Evidence-based umbrella review of 162 peripheral biomarkers for major mental disorders

André F Carvalho, Marco Solmi, Marcos Sanches, Myrela O Machado, Brendon Stubbs, Olesya Ajnakina, Chelsea Sherman, Yue Ran Sun, Celina S Liu, Andre R Brunoni, Giorgio Pigato, Brisa S Fernandes, Beatrice Bortolato, Muhammad I Husain, Elena Dragioti, Joseph Firth, Theodore D Cosco, Michael Maes, Michael Berk, Krista L Lanctôt, Eduard Vieta, Diego A Pizzagalli, Lee Smith, Paolo Fusar-Poli, Paul A Kurdyak, Michele Fornaro, Jürgen Rehm, Nathan Herrmann, André F Carvalho, Marco Solmi, Marcos Sanches, Myrela O Machado, Brendon Stubbs, Olesya Ajnakina, Chelsea Sherman, Yue Ran Sun, Celina S Liu, Andre R Brunoni, Giorgio Pigato, Brisa S Fernandes, Beatrice Bortolato, Muhammad I Husain, Elena Dragioti, Joseph Firth, Theodore D Cosco, Michael Maes, Michael Berk, Krista L Lanctôt, Eduard Vieta, Diego A Pizzagalli, Lee Smith, Paolo Fusar-Poli, Paul A Kurdyak, Michele Fornaro, Jürgen Rehm, Nathan Herrmann

Abstract

The literature on non-genetic peripheral biomarkers for major mental disorders is broad, with conflicting results. An umbrella review of meta-analyses of non-genetic peripheral biomarkers for Alzheimer's disease, autism spectrum disorder, bipolar disorder (BD), major depressive disorder, and schizophrenia, including first-episode psychosis. We included meta-analyses that compared alterations in peripheral biomarkers between participants with mental disorders to controls (i.e., between-group meta-analyses) and that assessed biomarkers after treatment (i.e., within-group meta-analyses). Evidence for association was hierarchically graded using a priori defined criteria against several biases. The Assessment of Multiple Systematic Reviews (AMSTAR) instrument was used to investigate study quality. 1161 references were screened. 110 met inclusion criteria, relating to 359 meta-analytic estimates and 733,316 measurements, on 162 different biomarkers. Only two estimates met a priori defined criteria for convincing evidence (elevated awakening cortisol levels in euthymic BD participants relative to controls and decreased pyridoxal levels in participants with schizophrenia relative to controls). Of 42 estimates which met criteria for highly suggestive evidence only five biomarker aberrations occurred in more than one disorder. Only 15 meta-analyses had a power >0.8 to detect a small effect size, and most (81.9%) meta-analyses had high heterogeneity. Although some associations met criteria for either convincing or highly suggestive evidence, overall the vast literature of peripheral biomarkers for major mental disorders is affected by bias and is underpowered. No convincing evidence supported the existence of a trans-diagnostic biomarker. Adequately powered and methodologically sound future large collaborative studies are warranted.

Conflict of interest statement

A.F.C., Marco Solmi, M. Sanches, M.O.M., B.S., O.A., C.S., J.S., C.S.L., A.R.B., G.P., B.S.F., B.B., M.I.H., E.D., J.F., T.D.C., M.M., L.S., P.F.-P., P.A.K., M.F., J.R., and N.H. have no conflicts of interest to declare. M.B. has been a speaker for Astra Zeneca, Lundbeck, Merck, Pfizer, and served as a consultant to Allergan, Astra Zeneca, Bioadvantex, Bionomics, Collaborative Medicinal Development, Lundbeck Merck, Pfizer and Servier. K.L.L. has received consulting fees from AbbVie, Lundbeck/Otsuka, Pfizer, ICG Pharma, and Kondor in the last 3 years. E.V. has served as consultant, advisor or CME speaker for the following entities: AB-Biotics, Abbott, Allergan, Angelini, AstraZeneca, Bristol-Myers Squibb, Dainippon Sumitomo Pharma, Farmindustria, Ferrer, Forest Research Institute, Gedeon Richter, Glaxo-Smith-Kline, Janssen, Lundbeck, Otsuka, Pfizer, Roche, SAGE, Sanofi-Aventis, Servier, Shire, Sunovion, Takeda. Over the past 3 years, D.A.P. has received consulting fees from Akili Interactive Labs, BlackThorn Therapeutics, Boehringer Ingelheim, Compass, Posit Science, and Takeda Pharmaceuticals and an honorarium from Alkermes for activities unrelated to the current work.

Figures

Fig. 1
Fig. 1
Study flowchart.

