Generic placeholder image

CNS & Neurological Disorders - Drug Targets


ISSN (Print): 1871-5273
ISSN (Online): 1996-3181

General Review Article

Prospects for Neurotrophic Factor-Based Early Intervention in Schizophrenia: Lessons Learned from the Effects of Antipsychotic Drugs on Cognition, Neurogenesis, and Neurotrophic Factors

Author(s): Mohammad M. Khan* and Vinay Parikh*

Volume 22, Issue 2, 2023

Published on: 27 May, 2022

Page: [289 - 303] Pages: 15

DOI: 10.2174/1871527321666220401124151

Price: $65


Although reducing psychotic symptoms in schizophrenia has been a major focus of therapeutic interventions for decades, improving cognition is considered a better predictor of functional outcomes. However, the most commonly prescribed antipsychotic drugs (APDs) show only marginal beneficial effects on cognition in patients with schizophrenia. The neural mechanisms underlying cognitive disturbances in schizophrenia remain unknown that making drug development efforts very challenging. Since neurotrophic factors are the primary architects of neurogenesis, synaptic plasticity, learning, and memory, the findings from preclinical and clinical studies that assess changes in neurogenesis and neurotrophic factors and their relationship to cognitive performance in schizophrenia, and how these mechanisms might be impacted by APD treatment, may provide valuable clues in developing therapies to combat cognitive deficit in schizophrenia. Numerous evidence produced over the years suggests a deficit in a wide spectrum of neurotrophic factors in schizophrenia. Since schizophrenia is considered a neurodevelopmental disorder, early intervention with neurotrophic factors may be more effective in ameliorating the cognitive deficits and psychopathological symptoms associated with this pathology. In this context, results from initial clinical trials with neurotrophic factors and their future potential to improve cognition and psychosocial functioning in schizophrenia are discussed.

Keywords: Antipsychotic drugs, neurogenesis, cognition, neurotrophic factors, early intervention, schizophrenia.

Graphical Abstract
Kraepelin E. Psychiatrie: Ein Lehrbuch fur Studirende und Aertze. (6th ed.), Lepizig, Germany: JA Barth 1899.
Falkai P, Rossner MJ, Schulze TG, et al. Kraepelin revisited: Schizophrenia from degeneration to failed regeneration. Mol Psychiatry 2015; 20(6): 671-6.
[] [PMID: 25824303]
Muench J, Hamer AM. Adverse effects of antipsychotic medications. Am Fam Physician 2010; 81(5): 617-22.
[PMID: 20187598]
Huhn M, Nikolakopoulou A, Schneider-Thoma J, et al. Comparative efficacy and tolerability of 32 oral antipsychotics for the acute treatment of adults with multi-episode schizophrenia: A systematic review and network meta-analysis. Lancet 2019; 394(10202): 939-51.
[] [PMID: 31303314]
Pillinger T, McCutcheon RA, Vano L, et al. Comparative effects of 18 antipsychotics on metabolic function in patients with schizophrenia, predictors of metabolic dysregulation, and association with psychopathology: A systematic review and network meta-analysis. Lancet Psychiatry 2020; 7(1): 64-77.
[] [PMID: 31860457]
Keefe RS, Buchanan RW, Marder SR, et al. Clinical trials of potential cognitive-enhancing drugs in schizophrenia: What have we learned so far? Schizophr Bull 2013; 39(2): 417-35.
[] [PMID: 22114098]
Fusar-Poli P, Papanastasiou E, Stahl D, et al. Treatments of negative symptoms in schizophrenia: Meta-analysis of 168 randomized placebo-controlled trials. Schizophr Bull 2015; 41(4): 892-9.
[] [PMID: 25528757]
Tani H, Suzuki T, Wolfgang Fleischhacker W, Tomita M, Mimura M, Uchida H. Clinical characteristics of patients with schizophrenia who successfully discontinued antipsychotics: A literature review. J Clin Psychopharmacol 2018; 38(6): 582-9.
[] [PMID: 30300291]
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(4): 360-8.
[] [PMID: 12457265]
Parikh V, Khan MM, Mahadik SP. Differential effects of antipsychotics on expression of antioxidant enzymes and membrane lipid peroxidation in rat brain. J Psychiatr Res 2003; 37(1): 43-51.
[] [PMID: 12482469]
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 (Berl) 2004; 172(4): 365-74.
[] [PMID: 14647958]
Khan MM, Parikh VV, Mahadik SP. Antipsychotic drugs differentially modulate apolipoprotein D in rat brain. J Neurochem 2003; 86(5): 1089-100.
[] [PMID: 12911617]
Khan MM, Evans DR, Gunna V, Scheffer RE, Parikh VV, Mahadik SP. Reduced erythrocyte membrane essential fatty acids and increased lipid peroxides in schizophrenia at the never-medicated first-episode of psychosis and after years of treatment with antipsychotics. Schizophr Res 2002; 58(1): 1-10.
[] [PMID: 12363384]
Flatow J, Buckley P, Miller BJ. Meta-analysis of oxidative stress in schizophrenia. Biol Psychiatry 2013; 74(6): 400-9.
[] [PMID: 23683390]
Hulshoff Pol HE, Brans RG, van Haren NE, et al. Gray and white matter volume abnormalities in monozygotic and same-gender dizygotic twins discordant for schizophrenia. Biol Psychiatry 2004; 55(2): 126-30.
[] [PMID: 14732591]
Haijma SV, Van Haren N, Cahn W, Koolschijn PC, Hulshoff Pol HE, Kahn RS. Brain volumes in schizophrenia: A meta-analysis in over 18 000 subjects. Schizophr Bull 2013; 39(5): 1129-38.
