Changes in kynurenine pathway metabolites and brain structure in response to behavioral activation therapy

Behavioral activation therapy (BA) is an efficacious treatment for major depressive disorder (MDD). However, the neurobiological mechanism of action is unclear. The present study is a secondary, multimodal analysis of data from two BA clinical trials, integrating previously reported kynurenine pathway (KP) measures with structural MRI. We tested (a) whether BA is associated with pre-post changes in gray matter volume (GMV) within a priori regions of interest (hippocampus, amygdala, and striatum), and (b) whether BA-associated changes in KP metabolites including kynurenic acid (KynA), quinolinic acid (QA), and KynA/QA relate to concomitant changes in GMV. Twenty-seven participants with mood and anxiety disorders and clinically significant depressive symptoms underwent 10 weeks of BA with pre- and post-treatment blood sampling and MRI. KP metabolites were measured with high-performance liquid chromatography and tandem mass spectrometry. Data were analyzed using linear mixed effects and regression models controlling for age, sex, BMI, therapy group, and intracranial volume (for MRI outcomes). All reported p-values were FDR-corrected. BA was associated with a pre- to post-treatment reduction in left putamen volume (β = -0.11, p < 0.05). At baseline, QA was negatively correlated with bilateral caudate volumes (left: r = -0.47, p < 0.05; right: r = -0.49, p < 0.05). Pre-post BA increases in KynA (β = 0.183, p < 0.01) and KynA/QA (β = 0.159, p < 0.05) were associated with increases in right hippocampal volume, and KynA changes were also positively associated with increases in right amygdala volume (β = 0.234, p < 0.05). Furthermore, QA increases were associated with GMV increases in both the right hippocampus (β = 0.148, p < 0.05) and nucleus accumbens (β = 0.224, p < 0.05). Exploratory analyses revealed additional associations between other KP metabolites (e.g., 3-hydroxykynurenine, tryptophan) and volumetric changes. Baseline KP metabolites and baseline GMV did not predict concurrent symptom change. In targeted prospective tests, larger pre- to post-treatment QA decreases predicted lower depression and anxiety symptoms at 3 months, whereas ΔGMV within a priori ROIs did not predict 3-month symptoms. Our findings suggest that BA is associated with changes in KP metabolism and GMV within affective neural circuitry, and that changes in QA may predict longer-term clinical outcomes. However, given the modest sample size and absence of a control group, these findings should be considered preliminary and cannot establish whether observed changes reflect BA-specific effects or nonspecific effects of time. Future research using randomized clinical designs, larger samples, and multimodal approaches will be critical to delineate the role of KP metabolites in supporting neuroplasticity with BA specifically, and psychotherapy more generally.