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

Fellendorf, Frederike T;Manchia, Mirko

Co-prime

Writing - Original Draft Preparation

;Squassina, Alessio;Pisanu, Claudia;Dall'Acqua, Stefano;Sut, Stefania;Nasini, Sofia;Congiu, Donatella;Reininghaus, Eva Z;Garzilli, Mario;Guiso, Beatrice;Suprani, Federico;Paribello, Pasquale;Pulcinelli, Vittoria;Iaselli, Maria Novella;Pinna, Ilaria;Somaini, Giulia;Arru, Laura;Corrias, Carolina;Pinna, Federica;Carpiniello, Bernardo

Last

;Comai, Stefano

2022-01-01

---

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.