiatry. 2001; 178: 399-405
        • Berk M.
        • Plein H.
        • Ferreira D.
        Platelet glutamate receptor supersensitivity in major depressive disorder.
        Clin Neuropharmacol. 2001; 24: 129-132
        • Bernstein H.G.
        • Stanarius A.
        • Baumann B.
        • Henning H.
        • Krell D.
        • Danos P.
        • et al.
        Nitric oxide synthase-containing neurons in the human hypothalamus.
        Neuroscience. 1998; 83: 867-875
        • Botteron K.N.
        • Raichle M.E.
        • Drevets W.C.
        • Heath A.C.
        • Todd R.D.
        Volumetric reduction in left subguanal prefrontal cortex in early onset depression.
        Biol Psychiatry. 2002; 51: 342-344
        • Bourdeau I.
        • Bard C.
        • Noel B.
        • Leclerc I.
        • Cordeau M.-P.
        • Belair M.
        • et al.
        Loss of brain volume in endogenous Cushing’s syndrome and its reversibility after correction of hypercortisolism.
        J Clin Endocrinol Metab. 2002; 87: 1949-1954
        • Boyer P.A.
        • Skolnick P.
        • Fossum L.H.
        Chronic administration of imipramine and citalopram alters the expression of NMDA receptor subunit mRNAs in mouse brain.
        J Mol Neurosci. 1998; 10: 219-233
        • Bremner J.
        • Narayan M.
        • Anderson E.
        • Staib L.H.
        • Miller H.L.
        • Charney D.S.
        Hippocampal volume reduction in major depression.
        Am J Psychiatry. 2000; 157: 115-118
        • Chrousos G.P.
        • Gold P.W.
        The concepts of stress and stress system disorders. Overview of physical and behavioral homeostasis.
        JAMA. 1992; 267: 1244-1252
        • Conrad C.D.
        • Magarinos A.M.
        • LeDoux J.E.
        • McEwen B.S.
        Repeated restraint stress facilitates fear conditioning independently of causing hippocampal CA3 dendritic atrophy.
        Behav Neurosci. 1999; 113: 902-913
        • Coupland N.J.
        • Bell C.J.
        • Potokar J.P.
        Serotonin reuptake inhibitor withdrawal.
        J Clin Psychopharmacol. 1996; 16: 356-362
        • Czeh B.
        • Michaelis T.
        • Watanabe T.
        • Frahm J.
        • de Biurrun G.
        • van Kampen M.
        • et al.
        Stress-induced changes in cerebral metabolites, hippocampal volume, and cell proliferation are prevented by antidepressant treatment with tianeptine.
        Proc Natl Acad Sci U S A. 2001; 98: 12796-12801
        • Dall’Olio R.
        • Gandolfi O.
        • Gaggi R.
        D-cycloserine, a positve modulator of NMDA receptors, inhibits serotonergic function.
        Behav Pharmacol. 2000; 11: 631-637
        • de Oliviera R.M.
        • Aparecida Del Bel E.
        • Mamede-Rosa M.L.
        • Padovan C.M.
        • Deakin J.F.
        • Guimaraes F.S.
        Expression of neuronal nitric oxide synthase mRNA in stress-related brain areas after restraint in rats.
        Neurosci Lett. 2000; 289: 123-126
        • De Paermentier F.
        • Mauger J.M.
        • Lowther S.
        • Crompton M.R.
        • Katona C.L.
        • Horton R.W.
        Brain alpha-adrenoceptors in depressed suicides.
        Brain Res. 1997; 757: 60-68
        • Di Cara B.
        • Dusticier N.
        • Forni N.
        • Lievens J.C.
        • Daszuta A.
        Serotonin depletion produces long-lasting increase in striatal glutamatergic transmission.
        J Neurochem. 2001; 78: 240-248
        • Dilsaver S.C.
        Antidepressant withdrawal syndromes.
        Acta Psychiatr Scand. 1989; 79: 113-117
        • Dowlatshahi D.
        • MacQueen G.M.
        • Wang J.F.
        • Reiach J.S.
        • Young L.T.
        G Protein-coupled cyclic AMP signaling in postmortem brain of subjects with mood disorders.
        J Neurochem. 1999; 73: 1121-1126
        • Dowlatshahi D.
        • MacQueen G.M.
        • Wang J.F.
        • Young L.T.
        Increased temporal cortex CREB concentrations and antidepressant treatment in major depression.