[] [PMID: 23042112]
Imayoshi I, Sakamoto M, Ohtsuka T, et al. Roles of continuous neurogenesis in the structural and functional integrity of the adult forebrain. Nat Neurosci 2008; 11(10): 1153-61.
[] [PMID: 18758458]
Spalding KL, Bergmann O, Alkass K, et al. Dynamics of hippocampal neurogenesis in adult humans. Cell 2013; 153(6): 1219-27.
[] [PMID: 23746839]
Clelland CD, Choi M, Romberg C, et al. A functional role for adult hippocampal neurogenesis in spatial pattern separation. Science 2009; 325(5937): 210-3.
[] [PMID: 19590004]
Rotheneichner P, Belles M, Benedetti B, et al. Cellular plasticity in the adult murine piriform cortex: Continuous maturation of dormant precursors into excitatory neurons. Cereb Cortex 2018; 28(7): 2610-21.
[] [PMID: 29688272]
Gould E, Beylin A, Tanapat P, Reeves A, Shors TJ. Learning enhances adult neurogenesis in the hippocampal formation. Nat Neurosci 1999; 2(3): 260-5.
[] [PMID: 10195219]
Saxe MD, Malleret G, Vronskaya S, et al. Paradoxical influence of hippocampal neurogenesis on working memory. Proc Natl Acad Sci USA 2007; 104(11): 4642-6.
[] [PMID: 17360577]
Boldrini M, Fulmore CA, Tartt AN, et al. Human hippocampal neurogenesis persists throughout aging. Cell Stem Cell 2018; 22(4): 589-599.e5.
[] [PMID: 29625071]
Dawirs RR, Hildebrandt K, Teuchert-Noodt G. Adult treatment with haloperidol increases dentate granule cell proliferation in the gerbil hippocampus. J Neural Transm (Vienna) 1998; 105(2-3): 317-27.
[] [PMID: 9660110]
Wakade CG, Mahadik SP, Waller JL, Chiu FC. Atypical neuroleptics stimulate neurogenesis in adult rat brain. J Neurosci Res 2002; 69(1): 72-9.
[] [PMID: 12111817]
Chikama K, Yamada H, Tsukamoto T, Kajitani K, Nakabeppu Y, Uchimura N. Chronic atypical antipsychotics, but not haloperidol, increase neurogenesis in the hippocampus of adult mouse. Brain Res 2017; 1676: 77-82.
[] [PMID: 28899760]
Keefe RS, Bilder RM, Davis SM, et al. Neurocognitive effects of antipsychotic medications in patients with chronic schizophrenia in the CATIE Trial. Arch Gen Psychiatry 2007; 64(6): 633-47.
[] [PMID: 17548746]
Johnsen E, Jørgensen HA, Kroken RA, Løberg EM. Neurocognitive effectiveness of quetiapine, olanzapine, risperidone, and ziprasidone: A pragmatic, randomized trial. Eur Psychiatry 2013; 28(3): 174-84.
[] [PMID: 22153730]
Kriegstein A, Alvarez-Buylla A. The glial nature of embryonic and adult neural stem cells. Annu Rev Neurosci 2009; 32(1): 149-84.
[] [PMID: 19555289]
Lyons DM, Buckmaster PS, Lee AG, et al. Stress coping stimulates hippocampal neurogenesis in adult monkeys. Proc Natl Acad Sci USA 2010; 107(33): 14823-7.
[] [PMID: 20675584]
Domingues HS, Portugal CC, Socodato R, Relvas JB. Oligodendrocyte, astrocyte, and microglia crosstalk in myelin development, damage, and repair. Front Cell Dev Biol 2016; 4: 71.
[PMID: 27551677]
Nieto R, Kukuljan M, Silva H. BDNF and schizophrenia: From neurodevelopment to neuronal plasticity, learning, and memory. Front Psychiatry 2013; 4: 45.
[] [PMID: 23785335]
Owen MJ, O’Donovan MC, Thapar A, Craddock N. Neurodevelopmental hypothesis of schizophrenia. Br J Psychiatry 2011; 198(3): 173-5.
[] [PMID: 21357874]
Kahn RS, Keefe RS. Schizophrenia is a cognitive illness: Time for a change in focus. JAMA Psychiatry 2013; 70(10): 1107-12.
[] [PMID: 23925787]
Kelly S, Guimond S, Lyall A, et al. Neural correlates of cognitive deficits across developmental phases of schizophrenia. Neurobiol Dis 2019; 131: 104353.
[] [PMID: 30582983]
Bora E, Murray RM. Meta-analysis of cognitive deficits in ultra-high risk to psychosis and first-episode psychosis: Do the cognitive deficits progress over, or after, the onset of psychosis? Schizophr Bull 2014; 40(4): 744-55.
[] [PMID: 23770934]
Bolt LK, Amminger GP, Farhall J, et al. Neurocognition as a predictor of transition to psychotic disorder and functional outcomes in ultra-high risk participants: Findings from the NEURAPRO randomized clinical trial. Schizophr Res 2019; 206: 67-74.
[] [PMID: 30558978]
Brewer WJ, Francey SM, Wood SJ, et al. Memory impairments identified in people at ultra-high risk for psychosis who later develop first-episode psychosis. Am J Psychiatry 2005; 162(1): 71-8.
[] [PMID: 15625204]
Meltzer HY, McGurk SR. The effects of clozapine, risperidone, and olanzapine on cognitive function in schizophrenia. Schizophr Bull 1999; 25(2): 233-55.
