- Brain-derived neurotropic factor
The role of neurotropins, predominantly brain-derived neurotropic factor (BDNF), has been implicated in the pathophysiology as well as treatment outcome of schizophrenia. Both human and rodent studies indicate that the beneficial effects of antipsychotic drugs are mediated, at least in part, through BDNF and its receptor, TrkB. This review will discuss the available data on the levels of BDNF and TrkB in subjects with schizophrenia and in animals with and without conventional antipsychotics. The data concerning the impact of the antipsychotic drugs on BDNF/TrkB signaling will also be discussed. More importantly, this review will provide future perspective on BDNF/TrkB signaling as a novel molecular target to correct the pathogenesis and improve the long-term clinical outcome by treatments with conventional and adjunctive drugs.
Copyright © 2008 S. Karger AG, Basel
- Rylett RJ, Williams LR: Role of neurotrophins in cholinergic-neuron function in the adult and aged CNS. Trends Neurosci 1994;17:486–490.
- Cellerino A, Carroll P, Thoenen H, Barde YA: Reduced size of retinal ganglion cell axons and hypomyelination in mice lacking brain-derived neurotrophic factor. Mol Cell Neurosci 1997;9:397–408.
- Pizzorusso T, Maffei L: Plasticity in the developing visual system. Curr Opin Neurol 1996;9:122–125.
- Berardi N, Pizzorusso T, Maffei L: Critical periods during sensory development. Curr Opin Neurobiol 2000;10:138–145.
- Buckley PF, Mahadik S, Pillai A, Terry A Jr: Neurotrophins and schizophrenia. Schizophr Res 2007;94:1–11.
- Shoval G, Weizman A: The possible role of neurotrophins in the pathogenesis and therapy of schizophrenia. Eur Neuropsychopharmacol 2005;15:319–329.
- Murer MG, Yan Q, Raisman-Vozari R: Brain-derived neurotrophic factor in the control human brain, and in Alzheimer’s disease and Parkinson’s disease. Prog Neurobiol 2001;63:71–124.
- Kuipers SD, Bramham CR: Brain-derived neurotrophic factor mechanisms and function in adult synaptic plasticity: new insights and implications for therapy. Curr Opin Drug Discov Devel 2006;9:580–586.
- Tyler WJ, Alonso M, Bramham CR, Pozzo-Miller LD: From acquisition to consolidation: on the role of brain-derived neurotrophic factor signaling in hippocampal- dependent learning. Learn Mem 2002;9:224–237.
- Wetmore C, Cao YH, Pettersson RF, Olson L: Brain-derived neurotrophic factor: subcellular compartmentalization and interneuronal transfer as visualized with anti-peptide antibodies. Proc Natl Acad Sci USA 1991;88:9843–9847.
- Arevalo JC, Wu SH: Neurotrophin signaling: many exciting surprises! Cell Mol Life Sci 2006;63:1523–1537.
- Biffo S, Offenhauser N, Carter BD, Barde YA: Selective binding and internalisation by truncated receptors restrict the availability of BDNF during development. Development 1995;121:2461–2470.
- Eide FF, Vining ER, Eide BL, Zang K, Wang XY, Reichardt LF: Naturally occurring truncated trkB receptors have dominant inhibitory effects on brain-derived neurotrophic factor signaling. J Neurosci 1996;16:3123–3129.
- Ninkina N, Adu J, Fischer A, Pinon LG, Buchman VL, Davies AM: Expression and function of TrkB variants in developing sensory neurons. EMBO J 1996;15:6385–6393.
- Tapia-Arancibia L, Rage F, Givalois L, Arancibia S: Physiology of BDNF: focus on hypothalamic function. Front Neuroendocrinol 2004;25:77–107.
- Schlessinger J: Cell signaling by receptor tyrosine kinases. Cell 2000;103:211–225.
- Berridge MJ, Irvine RF: Inositol phosphates and cell signalling. Nature 1989;341:197–205.
- Widmer HR, Kaplan DR, Rabin SJ, Beck KD, Hefti F, Knusel B: Rapid phosphorylation of phospholipase C gamma 1 by brain-derived neurotrophic factor and neurotrophin-3 in cultures of embryonic rat cortical neurons. J Neurochem 1993;60:2111–2123.
