Inflammation in Schizophrenia: Cytokine Levels and Their Relationships to Demographic and Clinical Variables

Abstract

Objective Inflammation may play a role in the accelerated physical aging reported in schizophrenia though biomarker findings and associations with demographic and clinical factors are inconsistent. Design Cross-sectional, case-control design Setting Community-dwelling participants tested in an academic laboratory. Participants 95 outpatients with schizophrenia (mean age ± SD: 48.1 ± 10.2 yrs) and 95 demographically-comparable healthy comparison subjects (HCs) (mean age ± SD: 48.1 ± 12.1 yrs) Measurements Sociodemographic and clinical data were collected, and plasma levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interferon-γ (IFN-γ) were assayed. We compared cytokine levels, examined demographic and clinical associations. and adjusted for relevant variables with linear models. Results Individuals with schizophrenia had higher levels of TNF-α and IL-6, but not IFN-γ, than HCs. Age was not related to cytokine levels, and age relationships did not differ between diagnostic groups. Women had higher levels of IL-6. TNF-α and IL-6 levels were significantly correlated with depressive symptoms, and adjustment for depression reduced the group effect for both. Within the HCs, TNF-α levels were associated with physical comorbidity and body mass index (BMI). IL-6 levels were significantly correlated with BMI, and within schizophrenia patients, with worse mental and physical well-being. Accounting for physical morbidity and mental well-being reduced group differences in TNF-α and IL-6 levels, respectively. Worse positive symptoms were associated with higher IL-6 levels. Conclusions Higher TNF-α and IL-6 levels in schizophrenia patients were associated with depression, physical comorbidity, and mental well-being. Further longitudinal studies are warranted to assess inflammation as a potential treatment target for a subgroup of schizophrenia.

Systemic Biomarkers of Accelerated Aging in Schizophrenia: A Critical Review and Future Directions

“…Consistent with previous reviews and meta-analyses, 66,67 73% of these reports observed elevated levels of pro-inflammatory cytokines and chemokines in schizophrenia, including interleukin (IL)-6, 23,28,38,48 IL-1β, 38,57 tumor necrosis factor alpha (TNFα), 48 Eotaxin-1, 35,45 Eotaxin-2, 35 monocyte chemoattractant protein-1, macrophage inflammatory protein-1β, thymus-and activation-regulated chemokine, macrophage-derived chemokine, 45 and lower levels of the anti-inflammatory cytokine IL-2. 30 For TNF-α and IL-6, group differences were reduced and in some cases nonsignificant after controlling for potential confounds.…”

“…57 Of the 11 articles, 3 reported effect sizes ranging from small to medium in size, for elevated levels in schizophrenia. 28,45,48 Other studies found no differences for C-reactive protein (CRP) 40 or intercellular adhesion molecule-1 (ICAM-1) 63 ; however, a more inclusive review and meta-analysis of all studies of CRP (without the specific study inclusion criteria that we used) has shown consistent elevations in CRP in schizophrenia. 68 Age Relationships Thirty-six percent of articles reported differential relationships between inflammation and age in schizophrenia and HCs.…”

“…30 For TNF-α and IL-6, group differences were reduced and in some cases nonsignificant after controlling for potential confounds. 48 Elevations were observed for other biomarkers related to inflammation, including markers of astrocyte and microglial activation (eg, S100B, glial fibrillary acid protein, CD11b), which can further induce cytokine production, 37,57 as well as enzymes and transcription factors for the arachidonic acid and nuclear factor kappa B (NF-κB) signaling pathways. 57 Of the 11 articles, 3 reported effect sizes ranging from small to medium in size, for elevated levels in schizophrenia.…”

“…59 Only one study investigated an age × group interaction, and did not observe a group-specific age association for any chemokine. 45 The remaining 64% of studies did not observe significant relationships between age and levels of cytokines (eg, IL-1β, IL-2, IL-6, TNFα), 30,38,48,57 chemokines, 35 CRP, 40 ICAM-1, 63 or brain mRNA levels of IL-1 receptor protein, markers of astrocyte and microglial activation, NF-κB transcription factor subunits, or arachidonic cascade enzymes. 57 Association With Other Factors Illness duration was reportedly associated with inflammation in 3 studies, suggesting that elevated levels may be related to disease progression.…”

“…35 No relationships were observed between IL-2, TNFα, IL-6, IL-1β, S100B, or ICAM-1 and illness duration, antipsychotic medication use or dose, or cigarette smoking. 28,30,37,38,48,63 Cytotoxicity. Group Differences Ten studies of TL met our inclusion criteria.…”