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Neuroinflammatory Biomarkers in Cerebrospinal Fluid From 106 Patients With Recent-Onset Depression Compared With 106 Individually Matched Healthy Control Subjects

  • Nina Vindegaard Sørensen
    Affiliations
    Biological and Precision Psychiatry, Copenhagen Research Centre for Mental Health, Mental Health Centre Copenhagen, Copenhagen University Hospital, Copenhagen, Denmark

    Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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  • Sonja Orlovska-Waast
    Affiliations
    Biological and Precision Psychiatry, Copenhagen Research Centre for Mental Health, Mental Health Centre Copenhagen, Copenhagen University Hospital, Copenhagen, Denmark
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  • Rose Jeppesen
    Affiliations
    Biological and Precision Psychiatry, Copenhagen Research Centre for Mental Health, Mental Health Centre Copenhagen, Copenhagen University Hospital, Copenhagen, Denmark

    Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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  • Amalie Wandel Klein-Petersen
    Affiliations
    Biological and Precision Psychiatry, Copenhagen Research Centre for Mental Health, Mental Health Centre Copenhagen, Copenhagen University Hospital, Copenhagen, Denmark
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  • Rune Haubo Bojesen Christensen
    Affiliations
    Biological and Precision Psychiatry, Copenhagen Research Centre for Mental Health, Mental Health Centre Copenhagen, Copenhagen University Hospital, Copenhagen, Denmark
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  • Michael Eriksen Benros
    Correspondence
    Address correspondence to Michael Eriksen Benros, M.D., Ph.D.
    Affiliations
    Biological and Precision Psychiatry, Copenhagen Research Centre for Mental Health, Mental Health Centre Copenhagen, Copenhagen University Hospital, Copenhagen, Denmark

    Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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Open AccessPublished:April 09, 2022DOI:https://doi.org/10.1016/j.biopsych.2022.04.002

      Abstract

      Background

      Neuroinflammation has been linked to depression; however, neuroinflammatory biomarkers in the cerebrospinal fluid (CSF) have not previously been thoroughly investigated in a large group of patients with recent-onset depression compared with healthy control subjects.

      Methods

      We conducted an individually matched case-control study comparing patients with recent-onset depression (ICD-10: F32) to control subjects. Primary outcomes were CSF white cell count (WCC), CSF-to-serum albumin ratio, CSF total protein, and immunoglobulin G (IgG) index. Secondary outcomes were CSF WCC differential count and CSF neutrophil-to-lymphocyte, CSF-to-serum IgG, and CSF-to-plasma glucose ratios. Linear models adjusting for sex and age were applied.

      Results

      We included 106 patients with recent-onset depression (84.0% outpatients) and 106 healthy control subjects. Patients had 18% higher CSF WCC relative to control subjects (relative mean difference [MD]: 1.18; 95% CI: 1.02–1.40; p = .025). CSF WCC differed with depression symptomatology (p = .034), and patients with severe depression (n = 29) had 43% higher CSF WCC relative to control subjects (MD: 1.43; 95% CI: 1.13–1.80, p = .003). Two (1.9%) patients and no controls (0.0%) had CSF WCC above the normal range (>5 × 106/L). No significant differences between groups were observed regarding CSF-to-serum albumin ratio (MD: 1.07; 95% CI: 0.97–1.18; p = .191), CSF total protein (MD: 1.01; 95% CI: 0.94–1.09; p = .775), or IgG index (MD: 1.05; 95% CI: 0.97–1.15; p = .235). Regarding secondary outcomes, the proportion of CSF neutrophils was lower among patients (MD: 0.22; 95% CI: 0.08–0.59; p = .003) relative to control subjects, whereas the remaining outcomes were not significantly different (all p > .06).

      Conclusions

      Patients had higher CSF WCC relative to control subjects, indicating increased neuroimmunologic activation, particularly for severe depression.

      Keywords

      Neuroinflammation can induce depressive-like symptoms in experimental animal models (
      • Ma L.
      • Demin K.A.
      • Kolesnikova T.O.
      • Khatsko S.L.
      • Zhu X.
      • Yuan X.
      • et al.
      Animal inflammation-based models of depression and their application to drug discovery [published correction appears in Expert Opin Drug Discov 2017; 12:1179].
      ) and has been proposed as a contributor to depression pathophysiology; however, the association between neuroinflammation and depression is still not fully elucidated (
      • Miller A.H.
      • Raison C.L.
      The role of inflammation in depression: From evolutionary imperative to modern treatment target.
      ). Biomarkers reflecting neuroinflammation can be measured in the cerebrospinal fluid (CSF) and are already established for diagnostics in neurology. Due to the blood-brain barrier (BBB) that tightly regulates molecular exchange between the periphery and central nervous system (
      • Daneman R.
      • Prat A.
      The blood-brain barrier.
      ,
      • Abbott N.J.
      • Rönnbäck L.
      • Hansson E.
      Astrocyte-endothelial interactions at the blood-brain barrier.
      ), CSF analyses are the gold standard when exploring neuroinflammation. Neuroinflammation can impair the BBB, and depression has been associated with increased permeability of the BBB (
      • Kealy J.
      • Greene C.
      • Campbell M.
      Blood-brain barrier regulation in psychiatric disorders.
      ). Among others, biomarkers of neuroinflammation include CSF white cell count (WCC) as a general marker of (acute) neuroinflammation, CSF-to-serum albumin ratio, and CSF total protein as markers of BBB impairment (
      • Andersson M.
      • Alvarez-Cermeño J.
      • Bernardi G.
      • Cogato I.
      • Fredman P.
      • Frederiksen J.
      • et al.
      Cerebrospinal fluid in the diagnosis of multiple sclerosis: A consensus report [published correction appears in J Neurol Neurosurg Psychiatry 2011; 82:826].
      ) and immunoglobulin G (IgG) index as a marker of intrathecal IgG synthesis (
      • Simonsen C.S.
      • Flemmen H.Ø.
      • Lauritzen T.
      • Berg-Hansen P.
      • Moen S.M.
      • Celius E.G.
      The diagnostic value of IgG index versus oligoclonal bands in cerebrospinal fluid of patients with multiple sclerosis.
      ).
      Of case-control studies reporting neuroinflammatory biomarkers, two found no significant difference in CSF WCC among patients with depression as compared with healthy control subjects [66 patients and 60 control subjects (
      • Hattori K.
      • Ota M.
      • Sasayama D.
      • Yoshida S.
      • Matsumura R.
      • Miyakawa T.
      • et al.
      Increased cerebrospinal fluid fibrinogen in major depressive disorder.
      ); 89 patients and 104 control subjects (
      • Omori W.
      • Hattori K.
      • Kajitani N.
      • Okada-Tsuchioka M.
      • Boku S.
      • Kunugi H.
      • et al.
      Increased matrix metalloproteinases in cerebrospinal fluids of patients with major depressive disorder and schizophrenia.
      )]; however, the studies did not have CSF WCC as a primary outcome and therefore did not further explore CSF WCC. Regarding BBB impairment related to depression, the largest study found higher levels of CSF total protein in the patient group (n = 90) than in healthy control subjects (n = 106) (
      • Omori W.
      • Hattori K.
      • Kajitani N.
      • Okada-Tsuchioka M.
      • Boku S.
      • Kunugi H.
      • et al.
      Increased matrix metalloproteinases in cerebrospinal fluids of patients with major depressive disorder and schizophrenia.
      ), and two additional case-control studies of CSF total protein also reported higher levels among patients with depression (
      • Mizui T.
      • Hattori K.
      • Ishiwata S.
      • Hidese S.
      • Yoshida S.
      • Kunugi H.
      • Kojima M.
      Cerebrospinal fluid BDNF pro-peptide levels in major depressive disorder and schizophrenia.
      ,
      • Pitts A.F.
      • Carroll B.T.
      • Gehris T.L.
      • Kathol R.G.
      • Samuelson S.D.
      Elevated CSF protein in male patients with depression.
      ), while two studies reported no significant group difference (
      • Hattori K.
      • Ota M.
      • Sasayama D.
      • Yoshida S.
      • Matsumura R.
      • Miyakawa T.
      • et al.
      Increased cerebrospinal fluid fibrinogen in major depressive disorder.
      ,
      • Vawter M.P.
      • Frye M.A.
      • Hemperly J.J.
      • VanderPutten D.M.
      • Usen N.
      • Doherty P.
      • et al.
      Elevated concentration of N-CAM VASE isoforms in schizophrenia.
      ). One study reported higher CSF-to-serum albumin ratio among patients (
      • Gudmundsson P.
      • Skoog I.
      • Waern M.
      • Blennow K.
      • Pálsson S.
      • Rosengren L.
      • Gustafson D.
      The relationship between cerebrospinal fluid biomarkers and depression in elderly women.
      ), while one found no significant difference (
      • Hampel H.
      • Kötter H.U.
      • Möller H.J.
      Blood-cerebrospinal fluid barrier dysfunction for high molecular weight proteins in Alzheimer disease and major depression: Indication for disease subsets.
      ). Considering intrathecal IgG synthesis, the only previous case-control study evaluating IgG index among 29 patients with depression compared with 11 healthy control subjects found no significant differences (
      • Hampel H.
      • Kötter H.U.
      • Padberg F.
      • Körschenhausen D.A.
      • Möller H.J.
      Oligoclonal bands and blood—Cerebrospinal-fluid barrier dysfunction in a subset of patients with Alzheimer disease: Comparison with vascular dementia, major depression, and multiple sclerosis.
      ). Overall, the previous studies of CSF WCC, BBB impairment, and IgG index are either small or without explorative analyses of association to disease severity, and no prior studies have conducted analysis of CSF WCC differential counts or CSF neutrophil-to-lymphocyte ratio (NLR). Thus, a large high-quality systematic case-control study of CSF WCC, BBB impairment, and intrathecal IgG synthesis related to depression and depression severity is needed to further increase the understanding of neuroinflammation as a contributing factor to depression pathophysiology.
      The aim of this individually matched case-control study was to investigate differences in well-established biomarkers of neuroinflammation between patients with recent-onset depression and healthy control subjects, exploring the hypothesis that patients with depression have higher levels of neuroinflammatory markers than healthy control subjects. These neuroinflammatory biomarkers include direct measurements of neuroinflammation (CSF total WCC), measurements of impaired BBB (CSF-to-serum albumin ratio, CSF total protein), and measurements of intrathecal IgG production (IgG index) as co-primary outcomes. To further investigate neuroinflammatory changes related to depression, we included CSF WCC differential count, CSF NLR, CSF-to-serum IgG ratio, and CSF-to-plasma glucose ratio as secondary outcomes.