- Wymann MP, Pirola L: Structure and function of phosphoinositide-3-kinases.Biochim Biophys Acta 1998;1436:127–150.
- Huang EJ, Reichardt LF: Trk receptors: roles in neuronal signal transduction. Annu Rev Biochem 2003;72:609–642.
- Song G, Ouyang G, Bao S: The activation of Akt/PKB signaling pathway and cell survival. J Cell Mol Med 2005;9:59–71.
- Campbell SL, Khosravi-Far R, Rossman KL, Clark GJ, Der CJ: Increasing complexity of Ras signaling. Oncogene 1998;17:1395–1413.
- Lewis TS, Shapiro PS, Ahn NG: Signal transduction through MAP kinase cascades. Adv Cancer Res 1998;74:49–139.
- Bloom FE: Advancing a neurodevelopmental origin for schizophrenia. Arch Gen Psychiatry 1993;50:224–227.
- Murray RM: Neurodevelopmental schizophrenia: the rediscovery of dementia praecox. Br J Psychiatr 1994;25(suppl):6–12.
- Weinberger DR: On the plausibility of the neurodevelopmental hypothesis of schizophrenia. Neuropsychopharmacology 1996;14:1S–11S.
- Wright IC, Rabe-Hesketh S, Woodruff PW, David AS, Murray RM, Bullmore ET: Meta-analysis of regional brain volumes in schizophrenia. Am J Psychiatry 2000;157:16–25.
- Keshavan M, Kennedy J, Murray R: Neurodevelopment and Schizophrenia. Cambridge, Cambridge University Press, 2004.
- Selemon LD, Rajkowska G, Goldman-Rakic PS: Abnormally high neuronal density in the schizophrenic cortex: a morphometric analysis of prefrontal area 9 and occipital area 17. Arch Gen Psychiatry 1995;52:805–818.
- Heckers S: Neuropathology of schizophrenia: cortex, thalamus, basal ganglia, and neurotransmitter-specific projection systems. Schizophr Bull 1997;23:403–421.
- Arnold SE, Trojanowski JQ, Gur RE, Blackwell P, Han LY, Choi C: Absence of neurodegeneration and neural injury in the cerebral cortex in a sample of elderly patients with schizophrenia. Arch Gen Psychiatry 1998;55:225–232.
- Linnarsson S, Willson CA, Ernfors P: Cell death in regenerating populations of neurons in BDNF mutant mice. Brain Res Mol Brain Res 2000;75:61–69.
- Zigova T, Pencea V, Wiegand SJ, Luskin MB: Intraventricular administration of BDNF increases the number of newly generated neurons in the adult olfactory bulb. Mol Cell Neurosci 1998;11:234–245.
- Durany N, Michel T, Zochling R, Boissl KW, Cruz-Sanchez FF, Riederer P, Thome J: Brain derived neurotrophic factor and neurotrophin-3 in schizophrenic psychoses. Schizophr Res 2001;52:79–86.
- Iritani S, Niizato K, Nawa H, Ikeda K, Emson PC: Immunohistochemical study of brain-derived neurotrophic factor and its receptor, TrkB, in the hippocampal formation of schizophrenic brains. Prog Neuro-Psychopharmacol Biol Psychiatry 2003;27:801–807.
- Takahashi M, Shirakawa O, Toyooka K, Kitamura N, Hashimoto T, Maeda K, Koizumi S, Wakabayashi K, Takahashi H, Someya T, Nawa H: Abnormal expression of brain-derived neurotrophic factor and its receptor in the corticolimbic system of schizophrenic patients. Mol Psychiatry 2000;5:292–300.
- Hashimoto T, Bergen SE, Nguyen QL, Xu B, Monteggia LM, Pierri JN, Sun Z, Sampson AR, Lewis DA: Relationship of brain-derived neurotrophic factor and its receptor TrkB to altered inhibitory prefrontal circuitry in schizophrenia. J Neurosci 2005;25:372–383.
- Weickert CS, Hyde TM, Lipska BK, Herman MM, Weinberger DR, Kleinman JE: Reduced brain derived neurotrophic factor in prefrontal cortex of patients with schizophrenia. Mol Psychiatry 2003;8:592–610.