References

    1. Fernandes BS, et al. The new field of ‘precision psychiatry’. BMC Med. 2017;15:80.
    1. Insel TR. The NIMH Research Domain Criteria (RDoC) Project: precision medicine for psychiatry. The. Am. J. Psychiatry. 2014;171:395–397.
    1. Collins PY, et al. Grand challenges in global mental health. Nature. 2011;475:27–30.
    1. Fusar-Poli P, Meyer-Lindenberg A. Forty years of structural imaging in psychosis: promises and truth. Acta Psychiatr. Scand. 2016;134:207–224.
    1. Leucht S, Hierl S, Kissling W, Dold M, Davis JM. Putting the efficacy of psychiatric and general medicine medication into perspective: review of meta-analyses. Br. J. Psychiatry. 2012;200:97–106.
    1. Pinto JV, Moulin TC, Amaral OB. On the transdiagnostic nature of peripheral biomarkers in major psychiatric disorders: a systematic review. Neurosci. Biobehav. Rev. 2017;83:97–108.
    1. 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.
    1. Kohler CA, et al. Peripheral cytokine and chemokine alterations in depression: a meta-analysis of 82 studies. Acta Psychiatr. Scand. 2017;135:373–387.
    1. Kohler CA, et al. Peripheral alterations in cytokine and chemokine levels after antidepressant drug treatment for major depressive disorder: systematic review and meta-analysis. Mol. Neurobiol. 2018;55:4195–4206.
    1. Lai KSP, et al. Peripheral inflammatory markers in Alzheimer’s disease: a systematic review and meta-analysis of 175 studies. J. Neurol. Neurosurg. Psychiatry. 2017;88:876–882.
    1. Masi A, et al. Cytokine aberrations in autism spectrum disorder: a systematic review and meta-analysis. Mol. Psychiatry. 2015;20:440–446.
    1. Brown NC, Andreazza AC, Young LT. An updated meta-analysis of oxidative stress markers in bipolar disorder. Psychiatry Res. 2014;218:61–68.
    1. Cuthbert BN, Insel TR. Toward the future of psychiatric diagnosis: the seven pillars of RDoC. BMC Med. 2013;11:126.
    1. Gandal MJ, et al. Shared molecular neuropathology across major psychiatric disorders parallels polygenic overlap. Science. 2018;359:693–697.
    1. Zhang B, et al. Mapping anhedonia-specific dysfunction in a transdiagnostic approach: an ALE meta-analysis. Brain Imaging Behav. 2016;10:920–939.
    1. McTeague LM, et al. Identification of common neural circuit disruptions in cognitive control across psychiatric disorders. Am. J. Psychiatry. 2017;174:676–685.
    1. Fusar-Poli P, et al. Transdiagnostic psychiatry: a systematic review. World Psychiatry. 2019;18:192–207.
    1. Papatheodorou S. Umbrella reviews: what they are and why we need them. Eur. J. Epidemiol. 2019;34:543–546.
    1. Fusar-Poli P, Radua J. Ten simple rules for conducting umbrella reviews. Evid. Based Ment. Health. 2018;21:95–100.
    1. Carvalho AF, et al. Bias in peripheral depression biomarkers. Psychother. Psychosom. 2016;85:81–90.
    1. Belbasis L, et al. Risk factors and peripheral biomarkers for schizophrenia spectrum disorders: an umbrella review of meta-analyse. Acta Psychiatr. Scand. 2018;137:88–97.
    1. Ioannidis JP. Integration of evidence from multiple meta-analyses: a primer on umbrella reviews, treatment networks and multiple treatments meta-analyses. Can. Med. Assoc. J. = J. l’Assoc. Med. Can. 2009;181:488–493.
    1. Davis J, et al. Towards a classification of biomarkers of neuropsychiatric disease: from encompass to compass. Mol. Psychiatry. 2015;20:152–153.
    1. Lau J, Ioannidis JP, Schmid CH. Quantitative synthesis in systematic reviews. Ann. Intern. Med. 1997;127:820–826.
    1. Polanin JR, Snilstveit B. Converting between effect sizes. Campbell Syst. Rev. 2016;12:1–13.
    1. IntHout J, Ioannidis JP, Rovers MM, Goeman JJ. Plea for routinely presenting prediction intervals in meta-analysis. BMJ Open. 2016;6:e010247.
    1. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ (Clin. Res. ed.) 2003;327:557–560.
    1. Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ (Clin. Res. ed.) 1997;315:629–634.
    1. Benjamin DJ, et al. Redefine statistical significance. Nat. Hum. Behav. 2018;2:6–10.
    1. Hedges LV, Pigott TD. The power of statistical tests in meta-analysis. Psychol. Methods. 2001;6:203–217.
    1. Ioannidis JP, Trikalinos TA. An exploratory test for an excess of significant findings. Clin. Trials (Lond., Engl.) 2007;4:245–253.
