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Peripheral inflammatory and neurotrophic biomarkers of cognitive impairment in schizophrenia: a meta-analysis

Published online by Cambridge University Press:  09 July 2019

Emre Bora Open the ORCID record for Emre Bora [Opens in a new window]
Emre Bora*
Affiliation:
Department of Psychiatry, Dokuz Eylul University Medical School, Izmir 35340, Turkey Department of Neuroscience, Dokuz Eylul University, Izmir 35340, Turkey Department of Psychiatry, Melbourne Neuropsychiatry Centre, University of Melbourne and Melbourne Health, Carlton South, Victoria 3053, Australia
*
Author for correspondence: Emre Bora, E-mail: [email protected]; [email protected]
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Abstract

Background

Schizophrenia is associated with significant cognitive impairment. However, the pathophysiological mechanisms underlying cognitive dysfunction in schizophrenia remain unclear. Brain-derived neurotrophic factor (BDNF) and C-reactive protein (CRP) are among the most commonly investigated peripheral markers of cognition in schizophrenia.

Methods

A systematic review in PubMed and Scopus databases was performed until 31 January 2019 to assess the relationship between cognitive impairment, CRP and BDNF levels in schizophrenia. A random-effects meta-analysis was conducted.

Results

Current meta-analysis included 21 studies including 2449 patients with schizophrenia-spectrum disorders. Overall, both BDNF [r = 0.12, confidence interval (CI) 0.04–0.19] and CRP (r = −0.13, CI 0.08–0.18) levels were very modestly but significantly related to cognitive functioning in schizophrenia (r = 0.12, CI 0.04–0.19). In meta-analyses of cognitive domains, BDNF levels were significantly associated with verbal memory (r = 0.16, CI 0.09–0.23), working memory (r = 0.14, CI 0.06–0.22), processing speed (r = 0.18, CI 0.10–0.26) and verbal fluency (r = 0.09, CI 0–0.18) performances. Elevated CRP levels were related to all cognitive domains (r = −0.09 to −0.13) except for fluency. Subgroup analyses suggested that the relationship between cognitive and BDNF levels were more pronounced in chronic samples.

Conclusions

Current findings suggest that cognitive impairment in schizophrenia is significantly related to elevated CRP and reduced BDNF levels in schizophrenia, particularly in chronic samples. However, small effect sizes of these correlations suggest that inflammation and decreased BDNF levels do not play a major role in cognitive dysfunction in most patients with schizophrenia. Further studies are needed to investigate the potential intermediating and confounding factors which can influence the level of relationship between inflammation, neurotrophic factors and cognition in schizophrenia.

Keywords

BDNFCRPcognitioninflammationneurotrophic factorsschizophrenia
Type
Review Article
Information
Psychological Medicine , Volume 49 , Issue 12 , September 2019 , pp. 1971 - 1979
Copyright
Copyright © Cambridge University Press 2019 