- Weickert CS, Ligons DL, Romanczyk T, Ungaro G, Hyde TM, Herman MM, Weinberger DR, Kleinman JE: Reductions in neurotrophin receptor mRNAs in the prefrontal cortex of patients with schizophrenia. Mol Psychiatry 2005;10:637–650.
- Toyooka K, Asama K, Watanabe Y, Muratake T, Takahashi M, Someya T, Nawa H: Decreased levels of brain-derived neurotrophic factor in serum of chronic schizophrenic patients. Psychiatry Res 2002;110:249–257.
- Tan YL, Zhou DF, Cao LY, Zou YZ, Zhang XY: Decreased BDNF in serum of patients with chronic schizophrenia on long-term treatment with antipsychotics. Neurosci Lett 2005;382:27–32.
- Grillo RW, Ottoni GL, Leke R, Souza DO, Portela LV, Lara DR: Reduced serum BDNF levels in schizophrenic patients on clozapine or typical antipsychotics. J Psychiatr Res 2007;41:31–35.
- Buckley PF, Pillai A, Evans D, Stirewalt E, Mahadik S: Brain derived neurotrophic factor in first-episode psychosis. Schizophr Res 2007;91:1–5.
- Egan MF, Weinberger DR, Lu B: Brain-derived neurotrophic factor and genetic risk. Am J Psychiatry 2003;160:1242.
- Xu MQ, St Clair D, Ott J, Feng GY, He L: Brain-derived neurotrophic factor gene C-270T and Val66Met functional polymorphisms and risk of schizophrenia: a moderate-scale population-based study and meta- analysis. Schizophr Res 2007;91:6–13.
- Agartz I, Sedvall GC, Terenius L, Kulle B, Frigessi A, Hall H, Jonsson EG: BDNF gene variants and brain morphology in schizophrenia. Am J Med Genet [B] 2006;141:513–523.
- Kunugi H, Nanko S, Hirasawa H, Kato N, Nabika T, Kobayashi S: Brain-derived neurotrophic factor gene and schizophrenia: polymorphism screening and association analysis. Schizophr Res 2003;62:281–283.
- Szekeres G, Juhasz A, Rimanoczy A, Keri S, Janka Z: The C270T polymorphism of the brain-derived neurotrophic factor gene is associated with schizophrenia. Schizophr Res 2003;65:15–18.
- Galderisi S, Maj M, Kirkpatrick B, Piccardi P, Mucci A, Invernizzi G, Rossi A, Pini S, Vita A, Cassano P, Stratta P, Severino G, Del Zompo M: COMT Val(158)Met and BDNF C(270)T polymorphisms in schizophrenia: a case-control study. Schizophr Res 2005;73:27–30.
- Anttila S, Illi A, Kampman O, Mattila KM, Lehtimaki T, Leinonen E: Lack of association between two polymorphisms of brain-derived neurotrophic factor and response to typical neuroleptics. J Neural Transm 2005;112:885–890.
- Szczepankiewicz A, Skibinska M, Czerski PM, Kapelski P, Leszczynska-Rodziewicz A, Slopien A, Dmitrzak-Weglarz M, Rybakowski F, Rybakowski J, Hauser J: No association of the brain-derived neurotrophic factor (BDNF) gene C-270T polymorphism with schizophrenia. Schizophr Res 2005;76:187–193.
- Jonsson EG, Edman-Ahlbom B, Sillen A, Gunnar A, Kulle B, Frigessi A, Vares M, Ekholm B, Wode-Helgodt B, Schumacher J, Cichon S, Agartz I, Sedvall GC, Hall H, Terenius L: Brain-derived neurotrophic factor gene (BDNF) variants and schizophrenia: an association study. Prog Neuro-Psychopharmacol Biol Psychiatry 2006;30:924–933.
- Hong CJ, Liu HC, Liu TY, Lin CH, Cheng CY, Tsai SJ: An association study of a brain-derived neurotrophic factor Val66Met polymorphism and clozapine response of schizophrenic patients. Neurosci Lett 2003;349:206–208.
- Skibinska M, Hauser J, Czerski PM, Leszczynska-Rodziewicz A, Kosmowska M, Kapelski P, Slopien A, Zakrzewska M, Rybakowski JK: Association analysis of brain- derived neurotrophic factor (BDNF) gene Val66Met polymorphism in schizophrenia and bipolar affective disorder. World J Biol Psychiatry 2004;5:215–220.