    1. Ioannidis. Clarifications on the application and interpretation of the test for excess significance and its extensions. J. Math. Psychol.57, 84–187 (2013).
    1. Papatheodorou SI, Tsilidis KK, Evangelou E, Ioannidis JP. Application of credibility ceilings probes the robustness of meta-analyses of biomarkers and cancer risk. J. Clin. Epidemiol. 2015;68:163–174.
    1. Shea BJ, et al. Development of AMSTAR: a measurement tool to assess the methodological quality of systematic reviews. BMC Med. Res. Methodol. 2007;7:10.
    1. Shea BJ, et al. AMSTAR is a reliable and valid measurement tool to assess the methodological quality of systematic reviews. J. Clin. Epidemiol. 2009;62:1013–1020.
    1. Mullan K, Cardwell CR, McGuinness B, Woodside JV, McKay GJ. Plasma antioxidant status in patients with Alzheimer’s disease and cognitively intact elderly: a meta-analysis of case-control studies. J. Alzheimer’s Dis. 2018;62:305–317.
    1. Xu L, et al. Circulatory levels of toxic metals (aluminum, cadmium, mercury, lead) in patients with Alzheimer's disease: a quantitative meta-analysis and systematic review. J. Alzheimer’s Dis. 2018;62:361–372.
    1. Shi Y, Gu L, Alsharif AA, Zhang Z. The distinction of amyloid-beta protein precursor (AbetaPP) ratio in platelet between Alzheimer’s disease patients and controls: a systematic review and meta-analysis. J. Alzheimer’s Dis. 2017;59:1037–1044.
    1. de Wilde MC, Vellas B, Girault E, Yavuz AC, Sijben JW. Lower brain and blood nutrient status in Alzheimer’s disease: results from meta-analyses. . Alzheimer's Dement. 2017;3:416–431.
    1. Annweiler C, Llewellyn DJ, Beauchet O. Low serum vitamin D concentrations in Alzheimer’s disease: a systematic review and meta-analysis. J. Alzheimer’s Dis. 2013;33:659–674.
    1. Song F, et al. Meta-analysis of plasma amyloid-beta levels in Alzheimer’s disease. J. Alzheimer’s Dis. 2011;26:365–375.
    1. Wang C, et al. Meta-analysis of peripheral blood apolipoprotein E levels in Alzheimer’s disease. PLoS ONE. 2014;9:e89041.
    1. Shanthi KB, Krishnan S, Rani P. A systematic review and meta-analysis of plasma amyloid 1-42 and tau as biomarkers for Alzheimer’s disease. SAGE Open Med. 2015;3:2050312115598250.
    1. Du Y, et al. Postmortem brain, cerebrospinal fluid, and blood neurotrophic factor levels in Alzheimer’s disease: a systematic review and meta-analysis. J. Mol. Neurosci. 2018;65:289–300.
    1. Yang C, et al. Association between clusterin concentration and dementia: a systematic review and meta-analysis. Metab. Brain Dis. 2019;34:129–140.
    1. Li DD, Zhang W, Wang ZY, Zhao P. Serum copper, zinc, and iron levels in patients with Alzheimer’s disease: a meta-analysis of case-control studies. Front. Aging Neurosci. 2017;9:300.
    1. Schneider LS, Hinsey M, Lyness S. Plasma dehydroepiandrosterone sulfate in Alzheimer’s disease. Biol. Psychiatry. 1992;31:205–208.
    1. Xu J, Xia LL, Song N, Chen SD, Wang G. Testosterone, estradiol, and sex hormone-binding globulin in Alzheimer’s disease: a meta-analysis. Curr. Alzheimer Res. 2016;13:215–222.
    1. Lopes da Silva S, et al. Plasma nutrient status of patients with Alzheimer’s disease: Systematic review and meta-analysis. Alzheimer’s Dement. 2014;10:485–502.
    1. Squitti R, et al. Meta-analysis of serum non-ceruloplasmin copper in Alzheimer’s disease. J. Alzheimer’s Dis. 2014;38:809–822.
    1. Du N, et al. Inverse association between serum uric acid levels and Alzheimer’s disease risk. Mol. Neurobiol. 2016;53:2594–2599.
    1. Inoshita M, et al. A significant causal association between C-reactive protein levels and schizophrenia. Sci. Rep. 2016;6:26105.
    1. Hu X, Yang Y, Gong D. Circulating insulin-like growth factor 1 and insulin-like growth factor binding protein-3 level in Alzheimer’s disease: a meta-analysis. Neurol. Sci. 2016;37:1671–1677.
