Membrane omega-3 Fatty Acid deficiency as a preventable risk factor for comorbid coronary heart disease in major depressive disorder

Abstract

Major depression disorder (MDD) significantly increases the risk for coronary heart disease (CHD) which is a leading cause of mortality in patients with MDD. Moreover, depression is frequently observed in a subset of patients following acute coronary syndrome (ACS) and increases risk for mortality. Here evidence implicating omega-3 (n-3) fatty acid deficiency in the pathoaetiology of CHD and MDD is reviewed, and the hypothesis that n-3 fatty acid deficiency is a preventable risk factor for CHD comorbidity in MDD patients is evaluated. This hypothesis is supported by cross-national and cross-sectional epidemiological surveys finding an inverse correlation between n-3 fatty acid status and prevalence rates of both CHD and MDD, prospective studies finding that lower dietary or membrane EPA+DHA levels increase risk for both MDD and CHD, case-control studies finding that the n-3 fatty acid status of MDD patients places them at high risk for emergent CHD morbidity and mortality, meta-analyses of controlled n-3 fatty acid intervention studies finding significant advantage over placebo for reducing depression symptom severity in MDD patients, and for secondary prevention of cardiac events in CHD patients, findings that n-3 fatty acid status is inversely correlated with other documented CHD risk factors, and patients diagnosed with MDD after ACS exhibit significantly lower n-3 fatty acid status compared with nondepressed ACS patients. This body of evidence provides strong support for future studies to evaluate the effects of increasing dietary n-3 fatty acid status on CHD comorbidity and mortality in MDD patients.

Figure 1

Diagram illustrating the biosynthetic pathway of n-3 and n-6 fatty acids from dietary precursors. The biosynthesis of EPA (20:5n-3) and DHA (22:6n-3) from dietary α-linolenic acid (18:3n-3), and arachidonic acid (20:4n-6) from linoleic acid (18:2n-6), requires a series of common and competitive microsomal elongation and delta-5 and delta-6 desaturase-mediated reactions. The final synthesis of DHA requires additional modifications within peroxisomes. Preformed DHA (22:6n-3), the principle membrane esterified n-3 fatty acid, and EPA can be obtained directly from the diet. COX-2 mediated metabolism of DHA and arachidonic acid yields anti-inflammatory docosenoids and proinflammatory eicosanoids, respectively. Because the n-6 and n-3 arms compete for common biosynthetic enzymes, elevations in the dietary LA : ALA ratio increase n-6 fatty acid biosynthesis (reflected as reductions in membrane LA and elevations in downstream fatty acid metabolites) and reduced n-3 fatty acid biosynthesis from ALA (reflected as reductions in membrane EPA+DHA).

Figure 2

Comparison of the “omega-3 index” (RBC EPA+DHA composition) in adult USA patients with acute coronary syndrome (ACS, n = 768) [100], adult MDD patients residing in the USA or UK (n = 42) [102, 105, 106], healthy adults (HAs) residing in the U.S. (n = 163) [58], and healthy adults residing in Japan (n = 456) [57]. Proposed risk zones for sudden cardiac death (SCD) derived from prior prospective longitudinal evidence are indicated [99]. Note that MDD patients exhibit an “omega-3 index” that is similar to patients with ACS and places them at high risk for SCD.