Search

The treatment of bipolar disorder (BD) still remains a challenge. Melatonin (MLT), acting through its two receptors MT1 and MT2, plays a key role in regulating circadian rhythms which are dysfunctional in BD. Using a translational approach, we examined the implication and potential of MT1 receptors in the pathophysiology and psychopharmacology of BD. We employed a murine model of the manic phase of BD (Clock mutant (ClockΔ19) mice) to study the activation of MT1 receptors by UCM871, a selective partial agonist, in behavioral pharmacology tests and in-vivo electrophysiology. We then performed a high-resolution Nuclear Magnetic Resonance study on isolated membranes to characterize the molecular mechanism of interaction of UCM871. Finally, in a cohort of BD patients, we investigated the link between clinical measures of BD and genetic variants located in the MT1 receptor and CLOCK genes. We demonstrated that: 1) UCM871 can revert behavioral and electrophysiological abnormalities of ClockΔ19 mice; 2) UCM871 promotes the activation state of MT1 receptors; 3) there is a significant association between the number of severe manic episodes and MLT levels, depending on the genetic configuration of the MT1 rs2165666 variant. Overall, this work lends support to the potentiality of MT1 receptors as target for the treatment of BD.

Background and Objectives: Alterations in hot cognition and in the tryptophan metabolism through serotonin (5-HT) and kynurenine (KYN) pathways have been associated with an increased risk of suicidal behavior. Here, we aim at probing the association between Stroop test performances and tryptophan pathway components in a sample of individuals with bipolar disorder (BD). Materials and Methods: We explored the association between the Emotion Inhibition Subtask (EIS) performances of the Brief Assessment of Cognition for Affective Disorders (BAC-A) and plasmatic levels of 5-hydroxytriptophan (5-HTP), 5-HT, KYN, 3-hydroxykynurenine (3-HK), quinolinic acid (QA), and kynurenic acid (KYNA) among subjects reporting lifetime suicide ideation (LSI) vs. non-LSI and subjects reporting lifetime suicide attempts (LSA) vs. non-LSA. Results: In a sample of 45 subjects with BD, we found a statistically significant different performance for LSA vs. non-LSA in the color naming (CN) and neutral words (NW) EIS subtasks. There was a significant association between CN performances and plasma 5-HTP levels among LSI and LSA subjects but not among non-LSI or non-LSA. Conclusions: In our sample, patients with LSA and LSI presented lower performances on some EIS subtasks compared to non-LSA and non-LSI. Moreover, we found an inverse correlation between plasma 5-HTP concentration and some EIS performances in LSA and LSI but not among non-LSA or non-LSI. This may represent an interesting avenue for future studies probing this complex association.

Abstract Background Bipolar disorder (BD) is characterized by recurrent episodes of depression and mania/hypomania alternating with intervals of well-being. The neurobiological underpinnings of BD are still veiled although there is evidence pointing to a malfunction of the circadian clock system that is regulated by the neuromodulator melatonin (MLT). Small sample size studies in BD patients have shown that changes in the levels of MLT are associated with shifts in illness status. Moreover, mood stabilizers (including lithium and valproic acid) influence the MLT system. Of interest, MLT also modulates intestinal microbiota, and recent work suggests an important role of microbiota alterations in neuropsychiatric disorders, including BD. This study is designed to explore whether the possible patterns of associations between changes in the levels of MLT and its precursors and BD mood phases are modulated by variants within the genes encoding for the elements of the MLT system and/or by the microbiota composition. Methods We will conduct a 2-year follow-up study in 50 BD patients during the three different mood phases of the disease. For each phase, we will perform a blood withdrawal for the analysis of MLT levels and of variants of the genes related to the MLT pathway between 8 and 10 a.m. after an overnight fasting, a stool specimen collection for the analysis of microbiota composition, and a detailed psychometric assessment for depression, mania, impulsivity and cognitive abilities. We will also recruit 50 healthy age-matched controls in whom we will perform a blood withdrawal between 8 and 10 a.m. after an overnight fasting, a stool specimen collection, and a psychometric assessment to exclude the presence of psychiatric disorders. Discussion In this cross sectional (case–control vs. BD comparisons) and longitudinal (24 months) study, we expect to clarify the link between the MLT system, microbiota and BD psychopathology. We expect to identify some typical BD symptomatic clusters that will be more strictly associated with variations in the MLT system. In a personalized medicine perspective, this subgroup of BD patients may benefit from a pharmacological therapy targeting the MLT system. Trial registration This study protocol was approved by the Ethics Committee of the University Hospital Agency of Cagliari (PG/2019/6277)

The kynurenine pathway (KP) may play a role in the pathophysiology of bipolar disorder (BD). We conducted a genome-wide association study (GWAS) to identify genetic variants associated with the plasma levels of the metabolites of tryptophan (TRP) via the serotonin (5-HT) and kynurenine (KYN) pathways in 44 patients with BD and 45 healthy controls. We assessed whether variants that were differentially associated with metabolite levels based on the diagnostic status improved the prediction accuracy of BD using penalized regression approaches. We identified several genetic variants that were significantly associated with metabolites (5-HT, 5-hydroxytryptophan (5-HTP), TRP, and quinolinic acid (QA) or metabolite ratios (5-HTP/TRP and KYN/TRP) and for which the diagnostic status exerted a significant effect. The inclusion of genetic variants led to increased accuracy in the prediction of the BD diagnostic status. Specifically, we obtained an accuracy of 0.77 using Least Absolute Shrinkage and Selection Operator (LASSO) regression. The predictors retained as informative in this model included body mass index (BMI), the levels of TRP, QA, and 5-HT, the 5-HTP/TRP ratio, and genetic variants associated with the levels of QA (rs6827515, rs715692, rs425094, rs4645874, and rs77048355) and TRP (rs292212) or the 5-HTP/TRP ratio (rs7902231). In conclusion, our study identified statistically significant associations between metabolites of TRP via the 5-HT and KYN pathways and genetic variants at the genome-wide level. The discriminative performance of penalized regression models incorporating clinical, genetic, and metabolic predictors warrants a follow-up analysis of this panel of determinants.