    1. Zhou F, Chen S. Effects of gender and other confounding factors on leptin concentrations in Alzheimer’s disease: evidence from the combined analysis of 27 case-control studies. J. Alzheimer’s Dis. 2018;62:477–486.
    1. Schrag M, et al. Oxidative stress in blood in Alzheimer’s disease and mild cognitive impairment: a meta-analysis. Neurobiol. Dis. 2013;59:100–110.
    1. Du K, Liu M, Pan Y, Zhong X, Wei M. Association of serum manganese levels with Alzheimeras disease and mild cognitive impairment: a systematic review and meta-analysis. Nutrients. 2017;9:pii: E231. doi: 10.3390/nu9030231.
    1. Liu D, et al. Soluble TREM2 changes during the clinical course of Alzheimer’s disease: a meta-analysis. Neurosci. Lett. 2018;686:10–16.
    1. Ho RC, et al. Is high homocysteine level a risk factor for cognitive decline in elderly? A systematic review, meta-analysis, and meta-regression. Am. J. Geriatr. Psychiatry. 2011;19:607–617.
    1. Shen L, Ji HF. Associations between homocysteine, folic acid, vitamin B12 and Alzheimer’s disease: insights from meta-analyses. J. Alzheimer’s Dis. 2015;46:777–790.
    1. Beydoun MA, et al. Epidemiologic studies of modifiable factors associated with cognition and dementia: systematic review and meta-analysis. BMC Public Health. 2014;14:643.
    1. Ventriglia M, et al. Zinc in Alzheimer’s disease: a meta-analysis of serum, plasma, and cerebrospinal fluid studies. J. Alzheimer’s Dis. 2015;46:75–87.
    1. Frustaci A, et al. Oxidative stress-related biomarkers in autism: systematic review and meta-analyses. Free Radic. Biol. Med. 2012;52:2128–2141.
    1. Zhu G, et al. Effects of exercise intervention in breast cancer survivors: a meta-analysis of 33 randomized controlled trails. OncoTargets Ther. 2016;9:2153–2168.
    1. Gabriele S, Sacco R, Persico AM. Blood serotonin levels in autism spectrum disorder: a systematic review and meta-analysis. Eur. Neuropsychopharmacol. 2014;24:919–929.
    1. Saghazadeh A, Rezaei N. Systematic review and meta-analysis links autism and toxic metals and highlights the impact of country development status: higher blood and erythrocyte levels for mercury and lead, and higher hair antimony, cadmium, lead, and mercury. Prog. Neuro-Psychopharmacol. Biol. Psychiatry. 2017;79:340–368.
    1. Mazahery H, et al. Relationship between long chain n-3 polyunsaturated fatty acids and autism spectrum disorder: systematic review and meta-analysis of case-control and randomised controlled trials. Nutrients. 2017;9:pii: E155. doi: 10.3390/nu9020155.
    1. Saghazadeh A, Rezaei N. Brain-derived neurotrophic factor levels in autism: a systematic review and meta-analysis. J. Autism Dev. Disord. 2017;47:1018–1029.
    1. Jafari T, Rostampour N, Fallah AA, Hesami A. The association between mercury levels and autism spectrum disorders: a systematic review and meta-analysis. J. Trace Elem. Med. Biol. 2017;44:289–297.
    1. Main PA, Angley MT, O’Doherty CE, Thomas P, Fenech M. The potential role of the antioxidant and detoxification properties of glutathione in autism spectrum disorders: a systematic review and meta-analysis. Nutr. Metab. 2012;9:35.
    1. Tseng PT, et al. Peripheral iron levels in children with autism spectrum disorders vs controls: a systematic review and meta-analysis. Nutr. Res. (N. Y., NY) 2018;50:44–52.
    1. Zheng Z, Zhu T, Qu Y, Mu D. Blood glutamate levels in autism spectrum disorder: a systematic review and meta-analysis. PLoS ONE. 2016;11:e0158688.
    1. Looney SW, el-Mallakh RS. Meta-analysis of erythrocyte Na,K-ATPase activity in bipolar illness. Depression Anxiety. 1997;5:53–65.
    1. Rao S, et al. Peripheral blood nerve growth factor levels in major psychiatric disorders. J. Psychiatr. Res. 2017;86:39–45.
    1. Babaknejad N, Sayehmiri F, Sayehmiri K, Mohamadkhani A, Bahrami S. The relationship between zinc levels and autism: a systematic review and meta-analysis. Iran. J. Child Neurol. 2016;10:1–9.
    1. Ogyu K, et al. Kynurenine pathway in depression: a systematic review and meta-analysis. Neurosci. Biobehav. Rev. 2018;90:16–25.
    1. Lin PY, Huang SY, Su KP. A meta-analytic review of polyunsaturated fatty acid compositions in patients with depression. Biol. Psychiatry. 2010;68:140–147.
