Fatty acid metabolism and its longitudinal relationship with the hypothalamic-pituitary-adrenal axis in major depression: Associations with prospective antidepressant response.

Background: Metabolism of dietary fatty acids (FAs), and its relationship with the hypothalamic-pituitary-adrenal (HPA)-axis, have been found to be altered in major depressive disorder (MDD). Moreover, indications exist that these factors are associated with antidepressant-response. If we better understand these associations, we might identify novel targets for add-on therapy to increase antidepressant-response, and/or early indicators to improve response prediction.

Objective: To determine whether alterations in FA-metabolism, and their relationship with the HPA-axis, are associated with prospective response to the antidepressant paroxetine in MDD.

Design: We first compared 70 initially unmedicated MDD-patients with 51 age- and gender-matched controls at study-entry, regarding salivary cortisol and erythrocyte membrane FAs [omega-3 docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), FA-chain length, -unsaturation and -peroxidizability]. Subsequently, we treated patients with 6 weeks 20mg/day selective serotonin reuptake inhibitor paroxetine. After 6 weeks, we continued this treatment in responders (i.e. showing ≥50% decrease in Hamilton depression rating scale-score), and randomized non-responders to a 6-week, double-blind, placebo-controlled dose-escalation up to 50mg/day. We repeated cortisol and FA-measures in patients after 6 and 12 weeks.

Results: Compared to controls, patients showed higher FA-chain length, FA-unsaturation and FA-peroxidation, and more negative relationships of FA-unsaturation and FA-peroxidation with cortisol. Moreover, these negative relationships were associated with paroxetine nonresponse. Nonresponse was also associated with low DHA, which was related to low fatty fish intake. Furthermore, early responders showed initial low FA-chain length, FA-peroxidation and EPA that increased during the study, while non-responders exhibited opposite patterns.

Conclusions: FA-metabolism alterations, and their relationship with cortisol, are associated with prospective paroxetine response in MDD, and may therefore form an early indicator of treatment effectiveness. Moreover, dietary fatty fish intake may improve antidepressant response through an effect on FA-metabolism.