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N-Methyl D-Aspartic Acid (NMDA) Receptors and Depression

Year 2009, Volume: 1 Issue: 1, 22 - 35, 01.03.2009

Abstract

The monoaminergic hypothesis of depression has provided the basis for extensive research into the pathophysiology of mood disorders and has been of great significance for the development of effective antidepressants. Current antidepressant treatments not only increase serotonin and/or noradrenaline bioavailability but also originate adaptive changes increasing synaptic plasticity. Novel approaches to depression and to antidepressant therapy are now focused on intracellular targets that regulate neuroplasticity and cell survival. Accumulating evidence indicates that there is an anatomical substrate for such a devastating neuropsychiatric disease as major depression. Loss of synaptic plasticity and hippocampal atrophy appear to be prominent features of this highly prevalent disorder. A combination of genetic susceptibility and environmental factors make hippocampal neurons more vulnerable to stress. Abundant experimental evidence indicates that stress causes neuronal damage in brain regions, notably in hippocampal subfields. Stress-induced activation of glutamatergic transmission may induce neuronal cell death through excessive stimulation of N-methyl-D-aspartic acid (NMDA) receptors. Recent studies mention that the increase of nitric oxide synthesis and inflammation in major depression may contribute to neurotoxicity through NMDA receptor. Both standard antidepressants and NMDA receptor antagonists are able to prevent stress-induced neuronal damage. NMDA antagonists are effective in widely used animal models of depression and some of them appear to be effective also in the few clinical trials performed to date. We are still far from understanding the complex cellular and molecular events involved in mood disorders. There appears to be an emerging role for glutamate neurotransmission in the search for the pathogenesis of major depression. Attenuation of NMDA receptor function mechanism appears to be a promising target in the search for a more effective antidepressant therapy.

