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

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

Study: The role of polyunsaturated fatty acids within the neurobiology of major depressive disorder and suicide risk. Image Credit: Danijela Maksimovic /

What are LC-PUFAs?

LC-PUFAs are fatty acids with 18 or more carbons and two or more double bonds. These fatty acids may be derived from either weight loss plan or biosynthesis process, by which enzymes act on essential shorter-chain fatty acids (SCFAs) within the liver, comparable to α-linolenic (ALA) and linoleic (LA) acids, to form LC-PUFAs. Notably, LC-PUFAs get transported through the blood and might cross the blood-brain barrier (BBB) to succeed in the brain.

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

Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), each of that are n-3 LC-PUFAs, in addition to arachidonic acid (AA), an n-6 LC-PUFA, are essentially 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 within the brain, these fatty acids also play key roles in brain health. Accordingly, low levels of DHA have been related to aberrations in cognition and behavior, in addition to neurological disorders like MDD.

In regards to the study

In the current 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 using n-3 LC-PUFA supplementation in depression.

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

Role of LC-PUFA supplements in MDD and suicide risk

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 weren’t as effective as antidepressants, EPA-rich or EPA-only complement formulations were effective. Importantly, these studies reported that effective every day doses of EPA supplements can range from 1,000-4,000 mg/day.

Of the 2 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. Each studies found greater efficacy when an EPA-rich complement was administered alongside SSRI treatment.

One other study evaluated the effect of EPA and DHA supplementation as in comparison with placebo for 12 weeks in a small sample of MDD patients who sought emergency visits to the hospital. While this treatment didn’t change depression severity, it reduced suicidal ideation within the LC-PUFA-treated group.

Data from interventional studies regarding the consequences of PUFA treatments on suicidal behavior are scarce. Moreover, there may be considerable heterogeneity in clinical trials examining the consequences of PUFAs in clinically diagnosed and self-reported symptoms of depressive disorders.

These clinical studies have also shown wide variations in PUFA composition in supplements and their bioavailability following ingestion, which appears to rely upon how they’re incorporated into dietary or supplementary sources. Storage conditions are also relevant, as PUFAs are vulnerable to oxidation by ultraviolet (UV) light or heat. Variability has also been attributed to genetic variations or epigenetic modifications in genes encoding proteins for PUFA metabolism, comparable to fatty acid desaturase (FAD).

LC-PUFA mechanisms of motion

Several studies have demonstrated that LC-PUFAs control cellular signaling in various brain cells through EPA and DHA uptake and esterification into plasma membrane phospholipids. Importantly, n-3 LC-PUFAs differentially manage the structure of the plasma membrane lipid raft.

Animal studies have shown that DHA manipulates the scale of lipid rafts in plasma membranes. Nonetheless, there may be an urgent need to know how homeostatic mechanisms reversing changes in membrane perturbation mitigate DHA-mediated changes in lipid raft organization. In an aging rat model, administration of n-3 LC-PUFAs also lowered oxidative stress in select brain regions in response to L-tyrosine. 

LC-PUFAs also play a task in various bioenergetic processes. For instance, in rats, administration of n3 LC-PUFA-enriched fish oil reversed the consequences mediated by increased turnover of DHA to its downstream metabolite D1. Likewise, neuroprotective effects, which were partly mediated by reduced reactive oxygen species (ROS) levels, were also reported in a rat model of amyloid beta-induced toxicity.


Animal-based studies have demonstrated the neurological advantages of LC-PUFA supplementation, which suppress microglial activation and subsequent neuroinflammation and ROS production and elicit effects on lipid raft regulation of monoaminergic receptors and transporters. 

Nonetheless, further scientific exploration is required to elucidate the neurobiology of LC-PUFAs regarding mood disorders and suicide risk. These studies will support personalized medicine approaches to profit vulnerable populations based on their weight loss plan, FADS genotype, inflammatory status, and peroxidation markers. 

Journal reference:

  • Sublette, M. E., Daray, F. M., Ganança, L., & Shaikh, S. R. (2023). The role of polyunsaturated fatty acids within the neurobiology of major depressive disorder and suicide risk. Molecular Psychiatry 1-18. doi:10.1038/s41380-023-02322-6
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