      Methods and Materials

      A prospective case-control study of 106 patients with recent-onset first-time depression (ICD-10: F32) and ongoing symptoms were compared with 106 individually matched (age and sex) healthy control subjects.
      The study was conducted at the facility of Biological and Precision Psychiatry, Copenhagen Research Centre for Mental Health, Mental Health Centre Copenhagen, Copenhagen, Denmark. It is part of the larger PSYCH-FLAME study. A detailed study protocol including publication plan was submitted prior to data analysis (
      • Sørensen N.V.
      • Orlovska-Waast S.
      • Jeppesen R.
      • Christensen R.H.
      • Benros M.E.
      Neuroimmunological investigations of cerebrospinal fluid in patients with recent onset depression—A study protocol.
      ).
      The study was approved by The Regional Committee on Health Research Ethics (Capital Region, j.no: H-16030985) and The Danish Data Protection Agency (j.no: RHP-2016-020, I-Suite no.: 04945). Written informed consent was obtained before enrollment.

      Outcomes

      Primary Outcomes

      CSF WCC, CSF-to-serum albumin ratio, CSF total protein, and IgG index were the four co-primary outcomes in this study.

      Secondary Outcomes

      CSF WCC differential count, CSF NLR, CSF-to-serum IgG ratio, and CSF-to-plasma glucose ratio were all secondary outcomes of this study.

      Participants

      Patients were recruited mainly from the Referral and Diagnostic Department of The Mental Health Services in the Capital Region of Denmark. Patients were not selected due to signs of neuroinflammation, and lumbar punctures were conducted for research purposes solely. Individually matched (age and sex) healthy control subjects were recruited from the same geographic area primarily by Internet advertisement. Participants were included from September 2018 to July 2021. Inclusion criteria for patients were 1) a first-time diagnosis of a depressive disorder (ICD-10: F32) within the past year, 2) ongoing depressive symptoms, 3) age 18 to 50 years, and 4) obtainment of written informed consent. Inclusion criteria for healthy control subjects were 1) healthy individual, 2) age 18 to 50 years, and 3) obtainment of written informed consent. Exclusion criteria for all participants were, in brief, 1) previous psychiatric diagnosis within ICD-10 F20 to F39, 2) contraindications to lumbar puncture, 3) conditions with known substantial impact on the immune system (specified in Table S1) and 4) conditions with impact on the World Health Organization Schedules for Clinical Assessment in Neuropsychiatry interview quality except from depressive symptoms. An additional exclusion criterion for healthy control subjects only was 5) present or previous psychiatric illness (revealed by Schedules for Clinical Assessment in Neuropsychiatry interview prior to lumbar puncture).

      Clinical Assessment

      The recent-onset depression diagnosis (ICD-10: F32) given by the treating clinician was confirmed by the study assessor after conducting the Schedules for Clinical Assessment in Neuropsychiatry interview (
      • Wing J.K.
      • Babor T.
      • Brugha T.
      • Burke J.
      • Cooper J.E.
      • Giel R.
      • et al.
      SCAN. Schedules for Clinical Assessment in Neuropsychiatry.
      ). Severity of depressive symptoms was assessed by the 17-item and 6-item Hamilton Depression Rating Scale (HAMD-17 and HAMD-6, respectively) (
      • Hamilton M.
      A rating scale for depression.
      ,
      • Timmerby N.
      • Andersen J.H.
      • Søndergaard S.
      • Østergaard S.D.
      • Bech P.
      A systematic review of the clinimetric properties of the 6-item version of the Hamilton Depression Rating Scale (HAM-D6).
      ), 10-item and 6-item Montgomery-Åsberg Depression Rating Scale (
      • Montgomery S.A.
      • Asberg M.
      A new depression scale designed to be sensitive to change.
      ,
      • Bech P.
      • Tanghøj P.
      • Cialdella P.
      • Andersen H.F.
      • Pedersen A.G.
      Escitalopram dose-response revisited: An alternative psychometric approach to evaluate clinical effects of escitalopram compared to citalopram and placebo in patients with major depression.
      ), and Major Depression Inventory (
      • Bech P.
      Quality of life instruments in depression.
      ). Severity of anxiety symptoms was assessed by the Hamilton Anxiety Rating Scale (
      • Hamilton M.
      The assessment of anxiety states by rating.
      ) and psychotic symptoms by the Positive and Negative Syndrome Scale (
      • Kay S.R.
      • Fiszbein A.
      • Opler L.A.
      The Positive and Negative Syndrome Scale (PANSS) for schizophrenia.
      ). Level of functioning was assessed by the Personal and Social Performance scale (
      • Morosini P.L.
      • Magliano L.
      • Brambilla L.
      • Ugolini S.
      • Pioli R.
      Development, reliability and acceptability of a new version of the DSM-IV Social and Occupational Functioning Assessment Scale (SOFAS) to assess routine social functioning.
      ) and Global Assessment of Functioning (
      • Startup M.
      • Jackson M.C.
      • Bendix S.
      The concurrent validity of the Global Assessment of Functioning (GAF).
      ), and quality of life was assessed by the EQ Visual Analog Scale (
      • Herdman M.
      • Gudex C.
      • Lloyd A.
      • Janssen M.
      • Kind P.
      • Parkin D.
      • et al.
      Development and preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L).
      ).
      Cognitive testing was assessed by the Brief Assessment of Cognition in Schizophrenia (
      • Keefe R.S.E.
      • Goldberg T.E.
      • Harvey P.D.
      • Gold J.M.
      • Poe M.P.
      • Coughenour L.
      The Brief Assessment of Cognition in Schizophrenia: Reliability, sensitivity, and comparison with a standard neurocognitive battery.
      ), Montreal Cognitive Assessment (
      • Nasreddine Z.S.
      • Phillips N.A.
      • Bédirian V.
      • Charbonneau S.
      • Whitehead V.
      • Collin I.
      • et al.
      The Montreal Cognitive Assessment, MoCA: A brief screening tool for mild cognitive impairment [published correction appears in Am J Geriatr Soc 2019; 67:1991].
      ), Mini-Mental State Examination (
      • Folstein M.F.
      • Robins L.N.
      • Helzer J.E.
      The Mini-Mental State Examination.
      ), and Trail Making Test A and B (
      • Bowie C.R.
      • Harvey P.D.
      Administration and interpretation of the Trail Making Test.
      ). All testers were certified in using the Brief Assessment of Cognition in Schizophrenia.
      All participants had a neurologic examination including the Neurological Evaluation Scale for evaluation of neurologic soft signs (
      • Dazzan P.
      • Lloyd T.
      • Morgan K.D.
      • Zanelli J.
      • Morgan C.
      • Orr K.
      • et al.
      Neurological abnormalities and cognitive ability in first-episode psychosis.
      ) prior to lumbar puncture.