References

  • Schechter LE, Ring RH, Beyer CE, Hughes ZA, Khawaja X, Malberg JE, Rosenzweig-Lipson S. Innovative approaches for the development of antidepressant drugs: Current and future strategies. NeuroTherapeutics 2005; 2:590-611.
  • Hashimoto K, Shimizu E, Iyo M. Critical role of brain-derived neurotrophic factor in mood disorders. Brain Res Rev 2004; 45:104-114.
  • Stahl SM. Temel Psikofarmakoloji Nörobilimsel Temeli ve Pratik Uygulamaları. Taneli B, Taneli Y (Çevirenler) 2. Baskı, İstanbul: Yelkovan Yayıncılık, 2003.
  • Kırlı S. Depresyon. 1. Baskı, Bursa: Psikiyatri ve Sanat Yayınevi, 2002: 26–30.
  • Sala M, Perez J, Soloff P, di Nemi SU, Caverzasi E, Soares JC, Brambilla P. Stress and hippocampus abnormalities in psychiatric disorders. Eur Neuropsychopharmacol 2004; 14:393–405.
  • Fuchs E, Czeh B, Kole MHP, Michaelis T, Lucassen PL. Alterations of neuroplasticity in depression: the hippocampus and beyond. Eur Neuropsychopharmacol 2004;14:481–490.
  • Eșel E. Depresyondaki nöroendokrinolojik bulgular. Klinik Psikiyatri 2002; 4:35– 50.
  • Mössner R, Mikova O, Koutsilieri E, Saoud M, Ehlis AC, Müler N, Fallgatter AJ, Riederer P. Consensus paper of the WFSBP Task Force on Biological Markers: Biological Markers in Depression. World J Biol Psychiatry 2007; 8; 3:141–174.
  • Schmidt HD, Duman RS. The role of neurotrophic factors in adult hippocampal neurogenesis, antidepressant treatments and animal models of depressive- like behavior. Behav Pharmacol 2007; 18:391–418.
  • Uzbay T. Nöroplastisite ve Depresyon. 1. Baskı, Ankara: Çizgi Tıp Yayınevi, 2005:39–42.
  • Czeh B, Michaelis T, Watanabe T, Frahm J, de Biurrun G, van Kampen M, Bartolomucci A, Fuchs E. Stress-induced changes in cerebral metabolites, hippocampal volume, and cell proliferation are prevented by antidepressant treatment with tianeptine. Proc Natl Acad Sci USA 2001; 98:12796–12801.
  • Gürpınar D, Erol A, Mete L. Depresyon ve nöroplastisite. Klinik Psikofarmakoloji Bülteni 2007; 17:100–110.
  • Gönül AS, Akdeniz F. Depresyon, nöroplastisite, nörogenesis ve nörotrofik faktörler. Klinik Psikiyatri 2002; 4:51–56.
  • Palizvan MR, Sohya K. Brain-derived neurotrophic factor increases inhibitory synapses, revealed in solitary neurons cultured from rat visual cortex. Neuroscience 2004; 126:955–966.
  • Frechilla D, Insausti R. Implanted BDNF-producing fibroblasts prevent neurotoxin-induced serotonergic denervation in the rat striatum. Brain Res Mol Brain Res 2000; 76: 306–314.
  • Yulug B, Ozan E, Gonul AS, Kilic E. ve ark. Brain-derived neurotrophic factor, stres and depression: A minireview. Brain Res Bull 2009; 78:267–269.
  • Shirayama Y, Chen AC, Nakagawa S. Brain-derived neurotrophic factor produces antidepressant effects in behavioral models of depression. J. Neurosci 2002; 22: 3251–3261.
  • Rot M, Mathew SJ, Charney DS. Neurobiological mechanisms in major depressive disorder. CMAJ 2009; 180; 3:305–313.
  • Karege F, Perret G, Bandolfi G, Schwald M, Bertschy G, Aubry JM. Decreased serum brain-derived neurotrophic factor levels in major depressive patients. Psychiatry Res 2002; 109; 2:143– 148.
  • Karege F, Bandolfi G, Gervasoni N, Schwald M, Aubry JM, Bertschy G. Low brain-derived neurotrophic factor (BDNF) levels in serum of depressed patients probably results from lowered platelet BDNF release unrelated to platelet reactivity. Biol Psychiatry 2005; 57:1068–1072.
  • Shimizu E, Hashimoto K, Okamura N, Koike K, Komatsu N. Alterations of serum levels of Brain-Derived Neurotrophic factor (BDNF) in depressed patients with or without Antidepressants. Biol Psychiatry 2003; 54:70–75.
  • Aydemir C, Yalcin ES, Aksaray S, Kisa C, Yildirim SG, Uzbay T, Goka E. Brain- derived neurotrophic factor (BDNF) changes in the serum of depressed women. Prog Neuropsychopharmacol Biol Psychiatry 2006; 30:1256–1260.
  • Lee BH, Kim H, Park SH, Kim YK. Decreased plasma BDNF level in depressive patients. J Affect Disord 2007; 101:239–244.
  • Kim YK, Lee HP, Won SD, Park EY, Lee HY. Low plasma BDNF is associated with suicidal behavior in major depression. Prog Neuropsychopharmacol Biol Psychiatry 2007; 31:78–85.
