Altered soluble epoxide hydrolase-derived oxylipins in patients with seasonal major depression: An exploratory study
Introduction
Unlike most other fields of medicine, the clinical management of major depressive disorder (MDD) remains without clinically useful biomarkers with which to predict and monitor the course of the disease. The field also lacks a unified pathophysiological model with which to integrate the observed biological phenomena. For instance, highly reproducible evidence supports elevated concentrations of inflammatory cytokines (Dowlati et al., 2010) and lower levels of omega-3 fatty acids (Lin et al., 2010) in peripheral blood of depressed patients compared to controls. Further evidence suggests that inflammatory markers such as cytokines may decline with treatment and/or symptomatic improvement (Hannestad et al., 2011); however, those markers lack clinical utility, in part due to poor sensitivity and specificity for the disease state, or a lack of quantitative assays that can be appropriately standardized between laboratories (Noble et al., 2008). The forgoing findings, however, do suggest the potential importance of inflammatory and lipid pathways in the pathophysiology of MDD, and in principle, the potential utility of these biomarkers to monitor MDD.
Of all the MDD subtypes, MDD with seasonal pattern (MDD-s; formerly referred to as Seasonal Affective Disorder) is perhaps the best validated and most predictable, with an onset of depressive episodes that typically occurs in winter (Rosenthal et al., 1984). Based on clinical diagnostic criteria, the prevalence of MDD-s has been estimated at 0.4% in the USA (Blazer et al., 1998) and 1.7–4.0% in Canada where it accounts for 18% of recurrent MDD cases (Levitt et al., 2000). Moreover, MDD-s is an excellent model of atypical depression because it is characterized mostly by hypersomnia, carbohydrate craving, increased appetite and weight gain (Garvey et al., 1988, Rosenthal et al., 1984). MDD-s is thought to be caused by a shift in circadian rhythm associated with a longer nocturnal melatonin secretion, and a dysregulation of monoamine neurotransmitter (serotonin, dopamine, and norepinephrine) systems (Lam and Levitan, 2000, Sohn and Lam, 2005). MDD-s can be treated with antidepressants such as selective serotonin reuptake inhibitors, cognitive behavioral therapy or light therapy (Westrin and Lam, 2007), but many who suffer from MDD-s do not seek treatment, facilitating observation of both unmedicated depressed and euthymic states within the same individuals within a short period of time. The effectiveness of treatment is limited, leading to a high rate of recurrence (Forneris et al., 2015, Gartlehner et al., 2015, Kaminski-Hartenthaler et al., 2015, Nussbaumer et al., 2015) and a necessity for a more comprehensive understanding of the pathophysiology.
The oxidation of polyunsaturated fatty acids (PUFA) produces bioactive lipid mediators known as oxylipins, which are involved in regulating pro-inflammatory and resolution pathways in blood and various tissues (Gabbs et al., 2015, Serhan et al., 2008). Oxylipins can be formed non-enzymatically due to auto-oxidation or enzymatically by cyclooxygenase (COX), lipoxygenase (LOX), cytochrome p450 (CYP) or soluble epoxide hydrolase (sEH) enzymes (Arnold et al., 2010b, Fer et al., 2008, Gabbs et al., 2015, Moghaddam et al., 1996, Morisseau et al., 2010, Nieves and Moreno, 2006, Reinaud et al., 1989, Yamamoto et al., 1988). CYP enzymes catalyze the epoxidation of PUFA into their epoxide metabolites that are converted to their corresponding diols by sEH (Imig and Hammock, 2009, Morisseau et al., 2010, Zeldin et al., 1993) (Fig. 1).
Changes in oxylipin metabolism may be related to depression. In mice, direct inhibition of sEH was reported to reduce immobility in the forced swim test and the tail suspension test, demonstrating anti-depressant-like effects, and the likely involvement of fatty acid epoxides or diols in depression-like behavior (Ren et al., 2016). Those findings are consistent with evidence of increased levels of the sEH protein in postmortem brain samples from patients with MDD or bipolar disorder compared to healthy controls (Ren et al., 2016); however, it remains to be determined whether peripheral blood concentrations of these lipid mediators are altered in depressed states in living people. A recent meta-analysis reported increased lipid peroxidation in major depression that was normalized following antidepressant treatment (Mazereeuw et al., 2015), but the basis for these changes remains unclear.