    1. Mokhtari M, Arfken C, Boutros N. The DEX/CRH test for major depression: a potentially useful diagnostic test. Psychiatry Res. 2013;208:131–139.
    1. Petridou ET, et al. Folate and B12 serum levels in association with depression in the aged: a systematic review and meta-analysis. Aging Ment. Health. 2016;20:965–973.
    1. Zorn JV, et al. Cortisol stress reactivity across psychiatric disorders: a systematic review and meta-analysis. Psychoneuroendocrinology. 2016;77:25–36.
    1. Fernandes BS, et al. C-reactive protein concentrations across the mood spectrum in bipolar disorder: a systematic review and meta-analysis. Lancet Psychiatry. 2016;3:1147–1156.
    1. Bartoli F, Crocamo C, Mazza MG, Clerici M, Carra G. Uric acid levels in subjects with bipolar disorder: a comparative meta-analysis. J. Psychiatr. Res. 2016;81:133–139.
    1. Tseng PT, et al. State-dependent increase in the levels of neurotrophin-3 and neurotrophin-4/5 in patients with bipolar disorder: a meta-analysis. J. Psychiatr. Res. 2016;79:86–92.
    1. Rutigliano G, et al. Peripheral oxytocin and vasopressin: biomarkers of psychiatric disorders? A comprehensive systematic review and preliminary meta-analysis. Psychiatry Res. 2016;241:207–220.
    1. Tu KY, et al. Significantly higher peripheral insulin-like growth factor-1 levels in patients with major depressive disorder or bipolar disorder than in healthy controls: a meta-analysis and review under guideline of PRISMA. Medicine. 2016;95:e2411.
    1. Pearlman DM, Najjar S. Meta-analysis of the association between N-methyl-d-aspartate receptor antibodies and schizophrenia, schizoaffective disorder, bipolar disorder, and major depressive disorder. Schizophr. Res. 2014;157:249–258.
    1. Fernandes BS, et al. Peripheral brain-derived neurotrophic factor (BDNF) as a biomarker in bipolar disorder: a meta-analysis of 52 studies. BMC Med. 2015;13:289.
    1. Belvederi Murri M, et al. The HPA axis in bipolar disorder: systematic review and meta-analysis. Psychoneuroendocrinology. 2016;63:327–342.
    1. Nascimento KK, Silva KP, Malloy-Diniz LF, Butters MA, Diniz BS. Plasma and cerebrospinal fluid amyloid-beta levels in late-life depression: a systematic review and meta-analysis. J. Psychiatr. Res. 2015;69:35–41.
    1. Romeo B, Choucha W, Fossati P, Rotge JY. Meta-analysis of central and peripheral gamma-aminobutyric acid levels in patients with unipolar and bipolar depression. J. Psychiatry Neurosci. 2018;43:58–66.
    1. Lin PY, Tseng PT. Decreased glial cell line-derived neurotrophic factor levels in patients with depression: a meta-analytic study. J. Psychiatr. Res. 2015;63:20–27.
    1. Inoshita M, et al. Elevated peripheral blood glutamate levels in major depressive disorder. Neuropsychiatr. Dis. Treat. 2018;14:945–953.
    1. You HJ, Cho SE, Kang SG, Cho SJ, Na KS. Decreased serum magnesium levels in depression: a systematic review and meta-analysis. Nord. J. Psychiatry. 2018;72:534–541.
    1. Mazza MG, et al. Neutrophil/lymphocyte ratio and platelet/lymphocyte ratio in mood disorders: a meta-analysis. Prog. Neuro-Psychopharmacol. Biol. Psychiatry. 2018;84:229–236.
    1. Shin JY, Suls J, Martin R. Are cholesterol and depression inversely related? A meta-analysis of the association between two cardiac risk factors. Ann. Behav. Med. 2008;36:33–43.
    1. Bartoli F, et al. Antioxidant uric acid in treated and untreated subjects with major depressive disorder: a meta-analysis and meta-regression. Eur. Arch. Psychiatry Clin. Neurosci. 2018;268:119–127.
    1. Anglin RE, Samaan Z, Walter SD, McDonald SD. Vitamin D deficiency and depression in adults: systematic review and meta-analysis. Br. J. Psychiatry. 2013;202:100–107.
    1. Swardfager W, et al. Zinc in depression: a meta-analysis. Biol. Psychiatry. 2013;74:872–878.
    1. Firth J, et al. Nutritional deficiencies and clinical correlates in first-episode psychosis: a systematic review and meta-analysis. Schizophrenia Bull. 2018;44:1275–1292.
    1. Chaumette B, et al. Salivary cortisol in early psychosis: new findings and meta-analysis. Psychoneuroendocrinology. 2016;63:262–270.
