Neurotrophins particularly brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) are crucial modulators in the neurodevelopment and maintenance of central and peripheral nervous systems. Neurotrophin hypothesis of schizophrenia (SCZ) postulated that the changes in the brains of SCZ patients are the result of disturbances of developing processes involving neurotrophic factors. This hypothesis was mainly supported by the abnormal regulation of BDNF in SCZ, especially the decreased peripheral blood BDNF levels in SCZ patients validated by several meta-analyses. However, the regulation of NGF in SCZ remains unclear because of the inconsistent findings from the clinical studies. Therefore, we undertook, to the best of our knowledge, the first systematic review with a meta-analysis to quantitatively summarize the peripheral blood NGF data in SCZ patients compared with healthy control (HC) subjects. A systematic search of Pubmed, PsycINFO and Web of Science identified 13 articles encompassing a sample of 1693 individuals for the meta-analysis. Random-effects meta-analysis showed that patients with SCZ had significantly decreased peripheral blood levels of NGF when compared with the HC subjects (Hedges’s g=−0.633, 95% confidence interval (CI)=−0.948 to −0.318, P<0.001). Subgroup analyses revealed reduced NGF levels both in serum (Hedges’s g=−0.671, 95% CI=−1.259 to −0.084, P=0.025) and plasma (Hedges’s g=−0.621, 95% CI=−0.980 to −0.261, P<0.001) of the patients, and in drug-free (Hedges’s g=−0.670, 95% CI=−1.118 to −0.222, P=0.003) and medicated (Hedges’s g=−0.357, 95% CI=−0.592 to −0.123, P=0.003) patients with SCZ. Furthermore, meta-regression analyses showed that age, gender and sample size had no moderating effects on the outcome of the meta-analysis, whereas disease severity might be a confounding factor for the meta-analysis. These results demonstrated that patients with SCZ are accompanied by the decreased peripheral blood NGF levels, strengthening the clinical evidence of an abnormal neurotrophin profile in the patients with SCZ.
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Gogtay N, Vyas NS, Testa R, Wood SJ, Pantelis C . Age of onset of schizophrenia: perspectives from structural neuroimaging studies. Schizophr Bull 2011; 37: 504–513.
Cassoli JS, Guest PC, Santana AG, Martins-de-Souza D . Employing proteomics to unravel the molecular effects of antipsychotics and their role in schizophrenia. Proteomics Clin Appl 2016; 10: 442–455.
Martins-de-Souza D, Guest PC, Rahmoune H, Bahn S . Proteomic approaches to unravel the complexity of schizophrenia. Exp Rev Proteomics 2012; 9: 97–108.
Weickert TW, Goldberg TE, Gold JM, Bigelow LB, Egan MF, Weinberger DR . Cognitive impairments in patients with schizophrenia displaying preserved and compromised intellect. Arch Gen Psychiatry 2000; 57: 907–913.
Owen MJ, Sawa A, Mortensen PB . Schizophrenia. Lancet 2016; 388: 86–97.
Akhondzadeh S . The 5-HT hypothesis of schizophrenia. IDrugs 2001; 4: 295–300.
Fatemi SH, Folsom TD . The neurodevelopmental hypothesis of schizophrenia, revisited. Schizophr Bull 2009; 35: 528–548.
Howes OD, Kapur S . The dopamine hypothesis of schizophrenia: version III—the final common pathway. Schizophr Bull 2009; 35: 549–562.
Moghaddam B, Javitt D . From revolution to evolution: the glutamate hypothesis of schizophrenia and its implication for treatment. Neuropsychopharmacology 2012; 37: 4–15.
Smith T, Weston C, Lieberman J . Schizophrenia (maintenance treatment). Am Fam Phys 2010; 82: 338–339.
Tandon R, Keshavan MS, Nasrallah HA . Schizophrenia, "Just the Facts": what we know in 2008 part 1: overview. Schizophr Res 2008; 100: 4–19.
Casey DE . Neuroleptic-induced acute extrapyramidal syndromes and tardive dyskinesia. Psychiatr Clin North Am 1993; 16: 589–610.