  • Deveci A, Aydemir O, Taksin O, Taneli F, Esen-Danaci A. Serum BDNF levels in suicide attempters related to psychosocial stressors: a comparative study with depression. Neuropsychobiology 2007; 56:93–97.
  • Aydemir O, Deveci A, Taneli F. The effect of chronic antidepressant treatment on serum brain-derived neurotrophic factor levels in depressed patients: a preliminary study. Prog Neuropsychopharmacol Biol Psychiatry 2005; 29: 261 –265.
  • Gonul AS, Akdeniz F, Taneli F, Ozlem D, Eker C, Vahip S. Effect of treatment on serum brain-derived neurotrophic factor levels in depressed patients. Eur Arch Psychiatry Clin Neurosci 2005; 255:381–386.
  • Huang TL, Lee CT, Liu YL. Serum brain-derived neurotrophic factor levels in patients with major depression: Effects of antidepressants. J Psychiatr Res 2008;42:521-525.
  • Piccinni A, Marazziti D, Catena M, Domenici L, Debbio AD, Bianchi C. Plasma and serum brain-derived neurotrophic factor (BDNF) in depressed patients during 1 year of antidepressant treatments. J Affect Disord 2008; 105:279–283.
  • Piccinni A, Debbio AD, Medda P, Bianchi C, Roncaglia I. Plasma Brain-Derived neurotrophic factor in treatment-resistant depressed patients receiving electroconvulsive therapy. Eur Neuropsychopharmacol 2009; 19: 349 – 355.
  • Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med 2003; 9: 669–676.
  • Palmer TD, Willhoite AR, Gage FH. Vascular niche for asdult hippocampal neurogenesis. J Comp Neurol 2000; 425:479–494.
  • Cao L, Jiao X, Zuzga DS, Liu Y, Fong DM, Young D. VEGF links hippocampal activity with neurogenesis, learning and memory. Nat Genet 2004; 36:827 – 835.
  • Raab S, Plate KH. Different networks, common growth factors: shared growth factors and receptors of the vascular and the nervous system. Acta Neuropathol 2007; 113:607 – 626.
  • Heine VM, Zareno J, Malsam S, Joels M, Lucassen PJ. Chronic stress in the adult dentate gyrus reduces cell proliferation near the vasculature and VEGF and Flk-1 protein expression. Eur J Neurosci 2005; 21:1304 –1314.
  • Newton SS, Collier EF, Hunsberger J, Adams D, Terwilliger R, Selvanayagam E. Gene profile of electroconvulsive seizures: induction of neurotrophic and angiogenic factors. J Neurosci 2003; 23:10841–10851.
  • Iga J, Ueno S, Yamauchi K, Numata S, Tayoshi-Shibuya S, Kinouchi S. Gene expression and association analysis of vascular endothelial growyh factor in major depressive disorder. Prog Neuropsychopharmacol Biol Psychiatry 2007; 31: 658–663.
  • Dome P, Teleki Z, Rihmer Z, Peter L, Dobos J, Kenessey I. Circulating endothelial progenitor cells and depression: apossible novel link between heart and soul. Mol Psychiatry 2008; doi:10.1038/sj.mp.4002138.
  • Ventriglia M, Zanardini R, Pedrini L, Placentino A. VEGF serum levels in depressed patients during SSRI antidepressant treatment. Prog Neuropsychopharmacol Biol Psychiatry 2009; 33:146–149.
  • Kahl KG, Bens S, Ziegler K Rudolf S, Kordon A, Dibbelt L, Schwieger U. Angiogenic factors in patients with current major depressive disorder comorbid with borderline personality disorder. Psychoneuroendocrinology 2009; 34: 353–357.
  • Hock C, Heese K, Muller-Spahn F, Huber P, Riesen W, Nitsch RM, Otten U. Increased cerebrospinal fluid levels of neurotrophin 3 (NT-3) in elderly patients with major depression. Mol Psychiatry 2000, 5: 510–513.
  • Dwivedi Y, Mondal AC, Rizavi HS, Conley RR. Suicide brain is associated with decreased expression of neurotrophins. Biol Psychiatry 2005; 58: 315–324.
  • Lu B, Pang PT, Woo NH. The yin and yang of neurotrophin action. Nat Rev Neurosci 2005, 6: 603–614.
  • Khawaja X, Xu J, Liang JJ, Barrett JE. Proteomic analysis of protein changes developing in rat hippocampus after chronic antidepressant treatment: implications for depressive disorders and future therapies. J Neurosci Res 2004; 75: 451–460.
  • Gaughran F, Payne J, Sedgwick PM Cotter D, Berry M. Hippocampal FGF – 2 and FGFR1 mRNA expression in major depression, schizophrenia and bipolar disorder. Brain Res Bull 2006; 70: 221–227.

