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Blood tests based on biomarker profiles have been used to gather information about the nervous system. Such tests have not yet been established within the primary headache field.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Case\u2010control and case\u2010crossover studies investigating whole blood, plasma, and serum were identified worldwide. The qualitative synthesis focused on 9 signaling molecules (serotonin [5\u2010HT], calcitonin gene\u2010related peptide [CGRP], endothelin\u20101 [ET\u20101], neurokinin A, neurokinin B, neuropeptide Y, pituitary adenylate cyclase\u2010activating peptide 38 [PACAP\u201038], substance P (SP), and vasoactive intestinal peptide) and the quantitative synthesis on 5\u2010HT and CGRP (\u22655 comparisons available). The meta\u2010analysis was conducted using standard and 3\u2010level random effect models.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Fifty\u2010four eligible studies were identified (87.0% migraine, 9.3% CH, 3.7% migraine, and CH), and 2768 headache patients and 1165 controls included. Comparable fluctuations of 5\u2010HT, CGRP, ET\u20101, PACAP\u201038, and SP in blood were generally observed between migraine and CH. Significant findings were observed for some subgroups and strata, for example, higher interictal and ictal 5\u2010HT venous blood levels (ratio of means = 1.32, 95% CI: 1.08; 1.61; ratio of means = 1.23, 95% CI: 1.01; 1.49) in episodic migraine with aura with a female\u2010dominated case group, higher interictal CGRP blood levels in episodic migraine (ratio of means = 1.63, 95% CI: 1.18; 2.26), and chronic migraine (ratio of means = 1.89, 95% CI: 1.33; 2.68), and higher ictal CGRP blood levels (ratio of means = 1.35, 95% CI: 1.09; 1.68) in episodic migraine were observed. In most subgroups, the quantitative synthesis revealed a high degree of heterogeneity between studies in part explained by the blood sampling site, specimen source, blood specimen, and sex distribution. Other potential confounders were age, aura, study quality, menstrual cycle, and methodology (eg, storage temperature).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Potential migraine and CH signaling molecule profiles and biomarkers were revealed. Nevertheless, the high degree of heterogeneity between studies impedes identification of valid biomarkers but allowed us to assess the presence of confounders. Consideration of the potential confounders identified in this SR\u2010MA might be of importance in the experimental planning of future studies. This consideration could be incorporated through establishment of specific guidelines.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/head.13802","type":"journal-article","created":{"date-parts":[[2020,4,15]],"date-time":"2020-04-15T09:30:45Z","timestamp":1586943045000},"page":"1132-1164","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":49,"title":["Serotonin and Neuropeptides in Blood From Episodic and Chronic Migraine and Cluster Headache Patients in Case\u2010Control and Case\u2010Crossover Settings: A Systematic Review and Meta\u2010Analysis"],"prefix":"10.1111","volume":"60","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9207-0350","authenticated-orcid":false,"given":"Simona D.","family":"Frederiksen","sequence":"first","affiliation":[{"name":"Independent Researcher Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Bekker\u2010Nielsen Dunbar","sequence":"additional","affiliation":[{"name":"Independent Researcher Salisbury England"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agneta H.","family":"Snoer","sequence":"additional","affiliation":[{"name":"Danish Headache Centre and Department of Neurology, Rigshospitalet Glostrup Faculty of Health and Medical Sciences University of Copenhagen Glostrup Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie","family":"Deen","sequence":"additional","affiliation":[{"name":"Danish Headache Centre and Department of Neurology, Rigshospitalet Glostrup Faculty of Health and Medical Sciences University of Copenhagen Glostrup Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lars","family":"Edvinsson","sequence":"additional","affiliation":[{"name":"Department of Clinical Experimental Research Glostrup Research Institute Rigshospitalet Glostrup Glostrup Denmark"},{"name":"Division of Experimental Vascular Research Department of Clinical Sciences Lund University Lund Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,4,15]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1526-4610.1988.hed2808568.x"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1177\/0333102417738202"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000003715"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1602\/neurorx.1.2.182"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1177\/0271678X17747188"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0304-3959(99)00240-7"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.peptides.2011.12.019"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/jcbfm.1989.31"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/0165-1838(89)90109-4"},{"key":"e_1_2_10_11_1","first-page":"230","article-title":"Neuropeptides in the cerebral circulation","volume":"1","author":"Uddman R","year":"1989","journal-title":"Cerebrovasc Brain Metab Rev"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00296-014-3172-2"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1177\/0333102415625614"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1177\/0333102414544976"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41582-018-0003-1"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1111\/head.13417"},{"key":"e_1_2_10_17_1","first-page":"235","article-title":"A correlation of 5\u2010hydroxytriptamine and cerebral vasoreactivity in patients with migraine","volume":"9","author":"Demarin V","year":"1994","journal-title":"Funct Neurol"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.39.9.1239"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1468-2982.1990.1005213.x"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1067\/mcp.2001.113989"},{"key":"e_1_2_10_21_1","unstructured":"FrederiksenSD Bekker\u2010Nielsen DunbarM SnoerAH et al.Serotonin and neuropeptides in blood from migraine and cluster headache patients in case\u2010control and case\u2010crossover settings: A systematic review and meta\u2010analysis. 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