Reus, V. | bioRxiv Science

bioRxiv2025

Kynurenine Metabolism is Associated with Antidepressant Response to Selective Serotonin Reuptake Inhibitors

Alterations in the kynurenine pathway, and in particular the balance of neuroprotective and neurotoxic metabolites, have been implicated in the pathophysiology of Major Depressive Disorder (MDD) and antidepressant treatment response. In this study, we examined the relationship between changes in kynurenine pathway activity (Kynurenine/Tryptophan ratio), focusing on the balance of neuroprotective-to neurotoxic metabolites (Kynurenic Acid/Quinolinic Acid and Kynurenic Acid/3-Hydroxykynurenine ratios), and response to 8 weeks of selective serotonin reuptake inhibitor (SSRI) treatment, including early changes four weeks after SSRI initiation. Additionally, we examined relationships between kynurenine metabolite ratios and three promising biomarkers of depression and antidepressant response: amygdala/hippocampal volume, and glutamate metabolites in the anterior cingulate cortex. Responders showed an increase in the Kynurenic Acid/3-Hydroxykynurenine ratio by week 8 (F(1,46) = 11.92, p = .001) and early increases in the Kynurenine/Tryptophan ratios at week 4 (F(2,58) = 5.224, p = .008), while Non-Responders did not. Pre-treatment Kynurenic Acid/Quinolinic Acid and Kynurenic Acid/3-Hydroxykynurenine ratios were positively associated with right amygdala volume ({beta} = . 247 p = .032 and {beta} = .245 p = .028, respectively). Lastly, in a subset of participants, pre-treatment Kynurenic Acid/3-Hydroxykynurenine ratio showed a positive, small effect size association with glutamate metabolites (Glx) in the anterior cingulate cortex ({beta} = .307 p = .079), which became significant post-treatment with a large effect size ({beta} = .652 p = .021). These results suggest that response to SSRIs may arise from shifting the balance from neurotoxic to neuroprotective kynurenine metabolites.

neuroscience↗

bioRxiv2018

Contribution of common and rare variants to bipolar disorder susceptibility in extended pedigrees from population isolates

Current evidence from case/control studies indicates that genetic risk for psychiatric disorders derives primarily from numerous common variants, each with a small phenotypic impact. The literature describing apparent segregation of bipolar disorder (BP) in numerous multigenerational pedigrees suggests that, in such families, large-effect inherited variants might play a greater role. To evaluate this hypothesis, we conducted genetic analyses in 26 Colombian (CO) and Costa Rican (CR) pedigrees ascertained for BP1, the most severe and heritable form of BP. In these pedigrees, we performed microarray SNP genotyping of 856 individuals and high-coverage whole-genome sequencing of 454 individuals. Compared to their unaffected relatives, BP1 individuals had higher polygenic risk scores estimated from SNPs associated with BP discovered in independent genome-wide association studies, and also displayed a higher burden of rare deleterious single nucleotide variants (SNVs) and rare copy number variants (CNVs) in genes likely to be relevant to BP1. Parametric and non-parametric linkage analyses identified 15 BP1 linkage peaks, encompassing about 100 genes, although we observed no significant segregation pattern for any particular rare SNVs and CNVs. These results suggest that even in extended pedigrees, genetic risk for BP appears to derive mainly from small to moderate effect rare and common variants.

genetics↗