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The role of polyunsaturated fatty acids in the neurobiology of major depressive disorder and suicide risk

Molecular Psychiatry (2023)Cite this article

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Abstract

Long-chain polyunsaturated fatty acids (LC-PUFAs) are obtained from diet or derived from essential shorter-chain fatty acids, and are crucial for brain development and functioning. Fundamentally, LC-PUFAs’ neurobiological effects derive from their physicochemical characteristics, including length and double bond configuration, which differentiate LC-PUFA species and give rise to functional differences between n(omega)-3 and n-6 LC-PUFAs. LC-PUFA imbalances are implicated in psychiatric disorders, including major depression and suicide risk. Dietary intake and genetic variants in enzymes involved in biosynthesis of LC-PUFAs from shorter chain fatty acids influence LC-PUFA status. Domains impacted by LC-PUFAs include 1) cell signaling, 2) inflammation, and 3) bioenergetics. 1) As major constituents of lipid bilayers, LC-PUFAs are determinants of cell membrane properties of viscosity and order, affecting lipid rafts, which play a role in regulation of membrane-bound proteins involved in cell-cell signaling, including monoaminergic receptors and transporters. 2) The n-3:n-6 LC-PUFA balance profoundly influences inflammation. Generally, metabolic products of n-6 LC-PUFAs (eicosanoids) are pro-inflammatory, while those of n-3 LC-PUFAs (docosanoids) participate in the resolution of inflammation. Additionally, n-3 LC-PUFAs suppress microglial activation and the ensuing proinflammatory cascade. 3) N-3 LC-PUFAs in the inner mitochondrial membrane affect oxidative stress, suppressing production of and scavenging reactive oxygen species (ROS), with neuroprotective benefits. Until now, this wealth of knowledge about LC-PUFA biomechanisms has not been adequately tapped to develop translational studies of LC-PUFA clinical effects in humans. Future studies integrating neurobiological mechanisms with clinical outcomes may suggest ways to identify depressed individuals most likely to respond to n-3 LC-PUFA supplementation, and mechanistic research may generate new treatment strategies.

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Fig. 1: Schematic of DHA effects on membrane-bound proteins in the cell membrane lipid bilayer.
Fig. 2: Schematic of n-3 LC-PUFA effects on microglial-mediated inflammatory pathways.

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Funding

This study was supported in part by NIMH grant MH090964.

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Authors and Affiliations

  1. Department of Psychiatry, Columbia University, New York, NY, USA

    M. Elizabeth Sublette

  2. Molecular Imaging & Neuropathology Area, New York State Psychiatric Institute, New York, NY, USA

    M. Elizabeth Sublette

  3. University of Buenos Aires, School of Medicine, Institute of Pharmacology, Buenos Aires, Argentina

    Federico Manuel Daray

  4. National Scientific and Technical Research Council, Buenos Aires, Argentina

    Federico Manuel Daray

  5. Clínica Universitária de Psiquiatria e Psicologia Médica, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal

    Licínia Ganança

  6. Departamento de Psiquiatria e Saúde Mental, Centro Hospitalar Universitário Lisboa Norte, Lisbon, Portugal

    Licínia Ganança

  7. Nutritional Obesity Research Center, Department of Nutrition, Gillings School of Global Public Health and School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Saame Raza Shaikh

Authors
  1. M. Elizabeth Sublette
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  2. Federico Manuel Daray
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  3. Licínia Ganança
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  4. Saame Raza Shaikh
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Contributions

MES conceptualized the review, researched and wrote overall first draft and compiled and integrated the manuscript. FD researched and wrote first draft of sections on animal models and inflammation. LC researched and generated tables and initial draft of text concerning clinical trials and meta-analyses of PUFAs and depression. SRS researched and wrote first draft of sections on lipid rafts. All authors read and collaboratively edited the entire manuscript prior to submission.

Corresponding author

Correspondence to M. Elizabeth Sublette.

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Competing interests

Dr. Shaikh has received funding from industry groups that produce omega-3 fatty acids related to the organizing of conferences and for scientific research. All other authors have no conflicts to declare.

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Sublette, M.E., Daray, F.M., Ganança, L. et al. The role of polyunsaturated fatty acids in the neurobiology of major depressive disorder and suicide risk. Mol Psychiatry (2023). https://doi.org/10.1038/s41380-023-02322-6

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  • DOI: https://doi.org/10.1038/s41380-023-02322-6

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