{
 "generated": "2026-06-13",
 "count": 56,
 "factors": [
  {
   "id": "B01",
   "domain": "Biological",
   "factor": "Neuroinflammation (IL-6, CRP, TNF-α)",
   "direction": "Risk",
   "evidence": "Causal (strong)",
   "mechanism": "Cytokines cross/breach the BBB, activate microglia, shift tryptophan to kynurenine, suppress BDNF.",
   "finding": "Meta-analyses show elevated IL-6/CRP/TNF-α; Mendelian randomization supports a causal role for IL-6.",
   "confounders": "Obesity, infection, smoking, stress all raise cytokines.",
   "note": "Proposed CONVERGENCE HUB of the whole system. ~30–50% of cases show an inflammatory subtype.",
   "detail": "The single most reproducible biological signal in depression. IL-6 has genetic (MR) causal support, making inflammation a target, not just a marker. Many external exposures appear to act through this funnel.",
   "shade": "C6E0B4"
  },
  {
   "id": "B02",
   "domain": "Biological",
   "factor": "HPA-axis dysregulation / chronic stress",
   "direction": "Risk",
   "evidence": "Robust",
   "mechanism": "Sustained cortisol/CRH damages the hippocampus, blunts feedback, and drives inflammation.",
   "finding": "Prospective cohorts: elevated morning cortisol predicts later depression (Zajkowska 2022 meta-analysis).",
   "confounders": "SES, trauma history, sleep.",
   "note": "The bridge turning 'environment' and adversity into measurable brain biology.",
   "detail": "Chronic stress keeps the stress-hormone thermostat high. It interacts with inflammation and is set partly by early-life experience.",
   "shade": "D9EAD3"
  },
  {
   "id": "B03",
   "domain": "Biological",
   "factor": "Oxidative stress & mitochondrial dysfunction",
   "direction": "Risk",
   "evidence": "Moderate",
   "mechanism": "Reactive oxygen species damage mitochondria; energy failure + DAMP release feed inflammation.",
   "finding": "Reviews map impaired biogenesis/mitophagy in MDD (Song 2023).",
   "confounders": "Hard to separate primary from secondary to inflammation.",
   "note": "Shared mechanism by which metals, plastics and particulates plausibly act.",
   "detail": "Most data are animal/cross-sectional, but it ties chemical exposures to the inflammation funnel.",
   "shade": "FFF2CC"
  },
  {
   "id": "B04",
   "domain": "Biological",
   "factor": "Low BDNF / impaired neuroplasticity",
   "direction": "Marker",
   "evidence": "Robust",
   "mechanism": "Stress, cortisol and inflammation suppress BDNF → dendritic spine loss → impaired connectivity.",
   "finding": "Reduced BDNF consistently found in post-mortem MDD hippocampus (Colucci-D'Amato 2020).",
   "confounders": "Peripheral BDNF is an imperfect proxy for brain levels.",
   "note": "A mediator, not a root cause — upstream drivers determine it.",
   "detail": "Explains why plasticity-promoting treatments (ketamine, psilocybin, exercise) help.",
   "shade": "D9EAD3"
  },
  {
   "id": "B05",
   "domain": "Biological",
   "factor": "Kynurenine / tryptophan pathway shift",
   "direction": "Risk",
   "evidence": "Robust",
   "mechanism": "Inflammation activates IDO, diverting tryptophan from serotonin to neurotoxic quinolinic acid.",
   "finding": "Well-characterised immune-serotonin link; gut microbiome modulates IDO (Kennedy 2016).",
   "confounders": "Mostly associative in humans.",
   "note": "Explains how inflammation lowers serotonin WITHOUT a primary serotonin 'deficiency'.",
   "detail": "A unifying node where immune, gut and serotonergic stories meet.",
   "shade": "D9EAD3"
  },
  {
   "id": "B06",
   "domain": "Biological",
   "factor": "Glutamatergic dysfunction",
   "direction": "Risk",
   "evidence": "Robust",
   "mechanism": "NMDA/AMPA imbalance and synaptic loss in prefrontal cortex/hippocampus.",
   "finding": "Ketamine rapidly restores synapses via AMPA/BDNF — validating the pathway.",
   "confounders": "May be parallel to, not upstream of, inflammation.",
   "note": "Target of the most important rapid-acting antidepressant (ketamine).",
   "detail": "Shifts focus from monoamines to synaptic/plasticity biology.",
   "shade": "D9EAD3"
  },
  {
   "id": "B07",
   "domain": "Biological",
   "factor": "Genetic / polygenic risk",
   "direction": "Risk",
   "evidence": "Robust",
   "mechanism": "Hundreds of common variants of small effect; risk expressed most under stress (GxE).",
