For decades, the story was simple: depression is a chemical imbalance, and the fix is a prescription SSRI. A recent review in Nutrition Research Reviews (Khiroya et al., 2023) makes the case for something more useful and more hopeful.
The authors don’t dismiss medication or psychotherapy. They ask a better question: what biological processes are contributing to this patient’s depression? Because depression isn’t one condition with one cause. Depression is a syndrome, and the drivers are often measurable and often modifiable.
This is the same lens I use in practice, especially when patients are navigating hormone shifts, autoimmune conditions, or the kind of chronic stress that never quite lets up. Mood changes are rarely random. There’s almost always a biological thread to pull.
Your Biology, Mapped
The paper points to several overlapping systems that can push a person toward depression.
Inflammation. Elevated CRP, IL-6, and TNF-alpha don’t just signal that something’s off, they actively interfere with serotonin and dopamine production and can push tryptophan down a pathway that produces neurotoxic byproducts instead of the feel-good neurotransmitters.
Nutrient status. Folate, B12, B6, iron, zinc, magnesium, vitamin D, and omega-3s aren’t extras. They’re raw materials your brain needs to build serotonin, dopamine, and GABA. Correcting a real deficiency can move the needle in a way medication alone can’t. Vitamin D is worth calling out because deficiency is common, and it’s an easy one to check on nearly every patient.
Neuroplasticity. Brain-derived neurotrophic factor (BDNF) supports the brain’s ability to adapt and rewire. Lower BDNF shows up alongside depression. Exercise, omega-3 fats, and overall diet quality all appear to support healthier BDNF signaling.
Methylation. Folate and B12 also regulate homocysteine, which has been linked to depression repeatedly in the literature. The evidence-based path: check homocysteine and folate/B12 first. Genetic testing (MTHFR) is a second step, not a starting point.
Metabolic health. Insulin resistance and metabolic syndrome show up again and again in depression research. Fasting glucose and HbA1c are enough to start you moving in the right direction.
Gut function. A diverse microbiome, fiber, fermented foods, and a Mediterranean pattern all support the gut-brain axis. The authors suggest that commercial stool microbiome tests aren’t validated for guiding depression treatment, even though GI symptoms may still warrant their own workup.
Thyroid. When thyroid involvement is suspected, a full panel — TSH, free T4, free T3, reverse T3, and antibodies — tells a more complete story than TSH alone.
Hormones. Estrogen, progesterone, and testosterone all influence mood directly, through their effects on serotonin, GABA, and stress-hormone regulation. This shows up clinically in perimenopause and menopause, postpartum, PMDD, and low testosterone in men. This wasn’t a focus of the review itself, but in my practice, it’s one of the most common threads I see. When the timing of someone’s mood symptoms tracks with a hormonal shift, a full hormone panel is worth considering.
What Actually Moves the Needle
Across the review, the strongest evidence for helping lower depression risk wasn’t a single supplement, it was diet. The diet that is most consistently linked with lower depression risk was a Mediterranean-style diet. This way of eating includes high-quality proteins, vegetables, fruit, legumes, nuts, seafood, olive oil, and minimal ultra-processed food.
For supplements, the strongest evidence sits with omega-3s (EPA-rich forms), folate, B12, zinc, iron, and vitamin D. Vitamins are best used for correcting a documented deficiency, not blanket dosing across the board.
A Note From My Practice
The review is intentionally conservative about two tools I use regularly: urinary organic acid testing (OAT) and comprehensive stool testing (GI MAP). The evidence for either as a stand-alone predictor of depression isn’t there yet, and I want to be upfront about that rather than oversell it.
But in the context of a full clinical picture — symptoms, history, and the labs above — I’ve found both genuinely useful. Urinary OAT test can flag metabolic patterns worth investigating further. GI-MAP goes well beyond general microbiome diversity. It screens for pathogens, dysbiosis, and inflammatory gut markers like calprotectin and zonulin, which often connect directly back to the gut-brain axis. I use them as one more data point, not the whole diagnosis.
The Takeaway
This is the functional medicine model at its best: identify what’s actually driving symptoms, test for it with evidence-backed labs, and build a protocol around the answer alongside therapy, sleep, movement, and medication when it’s needed. Not instead of. Alongside.
If you’ve been told your labs are “normal” but you don’t feel like yourself, that gap is often where the real answers live.
Curious what your biology is telling you? Book a visit to talk through evidence-based testing for your mood, hormones, energy, and metabolic health.
Dr. Joanne Gordon, ND
Naturopathic physician | Clinical Genomics consultant | Certified BioIdentical Hormone Practitioner
info@drjoannegordon.com | (503) 722-7776