[] [PMID: 10416729]
Woodward ND, Purdon SE, Meltzer HY, Zald DH. A meta-analysis of neuropsychological change to clozapine, olanzapine, quetiapine, and risperidone in schizophrenia. Int J Neuropsychopharmacol 2005; 8(3): 457-72.
[] [PMID: 15784157]
Riedel M, Spellmann I, Strassnig M, et al. Effects of risperidone and quetiapine on cognition in patients with schizophrenia and predominantly negative symptoms. Eur Arch Psychiatry Clin Neurosci 2007; 257(6): 360-70.
[] [PMID: 17629731]
Voruganti LP, Awad AG, Parker G, et al. Cognition, functioning and quality of life in schizophrenia treatment: Results of a one-year randomized controlled trial of olanzapine and quetiapine. Schizophr Res 2007; 96(1-3): 146-55.
[] [PMID: 17728106]
Urben S, Baumann P, Barcellona S, et al. Cognitive efficacy of quetiapine in early-onset first-episode psychosis: A 12-week open label trial. Psychiatr Q 2012; 83(3): 311-24.
[] [PMID: 22101738]
Goozee R, Reinders AATS, Handley R, et al. Effects of aripiprazole and haloperidol on neural activation during the n-back in healthy individuals: A functional MRI study. Schizophr Res 2016; 173(3): 174-81.
[] [PMID: 25778615]
Bervoets C, Morrens M, Vansteelandt K, et al. Effect of aripiprazole on verbal memory and fluency in schizophrenic patients: Results from the ESCAPE study. CNS Drugs 2012; 26(11): 975-82.
[] [PMID: 23018547]
Nielsen RE, Levander S, Kjaersdam Telléus G, Jensen SO, Østergaard Christensen T, Leucht S. Second-generation antipsychotic effect on cognition in patients with schizophrenia--a meta-analysis of randomized clinical trials. Acta Psychiatr Scand 2015; 131(3): 185-96.
[] [PMID: 25597383]
Désaméricq G, Schurhoff F, Meary A, et al. Long-term neurocognitive effects of antipsychotics in schizophrenia: A network meta-analysis. Eur J Clin Pharmacol 2014; 70(2): 127-34.
[] [PMID: 24145817]
Reif A, Fritzen S, Finger M, et al. Neural stem cell proliferation is decreased in schizophrenia, but not in depression. Mol Psychiatry 2006; 11(5): 514-22.
[] [PMID: 16415915]
Allen KM, Fung SJ, Weickert CS. Cell proliferation is reduced in the hippocampus in schizophrenia. Aust N Z J Psychiatry 2016; 50(5): 473-80.
[] [PMID: 26113745]
Barbeau D, Liang JJ, Robitalille Y, Quirion R, Srivastava LK. Decreased expression of the embryonic form of the neural cell adhesion molecule in schizophrenic brains. Proc Natl Acad Sci USA 1995; 92(7): 2785-9.
[] [PMID: 7708724]
Falkai P, Malchow B, Wetzestein K, et al. Decreased oligodendrocyte and neuron number in anterior hippocampal areas and the entire hippocampus in schizophrenia: A stereological postmortem study. Schizophr Bull 2016; 42 (Suppl. 1): S4-S12.
[] [PMID: 27460617]
Benes FM, McSparren J, Bird ED, SanGiovanni JP, Vincent SL. Deficits in small interneurons in prefrontal and cingulate cortices of schizophrenic and schizoaffective patients. Arch Gen Psychiatry 1991; 48(11): 996-1001.
[] [PMID: 1747023]
Konradi C, Yang CK, Zimmerman EI, et al. Hippocampal interneurons are abnormal in schizophrenia. Schizophr Res 2011; 131(1-3): 165-73.
[] [PMID: 21745723]
Bernstein HG, Dobrowolny H, Keilhoff G, Bogerts B, Steiner J. Reduced density of DISC1 expressing astrocytes in the dentate gyrus but not in the subventricular zone in schizophrenia. Neuropsychopharmacology 2018; 43(3): 457-8.
[] [PMID: 29326433]
Jarskog LF, Selinger ES, Lieberman JA, Gilmore JH. Apoptotic proteins in the temporal cortex in schizophrenia: High Bax/Bcl-2 ratio without caspase-3 activation. Am J Psychiatry 2004; 161(1): 109-15.
[] [PMID: 14702258]
Weissleder C, North HF, Bitar M, et al. Reduced adult neurogenesis is associated with increased macrophages in the subependymal zone in schizophrenia. Mol Psychiatry 2021; 26(11): 6880-95.
[] [PMID: 34059796]
Malberg JE, Eisch AJ, Nestler EJ, Duman RS. Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. J Neurosci 2000; 20(24): 9104-10.
[] [PMID: 11124987]
Duman RS, Nakagawa S, Malberg J. Regulation of adult neurogenesis by antidepressant treatment. Neuropsychopharmacology 2001; 25(6): 836-44.
[] [PMID: 11750177]
Wang HD, Dunnavant FD, Jarman T, Deutch AY. Effects of antipsychotic drugs on neurogenesis in the forebrain of the adult rat. Neuropsychopharmacology 2004; 29(7): 1230-8.
[] [PMID: 15085089]
Lasut B, Palasz A, Filipczyk L, et al. Long-term treatment with olanzapine increases the number of sox2 and doublecortin expressing cells in the adult subventricular zone. CNS Neurol Disord Drug Targets 2018; 17(6): 458-63.
[] [PMID: 29952270]
Piontkewitz Y, Bernstein HG, Dobrowolny H, Bogerts B, Weiner I, Keilhoff G. Effects of risperidone treatment in adolescence on hippocampal neurogenesis, parvalbumin expression, and vascularization following prenatal immune activation in rats. Brain Behav Immun 2012; 26(2): 353-63.