   "finding": "2024 trans-ancestry GWAS (n=688,808) found 697 associations; twin heritability ~37%.",
   "confounders": "No single gene matters much; PRS predictive power still modest.",
   "note": "Genes load the gun; environment/exposome pulls the trigger.",
   "detail": "Polygenic risk interacts with exposures (e.g., air pollution effect is larger at higher PRS).",
   "shade": "D9EAD3"
  },
  {
   "id": "B08",
   "domain": "Biological",
   "factor": "Serotonin 'chemical imbalance'",
   "direction": "Risk",
   "evidence": "Contested",
   "mechanism": "Hypothesised global serotonin deficiency causes low mood.",
   "finding": "Moncrieff 2022 umbrella review: no consistent evidence; 36-expert rebuttal notes nuance.",
   "confounders": "Antidepressant use; subtype heterogeneity.",
   "note": "CORRECTION: do NOT build the program on this. Serotonin still matters in subtypes/indirectly.",
   "detail": "The simplistic deficiency story is dead; SSRIs likely work via plasticity/anti-inflammatory effects.",
   "shade": "F4CCCC"
  },
  {
   "id": "B09",
   "domain": "Biological",
   "factor": "Blood–brain barrier permeability",
   "direction": "Risk",
   "evidence": "Emerging",
   "mechanism": "Inflammation/oxidative stress degrade tight junctions, letting peripheral cytokines into the brain.",
   "finding": "Lung-brain 'inflammatory spill-over' MR + experimental work (2025).",
   "confounders": "Hard to measure in living humans.",
   "note": "A gate that converts peripheral exposures into brain inflammation.",
   "detail": "Helps explain how smoking, pollution and infection reach the brain.",
   "shade": "FCE5CD"
  },
  {
   "id": "E01",
   "domain": "Environmental",
   "factor": "Air pollution (PM2.5, NO2)",
   "direction": "Risk",
   "evidence": "Robust",
   "mechanism": "Particulates → systemic + neuroinflammation, oxidative stress, BBB effects.",
   "finding": "UK Biobank prospective cohort (n=389k, ~11y): higher PM2.5/NO2 → incident depression; no safe threshold.",
   "confounders": "Urbanicity, SES, noise, greenspace.",
   "note": "One of the strongest ENVIRONMENTAL exposures; was not on the original list.",
   "detail": "Among the few exposures with large prospective cohorts, dose-response and a clean mechanism.",
   "shade": "D9EAD3"
  },
  {
   "id": "E02",
   "domain": "Environmental",
   "factor": "Cadmium (heavy metal)",
   "direction": "Risk",
   "evidence": "Moderate",
   "mechanism": "Oxidative stress, neuroinflammation; disrupts neurotransmitter metabolism; 10–30y half-life.",
   "finding": "NHANES mixture analyses: cadmium the leading metal contributor to depression.",
   "confounders": "Smoking is the dominant non-occupational source AND a depression risk — major confounder.",
   "note": "Quitting smoking is the highest-yield cadmium-reduction step.",
   "detail": "Real signal, but heavily entangled with smoking; needs causal designs.",
   "shade": "FFF2CC"
  },
  {
   "id": "E03",
   "domain": "Environmental",
   "factor": "Lead (heavy metal)",
   "direction": "Risk",
   "evidence": "Moderate",
   "mechanism": "Neurotoxic; oxidative stress; lifelong CNS effects, especially developmental.",
   "finding": "Associated with depression in NHANES mixtures.",
   "confounders": "Housing age, SES, co-exposures.",
   "note": "Strongest as a developmental risk; chelation only for true poisoning.",
   "detail": "Best studied via remediation natural experiments.",
   "shade": "FFF2CC"
  },
  {
   "id": "E04",
   "domain": "Environmental",
   "factor": "Mercury",
   "direction": "Risk",
   "evidence": "Contested",
   "mechanism": "Neurotoxic at high dose; main exposure via fish.",
   "finding": "NHANES shows null/INVERSE association — a healthy-eater (omega-3) confounder.",
   "confounders": "Fish eaters have healthier diets overall.",
   "note": "CORRECTION: fish-mercury is not a established depression driver at population levels.",
   "detail": "A good example of confounding flipping a naive expectation.",
   "shade": "F4CCCC"
  },
  {
   "id": "E05",
   "domain": "Environmental",
   "factor": "PFAS ('forever chemicals')",
   "direction": "Risk",
   "evidence": "Contested",
   "mechanism": "Endocrine/immune disruption; persist in serum for years.",