Depresyon ve N-Metil D-Aspartik Asit (NMDA) Reseptör İlişkisi

Year 2009, Volume: 1 Issue: 1, 22 - 35, 01.03.2009

Abstract

Depresyonun monoaminerjik hipotezi, duygu durum bozukluklarının patofizyolojisini araştırma ve önemli etkinliğe sahip antidepresanların geliştirilmesinde bir temel oluşturmuştur. Günümüzün antidepresan tedavileri yalnızca serotonin ve/veya noradrenalin biyoyararlanımını arttırmayıp, aynı zamanda sinaptik plastisiteyi artırarak adaptif değişiklikler ortaya çıkarmaktadır. Major depresif bozukluk (MDB) patogenezi ve antidepresan tedavilere yeni yaklaşımlar hücresel hayatta kalım ve nöroplastisiteyi düzenleyen hücreiçi hedeflere yöneliktir. Sinaptik plastisitenin kaybı ve hipokampal atrofi bu yaygın hastalığın belirgin özellikleri gibi görünmektedir. Genetik duyarlılık ve çevresel faktörlerin bir araya gelmesi ile hipokampal nöronlar strese daha duyarlı hale gelmektedir. Stresin hipokampal alanlar başta olmak üzere beyinde nöronal hasara sebep olduğu deneysel kanıtlarla gösterilmiştir. Glutamaterjik transmisyon aktivasyonunun stresle indüksiyonu aşırı N-metil-D-aspartik asit (NMDA) reseptör stimülasyonu aracılığıyla nöronal hücre ölümünü tetikleyebilmektedir. Son yıllarda MDB'de arttığı ileri sürülen inflamasyon ve nitrik oksit (NO) düzeylerinin de, NMDA reseptörü üzerinden nörotoksisiteyi arttırdığı düşünülmektedir. Hem standart antidepresanlar hem de NMDA reseptör antagonistleri stresle indüklenen nöronal hasarı önleyebilmektedir. NMDA antagonistleri depresyonun hayvan modellerinde belirgin şekilde, klinik denemelerde de kısmen etkin bulunmuştur. Bugün hala duygu durum bozukluklarında yeri olan kompleks hücresel ve moleküler olayları anlamaya uzak olunsa da, MDB patogenezinin araştırılmasında glutamat nörotransmisyonunun önemli bir yere sahip olduğu söylenebilir. Daha etkin antidepresan tedavi araştırmasında, NMDA reseptör fonksiyonunun azaltılması umut vaad eden bir mekanizmadır.