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References

Aas, M, Dazzan, P, Fisher, HL, Morgan, C, Morgan, K, Reichenberg, A, Zanelli, J, Fearon, P, Jones, PB, Murray, RM and Pariante, CM (2011) Childhood trauma and cognitive function in first-episode affective and non-affective psychosis. Schizophrenia Research 129, 12–19.Google Scholar
Aas, M, Dieset, I, Morch, R, Steen, NE, Hope, S, Reponen, EJ, Laskemoen, JF, Ueland, T, Aukrust, P, Melle, I, Agartz, I and Andreassen, OA (2019) Reduced brain-derived neurotrophic factor is associated with childhood trauma experiences and number of depressive episodes in severe mental disorders. Schizophrenia Research 205, 45–50.Google Scholar
Agnew-Blais, J and Seidman, LJ (2013) Neurocognition in youth and young adults under age 30 at familial risk for schizophrenia: a quantitative and qualitative review. Cognitive Neuropsychiatry 18, 44–82.Google Scholar
Ahmed, AO, Mantini, AM, Fridberg, DJ and Buckley, PF (2015) Brain-derived neurotrophic factor (BDNF) and neurocognitive deficits in people with schizophrenia: a meta-analysis. Psychiatry Research 226, 1–13.Google Scholar
Asevedo, E, Gadelha, A, Noto, C, Mansur, RB, Zugman, A, Belangero, SI, Berberian, AA, Scarpato, BS, Leclerc, E, Teixeira, AL, Gama, CS, Bressan, RA and Brietzke, E (2013) Impact of peripheral levels of chemokines, BDNF and oxidative markers on cognition in individuals with schizophrenia. Journal of Psychiatric Research 47, 1376–1382.Google Scholar
Bauer, IE, Pascoe, MC, Wollenhaupt-Aguiar, B, Kapczinski, F and Soares, JC (2014) Inflammatory mediators of cognitive impairment in bipolar disorder. Journal of Psychiatric Research 56, 18–27.Google Scholar
Boozalis, T, Teixeira, AL, Cho, RY and Okusaga, O (2018) C-Reactive protein correlates with negative symptoms in patients with schizophrenia. Frontiers in Public Health 5, 360.Google Scholar
Bora, E (2015) Neurodevelopmental origin of cognitive impairment in schizophrenia. Psychological Medicine 45, 1–9.Google Scholar
Bora, E and Murray, RM (2014) 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? Schizophrenia Bulletin 40, 744–755.Google Scholar
Bora, E and Pantelis, C (2015) Meta-analysis of cognitive impairment in first-episode bipolar disorder: comparison with first-episode schizophrenia and healthy controls. Schizophrenia Bulletin 41, 1095–1104.Google Scholar
Bora, E, Yücel, M and Pantelis, C (2010) Cognitive impairment in schizophrenia and affective psychoses: implications for DSM-V criteria and beyond. Schizophrenia Bulletin 36, 36–42.Google Scholar
Bora, E, Lin, A, Wood, SJ, Yung, AR, McGorry, PD and Pantelis, C (2014) Cognitive deficits in youth with familial and clinical high risk to psychosis: a systematic review and metaanalysis. Acta Psychiatrica Scandinavica 130, 1–15.Google Scholar
Bora, E, Binnur Akdede, B and Alptekin, K (2017 a) Neurocognitive impairment in deficit and non-deficit schizophrenia: a meta-analysis. Psychological Medicine 47, 2401–2413.Google Scholar
Bora, E, Akdede, BB and Alptekin, K (2017 b) The relationship between cognitive impairment in schizophrenia and metabolic syndrome: a systematic review and meta-analysis. Psychological Medicine 47, 1030–1040.Google Scholar
Bulzacka, E, Boyer, L, Schürhoff, F, Godin, O, Berna, F, Brunel, L, Andrianarisoa, M, Aouizerate, B, Capdevielle, D, Chéreau-Boudet, I, Chesnoy-Servanin, G, Danion, JM, Dubertret, C, Dubreucq, J, Faget, C, Gabayet, F, Le Gloahec, T, Llorca, PM, Mallet, J, Misdrahi, D, Rey, R, Richieri, R, Passerieux, C, Roux, P, Yazbek, H, Leboyer, M, Fond, G and FACE-SZ (FondaMental Academic Centers of Expertise for Schizophrenia) Group (2016) Chronic peripheral inflammation is associated with cognitive impairment in schizophrenia: results from the multicentric FACE-SZ dataset. Schizophrenia Bulletin 42, 1290–1302.Google Scholar
Carlino, D, Leone, E, Di Cola, F, Baj, G, Marin, R, Dinelli, G, Tongiorgi, E and De Vanna, M (2011) Low serum truncated-BDNF isoform correlates with higher cognitive impairment in schizophrenia. Journal of Psychiatric Research 45, 273–279.Google Scholar