   "finding": "Cross-sectional links are inconsistent; in mixtures PFAS sometimes ANTAGONISTIC.",
   "confounders": "Co-pollutants, SES; cross-sectional only.",
   "note": "CORRECTION: weaker/more mixed than the popular narrative.",
   "detail": "Body burden IS reducible (fibre, blood donation, anion-exchange resin) — but mood benefit untested.",
   "shade": "F4CCCC"
  },
  {
   "id": "E06",
   "domain": "Environmental",
   "factor": "Microplastics / nanoplastics",
   "direction": "Risk",
   "evidence": "Emerging",
   "mechanism": "Cross BBB; carry additives; provoke oxidative stress, neuroinflammation, gut dysbiosis.",
   "finding": "Nature Medicine 2024: bioaccumulation in human brain ('~a spoonful'), rising over time, higher in dementia brains; animal models show depressive-like behaviour.",
   "confounders": "Reverse causation (leaky BBB lets more in); measurement immature.",
   "note": "NOVEL FRONTIER. Pair with ultra-processed food as the exposure vector.",
   "detail": "Human causation unproven; among the most promising under-explored angles.",
   "shade": "FCE5CD"
  },
  {
   "id": "E07",
   "domain": "Environmental",
   "factor": "Aluminium",
   "direction": "Risk",
   "evidence": "Emerging",
   "mechanism": "Crosses BBB; oxidative stress, neuroinflammation, BDNF suppression.",
   "finding": "Occupational cohorts show more depression/fatigue; animal AlCl3 models robust.",
   "confounders": "Occupational co-exposures; kidney function.",
   "note": "CORRECTION: main dietary source = baked/processed goods, tea, cocoa, additives, antacids — NOT energy drinks/cans (lined).",
   "detail": "Keep on the list as an exposure; fix the source attribution.",
   "shade": "FCE5CD"
  },
  {
   "id": "E08",
   "domain": "Environmental",
   "factor": "Pesticides / organophosphates",
   "direction": "Risk",
   "evidence": "Moderate",
   "mechanism": "Acetylcholinesterase inhibition; HPA and neuroinflammatory effects.",
   "finding": "Occupational reviews link exposure to depression; pesticide POISONING strongly so (OR~2.9).",
   "confounders": "Farming poverty, isolation, injury.",
   "note": "Acute poisoning ≠ chronic low-level exposure.",
   "detail": "Agricultural worker mental health is a real, under-served signal.",
   "shade": "FFF2CC"
  },
  {
   "id": "E09",
   "domain": "Environmental",
   "factor": "Endocrine disruptors (BPA, phthalates)",
   "direction": "Risk",
   "evidence": "Moderate",
   "mechanism": "Disrupt oestrogen/androgen/thyroid signalling tied to mood.",
   "finding": "Cross-sectional links; stress×chemical synergy in pregnancy cohorts.",
   "confounders": "Psychosocial stress co-exposure.",
   "note": "Developmental windows (pregnancy, adolescence) may matter most.",
   "detail": "Mixture and timing effects are the key research questions.",
   "shade": "FFF2CC"
  },
  {
   "id": "E10",
   "domain": "Environmental",
   "factor": "Mould / damp housing",
   "direction": "Risk",
   "evidence": "Moderate",
   "mechanism": "Possible mycotoxin neuroinflammation AND a strong psychosocial pathway.",
   "finding": "State-of-science review: ~34–44% higher depression risk; effect partly mediated by PERCEIVED CONTROL (Shenassa 2007).",
   "confounders": "Poverty, housing quality.",
   "note": "CORRECTION: partly psychosocial, not purely toxicological; indoor mycotoxins usually below toxic thresholds.",
   "detail": "Remediation helps both the exposure and the sense of control.",
   "shade": "FFF2CC"
  },
  {
   "id": "D01",
   "domain": "Diet & gut",
   "factor": "Gut microbiome dysbiosis",
   "direction": "Risk",
   "evidence": "Moderate",
   "mechanism": "Gut-brain axis via vagus, immune signalling, SCFAs, neurotransmitter precursors.",
   "finding": "FMT meta-analysis (12 RCTs, n=681): SMD −1.21; germ-free mice adopt depression-like behaviour from patient microbiota.",
   "confounders": "Diet, antibiotics, BMI; small/unblinded trials.",
   "note": "Supports the gut hypothesis with real RCT signal; durability unproven.",
   "detail": "Emerging causal; psychobiotics/fibre/diet are the practical levers.",
   "shade": "FFF2CC"
  },
  {
   "id": "D02",
   "domain": "Diet & gut",
   "factor": "Ultra-processed food (UPF)",
   "direction": "Risk",
   "evidence": "Robust",
   "mechanism": "Pro-inflammatory; carries additives, microplastics, aluminium; low fibre; high glycaemic load; displaces omega-3.",