In view of preclinical and post-mortem evidence implicating sEH in depressive disorders, we hypothesized that fatty acid diols produced through sEH activity would be higher in the plasma of MDD-s patients during the winter compared to summer. Therefore, in patients with a history of MDD-s recruited in the summer and followed into winter depression, we quantified plasma oxylipins and their precursor fatty acids in both states. We screened for 84 oxidized fatty acid metabolites in plasma (Supplementary Table 1) derived from different polyunsaturated fatty acids (Fig. 1). To our knowledge, no data are currently available on plasma concentrations of these metabolites in any subtype of major depression, and we explored both total oxylipins, representing unesterifed and esterified fractions, and free (unesterified) oxylipins. Unesterifed oxylipins are considered to constitute the bioactive pool, whereas total oxylipins include the esterified pool, the primary transport and storage form that could be released via lipase enzymes (Shearer and Newman, 2008).
Section snippets
Participants
Ethical approval for this study was obtained from the local Research Ethics Board. All participants provided informed written consent prior to beginning the study. Participants aged between 18–65 years were recruited. All participants had a history of MDD-s based on at least two episodes of depression that presented a seasonal pattern over the past 3 years. Subjects who used an antidepressant, hypnotic or antipsychotic, or had abnormal liver, kidney or lung function, anemia, hypothyroidism,
Participants and characteristics
A total of 15 participants were recruited into the study. Four participants dropped out before the end of the study and two did not meet depression criteria in the winter. After excluding these subjects, nine met study criteria for current MDD-s and were included in this analysis. These nine participants were 46.7±14 years old and included 4 men and 5 women. The average number of previous depressive episodes was 3.3±1.2. A significant increase in BDI-II score (t=5.785, df=8, p=0.0004) was
Discussion
This exploratory targeted lipidomic study showed for the first time a possible association between plasma oxylipin concentrations and a state of winter depression. More specifically, concentrations of 4 products of the sEH pathway increased, while one sEH substrate decreased, emerging as the most consistent candidate biomarkers. Of these, the omega-6 derived sEH product 12,13-DiHOME increased in winter depression consistently in both free and total oxylipin pools. Because the assays used here
Conclusions
This preliminary study suggests that oxylipin concentrations fluctuate between depression states in a small MDD-s cohort. The most consistent findings were changes in sEH oxylipin metabolites of long chain dietary omega-6 (LA, AA) and omega-3 (EPA and DHA) fatty acids. Owing to their spectra of biological activities, these changes in oxylipin mediators during the onset of mood symptoms would be consistent with previously established inflammatory and oxidative phenomenology. Of itself, this
Ethics approval and consent to participate
This study was approved by the Research Ethics Board of Sunnybrook Health Sciences Centre (ID 300-2014).
Consent for publication
Not applicable.
Availability of data and material
The datasets generated during and/or analyzed during the current study are not publicly available due to privacy considerations but some data could be available from the corresponding author on reasonable request.
Competing interests
No relevant competing interests.
Funding
Partial support was provided by NIEHS R01 ES002710, Superfund Research Program P42 ES04699, and NIHWest Coast Comprehensive Metabolomics Core U24 DK097154. WS acknowledges support from the Centre for Collaborative Drug Research, the Canadian Partnership for Stroke Recovery and from the Department of Psychiatry, Sunnybrook Health Sciences Centre. AYT acknowledges financial support from the UC Davis College of Agriculture and Environmental Sciences.
Authors’ contributions
WS and AJL designed the clinical study and carried out recruitment and participant assessments. MH, YO, JY, BDH and AYT designed and carried out the lipidomic assays. MH, WS and AYT planned and conducted the statistical analyses. MH, AYT and WS contributed to drafting the manuscript. YO, JY, BDH and AJL edited/critically reviewed the manuscript. All authors approved the final version.
Acknowledgements
BDH is a George and Judy Marcus Fellow of the American Asthma Society. WS gratefully acknowledges support from the Department of Psychiatry at Sunnybrook Health Sciences Centre.
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- 1
84 oxylipins measured and their abbreviations are listed in Supplementary Table 1.