Chiang, MC, Barysheva, M, Toga, AW, Medland, SE, Hansell, NK, James, MR, McMahon, KL, de Zubicaray, GI, Martin, NG, Wright, MJ and Thompson, PM (2011) BDNF gene effects on brain circuitry replicated in 455 twins. NeuroImage 55, 448–454.Google Scholar
De Herdt, A, Wampers, M, Vancampfort, D, De Hert, M, Vanhees, L, Demunter, H, Van Bouwel, L, Brunner, E and Probst, M (2013) Neurocognition in clinical high risk young adults who did or did not convert to a first schizophrenic psychosis: a meta-analysis. Schizophrenia Research 149, 48–55.Google Scholar
Dickerson, F, Stallings, C, Origoni, A, Vaughan, C, Khushalani, S and Yolken, R (2012) Additive effects of elevated C-reactive protein and exposure to Herpes Simplex Virus type 1 on cognitive impairment in individuals with schizophrenia. Schizophrenia Research 134, 83–88.Google Scholar
Dorofeikova, M, Neznanov, N and Petrova, N (2018) Cognitive deficit in patients with paranoid schizophrenia: its clinical and laboratory correlates. Psychiatry Research 262, 542–548.Google Scholar
Fernandes, BS, Steiner, J, Berk, M, Molendijk, ML, Gonzalez-Pinto, A, Turck, CW, Nardin, P and Gonçalves, CA (2015) Peripheral brain-derived neurotrophic factor in schizophrenia and the role of antipsychotics: meta-analysis and implications. Molecular Psychiatry 20, 1108–1119.Google Scholar
Fernandes, BS, Steiner, J, Bernstein, HG, Dodd, S, Pasco, JA, Dean, OM, Nardin, P, Gonçalves, CA and Berk, M (2016) C-reactive protein is increased in schizophrenia but is not altered by antipsychotics: meta-analysis and implications. Molecular Psychiatry 21, 554–564.Google Scholar
Fett, AK, Viechtbauer, W, Dominguez, MD, Penn, DL, van Os, J and Krabbendam, L (2011) The relationship between neurocognition and social cognition with functional outcomes in schizophrenia: a meta-analysis. Neuroscience & Biobehavioral Reviews 35, 573–588.Google Scholar
Fond, G, Lançon, C, Auquier, P and Boyer, L (2018) C-Reactive protein as a peripheral biomarker in schizophrenia. An updated systematic review. Frontiers in Psychiatry 9, 392.Google Scholar
Fourrier, C, Singhal, G and Baune, BT (2019) Neuroinflammation and cognition across psychiatric conditions. CNS Spectrums 24, 4–15.Google Scholar
Fraguas, D, Díaz-Caneja, CM, Ayora, M, Hernández-Álvarez, F, Rodríguez-Quiroga, A, Recio, S, Leza, JC and Arango, C (2018) Oxidative stress and inflammation in first-episode psychosis: a systematic review and meta-analysis. Schizophrenia Bulletin 45, 742–751.Google Scholar
Frydecka, D, Misiak, B, Pawlak-Adamska, E, Karabon, L, Tomkiewicz, A, Sedlaczek, P, Kiejna, A and Beszłej, JA (2015) Interleukin-6: the missing element of the neurocognitive deterioration in schizophrenia? The focus on genetic underpinnings, cognitive impairment and clinical manifestation. European Archives of Psychiatry and Clinical Neuroscience 265, 449–459.Google Scholar
Giese, M, Unternaehrer, E, Brand, S, Calabrese, P, Holsboer-Trachsler, E and Eckert, A (2013) The interplay of stress and sleep impacts BDNF level. PLoS One 8, e76050.Google Scholar
Goldsmith, DR, Rapaport, MH and Miller, BJ (2016) A meta-analysis of blood cytokine network alterations in psychiatric patients: comparisons between schizophrenia, bipolar disorder and depression. Molecular Psychiatry 21, 1696–1709.Google Scholar
Gonzalez-Blanco, L, Garcia-Portilla, MP, Garcia-Alvarez, L, de la Fuente-Tomas, L, Garcia, CI, Saiz, PA and Julio, B (2018) Elevated C-reactive protein as a predictor of a random one-year clinical course in the first ten years of schizophrenia. Psychiatry Research 269, 688–691.Google Scholar
Goto, N, Yoshimura, R, Kakeda, S, Moriya, J, Hayashi, K, Ikenouchi-Sugita, A, Umene-Nakano, W, Hori, H, Ueda, N, Korogi, Y and Nakamura, J (2009) Associations between plasma levels of 3-methoxy-4-hydroxyphenylglycol (MHPG) and negative symptoms or cognitive impairments in early-stage schizophrenia. Human Psychopharmacology 24, 639–645.Google Scholar