Aloe L, Iannitelli A, Angelucci F, Bersani G, Fiore M . Studies in animal models and humans suggesting a role of nerve growth factor in schizophrenia-like disorders. Behav Pharmacol 2000; 11: 235–242.
Angelucci F, Brene S, Mathe AA . BDNF in schizophrenia, depression and corresponding animal models. Mol Psychiatry 2005; 10: 345–352.
Fernandes BS, Steiner J, Berk M, Molendijk ML, Gonzalez-Pinto A, Turck CW et al. Peripheral brain-derived neurotrophic factor in schizophrenia and the role of antipsychotics: meta-analysis and implications. Mol Psychiatry 2015; 20: 1108–1119.
Green MJ, Matheson SL, Shepherd A, Weickert CS, Carr VJ . Brain-derived neurotrophic factor levels in schizophrenia: a systematic review with meta-analysis. Mol Psychiatry 2011; 16: 960–972.
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.
Thome J, Foley P, Riederer P . Neurotrophic factors and the maldevelopmental hypothesis of schizophrenic psychoses. Review article. J Neural Trans 1998; 105: 85–100.
Greenberg ME, Xu B, Lu B, Hempstead BL . New insights in the biology of BDNF synthesis and release: implications in CNS function. J Neurosci 2009; 29: 12764–12767.
Hempstead BL . Brain-derived neurotrophic factor: three ligands, many actions. Trans Am Clin Climatol Associ 2015; 126: 9–19.
Lu Y, Christian K, Lu B . BDNF: a key regulator for protein synthesis-dependent LTP and long-term memory? Neurobiol Learn Memory 2008; 89: 312–323.
Sofroniew MV, Howe CL, Mobley WC . Nerve growth factor signaling, neuroprotection, and neural repair. Annu Rev Neurosci 2001; 24: 1217–1281.
Durany N, Michel T, Zochling R, Boissl KW, Cruz-Sanchez FF, Riederer P et al. Brain-derived neurotrophic factor and neurotrophin 3 in schizophrenic psychoses. Schizophr Res 2001; 52: 79–86.
Jindal RD, Pillai AK, Mahadik SP, Eklund K, Montrose DM, Keshavan MS . Decreased BDNF in patients with antipsychotic naive first episode schizophrenia. Schizophr Res 2010; 119: 47–51.
Cui H, Jin Y, Wang J, Weng X, Li C . Serum brain-derived neurotrophic factor (BDNF) levels in schizophrenia: A systematic review. Shanghai Arch Psychiatry 2012; 24: 250–261.
Kale A, Joshi S, Pillai A, Naphade N, Raju M, Nasrallah H et al. Reduced cerebrospinal fluid and plasma nerve growth factor in drug-naive psychotic patients. Schizophr Res 2009; 115: 209–214.
Bersani G, Iannitelli A, Massoni E, Garavini A, Grilli A, Di Giannantonio M et al. Ultradian variation of nerve growth factor plasma levels in healthy and schizophrenic subjects. Int J Immunopathol Pharmacol 2004; 17: 367–372.
Xiong P, Zeng Y, Wan J, Xiaohan DH, Tan D, Lu J et al. The role of NGF and IL-2 serum level in assisting the diagnosis in first episode schizophrenia. Psychiatr Res 2011; 189: 72–76.
Xiong P, Zeng Y, Wu Q, Han Huang DX, Zainal H, Xu X et al. Combining serum protein concentrations to diagnose schizophrenia: a preliminary exploration. J Clin Psychiatry 2014; 75: e794–e801.
Jockers-Scherubl MC, Matthies U, Danker-Hopfe H, Lang UE, Mahlberg R, Hellweg R . Chronic cannabis abuse raises nerve growth factor serum concentrations in drug-naive schizophrenic patients. J Psychopharmacol 2003; 17: 439–445.
Jockers-Scherubl MC, Rentzsch J, Danker-Hopfe H, Radzei N, Schurer F, Bahri S et al. Adequate antipsychotic treatment normalizes serum nerve growth factor concentrations in schizophrenia with and without cannabis or additional substance abuse. Neurosci lett 2006; 400: 262–266.
