Correlations of Kynurenic Acid, 3-Hydroxykynurenine, sIL-2R, IFN-α, and IL-4 with Clinical Symptoms During Acute Relapse of Schizophrenia

Abstract

Several lines of evidence suggest that up-regulation of immune response and alterations of kynurenine pathway function are involved in pathogenesis of schizophrenia. Correlations among clinical status (using PANNS, SANS and SAPS scales) and blood levels of kynurenic acid (KYNA), 3-hydroxykynurenine (3-HK) and levels of selected immunoactive molecules, soluble interleukin-2 receptor (sIL-2R), interferon-α (IFN-α) and IL-4 were analyzed in 51 chronic schizophrenia patients during acute relapse, after four weeks of therapy and at remission. KYNA levels were significantly lower in comparison with controls (N=45) throughout the study, whereas 3-HK did not differ from controls at admission and during therapy, but increased at remission. The KYNA/3-HK ratio and IL-4 levels, but not sIL-2R and IFN-α levels, were consistently decreased in schizophrenia patients at all analyzed time points. KYNA level and KYNA/3-HK ratio measured at admission correlated negatively with the duration of illness, whereas 3-HK level correlated negatively with the improvement of SANS score at discharge. sIL-2R level before treatment was positively linked with number of relapses. In the subgroup of patients with poor response to pharmacotherapy, treated with clozapine later on, initial KYNA level and the ratio KYNA/3-HK correlated negatively with number of relapses. Positive association of sIL-2R level with number of relapses was also evident in this subgroup. Furthermore, among these patients, starting IFN-α level was negatively linked with the improvement of total PANSS score at discharge. Presented here data support the concept of disturbed kynurenine pathway function in schizophrenia and suggest that assessment of KYNA and 3-HK levels during acute relapse might be useful in prediction of response to antipsychotic therapy. Deficit of peripheral KYNA and higher 3-HK levels could be associated with more severe symptoms of schizophrenia. Further studies with larger samples size are needed to validate our results.

Influence of plasma cytokines on kynurenine and kynurenic acid in schizophrenia

“…In line with previous studies in SZ and schizoaffective disorders [16,33,34], we found plasma KYNA to be significantly lower in patients with SSD compared to controls. As also noted by others, this result is inconsistent with findings in post-mortem brains [6][7][8]15] and CSF [9][10][11]23].…”

Immune and Neuroendocrine Trait and State Markers in Psychotic Illness: Decreased Kynurenines Marking Psychotic Exacerbations

“…KA levels were found to be increased in their study, however this result may have been confounded by a gender imbalance in this study (69% male in patients vs. 44% in controls), considering KA levels are lower in females than males (33,34). Szymona et al (30) analyzed blood levels of KA and 3-HK in 51 chronic schizophrenia patients during acute relapse, after 4 weeks of therapy and at remission. KA levels were significantly lower in comparison with controls throughout the study, whereas 3-HK did not differ from controls at admission and during therapy but increased at remission and correlated negatively with the improvement of negative symptoms (SANS scores) at discharge-matching our findings for PANSS negative scale scores.…”

“…Furthermore, subgroup analyses of a recent meta-analysis by Plitman et al of 13 studies in schizophrenia demonstrated that KA levels were increased centrally (cerebrospinal fluid and brain tissue, n = 7 studies) but not peripherally (n = 5 studies) (28). However, two studies of peripheral IDO pathway metabolites which have emerged since then suggest a relative decrease in KA even in the presence of a pro-inflammatory state (29,30). We therefore repeated this meta-analysis using the same methods, while adding the data of the two newer studies plus our own findings.…”

<p>Increased Plasma Kynurenic Acid Levels are Associated with Impaired Attention/Vigilance and Social Cognition in Patients with Schizophrenia</p>

“…In this study, we found that plasma KYNA levels were significantly higher in SCZ patients than in healthy controls, which is consistent with three previous studies. 23,31,32 In contrast, two studies reported a decrease in blood KYNA levels in untreated SCZ patients, 33,34 and two other studies reported no significant differences in blood KYNA levels between medicated SCZ patients and controls. 35,36 Several factors, such as differences in demographic data (sex, age), technical differences in measuring KYN metabolite levels, and differences in tested materials or antipsychotic treatments, may have an impact on blood KYNA levels, and lead to differences in study results.…”