        Lancet. 1998; 352: 1754-1755
        • Drevets W.C.
        Functional anatomical abnormalities in limbic and prefrontal cortical structures in major depression.
        Prog Brain Res. 2000; 126: 413-431
        • Drevets W.C.
        • Bogers W.
        • Raichle M.E.
        Functional anatomical correlates of antidepressant drug treatment assessed using PET measures of regional glucose metaboilism.
        Eur Neuropsychopharmacol. 2002; 12: 527-544
        • Drevets W.C.
        • Price J.L.
        • Simpson Jr, J.R.
        • Todd R.D.
        • Reich T.
        • Vannier M.
        • et al.
        Subgenual prefrontal cortex abnormalities in mood disorders.
        Nature. 1997; 386: 824-827
        • D’Sa C.
        • Duman R.S.
        Antidepressants and neuroplasticity.
        Bipolar Disord. 2002; 4: 184-194
        • Duman R.S.
        • Heninger G.R.
        • Nestler E.J.
        A molecular and cellular theory of depression.
        Arch Gen Psychiatry. 1997; 54: 597-606
        • Duman R.S.
        • Nakagawa S.
        • Malberg J.
        Regulation of adult neurogenesis by antidepressant treatment.
        Neuropsychopharmacology. 2001; 25: 836-844
        • Engelmann M.
        • Wolf G.
        • Horn T.F.W.
        Release patterns of excitatory and inhibitory amino acids within the hypothalamic supraoptic nucleus in response to direct nitric oxide administration during forced swimming in rats.
        Neurosci Lett. 2002; 324: 252-254
        • Frodl T.
        • Meisenzahl E.M.
        • Zetzsche T.
        • Born C.
        • Jager M.
        • Groll C.
        • et al.
        Larger amygdala volumes in first depressive episode as compared to recurrent major depression and healthy control subjects.
        Biol Psychiatry. 2003; 53: 338-344
        • Frodl T.
        • Meisenzahl E.M.
        • Zetzsche T.
        • Bottlender R.
        • Born C.
        • Groll C.
        • et al.
        Enlargement of the amygdala in patients with a first episode of major depression.
        Biol Psychiatry. 2002; 51: 708-714
        • Gilbertson M.W.
        • Shenton M.E.
        • Ciszewski A.
        • Kasai K.
        • Lasko N.B.
        • Orr S.P.
        • et al.
        Smaller hippocampal volume predicts pathologic vulnerability to psychological trauma.
        Nature Neurosci. 2002; 5: 1242-1247
        • Golembiowska K.
        • Dziubina A.
        Effect of acute and chronic administration of citalopram on glutamate and aspartate release in the rat prefrontal cortex.
        Pol J Pharmacol. 2000; 52: 441-448
        • Gould E.
        • Tanapat P.
        • McEwen B.S.
        • Flugge G.
        • Fuchs E.
        Proliferation of granule cell precursors in the dentate gyrus of adult monkeys is diminished by stress.
        Proc Natl Acad Sci U S A. 1998; 95: 3168-3171
        • Greden J.F.
        Antidepressant maintenance medications.
        J Clin Psychiatry. 1993; 54: 39-45
        • Harkin A.
        • Nowak G.
        • Paul I.A.
        Noradrenergic lesion antagonises desimipramine-induced adaptation of NMDA receptors.
        Eur J Pharmacol. 2000; 389: 187-192
        • Harkin A.J.
        • Bruce K.H.
        • Craft B.
        • Paul I.A.
        Nitric oxide synthase inhibitors have antidepressant-like properties in mice.
        Eur J Pharmacol. 1999; 372: 207-213
        • Harvey B.H.
        Affective disorders and nitric oxide.
        Hum Psychopharmacol. 1996; 11: 309-319
        • Harvey B.H.
        The neurobiology and pharmacology of depression.
        S Afr Med J. 1997; 87: 540-552
        • Harvey B.H.
        • Jonker L.P.
        • Brand L.
        • Heenop M.
        • Stein D.J.
        NMDA receptor involvement in imipramine withdrawal-associated effects on swim stress, GABA levels and NMDA receptor binding in rat hippocampus.
        Life Sci. 2002; 71: 43-54
        • Heiberg I.L.
        • Wegener G.
        • Rosenberg R.
        Reduction of cGMP and nitric oxide has antidepressant-like effects in the forced swimming test in rats.
        Behav Brain Res. 2002; 134: 479-484
        • Henry M.E.
