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Biomarkers in the cerebrospinal fluid of patients with psychotic disorders compared to healthy controls: a systematic review and meta-analysis

Molecular Psychiatry volume 28, pages 2277–2290 (2023)Cite this article

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Abstract

Psychotic disorders are severe mental disorders with poorly understood etiology. Biomarkers in the cerebrospinal fluid (CSF) could provide etiological clues and diagnostic tools for psychosis; however, an unbiased overview of CSF alterations in individuals with psychotic disorders is lacking. The objective of this study was to summarize all quantifiable findings in CSF from individuals with psychotic disorders compared to healthy controls (HC). Studies published before January 25th, 2023 were identified searching PubMed, EMBASE, Cochrane Library, Web of Science, ClinicalTrials.gov, and PsycINFO. Screening, full-text review, data extraction, and risk of bias assessments were performed by two independent reviewers following PRISMA guidelines. Findings in patients and healthy controls were compared and summarized using random-effects analyses and assessment of publication bias, subgroup and sensitivity analyses were performed. 145 studies, covering 197 biomarkers, were included, of which 163 biomarkers have not previously been investigated in meta-analyses. All studies showed some degree of bias. 55 biomarkers measured in CSF were associated with psychosis and of these were 15 biomarkers measured in ≥2 studies. Patients showed increased levels of noradrenaline (standardized mean difference/SMD, 0.53; 95% confidence interval/CI, 0.16 to 0.90) and its metabolite 3-methoxy-4-hydroxyphenylglycol (SMD, 0.30; 95% CI: 0.05 to 0.55), the serotonin metabolite 5-hydroxyindoleacetic acid (SMD, 0.11; 95% CI: 0.01 to 0.21), the pro-inflammatory neurotransmitter kynurenic acid (SMD, 1.58; 95% CI: 0.34 to 2.81), its precursor kynurenine (SMD,0.99; 95% CI: 0.60 to 1.38), the cytokines interleukin-6 (SMD, 0.58; 95% CI: 0.39 to 0.77) and interleukin-8 (SMD, 0.43; 95% CI: 0.24 to 0.62), the endocannabinoid anandamide (SMD, 0.78; 95% CI: 0.53 to 1.02), albumin ratio (SMD, 0.40; 95% CI: 0.08 to 0.72), total protein (SMD, 0.29; 95% CI: 0.16 to 0.43), immunoglobulin ratio (SMD, 0.45; 95% CI: 0.06 to 0.85) and glucose (SMD, 0.48; 95% CI: 0.01 to 0.94). Neurotensin (SMD, −0.67; 95% CI: −0.89 to −0.46) and γ-aminobutyric acid (SMD, −0.29; 95% CI: −0.50 to −0.09) were decreased. Most biomarkers showed no significant differences, including the dopamine metabolites homovanillic acid and 3,4-dihydroxyphenylacetic acid. These findings suggest that dysregulation of the immune and adrenergic system as well as blood-brain barrier dysfunction are implicated in the pathophysiology of psychotic disorders.

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Fig. 1: Meta-analysis of CSF markers measured in patients with psychotic disorders and healthy controls in ≥2 independent studies.
Fig. 2: Neurotransmitters and related metabolites: significant differences in CSF levels in patients with psychotic disorders compared to healthy controls.
Fig. 3: Immune-related markers: significant differences in CSF levels in patients with psychotic disorders compared to healthy controls.
Fig. 4: Neuropeptids/opioids: significant differences in CSF levels in patients with psychotic disorders compared to healthy controls.
Fig. 5: Significant differences (not reported in previous figures) in CSF biomarker levels in patients with psychotic disorders compared to healthy controls.

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Data availability

All data used in this study can be found in the Supplementary Materials, which is available at the Molecular Psychiatry website.

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Acknowledgements

The authors would like to thank Dr. Daniel P. Van Kammen, Dr. Göran Engberg, Dr. Sophie Erhardt, Dr. Viktoria Johansson, Dr. Craig Wheelock, Dr. Kärt Mätlik, Dr. Kotaro Hattori and Dr. Dhamidhu Eratne for providing data for the study and information specialist Susie Rimborg for assistance in the design of the search string. The project was funded by the Independent Research Fund Denmark (grant number 7025-00078B) and an unrestricted grant from the Lundbeck Foundation (R268-2016-3925). The sponsors had no role in the acquisition of the data, interpretation of the results, or the decision to publish the findings.

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  1. Biological and Precision Psychiatry, Copenhagen Research Center for Mental Health, Mental Health Centre Copenhagen, Copenhagen University Hospital, Copenhagen, Denmark

    Troels Boldt Rømer, Rose Jeppesen, Rune Haubo Bojesen Christensen & Michael Eriksen Benros

  2. Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark

    Troels Boldt Rømer

  3. Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark

    Troels Boldt Rømer, Rose Jeppesen & Michael Eriksen Benros

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MEB, TBR, and RJ conceived and designed the study. TBR and RJ performed screening, review and data extraction. RHBC conducted the statistical analysis. TBR drafted the manuscript. All authors contributed to the critical revision of the manuscript, approved the final version before submission and agree to be accountable for all aspects of the work.

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Rømer, T.B., Jeppesen, R., Christensen, R.H.B. et al. Biomarkers in the cerebrospinal fluid of patients with psychotic disorders compared to healthy controls: a systematic review and meta-analysis. Mol Psychiatry 28, 2277–2290 (2023). https://doi.org/10.1038/s41380-023-02059-2

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