The effect of electroconvulsive therapy (ECT) on serum tryptophan metabolites

Background: Prior studies suggest that activation of the tryptophan catabolism via the kynurenine pathway by proinflammatory cytokines may be involved in the pathophysiology of depression. Electroconvulsive therapy (ECT) is an effective treatment for major depression (MD) with immunomodulation as one of the proposed modes of action. Objective: The aim of this study was to investigate serum concentrations of tryptophan and kynurenine pathway metabolites in MD patients and healthy controls, and to explore the effect of ECT on components of the kynurenine pathway. Methods: The study included 27 moderately to severely depressed patients referred to ECT. Blood samples were collected prior to treatment and after the completed ECT-series. Baseline samples were also collected from 14 healthy, age- and sex-matched controls. Serum concentrations of tryptophan, kynurenine, 3-hydroxykynurenine (HK), kynurenic acid (KA), xanthurenic acid (XA), anthranilic acid (AA), 3-hydroxyanthranilic acid (HAA), quinolinic acid (QA), picolinic acid (Pic), pyridoxal 5′-phosphat (PLP), riboflavin, neopterin and cotinine were measured. Results: Patients with MD had lower levels of neuroprotective kynurenine-pathway metabolites (KA, XA and Pic) and lower metabolite ratios (KA/Kyn and KA/QA) reflecting reduced neuroprotection compared to controls. The concentration of the inflammatory marker neopterin was increased after ECT, along with Pic and the redox active and immunosuppressive metabolite HAA. Conclusion: In this pilot study, we found increased concentrations of inflammatory marker neopterin and putative neuroprotective kynurenine metabolites HAA and Pic in MD patients after ECT. Further research in larger cohorts is required to conclude whether ECT exerts its therapeutic effects via changes in the kynurenine pathway.publishedVersio

Tryptophan and kynurenine pathway metabolites in neuropsychiatric disorders

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.Doktorgradsavhandlin

The effect of electroconvulsive therapy (ECT) on serum kynurenine pathway metabolites in late-life depression

Background: Depression is reportedly associated with alterations in kynurenine pathway metabolites (kynurenines). Several kynurenines are involved in glutamate signaling, and some have potentially neurotoxic effects while others are considered neuroprotective. The pathway is upregulated under inflammatory conditions, which is associated with depression. Modulation of kynurenine metabolism has been investigated as a potential mechanism in electroconvulsive therapy (ECT), an effective treatment for major depressive disorder, particularly in late-life depression. However, results have been inconclusive. Here we aimed to investigate changes in tryptophan and kynurenines in older patients treated with ECT. Methods: We analyzed levels of tryptophan, eight kynurenine pathway metabolites and the inflammation marker neopterin in serum samples collected at baseline and after a full ECT series for 48 patients with late-life depression from the Dutch MODECT study. Results: There were no significant changes in the concentration of single metabolites after ECT, but a significant reduction in the ratio of kynurenic acid to 3-hydroxykynurenine (KA/HK). Analyses of change in kynurenines after ECT in remitters and non-remitters revealed no clear patterns or link to the therapeutic effect of ECT. There was considerable covariation between neopterin and several kynurenines. Limitations: Variations in diet and serum collection timing may have impacted the results. Conclusions: This study did not show consistent changes in the kynurenine pathway activation or balance between neuroactive metabolites after ECT. Still, changes in kynurenines were strongly related to changes in neopterin concentrations. This demonstrates the importance of considering inflammation when investigating the effect of ECT on the kynurenine pathway

Changes in Tryptophan-Kynurenine Metabolism in Patients with Depression Undergoing ECT-A Systematic Review

The kynurenine pathway of tryptophan (Trp) metabolism generates multiple biologically active metabolites (kynurenines) that have been implicated in neuropsychiatric disorders. It has been suggested that modulation of kynurenine metabolism could be involved in the therapeutic effect of electroconvulsive therapy (ECT). We performed a systematic review with aims of summarizing changes in Trp and/or kynurenines after ECT and assessing methodological issues. The inclusion criterium was measures of Trp and/or kynurenines before and after ECT. Animal studies and studies using Trp administration or Trp depletion were excluded. Embase, MEDLINE, PsycInfo and PubMed were searched, most recently in July 2022. Outcomes were levels of Trp, kynurenines and ratios before and after ECT. Data on factors affecting Trp metabolism and ECT were collected for interpretation and discussion of the reported changes. We included 17 studies with repeated measures for a total of 386 patients and 27 controls. Synthesis using vote counting based on the direction of effect found no evidence of effect of ECT on any outcome variable. There were considerable variations in design, patient characteristics and reported items. We suggest that future studies should include larger samples, assess important covariates and determine between- and within-subject variability. PROSPERO (CRD42020187003).publishedVersio

