Tryptophan and kynurenine pathway metabolites in neuropsychiatric disorders

Abstract

Bakgrunn: Kynureninar er ei gruppe metabolittar av den kosthaldsavhengige aminosyra tryptofan (Trp) som er involverte i ei rekkje biologiske mekanismar, mellom anna inflammasjon og reguleringa av nevrotransmitteren glutamat. Det er funne forandringar i kynureninnivå hjå pasientar med ulike psykiatriske lidingar samanlikna med kontrollar, men det er usikkert kva som ligg bakom denne samanhengen. Mål: Me ynskte å 1) undersøkja kynureninstoffskiftet hjå vaksne med attention-deficit hyperactivity disorder (ADHD) og depresjon, 2) å studera endringar i nivået av kynureninar etter elektrokonvulsiv behandling (ECT), 3) samt å kartleggja faktorar som kan påverka analysar av Trp og kynureninar i kliniske studiar. Materialar og metodar: 1) Me samanlikna serumnivået av Trp, kynureninar og relaterte stoff hjå 133 vaksne med ADHD mot 131 vaksne kontrollar, og hjå 27 vaksne med alvorleg depresjon mot 14 vaksne kontrollar. 2) Endringar i serumnivået av desse biomarkørane vart vurdert i to grupper på 21 og 48 pasientar behandla med ECT. 3) Dei samla resultata frå studiar på endring etter ECT og tilhøyrande metodologiske utfordringar vart diskuterte i ein systematisk litteraturgjennomgang. Resultat: 1) Me fann relativt låge serumnivå av fleire kynureninar både hjå vaksne med ADHD og vaksne med depresjon. 2) Etter ECT steig nivået av fleire metabolittar i den eine gruppa, men ikkje i den andre. I begge gruppene var det teikn til at endringane i kynureninverdiane hang saman med endringar i inflammasjon. 3) I oppsummeringa vår av 19 studiar fann me ingen prov for endringar i nivået av Trp eller tre andre kynureninmarkørar etter ECT. Det var stor variasjon i studiedesign, deltakarar og handsaminga av faktorar som påverkar serumverdiane av kynureninar. Konklusjonar: Me fann forandringar i serumveridar av kynureninar og relaterte stoff hjå vaksne med ADHD og depresjon. Endringane etter ECT var inkonsistente, men tyda på at inflammasjon kan spela ei rolle. Framtidige studiar på kynureninstoffskiftet ved psykiatriske lidingar bør nytta større og betre definerte pasientgrupper. Det trengst òg auka kunnskap om kva rolle livsstilsfaktorar og inflammasjon speler for samanhengen mellom kynureninstoffskiftet og psykiatriske lidingar.

Background: The kynurenine pathway constitutes the major route for metabolism of the essential amino acid tryptophan (Trp), also a precursor of serotonin. Kynurenine pathway metabolites, collectively termed kynurenines, have many biological properties, including regulation of glutamatergic signalling and immune activity, production of cellular energy, as well as the production and scavenging of reactive oxygen species. The pathway activity is upregulated by pro-inflammatory processes, which has also been reported in psychiatric disorders. Thus, with its relation to both neurotransmitters and inflammation, the kynurenine pathway could potentially be involved in the pathophysiology of psychiatric disorders. Meta-analyses have showed altered levels of Trp and kynurenines in patients with major depressive disorder, bipolar disorder, and schizophrenia compared to controls. However, the nature of the relationship between kynurenines and psychiatric disorders is unclear, and there is limited knowledge about how inflammation, comorbidity, medication, and lifestyle factors affect this association. Aims: We aimed to investigate the kynurenine pathway in patients with attention- deficit hyperactivity disorder (ADHD) and depression, and to explore methodological issues in such studies. The specific aims were to 1) examine the status of Trp, kynurenines, and B vitamins in adults with ADHD and depression compared to healthy controls, to 2) investigate changes in levels of Trp, kynurenines and neopterin in patients with depression after electroconvulsive therapy (ECT), and to 3) review factors that affect analyses of Trp and kynurenines in clinical studies and propose strategies for future studies on Trp metabolism in psychiatric disorders. Materials and methods: We investigated levels of Trp and kynurenines, B vitamins, and cotinine in 133 adults with ADHD and 131 adult controls from the project “ADHD in adults in Norway” in Bergen, Norway. The same markers, and the inflammatory marker neopterin, were compared between 27 adults with severe, treatment-resistant depression referred to ECT and 14 healthy controls from the project “ECT and neuroradiology” in Bergen, Norway. Changes in biomarker levels after ECT were analysed using paired Wilcoxon signed-rank tests in all patients and in subgroups based on treatment response and remission. The same method was used to analyse changes in these biomarkers after ECT in 48 depressed patients from the “Mood Disorders in Elderly treated with Electroconvulsive Therapy” (MODECT) study in Amsterdam, the Netherlands. Here potential roles of inflammation and somatic comorbidity were explored in two subgroups based on changes in neopterin, and in two other subgroups based on the presence of somatic disorders. Lastly, we performed a systematic literature search for studies on changes in Trp and/or kynurenines after ECT and used vote counting based on the direction of effect to establish if there was any evidence for significant changes in single metabolites or ratios after ECT. We also extracted data on known determinants of Trp and kynurenines, as well as factors related to patient characteristics, intervention, and study design, to shed light on factors that could affect analyses of change. Results: Adults with ADHD had significantly lower serum concentrations of KA, XA, HAA, riboflavin and vitamin B6, and higher cotinine compared to controls. There was also a significant inverse correlation between levels of Trp and kynurenine and ADHD symptom scores in the whole sample. Compared to healthy controls, depressed patients in study II had lower levels KA, XA and Pic, as well as lower KA/Kyn, KA/QA, XA/HK and Pic/QA. After ECT, the levels of HAA, Pic, Pic/QA and neopterin increased significantly. Depressed patients in study III showed a reduction in KA/HK after ECT. However, summarising the results of 19 studies included in the systematic review, there was no evidence for change in free Trp, total Trp, Kyn, KA or KTR after ECT. There was large variation in study designs and clinical characteristics of participants, and no consistent handling of determinants of Trp and kynurenine pathway metabolite levels. Conclusions: Our results showed altered baseline levels of Trp and kynurenines in patients with ADHD and severe depression. Changes after ECT were inconsistent but indicated a role for pro inflammatory processes. Future studies on kynurenine metabolism in psychiatric disorders should use larger and better-defined patient samples. Such studies may also shed light on the role of life-style factors and inflammation in these conditions.