- Neves-Pereira M, Cheung JK, Pasdar A, Zhang F, Breen G, Yates P, Sinclair M, Crombie C, Walker N, St Clair DM: BDNF gene is a risk factor for schizophrenia in a Scottish population. Mol Psychiatry 2005;10:208–212.
- Nanko S, Kunugi H, Hirasawa H, Kato N, Nabika T, Kobayashi S: Brain-derived neurotrophic factor gene and schizophrenia: polymorphism screening and association analysis. Schizophr Res 2003;62:281–283.
- Schumacher J, Jamra RA, Becker T, Ohlraun S, Klopp N, Binder EB, Schulze TG, Deschner M, Schmal C, Hofels S, Zobel A, Illig T, Propping P, Holsboer F, Rietschel M, Nothen MM, Cichon S: Evidence for a relationship between genetic variants at the brain-derived neurotrophic factor (BDNF) locus and major depression. Biol Psychiatry 2005;58:307–314.
- Chen QY, Chen Q, Feng GY, Wan CL, Lindpaintner K, Wang LJ, Chen ZX, Gao ZS, Tang JS, Li XW, He L: Association between the brain-derived neurotrophic factor (BDNF) gene and schizophrenia in the Chinese population. Neurosci Lett 2006;397:285–290.
- Watanabe Y, Muratake T, Kaneko N, Nunokawa A, Someya T: No association between the brain-derived neurotrophic factor gene and schizophrenia in a Japanese population. Schizophr Res 2006;84:29–35.
- Davis KL, Kahn RS, Ko G, Davidson M: Dopamine in schizophrenia: a review and reconceptualization. Am J Psychiatry 1991;148:1474–1486.
- Abi-Dargham A: Do we still believe in the dopamine hypothesis? New data bring new evidence. Int J Neuropsychopharmacol 2004;7:S1–S5.
- Laruelle M: Imaging dopamine transmission in schizophrenia: a review and meta-analysis. Q J Nucl Med 1998;42:211–221.
- Okubo Y, Suhara T, Suzuki T, Kobayashi K, Inoue O, Terasaki O, Someya Y, Sassa S, Sudo Y, Matsushima E, Iyo M, Tateno Y, Toru M: Decreased prefrontal dopamine D1 receptors in schizophrenia revealed by PET. Nature 1997;385:634.
- Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO, Keefe RS, Davis SM, Davis CE, Lebowitz BD, Severe J, Hsiao JK, Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Investigators: Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 2005;353:1209–1223.
- Kirkpatrick B, Buchanan RW, Ross DE, Carpenter WT Jr: A separate disease within the syndrome of schizophrenia. Arch Gen Psychiatry 2001;58:165–171.
- McBain CJ, Fisahn A: Interneurons unbound. Nat Rev Neurosci 2001;2:11–23.
- Simpson MD, Slater P, Deakin JF, Royston MC, Skan WJ: Reduced GABA uptake sites in the temporal lobe in schizophrenia. Neurosci Lett 1989;107:211–215.
- Hanada S, Mita T, Nishino N, Tanaka C: [3H]muscimol binding sites increased in autopsied brains of chronic schizophrenics. Life Sci 1987;40:259–266.
- Dean B, Hussain T, Hayes W, Scarr E, Kitsoulis S, Hill C, Opeskin K, Copolov DL: Changes in serotonin2A and GABA(A) receptors in schizophrenia: studies on the human dorsolateral prefrontal cortex. J Neurochem 1999;72:1593–1599.
- Akbarian S, Huang HS: Molecular and cellular mechanisms of altered GAD1/GAD67 expression in schizophrenia and related disorders. Brain Res Rev 2006;52:293–304.
- Dracheva S, Elhakem SL, McGurk SR, Davis KL, Haroutunian V: GAD67 and GAD65 mRNA and protein expression in cerebrocortical regions of elderly patients with schizophrenia. J Neurosci Res 2004;76:581–592.
- Wassef AA, Hafiz NG, Hampton D, Molloy M: Divalproex sodium augmentation of haloperidol in hospitalized patients with schizophrenia: clinical and economic implications. J Clin Psychopharmacol 2001;21:21–26.
