This study revealed that depression that responds well to escitalopram is characterized by lower plasma KYN level and resting-state regional brain activity in the left DLPFC. Both were significantly lower in the Responders than in both Nonresponders and HC. The degree of increase in both left DLPFC activity and plasma KYN level before and after treatment reflected a favorable treatment response, suggesting an association with a condition that improves with escitalopram. Furthermore, there was a significant correlation between individual differences in pretreatment regional brain activity of the left DLPFC and plasma KYN level in both MDD and HC, suggesting a relationship between them. However, there was no significant correlation between the degree of increase in KYN level before and after treatment and degree of increase in regional brain activity of the left DLPFC, indicating that the increase in KYN caused by escitalopram treatment does not immediately lead to an increase in regional brain activity of the left DLPFC.
KYN is a metabolite that crosses the blood–brain barrier26,27, and in the central nervous system, approximately 60–80% of KYN is supplied from the periphery28–30, and plasma KYN level and cerebrospinal fluid KYN level have been reported to be correlated to some extent31,32. Pretreatment plasma KYN/TRP and plasma KYN levels have been reported in previous studies to be negatively correlated with treatment response to antidepressants9,32,33, and the present results are consistent with these findings. Kocki et al. (2012) reported that treatment with SSRIs increased KYN levels34, and in this study, plasma KYN levels increased significantly before and after treatment. Moreover, the degree of increase in KYN level before and after treatment correlated positively with treatment response. Taken together, the decrease in plasma KYN level reflects part of the pathology of depression in response to escitalopram treatment, suggesting that escitalopram contributes to treatment response by correcting pathologies related to KYN pathway.
The left DLPFC plays an important role in cognitive functions, such as working memory and attention35–38, and depression is known to reduce brain activity in the left DLPFC during rest and task execution39–45. This study revealed that patients with depression with low fALFF value of left DLPFC responded better to treatment with escitalopram.
As for the effects of SSRIs on the DLPFC, it has been reported that glucose metabolism in the left DLPFC increases in depression that responds well to 6 weeks of treatment with paroxetine46 and that activation of the right DLPFC during performance of cognitive tasks is increased after 8 weeks of treatment with escitalopram, sertraline, and paroxetine47. Conversely, Ichikawa et al. (2020) reported that the resting-state functional connectivity of the left DLPFC and posterior cingulate cortex was still not in the same direction of correlation as in healthy subjects after 6–8 weeks of antidepressant treatment but was in the same direction of correlation as in healthy subjects during the recovery period48, and Okada et al. (2009) found that the activation of the left DLPFC during verbal fluency task remained lower in patients with depression in remission than in healthy subjects44. Furthermore, Takami et al. (2007) reported that left DLPFC activity did not differ from that of healthy subjects during recovery49. It is conceivable that the activity of the left DLPFC has not fully improved in terms of its function and activity at 6–8 weeks of antidepressant treatment and that it may recover later than the improvement in abnormal KYN metabolism, which may disrupt the correlation between the treatment change in KYN level and treatment change in fALFF value of the left DLPFC.
Although KYN itself does not directly excite or inhibit neural activity, the downstream metabolites of KYN, quinolinic acid and 3-HK, are known to have N-methyl-D-aspartate (NMDA) receptor agonist effects, while KYNA is known to have NMDA receptor antagonist effects50. The balance of both affects neural activity via NMDA receptors51, and therefore, it may be related to brain functions, such as attention and working memory, in which NMDA receptors play an important role52–55. In the DLPFC, a brain region important for working memory and attention, NMDA receptors are known to be involved in attention and working memory by activating pyramidal cells to fire synapses persistently56,57. Therefore, it is presumed that the neural activity of DLPFC is indirectly influenced by the downstream metabolites of KYN on NMDA receptors. In the present study, we found a positive correlation between plasma KYN level and fALFF of the left DLPFC in healthy subjects and patients with depression. This suggests that blood KYN is supplied to the brain and has an indirect effect on regional brain activity in the left DLPFC, which may also be related to treatment response to escitalopram.
Our study has several limitations that should be mentioned. First, the sample size of the recruited participants was relatively small. Larger-scale studies are needed for reproduction and validation. Second, all participants are in the same ethnic group. To verify whether they are replicated across regions and species, studies that recruit participants from different regions are needed. Third, we did not distinguish between placebo responses; to evaluate the escitalopram treatment response, it is necessary to exclude patients who may respond to placebo in advance. Fourth, this study did not consider the potential effects such as diet, exercise, renal function, and smoking status, which may affect the concentrations of metabolites of the KYN pathway58–60. Fifth, since the purpose of this study was not to identify new metabolomic biomarkers, sample size was small for that purpose and multiple testing correction was not performed. Therefore, no conclusions can be drawn about metabolites other than KYN. Finally, the level of metabolites downstream of KYN pathway has not been measured. Downstream metabolites of KYN pathway, such as KYNA and quinolinic acid, have antagonist and agonist effects on NMDA receptors, as described above. Although there is a problem that these metabolites do not cross the blood–brain barrier, it seems necessary to add these measurements to the study to promote understanding of the pathophysiology.
Despite the abovementioned limitations, this is the first study to use metabolomics and fMRI to measure blood metabolites and regional brain activity related to the therapeutic effects of escitalopram in the same group of subjects and examines the relationship between the two. This study suggests that decreased KYN levels and decreased resting-state regional brain activity of the left DLPFC may be involved in the pathophysiology of depression in response to escitalopram and may serve as biomarkers for predicting treatment response. Furthermore, there was a correlation between individual differences in plasma KYN level and individual differences in regional brain activity of the left DLPFC, suggesting an association between the two, but the increase in KYN level was not correlated with the increase in the left DLPFC activity before and after treatment. Previous studies have suggested that the brain activity of the DLPFC is mediated by downstream metabolites of KYN, which has a neural effect on NMDA receptors, and that recovery of DLPFC activity and function is delayed compared to the improvement of depressive symptoms. Further studies are needed to clarify these complex relationships.