   "finding": "BMJ 2024 umbrella review (~9.9M): higher UPF → depression (HR~1.22); Werneck 2024 pooled HR~1.32.",
   "confounders": "SES, food insecurity, reverse causation.",
   "note": "NOVEL UNIFYING VECTOR bundling several exposures; observational only.",
   "detail": ">50% of US energy intake. Targeting UPF may move many dials at once.",
   "shade": "D9EAD3"
  },
  {
   "id": "D03",
   "domain": "Diet & gut",
   "factor": "Mediterranean / whole-food diet",
   "direction": "Protective",
   "evidence": "Moderate",
   "mechanism": "High fibre, polyphenols, omega-3; anti-inflammatory; feeds protective microbiome.",
   "finding": "SMILES RCT (2017): 32% vs 8% remission; 2025 meta-analyses confirm symptom reduction.",
   "confounders": "Diet RCTs cannot be blinded; attention effects.",
   "note": "Best-evidenced dietary PATTERN for prevention and as adjunct.",
   "detail": "A modifiable lever supporting the anti-inflammatory model.",
   "shade": "FFF2CC"
  },
  {
   "id": "D04",
   "domain": "Diet & gut",
   "factor": "Omega-3 (EPA) insufficiency",
   "direction": "Risk",
   "evidence": "Robust",
   "mechanism": "Low EPA tilts eicosanoid balance pro-inflammatory; affects membranes/receptors.",
   "finding": "67-RCT dose-response meta-analysis: ~1–2 g/day EPA helps EXISTING depression (esp. inflamed); no prevention in healthy.",
   "confounders": "Publication bias; overall diet.",
   "note": "CORRECTION: treats existing depression in inflamed patients; does NOT prevent it in healthy people.",
   "detail": "A precision lever for the inflammatory subtype.",
   "shade": "D9EAD3"
  },
  {
   "id": "D05",
   "domain": "Diet & gut",
   "factor": "High sugar / glycaemic load",
   "direction": "Risk",
   "evidence": "Moderate",
   "mechanism": "Insulin resistance, oxidative stress, neuroinflammation.",
   "finding": "Whitehall II: high sugar predicts incident depression in men.",
   "confounders": "Overall diet, obesity, activity.",
   "note": "Part of the UPF/metabolic cluster.",
   "detail": "Mechanistically coherent; few isolated trials.",
   "shade": "FFF2CC"
  },
  {
   "id": "D06",
   "domain": "Diet & gut",
   "factor": "Vitamin D deficiency",
   "direction": "Risk",
   "evidence": "Moderate",
   "mechanism": "Brain vitamin-D receptors; immune modulation; light links to circadian/serotonergic tone.",
   "finding": "Consistent association (esp. postpartum); supplementation helps mainly when deficient.",
   "confounders": "Outdoor activity, adiposity, season; reverse causation.",
   "note": "CORRECTION: weaker than popularly assumed; supplements rarely help non-deficient people.",
   "detail": "Correct deficiency; don't expect a cure.",
   "shade": "FFF2CC"
  },
  {
   "id": "D07",
   "domain": "Diet & gut",
   "factor": "Metabolic syndrome / insulin resistance / obesity",
   "direction": "Risk",
   "evidence": "Robust",
   "mechanism": "Adipose tissue is an immune organ; shared inflammatory + HPA pathways; impaired brain glucose use.",
   "finding": "Bidirectional MR (Zhang 2021): depression causally increases metabolic syndrome.",
   "confounders": "Diet, activity, SES.",
   "note": "Strong shared biology; 'metabolic psychiatry' (e.g., ketogenic) is emerging.",
   "detail": "Treating metabolic health addresses shared pathophysiology.",
   "shade": "D9EAD3"
  },
  {
   "id": "L01",
   "domain": "Lifestyle",
   "factor": "Smoking / tobacco",
   "direction": "Risk",
   "evidence": "Causal (strong)",
   "mechanism": "Toxicant load → inflammation (IL-6), oxidative stress, cadmium delivery, vascular effects.",
   "finding": "Bidirectional MR; smoking→depression partly mediated by IL-6 (Galan 2022).",
   "confounders": "Reverse causation (self-medication); SES.",
   "note": "Among the firmest causal exposures; smoke ≈ 7,000 chemicals (~70 carcinogens), not 1,600.",
   "detail": "A clean worked example of the inflammation funnel.",
   "shade": "C6E0B4"
  },
  {
   "id": "L02",
   "domain": "Lifestyle",
   "factor": "Alcohol",
   "direction": "Risk",
   "evidence": "Robust",
   "mechanism": "GABA/NMDA effects; depletes folate/tryptophan; raises cortisol; wrecks sleep.",
   "finding": "Bidirectional MR: higher drinking frequency → MDD; 'moderate is protective' is sick-quitter bias.",