References

  • Schechter LE, Ring RH, Beyer CE, Hughes ZA, Khawaja X, Malberg JE, Rosenzweig-Lipson S. Innovative approaches for the development of antidepressant drugs: Current and future strategies. NeuroTherapeutics 2005; 2:590-611.
  • Hashimoto K, Shimizu E, Iyo M. Critical role of brain-derived neurotrophic factor in mood disorders. Brain Res Rev 2004; 45:104-114.
  • Stahl SM. Temel Psikofarmakoloji Nörobilimsel Temeli ve Pratik Uygulamaları. Taneli B, Taneli Y (Çevirenler) 2. Baskı, İstanbul: Yelkovan Yayıncılık, 2003.
  • Kırlı S. Depresyon. 1. Baskı, Bursa: Psikiyatri ve Sanat Yayınevi, 2002: 26–30.
  • Sala M, Perez J, Soloff P, di Nemi SU, Caverzasi E, Soares JC, Brambilla P. Stress and hippocampus abnormalities in psychiatric disorders. Eur Neuropsychopharmacol 2004; 14:393–405.
  • Fuchs E, Czeh B, Kole MHP, Michaelis T, Lucassen PL. Alterations of neuroplasticity in depression: the hippocampus and beyond. Eur Neuropsychopharmacol 2004;14:481–490.
  • Eșel E. Depresyondaki nöroendokrinolojik bulgular. Klinik Psikiyatri 2002; 4:35– 50.
  • Mössner R, Mikova O, Koutsilieri E, Saoud M, Ehlis AC, Müler N, Fallgatter AJ, Riederer P. Consensus paper of the WFSBP Task Force on Biological Markers: Biological Markers in Depression. World J Biol Psychiatry 2007; 8; 3:141–174.
  • Schmidt HD, Duman RS. The role of neurotrophic factors in adult hippocampal neurogenesis, antidepressant treatments and animal models of depressive- like behavior. Behav Pharmacol 2007; 18:391–418.
  • Uzbay T. Nöroplastisite ve Depresyon. 1. Baskı, Ankara: Çizgi Tıp Yayınevi, 2005:39–42.
  • Czeh B, Michaelis T, Watanabe T, Frahm J, de Biurrun G, van Kampen M, Bartolomucci A, Fuchs E. Stress-induced changes in cerebral metabolites, hippocampal volume, and cell proliferation are prevented by antidepressant treatment with tianeptine. Proc Natl Acad Sci USA 2001; 98:12796–12801.
  • Gürpınar D, Erol A, Mete L. Depresyon ve nöroplastisite. Klinik Psikofarmakoloji Bülteni 2007; 17:100–110.
  • Gönül AS, Akdeniz F. Depresyon, nöroplastisite, nörogenesis ve nörotrofik faktörler. Klinik Psikiyatri 2002; 4:51–56.
  • Palizvan MR, Sohya K. Brain-derived neurotrophic factor increases inhibitory synapses, revealed in solitary neurons cultured from rat visual cortex. Neuroscience 2004; 126:955–966.
  • Frechilla D, Insausti R. Implanted BDNF-producing fibroblasts prevent neurotoxin-induced serotonergic denervation in the rat striatum. Brain Res Mol Brain Res 2000; 76: 306–314.
  • Yulug B, Ozan E, Gonul AS, Kilic E. ve ark. Brain-derived neurotrophic factor, stres and depression: A minireview. Brain Res Bull 2009; 78:267–269.
  • Shirayama Y, Chen AC, Nakagawa S. Brain-derived neurotrophic factor produces antidepressant effects in behavioral models of depression. J. Neurosci 2002; 22: 3251–3261.
  • Rot M, Mathew SJ, Charney DS. Neurobiological mechanisms in major depressive disorder. CMAJ 2009; 180; 3:305–313.
  • Karege F, Perret G, Bandolfi G, Schwald M, Bertschy G, Aubry JM. Decreased serum brain-derived neurotrophic factor levels in major depressive patients. Psychiatry Res 2002; 109; 2:143– 148.
  • Karege F, Bandolfi G, Gervasoni N, Schwald M, Aubry JM, Bertschy G. Low brain-derived neurotrophic factor (BDNF) levels in serum of depressed patients probably results from lowered platelet BDNF release unrelated to platelet reactivity. Biol Psychiatry 2005; 57:1068–1072.
  • Shimizu E, Hashimoto K, Okamura N, Koike K, Komatsu N. Alterations of serum levels of Brain-Derived Neurotrophic factor (BDNF) in depressed patients with or without Antidepressants. Biol Psychiatry 2003; 54:70–75.
  • Aydemir C, Yalcin ES, Aksaray S, Kisa C, Yildirim SG, Uzbay T, Goka E. Brain- derived neurotrophic factor (BDNF) changes in the serum of depressed women. Prog Neuropsychopharmacol Biol Psychiatry 2006; 30:1256–1260.
  • Lee BH, Kim H, Park SH, Kim YK. Decreased plasma BDNF level in depressive patients. J Affect Disord 2007; 101:239–244.
  • Kim YK, Lee HP, Won SD, Park EY, Lee HY. Low plasma BDNF is associated with suicidal behavior in major depression. Prog Neuropsychopharmacol Biol Psychiatry 2007; 31:78–85.
  • Deveci A, Aydemir O, Taksin O, Taneli F, Esen-Danaci A. Serum BDNF levels in suicide attempters related to psychosocial stressors: a comparative study with depression. Neuropsychobiology 2007; 56:93–97.