    1. Pillinger T, et al. Impaired glucose homeostasis in first-episode schizophrenia: a systematic review and meta-analysis. JAMA Psychiatry. 2017;74:261–269.
    1. Hoen WP, et al. Red blood cell polyunsaturated fatty acids measured in red blood cells and schizophrenia: a meta-analysis. Psychiatry Res. 2013;207:1–12.
    1. Haapakoski R, Mathieu J, Ebmeier KP, Alenius H, Kivimaki M. Cumulative meta-analysis of interleukins 6 and 1beta, tumour necrosis factor alpha and C-reactive protein in patients with major depressive disorder. Brain Behav. Immun. 2015;49:206–215.
    1. Ni M, You Y, Chen J, Zhang L. Copper in depressive disorder: a systematic review and meta-analysis of observational studies. Psychiatry Res. 2018;267:506–515.
    1. Ciufolini S, Dazzan P, Kempton MJ, Pariante C, Mondelli V. HPA axis response to social stress is attenuated in schizophrenia but normal in depression: evidence from a meta-analysis of existing studies. Neurosci. Biobehav. Rev. 2014;47:359–368.
    1. Wang D, Zhai JX, Liu DW. Serum folate levels in schizophrenia: a meta-analysis. Psychiatry Res. 2016;235:83–89.
    1. Fernandes BS, et al. C-reactive protein is increased in schizophrenia but is not altered by antipsychotics: meta-analysis and implications. Mol. Psychiatry. 2016;21:554–564.
    1. Tseng PT, Cheng YS, Chen YW, Wu CK, Lin PY. Increased levels of vascular endothelial growth factor in patients with major depressive disorder: A meta-analysis. Eur. Neuropsychopharmacol. 2015;25:1622–1630.
    1. Zhu G, et al. Serum DHEAS levels are associated with the development of depression. Psychiatry Res. 2015;229:447–453.
    1. Flatow J, Buckley P, Miller BJ. Meta-analysis of oxidative stress in schizophrenia. Biol. Psychiatry. 2013;74:400–409.
    1. Molendijk ML, et al. 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.
    1. Wu CK, Tseng PT, Chen YW, Tu KY, Lin PY. Significantly higher peripheral fibroblast growth factor-2 levels in patients with major depressive disorder: a preliminary meta-analysis under MOOSE guidelines. Medicine. 2016;95:e4563.
    1. Persons JE, Fiedorowicz JG. Depression and serum low-density lipoprotein: a systematic review and meta-analysis. J. Affect. Disord. 2016;206:55–67.
    1. Ogawa S, et al. Plasma l-tryptophan concentration in major depressive disorder: new data and meta-analysis. J. Clin. Psychiatry. 2014;75:e906–e915.
    1. Greenhalgh AM, et al. Meta-analysis of glucose tolerance, insulin, and insulin resistance in antipsychotic-naive patients with nonaffective psychosis. Schizophrenia Res. 2017;179:57–63. doi: 10.1016/j.schres.2016.09.026.
    1. Chen YW, et al. Significantly lower nerve growth factor levels in patients with major depressive disorder than in healthy subjects: a meta-analysis and systematic review. Neuropsychiatr. Dis. Treat. 2015;11:925–933.
    1. Fernandes BS, et al. Peripheral brain-derived neurotrophic factor in schizophrenia and the role of antipsychotics: meta-analysis and implications. Mol. Psychiatry. 2015;20:1108–1119.
    1. Aleksovska K, et al. Systematic review and meta-analysis of circulating S100B blood levels in schizophrenia. PLoS ONE. 2014;9:e106342.
    1. Lachance LR, McKenzie K. Biomarkers of gluten sensitivity in patients with non-affective psychosis: a meta-analysis. Schizophrenia Res. 2014;152:521–527.
    1. Berger M, et al. Cortisol awakening response in patients with psychosis: systematic review and meta-analysis. Neurosci. Biobehav. Rev. 2016;68:157–166.
    1. Plitman E, et al. Kynurenic acid in schizophrenia: a systematic review and meta-analysis. Schizophrenia Bull. 2017;43:764–777.
    1. Stubbs B, Wang AK, Vancampfort D, Miller BJ. Are leptin levels increased among people with schizophrenia versus controls? A systematic review and comparative meta-analysis. Psychoneuroendocrinology. 2016;63:144–154.
    1. 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;22:1306–1312.
    1. Tomioka Y, et al. Decreased serum pyridoxal levels in schizophrenia: meta-analysis and Mendelian randomization analysis. J. Psychiatry Neurosci. 2018;43:194–200.
    1. Misiak B, Stramecki F, Stanczykiewicz B, Frydecka D, Lubeiro A. Vascular endothelial growth factor in patients with schizophrenia: a systematic review and meta-analysis. Prog. Neuro-Psychopharmacol. Biol. Psychiatry. 2018;86:24–29.