[] [PMID: 22154704]
Kippin TE, Kapur S, van der Kooy D. Dopamine specifically inhibits forebrain neural stem cell proliferation, suggesting a novel effect of antipsychotic drugs. J Neurosci 2005; 25(24): 5815-23.
[] [PMID: 15958748]
Khan MM, Hwisa NT, El-Tumi AR, Mehemed AE, Mahadik SP. Early antipsychotics response in first-episode male schizophrenia patients coincides with rapid modulation of cognitive behaviors and neuronal plasticity in adult male rats. Society for Neuroscience Abstracts 2013.
Rasmussen SA, Rosebush PI, Anglin RE, Mazurek MF. The predictive value of early treatment response in antipsychotic-naive patients with first-episode psychosis: Haloperidol versus olanzapine. Psychiatry Res 2016; 241: 72-7.
[] [PMID: 27156027]
Kodama M, Fujioka T, Duman RS. Chronic olanzapine or fluoxetine administration increases cell proliferation in hippocampus and prefrontal cortex of adult rat. Biol Psychiatry 2004; 56(8): 570-80.
[] [PMID: 15476686]
Bartzokis G, Lu PH, Nuechterlein KH, et al. Differential effects of typical and atypical antipsychotics on brain myelination in schizophrenia. Schizophr Res 2007; 93(1-3): 13-22.
[] [PMID: 17407804]
Steiner J, Martins-de-Souza D, Schiltz K, et al. Clozapine promotes glycolysis and myelin lipid synthesis in cultured oligodendrocytes. Front Cell Neurosci 2014; 8: 384.
[] [PMID: 25477781]
Luo C, Xu H, Li XM. Quetiapine reverses the suppression of hippocampal neurogenesis caused by repeated restraint stress. Brain Res 2005; 1063(1): 32-9.
[] [PMID: 16271709]
Maeda K, Sugino H, Hirose T, et al. Clozapine prevents a decrease in neurogenesis in mice repeatedly treated with phencyclidine. J Pharmacol Sci 2007; 103(3): 299-308.
[] [PMID: 17341843]
Xue F, Chen YC, Zhou CH, et al. Risperidone ameliorates cognitive deficits, promotes hippocampal proliferation, and enhances Notch signaling in a murine model of schizophrenia. Pharmacol Biochem Behav 2017; 163: 101-9.
[] [PMID: 29037878]
Xu H, Qing H, Lu W, et al. Quetiapine attenuates the immobilization stress-induced decrease of brain-derived neurotrophic factor expression in rat hippocampus. Neurosci Lett 2002; 321(1-2): 65-8.
[] [PMID: 11872258]
Seibt KJ, Piato AL, da Luz Oliveira R, Capiotti KM, Vianna MR, Bonan CD. Antipsychotic drugs reverse MK-801-induced cognitive and social interaction deficits in zebrafish (Danio rerio). Behav Brain Res 2011; 224(1): 135-9.
[] [PMID: 21669233]
Song JC, Seo MK, Park SW, Lee JG, Kim YH. Differential effects of olanzapine and haloperidol on MK-801-induced memory impairment in mice. Clin Psychopharmacol Neurosci 2016; 14(3): 279-85.
[] [PMID: 27489382]
Liu X, Li J, Guo C, et al. Olanzapine reverses MK-801-induced cognitive deficits and region-specific alterations of NMDA receptor subunits. Front Behav Neurosci 2018; 11: 260.
[] [PMID: 29375333]
Yu W, Zhu M, Fang H, et al. Risperidone reverses the downregulation of BDNF in hippocampal neurons and MK801-induced cognitive impairment in rats. Front Behav Neurosci 2019; 13: 163.
[] [PMID: 31396062]
Scharfman H, Goodman J, Macleod A, Phani S, Antonelli C, Croll S. Increased neurogenesis and the ectopic granule cells after intrahippocampal BDNF infusion in adult rats. Exp Neurol 2005; 192(2): 348-56.
[] [PMID: 15755552]
Schäbitz WR, Steigleder T, Cooper-Kuhn CM, et al. Intravenous brain-derived neurotrophic factor enhances poststroke sensorimotor recovery and stimulates neurogenesis. Stroke 2007; 38(7): 2165-72.
[] [PMID: 17510456]
Aberg MA, Aberg ND, Hedbäcker H, Oscarsson J, Eriksson PS. Peripheral infusion of IGF-I selectively induces neurogenesis in the adult rat hippocampus. J Neurosci 2000; 20(8): 2896-903.
[] [PMID: 10751442]
Bracko O, Singer T, Aigner S, et al. Gene expression profiling of neural stem cells and their neuronal progeny reveals IGF2 as a regulator of adult hippocampal neurogenesis. J Neurosci 2012; 32(10): 3376-87.
[] [PMID: 22399759]
Frielingsdorf H, Simpson DR, Thal LJ, Pizzo DP. Nerve growth factor promotes survival of new neurons in the adult hippocampus. Neurobiol Dis 2007; 26(1): 47-55.
[] [PMID: 17270453]
Zhang H, Petit GH, Gaughwin PM, et al. NGF rescues hippocampal cholinergic neuronal markers, restores neurogenesis, and improves the spatial working memory in a mouse model of Huntington’s Disease. J Huntingtons Dis 2013; 2(1): 69-82.
[] [PMID: 25063430]
Jin K, Zhu Y, Sun Y, Mao XO, Xie L, Greenberg DA. Vascular endothelial growth factor (VEGF) stimulates neurogenesis in vitro and in vivo. Proc Natl Acad Sci USA 2002; 99(18): 11946-50.
