IMPORTANCE Depression has been associated with alterations in neurotransmitters, hormones, and inflammatory and neurodegenerative biomarkers, and biomarkers quantified in the cerebrospinal fluid (CSF) are more likely to reflect ongoing biochemical changes within the brain. However, a comprehensive overview of CSF biomarkers is lacking and could contribute to the pathophysiological understanding of depression.OBJECTIVE To investigate differences in quantified CSF biomarkers in patients with unipolar depression compared with healthy control individuals.DATA SOURCES PubMed, EMBASE, PsycINFO, Cochrane Library, Web of Science, and ClinicalTrials.gov were searched for eligible trials from database inception to August 25, 2021.STUDY SELECTION All studies investigating CSF biomarkers in individuals 18 years and older with unipolar depression and healthy control individuals were included. One author screened titles and abstracts, and 2 independent reviewers examined full-text reports. Studies that did not include healthy control individuals or included control individuals with recent hospital contacts or admissions that might affect CSF biomarker concentrations were excluded. DATA EXTRACTION AND SYNTHESISData extraction and quality assessment were performed by 2 reviewers following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) and Meta-analysis of Observational Studies in Epidemiology (MOOSE) reporting guidelines. Meta-analyses were performed using standardized mean differences (SMDs) calculated with random-effects models. A third investigator was consulted if the 2 reviewers reached different decisions or when in doubt. MAIN OUTCOMES AND MEASURES Quantifiable CSF biomarkers.RESULTS A total of 167 studies met eligibility criteria, and 97 had available data and were included in the meta-analysis. These 97 studies comprised 165 biomarkers, 42 of which were quantified in 2 or more studies. CSF levels of interleukin 6 (7 studies; SMD, 0.35; 95% CI, 0.12 to 0.59; I 2 = 16%), total protein (5 studies; SMD, 0.53; 95% CI, 0.35 to 0.72; I 2 = 0%), and cortisol (2 studies; SMD, 1.23; 95% CI, 0.89 to 1.57; I 2 = 0%) were higher in patients with unipolar depression compared with healthy control individuals, whereas homovanillic acid (17 studies; SMD, −0.26; 95% CI, −0.39 to −0.14; I 2 = 11%), γ-aminobutyric acid (4 studies; SMD, −0.50; 95% CI, −0.92 to −0.08; I 2 = 55%), somatostatin (5 studies; SMD, −1.49; 95% CI, −2.53 to −0.45; I 2 = 91%), brain-derived neurotrophic factor (3 studies; SMD, −0.58; 95% CI, −0.97 to −0.19; I 2 = 0%), amyloid-β 40 (3 studies; SMD, −0.80; 95% CI, −1.14 to −0.46; I 2 = 0%), and transthyretin (2 studies; SMD, −0.82; 95% CI, −1.37 to −0.27; I 2 = 0%) were lower. The remaining 33 biomarkers had nonsignificant results. CONCLUSIONS AND RELEVANCEThe findings of this systematic review and meta-analysis point toward a dysregulated dopaminergic system, a compromised inhibitory system, hypothalamic-pituitary-adrenal axis hyperactivity, increased neuroinflammation and blood-brain ...