The convergence model
Why do dozens of unrelated-seeming exposures each nudge depression risk? The most defensible answer is that they share a destination: chronic neuroinflammation, a dysregulated HPA stress axis, and oxidative stress form a self-reinforcing loop that degrades neuroplasticity and mood.
Examples that feed the funnel include smoking, ultra-processed food, alcohol, excess caffeine, air pollution, heavy metals, microplastics, mould, chronic stress, childhood adversity, loneliness, and poor sleep.
Neuroinflammation
Elevated IL-6, CRP, TNF-α are the most reproducible biological signal; Mendelian randomization supports a causal role for IL-6. ~30–50% of patients show an inflammatory subtype.
HPA / stress axis
Chronic stress keeps cortisol elevated, damaging the hippocampus and feeding inflammation; elevated morning cortisol prospectively predicts depression.
Oxidative stress
Metals, particulates and plastics generate reactive oxygen species and mitochondrial damage, releasing inflammatory signals that close the loop.
Shared nodes
The loops meet at the kynurenine pathway (inflammation diverts tryptophan from serotonin to neurotoxic metabolites — explaining how inflammation lowers serotonin without a primary "deficiency"), at suppressed BDNF/neuroplasticity, and at a leakier blood–brain barrier.