    1. Goetz RL, Miller BJ. Meta-analysis of ghrelin alterations in schizophrenia: effects of olanzapine. Schizophrenia Res. 2019;206:21–26.
    1. Fang X, Zhang Y, Fan W, Tang W, Zhang C. Interleukin-17 alteration in first-episode psychosis: a meta-analysis. Mol. Neuropsychiatry. 2018;3:135–140.
    1. Cao B, et al. Leptin and adiponectin levels in major depressive disorder: a systematic review and meta-analysis. J. Affect. Disord. 2018;238:101–110.
    1. Joe P, Petrilli M, Malaspina D, Weissman J. Zinc in schizophrenia: a meta-analysis. Gen. Hosp. Psychiatry. 2018;53:19–24.
    1. Salagre E, et al. Homocysteine as a peripheral biomarker in bipolar disorder: a meta-analysis. Eur. Psychiatry. 2017;43:81–91.
    1. Bender A, Hagan KE, Kingston N. The association of folate and depression: a meta-analysis. J. Psychiatr. Res. 2017;95:9–18.
    1. Song J, Viggiano A, Monda M, De Luca V. Peripheral glutamate levels in schizophrenia: evidence from a meta-analysis. Neuropsychobiology. 2014;70:133–141.
    1. Guo J, Liu C, Wang Y, Feng B, Zhang X. Role of T helper lymphokines in the immune-inflammatory pathophysiology of schizophrenia: systematic review and meta-analysis. Nord. J. Psychiatry. 2015;69:364–372.
    1. Nishi A, et al. Meta-analyses of blood homocysteine levels for gender and genetic association studies of the MTHFR C677T polymorphism in schizophrenia. Schizophr. Bull. 2014;40:1154–1163.
    1. Maia-de-Oliveira JP, et al. Nitric oxide plasma/serum levels in patients with schizophrenia: a systematic review and meta-analysis. Rev. Bras. Psiquiatr. (Sao Paulo, Braz.: 1999) 2012;34(Suppl. 2):S149–S155.
    1. Brouwer A, Luykx JJ, van Boxmeer L, Bakker SC, Kahn RS. NMDA-receptor coagonists in serum, plasma, and cerebrospinal fluid of schizophrenia patients: a meta-analysis of case-control studies. Neurosci. Biobehav. Rev. 2013;37:1587–1596.
    1. Valipour G, Saneei P, Esmaillzadeh A. Serum vitamin D levels in relation to schizophrenia: a systematic review and meta-analysis of observational studies. J. Clin. Endocrinol. Metab. 2014;99:3863–3872.
    1. Bartoli F, Crocamo C, Clerici M, Carra G. Second-generation antipsychotics and adiponectin levels in schizophrenia: a comparative meta-analysis. Eur. Neuropsychopharmacol. 2015;25:1767–1774.
    1. Mazereeuw G, Herrmann N, Andreazza AC, Khan MM, Lanctot KL. A meta-analysis of lipid peroxidation markers in major depression. Neuropsychiatr. Dis. Treat. 2015;11:2479–2491.
    1. Carvalho AF, et al. Adipokines as emerging depression biomarkers: a systematic review and meta-analysis. J. Psychiatr. Res. 2014;59:28–37.
    1. Watson S, et al. A randomized trial to examine the effect of mifepristone on neuropsychological performance and mood in patients with bipolar depression. Biol. Psychiatry. 2012;72:943–949.
    1. Soria V, et al. Targeting hypothalamic-pituitary-adrenal axis hormones and sex steroids for improving cognition in major mood disorders and schizophrenia: a systematic review and narrative synthesis. Psychoneuroendocrinology. 2018;93:8–19.
    1. Sole B, et al. Cognitive impairment in bipolar disorder: treatment and prevention strategies. Int. J. Neuropsychopharmacol. 2017;20:670–680.
    1. Fusar-Poli P, et al. Treatments of negative symptoms in schizophrenia: meta-analysis of 168 randomized placebo-controlled trials. Schizophr. Bull. 2015;41:892–899.
    1. Sakuma K, et al. Folic acid/methylfolate for the treatment of psychopathology in schizophrenia: a systematic review and meta-analysis. Psychopharmacology. 2018;235:2303–2314.
    1. Firth J, et al. The efficacy and safety of nutrient supplements in the treatment of mental disorders: a meta-review of meta-analyses of randomized controlled trials. World Psychiatry. 2019;18:308–324. doi: 10.1002/wps.20672.
    1. De La Rosa M, Rutz S, Dorninger H, Scheffold A. Interleukin‐2 is essential for CD4+ CD25+ regulatory T cell function. Eur. J. Immunol. 2004;34:2480–2488.
