Omega-3 polyunsaturated fatty acid supplementation and white matter changes in major depression

Abstract

White matter abnormalities are implicated in major depressive disorder (MDD). As omega-3 polyunsaturated fatty acids (PUFAs) are low in MDD and affect myelination, we hypothesized that PUFA supplementation may alleviate depression through improving white matter integrity. Acutely depressed MDD patients (n=16) and healthy volunteers (HV, n=12) had 25-direction diffusion tensor imaging before and after 6 weeks of fish oil supplementation. Plasma phospholipid omega-3 PUFAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and omega-6 PUFA arachidonic acid (AA) levels were determined before and after supplementation using high-throughput extraction and gas chromatography and expressed as a percentage of total phospholipids (PUFA%). Fractional anisotropy (FA) was computed using a least-squares-fit diffusion tensor with non-linear optimization. Regression analyses were performed with changes in PUFA levels or Hamilton Depression Rating Scale scores as predictors, voxel-wise difference maps of FA as outcome, covariates age and sex, with family-wise correction for multiple comparisons. Increases in plasma phospholipid DHA% (but not EPA% or AA%) after fish oil predicted increases in FA in MDD but not HV, in a cluster including genu and body of the corpus callosum, and anterior corona radiata and cingulum (cluster-level p<0.001, peak t-score=8.10, p=0.002). There was a trend for greater change in FA in MDD responders over nonresponders (t=−1.874, df=13.56, p=0.08). Decreased depression severity predicted increased FA in left corticospinal tract and superior longitudinal fasciculus (cluster-level p<0.001, peak t-score=5.04, p=0.0001). Increased FA correlated with increased DHA% and decreased depression severity after fish oil supplementation suggests therapeutic effects of omega-3 PUFAs may be related to improvements in white matter integrity.

Deficits in Docosahexaenoic Acid Accrual during Adolescence Reduce Rat Forebrain White Matter Microstructural Integrity: An in vivo Diffusion Tensor Imaging Study

“…While our results indicate that DEF rats do not entirely recapitulate this general pattern, other factors associated with the human condition, including stress, inflammation, and genotype, may contribute and interact with n-3 PUFA status. It is notable, however, that, in healthy older adults [24] and patients with unipolar depression [25] fish oil supplementation is associated with increases in FA in multiple WM tracts, suggesting these variables are interrelated in human subjects.…”

“…Omega-3 (n-3) PUFAs including docosahexaenoic acid (DHA) and the omega-6 PUFA arachidonic acid (AA) have opposing effects on immuneinflammatory signaling, and metabolites of DHA have inflammation-resolving properties [16][17][18][19][20][21]. Importantly, emerging evidence suggests that PUFAs are associated with WMI in healthy subjects [22][23][24] and in patients with psychiatric disorders [25,26]. Meta-analyses indicate that schizophrenia [27], bipolar disorder [28], and unipolar depression [29] are associated with PUFA deficits including DHA.…”

Polyunsaturated fatty acids and recurrent mood disorders: Phenomenology, mechanisms, and clinical application

“…Frontal lobe connectivity with limbic structures is mediated in part by the uncinate fasciculus and superior longitudinal fasciculus, prominent white matter tracts that develop during gestation and undergo significant maturation during childhood and adolescence. Accumulating evidence suggests that n -3 PUFAs promote cortical white matter microstructural integrity [215], and a recent study found that fish oil supplementation increased white matter microstructural integrity and decreased depressive symptom severity in MDD patients [216]. Moreover, perinatal n -3 PUFA deficiency in monkeys [217], or low erythrocyte DHA biostatus in typically developing children [218], are both associated with reduced functional connectivity within prefrontal cortical networks.…”

White matter integrity as a mediator in the relationship between dietary nutrients and cognition in the elderly

“…In animal experiments, thiamine-deprived rats had lower FA values 16 , while calorie restriction in rhesus macaques had increased FA 17 . Studies in human are also rare with limited evidence suggesting that vitamin B12 supplementation 18 , higher serum level of 25-hydroxyvitamin D 19 , plasma PUFA concentration 20 , and supplementation of Ω-3 PUFA 4 or fish oil 21 might be associated with favorable DTI metrics like higher FA values. However, except for one study showing adherence to the Mediterranean diet 22 was associated with higher FA values, whether and which nutritional or dietary factors directly from foods are related to white matter integrity is largely unknown.…”