   "confounders": "Genetic correlation with depression.",
   "note": "CORRECTION: no real protective effect of moderate drinking.",
   "detail": "Self-medication makes the link bidirectional.",
   "shade": "D9EAD3"
  },
  {
   "id": "L03",
   "domain": "Lifestyle",
   "factor": "Cannabis (adolescent)",
   "direction": "Risk",
   "evidence": "Moderate",
   "mechanism": "Chronic CB1 effects blunt reward; disrupts adolescent prefrontal maturation.",
   "finding": "30-year cohort: adolescent use → adult depression (aOR~1.7), dose-dependent.",
   "confounders": "Reverse causation; shared genetics (CADM2).",
   "note": "Rising THC potency may make older studies underestimate risk.",
   "detail": "Causality contested but adolescent dose-response is concerning.",
   "shade": "FFF2CC"
  },
  {
   "id": "L04",
   "domain": "Lifestyle",
   "factor": "Energy drinks (caffeine + sugar)",
   "direction": "Risk",
   "evidence": "Moderate",
   "mechanism": "High caffeine + sugar → sleep disruption, anxiety, crashes, dependence.",
   "finding": "2024 systematic review: more anxiety, depression, suicidality (males more affected).",
   "confounders": "Reverse causation; sleep; risk-taking.",
   "note": "CORRECTION: blame caffeine/sugar/sleep — taurine is benign/likely beneficial.",
   "detail": "Cross-sectional; likely acts via sleep disruption.",
   "shade": "FFF2CC"
  },
  {
   "id": "L05",
   "domain": "Lifestyle",
   "factor": "Physical inactivity (exercise protects)",
   "direction": "Protective",
   "evidence": "Causal (strong)",
   "mechanism": "Exercise raises BDNF/irisin, lowers cytokines, normalises cortisol, improves sleep.",
   "finding": "MR (Choi 2019): objective activity causally protects; BMJ 2024 (218 RCTs): effect comparable to antidepressants.",
   "confounders": "Self-report PA is noisy; RCT blinding impossible.",
   "note": "One of the most multi-target, evidence-based levers.",
   "detail": "Protective factor with both MR and large RCT support.",
   "shade": "C6E0B4"
  },
  {
   "id": "L06",
   "domain": "Lifestyle",
   "factor": "Sedentary behaviour / TV / screens",
   "direction": "Risk",
   "evidence": "Moderate",
   "mechanism": "Displaces activity and light; disrupts circadian; social comparison (interactive use).",
   "finding": "MR: leisure TV watching causally raises depression risk; interactive use correlates more in youth.",
   "confounders": "SES (a stronger predictor than screen time per ABCD).",
   "note": "Distinguish passive TV (MR signal) from interactive/social media (contested).",
   "detail": "Sedentariness, not screens per se, may be the causal core.",
   "shade": "FFF2CC"
  },
  {
   "id": "L07",
   "domain": "Lifestyle",
   "factor": "Sleep loss / insomnia / circadian disruption",
   "direction": "Risk",
   "evidence": "Causal (strong)",
   "mechanism": "Disrupted sleep raises cortisol/cytokines, impairs emotion regulation; circadian misalignment amplifies HPA.",
   "finding": "Bidirectional MR: insomnia↔MDD (strongest single sleep signal); short sleep causal.",
   "confounders": "Reverse causation; shift work.",
   "note": "Often the highest-yield, most-modifiable lever; mediates other exposures.",
   "detail": "CBT-I reduces incident depression — a prevention tool.",
   "shade": "C6E0B4"
  },
  {
   "id": "P01",
   "domain": "Psychosocial",
   "factor": "Childhood adversity / trauma (ACEs)",
   "direction": "Risk",
   "evidence": "Causal (strong)",
   "mechanism": "Programs HPA axis and immune/threat systems via epigenetic change (NR3C1, FKBP5).",
   "finding": "Umbrella review (n=14.7M): pooled AOR~1.9; clear dose-response; top exposome factor.",
   "confounders": "Shared family genetics (partly addressed by sibling designs); recall bias.",
   "note": "The single strongest exposome factor — must stay central.",
   "detail": "Highest-leverage single PREVENTION target at population scale.",
   "shade": "C6E0B4"
  },
  {
   "id": "P02",
   "domain": "Psychosocial",
   "factor": "Loneliness / social isolation",
   "direction": "Risk",
   "evidence": "Causal (strong)",
   "mechanism": "Chronic social threat → inflammation, HPA, poor sleep, low positive affect.",
   "finding": "Bidirectional MR (Zhao 2023): loneliness↔depression.",
   "confounders": "Health, SES, personality.",