- Menzies L, Ooi C, Kamath S, Suckling J, McKenna P, Fletcher P, Bullmore E, Stephenson C: Effects of gamma-aminobutyric acid-modulating drugs on working memory and brain function in patients with schizophrenia. Arch Gen Psychiatry 2007;64:156–167.
- Mizuno K, Carnahan J, Nawa H: Brain-derived neurotrophic factor promotes differentiation of striatal GABAergic neurons. Dev Biol 1994;165:243–256.
- Ventimiglia R, Mather PE, Jones BE, Lindsay RM: The neurotrophins BDNF, NT-3 and NT-4/5 promote survival and morphological and biochemical differentiation of striatal neurons in vitro. Eur J Neurosci 1995;7:213–222.
- Arenas E, Akerud P, Wong V, Boylan C, Persson H, Lindsay RM, Altar CA: Effects of BDNF and NT-4/5 on striatonigral neuropeptides or nigral GABA neurons in vivo. Eur J Neurosci 1996;8:1707–1717.
- Huang ZJ, Kirkwood A, Pizzorusso T, Porciatti V, Morales B, Bear MF, Maffei L, Tonegawa S: BDNF regulates the maturation of inhibition and the critical period of plasticity in mouse visual cortex. Cell 1999;98:739–755.
- Lipska BK, Weinberger DR: Prefrontal cortical and hippocampal modulation of dopamine-mediated effects. Adv Pharmacol 1998;42:806–809.
- Lipska BK, Weinberger DR: To model a psychiatric disorder in animals: Schizophrenia as a reality test. Neuropsychopharmacology 2000;23:223–239.
- Becker A, Grecksch G, Bernstein HG, Hollt V, Bogerts B: Social behaviour in rats lesioned with ibotenic acid in the hippocampus: quantitative and qualitative analysis. Psychopharmacology (Berl) 1999;144:333–338.
- Le Pen G, Grottick AJ, Higgins GA, Martin JR, Jenck F, Moreau JL: Spatial and associative learning deficits induced by neonatal excitotoxic hippocampal damage in rats: further evaluation of an animal model of schizophrenia. Behav Pharmacol 2000;11:257–268.
- Lipska BK, Aultman JM, Verma A, Weinberger DR, Moghaddam B: Neonatal damage of the ventral hippocampus impairs working memory in the rat. Neuropsychopharmacology 2002;27:47–54.
- Lipska BK, Jaskiw GE, Weinberger DR: Postpubertal emergence of hyperresponsiveness to stress and to amphetamine after neonatal excitotoxic hippocampal damage: A potential animal model of schizophrenia. Neuropsychopharmacology 1993;9:67–75.
- Ashe PC, Chlan-Fourney J, Juorio AV, Li XM: Brain-derived neurotrophic factor (BDNF) mRNA in rats with neonatal ibotenic acid lesions of the ventral hippocampus. Brain Res 2002;956:126–135.
- Featherstone RE, Rizos Z, Nobrega JN, Kapur S, Fletcher PJ: Gestational methylazoxymethanol acetate treatment impairs select cognitive functions: parallels to schizophrenia. Neuropsychopharmacology 2007;32:483–492.
- Fiore M, Korf J, Antonelli A, Talamini L, Aloe L: Long-lasting effects of prenatal MAM treatment on water maze performance in rats: associations with altered brain development and neurotrophin levels. Neurotoxicol Teratol 2002;24:179–191.
- Angelucci F, Gruber SH, El Khoury A, Tonali PA, Mathe AA: Chronic amphetamine treatment reduces NGF and BDNF in the rat brain. Eur Neuropsychopharmacol 2007;17:756–762.
- Castren E, da Penha Berzaghi M, Lindholm D, Thoenen H: Differential effects of MK-801 on brain-derived neurotrophic factor mRNA levels in different regions of the rat brain. Exp Neurol 1993;122:244–252.
- Pirildar S, Gonul AS, Taneli F, Akdeniz F: Low serum levels of brain-derived neurotrophic factor in patients with schizophrenia do not elevate after antipsychotic treatment. Prog Neuropsychopharmacol Biol Psychiatry 2004;28:709–713.
- Hori H, Yoshimura R, Yamada Y, Ikenouchi A, Mitoma M, Ida Y, Nakamura J: Effects of olanzapine on plasma levels of catecholamine metabolites, cytokines, and brain-derived neurotrophic factor in schizophrenic patients. Int Clin Psychopharmacol 2007;22:21–27.