      Biological Samples and Measures

      Blood Samples

      Before lumbar puncture, 8 mL of venous blood were collected, with 90% of the samples collected between 9:25 am and 11:25 am.

      CSF Samples

      Lumbar punctures were carried out as an aseptic procedure according to current consensus (
      • Teunissen C.E.
      • Petzold A.
      • Bennett J.L.
      • Berven F.S.
      • Brundin L.
      • Comabella M.
      • et al.
      A consensus protocol for the standardization of cerebrospinal fluid collection and biobanking.
      ), and 90% of the samples were collected between 9:55 am and 12:00 pm. The participants were preferably placed in a lateral decubitus position. The L3/L4 or L4/L5 space was identified. Local anesthesia was given after disinfection of skin area. Lumbar puncture was carried out primarily with an atraumatic 22G needle. For this study, 2 mL of CSF was collected. The samples were analyzed as fast as possible, >90% within 1 hour from the first droplet of CSF (mean minutes = 44.3 [±14.3] with no significant difference between groups [p = .335]).

      Sample Analyses

      Blood and CSF were analyzed at the Department of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark. Technicians were blinded to case-control status.
      Blood analyses included white blood cell count (Sysmex XN9000; Sysmex), differential count (DM96; CellaVision), IgG (cobas 8000 Modul c502; Roche), albumin, and glucose (cobas 8000 Modul c702; Roche).
      CSF analyses included WCC (Sysmex XN9000; Sysmex and DM96; CellaVision), differential count (DM96; CellaVision), albumin, IgG, total protein (cobas 8000 Modul c502; Roche), erythrocytes (Sysmex XN9000; Sysmex), and glucose (ABL800 FLEX; Radiometer).

      Statistics

      Power calculations are presented in the protocol paper (
      • Sørensen N.V.
      • Orlovska-Waast S.
      • Jeppesen R.
      • Christensen R.H.
      • Benros M.E.
      Neuroimmunological investigations of cerebrospinal fluid in patients with recent onset depression—A study protocol.
      ). Baseline characteristics were assessed by either Welch two-sample t tests (continuous data) or Pearson’s χ2 tests (categorical data). CSF WCC, albumin ratio, and IgG index were adjusted for blood contamination by the formula suggested for WCC by Tunkel (
      • Tunkel A.R.
      Approach to the patient with central nervous system infection.
      ), which is superior in the detection of minor elevations of CSF WCC in blood-contaminated CSF samples (
      • Pfausler B.
      • Beer R.
      • Engelhardt K.
      • Kemmler G.
      • Mohsenipour I.
      • Schmutzhard E.
      Cell index—A new parameter for the early diagnosis of ventriculostomy (external ventricular drainage)-related ventriculitis in patients with intraventricular hemorrhage?.
      ):
      Outcomecorrected=CSFoutcome(Bloodoutcome×CSFerythrocytes/Blooderythrocytes).


      CSF protein was adjusted for blood contamination by the formula suggested by Seehusen et al. (
      • Seehusen D.A.
      • Reeves M.M.
      • Fomin D.A.
      Cerebrospinal fluid analysis.
      ):
      CSF-Proteincorrected=CSF-Protein(0.01g/L×[Blooderythrocytes×106/1000Blooderythrocytes×106]).