Green, MF (2016) Impact of cognitive and social cognitive impairment on functional outcomes in patients with schizophrenia. Journal of Clinical Psychiatry 77(suppl. 2), 8–11.Google Scholar
Heinrichs, RW and Zakzanis, KK (1998) Neurocognitive deficit in schizophrenia: a quantitative review of the evidence. Neuropsychology 12, 426–445.Google Scholar
Hori, H, Yoshimura, R, Katsuki, A, Atake, K, Igata, R, Konishi, Y and Nakamura, J (2017) Relationships between serum brain-derived neurotrophic factor, plasma catecholamine metabolites, cytokines, cognitive function and clinical symptoms in Japanese patients with chronic schizophrenia treated with atypical antipsychotic monotherapy. World Journal of Biological Psychiatry 18, 401–408.Google Scholar
Jacomb, I, Stanton, C, Vasudevan, R, Powell, H, O'Donnell, M, Lenroot, R, Bruggemann, J, Balzan, R, Galletly, C, Liu, D, Weickert, CS and Weickert, TW (2018) C-reactive protein: higher during acute psychotic episodes and related to cortical thickness in schizophrenia and healthy controls. Frontiers in Immunology 9, 2230.Google Scholar
Johnsen, E, Fathian, F, Kroken, RA, Steen, VM, Jørgensen, HA, Gjestad, R and Løberg, EM (2016) The serum level of C-reactive protein (CRP) is associated with cognitive performance in acute phase psychosis. BMC Psychiatry 16, 60.Google Scholar
Joseph, J, Depp, C, Martin, AS, Daly, RE, Glorioso, DK, Palmer, BW and Jeste, DV (2015) Associations of high sensitivity C-reactive protein levels in schizophrenia and comparison groups. Schizophrenia Research 168, 456–460.Google Scholar
Khandaker, GM, Cousins, L, Deakin, J, Lennox, BR, Yolken, R and Jones, PB (2015) Inflammation and immunity in schizophrenia: implications for pathophysiology and treatment. The Lancet. Psychiatry 2, 258–270.Google Scholar
Kirkpatrick, B and Miller, BJ (2013) Inflammation and schizophrenia. Schizophrenia Bulletin 39, 1174–1179.Google Scholar
Leal, G, Afonso, PM, Salazar, IL and Duarte, CB (2015) Regulation of hippocampal synaptic plasticity by BDNF. Brain Research 1621, 82–101.Google Scholar
Lin, IM, Ling, HL and Huang, TL (2017) Serum brain-derived neurotrophic factor, social cognition and social function in patients with schizophrenia. Taiwanese Journal of Psychiatry (Taipei) 31, 1.Google Scholar
Man, L, Lv, X, Du, XD, Yin, G, Zhu, X, Zhang, Y, Soares, JC, Yang, XN, Chen, X and Zhang, XY (2018) Cognitive impairments and low BDNF serum levels in first-episode drug-naïve patients with schizophrenia. Psychiatry Research 263, 1–6.Google Scholar
Meng, J, Hao, L, Wei, D, Sun, J, Li, Y and Qiu, J (2017) BDNF val66met polymorphism modulates the effect of loneliness on white matter microstructure in young adults. Biological Psychology 130, 41–49.Google Scholar
Mesholam-Gately, RI, Giuliano, AJ, Goff, KP, Faraone, SV and Seidman, LJ (2009) Neurocognition in first-episode schizophrenia: a meta-analytic review. Neuropsychology 23, 315–336.Google Scholar
Micoulaud-Franchi, JA, Faugere, M, Boyer, L, Fond, G, Richieri, R, Faget, C, Cermolacce, M, Philip, P, Vion-Dury, J and Lancon, C (2015) Elevated C-reactive protein is associated with sensory gating deficit in schizophrenia. Schizophrenia Research 165, 94–96.Google Scholar
Minichiello, L (2009) Trkb signalling pathways in LTP and learning. Nature Reviews 10, 850–860.Google Scholar
Misiak, B, Stańczykiewicz, B, Kotowicz, K, Rybakowski, JK, Samochowiec, J and Frydecka, D (2018) Cytokines and C-reactive protein alterations with respect to cognitive impairment in schizophrenia and bipolar disorder: a systematic review. Schizophrenia Research 192, 16–29.Google Scholar
Moher, D, Liberati, A, Tetzlaff, J and Altman, DG (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ 339, b2535.Google Scholar
Müller, N (2018) Inflammation in schizophrenia: pathogenetic aspects and therapeutic considerations. Schizophrenia Bulletin 44, 973–982.Google Scholar
Najjar, S and Pearlman, DM (2015) Neuroinflammation and white matter pathology in schizophrenia: systematic review. Schizophrenia Research 161, 102–112.Google Scholar