- Yoshimura R, Hori H, Sugita A, Ueda N, Kakihara S, Umene W, Nakano Y, Shinkai K, Mitoma M, Ohta M, Shinkai T, Nakamura J: Treatment with risperidone for 4 weeks increased plasma 3-methoxy-4-ydroxypnenylglycol (MHPG) levels, but did not alter plasma brain-derived neurotrophic factor (BDNF) levels in schizophrenic patients. Prog Neuropsychopharmacol Biol Psychiatry 2007;31:1072–1077.
- Alleva E, Della Seta D, Cirulli F, Aloe L: Haloperidol treatment decreases nerve growth factor levels in the hypothalamus of adult mice. Prog Neuropsychopharmacol Biol Psychiatry 1996;20:483–489.
- Parikh V, Khan MM, Mahadik SP: Olanzapine counteracts reduction of brain-derived neurotrophic factor and TrkB receptors in rat hippocampus produced by haloperidol. Neurosci Lett 2004a;356:135–139.
- Parikh V, Khan MM, Terry A, Mahadik SP: Differential effects of typical and atypical antipsychotics on nerve growth factor and choline acetyltransferase expression in the cortex and nucleus basalis of rats. J Psychiatr Res 2004b;38:521–529.
- Parikh V, Terry AV, Khan MM, Mahadik SP: Modulation of nerve growth factor and choline acetyltransferase expression in rat hippocampus after chronic exposure to haloperidol, risperidone, and olanzapine. Psychopharmacology 2004c;172:365–374.
- Angelucci F, Aloe L, Gruber SH, Fiore M, Mathe AA: Chronic antipsychotic treatment selectively alters nerve growth factor and neuropeptide Y immunoreactivity and the distribution of choline acetyl transferase in rat brain regions. Int J Neuropsychopharmacol 2000;3:13–25.
- Angelucci F, Mathe AA, Aloe L: Brain-derived neurotrophic factor and tyrosine kinase receptor TrkB in rat brain are significantly altered after haloperidol and risperidone administration. J Neurosci Res 2000;60:783–794.
- Angelucci F, Aloe L, Iannitelli A, Gruber SH, Mathe AA: Effect of chronic olanzapine treatment on nerve growth factor and brain-derived neurotrophic factor in the rat brain. Eur Neuropsychopharmacol 2005;15:311–317.
- Lipska BK, Khaing ZZ, Weickert CS, Weinberger DR: BDNF mRNA expression in rat hippocampus and prefrontal cortex: effects of neonatal ventral hippocampal damage and antipsychotic drugs. Eur J Neurosci 2001;14:135–144.
- Bai O, Chlan-Fourney J, Bowen R, Keegan D, Li XM: Expression of brain-derived neurotrophic factor mRNA in rat hippocampus after treatment with antipsychotic drugs. J Neurosci Res 2003;71:127–131.
- Terry AV Jr, Hill WD, Parikh V, Evans DR, Waller JL, Mahadik SP: Differential effects of chronic haloperidol and olanzapine exposure on brain cholinergic markers and spatial learning in rats. Psychopharmacology (Berl.) 2002;164:360–368.
- Terry AV Jr, Hill WD, Parikh V, Waller JL, Evans DR, Mahadik SP: Differential effects of haloperidol, risperidone, and clozapine exposure on cholinergic markers and spatial learning performance in rats. Neuropsychopharmacology 2003;28:300–309.
- Sharma T, Mockler D: The cognitive efficacy of atypical antipsychotics in schizophrenia. J Clin Psychopharmacol 1998;18:12S–19S.
- Cuesta MJ, Peralta V, Zarzuela A: Effects of olanzapine and other antipsychotics on cognitive function in chronic schizophrenia: a longitudinal study. Schizophr Res 2001;48:17–28.
- Xu H, Qing H, Lu W, Keegan D, Richardson JS, Chlan-Fourney J, Li XM: Quetiapine attenuates the immobilization stress-induced decrease of brain-derived neurotrophic factor expression in rat hippocampus. Neurosci Lett 2002;321:65–68.
- Fumagalli F, Molteni R, Roceri M, Bedogni F, Santero R, Fossati C, Gennarelli M, Racagni G, Riva MA: Effect of antipsychotic drugs on brain-derived neurotrophic factor expression under reduced N-methyl-D-aspartate receptor activity. J Neurosci Res 2003;72:622–628.