   "note": "Key to why connected communities fare better (connection > chemicals).",
   "detail": "A leading, modifiable population lever; needs social infrastructure, not just befriending.",
   "shade": "C6E0B4"
  },
  {
   "id": "P03",
   "domain": "Psychosocial",
   "factor": "Low SES / poverty / food insecurity",
   "direction": "Risk",
   "evidence": "Robust",
   "mechanism": "Material hardship, precarity, low control, reduced buffers.",
   "finding": "Cash-transfer natural experiments show causal poverty→depression; food insecurity effects reverse on restoration.",
   "confounders": "Reverse causation (depression lowers income).",
   "note": "Income/food-security interventions have rapid antidepressant effects.",
   "detail": "Structural and modifiable through policy.",
   "shade": "D9EAD3"
  },
  {
   "id": "P04",
   "domain": "Psychosocial",
   "factor": "Discrimination / minority stress",
   "direction": "Risk",
   "evidence": "Robust",
   "mechanism": "Chronic stigma/threat raises distress and inflammation; limits resources.",
   "finding": "Hundreds of studies link racism to depression across groups (minority-stress model).",
   "confounders": "Self-report mood bias; confounded with SES.",
   "note": "Gender gap (women ~2x) reflects exposure (violence, caregiving) + measurement, not mainly biology.",
   "detail": "Structural drivers needing structural responses.",
   "shade": "D9EAD3"
  },
  {
   "id": "P05",
   "domain": "Psychosocial",
   "factor": "Work stress / job strain",
   "direction": "Risk",
   "evidence": "Robust",
   "mechanism": "High demand + low control → sustained cortisol dysregulation; effort-reward imbalance.",
   "finding": "IPD-Work consortium: job strain → clinical depression (RR~1.3–1.8).",
   "confounders": "Healthy-worker bias; burnout/depression overlap.",
   "note": "A labour-policy issue (psychosocial risk assessment), not just individual coping.",
   "detail": "Prospective evidence is fairly strong and partly causal.",
   "shade": "D9EAD3"
  },
  {
   "id": "P06",
   "domain": "Psychosocial",
   "factor": "Urbanicity / low greenspace / poor housing",
   "direction": "Risk",
   "evidence": "Moderate",
   "mechanism": "Noise, crowding, pollution, low nature contact raise allostatic load.",
   "finding": "18-country study: greenspace linked to better wellbeing and less antidepressant use.",
   "confounders": "Greenspace correlates with SES.",
   "note": "Greenspace equity is a scalable, ignored intervention.",
   "detail": "Consistent cross-sectional signal; fewer causal designs.",
   "shade": "FFF2CC"
  },
  {
   "id": "P07",
   "domain": "Psychosocial",
   "factor": "Social media (adolescents)",
   "direction": "Risk",
   "evidence": "Contested",
   "mechanism": "Sleep/▶socialising displacement, social comparison, cyberbullying, algorithmic amplification.",
   "finding": "2026 meta-analysis (153 studies): small-moderate association (r~0.09–0.21), larger for girls/younger; bidirectional.",
   "confounders": "Self-reported screen time; analytical flexibility; SES.",
   "note": "CORRECTION: the science is genuinely CONTESTED (Haidt vs Odgers/Orben); effects are real but modest.",
   "detail": "Regulate algorithm/age design rather than claim settled causation.",
   "shade": "F4CCCC"
  },
  {
   "id": "M01",
   "domain": "Medical & hormonal",
   "factor": "Hypothyroidism",
   "direction": "Risk",
   "evidence": "Robust",
   "mechanism": "Thyroid hormone regulates monoamine synthesis, myelination & mitochondrial function; deficiency lowers mood.",
   "finding": "Even subclinical hypothyroidism produces depressive symptoms; ~1/3 of treated patients have residual depression.",
   "confounders": "Often missed; depression can precede diagnosis.",
   "note": "",
   "detail": "A textbook reversible cause routinely missed in psychiatric workups — check TSH/free T4.",
   "shade": "D9EAD3"
  },
  {
   "id": "M02",
   "domain": "Medical & hormonal",
   "factor": "Perimenopause & menopause",
   "direction": "Risk",
   "evidence": "Moderate",
   "mechanism": "Falling/fluctuating oestrogen affects serotonergic tone, sleep and the stress axis.",
   "finding": "Perimenopause carries a window of elevated depression risk, especially with vasomotor symptoms.",
   "confounders": "Sleep disruption & life stage confound.",