        • Kaufman M.J.
        • Hennen J.
        • Michelson D.
        • Schmidt M.E.
        • Stoddard E.
        • et al.
        Cerebral blood volume and clinical changes on the third day of placebo substitution for SSRI treatment.
        Biol Psychiatry. 2003; 53: 100-105
        • Ichimiya T.
        • Suhara T.
        • Sudo Y.
        • Okubo Y.
        • Nakayama Y.
        • Nankai M.
        • et al.
        Serotonin transporter binding in patients with mood disorders.
        Biol Psychiatry. 2002; 51 ([11C](+)McN5652): 715-722
        • Ishizuka Y.
        • Ishida Y.
        • Jin Q.H.
        • Mitsuyama Y.
        • Kannan H.
        GABA(A) and GABA(B) receptors modulating basal and footshock-induced nitric oxide releases in rat prefrontal cortex.
        Brain Res. 2000; 872: 266-270
        • Izumi Y.
        • Shimamoto K.
        • Benz A.M.
        • Hammerman S.B.
        • Olney J.W.
        • Zorumski C.F.
        Glutamate transporters and retinal excitotoxicity.
        Glia. 2002; 39: 58-68
        • Judd L.L.
        • Akiskal H.S.
        • Maser J.D.
        • Zeller P.J.
        • Endicott J.
        • Coryell W.
        • et al.
        Major depressive disorder.
        J Affect Disord. 1998; 50: 97-108
        • Kasper S.
        • Tauscher J.
        • Willeit M.
        • Stamenkovic M.
        • Neumeister A.
        • Kufferle B.
        • et al.
        Receptor and transporter imaging studies in schizophrenia, depression, bulimia and Tourette’s disorder-implications for psychopharmacology.
        World J Biol Psychiatry. 2002; 3: 133-146
      1. Kaufman MJ, Henry ME, Blaise F, Hennen J, Villafurete RA, Stoddard E, et al (2003): Selective serotonin reuptake inhibitor discontinuation syndrome is associated with a rostral anterior cingulate choline metabolite decrease: A proton magnetic resonance spectroscopic imaging study. Biol Psychiatry 54:534–539

        • Keller M.B.
        • Boland R.J.
        Implications of failing to achieve successful long-term maintenance treatment of recurrent unipolar major depression.
        Biol Psychiatry. 1998; 44: 348-360
        • Keller M.B.
        • Hirschfield R.M.
        • Demyttenaere K.
        • Baldwin D.S.
        Optimizing outcomes in depression.
        Int Clin Psychopharmacol. 2002; 17: 265-271
        • Kendler K.S.
        • Thornton L.M.
        • Gardner C.O.
        Genetic risk, number of previous depressive episodes, and stressful life events in predicting onset of major depression.
        Am J Psychiatry. 2001; 158: 582-586
        • Kendler K.S.
        • Thornton L.M.
        • Gardner C.O.
        Stressful life events and previous episodes in the etiology of major depression in women.
        Am J Psychiatry. 2001; 157: 1243-1251
        • Kim Y.
        • Oh S.
        Changes of GABAA receptor binding and subunit mRNA level in rat brain by infusion of NOS inhibitor.
        Brain Res. 2002; 952: 246-256
        • Kraepelin E.
        Manic-Depressive Insanity and Paranoia. ES Livingstone Press, Edinburgh1921
        • Kroczka B.
        • Branski P.
        • Palucha A.
        • Pilc A.
        • Nowak G.
        Antidepressant-like properties of zinc in rodent forced swim test.
        Brain Res Bull. 2001; 55: 297-300
        • Krukoff T.L.
        • Khalili P.
        Stress-induced activation of nitric oxide-producing neurons in the rat brain.
        J Comp Neurol. 1997; 377: 509-519
        • Krystal J.H.
        • Sanacora G.
        • Blumberg H.
        • Anand A.
        • Charney D.S.
        • Marek G.
        • et al.
        Glutamate and GABA systems as targets for novel antidepressant and mood-stabilising treatments.
        Mol Psychiatry. 2002; 7: S71-S80
        • Kuhn K.U.
        • Quednow B.B.
        • Barkow K.
        • Heun R.
        • Linden M.
        • Maier W.
        Chronic course and psychosocial disability caused by depressive illnesses in general practice patients during a one year period. Results of a study by the World Health Organization.
        Nervenarzt. 2002; 73: 644-650
        • Law A.J.