    1. Thornton AM, Donovan EE, Piccirillo CA, Shevach EM. Cutting edge: IL-2 is critically required for the in vitro activation of CD4+ CD25+ T cell suppressor function. J. Immunol. 2004;172:6519–6523.
    1. Maes M, Carvalho AF. The Compensatory Immune-Regulatory Reflex System (CIRS) in depression and bipolar disorder. Mol. Neurobiol. 2018;55:8885–8903.
    1. Roomruangwong C, et al. The role of aberrations in the immune-inflammatory response system (IRS) and the compensatory immune-regulatory reflex system (CIRS) in different phenotypes of schizophrenia: the IRS-CIRS theory of schizophrenia. Mol. Neurobiol. 2020;57:778–797. doi: 10.1007/s12035-019-01737-z.
    1. Masdeu JC, Dalmau J, Berman KF. NMDA receptor internalization by autoantibodies: a reversible mechanism underlying psychosis? Trends Neurosci. 2016;39:300–310.
    1. Leon-Caballero J, et al. Bipolar disorder and antibodies against the N-methyl-d-aspartate receptor: a gate to the involvement of autoimmunity in the pathophysiology of bipolar illness. Neurosci. Biobehav. Rev. 2015;55:403–412.
    1. Nestler EJ, et al. Neurobiology of depression. Neuron. 2002;34:13–25.
    1. Diniz BS, Teixeira AL. Brain-derived neurotrophic factor and Alzheimer’s disease: physiopathology and beyond. Neuromolecular Med. 2011;13:217–222.
    1. Mainardi M, Fusco S, Grassi C. Modulation of hippocampal neural plasticity by glucose-related signaling. Neural Plast. 2015;2015:657928.
    1. Park SE, Dantzer R, Kelley KW, McCusker RH. Central administration of insulin-like growth factor-I decreases depressive-like behavior and brain cytokine expression in mice. J. Neuroinflamm. 2011;8:12.
    1. Duman CH, et al. Peripheral insulin-like growth factor-I produces antidepressant-like behavior and contributes to the effect of exercise. Behav. Brain Res. 2009;198:366–371.
    1. Hossain MM, Mukheem A, Kamarul T. The prevention and treatment of hypoadiponectinemia-associated human diseases by up-regulation of plasma adiponectin. Life Sci. 2015;135:55–67.
    1. Solmi M, et al. Safety, tolerability, and risks associated with first- and second-generation antipsychotics: a state-of-the-art clinical review. Ther. Clin. Risk Manag. 2017;13:757–777.
    1. Kalkman HO, Feuerbach D. Antidepressant therapies inhibit inflammation and microglial M1-polarization. Pharmacol. Ther. 2016;163:82–93.
    1. Button KS, et al. Power failure: why small sample size undermines the reliability of neuroscience. Nat. Rev. Neurosci. 2013;14:365–376.
    1. Thompson PM, et al. The ENIGMA Consortium: large-scale collaborative analyses of neuroimaging and genetic data. Brain Imaging Behav. 2014;8:153–182.
    1. Stokes CS, et al. Vitamin D supplementation reduces depressive symptoms in patients with chronic liver disease. Clin. Nutr. 2016;35:950–957.
    1. Feczko E, et al. The heterogeneity problem: approaches to identify psychiatric subtypes. Trends Cogn. Sci. 2019;23:584–601.
    1. Andreazza AC, et al. Guidelines for the standardized collection of blood-based biomarkers in psychiatry: steps for laboratory validity—a consensus of the Biomarkers Task Force from the WFSBP. World J. Biol. Psychiatry. 2019;20:340–351.
    1. Beijers L, Wardenaar KJ, van Loo HM, Schoevers RA. Data-driven biological subtypes of depression: systematic review of biological approaches to depression subtyping. Mol. Psychiatry. 2019;24:888–900.
    1. Bartoli F, Lax A, Crocamo C, Clerici M, Carra G. Plasma adiponectin levels in schizophrenia and role of second-generation antipsychotics: a meta-analysis. Psychoneuroendocrinology. 2015;56:179–189.
    1. Fu SP, et al. BHBA suppresses LPS-induced inflammation in BV-2 cells by inhibiting NF-kappaB activation. Mediators Inflamm. 2014;2014:983401.
    1. Girshkin L, Matheson SL, Shepherd AM, Green MJ. Morning cortisol levels in schizophrenia and bipolar disorder: a meta-analysis. Psychoneuroendocrinology. 2014;49:187–206.

Source: PubMed

Szponzorok és közreműködők

Egészségi állapot

Kábítószer-beavatkozások

3
Iratkozz fel