[] [PMID: 12181492]
Cheng Y, Tao Y, Black IB, DiCicco-Bloom E. A single peripheral injection of basic fibroblast growth factor (bFGF) stimulates granule cell production and increases cerebellar growth in newborn rats. J Neurobiol 2001; 46(3): 220-9.
[<220::AIDNEU1004>3.0.CO;2-P] [PMID: 11169507]
Wagner JP, Black IB, DiCicco-Bloom E. Stimulation of neonatal and adult brain neurogenesis by subcutaneous injection of basic fibroblast growth factor. J Neurosci 1999; 19(14): 6006-16.
[] [PMID: 10407038]
Yang Z, Zhang A, Duan H, et al. NT3-chitosan elicits robust endogenous neurogenesis to enable functional recovery after spinal cord injury. Proc Natl Acad Sci USA 2015; 112(43): 13354-9.
[] [PMID: 26460015]
Emsley JG, Hagg T. Endogenous and exogenous ciliary neurotrophic factor enhances forebrain neurogenesis in adult mice. Exp Neurol 2003; 183(2): 298-310.
[] [PMID: 14552871]
Kokoeva MV, Yin H, Flier JS. Neurogenesis in the hypothalamus of adult mice: Potential role in energy balance. Science 2005; 310(5748): 679-83.
[] [PMID: 16254185]
Chen Y, Ai Y, Slevin JR, Maley BE, Gash DM. Progenitor proliferation in the adult hippocampus and substantia nigra induced by glial cell line-derived neurotrophic factor. Exp Neurol 2005; 196(1): 87-95.
[] [PMID: 16112112]
Kobayashi T, Ahlenius H, Thored P, Kobayashi R, Kokaia Z, Lindvall O. Intracerebral infusion of glial cell line-derived neurotrophic factor promotes striatal neurogenesis after stroke in adult rats. Stroke 2006; 37(9): 2361-7.
[] [PMID: 16873711]
Kuhn HG, Winkler J, Kempermann G, Thal LJ, Gage FH. Epidermal growth factor and fibroblast growth factor-2 have different effects on neural progenitors in the adult rat brain. J Neurosci 1997; 17(15): 5820-9.
[] [PMID: 9221780]
Decressac M, Wright B, David B, et al. Exogenous neuropeptide Y promotes in vivo hippocampal neurogenesis. Hippocampus 2011; 21(3): 233-8.
[] [PMID: 20095007]
Agasse F, Bernardino L, Kristiansen H, et al. Neuropeptide Y promotes neurogenesis in murine subventricular zone. Stem Cells 2008; 26(6): 1636-45.
[] [PMID: 18388302]
Mahar I, MacIsaac A, Kim JJ, et al. Effects of neuregulin-1 administration on neurogenesis in the adult mouse hippocampus, and characterization of immature neurons along the septotemporal axis. Sci Rep 2016; 6(1): 30467.
[] [PMID: 27469430]
Ransome MI, Turnley AM. Systemically delivered Erythropoietin transiently enhances adult hippocampal neurogenesis. J Neurochem 2007; 102(6): 1953-65.
[] [PMID: 17555554]
Hassouna I, Ott C, Wüstefeld L, et al. Revisiting adult neurogenesis and the role of erythropoietin for neuronal and oligodendroglial differentiation in the hippocampus. Mol Psychiatry 2016; 21(12): 1752-67.
[] [PMID: 26809838]
Waterhouse EG, An JJ, Orefice LL, et al. BDNF promotes differentiation and maturation of adult-born neurons through GABAergic transmission. J Neurosci 2012; 32(41): 14318-30.
[] [PMID: 23055503]
Kirschenbaum B, Goldman SA. Brain-derived neurotrophic factor promotes the survival of neurons arising from the adult rat forebrain subependymal zone. Proc Natl Acad Sci USA 1995; 92(1): 210-4.
[] [PMID: 7816819]
Zhang Y, Fang X, Fan W, et al. Brain-derived neurotrophic factor as a biomarker for cognitive recovery in acute schizophrenia: 12-week results from a prospective longitudinal study. Psychopharmacology (Berl) 2018; 235(4): 1191-8.
[] [PMID: 29392373]
Man L, Lv X, Du XD, et al. Cognitive impairments and low BDNF serum levels in first-episode drug-naive patients with schizophrenia. Psychiatry Res 2018; 263: 1-6.
[] [PMID: 29482040]
Shimazu K, Zhao M, Sakata K, et al. NT-3 facilitates hippocampal plasticity and learning and memory by regulating neurogenesis. Learn Mem 2006; 13(3): 307-15.
[] [PMID: 16705139]
Fiore M, Triaca V, Amendola T, Tirassa P, Aloe L. Brain NGF and EGF administration improves passive avoidance response and stimulates brain precursor cells in aged male mice. Physiol Behav 2002; 77(2-3): 437-43.
[] [PMID: 12419420]
Parikh V, Evans DR, Khan MM, Mahadik SP. Nerve growth factor in never-medicated first-episode psychotic and medicated chronic schizophrenic patients: Possible implications for treatment outcome. Schizophr Res 2003; 60(2-3): 117-23.
[] [PMID: 12591576]
Pillai A, Kale A, Joshi S, et al. Decreased BDNF levels in CSF of drug-naive first-episode psychotic subjects: Correlation with plasma BDNF and psychopathology. Int J Neuropsychopharmacol 2010; 13(4): 535-9.
[] [PMID: 19941699]
Murphy BP, Pang TY, Hannan AJ, et al. Vascular endothelial growth factor and brain-derived neurotrophic factor in quetiapine treated first-episode psychosis. Schizophr Res Treatment 2014; 2014: 719395.
