The potential of polyunsaturated fatty acids in alleviating depression and reducing suicide risk

In a recent article published in the journal Molecular Psychiatry, researchers investigate the clinical relevance of long-chain polyunsaturated fatty acids (LC-PUFAs) in the underlying neuropathology of major depressive disorder (MDD).

LC-PUFAs are fatty acids with 18 or more carbons and two or more double bonds. These fatty acids can be derived from either diet or biosynthesis process, in which enzymes act on essential shorter-chain fatty acids (SCFAs) in the liver, such as α-linolenic (ALA) and linoleic (LA) acids, to form LC-PUFAs. Notably, LC-PUFAs get transported through the blood and can cross the blood-brain barrier (BBB) to reach the brain.

LC-PUFAs are crucial for neurobiological development and function, with n(omega)-3 and n-6 LC-PUFA species having varied physicochemical characteristics, such as degree of unsaturation, thereby exerting different biologically relevant effects.

Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), both of which are n-3 LC-PUFAs, as well as arachidonic acid (AA), an n-6 LC-PUFA, are the most biologically relevant LC-PUFAs. N-3 and n-6 LC-PUFAs comprise about 35% of total brain lipids, which exist in phospholipids of the cell membrane lipid bilayer of neurons, glial, and endothelial cells.

Given the high concentration of DHA and AA in the brain, these fatty acids also play key roles in brain health. Accordingly, low levels of DHA have been associated with aberrations in cognition and behavior, as well as neurological disorders like MDD.

In the present study, researchers searched PubMed using keywords including ‘depression’ and ‘PUFAs.’ This led to the identification of over 5,000 articles, including 73 randomized clinical trials (RCTs) and 24 meta-analyses, describing the use of n-3 LC-PUFA supplementation in depression.

Given the magnitude of research in this area, the researchers were interested in surveying the mechanisms of LC-PUFAs that can impact brain functioning, as results from clinical trials have yielded mixed results.

Prior RCTs and meta-analyses have established that omega-3 PUFA supplementation was ineffective in treating depressed mood or depression in a general population. Likewise, meta-analyses have also demonstrated that although DHA-rich supplements were not as effective as antidepressants, EPA-rich or EPA-only supplement formulations were effective. Importantly, these studies reported that effective daily doses of EPA supplements can range from 1,000-4,000 mg/day.

Of the two studies comparing treatment with n-3 LC-PUFA supplements to selective serotonin reuptake inhibitors (SSRIs), comparable effect sizes were observed for EPA monotherapy and fluoxetine. Both studies found greater efficacy when an EPA-rich supplement was administered alongside SSRI treatment.

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