      Linear models were applied for comparison of all continuous primary and secondary outcomes, adjusting for sex and age. Bootstrap simulations were used to obtain confidence intervals and p values for CSF WCC (see Supplemental Methods for details). All continuous outcomes were log-transformed before analysis, and the effect estimates are given as relative mean difference (MD) between groups with 95% confidence intervals. Means of continuous outcomes are reported as geometric mean ± geometric SD.
      Analyses of values above normal clinical range for the four co-primary outcomes were done by logistic regression, adjusting for sex and age. Two sets of thresholds for values above normal clinical range were applied for CSF-to-serum albumin ratio, CSF total protein, and IgG index, defined by the laboratory at Rigshospitalet (
      Rigshospitalets Labportal
      Laboratory study: NPU03276.
      ,
      Rigshospitalet Labportal
      Laboratory study: NPU19659.
      ,
      Rigshospitalets Labportal
      Laboratory study: NPU19811.
      ) and in previous literature (
      • Endres D.
      • Perlov E.
      • Dersch R.
      • Baumgartner A.
      • Hottenrott T.
      • Berger B.
      • et al.
      Evidence of cerebrospinal fluid abnormalities in patients with depressive syndromes.
      ). CSF WCC differential counts were analyzed using quasi-Poisson models adjusting for sex and age, with the total cell count as log-offset. CSF NLR was analyzed using a proportional odds model adjusting for sex and age and reporting the cumulative odds ratio as measure of effect. Post hoc subgroup analyses for primary outcomes were done by adding the interaction with the subgroup variable to a linear model for each outcome. Sensitivity analyses were conducted post hoc to explore the impact of smoking (
      • Elisia I.
      • Lam V.
      • Cho B.
      • Hay M.
      • Li M.Y.
      • Yeung M.
      • et al.
      The effect of smoking on chronic inflammation, immune function and blood cell composition.
      ) and medication (
      • Coe C.L.
      • Hou F.Y.
      • Clarke A.S.
      Fluoxetine treatment alters leukocyte trafficking in the intrathecal compartment of the young primate.
      ), blood contamination, outliers, time from sample collection to laboratory analysis [because this factor is known to impact CSF WCC substantially (
      • Steele R.W.
      • Marmer D.J.
      • O’Brien M.D.
      • Tyson S.T.
      • Steele C.R.
      Leukocyte survival in cerebrospinal fluid.
      )], and use of the censored log-normal models due to concerns about distributional assumptions. p values < .05 were considered significant. All analyses were done in the program R (version 4.0.5) (
      R Core Team
      R: A language and environment for statistical computing. R Foundation for Statistical Computing.
      ).
      Table 1Characteristics of the Population
      CharacteristicsPatients With Depression, n = 106Healthy Control Subjects, n = 106p Value
      Demographics
       Female, n (%)71 (67.0%)71 (67.0%)1.000
       Male, n (%)35 (33.0%)35 (33.0%)1.000
       Age, years, mean (SD)26.0 (7.6)26.4 (6.8).701
       BMI, mean (SD)24.0 (5.5)23.7 (4.2).698
       Weekly use of alcohol in units, mean (SD)3.2 (3.9)5.0 (6.5).016
       Smokers, n (%)32 (30.2%)13 (12.3%).001
       Recreational use of cannabis, n (%)4 (3.8%)5 (4.8%).711
      Medication
       AD medication, n (%)35 (33.0%)0 (0.0%)<.001
      SSRI, n (% of AD medicated)21 (60.0%)0 (0.0%)<.001
      SnRI, n (% of AD medicated)9 (25.7%)0 (0.0%).002
      TCA, n (% of AD medicated)4 (11.4%)0 (0.0%).043
      Other AD, n (% of AD medicated)1 (2.9%)0 (0.0%).316
       Antipsychotic medication, n (%)12 (11.3%)0 (0.0%)<.001
       Other psychotropic medication, n (%)20 (18.9%)0 (0.0%)<.001
       Other current medication, n (%)54 (50.9%)48 (45.3%).410
      Duration and Psychopathology
       Time from diagnosis to inclusion, weeks, mean (SD)4.0 (5.5)NANA
       Outpatients, n (%)89 (84.0%)NANA
       Rating scale scores, mean (SD)
      HAMD-1720.6 (6.3)1.1 (1.5)<.001
      HAMD-611.2 (2.8)0.5 (0.9)<.001
      MADRS-1029.5 (7.6)1.2 (1.7)<.001
      MADRS-618.8 (4.7)0.6 (1.1)<.001
      MDI33.2 (7.9)5.0 (3.2)<.001
      HAMA20.7 (9.3)2.0 (2.2)<.001
      PANSS total48.8 (7.2)31.5 (2.1)<.001
      Function and Quality of Life, Mean (SD)
       PSP total53.5 (14.8)88.9 (4.8)<.001
       EQ VAS53.8 (20.6)85.3 (10.5)<.001
       GAF-Functioning49.4 (12.9)88.9 (5.1)<.001
       GAF-Symptoms46.1 (7.9)87.7 (5.5)<.001
      Cognition, Mean (SD)
       BACS composite
      Reference for z-score: healthy control subjects.
      −0.4 (0.6)0.0 (0.6)<.001
       TMT-A, seconds23.0 (7.5)19.7 (5.5)<.001
       TMT B-A, seconds33.8 (18.8)28.4 (14.9).023
       MMSE total29.1 (1.2)29.4 (1.0).053
       MoCA total27.6 (2.0)28.0 (2.0).143
      Neurologic Measures
       Neurologic examination, n (% minor findings)8 (7.5%)7 (6.6%).789
       Neurologic soft signs total score, mean (SD)6.0 (3.9)4.2 (3.1)<.001
      Categorical variables are shown in absolute numbers (%). Continuous variables are shown as mean (SD). p Values are based on Pearson’s χ2 test for categorical variables and Welch two-sample t test for continuous variables.
      AD, antidepressant; BACS, Brief Assessment of Cognition in Schizophrenia; BMI, body mass index; EQ VAS, EQ Visual Analog Scale; GAF, Global Assessment of Functioning scale; HAMA, Hamilton Anxiety Rating Scale; HAMD, Hamilton Depression Rating Scale; MADRS, Montgomery-Åsberg Depression Rating Scale; MDI, Major Depression Inventory; MMSE, Mini-Mental State Examination; MoCA, Montreal Cognitive Assessment; PANSS, Positive and Negative Syndrome Scale; PSP, Personal and Social Performance scale; SSRI, selective serotonin reuptake inhibitor; SnRI, serotonin-norepinephrine reuptake inhibitor; TCA, tricyclic antidepressant; TMT, Trail Making Test.
      a Reference for z-score: healthy control subjects.
      Table 2Neuroinflammatory Markers in Recent-Onset Depression
      Neuroinflammatory MarkersPatients With Depression, n = 106Healthy Control Subjects, n = 106Relative Mean Difference (95% CI)p Value
      Primary Outcomes
      Total CSF WCC ×106/L
      Adjusted for blood contamination.
      1.18 (1.02–1.40)
      Prespecified linear model for log(CSF WCC + α) with confidence interval and p value based on bootstrap and the profile likelihood estimate of α being 0.442.
      .025
       Mean (SD)
      Based on log(CSF WCC + 0.448), where 0.448 is the profile likelihood estimate. Presented means are transformed back to the original scale.
      1.49 (1.79)1.20 (1.77)
       Range0.00–100.000.00–5.00
      CSF-to-Serum Albumin Ratio
      Adjusted for blood contamination.
      1.07 (0.97–1.18)
      Linear model as prespecified. All linear models are adjusted for age and sex as covariates.
      .191
       Mean (SD)4.71 (1.44)4.43 (1.53)
       Range1.49–10.901.91–14.02
      CSF Total Protein in g/L
      Adjusted for blood contamination.
      1.01 (0.94–1.09)
      Linear model as prespecified. All linear models are adjusted for age and sex as covariates.
      .775
       Mean (SD)0.30 (1.36)0.30 (1.41)
       Range0.15–0.590.16–0.78
      IgG Index
      Adjusted for blood contamination.
      1.05 (0.97–1.15)
      Linear model as prespecified. All linear models are adjusted for age and sex as covariates.
      .235
       Mean (SD)0.40 (1.12)0.38 (1.53)
       Range0.30–0.540.01–0.56
      Secondary Outcomes
      % CSF Neutrophils
      Outcome: CSF differential count.
      ,
      Missing data of 8 patients and 3 control subjects.
      0.22 (0.08–0.59)
      Effect: ratio of cell count in patients relative to control subjects.
      .003
       Mean (SD)
      Arithmetic mean and SD.
      0.78 (2.51)2.68 (7.69)
       Range0.00–14.710.00–54.77
      % CSF Lymphocytes
      Outcome: CSF differential count.
      ,
      Missing data of 8 patients and 2 control subjects.
      1.04 (1.00–1.09)
      Effect: ratio of cell count in patients relative to control subjects.
      .061
       Mean (SD)
      Effect: ratio of cell count in patients relative to control subjects.
      79.41 (12.33)77.08 (14.92)
       Range41.67–100.0023.08–100.00
      % CSF Monocytes
      Outcome: CSF differential count.
      ,
      Missing data of 8 patients and 2 control subjects.
      0.97 (0.84–1.13)
      Effect: ratio of cell count in patients relative to control subjects.
      .730
       Mean (SD)
      Arithmetic mean and SD.
      19.80 (12.08)20.21 (13.48)
       Range0.00–58.330.00–76.92
      % CSF Eosinophils
      Outcome: CSF differential count.
      ,
      Missing data of 8 patients and 3 control subjects.
      0.36 (0.08–1.60)
      Effect: ratio of cell count in patients relative to control subjects.
      .181
       Mean (SD)
      Arithmetic mean and SD.
      0.02 (0.12)0.05 (0.27)
       Range0.00–1.080.00–1.94
      CSF NLR (Distribution)
      Missing data of 8 patients and 3 control subjects.
      0.62 (0.33–1.15)
      Ordinal model for categorized CSF NLR (effect: cumulative odds ratio).
      .131
       075 (76.5%)71 (68.9%)
       >0 to ≥0.018 (8.2%)5 (4.9%)
       >0.01 to ≥0.111 (11.2%)17 (16.5%)
       >0.1 to ≥14 (4.1%)9 (8.7%)
       >10 (0.0%)1 (1.0%)
      CSF-to-Serum IgG Ratio
      Adjusted for blood contamination.
      1.12 (0.98–1.29)
      Linear model as prespecified. All linear models are adjusted for age and sex as covariates.
      .106
       Mean (SD)1.88 (1.49)1.69 (1.93)
       Range0.51–4.340.01–5.21
      CSF-to-Plasma Glucose Ratio
      Adjusted for blood contamination.
      ,
      Missing data of 1 patient.
      1.00 (0.96–1.04)
      Linear model as prespecified. All linear models are adjusted for age and sex as covariates.
      .954
       Mean (SD)0.67 (1.18)0.67 (1.14)
       Range0.48–1.130.49–0.97
      Mean (SD) are geometric means and standard deviations unless otherwise noted.
      CSF, cerebrospinal fluid; IgG, immunoglobulin G; NLR, neutrophil-to-lymphocyte ratio; WCC, white cell count.
      a Adjusted for blood contamination.
      b Prespecified linear model for log(CSF WCC + α) with confidence interval and p value based on bootstrap and the profile likelihood estimate of α being 0.442.
      c Based on log(CSF WCC + 0.448), where 0.448 is the profile likelihood estimate. Presented means are transformed back to the original scale.
      d Linear model as prespecified. All linear models are adjusted for age and sex as covariates.
      e Outcome: CSF differential count.
      f Missing data of 8 patients and 3 control subjects.
      g Effect: ratio of cell count in patients relative to control subjects.
      h Arithmetic mean and SD.
      i Missing data of 8 patients and 2 control subjects.
      j Ordinal model for categorized CSF NLR (effect: cumulative odds ratio).
      k Missing data of 1 patient.
      Table 3Primary Outcomes (Unadjusted and Adjusted for Blood Contamination) Above Normal Clinical Range
      Primary OutcomesPatients With Depression, n = 106Healthy Control Subjects, n = 106p Value
      p values are based on measurements adjusted for blood contamination and a logistic regression adjusted for sex and age.
      Unadjusted, n (%)Adjusted, n (%)Unadjusted, n (%)Adjusted, n (%)
      Total CSF WCC > 5 × 106/L2 (1.9%)1 (0.9%)0 (0.0%)0 (0.0%)1.000
      Total CSF WCC > 3 × 106/L5 (4.7%)5 (4.7%)3 (2.8%)3 (2.8%).473
      CSF-to-Serum Albumin Ratio
      CSF/serum albumin ratio was age stratified, with >6.5 considered abnormal for age <45.0 years and >8.0 for age ≥45.0 years.
      19 (17.9%)18 (17.0%)22 (20.8%)22 (20.8%).465
      CSF-to-Serum Albumin Ratio > 13.9
      Upper reference values from Department of Clinical Biochemistry, Rigshospitalet, Denmark.
      0 (0.0%)0 (0.0%)1 (0.9%)1 (0.9%)1.000
      CSF Total Protein in g/L > 0.459 (8.5%)9 (8.5%)16 (15.1%)16 (15.1%).126
      CSF Total Protein in g/L > 0.50
      Upper reference values from Department of Clinical Biochemistry, Rigshospitalet, Denmark.
      7 (6.6%)7 (6.6%)10 (9.4%)10 (9.4%).436
      IgG Index > 0.70 (0.0%)0 (0.0%)0 (0.0%)0 (0.0%)1.000
      IgG Index > 0.67
      Upper reference values from Department of Clinical Biochemistry, Rigshospitalet, Denmark.
      0 (0.0%)0 (0.0%)0 (0.0%)0 (0.0%)1.000
      CSF, cerebrospinal fluid; IgG, immunoglobulin G; WCC, white cell count.
      a p values are based on measurements adjusted for blood contamination and a logistic regression adjusted for sex and age.
      b CSF/serum albumin ratio was age stratified, with >6.5 considered abnormal for age <45.0 years and >8.0 for age ≥45.0 years.
      c Upper reference values from Department of Clinical Biochemistry, Rigshospitalet, Denmark.

