Abstract
Objective: Different patterns of immune system upregulation are present in the acute vs. post-treatment states of psychotic illness. We explored the existence of state and trait markers in the peripheral immune system and two immune-associated neuroendocrine pathways (IDO and GTP-CH1 pathway) in a longitudinal sample of psychosis patients. We also evaluated the association of these markers with neuropsychiatric symptomatology.Method: Plasma concentrations of peripheral blood markers were measured in a transdiagnostic group of 49 inpatients with acute psychosis and 52 matched healthy control subjects. Samples were obtained in patients within 48 h after hospital admission for an acute psychotic episode (before initiation of antipsychotics), after 1–2 weeks and again after 8 weeks of treatment. Kynurenine, kynurenic acid (KA), 3-hydroxykynurenine (3-HK), quinolinic acid (QA), phenylalanine, tyrosine, nitrite, and neopterin were measured using HPLC and LC-MS/MS analysis. Concentrations of CRP, CCL2 (MCP1) and cytokines were determined with multiplex immunoassay. PANSS interviews and cognitive tests were performed at baseline and follow-up. Mixed model analyses were used to identify trait and state markers.Results: Patients had significantly higher plasma concentrations of CRP, CCL2, IL1RA, and lower concentrations of KA and KA/Kyn at all time points (F7.5–17.5, all p < 0.001). Increased concentrations of IL6, IL8, IL1RA, TNFα, and CCL2 and decreased QA and 3-HK (F8.7–21.0, all p < 0.005) were found in the acute psychotic state and normalized after treatment. Low nitrite concentrations at admission rose sharply after initiation of antipsychotic medication (F42.4, p < 0.001). PANSS positive scale scores during the acute episode correlated with pro-inflammatory immune markers (r ≥ |0.5|), while negative scale scores correlated inversely with IDO pathway markers (r ≥ |0.4|). Normalization of KA and 3-HK levels between admission and follow-up corresponded to a larger improvement of negative symptoms (r = 0.5, p < 0.030) A reverse association was found between relative improvement of SDST scores and decreasing KA levels (r = 0.5, p < 0.010).Conclusion: The acute psychotic state is marked by state-specific increases of immune markers and decreases in peripheral IDO pathway markers. Increased CRP, CCL2, and IL1RA, and decreased KA and KA/Kyn are trait markers of psychotic illness.
Highlights
Premorbid dysregulation of the immune system has been identified as an important factor of vulnerability for schizophrenia [1,2,3]
A reverse association was found between relative improvement of SDST scores and decreased KA levels, which could represent the first evidence in humans of the preclinical findings that sudden increases in brain kynurenic acid impair cognitive flexibility [8]
Our study confirmed that the acutely psychotic state is marked by specific state increases of immune markers (IL6, IL8, TNFα, CCL2, IL1RA) and decreased Nitrite
Summary
Premorbid dysregulation of the immune system has been identified as an important factor of vulnerability for schizophrenia [1,2,3]. Immune system activation could be involved in schizophrenia symptom development by upregulating two neuroendocrine pathways which affect the biological availability of the two main monoamine neurotransmitter precursors: tryptophan (Trp) and tyrosine (Tyr) Stimulation by inflammatory molecules, IFNγ, strongly activates indoleamine-2,3-dioxygenase (IDO) and the closely related tryptophan 2,3-dioxygenase 2 (TDO2), the first and rate-limiting enzymes of tryptophan breakdown into kynurenine (Kyn). In particular IDO has been linked to immune functioning: the enzyme is found in a variety of immune cells, including microglia in the central nervous system (CNS), and is often upregulated when the immune response is activated [4]. Kynurenine is further degraded into downstream metabolites such as 3-hydroxykynurenine (3-HK), quinolinic acid (QA), and kynurenic acid (KA), which directly affect neuronal functioning. In animal models, elevated KA levels are associated with sensory gating deficits and schizophrenia-like cognitive dysfunctions (e.g., deficits in set-shifting tasks, spatial working memory, hippocampal long-term potentiation, and attentional processing of environmental stimuli) [8,9,10,11,12]
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