Metabolic features of recurrent major depressive disorder in remission, and the risk of future recurrence

Abstract

Recurrent major depressive disorder (rMDD) is a relapsing-remitting disease with high morbidity and a 5-year risk of recurrence of up to 80%. This was a prospective pilot study to examine the potential diagnostic and prognostic value of targeted plasma metabolomics in the care of patients with rMDD in remission. We used an established LC-MS/MS platform to measure 399 metabolites in 68 subjects with rMDD (n = 45 females and 23 males) in antidepressant-free remission and 59 age- and sex-matched controls (n = 40 females and 19 males). Patients were then followed prospectively for 2.5 years. Metabolomics explained up to 43% of the phenotypic variance. The strongest biomarkers were gender specific. 80% of the metabolic predictors of recurrence in both males and females belonged to 6 pathways: (1) phospholipids, (2) sphingomyelins, (3) glycosphingolipids, (4) eicosanoids, (5) microbiome, and (6) purines. These changes traced to altered mitochondrial regulation of cellular redox, signaling, energy, and lipid metabolism. Metabolomics identified a chemical endophenotype that could be used to stratify rrMDD patients at greatest risk for recurrence with an accuracy over 0.90 (95%CI = 0.69–1.0). Power calculations suggest that a validation study of at least 198 females and 198 males (99 cases and 99 controls each) will be needed to confirm these results. Although a small study, these results are the first to show the potential utility of metabolomics in assisting with the important clinical challenge of prospectively identifying the patients at greatest risk of recurrence of a depressive episode and those who are at lower risk.

Predicting relapse or recurrence of depression: systematic review of prognostic models

“…Of the included studies (Table 1), three were development and external validation studies, [28][29][30] eight were development-only studies 25,[31][32][33][34][35][36][37] and one 24 was an external validation study. Three 25,35,36 of the development-only studies reported internal validation. No prognostic model was externally validated in more than one included study and, therefore, a meta-analysis was not necessary.…”

“…Most commonly, these were disease-related characteristics and demographic factors. Some studies explored some less common predictors such as: neuropsychological predictors (emotional categorisation, emotional memory, and facial expression recognition); 36 personality characteristics such as neuroticism; 32 psychosocial predictors such as life stress and interpersonal difficulties; 31 biochemical predictors such as results from the corticotrophin-releasing factor test; 37 peripheral blood metabolomic markers; 35 and combinations of items from the Symptom Checklist (SCL-90). 34 Of the 11 development studies, nine used regression analysis (five used logistic regression 30,[32][33][34]37 and four used Cox proportional hazards regression to study time to recurrence.…”

Low omega‐3 polyunsaturated fatty acids predict reduced response to standard antidepressants in patients with major depressive disorder

“…In contrast, on a different cohort of MDD patients undergoing 6 weeks of paroxetine treatment, low DHA was associated with non‐response (R. J. Mocking et al, 2015). Other clinical studies have shown significant associations between fatty acids and antidepressant response (T. Dinan et al, 2009; R. J. T. Mocking et al, 2021); however, it is challenging to compare them due to different technical approaches, sample sizes and type of antidepressant drug administered.…”

Inosine as a Tool to Understand and Treat Central Nervous System Disorders: A Neglected Actor?

“…However, the authors did not observe any statistically significant difference in inosine plasma levels between the remitted and non-remitted groups ( Ali-Sisto et al, 2016 ). On the other hand, Mocking et al (2021) demonstrated that inosine plasma levels were decreased in both males and females with recurrent major depressive disorder in remission. Zhou et al (2019) studied the potential biomarkers of depression in children and adolescents with MDD.…”