      Results

      A total of 106 patients with recent-onset first-episode depression and 106 individually matched (age and sex) healthy control subjects were included in this study (71 women and 35 men in each group). Average age of patients was 26.0 years (range: 18.1–50.4), and average age of healthy control subjects was 26.4 years (range: 18.6–49.5). The patient group had a higher percentage of smokers (p = .001) and a lower intake of alcohol units per week in the prior month (p = .016) than the healthy control subjects. A full characterization of the population is provided in Table 1 and minor somatic disorders in Table S2.
      Patients had moderate depression, with mean HAMD-17 score of 20.6 (±6.3), mean 10-item Montgomery-Åsberg Depression Rating Scale score of 29.5 (±7.6), and mean Major Depression Inventory score of 33.2 (±7.9). Average time from diagnosis to enrollment was 4.0 (±5.5) weeks. Among patients, 33.0% were treated with antidepressant medication at the time of assessment, and 84.0% were outpatients. Patients reported lower general health on the EQ Visual Analog Scale, lower level of function on the Personal and Social Performance scale and Global Assessment of Functioning–Functioning scale, and higher scores on the neurologic soft signs scale (all p < .001). In the cognitive assessment, patients performed poorer in the Brief Assessment of Cognition in Schizophrenia and Trail Making Test A compared with control subjects (p < .001), while no significant differences were observed in the cognition screening tests (Mini-Mental State Examination, p = .053; Montreal Cognitive Assessment, p = .143). More samples from healthy control subjects were blood contaminated (p = .010), and among patients, 7 (6.6%) had tranquilizers prior to lumbar puncture compared with none (0%) in the control group (p = .007). No other significant differences in lumbar puncture practice or side effects were observed (Table S3).