        • Deakin J.F.
        Asymmetrical reductions of hippocampal NMDAR1 glutamate receptor mRNA in the psychoses.
        Neuroreport. 2001; 12: 2971-2974
        • Lee H.J.
        • Kim J.W.
        • Yim S.V.
        • Kim M.J.
        • Kim S.A.
        • Kim Y.J.
        • et al.
        Fluoxetine enhances cell proliferation and prevents apoptosis in dentate gyrus of maternally separated rats.
        Mol Psychiatry. 2001; 6: 725-728
        • Lievens J.C.
        • Woodman B.
        • Mahal A.
        • Spasic-Boscovic O.
        • Samuel D.
        • Kerkerian-Le Goff L.
        • et al.
        Impaired glutamate uptake in the R6 Huntington’s disease transgenic mice.
        Neurobiol Dis. 2001; 8: 807-821
        • Lowy M.T.
        • Gault L.
        • Yamamoto B.K.
        Adrenalectomy attenuates stress-induced elevations in extracellular glutamate concentrations in the hippocampus.
        J Neurochem. 1993; 61: 1957-1960
        • Lucassen P.J.
        • Muller M.B.
        • Holsboer F.
        • Bauer J.
        • Holtrop A.
        • Wouda J.
        • et al.
        Hippocampal apoptosis in major depression is a minor event and absent from subareas at risk for glucocorticoid overexposure.
        Am J Pathol. 2001; 158: 453-468
        • MacQueen G.M.
        • Campbell S.
        • McEwen B.S.
        • MacDonald K.
        • Amano S.
        • Joffe R.T.
        • et al.
        Course of illness, hippocampal function, and hippocampal volume in major depression.
        Proc Natl Acad Sci U S A. 2003; 100: 1387-1392
        • Maes M.
        • Haese P.C.D.
        • Scharpe S.
        • D’Hondt P.
        • Cosyns P.
        • De Broe M.E.
        Hypozincemia in depression.
        J Affect Disord. 1994; 31: 135-140
        • Maes M.
        • Verkerk R.
        • Vandoolaeghe E.
        • Lin A.
        • Scharpe S.
        Serum levels of excitatory amino acids, serine, glycine, histidine, threonine, taurine, alanine and arginine in treatment-resistant depression.
        Acta Psychiatr Scand. 1998; 97: 302-308
        • Malberg J.E.
        • Eisch A.J.
        • Nestler E.J.
        • Duman R.S.
        Chronic antidepressant administration increases granule cell proliferation in the hippocampus of the adult male rat.
        Abstr Soc Neurosci. 1999; 25: 1029
        • Manier D.H.
        • Shelton R.C.
        • Ellis T.C.
        • Peterson C.S.
        • Eiring A.
        • Sulser F.
        Human fibroblasts as a relevant model to study signal transduction in affective disorders.
        J Affect Disord. 2000; 61: 51-58
        • Matute C.
        • Alberdi E.
        • Domercq M.
        • Perez-Cerda F.
        • Perez-Samartin A.
        • Sanchez-Gomez M.V.
        The link between excitotoxic oligodendroglial death and demyelinating diseases.
        Trends Neurosci. 2001; 24: 224-230
        • Mauri M.C.
        • Ferrara A.
        • Boscati L.
        • Bravin S.
        • Zamberlan F.
        • Alecci M.
        • et al.
        Plasma and platelet amino acid concentrations in patients affected by major depression and under fluvoxamine treatment.
        Neuropsychobiology. 1998; 37: 124-129
        • McCullumsmith R.E.
        • Meador-Woodruff J.H.
        Striatal excitatory amino acid transporter transcript expression in schizophrenia, bipolar disorder, and major depressive disorder.
        Neuropsychopharmacology. 2002; 26: 368-375
        • McEwen B.S.
        Possible mechanisms for atrophy of the human hippocampus.
        Mol Psychiatry. 1997; 2: 255-262
        • McEwen B.S.
        Stress and hippocampal plasticity.
        Annu Rev Neurosci. 1999; 22: 105-122
        • McEwen B.S.
        The neurobiology of stress.
        Brain Res. 2000; 886: 172-189
        • McEwen B.S.
        • Conrad C.D.
        • Kuroda Y.
        • Frankfurt M.
        • Magarinos M.A.
        • McKittrick C.
        Prevention of stress-induced morphological and cognitive consequences.