- Luo C, Xu H, Li XM: Post-stress changes in BDNF and Bcl-2 immunoreactivities in hippocampal neurons: effect of chronic administration of olanzapine. Brain Res 2004;1025:194–202.
- Pillai A, Terry AV Jr, Mahadik SP: Differential effects of long-term treatment with typical and atypical antipsychotics on NGF and BDNF levels in rat striatum and hippocampus. Schizophr Res 2006;82:95–106.
- Terry AV Jr, Mahadik SP: Time-dependent cognitive deficits associated with first and second generation antipsychotics: cholinergic dysregulation as a potential mechanism. J Pharmacol Exp Ther 2007;320:961–968.
- Lieberman JA, Tollefson GD, Charles C, Zipursky R, Sharma T, Kahn RS, Keefe RS, Green AI, Gur RE, McEvoy J, Perkins D, Hamer RM, Gu H, Tohen M; HGDH Study Group: Antipsychotic drug effects on brain morphology in first-episode psychosis. Arch Gen Psychiatry 2005;62:361–370.
- Godleski LS, Goldsmith LJ, Vieweg WV, Zettwoch NC, Stikovac DM, Lewis SJ: Switching from depot antipsychotic drugs to olanzapine in patients with chronic schizophrenia. J Clin Psychiatry 2003;64:119–122.
- Zhang F, Signore AP, Zhou Z, Wang S, Cao G, Chen J: Erythropoietin protects CA1 neurons against global cerebral ischemia in rat: potential signaling mechanisms. J Neurosci Res 2006;83:1241–1251.
- Sakanaka M, Wen TC, Matsuda S, Masuda S, Morishita E, Nagao M, Sasaki R: In vivo evidence that erythropoietin protects neurons from ischemic damage. Proc Natl Acad Sci USA 1998;95:4635–4640.
- Siren AL, Fratelli M, Brines M, Goemans C, Casagrande S, Lewczuk P, Keenan S, Gleiter C, Pasquali C, Capobianco A, Mennini T, Heumann R, Cerami A, Ehrenreich H, Ghezzi P: Erythropoietin prevents neuronal apoptosis after cerebral ischemia and metabolic stress. Proc Natl Acad Sci USA 2001;98:4044–4049.
- Dzietko M, Felderhoff-Mueser U, Sifringer M, Krutz B, Bittigau P, Thor F, Heumann R, Buhrer C, Ikonomidou C, Hansen HH: Erythropoietin protects the developing brain against N-methyl-D-aspartate receptor antagonist neurotoxicity. Neurobiol Dis 2004;15:177–187.
- Spandou E, Soubasi V, Papoutsopoulou S, Karkavelas G, Simeonidou C, Kaiki-Astara A, Guiba-Tziampiri O: Erythropoietin prevents hypoxia/ischemia-induced DNA fragmentation in an experimental model of perinatal asphyxia. Neurosci Lett 2004;366:24–28.
- Pillai A, Dhandapani KM, Pillai BA, Terry AV Jr, Mahadik SP: Erythropoietin prevents haloperidol treatment-induced neuronal apoptosis through regulation of BDNF. Neuropsychopharmacology 2007; [Epub ahead of print].
- Ehrenreich H, Hinze-Selch D, Stawicki S, et al: Improvement of cognitive functions in chronic schizophrenic patients by recombinant human erythropoietin. Mol Psychiatry 2007;12:206–220.
- Abicht A, Lochmuller H: Technology evaluation: CRIB (CNTF delivery). CytoTherapeutics Inc Curr Opin Mol Ther 1999;1:645–650.
- Horina JH, Schmid CR, Roob JM, Winkler HM, Samitz MA, Hammer HF, Pogglitsch H, Krejs GJ: Bone marrow changes following treatment of renal anemia with erythropoietin. Kidney Int 1991;40:917–922.
- Pae CU, Lee C, Paik IH: Therapeutic possibilities of cysteamine in the treatment of schizophrenia. Med Hypotheses 2007;69:199–202.
- Martin-Iverson MT, Radke JM, Vincent SR: The effects of cysteamine on dopamine-mediated behaviors: evidence for dopamine-somatostatin interactions in the striatum. Pharmacol Biochem Behav 1986;24:1707–1714.