      Primary Outcomes

      Total CSF WCC was 18% higher among patients relative to healthy control subjects after adjusting data for blood contamination (MD: 1.18; 95% CI: 1.02–1.40; p = .025) (Table 2 and Figure 1). The difference between groups remained robust when analyzed by a censored log-normal model (MD: 1.24; 95% CI: 1.03–1.55; p = .020), when adjusting for time from sample collection to laboratory analysis (MD: 1.19; 95% CI: 1.03–1.41; p = .033), when post hoc adjusting for smoking status (MD: 1.18; 95% CI: 1.02–1.39; p = .026) (Tables S4–S6), and when accounting for medication status (Table S7). Moreover, when post hoc excluding the patient with CSF WCC of 100 × 106/L, the geometric mean (SD) CSF WCC among patients changed from 1.49 (1.79) to 1.42 (1.55) as compared with 1.20 (1.77) among healthy control subjects, although only with statistically significant group differences by the censored log-normal model adjusted for time from sample collection to analysis when post hoc excluding the patient with CSF WCC of 100 × 106/L (MD: 1.20; 95% CI: 1.00–1.43; p = .044); however, it was not significantly different by the linear model (MD: 1.08; 95% CI: 0.98–1.18; p = .105). When excluding participants with CSF erythrocytes ≥1000 × 106/L and ≥1500 × 106/L, significance could still be reached (Tables S5 and S6).
      Figure thumbnail gr1
      Figure 1Relative mean difference of total cerebrospinal fluid white cell count relative to control subjects (with 95% confidence intervals). Cerebrospinal fluid white cell count was 18% higher among all patients with depression as compared with control subjects (left side). Cerebrospinal fluid white cell count was 43% higher among patients with severe depression (17-item Hamilton Depression Rating Scale score > 24) (n = 29) as compared with control subjects, and the relative mean difference to control subjects was significantly higher in patients with severe depression than in patients with mild or moderate depression (17-item Hamilton Depression Rating Scale score ≤ 24) (n = 77) (p = .034) based on an interaction test for effect heterogeneity (right side). Vertical lines represent 95% confidence intervals. ∗p < .05.
      Total CSF WCC was 43% higher among patients with severe depression (HAMD-17 > 24) relative to controls (MD: 1.43; 95% CI: 1.13–1.80, p = .003). CSF WCC was also higher among patients with severe depression (n = 29) than patients with moderate or mild depression (n = 77) (p = .034) revealed in a post hoc subgroup analysis (Table 4 and Figure 1; Figure S1). This was not influenced by medication status (Table S8). Analyses of outcomes unadjusted for blood contamination are found in Table S9, and the distributions of primary outcome measures are shown in Figures S2 and S3. Prior to adjustment for blood contamination, 2 (1.9%) patients had total CSF WCC >5 × 106/L. After full adjustment for blood contamination, only 1 patient (0.9%) had total CSF WCC >5 × 106/L, with CSF WCC of 100 × 106/L (Table 3; Table S10), whereas none of the healthy control subjects had total CSF WCC >5 × 106/L. The two patients differed on several demographic parameters including sex; however, both had severe depression, and the patient with CSF WCC of 100 × 106/L scored >1 standard deviation lower on the Personal and Social Performance scale and Global Assessment of Functioning and >1 standard deviation higher on neurologic soft signs than the mean for all patients (Table S10). Due to CSF pleocytosis, the patient was referred to a neurologic department; however, despite extensive neurologic investigation, no cause was found.
      Table 4Subgroup Analysis of HAMD-17 Score for Primary Outcomes
      GroupnMean (95% CI)
      Estimated means based on fitted models.
      Relative Mean Difference to Control Subjects (95% CI)p Value
      p value for relative mean difference versus control subjects within subgroup.
      Effect Heterogeneity p Value
      p value for effect heterogeneity based on test of interaction between group and categorized HAMD-17 score.
      CSF WCC ×106/L
       Patients1061.49 (1.29–1.71)1.18 (1.02–1.40)
      Confidence interval and p value based on bootstrap.
      .025
      Confidence interval and p value based on bootstrap.
      HAMD-17 score > 24291.87 (1.43–2.41)1.43 (1.13–1.80).003.034
      HAMD-17 ≤ 24771.36 (1.14–1.61)1.09 (0.92–1.29).300
       Healthy control subjects (ref)1061.20 (1.03–1.39)1.00 (ref)
      CSF-to-Serum Albumin Ratio
       Patients1064.72 (4.40–5.06)1.07 (0.97–1.18).191
      HAMD-17 score > 24294.72 (4.14–5.39)1.09 (0.94–1.26).280.764
      HAMD-17 ≤ 24774.72 (4.35–5.12)1.06 (0.95–1.18).282
       Healthy control subjects (ref)1064.42 (4.13–4.74)1.00 (ref)
      CSF Total Protein
       Patients1060.30 (0.29–0.32)1.01 (0.94–1.09).775
      HAMD-17 score > 24290.30 (0.27–0.34)1.02 (0.91–1.15).732.837
      HAMD-17 ≤ 24770.30 (0.28–0.32)1.01 (0.93–1.10).858
       Healthy control subjects (ref)1060.30 (0.28–0.32)1.00 (ref)
      IgG Index
       Patients1060.40 (0.38–0.43)1.05 (0.97–1.15).235
      HAMD-17 score > 24290.40 (0.35–0.44)1.04 (0.91–1.18).559.798
      HAMD-17 ≤ 24770.40 (0.37–0.43)1.06 (0.96–1.16).235
       Healthy control subjects (ref)1060.38 (0.36–0.40)1.00 (ref)
      Subgroup analyses are similar to prespecified models adjusting for sex and age and including the interaction between group and a categorized version of HAMD-17 score. Outcomes are adjusted for blood contamination.
      CSF, cerebrospinal fluid; HAMD-17, 17-item Hamilton Depression Rating Scale; IgG, immunoglobulin G; WCC, white cell count.
      a Estimated means based on fitted models.
      b p value for relative mean difference versus control subjects within subgroup.
      c p value for effect heterogeneity based on test of interaction between group and categorized HAMD-17 score.
      d Confidence interval and p value based on bootstrap.
      No significant differences were found between groups for CSF-to-serum albumin ratio (MD: 1.07; 95% CI: 0.97–1.18; p = .191), CSF total protein (MD: 1.01; 95% CI: 0.94–1.09; p = .775), or IgG index (MD: 1.05; 95% CI: 0.97–1.15; p = .235) (Table 2; Figure S4). The estimated prevalences of findings above normal clinical range by thresholds from the Department of Clinical Biochemistry (Rigshospitalet) were as follows for patients and control subjects, respectively: CSF-to-serum albumin ratio: 0.0% and 0.9%, CSF total protein: 6.6% and 9.4%, and IgG index: 0.0% and 0.0%. The prevalence estimates by thresholds from previous studies (
      • Endres D.
      • Perlov E.
      • Dersch R.
      • Baumgartner A.
      • Hottenrott T.
      • Berger B.
      • et al.
      Evidence of cerebrospinal fluid abnormalities in patients with depressive syndromes.
      ) were as follows for patients and control subjects, respectively: CSF-to-serum albumin ratio: 17.0% and 20.8%, CSF total protein: 8.5% and 15.1%, and IgG index: 0.0% and 0.0% (Table 3). Regardless of threshold, there were no significant differences between groups in prevalences of measurements above normal clinical range for any of these primary outcomes (all p > .1) (Table 3), and post hoc subgroup analyses did not reveal any significant differences related to disease severity (all p > .2) (Table 4). One healthy control subject had markedly above normal levels of CSF-to-serum albumin ratio and CSF total protein (Figure S2); however, exclusion of this individual did not significantly alter primary results (Table S11 and Figure S5).

      Secondary Outcomes

      The mean proportion of CSF neutrophils was 78% lower in patients relative to control subjects (MD: 0.22; 95% CI: 0.08–0.59; p = .003), while there were no significant differences for the remaining secondary outcomes: CSF lymphocytes (MD: 1.04; 95% CI: 1.00–1.09; p = .061), CSF monocytes (MD: 0.97; 95% CI: 0.84–1.13; p = .730), CSF eosinophils (MD: 0.36; 95% CI: 0.08–1.60; p = .181) (Table 2, Figure S6), CSF NLR (cumulative odds ratio: 0.62; 95% CI: 0.33–1.15; p = .131), CSF-to-serum IgG ratio (MD: 1.12; 95% CI: 0.98–1.29; p = .106), and CSF-to-plasma glucose ratio (MD: 1.00; 95% CI: 0.96–1.04; p = .954) (Table 2; and Figure S7).