        Eur Neuropsychopharmacol. 1997; 7: 323-328
        • McLeod T.M.
        • Lopez-Figueroa A.L.
        • Lopez-Figueroa M.O.
        Nitric oxide, stress, and depression.
        Psychopharmacol Bull. 2001; 35: 24-41
        • Mervaala E.
        • Fohr J.
        • Kononen M.
        • Valkonen-Korhonen M.
        • Vainio P.
        • Partanen K.
        • et al.
        Quantitative MRI of the hippocampus and amygdala in severe depression.
        Psychol Med. 2000; 30: 117-125
        • Michelson D.
        • Amsterdam J.
        • Apter J.
        • Fava M.
        • Londborg P.
        • Tamura R.
        • et al.
        Hormonal markers of stress response following interruption of selective serotonin reupake inhibitor treatment.
        Psychoneuroendocrinology. 2000; 25: 169-177
        • Miller K.J.
        • Hoffman B.J.
        Adenosine A3 receptors regulate serotonin transport via nitric oxide and cGMP.
        J Biol Chem. 1994; 269: 27351-27356
        • Mischoulon D.
        • Dougherty D.D.
        • Bottonari K.A.
        • Gresham R.L.
        • Sonawalla S.B.
        • Fischman A.J.
        • et al.
        An open lable pilot study of nefazodone in depression with anger attacks.
        Psychiatry Res. 2002; 116: 151-161
        • Miyamoto Y.
        • Yamada K.
        • Noda Y.
        • Mori H.
        • Mishina M.
        • Nabeshima T.
        Lower sensitivity to stress and altered monoaminergic neuronal function in mice lacking the NMDA receptor epsilon 4 subunit.
        J Neurosci. 2002; 22: 2335-2342
        • Moore G.J.
        • Bebchuk J.M.
        • Hasanat K.
        • Chen G.
        • Saraji-Bozorgzad N.
        • Wilds I.B.
        • et al.
        Lithium increases N-acetyl-aspartate in the human brain.
        Biol Psychiatry. 2000; 48: 1-8
        • Moore G.J.
        • Bebchuck J.M.
        • Wilds I.B.
        • Chen G.
        • Manji H.K.
        Lithium-induced increase in human brain grey matter.
        Lancet. 2000; 356: 1241-1242
        • Mueller T.I.
        • Leon A.C.
        • Keller M.B.
        • Solomon D.A.
        • Endicott J.
        • Coryell W.
        • et al.
        Recurrence after recovery from major depressive disorder during 15 years of observational follow-up.
        Am J Psychiatry. 1999; 156: 1000-1006
        • Nierenberg A.A.
        Long-term management of chronic depression.
        J Clin Psychiatry. 2001; 62: 17-21
        • Nowak G.
        • Ordway G.A.
        • Paul I.A.
        Alterations in the N-methyl-D-aspartate (NMDA) receptor complex in the frontal cortex of suicide victims.
        Brain Res. 1995; 675: 157-164
        • Ohkuma S.
        • Narihara H.
        • Katsure M.
        • Hasegawa T.
        • Kuriyama K.
        Nitric oxide-induced.
        J Neurochem. 1995; 65 ([3H]-GABA release from cerebral cortical neurons in mediated by peroxynitrite): 1109-1114
        • Pandey G.N.
        • Conley R.R.
        • Pandey S.C.
        • Goel S.
        • Roberts R.C.
        • Tamminga C.A.
        • et al.
        Benzodiazepine receptors in the post-mortem brain of suicide victims and schizophrenic subjects.
        Psychiatry Res. 1997; 71: 137-149
        • Paul I.
        Antidepressant activity and calcium signaling cascades.
        Hum Psychopharmacol. 2001; 16: 71-80
        • Pawlak R.
        • Magarinos A.M.
        • Melchor J.
        • McEwen B.
        • Strickland S.
        Tissue plasminogen activator in the amygdala is critical for stress-induced anxiety-like behavior.
        Nat Neurosci. 2003; 6: 168-174
        • Pham K.
        • Nacher J.
        • Hof P.R.
        • McEwen B.S.
        Repeated restraint stress suppresses neurogenesis and induces biphasic PSA-NCAM expression in the adult rat dentate gyrus.
        Eur J Neurosci. 2003; 17: 1-8
        • Popoli M.
        • Gennarelli M.
        • Racagni G.
        Modulation of synaptic plasticity by stress and antidepressants.
