3-Hydroxykynurenine and clinical symptoms in first-episode neuroleptic-naive patients with schizophrenia

Abstract

One branch of the tryptophan catabolic cascade is the kynurenine pathway, which produces neurotoxic [3-hydroxykynurenine (3-OHKY), quinolinic acid] and neuroinhibitory (kynurenic acid) compounds. Kynurenic acid acts as a competitive antagonist at the glycine site of N-methyl-d-asparate receptors at high concentrations and as a non-competitive antagonist on the α7-nicotinic acetylcholine receptor at low concentrations. Kynurenine compounds also influence cognitive functions known to be disrupted in schizophrenia. Alterations in tryptophan metabolism are therefore of potential significance for the pathophysiology of this disorder. In this paper, tryptophan metabolites were measured from plasma using high-pressure liquid chromatography coupled with electrochemical coulometric array detection, and relationships were tested between these metabolic signatures and clinical symptoms for 25 first-episode neuroleptic-naive schizophrenia patients. Blood samples were collected and clinical and neurological symptoms were rated at baseline and again at 4 wk following initiation of treatment. Level of 3-OHKY and total clinical symptom scores were correlated when patients were unmedicated and neuroleptic-naive, and this relationship differed significantly from the correlation observed for patients 4 wk after beginning treatment. Baseline psychosis symptoms were predicted only by neurological symptoms. Moreover, baseline 3-OHKY predicted clinical change at 4 wk, with the lowest concentrations of 3-OHKY being associated with the greatest improvement in symptoms. Taken together, our findings suggest a neurotoxic product of tryptophan metabolism, 3-OHKY, predicts severity of clinical symptoms during the early phase of illness and before exposure to antipsychotic drugs. Baseline level of 3-OHKY may also predict the degree of clinical improvement following brief treatment with antipsychotics.

Fig. 1

Association between 3-hydroxykynurenine (ln) and clinical symptoms (ln) in first-episode neuroleptic-naive schizophrenia (FENNS) patients. (a) FENNS patients at baseline ; (b) FENNS patients after 4-wk antipsychotic treatment. The between-group correlation difference was significant at p=0.009 (Monte Carlo simulation 10 000 randomly generated datasets). The correlation coefficients (r) and simultaneous p values were calculated according to the Larntz–Perlman procedure (Larntz & Perlman 1988). ln, natural log.

Fig. 2

Baseline 3-hydroxykynurenine (3-OHKY) (ln) predicts clinical change at 4 wk for (a) total symptoms (sqrt) ; (b) psychosis symptoms (sqrt) ; (c) mood symptoms (sqrt). The regression coefficient or slope (β) and p values were calculated by multiple regression analyses. ln, natural log ; sqrt, square root.