Is Poor Lithium Response in Individuals with Bipolar Disorder Associated with Increased Degradation of Tryptophan along the Kynurenine Pathway? Results of an Exploratory Study

Abstract

Bipolar disorder is associated with an inflammation-triggered elevated catabolism of tryptophan to the kynurenine pathway, which impacts psychiatric symptoms and outcomes. The data indicate that lithium exerts anti-inflammatory effects by inhibiting indoleamine-2,3-dioxygenase (IDO)-1 activity. This exploratory study aimed to investigate the tryptophan catabolism in individuals with bipolar disorder (n = 48) compared to healthy controls (n = 48), and the associations with the response to mood stabilizers such as lithium, valproate, or lamotrigine rated with the Retrospective Assessment of the Lithium Response Phenotype Scale (or the Alda scale). The results demonstrate an association of a poorer response to lithium with higher levels of kynurenine, kynurenine/tryptophan ratio as a proxy for IDO-1 activity, as well as quinolinic acid, which, overall, indicates a pro-inflammatory state with a higher degradation of tryptophan towards the neurotoxic branch. The treatment response to valproate and lamotrigine was not associated with the levels of the tryptophan metabolites. These findings support the anti-inflammatory properties of lithium. Furthermore, since quinolinic acid has neurotoxic features via the glutamatergic pathway, they also strengthen the assumption that the clinical drug response might be associated with biochemical processes. The relationship between the lithium response and the measurements of the tryptophan to the kynurenine pathway is of clinical relevance and may potentially bring advantages towards a personalized medicine approach to bipolar disorder that allows for the selection of the most effective mood-stabilizing drug.

Serum neuroactive metabolites of the tryptophan pathway in patients with acute phase of affective disorders

“…Our study found that tryptophan metabolites did not seem to be closely related to mania symptoms and reduction ratio. It has also been shown previously that tryptophan metabolites have no effect on lamotrigine and valproate response, only high levels of TRP, KYN/TRP, QUIN were associated with poor response to lithium, but less than one fifth of our BD-D patients were taking lithium (7). Previous studies have also shown that tryptophan metabolic index (plasma tryptophan/amino acids) was related to YMRS reduction ratio (62).…”

“…This pathway regulates the level of tryptophan (6). Kynurenic acid (KYNA) and quinolinic acid (QUIN) as produced by the metabolism have neuroprotective and neurotoxic effects, respectively, and the balance between the two metabolites plays important role in glutamatergic neurotransmission (7,8). The remaining 5% of tryptophan is metabolized into 5hydroxytryptophan (5-HTP) under the action of tryptophan hydroxylase, and 5-HTP is further metabolized into serotonin or 5-HT; under the action of aromatic L-amino acid decarboxylase.…”

The association of kynurenine pathway metabolites with symptom severity and clinical features of bipolar disorder: An overview

“…For example, lithium, a highly pleiotropic agent, interacting with several different molecular targets, may counteract TRP catabolism by inhibiting the inflammation-induced TRP breakdown [38]. Consistently, a recent study estimated an association of poorer response to lithium with higher levels of KYN, the KYN/TRP ratio, and QA, which could indicate a pro-inflammatory state with a higher degradation of TRP towards the neurotoxic branch [39].…”

Probing the Association between Cognition, Suicidal Behavior and Tryptophan Metabolism in a Sample of Individuals Living with Bipolar Disorder: A Secondary Analysis

“…The study sample has been the subject of previous reports [ 24 , 25 ] and comprises 50 individuals affected by BD and 48 healthy controls (HC) recruited consecutively from 2019 to 2021 at the Unit of Psychiatry of the University of Cagliari and University Hospital Agency. This study aims to test for the association between genetics, gut microbiota, TRP metabolism through KYN and 5-HT with BD illness trajectories.…”

“…The employed laboratory analyses have been described in previous reports [ 24 , 25 , 36 , 37 , 38 ]. Blood samples were gathered in the early morning for each of the recruited subjects with EDTA tubes, immediately centrifuged at 2500 rpm at 4 °C for 10 min.…”