   "note": "",
   "detail": "A sex-specific, time-limited risk window; hormone therapy helps some.",
   "shade": "FFF2CC"
  },
  {
   "id": "M03",
   "domain": "Medical & hormonal",
   "factor": "PMDD / hormonal-cycle sensitivity",
   "direction": "Risk",
   "evidence": "Robust",
   "mechanism": "Abnormal neural sensitivity to normal ovarian-steroid shifts (allopregnanolone/GABA-A, oestrogen-kynurenine).",
   "finding": "PMDD affects ~3-8% of reproductive-age women; a clean model of hormone-neuroinflammation interaction.",
   "confounders": "Cyclic timing distinguishes it.",
   "note": "",
   "detail": "Not a hormone 'deficiency' but a sensitivity; bridges hormonal and immune axes.",
   "shade": "D9EAD3"
  },
  {
   "id": "M04",
   "domain": "Medical & hormonal",
   "factor": "PCOS",
   "direction": "Risk",
   "evidence": "Moderate",
   "mechanism": "Hyperandrogenism + insulin resistance + chronic inflammation; HPO-axis disruption.",
   "finding": "PCOS (~11-13% of women) carries elevated depression beyond body-image/infertility effects.",
   "confounders": "Obesity/insulin resistance overlap.",
   "note": "",
   "detail": "A distinct androgen-insulin-inflammation cluster.",
   "shade": "FFF2CC"
  },
  {
   "id": "M05",
   "domain": "Medical & hormonal",
   "factor": "Hormonal contraceptives",
   "direction": "Risk",
   "evidence": "Contested",
   "mechanism": "Synthetic progestins/oestrogen may affect mood circuitry; effect likely subgroup-specific.",
   "finding": "Danish cohort (>1M): ~23% higher first-antidepressant rate, highest in adolescents; causality contested.",
   "confounders": "Confounding by indication; many users unaffected.",
   "note": "",
   "detail": "Real signal in teens; for most users it is well tolerated — individual, not universal.",
   "shade": "F4CCCC"
  },
  {
   "id": "M06",
   "domain": "Medical & hormonal",
   "factor": "Long COVID / SARS-CoV-2",
   "direction": "Risk",
   "evidence": "Robust",
   "mechanism": "Neuroinvasion via ACE2, persistent microglial activation, cytokines, BBB disruption, demyelination.",
   "finding": ">30% of COVID inpatients develop persistent depression/anxiety/cognitive symptoms.",
   "confounders": "Overlaps post-ICU syndrome; severity varies.",
   "note": "",
   "detail": "The largest new immune-triggered cause of depression since 2020.",
   "shade": "D9EAD3"
  },
  {
   "id": "M07",
   "domain": "Medical & hormonal",
   "factor": "Autoimmune / encephalitis depression",
   "direction": "Risk",
   "evidence": "Moderate",
   "mechanism": "Anti-neuronal antibodies (anti-NMDAR, CASPR2) and low-grade CNS autoimmunity disrupt mood circuits.",
   "finding": "~95% of anti-NMDAR encephalitis cases show psychiatric symptoms, often misdiagnosed as primary depression.",
   "confounders": "Rare as a pure cause; broader hypothesis emerging.",
   "note": "",
   "detail": "High-stakes: a treatable, often-missed cause of treatment-resistant cases — antibody screen can find it.",
   "shade": "FFF2CC"
  },
  {
   "id": "M08",
   "domain": "Medical & hormonal",
   "factor": "Post-stroke / vascular depression",
   "direction": "Risk",
   "evidence": "Causal (strong)",
   "mechanism": "Frontal-basal-ganglia lesions disrupt monoamine pathways; neuroinflammation + small-vessel disease.",
   "finding": "~1/3 of stroke survivors develop depression within a year; bidirectional with stroke risk.",
   "confounders": "Disability & life change also contribute.",
   "note": "",
   "detail": "A discrete neuroanatomical cause; rising with an ageing population.",
   "shade": "C6E0B4"
  },
  {
   "id": "M09",
   "domain": "Medical & hormonal",
   "factor": "Traumatic brain injury",
   "direction": "Risk",
   "evidence": "Causal (strong)",
   "mechanism": "Axonal injury to prefrontal-limbic circuits, microglial activation, network & HPA disruption.",
   "finding": "Lifetime depression exceeds 50% after moderate-severe TBI.",
   "confounders": "Pre-injury risk, pain, disability.",
   "note": "",
   "detail": "Major and rising (sports/military); a clear causal cause.",
   "shade": "C6E0B4"
  },
  {
   "id": "M10",
   "domain": "Medical & hormonal",
   "factor": "Chronic pain",
   "direction": "Risk",
   "evidence": "Robust",
   "mechanism": "Shared inflammatory pathways (IL-6/CRP), central sensitisation, disrupted reward circuitry.",