  • Aydemir O, Deveci A, Taneli F. The effect of chronic antidepressant treatment on serum brain-derived neurotrophic factor levels in depressed patients: a preliminary study. Prog Neuropsychopharmacol Biol Psychiatry 2005; 29: 261 –265.
  • Gonul AS, Akdeniz F, Taneli F, Ozlem D, Eker C, Vahip S. Effect of treatment on serum brain-derived neurotrophic factor levels in depressed patients. Eur Arch Psychiatry Clin Neurosci 2005; 255:381–386.
  • Huang TL, Lee CT, Liu YL. Serum brain-derived neurotrophic factor levels in patients with major depression: Effects of antidepressants. J Psychiatr Res 2008;42:521-525.
  • Piccinni A, Marazziti D, Catena M, Domenici L, Debbio AD, Bianchi C. Plasma and serum brain-derived neurotrophic factor (BDNF) in depressed patients during 1 year of antidepressant treatments. J Affect Disord 2008; 105:279–283.
  • Piccinni A, Debbio AD, Medda P, Bianchi C, Roncaglia I. Plasma Brain-Derived neurotrophic factor in treatment-resistant depressed patients receiving electroconvulsive therapy. Eur Neuropsychopharmacol 2009; 19: 349 – 355.
  • Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med 2003; 9: 669–676.
  • Palmer TD, Willhoite AR, Gage FH. Vascular niche for asdult hippocampal neurogenesis. J Comp Neurol 2000; 425:479–494.
  • Cao L, Jiao X, Zuzga DS, Liu Y, Fong DM, Young D. VEGF links hippocampal activity with neurogenesis, learning and memory. Nat Genet 2004; 36:827 – 835.
  • Raab S, Plate KH. Different networks, common growth factors: shared growth factors and receptors of the vascular and the nervous system. Acta Neuropathol 2007; 113:607 – 626.
  • Heine VM, Zareno J, Malsam S, Joels M, Lucassen PJ. Chronic stress in the adult dentate gyrus reduces cell proliferation near the vasculature and VEGF and Flk-1 protein expression. Eur J Neurosci 2005; 21:1304 –1314.
  • Newton SS, Collier EF, Hunsberger J, Adams D, Terwilliger R, Selvanayagam E. Gene profile of electroconvulsive seizures: induction of neurotrophic and angiogenic factors. J Neurosci 2003; 23:10841–10851.
  • Iga J, Ueno S, Yamauchi K, Numata S, Tayoshi-Shibuya S, Kinouchi S. Gene expression and association analysis of vascular endothelial growyh factor in major depressive disorder. Prog Neuropsychopharmacol Biol Psychiatry 2007; 31: 658–663.
  • Dome P, Teleki Z, Rihmer Z, Peter L, Dobos J, Kenessey I. Circulating endothelial progenitor cells and depression: apossible novel link between heart and soul. Mol Psychiatry 2008; doi:10.1038/sj.mp.4002138.
  • Ventriglia M, Zanardini R, Pedrini L, Placentino A. VEGF serum levels in depressed patients during SSRI antidepressant treatment. Prog Neuropsychopharmacol Biol Psychiatry 2009; 33:146–149.
  • Kahl KG, Bens S, Ziegler K Rudolf S, Kordon A, Dibbelt L, Schwieger U. Angiogenic factors in patients with current major depressive disorder comorbid with borderline personality disorder. Psychoneuroendocrinology 2009; 34: 353–357.
  • Hock C, Heese K, Muller-Spahn F, Huber P, Riesen W, Nitsch RM, Otten U. Increased cerebrospinal fluid levels of neurotrophin 3 (NT-3) in elderly patients with major depression. Mol Psychiatry 2000, 5: 510–513.
  • Dwivedi Y, Mondal AC, Rizavi HS, Conley RR. Suicide brain is associated with decreased expression of neurotrophins. Biol Psychiatry 2005; 58: 315–324.
  • Lu B, Pang PT, Woo NH. The yin and yang of neurotrophin action. Nat Rev Neurosci 2005, 6: 603–614.
  • Khawaja X, Xu J, Liang JJ, Barrett JE. Proteomic analysis of protein changes developing in rat hippocampus after chronic antidepressant treatment: implications for depressive disorders and future therapies. J Neurosci Res 2004; 75: 451–460.
  • Gaughran F, Payne J, Sedgwick PM Cotter D, Berry M. Hippocampal FGF – 2 and FGFR1 mRNA expression in major depression, schizophrenia and bipolar disorder. Brain Res Bull 2006; 70: 221–227.
There are 45 citations in total.

Details

Primary Language Turkish
Journal Section Review
Authors

Vahap Ozan Kotan This is me

Salih Saygın Eker This is me

Enver Yusuf Sivrioglu This is me

Cengiz Akkaya This is me

Publication Date March 1, 2009
Published in Issue Year 2009 Volume: 1 Issue: 1

Cite

AMA Kotan VO, Eker SS, Sivrioglu EY, Akkaya C. Depresyon ve N-Metil D-Aspartik Asit (NMDA) Reseptör İlişkisi. Psikiyatride Güncel Yaklaşımlar - Current Approaches in Psychiatry. March 2009;1(1):22-35.

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