Retinoid homeostasis in major depressive disorder

Abstract

The small, hormone-like molecule retinoic acid (RA) is a vital regulator in several neurobiological processes that are affected in depression. Next to its involvement in dopaminergic signal transduction, neuroinflammation, and neuroendocrine regulation, recent studies highlight the role of RA in homeostatic synaptic plasticity and its link to neuropsychiatric disorders. Furthermore, experimental studies and epidemiological evidence point to the dysregulation of retinoid homeostasis in depression. Based on this evidence, the present study investigated the putative link between retinoid homeostasis and depression in a cohort of 109 patients with major depressive disorder (MDD) and healthy controls. Retinoid homeostasis was defined by several parameters. Serum concentrations of the biologically most active Vitamin A metabolite, all-trans RA (at-RA), and its precursor retinol (ROL) were quantified and the individual in vitro at-RA synthesis and degradation activity was assessed in microsomes of peripheral blood-derived mononuclear cells (PBMC). Additionally, the mRNA expression of enzymes relevant to retinoid signaling, transport, and metabolism were assessed. Patients with MDD had significantly higher ROL serum levels and greater at-RA synthesis activity than healthy controls providing evidence of altered retinoid homeostasis in MDD. Furthermore, MDD-associated alterations in retinoid homeostasis differed between men and women. This study is the first to investigate peripheral retinoid homeostasis in a well-matched cohort of MDD patients and healthy controls, complementing a wealth of preclinical and epidemiological findings that point to a central role of the retinoid system in depression.

Fig. 1. Retinoid serum levels and metabolism in patients with major depressive disorder and healthy controls.

Group differences between MDD patients and healthy controls (HC) in A ROL serum levels. B at-RA serum levels. C the ratio of at-RA to ROL. D at-RA synthesis activity in PBMC. E at-RA catabolism activity in PBMC. All error bars depict the median with 95%CI. t-tests were used for group comparisons.

Fig. 2. Gender differences in retinoid homeostasis parameters.

* marks significant within-group gender differences (i.e., male vs female in MDD or HC). ▲ marks significant group differences for within-gender comparisons (i.e., female MDD vs female HC) A ROL serum levels. B at-RA serum levels. C the ratio of at-RA to ROL. D at-RA synthesis activity in PBMC. E–H Gene transcription of retinoid pathway-related genes in PBMC, fold change values presented as the 2^−ΔCt. Error bars depict the median (A–D) or geometric mean (E–H) with 95% CI. t-tests were used for group comparisons.