[] [PMID: 24672724]
Neugebauer K, Hammans C, Wensing T, et al. Nerve growth factor serum levels are associated with regional gray matter volume differences in schizophrenia patients. Front Psychiatry 2019; 10: 275.
[] [PMID: 31105606]
Qin XY, Wu HT, Cao C, Loh YP, Cheng Y. A meta-analysis of peripheral blood nerve growth factor levels in patients with schizophrenia. Mol Psychiatry 2017; 22(9): 1306-12.
[] [PMID: 28070123]
Venkatasubramanian G, Chittiprol S, Neelakantachar N, Shetty T, Gangadhar BN. Effect of antipsychotic treatment on Insulin-like Growth Factor-1 and cortisol in schizophrenia: A longitudinal study. Schizophr Res 2010; 119(1-3): 131-7.
[] [PMID: 20226630]
Yang YJ, Luo T, Zhao Y, et al. Altered insulin-like growth factor-2 signaling is associated with psychopathology and cognitive deficits in patients with schizophrenia. PLoS One 2020; 15(3): e0226688.
[] [PMID: 32191705]
Ye F, Zhan Q, Xiao W, et al. Altered serum levels of vascular endothelial growth factor in first-episode drug-naïve and chronic medicated schizophrenia. Psychiatry Res 2018; 264: 361-5.
[] [PMID: 29677618]
Xiao W, Zhan Q, Ye F, et al. Baseline serum vascular endothelial growth factor levels predict treatment response to antipsychotic medication in patients with schizophrenia. Eur Neuropsychopharmacol 2018; 28(5): 603-9.
[] [PMID: 29602597]
Zhang X, Xiao W, Chen K, et al. Serum epidermal growth factor is low in schizophrenia and not affected by antipsychotics alone or combined with electroconvulsive therapy. Front Psychiatry 2020; 11: 104.
[] [PMID: 32194452]
Gøtzsche CR, Woldbye DP. The role of NPY in learning and memory. Neuropeptides 2016; 55: 79-89.
[] [PMID: 26454711]
Mellios N, Huang HS, Baker SP, Galdzicka M, Ginns E, Akbarian S. Molecular determinants of dysregulated GABAergic gene expression in the prefrontal cortex of subjects with schizophrenia. Biol Psychiatry 2009; 65(12): 1006-14.
[] [PMID: 19121517]
Nikisch G, Baumann P, Liu T, Mathé AA. Quetiapine affects neuropeptide Y and corticotropin-releasing hormone in cerebrospinal fluid from schizophrenia patients: Relationship to depression and anxiety symptoms and to treatment response. Int J Neuropsychopharmacol 2012; 15(8): 1051-61.
[] [PMID: 22008251]
Huang XF, Deng C, Zavitsanou K. Neuropeptide Y mRNA expression levels following chronic olanzapine, clozapine and haloperidol administration in rats. Neuropeptides 2006; 40(3): 213-9.
[] [PMID: 16516965]
Nekoui A, Blaise G. Erythropoietin and nonhematopoietic effects. Am J Med Sci 2017; 353(1): 76-81.
[] [PMID: 28104107]
Pillai A, Mahadik SP. Differential effects of haloperidol and olanzapine on the expression of erythropoietin and its receptor in rat hippocampus and striatum. J Neurochem 2006; 98(5): 1411-22.
[] [PMID: 16923156]
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(2): 206-20.
[] [PMID: 17033631]
Goetghebeur PJ, Lerdrup L, Sylvest A, Dias R. Erythropoietin reverses the attentional set-shifting impairment in a rodent schizophrenia disease-like model. Psychopharmacology (Berl) 2010; 212(4): 635-42.
[] [PMID: 20734030]
Durany N, Michel T, Zöchling R, et al. Brain-derived neurotrophic factor and neurotrophin 3 in schizophrenic psychoses. Schizophr Res 2001; 52(1-2): 79-86.
[] [PMID: 11595394]
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(6): 592-610.
[] [PMID: 12851636]
Chao XL, Jiang SZ, Xiong JW, et al. The association between serum insulin-like growth factor 1 and cognitive impairments in patients with schizophrenia. Psychiatry Res 2020; 285: 112731.
[] [PMID: 31839419]
Hashimoto K, Shimizu E, Komatsu N, et al. Increased levels of serum basic fibroblast growth factor in schizophrenia. Psychiatry Res 2003; 120(3): 211-8.
[] [PMID: 14561432]
Li XS, Wu HT, Yu Y, et al. Increased serum FGF2 levels in first-episode, drug-free patients with schizophrenia. Neurosci Lett 2018; 686: 28-32.
[] [PMID: 30172685]
Yu Y, Xie GJ, Hu Y, et al. Dysregulation of fibroblast growth factor 10 in the peripheral blood of patients with schizophrenia. J Mol Neurosci 2019; 69(1): 69-74.
[] [PMID: 31256336]
Misiak B, Stramecki F. Stańczykiewicz B, Frydecka D, Lubeiro A. Vascular endothelial growth factor in patients with schizophrenia: A systematic review and meta-analysis. Prog Neuropsychopharmacol Biol Psychiatry 2018; 86: 24-9.
[] [PMID: 29772306]
Vargas HE, Gama CS, Andreazza AC, et al. Decreased serum neurotrophin 3 in chronically medicated schizophrenic males. Neurosci Lett 2008; 440(3): 197-201.
[] [PMID: 18572319]
Liu Y, Huang L, Tong Y, Chen J, Gao D, Yang F. Association of retinal nerve fiber abnormalities with serum CNTF and cognitive functions in schizophrenia patients. PeerJ 2020; 8: e9279.
