The evidence for depression as an inflammatory disease is pretty strong at this point, and several pharma companies are working on clinical trials trying to repurpose anti-inflammatory drugs as antidepressants. As such, there have been studies with aspirin – one of the well-known members of the NSAID group – to prevent/treat depression and the results from those animal trials have been very positive across the board. However, mainstream medicine has managed to scare the population and their doctors by labeling aspirin a very “dangerous” drug has potentially lethal risks of bleeding, despite human studies showing aspirin actually decreases the risk of dying from brain or GI bleeding.
Be that as it may, the study below is yet another one that shows even low-dose (HED 1.5mg/kg daily) aspirin can reverse the depression caused by chronic inflammation. More importantly, the study confirms that a high-fat (low-carb) diet, containing a significant percentage of PUFA, reliably caused systemic inflammation and depression largely through the metabolism of PUFA into the inflammatory prostaglandins, whose synthesis aspirin is known to block. The study replicated the effects of the high-fat diet by injecting much smaller amounts of the direct prostaglandin precursor known as arachidonic acid (also a PUFA). So, there we have it – i.e. high-fat (l0w-carb) diet containing a significant percentage of PUFA can directly causes depression through inducing systemic inflammation, and aspirin can reverse both states. Given that systemic inflammation is at the core of every chronic disease, I suspect the effects of aspirin in this study are not limited to depression alone.
https://www.nature.com/articles/s41380-026-03752-8
“…While Western dietary patterns are increasingly linked to neuropsychiatric disorders, the causal mechanisms by which chronic high-fat diet (HFD) contributes to depression remain elusive. Here, we demonstrate that prolonged ( ≥ 10 weeks) HFD exposure in mice robustly induces depressive-like behaviors, phenocopying chronic stress models. Integrating multi-omics and targeted lipidomics, we reveal that HFD-induced behavioral deficits are underpinned by gut microbiota dysbiosis and a profound disruption of polyunsaturated fatty acid (PUFA) homeostasis. This disruption is characterized by a surge in pro-inflammatory ω-6 metabolites, particularly arachidonic acid (AA), alongside a concomitant reduction in anti-inflammatory ω-3 metabolites. These lipid perturbations strongly correlate with marked microglial activation and elevated pro-inflammatory cytokine levels (IL-6, TNF-α, CCL2) in the prefrontal cortex and hippocampus. Functionally, AA supplementation alone was sufficient to recapitulate depressive-like behaviors in vivo and, through neuron-microglia co-culture assays, directly induce pro-inflammatory microglial activation, NF-κB pathway upregulation, and subsequent synaptic impairment in vitro. Critically, therapeutic intervention with aspirin, a dual COX-1/COX-2 inhibitor, effectively reversed HFD-induced behavioral deficits. This protection was mediated by a dual mechanism: directly inhibiting microglial hyperactivation and normalizing the neuroinflammatory milieu by suppressing the biosynthesis of pro-inflammatory ω-6-derived prostanoids, including AA and 12-HETE. Collectively, our findings identify AA as a critical etiological link between HFD and neuroinflammation, establishing a mechanistic framework for “metabolic depression.” The profound therapeutic efficacy of aspirin validates the AA metabolic pathway, specifically COX-1/COX-2, as a promising and targetable node for intervention, offering translational insights for the burgeoning field of nutritional psychiatry.”