Martinez-Cengotitabengoa M, MacDowell KS, Alberich S, Diaz FJ, Garcia-Bueno B, Rodriguez-Jimenez R et al. BDNF and NGF signalling in early phases of psychosis: relationship with inflammation and response to antipsychotics after 1 year. Schizophr Bull 2016; 42: 142–151.
Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gotzsche PC, Ioannidis JP et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. J Clin Epidemiol 2009; 62: e1–34.
Qin XY, Feng JC, Cao C, Wu HT, Loh YP, Cheng Y . Association of peripheral blood levels of brain-derived neurotrophic factor with autism spectrum disorder in children: a systematic review and meta-analysis. JAMA Pediatr 2016; 170: 1079–1086.
Masi A, Quintana DS, Glozier N, Lloyd AR, Hickie IB, Guastella AJ . Cytokine aberrations in autism spectrum disorder: a systematic review and meta-analysis. Mol Psychiatry 2015; 20: 440–446.
Higgins JP, Thompson SG, Deeks JJ, Altman DG . Measuring inconsistency in meta-analyses. Br Med J 2003; 327: 557–560.
Qin XY, Cao C, Cawley NX, Liu TT, Yuan J, Loh YP et al. Decreased peripheral brain-derived neurotrophic factor levels in Alzheimer's disease: a meta-analysis study (N=7277). Mol Psychiatry; advance online publication, 26 April 2016; doi: 10.1038/mp.2016.62.
Egger M, Davey Smith G, Schneider M, Minder C . Bias in meta-analysis detected by a simple, graphical test. Brit Med J 1997; 315: 629–634.
Molendijk ML, Spinhoven P, Polak M, Bus BA, Penninx BW, Elzinga BM . Serum BDNF concentrations as peripheral manifestations of depression: evidence from a systematic review and meta-analyses on 179 associations (N=9484). Mol Psychiatry 2014; 19: 791–800.
Soeken KL, Sripusanapan A . Assessing publication bias in meta-analysis. Nurs Res 2003; 52: 57–60.
Buckley PF, Pillai A, Evans D, Stirewalt E, Mahadik S . Brain derived neurotropic factor in first-episode psychosis. Schizophr Res 2007; 91: 1–5.
Miyatake R, Furukawa A, Suwaki H . Identification of a novel variant of the human NR2B gene promoter region and its possible association with schizophrenia. Mol Psychiatry 2002; 7: 1101–1106.
Roussos P, Giakoumaki SG, Zouraraki C, Fullard JF, Karagiorga VE, Tsapakis EM et al. The relationship of common risk variants and polygenic risk for schizophrenia to sensorimotor gating. Biol Psychiatry 2016; 79: 988–996.
Klyushnik TP, Danilovskaya EV, Vatolkina OE, Turkova IL, Tsutsul'kovskaya M, Orlova VA et al. Changes in the serum levels of autoantibody to nerve growth factor in patients with schizophrenia. Neurosci Behav Physiol 1999; 29: 355–357.
Klyushnik TP, Turkova IL, Danilovskaya EV, Kozlova IA, Bashina VM, Simashkova NV et al. Correlation between levels of autoantibodies to nerve growth factor and the clinical features of schizophrenia in children. Neurosci Behav Physiol 2000; 30: 119–121.
Shcherbakova IV, Siryachenko TM, Mazaeva NA, Kaleda VG, Krasnolobova SA, Klyushnik TP . Leukocyte elastase and autoantibodies to nerve growth factor in the acute phase of schizophrenia and their relationship to symptomatology. World J Biol Psychiatry 2004; 5: 143–148.
Bersani G, Aloe L, Iannitelli A, Maselli P, Venturi P, Garavini A et al. Low nerve growth factor (NGF) plasma levels in schizophrenic patients: a pilot study. Schizophr Res 1996; 18: 159–160.
Xiong P, Zeng Y, Zhu Z, Tan D, Xu F, Lu J et al. Reduced NGF serum levels and abnormal P300 event-related potential in first episode schizophrenia. Schizophr Res 2010; 119: 34–39.