[] [PMID: 32676219]
Chana G, Lucero G, Salaria S, et al. Upregulation of NRG-1 and VAMP-1 in human brain aggregates exposed to clozapine. Schizophr Res 2009; 113(2-3): 273-6.
[] [PMID: 19502011]
Mostaid MS, Lee TT, Chana G, et al. Elevated peripheral expression of neuregulin-1 (NRG1) mRNA isoforms in clozapine-treated schizophrenia patients. Transl Psychiatry 2017; 7(12): 1280.
[] [PMID: 29225331]
Xiao W, Ye F, Ma L, et al. Atypical antipsychotic treatment increases glial cell line-derived neurotrophic factor serum levels in drug-free schizophrenic patients along with improvement of psychotic symptoms and therapeutic effects. Psychiatry Res 2016; 246: 617-22.
[] [PMID: 27836239]
Tang X, Zhou C, Gao J, et al. Serum BDNF and GDNF in Chinese male patients with deficit schizophrenia and their relationships with neurocognitive dysfunction. BMC Psychiatry 2019; 19(1): 254.
[] [PMID: 31420036]
Futamura T, Toyooka K, Iritani S, et al. Abnormal expression of epidermal growth factor and its receptor in the forebrain and serum of schizophrenic patients. Mol Psychiatry 2002; 7(7): 673-82.
[] [PMID: 12192610]
Shi Y, Zhao X, Hsieh J, et al. MicroRNA regulation of neural stem cells and neurogenesis. J Neurosci 2010; 30(45): 14931-6.
[] [PMID: 21068294]
Oliver RJ, Mandyam CD. Regulation of adult neurogenesis by non-coding RNAs: Implications for substance use disorders. Front Neurosci 2018; 12: 849.
[] [PMID: 30524229]
Horai T, Boku S, Okazaki S, et al. miR-19b is elevated in peripheral blood of schizophrenic patients and attenuates proliferation of hippocampal neural progenitor cells. J Psychiatr Res 2020; 131: 102-7.
[] [PMID: 32950706]
Beveridge NJ, Gardiner E, Carroll AP, Tooney PA, Cairns MJ. Schizophrenia is associated with an increase in cortical microRNA biogenesis. Mol Psychiatry 2010; 15(12): 1176-89.
[] [PMID: 19721432]
Santarelli DM, Beveridge NJ, Tooney PA, Cairns MJ. Upregulation of dicer and microRNA expression in the dorsolateral prefrontal cortex Brodmann area 46 in schizophrenia. Biol Psychiatry 2011; 69(2): 180-7.
[] [PMID: 21111402]
Varendi K, Mätlik K, Andressoo JO. From microRNA target validation to therapy: Lessons learned from studies on BDNF. Cell Mol Life Sci 2015; 72(9): 1779-94.
[] [PMID: 25601223]
Peng Y, Dai Y, Hitchcock C, et al. Insulin growth factor signaling is regulated by microRNA-486, an underexpressed microRNA in lung cancer. Proc Natl Acad Sci USA 2013; 110(37): 15043-8.
[] [PMID: 23980150]
Kmecova Z, Radik M, Veteskova J, et al. Increased expression of the nerve growth factor (NGF) in pulmonary artery is accompanied by changes of particular microRNAs level in monocratoline-induced pulmonary hypertension. J Hypertens 2019; 37: e26.
Watanabe Y, Nunokawa A, Someya T. Association of the BDNF C270T polymorphism with schizophrenia: Updated meta-analysis. Psychiatry Clin Neurosci 2013; 67(2): 123-5.
[] [PMID: 23438165]
Szeszko PR, Lipsky R, Mentschel C, et al. Brain-derived neurotrophic factor val66met polymorphism and volume of the hippocampal formation. Mol Psychiatry 2005; 10(7): 631-6.
[] [PMID: 15768049]
Bonaccorso S, Sodhi M, Li J, et al. The brain-derived neurotrophic factor (BDNF) Val66Met polymorphism is associated with increased body mass index and insulin resistance measures in bipolar disorder and schizophrenia. Bipolar Disord 2015; 17(5): 528-35.
[] [PMID: 25874530]
Gratacòs M, González JR, Mercader JM, de Cid R, Urretavizcaya M, Estivill X. Brain-derived neurotrophic factor Val66Met and psychiatric disorders: Meta-analysis of case-control studies confirm association to substance-related disorders, eating disorders, and schizophrenia. Biol Psychiatry 2007; 61(7): 911-22.
[] [PMID: 17217930]
Zakharyan R, Atshemyan S, Gevorgyan A, Boyajyan A. Nerve growth factor and its receptor in schizophrenia. BBA Clin 2014; 1: 24-9.
[] [PMID: 26675984]
Park JK, Lee SM, Wang WS, Kim SK, Cho AR. NGF polymorphisms and haplotypes are associated with schizophrenia in Korean population. Mol Cell Toxicol 2011; 7(4): 375-80.
Jungerius BJ, Hoogendoorn ML, Bakker SC, et al. An association screen of myelin-related genes implicates the chromosome 22q11 PIK4CA gene in schizophrenia. Mol Psychiatry 2008; 13(11): 1060-8.
[] [PMID: 17893707]
Terwisscha van Scheltinga AF, Bakker SC, van Haren NE, et al. Genetic schizophrenia risk variants jointly modulate total brain and white matter volume. Biol Psychiatry 2013; 73(6): 525-31.
[] [PMID: 23039932]
Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature 2014; 511(7510): 421-7.