Niitsu, T, Shirayama, Y, Matsuzawa, D, Hasegawa, T, Kanahara, N, Hashimoto, T, Shiraishi, T, Shiina, A, Fukami, G, Fujisaki, M, Watanabe, H, Nakazato, M, Asano, M, Kimura, S, Hashimoto, K and Iyo, M (2011) Associations of serum brain-derived neurotrophic factor with cognitive impairments and negative symptoms in schizophrenia. Progress in Neuropsychopharmacology and Biological Psychiatry 35, 1836–1840.Google Scholar
Niitsu, T, Shirayama, Y, Matsuzawa, D, Shimizu, E, Hashimoto, K and Iyo, M (2014) Association between serum levels of glial cell-line derived neurotrophic factor and attention deficits in schizophrenia. Neuroscience Letters 575, 37–41.Google Scholar
Omachi, Y and Sumiyoshi, T (2018) Dose reduction/discontinuation of antipsychotic drugs in psychosis; effect on cognition and functional outcomes. Frontiers in Psychiatry 9, 447.Google Scholar
Parellada, M, Gomez-Vallejo, S, Burdeus, M and Arango, C (2017) Developmental differences between schizophrenia and bipolar disorder. Schizophrenia Bulletin 43, 1176–1189.Google Scholar
Potvin, S, Joyal, CC, Pelletier, J and Stip, E (2008) Contradictory cognitive capacities among substance-abusing patients with schizophrenia: a meta-analysis. Schizophrenia Research 100, 242–251.Google Scholar
Ruiz de Azua, S, Matute, C, Stertz, L, Mosquera, F, Palomino, A, de la Rosa, I, Barbeito, S, Vega, P, Kapczinski, F and González-Pinto, A (2013) Plasma brain-derived neurotrophic factor levels, learning capacity and cognition in patients with first episode psychosis. BMC Psychiatry 13, 27.Google Scholar
Saeedi, S, Israel, S, Nagy, C and Turecki, G (2019) The emerging role of exosomes in mental disorders. Translational Psychiatry 9, 122.Google Scholar
Sahu, G, Malavade, K and Jacob, T (2016) Cognitive impairment in schizophrenia: interplay of BDNF and childhood trauma? A review of literature. The Psychiatric Quarterly 87, 559–569.Google Scholar
Schaefer, J, Giangrande, E, Weinberger, DR and Dickinson, D (2013) The global cognitive impairment in schizophrenia: consistent over decades and around the world. Schizophrenia Research 150, 42–50.Google Scholar
Theleritis, C, Fisher, HL, Shäfer, I, Winters, L, Stahl, D, Morgan, C, Dazzan, P, Breedvelt, J, Sambath, I, Vitoratou, S, Russo, M, Reichenberg, A, Falcone, MA, Mondelli, V, O'Connor, J, David, A, McGuire, P, Pariante, C, Di Forti, M, Murray, RM and Bonaccorso, S (2014) Brain derived Neurotropic Factor (BDNF) is associated with childhood abuse but not cognitive domains in first episode psychosis. Schizophrenia Research 159, 56–61.Google Scholar
Thoma, P and Daum, I (2013) Comorbid substance use disorder in schizophrenia: a selective overview of neurobiological and cognitive underpinnings. Psychiatry and Clinical Neuroscience 67, 367–383.Google Scholar
Vinogradov, S, Fisher, M, Holland, C, Shelly, W, Wolkowitz, O and Mellon, SH (2009) Is serum brain-derived neurotrophic factor a biomarker for cognitive enhancement in schizophrenia? Biological Psychiatry 66, 549–553.Google Scholar
Weinberger, DR (1986) The pathogenesis of schizophrenia: a neurodevelopmental theory. In Nasrallah, RA and Weinberger, DR (eds), The Neurology of Schizophrenia. Amsterdam: Elsevier, pp. 387–405.Google Scholar
Wells, GA, Shea, B, O'Connell, D, Peterson, J, Welch, V and Tugwell, P (2000). The Newcastle-Ottawa Scale (NOS) for Assessing the Quality of Nonrandomised Studies in Metaanalyses. Ottawa Hospital Research Institute.Google Scholar
Xiao, W, Ye, F, Liu, C, Tang, X, Li, J, Dong, H, Sha, W and Zhang, X (2017) Cognitive impairment in first-episode drug-naïve patients with schizophrenia: relationships with serum concentrations of brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor. Progress in Neuropsychopharmacology and Biological Psychiatry 76, 163–168.Google Scholar
Zhang, XY, Liang, J, Chen, DC, Xiu, MH, Yang, FD, Kosten, TA and Kosten, TR (2012) Low BDNF is associated with cognitive impairment in chronic patients with schizophrenia. Psychopharmacology (Berl) 222, 277–284.Google Scholar
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