        Bipolar Disord. 2002; 4: 166-182
        • Post R.M.
        Transduction of psychosocial stress into the neurobiology of recurrent affective disorder.
        Am J Psychiatry. 1992; 149: 999-1010
        • Post R.M.
        • Weiss S.R.B.
        Sensitization and kindling phenomena in mood, anxiety, and obsessive-compulsive disorders.
        Biol Psychiatry. 1998; 44: 193-206
        • Rajkowska G.
        Postmortem studies in mood disorders indicate altered numbers of neurons and glial cells.
        Biol Psychiatry. 2000; 48: 766-777
        • Rao V.L.
        • Dogan A.
        • Bowen K.K.
        • Todd K.G.
        • Dempsey R.J.
        Antisense knockdown of the glial glutamate transporter GLT-1 exacerbates hippocampal neuronal damage following traumatic injury to rat brain.
        Eur J Neurosci. 2001; 13: 119-128
        • Rasmussen A.M.
        • Shi L.
        • Duman R.
        Downregulation of BDNF mRNA in the hippocampal dentate gyrus after re-exposure to cues previously associated with footshock.
        Neuropsychopharmacology. 2002; 27: 133-142
        • Rogoz Z.
        • Skuza G.
        • Maj J.
        • Danysz W.
        Synergistic effects of uncompetitive NMDA receptor antagonists and antidepressant drugs in the forced swimming test in rats.
        Neuropharmacology. 2002; 42: 1024-1030
        • Sapolsky R.M.
        Glucocorticoids and hippocampal atrophy in neuropsychiatric disorders.
        Arch Gen Psychiatry. 2000; 57: 925-935
        • Saransaari P.
        • Oja S.S.
        Enhanced GABA release in cell-damaging conditions in the adult and developing mouse hippocampus.
        Int J Dev Neurosci. 1997; 15: 163-174
        • Schatzberg A.F.
        • Haddad P.
        • Kaplan E.M.
        • Lejoyeux M.
        • Rosenbaum J.F.
        • Young A.H.
        • et al.
        Possible biological mechanisms of the serotonin reuptake inhibitor discontinuation syndrome.
        J Clin Psychiatry. 1997; 58: 23-27
        • Sheline Y.
        • Sanghavi M.
        • Mintun M.
        • Gado M.
        Depression duration but not age predicts hippocampal volume loss in medical healthy women with recurrent major depression.
        J Neurosci. 1999; 19: 5034-5043
        • Sheline Y.I.
        • Gado M.H.
        • Price J.L.
        Amygdala core nuclei volumes are decreased in recurrent major depression.
        Neuroreport. 1998; 9: 2023-2028
        • Shiah I.S.
        • Yatham L.S.
        GABA function in mood disorders.
        Life Sci. 1998; 63: 1289-1303
        • Skolnick P.
        Antidepressants for the new millenium.
        Eur J Pharmacol. 1999; 375: 31-40
        • Skolnick P.
        • Layer R.T.
        • Popik P.
        • Nowak G.
        • Paul I.A.
        • Trullas R.
        • et al.
        Adaptation of N-methyl-D-aspartate receptors following antidepressant treatment.
        Pharmacopsychiatry. 1996; 29: 23-26
        • Smith M.A.
        • Makino S.
        • Kvetnansky R.
        • Post R.M.
        Stress and glucocorticoids affect the expression of brain-derived neurotrophic factor and neurotrophin-3 mRNAs in the hippocampus.
        J Neurosci. 1995; 15: 1768-1777
        • Sousa N.
        • Lukoyanov N.V.
        • Madeira M.D.
        • Almeida O.F.X.
        • Paula-Barbosa M.M.
        Reorganization of the morphology of hippocampal neurites and synapses after stress-induced damage correlates with behavioral improvement.
        Neuroscience. 2000; 97: 253-266
        • Spadone C.
        Treatment adherence in the recurrent depressive disorders.
        Encephale. 2002; 28: 255-259
        • Stahl S.
        Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. Cambridge University Press, Cambridge, UK1996
        • Starkman M.N.
        • Gebarski S.S.
        • Berent S.
        • Schteingart D.E.
        Hippocampoal formation volume, memory dysfunction, and cortisol levels in patients with Cushings syndrome.
        Biol Psychiatry. 1992; 32: 756-765
        • Starkman M.N.
        • Giordani B.
        • Berent S.
        • Schork M.A.
        • Schteingart D.E.