      Discussion

      In this study, we included 106 patients with recent-onset first-time depression (ICD-10: F32) compared with 106 individually matched (age and sex) healthy control subjects. The patients had moderate depression with an average of 4 weeks from diagnosis to enrollment, and when enrolled, only 33.0% of the patients had initiated antidepressant medication. Total CSF WCC was 18% higher among patients than healthy control subjects, whereas total CSF WCC was 43% higher among patients with severe depression relative to control subjects and was significantly higher than that of patients with mild or moderate depression. CSF WCC >5 × 106/L was observed among 0.9% of patients, whereas none of the control subjects had elevated CSF WCC.
      Our findings of 18% higher total CSF WCC among patients relative to control subjects and 43% higher total CSF WCC among patients with severe depression relative to control subjects demonstrate that CSF WCC elevation is associated with depression and indicate a relationship to depression severity. Previous case-control studies reporting CSF WCC from unselected patients with depression compared with healthy control subjects did not have CSF WCC as a primary outcome and reported no significant differences between groups (
      • Hattori K.
      • Ota M.
      • Sasayama D.
      • Yoshida S.
      • Matsumura R.
      • Miyakawa T.
      • et al.
      Increased cerebrospinal fluid fibrinogen in major depressive disorder.
      ,
      • Omori W.
      • Hattori K.
      • Kajitani N.
      • Okada-Tsuchioka M.
      • Boku S.
      • Kunugi H.
      • et al.
      Increased matrix metalloproteinases in cerebrospinal fluids of patients with major depressive disorder and schizophrenia.
      ). Noteworthy, the patients of the two studies had considerably lower mean HAMD-17 scores [16.5 ± 8.0 (
      • Hattori K.
      • Ota M.
      • Sasayama D.
      • Yoshida S.
      • Matsumura R.
      • Miyakawa T.
      • et al.
      Increased cerebrospinal fluid fibrinogen in major depressive disorder.
      ) and 9.9 ± 8.2 (
      • Omori W.
      • Hattori K.
      • Kajitani N.
      • Okada-Tsuchioka M.
      • Boku S.
      • Kunugi H.
      • et al.
      Increased matrix metalloproteinases in cerebrospinal fluids of patients with major depressive disorder and schizophrenia.
      )] at time of enrollment than our sample (20.6 ± 6.3), which is important because our findings indicate higher total CSF WCC to be related to depression severity. Increased total CSF WCC is an unspecific marker of neuroinflammation and absolute cell counts found in this study were not pathologically high in most cases, indicating primarily low-grade neuroinflammation to be associated with depression. Previous meta-analyses have demonstrated peripheral low-grade inflammation to be associated with depression, e.g., higher levels of the proinflammatory cytokines, such as interleukin 6 and C-reactive protein (
      • Köhler C.A.
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      Peripheral cytokine and chemokine alterations in depression: A meta-analysis of 82 studies.
      ,
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      Associations of depression with C-reactive protein, IL-1, and IL-6: A meta-analysis.
      ,
      • Goldsmith D.R.
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      • Miller B.J.
      A meta-analysis of blood cytokine network alterations in psychiatric patients: Comparisons between schizophrenia, bipolar disorder and depression.
      ,
      • Osimo E.F.
      • Pillinger T.
      • Rodriguez I.M.
      • Khandaker G.M.
      • Pariante C.M.
      • Howes O.D.
      Inflammatory markers in depression: A meta-analysis of mean differences and variability in 5,166 patients and 5,083 controls.
      ), and Mendelian randomization studies suggest that interleukin 6 (
      • Ye Z.
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      • Davey Smith G.
      • Burgess S.
      • Jones P.B.
      • Khandaker G.M.
      Role of inflammation in depression and anxiety: Tests for disorder specificity, linearity and potential causality of association in the UK Biobank.
      ) and C-reactive protein could be causally linked to depression (
      • Khandaker G.M.
      • Zuber V.
      • Rees J.M.B.
      • Carvalho L.
      • Mason A.M.
      • Foley C.N.
      • et al.
      Shared mechanisms between coronary heart disease and depression: Findings from a large UK general population-based cohort [published correction appears in Mol Psychiatry 2021; 26:3659–3661].
      ,
      • Khandaker G.M.
      • Zuber V.
      • Rees J.M.B.
      • Carvalho L.
      • Mason A.M.
      • Foley C.N.
      • et al.
      Correction: Shared mechanisms between coronary heart disease and depression: Findings from a large UK general population-based cohort.
      ). High levels of CSF WCC indicate acute neuroinflammation, as in the patient with CSF WCC of 100; however, minor increases in CSF WCC, as observed on a group level in our study, can also reflect a low-grade neuroinflammatory response in depression (a difference was still observed by the censored log-normal model when excluding the patient with CSF WCC of 100). Other than the total CSF cell count, the specific proportional distribution of immune cells could be of disease importance. Neutrophils are the immune cells mainly involved in acute inflammation, whereas lymphocytes are the main cells of chronic inflammation (
      • Rankin J.A.
      Biological mediators of acute inflammation.
      ). Thus, our data showing a relative proportional neutrophil decrease among patients could therefore represent chronic or low-grade neuroinflammation among patients with depression (most pronounced among patients with severe depression).
      We found no significant differences between groups in measurements of BBB impairment (CSF-to-serum albumin ratio and CSF total protein), neither when comparing relative MDs nor prevalence of measurements above normal clinical range (the latter regardless of applied thresholds). Of previous studies with healthy control subjects (
      • Hattori K.
      • Ota M.
      • Sasayama D.
      • Yoshida S.
      • Matsumura R.
      • Miyakawa T.
      • et al.
      Increased cerebrospinal fluid fibrinogen in major depressive disorder.
      ,
      • Omori W.
      • Hattori K.
      • Kajitani N.
      • Okada-Tsuchioka M.
      • Boku S.
      • Kunugi H.
      • et al.
      Increased matrix metalloproteinases in cerebrospinal fluids of patients with major depressive disorder and schizophrenia.
      ,
      • Mizui T.
      • Hattori K.
      • Ishiwata S.
      • Hidese S.
      • Yoshida S.
      • Kunugi H.
      • Kojima M.
      Cerebrospinal fluid BDNF pro-peptide levels in major depressive disorder and schizophrenia.
      ,
      • Pitts A.F.
      • Carroll B.T.
      • Gehris T.L.
      • Kathol R.G.
      • Samuelson S.D.
      Elevated CSF protein in male patients with depression.
      ,
      • Vawter M.P.
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      • Hemperly J.J.
      • VanderPutten D.M.
      • Usen N.
      • Doherty P.
      • et al.
      Elevated concentration of N-CAM VASE isoforms in schizophrenia.
      ,
      • Gudmundsson P.
      • Skoog I.
      • Waern M.
      • Blennow K.
      • Pálsson S.
      • Rosengren L.
      • Gustafson D.
      The relationship between cerebrospinal fluid biomarkers and depression in elderly women.
      ,
      • Hampel H.
      • Kötter H.U.
      • Möller H.J.
      Blood-cerebrospinal fluid barrier dysfunction for high molecular weight proteins in Alzheimer disease and major depression: Indication for disease subsets.
      ), four indicated BBB impairment to be associated with depression (
      • Omori W.
      • Hattori K.
      • Kajitani N.
      • Okada-Tsuchioka M.
      • Boku S.
      • Kunugi H.
      • et al.
      Increased matrix metalloproteinases in cerebrospinal fluids of patients with major depressive disorder and schizophrenia.
      ,
      • Mizui T.
      • Hattori K.
      • Ishiwata S.
      • Hidese S.
      • Yoshida S.
      • Kunugi H.
      • Kojima M.
      Cerebrospinal fluid BDNF pro-peptide levels in major depressive disorder and schizophrenia.
      ,
      • Pitts A.F.
      • Carroll B.T.
      • Gehris T.L.
      • Kathol R.G.
      • Samuelson S.D.
      Elevated CSF protein in male patients with depression.
      ,
      • Gudmundsson P.
      • Skoog I.
      • Waern M.
      • Blennow K.
      • Pálsson S.
      • Rosengren L.
      • Gustafson D.
      The relationship between cerebrospinal fluid biomarkers and depression in elderly women.
      ). Furthermore, serum S100B, another potential marker of BBB impairment (
      • Blyth B.J.
      • Farhavar A.
      • Gee C.
      • Hawthorn B.
      • He H.
      • Nayak A.
      • et al.
      Validation of serum markers for blood-brain barrier disruption in traumatic brain injury.
      ,
      • Kanner A.A.
      • Marchi N.
      • Fazio V.
      • Mayberg M.R.
      • Koltz M.T.
      • Siomin V.
      • et al.
      Serum S100beta: A noninvasive marker of blood-brain barrier function and brain lesions [published correction appears in Cancer 2006; 107:2314].
      ), has been found elevated among patients with acute depression, and the elevation of serum S100B has been found to be more pronounced among older than younger individuals with depression as compared with age-matched healthy control subjects (
      • Schroeter M.L.
      • Steiner J.
      • Mueller K.
      Glial pathology is modified by age in mood disorders—A systematic meta-analysis of serum S100B in vivo studies.
      ). Thus, BBB impairment may be more pronounced in an older cohort of patients with depression than in our cohort, with a mean age of 26.0 years and where the CSF-to-serum albumin ratio did not reach a significant difference.
      IgG index was not found to differ significantly between groups regardless of threshold, which is in line with the only previous study of patients with depression (
      • Hampel H.
      • Kötter H.U.
      • Padberg F.
      • Körschenhausen D.A.
      • Möller H.J.
      Oligoclonal bands and blood—Cerebrospinal-fluid barrier dysfunction in a subset of patients with Alzheimer disease: Comparison with vascular dementia, major depression, and multiple sclerosis.
      ). IgG index indicates intrathecal synthesis of IgG and is therefore an important biomarker of autoimmune brain disorders such as multiple sclerosis (
      • Simonsen C.S.
      • Flemmen H.Ø.
      • Lauritzen T.
      • Berg-Hansen P.
      • Moen S.M.
      • Celius E.G.
      The diagnostic value of IgG index versus oligoclonal bands in cerebrospinal fluid of patients with multiple sclerosis.
      ). Based on our findings, an adaptive immune response with plasma cells (leading to IgG production) is probably less likely to be significantly involved in depression pathophysiology in unselected cases with recent-onset depression. Moreover, alterations related to adaptive immunity might be more pronounced among patients with treatment-resistant depression than in our broad screening of patients with recent-onset depression.
      Regarding the prevalence of participants with CSF WCC >5 × 106/L, our estimate of 0.9% (1.9% prior to full adjustment for blood contamination) among patients and none among control subjects reveals that pathologically increased CSF WCC is evident even in an unselected group of mainly outpatients with depression. The prevalence of CSF WCC above normal clinical range was lower in our study than in previous studies with selected patients (4.0%) (
      • Endres D.
      • Perlov E.
      • Dersch R.
      • Baumgartner A.
      • Hottenrott T.
      • Berger B.
      • et al.
      Evidence of cerebrospinal fluid abnormalities in patients with depressive syndromes.
      ). This is in line with our results indicating that patients with severe depression have a more pronounced neuroinflammatory response on a group level. However, identifying clearly distinct immune-related subgroups will likely require a much larger sample size due to the heterogeneity of depression. Nonetheless, we identified a very small subgroup with pronounced neuroinflammation among patients with depression, indicating that lumbar puncture could be considered as part of the standard examination for patients with first-episode depression, especially those with severe depression.