   "finding": "Depression-pain comorbidity is 30-50%; bidirectional.",
   "confounders": "Sleep loss, disability, opioids.",
   "note": "",
   "detail": "Treating one often helps the other; a high-burden, under-counted cause.",
   "shade": "D9EAD3"
  },
  {
   "id": "M11",
   "domain": "Medical & hormonal",
   "factor": "Medication-induced depression",
   "direction": "Risk",
   "evidence": "Moderate",
   "mechanism": "Certain drugs perturb monoamines, HPA axis or retinoic-acid signalling.",
   "finding": "Corticosteroids, interferon, some beta-blockers, isotretinoin and hormonal agents carry depression signals.",
   "confounders": "Confounding by indication; signal varies by drug.",
   "note": "",
   "detail": "An iatrogenic cause worth screening for — especially isotretinoin in adolescents.",
   "shade": "FFF2CC"
  },
  {
   "id": "X01",
   "domain": "Lifestyle",
   "factor": "Whole-body hyperthermia / sauna",
   "direction": "Protective",
   "evidence": "Emerging",
   "mechanism": "Heat triggers an IL-6 response that may shift inflammatory signalling and lift mood.",
   "finding": "A double-blind RCT: the IL-6 response to whole-body hyperthermia predicted symptom reduction.",
   "confounders": "Small samples; mechanism provisional.",
   "note": "",
   "detail": "A novel, scalable, biologically-grounded protective lever.",
   "shade": "FCE5CD"
  },
  {
   "id": "X02",
   "domain": "Lifestyle",
   "factor": "Bright-light therapy",
   "direction": "Protective",
   "evidence": "Robust",
   "mechanism": "Entrains circadian rhythm via the SCN, suppresses nocturnal melatonin, raises serotonergic tone.",
   "finding": "Robust for seasonal depression; 2024 meta-analysis supports non-seasonal MDD too (~41% remission).",
   "confounders": "Adherence; timing matters.",
   "note": "",
   "detail": "Low-cost, low-harm; under-used beyond seasonal depression.",
   "shade": "D9EAD3"
  },
  {
   "id": "X03",
   "domain": "Psychosocial",
   "factor": "Purpose & meaning in life",
   "direction": "Protective",
   "evidence": "Robust",
   "mechanism": "Coherent life narrative engages vmPFC and dampens HPA reactivity; buffers stress.",
   "finding": "UK Biobank (n~153k): higher meaning linked to lower mortality, effect present even with depression.",
   "confounders": "Reverse causation possible.",
   "note": "",
   "detail": "Interventionable (meaning-centred therapy) with unusually large effect sizes.",
   "shade": "D9EAD3"
  },
  {
   "id": "X04",
   "domain": "Lifestyle",
   "factor": "Breathwork / HRV biofeedback",
   "direction": "Protective",
   "evidence": "Moderate",
   "mechanism": "Slow breathing shifts autonomic tone to parasympathetic, lowers cortisol, calms limbic reactivity.",
   "finding": "Meta-analyses (RCTs): medium effect sizes for depression and HRV improvement.",
   "confounders": "Heterogeneous protocols.",
   "note": "",
   "detail": "Free, scalable, mechanistically coherent; distinct from mindfulness.",
   "shade": "FFF2CC"
  },
  {
   "id": "L08",
   "domain": "Lifestyle",
   "factor": "Coffee / caffeine",
   "direction": "Mixed",
   "evidence": "Moderate",
   "mechanism": "Adenosine antagonism raises dopamine/alertness; also raises cortisol and, in sensitive people, anxiety; disrupts sleep if consumed late.",
   "finding": "Moderate coffee is associated with ~24-28% LOWER depression risk (J-shaped, peak ~4 cups), but high or late-day caffeine raises cortisol, anxiety/panic and impulsivity.",
   "confounders": "Reverse causation (anxious/poor sleepers cut back); genetics (CYP1A2, ADORA2A).",
   "note": "Nuance: moderate coffee is net protective for depression; harms (anxiety, cortisol, poor sleep, impulsive decisions) concentrate at high doses, late timing, and in caffeine-sensitive or anxiety-prone people.",
   "detail": "Meta-analyses (~347k people): coffee RR~0.76, caffeine RR~0.72 vs lowest intake; protection plateaus/reverses above ~400 mg/day. Caffeine reliably raises plasma cortisol and is panicogenic at ~5 cups, with ~54% of panic-disorder patients reacting vs ~2% of controls. Nighttime caffeine increases motor impulsivity and impairs inhibitory control; the main indirect harm is sleep disruption, itself a strong depression driver.",
   "shade": "FFF2CC"
  }
 ]
}