        Elevated cortisol levels in Cushings disease are associated with cognitive decrements.
        Psychosom Med. 2001; 63: 985-993
        • Starkman M.N.
        • Giordani B.
        • Gebarski S.S.
        • Berent S.
        • Schork M.A.
        • Schteingart D.E.
        Decrease in cortisol reverses human hippocampal atrophy following treatment of Cushings disease.
        Biol Psychiatry. 1999; 46: 1595-1602
        • Starkman M.N.
        • Giordani B.
        • Gebarski S.S.
        • Schteingart D.E.
        Improvement in learning associated with increase in hippocampal formation volume.
        Biol Psychiatry. 2003; 53: 233-238
        • Stewart C.A.
        • Reid I.C.
        Antidepressant mechanisms.
        Mol Psychiatry. 2002; 7: S15-S22
        • Strakowski S.M.
        • DelBello M.P.
        • Sax K.W.
        • Zimmerman M.E.
        • Shear P.K.
        • Hawkins J.M.
        • et al.
        Brain magnetic resonance imaging of structural abnormalities in bipolar disorder.
        Arch Gen Psychiatry. 1999; 56: 254-260
        • Stryjer R.
        • Strous R.D.
        • Shaked G.
        • Bar F.
        • Feldman B.
        • Kotler M.
        • et al.
        Amantadine as augmentation therapy in the management of treatment resistant depression.
        Int Clin Psychopharmacol. 2003; 18: 93-96
        • Sullivan E.V.
        • Pfefferbaum A.
        • Swan G.E.
        • Carmelli D.
        Heritability of hippocampal size in elderly men.
        Hippocampus. 2001; 11: 754-762
        • Suzuki E.
        • Yagi G.
        • Nakaki T.
        • Kanba S.
        • Asai M.
        Elevated plasma nitrate levels in depressive states.
        J Affect Disord. 2001; 63: 221-224
        • Tagliaferro P.
        • Ramos A.J.
        • Lopez-Costa J.J.
        • Lopez E.M.
        • Saavedra J.P.
        • Brusco A.
        Increased nitric oxide synthase activity in a model of serotonin depletion.
        Brain Res Bull. 2001; 54: 199-205
        • Tebartz van Elst L.
        • Woermann F.
        • Lemieux L.
        • Trimble M.R.
        Increased amygdala volume in female and depressed humans.
        Neurosci Lett. 2000; 281: 103-106
        • Vaidya V.A.
        • Rewilliger R.M.Z.
        • Duman R.S.
        Role of 5HT2A receptors in the stress-induced down-regulation of brain-derived neurotrophic factor expression in rat hippocampus.
        Neurosci Lett. 1999; 262: 1-4
        • Vyas A.
        • Mitra R.
        • Rao B.S.S.
        • Chattarji S.
        Chronic stress induces contrasting patterns of dendritic remodeling in hippocampal and amygdaloid neurons.
        J Neurosci. 2002; 22: 6810-6818
        • Wegener G.
        • Volke V.
        • Rosenberg R.
        Endogenous nitric oxide decreases hippocampal levels of serotonin and dopamine in vivo.
        Br J Pharmacol. 2000; 130: 575-580
        • Xing G.
        • Chavko M.
        • Zhang L.X.
        • Yang S.
        • Post R.M.
        Decreased calcium-dependent constitutive nitric oxide synthase (cNOS) activity in prefrontal cortex in schizophrenia and depression.
        Schizophr Res. 2002; 58: 21-30
        • Yamada J.
        • Saitow F.
        • Satake S.
        • Kiyohara T.
        • Konoshi S.
        GABAB receptor-mediated presynaptic inhibition of glutamatergic and GABA’ergic transmission in the basolateral amygdala.
        Neuropharmacology. 1999; 38: 1743-1753
        • Yuan J.
        • Yankner B.A.
        Apoptosis in the nervous system.
        Nature. 2000; 407: 802-809
        • Zajecka J.
        • Tracy K.A.
        • Mitchell S.
        Discontinuation symptoms after treatment with serotonin reuptake inhibitors.
        J Clin Psychiatry. 1997; 58: 291-297
        • Zetterström T.S.C.
        • Pei Q.
        • Madhev T.R.
        • Coppel A.L.
        • Lewis L.
        • Grahame-Smith D.G.
        Manipulations of brain 5HT levels affect gene expression for BDNF in rat brain.
        Neuropharmacology. 1999; 38: 1063-1073