Serum concentrations of kynurenines in adult patients with attention-deficit hyperactivity disorder (ADHD): a case–control study

Background: The essential amino acid tryptophan is catabolised mainly through the kynurenine pathway. Altered circulating levels of kynurenines have been reported in chronic inflammatory conditions and in several neuropsychiatric disorders, including depression and schizophrenia. Candidate gene studies suggest that genes related to the kynurenine catabolism may be associated with attention-deficit hyperactivity disorder (ADHD). Additionally, ADHD patients often report comorbid depression or anxiety. In this study we investigated serum levels of kynurenines in Norwegian adult ADHD patients and adult controls. Methods: We compared serum levels of tryptophan and the seven tryptophan metabolites kynurenine, kynurenic acid, anthranilic acid, 3-hydroxykynurenine, xanthurenic acid, 3-hydroxyanthranilic acid and quinolinic acid in 133 adult patients with ADHD and 131 adult controls (18–40 years). Riboflavin (vitamin B2), total vitamin B6 and the nicotine metabolite cotinine were also measured. Serum samples were analysed using mass spectrometry. Patients and controls reported comorbid disorders and past (childhood) and current ADHD symptoms using the Wender Utah Rating Scale (WURS) and the Adult ADHD Self-report Scale (ASRS). Logistic regression was used to calculate odds ratios for having an ADHD diagnosis for different serum levels of each metabolite. In addition, we used Spearman’s correlation analysis to investigate the correlation between serum levels of tryptophan and kynurenines and ADHD symptom scores. Results: Lower serum concentrations of tryptophan [odds ratio 0.61 (95 % confidence interval 0.45–0.83)], kynurenic acid [0.73 (0.53–0.99)], xanthurenic acid [0.65 (0.48–0.89)] and 3-hydroxyanthranilic acid [0.63 (0.46–0.85)], and higher levels of cotinine [7.17 (4.37–12.58)], were significantly associated with ADHD. After adjusting for tryptophan levels, only 3-hydroxyanthranilic acid and cotinine remained significant. Lower levels of tryptophan and kynurenine were also found to be correlated with higher total ASRS score and higher total WURS score, when adjusting for smoking and age. Conclusions: Our results suggest that there may be differences in serum levels of tryptophan and kynurenines between adult ADHD patients and adult controls. Although our findings do not suggest a chronic immune activation in ADHD, the underlying mechanisms and possible clinical implications of the differences should be further explored

The effect of electroconvulsive therapy (ECT) on serum tryptophan metabolites

Background: Prior studies suggest that activation of the tryptophan catabolism via the kynurenine pathway by proinflammatory cytokines may be involved in the pathophysiology of depression. Electroconvulsive therapy (ECT) is an effective treatment for major depression (MD) with immunomodulation as one of the proposed modes of action. Objective: The aim of this study was to investigate serum concentrations of tryptophan and kynurenine pathway metabolites in MD patients and healthy controls, and to explore the effect of ECT on components of the kynurenine pathway. Methods: The study included 27 moderately to severely depressed patients referred to ECT. Blood samples were collected prior to treatment and after the completed ECT-series. Baseline samples were also collected from 14 healthy, age- and sex-matched controls. Serum concentrations of tryptophan, kynurenine, 3-hydroxykynurenine (HK), kynurenic acid (KA), xanthurenic acid (XA), anthranilic acid (AA), 3-hydroxyanthranilic acid (HAA), quinolinic acid (QA), picolinic acid (Pic), pyridoxal 5′-phosphat (PLP), riboflavin, neopterin and cotinine were measured. Results: Patients with MD had lower levels of neuroprotective kynurenine-pathway metabolites (KA, XA and Pic) and lower metabolite ratios (KA/Kyn and KA/QA) reflecting reduced neuroprotection compared to controls. The concentration of the inflammatory marker neopterin was increased after ECT, along with Pic and the redox active and immunosuppressive metabolite HAA. Conclusion: In this pilot study, we found increased concentrations of inflammatory marker neopterin and putative neuroprotective kynurenine metabolites HAA and Pic in MD patients after ECT. Further research in larger cohorts is required to conclude whether ECT exerts its therapeutic effects via changes in the kynurenine pathway