- Lee N, Radke JM, Vincent SR: Intra-cerebral cysteamine infusions attenuate the motor response to dopaminergic agonists. Behav Brain Res 1988;29:179–183.
- Feifel D, Minor KL: Cysteamine blocks amphetamine-induced deficits in sensorimotor gating. Pharmacol Biochem Behav 1997;58:689–693.
- Mao Z, Choo YS, Lesort M: Cystamine and cysteamine prevent 3-NP-induced mitochondrial depolarization of Huntington’s disease knock-in striatal cells. Eur J Neurosci 2006;23:1701–1710.
- Cabungcal JH, Nicolas D, Kraftsik R, Cuenod M, Do KQ, Hornung JP: Glutathione deficit during development induces anomalies in the rat anterior cingulate GABAergic neurons: relevance to schizophrenia. Neurobiol Dis 2006;22:624–637.
- Haroutunian V, Mantin R, Campbell GA, Tsuboyama GK, Davis KL: Cysteamine-induced depletion of central somatostatin-like immunoactivity: effects on behavior, learning, memory and brain neurochemistry. Brain Res 1987;403:234–242.
- Hruska RE: Modulatory role for prolactin in the elevation of striatal dopamine receptor density induced by chronic treatment with dopamine receptor antagonists. Brain Res Bull 1986;16:331–339.
- Borrell-Pages M, Canals JM, Cordelieres FP, Parker JA, Pineda JR, Grange G, Bryson EA, Guillermier M, Hirsch E, Hantraye P, Cheetham ME, Neri C, Alberch J, Brouillet E, Saudou F, Humbert S: Cystamine and cysteamine increase brain levels of BDNF in Huntington disease via HSJ1b and transglutaminase. J Clin Invest 2006;116:1410–1424.
- Peet M: Eicosapentaenoic acid in the treatment of schizophrenia and depression: rationale and preliminary double-blind clinical trial results. Prostaglandins Leukotrienes Fatty Acids 2003;69:477–485.
- Mahadik SP, Yao JK: Phospholipids in schizophrenia; in Lieberman JA, Stroup TS, Perkins DO (eds): Textbook of Schizophrenia. Washington, American Psychiatric Publishing, 2006, pp 117–135.
- Simopoulos AP: Omega-3 fatty acids in health and disease, and growth and development. Am J Clin Nutr 1991;54:438–463.
- Wainwright PE, Huang YS, Bulman-Fleming B, Dalby D, Mills DE, Redden P, McCutcheon D: The effects of dietary n–3/n–6 ratio on brain development in the mouse: a dose response study with long-chain n–3 fatty acids. Lipids 1992;27:98–103.
- Innis SM: Dietary (n–3) fatty acids and brain development. J Nutr 2007;137:855–859.
- McNamara RK, Carlson SE: Role of omega–3 fatty acids in brain development and function: potential implications for the pathogenesis and prevention of psychopathology. Prostaglandins Leukotrienes Essent Fatty Acids 2006;74:329–349.
- Young G, Conquer J: Omega–3 fatty acids and neuropsychiatric disorders. Reprod Nutr Dev 2005;45:1–28.
- Du Bois TM, Deng C, Huang HF: Membrane phospholipid composition, alterations in neurotransmitter systems and schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2005;29:878–888.
- Rao JS, Ertley RN, Lee HJ, DeMar JC Jr, Arnold JT, Rapoport SI, Bazinet RP: n-3 polyunsaturated fatty acid deprivation in rats decreases frontal cortex BDNF via a p38 MAPK-dependent mechanism. Mol Psychiatry 2007;12:36–46.
- Arvindakshan M, Ghate M, Ranjekar PK, Evans DR, Mahadik SP: Supplementation with a combination of omega-3 fatty acids and antioxidants (vitamins E and C) improves the outcome of schizophrenia. Schizophr Res 2003;62:195–204.
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Published online: February 5, 2008
Number of Print Pages : 11
Number of Figures : 1, Number of Tables : 0, Number of References : 139
Vol. 16, No. 2-3, Year 2008 (Cover Date: February 2008)
Journal Editor: Ip, N.Y. (Hong Kong)
ISSN: 1424–862X (Print), eISSN: 1424–8638 (Online)
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