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).
Study: The role of polyunsaturated fatty acids in the neurobiology of major depressive disorder and suicide risk. Image Credit: Danijela Maksimovic / Shutterstock.com
What are LC-PUFAs?
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.
About the study
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.
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 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.
Another study evaluated the effect of EPA and DHA supplementation as compared to placebo for 12 weeks in a small sample of MDD patients who sought emergency visits to the hospital. While this treatment did not change depression severity, it reduced suicidal ideation in the LC-PUFA-treated group.
Data from interventional studies regarding the effects of PUFA treatments on suicidal behavior are scarce. Furthermore, there is considerable heterogeneity in clinical trials examining the effects 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 depend on how they are 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, such as fatty acid desaturase (FAD).
LC-PUFA mechanisms of action
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 size of lipid rafts in plasma membranes. However, there is an urgent need to understand 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 role in various bioenergetic processes. For example, in rats, administration of n3 LC-PUFA-enriched fish oil reversed the effects 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 benefits 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.
However, further scientific exploration is needed to elucidate the neurobiology of LC-PUFAs regarding mood disorders and suicide risk. These studies will support personalized medicine approaches to benefit vulnerable populations based on their diet, FADS genotype, inflammatory status, and peroxidation markers.
- Sublette, M. E., Daray, F. M., Ganança, L., & Shaikh, S. R. (2023). The role of polyunsaturated fatty acids in the neurobiology of major depressive disorder and suicide risk. Molecular Psychiatry 1-18. doi:10.1038/s41380-023-02322-6