Aloe L, Iannitelli A, Bersani G, Alleva E, Angelucci F, Maselli P et al. Haloperidol administration in humans lowers plasma nerve growth factor level: evidence that sedation induces opposite effects to arousal. Neuropsychobiology 1997; 36: 65–68.
Ajami A, Hosseini SH, Taghipour M, Khalilian A . Changes in serum levels of brain derived neurotrophic factor and nerve growth factor-beta in schizophrenic patients before and after treatment. Scand J Immunol 2014; 80: 36–42.
Bersani G, Iannitelli A, Maselli P, Pancheri P, Aloe L, Angelucci F et al. Low nerve growth factor plasma levels in schizophrenic patients: a preliminary study. Schizophr Res 1999; 37: 201–203.
Lee BH, Kim YK . Increased plasma brain-derived neurotropic factor, not nerve growth factor-Beta, in schizophrenia patients with better response to risperidone treatment. Neuropsychobiology 2009; 59: 51–58.
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: 117–123.
Perez-Polo JR, Dy P, Westlund K, Hall K, Livingston K . Levels of serum nerve growth factor in schizophrenia. Birth Defects Orig Artic Ser 1978; 14: 311–321.
Zakharyan R, Atshemyan S, Gevorgyan A, Boyajyan A . Nerve growth factor and its receptor in schizophrenia. BBA Clin 2014; 1: 24–29.
Black JE, Kodish IM, Grossman AW, Klintsova AY, Orlovskaya D, Vostrikov V et al. Pathology of layer V pyramidal neurons in the prefrontal cortex of patients with schizophrenia. Am J Psychiatry 2004; 161: 742–744.
Glantz LA, Lewis DA . Decreased dendritic spine density on prefrontal cortical pyramidal neurons in schizophrenia. Arch Gen Psychiatry 2000; 57: 65–73.
Kheirollahi M, Kazemi E, Ashouri S . Brain-derived neurotrophic factor gene Val66Met polymorphism and risk of schizophrenia: a meta-analysis of case-control studies. Cell Mol Neurobiol 2016; 36: 1–10.
Watanabe Y, Nunokawa A, Someya T . Association of the BDNF C270T polymorphism with schizophrenia: updated meta-analysis. Psychiatr Clin Neurosci 2013; 67: 123–125.
Sokolowski M, Wasserman J, Wasserman D . Polygenic associations of neurodevelopmental genes in suicide attempt. Mol Psychiatry 2016; 21: 1381–1390.
Sokolowski M, Wasserman J, Wasserman D . An overview of the neurobiology of suicidal behaviors as one meta-system. Mol Psychiatry 2015; 20: 56–71.
Goldsmith DR, Rapaport MH, Miller BJ . A meta-analysis of blood cytokine network alterations in psychiatric patients: comparisons between schizophrenia, bipolar disorder and depression. Mol Psychiatry 2016; 21: 1696–1709.
Merenlender-Wagner A, Malishkevich A, Shemer Z, Udawela M, Gibbons A, Scarr E et al. Autophagy has a key role in the pathophysiology of schizophrenia. Mol Psychiatry 2015; 20: 126–132.
Shoval G, Weizman A . The possible role of neurotrophins in the pathogenesis and therapy of schizophrenia. Eur Neuropsychopharmacol 2005; 15: 319–329.
D'Onofrio M, Paoletti F, Arisi I, Brandi R, Malerba F, Fasulo L et al. NGF and proNGF regulate functionally distinct mRNAs in PC12 cells: an early gene expression profiling. PLoS ONE 2011; 6: e20839.
Fahnestock M, Yu G, Coughlin MD . ProNGF: a neurotrophic or an apoptotic molecule? Progr Brain Res 2004; 146: 101–110.
This research was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, USA, and the Minzu University Research Fund (ydzxxk201619&18, 2016SHXY01) and the 111 Project of China (B08044).
X-YQ and YC conceived and designed the study; CC and H-TW collected the data. X-YQ, CC, H-TW and YC analyzed and interpreted the data. YC drafted the manuscript with critical revisions from all the authors.
The authors declare no conflict of interest.
Supplementary Information accompanies the paper on the Molecular Psychiatry website
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