Research Submissions
Serotonin and Neuropeptides in Blood From Episodic and Chronic Migraine and Cluster Headache Patients in Case-Control and Case-Crossover Settings: A Systematic Review and Meta-Analysis
Simona D. Frederiksen PhD,
Maria Bekker-Nielsen Dunbar MSc,
Agneta H. Snoer MD,
Marie Deen MD, PhD,
Lars Edvinsson MD, PhD,
Corresponding Author
Simona D. Frederiksen PhD
Independent Researcher, Copenhagen, Denmark
Address all correspondence to S.D. Frederiksen, Independent Researcher, Copenhagen, Denmark, email: [email protected]
Search for more papers by this authorMaria Bekker-Nielsen Dunbar MSc
Independent Researcher, Salisbury, England
Search for more papers by this authorAgneta H. Snoer MD
Danish Headache Centre and Department of Neurology, Rigshospitalet Glostrup Faculty of Health and Medical Sciences, University of Copenhagen, Glostrup, Denmark
Search for more papers by this authorMarie Deen MD, PhD
Danish Headache Centre and Department of Neurology, Rigshospitalet Glostrup Faculty of Health and Medical Sciences, University of Copenhagen, Glostrup, Denmark
Search for more papers by this authorLars Edvinsson MD, PhD
Department of Clinical Experimental Research, Glostrup Research Institute, Rigshospitalet Glostrup, Glostrup, Denmark
Division of Experimental Vascular Research, Department of Clinical Sciences, Lund University, Lund, Sweden
Search for more papers by this authorSimona D. Frederiksen PhD,
Maria Bekker-Nielsen Dunbar MSc,
Agneta H. Snoer MD,
Marie Deen MD, PhD,
Lars Edvinsson MD, PhD,
Corresponding Author
Simona D. Frederiksen PhD
Independent Researcher, Copenhagen, Denmark
Address all correspondence to S.D. Frederiksen, Independent Researcher, Copenhagen, Denmark, email: [email protected]
Search for more papers by this authorMaria Bekker-Nielsen Dunbar MSc
Independent Researcher, Salisbury, England
Search for more papers by this authorAgneta H. Snoer MD
Danish Headache Centre and Department of Neurology, Rigshospitalet Glostrup Faculty of Health and Medical Sciences, University of Copenhagen, Glostrup, Denmark
Search for more papers by this authorMarie Deen MD, PhD
Danish Headache Centre and Department of Neurology, Rigshospitalet Glostrup Faculty of Health and Medical Sciences, University of Copenhagen, Glostrup, Denmark
Search for more papers by this authorLars Edvinsson MD, PhD
Department of Clinical Experimental Research, Glostrup Research Institute, Rigshospitalet Glostrup, Glostrup, Denmark
Division of Experimental Vascular Research, Department of Clinical Sciences, Lund University, Lund, Sweden
Search for more papers by this authorAgneta H. Snoer and Marie Deen contributed equally to the work.
Conflict of Interest: AHS is a sub-investigator in 3 clinical trials for Eli Lilly and LE is past President of the International Headache Society, Associate Editor for the Journal of Headache and Pain, and Amgen, Novartis and TEVA have provided support for talks given about CGRP. The other authors declare no conflict.
Funding: AHS was funded by TrygFonden, Denmark. SDF, MBND, MD and LE did not receive any funding related to this study.
Systematic review registration: Registered in PROSPERO on 3 July 2018 (study protocol id: CRD42018102488).
Abstract
Objective
The aim of this systematic review and meta-analysis (SR-MA) was to identify signaling molecule profiles and blood-derived biomarkers in migraine and cluster headache (CH) patients.
Background
Currently no migraine and CH valid biomarkers are available. 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.
Methods
Case-control and case-crossover studies investigating whole blood, plasma, and serum were identified worldwide. The qualitative synthesis focused on 9 signaling molecules (serotonin [5-HT], calcitonin gene-related peptide [CGRP], endothelin-1 [ET-1], neurokinin A, neurokinin B, neuropeptide Y, pituitary adenylate cyclase-activating peptide 38 [PACAP-38], substance P (SP), and vasoactive intestinal peptide) and the quantitative synthesis on 5-HT and CGRP (≥5 comparisons available). The meta-analysis was conducted using standard and 3-level random effect models.
Results
Fifty-four 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-HT, CGRP, ET-1, PACAP-38, 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-HT 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-dominated 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).
Conclusions
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-MA might be of importance in the experimental planning of future studies. This consideration could be incorporated through establishment of specific guidelines.
Supporting Information
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