      Strengths and Limitations

      This study had several strengths. The study was designed to maximize quality by fulfilling the Newcastle-Ottawa scale criteria for case-control studies (
      • Wells G.A.
      • Shea B.
      • O’Connell D.
      • Peterson J.
      • Welch V.
      • Losos M.
      • Tugwell P.
      The Ottawa Hospital Research Institute. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses.
      ), and furthermore, the STROBE checklist for case-control studies was followed (Table S12). The number of included participants exceeded any previous study of neuroinflammatory markers in CSF from patients with depression compared with healthy control subjects. The case and control groups were individually matched on sex and age. The female-to-male ratio of 2:1 resembled the expected sex ratio (
      • Bromet E.
      • Andrade L.H.
      • Hwang I.
      • Sampson N.A.
      • Alonso J.
      • de Girolamo G.
      • et al.
      Cross-national epidemiology of DSM-IV major depressive episode.
      ). There were no significant differences between groups in most factors known to cause low-grade inflammation (e.g., body mass index, mild somatic diseases, nonmedical allergies, or asthma). Diurnal variation was minimized by collecting 90% of CSF samples within a time range of 2 hours. The time from sample collection to analysis was short (44.3 minutes in average) and was accounted for in the sensitivity analyses. The short time from diagnosis to enrollment led to a high percentage of unmedicated patients that should not be interpreted as low symptom burden, because the rating scale mean scores revealed symptom severity equivalent to moderate depression. Furthermore, it is a strength that patients had ongoing symptoms.
      Nonetheless, depression is a heterogeneous disorder (
      • Malhi G.S.
      • Mann J.J.
      Depression.
      ), and the study is limited hereby since there are no currently available subgroup markers. Furthermore, lumbar puncture introduces a risk of selection bias due to the invasiveness of the procedure (
      • Sørensen N.V.
      • Orlovska-Waast S.
      • Jeppesen R.
      • Christensen R.H.
      • Benros M.E.
      Neuroimmunological investigations of cerebrospinal fluid in patients with recent onset depression—A study protocol.
      ). As prespecified in our study protocol, the four primary outcomes were not corrected for multiple testing; however, the findings would not survive correction for multiple comparison if applying a Bonferroni p value threshold of .0125. Moreover, even though we carefully included potential confounding factors in the analyses and potential effects of outliers, we cannot rule out that the results could nevertheless be influenced by unmeasured confounding or participants that could be considered as outliers for generalizability in other cohorts of individuals with depression. Thus, a replication sample could have further strengthened the paper and needs to be conducted in even larger cohorts than ours but with similarly detailed information and matched healthy control subjects.

      Conclusions

      In this largest case-control study of neuroinflammatory biomarkers in CSF from patients with recent-onset depression compared with healthy control subjects to date, CSF WCC was 18% higher among patients than among control subjects. Patients with severe depression had 43% higher CSF WCC compared with healthy control subjects, and CSF WCC compared with control subjects was significantly higher for patients with severe depression than for patients with mild or moderate depression (post hoc subgroup analysis). One (0.9%) patient and no control subjects (0.0%) had CSF WCC above normal clinical range after adjustment for blood contamination; however, prior to full adjustment, 2 (1.9%) patients had CSF WCC above normal clinical range. No significant differences were observed for the remaining co-primary outcomes. Our study reveals increased neuroinflammatory activity to be present among patients in this unselected group of mainly outpatients with depression and suggests that higher neuroinflammatory activity is related to disease severity.

      Acknowledgments and Disclosures

      This study was funded by an unrestricted grant from The Lundbeck Foundation (Grant No. R268-2016-3925 [to MEB]). The funder had no role in the acquisition of the data, interpretation of the results, or decision to publish the findings.
      We thank all who helped directly or indirectly, particularly the participants of the study and the clinicians at the recruiting centers who helped us with recruitment of patients, especially the Referral and Diagnostic Department.
      The authors report no biomedical financial interests or potential conflicts of interest.

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      Linked Article

      • Cerebrospinal Fluid Biomarkers for the Detection of Autoimmune Depression
        Biological PsychiatryVol. 92Issue 7
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          The discovery of anti–NMDA receptor encephalitis in 2007 provided enormous boosts to immunological research in neurology and psychiatry. Anti–NMDA receptor encephalitis is associated with severe neurological and a plethora of psychiatric symptoms, including psychotic and affective phenomena (1,2). To date, several more well-characterized neuronal autoantibodies have been described (1,2). According to current international consensus criteria, a diagnosis of possible autoimmune encephalitis (AE) should be considered in the presence of a subacute neuropsychiatric syndrome (with severe working memory deficits, an altered mental state, or psychiatric symptoms) in combination with at least one further organic sign, such as inflammatory cerebrospinal fluid (CSF) changes with an increased white blood cell (WBC) count, suspicious magnetic resonance imaging (MRI) changes, epileptic seizures, or focal neurological signs (2).
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