[] [PMID: 25056061]
Goldberg TE, Straub RE, Callicott JH, et al. The G72/G30 gene complex and cognitive abnormalities in schizophrenia. Neuropsychopharmacology 2006; 31(9): 2022-32.
[] [PMID: 16554747]
Hattori M, Nanko S. Association of neurotrophin-3 gene variant with severe forms of schizophrenia. Biochem Biophys Res Commun 1995; 209(2): 513-8.
[] [PMID: 7733919]
Itokawa M, Arai M, Kato S, et al. Association between a novel polymorphism in the promoter region of the neuropeptide Y gene and schizophrenia in humans. Neurosci Lett 2003; 347(3): 202-4.
[] [PMID: 12875921]
Tiwari AK, Brandl EJ, Weber C, et al. Association of a functional polymorphism in neuropeptide Y with antipsychotic-induced weight gain in schizophrenia patients. J Clin Psychopharmacol 2013; 33(1): 11-7.
[] [PMID: 23277265]
Stefansson H, Sigurdsson E, Steinthorsdottir V, et al. Neuregulin 1 and susceptibility to schizophrenia. Am J Hum Genet 2002; 71(4): 877-92.
[] [PMID: 12145742]
He BS, Zhang LY, Pan YQ, et al. Association of the DISC1 and NRG1 genetic polymorphisms with schizophrenia in a Chinese population. Gene 2016; 590(2): 293-7.
[] [PMID: 27236031]
Law AJ, Lipska BK, Weickert CS, et al. Neuregulin 1 transcripts are differentially expressed in schizophrenia and regulated by 5′ SNPs associated with the disease. Proc Natl Acad Sci USA 2006; 103(17): 6747-52.
[] [PMID: 16618933]
Meier S, Strohmaier J, Breuer R, et al. Neuregulin 3 is associated with attention deficits in schizophrenia and bipolar disorder. Int J Neuropsychopharmacol 2013; 16(3): 549-56.
[] [PMID: 22831755]
Hänninen K, Katila H, Anttila S, et al. Epidermal growth factor a61g polymorphism is associated with the age of onset of schizophrenia in male patients. J Psychiatr Res 2007; 41(1-2): 8-14.
[] [PMID: 16115648]
Li W, Zhou N, Yu Q, et al. Association of BDNF gene polymorphisms with schizophrenia and clinical symptoms in a Chinese population. Am J Med Genet B Neuropsychiatr Genet 2013; 162B(6): 538-45.
[] [PMID: 23832605]
Suchanek R, Owczarek A, Paul-Samojedny M, Kowalczyk M, Kucia K, Kowalski J. BDNF val66met polymorphism is associated with age at onset and intensity of symptoms of paranoid schizophrenia in a Polish population. J Neuropsychiatry Clin Neurosci 2013; 25(1): 88-94.
[] [PMID: 23487199]
Notaras M, Hill R, van den Buuse M. The BDNF gene Val66Met polymorphism as a modifier of psychiatric disorder susceptibility: Progress and controversy. Mol Psychiatry 2015; 20(8): 916-30.
[] [PMID: 25824305]
Zhang XY, Chen DC, Tan YL, et al. BDNF polymorphisms are associated with schizophrenia onset and positive symptoms. Schizophr Res 2016; 170(1): 41-7.
[] [PMID: 26603468]
Zhang XY, Chen DC, Xiu MH, et al. Cognitive and serum BDNF correlates of BDNF Val66Met gene polymorphism in patients with schizophrenia and normal controls. Hum Genet 2012; 131(7): 1187-95.
[] [PMID: 22362486]
Ehrenreich H, Degner D, Meller J, et al. Erythropoietin: A candidate compound for neuroprotection in schizophrenia. Mol Psychiatry 2004; 9(1): 42-54.
[] [PMID: 14581931]
Petersen JZ, Schmidt LS, Vinberg M, et al. Effects of recombinant human erythropoietin on cognition and neural activity in remitted patients with mood disorders and first-degree relatives of patients with psychiatric disorders: A study protocol for a randomized controlled trial. Trials 2018; 19(1): 611.
[] [PMID: 30400939]
Nakagawa T, Tsuchida A, Itakura Y, et al. Brain-derived neurotrophic factor regulates glucose metabolism by modulating energy balance in diabetic mice. Diabetes 2000; 49(3): 436-44.
[] [PMID: 10868966]
Tuszynski MH, Thal L, Pay M, et al. A phase 1 clinical trial of nerve growth factor gene therapy for Alzheimer disease. Nat Med 2005; 11(5): 551-5.
[] [PMID: 15852017]
Eyjolfsdottir H, Eriksdotter M, Linderoth B, et al. Targeted delivery of nerve growth factor to the cholinergic basal forebrain of Alzheimer’s disease patients: Application of a second-generation encapsulated cell biodelivery device. Alzheimers Res Ther 2016; 8(1): 30.
[] [PMID: 27389402]
Meier MH, Shalev I, Moffitt TE, et al. Microvascular abnormality in schizophrenia as shown by retinal imaging. Am J Psychiatry 2013; 170(12): 1451-9.
[] [PMID: 24030514]
Weissmiller AM, Wu C. Current advances in using neurotrophic factors to treat neurodegenerative disorders. Transl Neurodegener 2012; 1(1): 14.
[] [PMID: 23210531]
Schwieger J, Hamm A, Gepp MM, et al. Alginate-encapsulated brain-derived neurotrophic factor-overexpressing mesenchymal stem cells are a promising drug delivery system for protection of auditory neurons. J Tissue Eng 2020; 11: 2041731420911313.
[] [PMID: 32341778]

Rights & Permissions Print Export Cite as
© 2023 Bentham Science Publishers | Privacy Policy