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TOBIN Intelligence Library · evidence review

Depressive & Anxiety Disorders

Mood symptoms are organized, not explained away. Sleep, stress, medications, endocrine factors, nutrient status, metabolic dysfunction, inflammation, substance use, social determinants and exposures are each examined as possible contributors, with validated screening and escalation built in.

Depressive & Anxiety Disorders on TOBINintel.org →

What is well established

2 links
  • Chronic sleep restriction → Mood symptom severityA

    Experimental sleep restriction worsens affect; insomnia treatment improves depressive symptoms.

    Randomized evidence · Multiple high-quality guidelines or meta-analyses

  • Thyroid dysfunction → Depressive presentationA

    Hypothyroidism can present with depressed mood and reverses with treatment.

    Established causal · Multiple high-quality guidelines or meta-analyses

What is suspected, not proven

2 links
  • Systemic inflammation → Anhedonia and fatigueB

    Cytokine-induced behavior change is well described; causal direction in primary depression is unsettled.

    Open question: the association may reflect confounding or reverse causation; intervention trials would settle it.

  • B12, folate or iron deficiency → Fatigue and low moodB

    Deficiency states produce overlapping symptoms and should be corrected before attribution.

    Open question: the association may reflect confounding or reverse causation; intervention trials would settle it.

iDetection of an exposure does not establish that it caused a disease. This platform separates exposure, association, plausible mechanism, clinical evidence and demonstrated causation.

Domain emphasis

B Hormonal Balance · 0.8I Inflammation & Infection · 0.7N Nutrition · 0.7O Oxidative Stress · 0.6T Toxins · 0.5

Gut–brain microbial hypotheses are presented as exploratory. No antimicrobial or probiotic protocol is framed as a treatment for a mood disorder.

Related Quadpandemics

  • I · Estrogen & Endocrine Disruption

    Endocrine-active chemicals are widely measurable in the population; their health effects must be evaluated exposure by exposure.

  • II · Obesity & Metabolic Dysfunction

    Obesity is a signaling and exposure problem, not a number on a scale.

  • III · Allergy & Immune Dysregulation

    Allergic and immune-complex disease is the fastest-rising chronic burden of the century.

  • IV · Anxiety, Depression & Neurobehavioral Health

    Mood symptoms are assessed responsibly — never automatically attributed to toxins or hormones.

Labs that inform this review

  • Fasting insulin (2.0–8.0 µIU/mL) — Insulin signaling load; pairs with glucose for HOMA-IR. Marked elevation with symptoms warrants clinician review.
  • ApoB (< 90 (lower if high risk) mg/dL) — Atherogenic particle count; better risk discrimination than LDL-C alone. Persistently high values deserve a cardiovascular risk discussion.
  • hs-CRP (< 1.0 mg/L) — Non-specific inflammatory burden. Values above 10 mg/L usually indicate an acute process needing evaluation.
  • TSH (0.4–4.0 mIU/L) — First-line thyroid signaling test. Any abnormal result should be confirmed and reviewed clinically.
  • Estradiol (Cycle- and sex-dependent pg/mL) — Central to Pandemic I assessment, interpreted with cycle timing. Interpretation requires a clinician who knows your cycle and medication context.
  • Free T4 (0.8–1.8 ng/dL) — Circulating thyroid hormone; confirms whether an abnormal TSH reflects true thyroid under- or over-function. Low free T4 with symptoms, or any high value with palpitations, needs clinician review promptly.
  • Free T3 (2.3–4.2 pg/mL) — Active thyroid hormone, formed mostly by conversion of T4 in tissues. High free T3 with low TSH suggests hyperthyroidism — see a clinician.
  • Reverse T3 (9–24 ng/dL) — Inactive T4 metabolite that rises in stress, illness and calorie restriction. Do not change thyroid medication on rT3 alone; discuss with a clinician.
  • Anti-TPO antibodies (< 35 (assay-specific) IU/mL) — Thyroid peroxidase antibodies — the main marker of autoimmune (Hashimoto's) thyroiditis. Positive antibodies in pregnancy or with rising TSH deserve clinician follow-up.
  • Thyroglobulin antibodies (≤ 4 (assay-specific) IU/mL) — Second autoimmune thyroid marker; occasionally positive when anti-TPO is negative. Review with a clinician alongside TSH and free T4.
  • Lp-PLA2 activity (≤ 123 nmol/min/mL) — Vascular-specific inflammatory enzyme (PLAC test, FDA-cleared). Review with a clinician as part of cardiovascular risk.

Score cutoffs used

  • HbA1c ADA Standards of Care: 5.7–6.4% prediabetes, ≥6.5% diabetes range
  • Fasting insulin Common functional reference; interpret only with a true fasting sample
  • hs-CRP AHA/CDC: <1 lower, 1–3 average, >3 higher cardiovascular-inflammatory risk; >10 suggests acute process
  • TSH ATA/Endocrine Society: 0.4–4.5 mIU/L; >10 overt range
  • Ferritin AGA 2020: ferritin <45 ng/mL supports iron deficiency; WHO <15 depleted
  • Eosinophils (absolute) >500 cells/µL eosinophilia; ≥1500 hypereosinophilia
  • Total IgE Adult reference typically <100 IU/mL; context-dependent
  • White blood cells Reference ≈ 4.0–11.0 ×10³/µL
  • Free T4 Typical reference 0.8–1.8 ng/dL (assay-specific); interpret with TSH (ATA)
  • Free T3 Typical reference 2.3–4.2 pg/mL; low T3 also occurs in illness and calorie restriction
  • Reverse T3 Typical reference 9–24 ng/dL; guidelines (ATA) do not recommend rT3 for routine diagnosis — grade D
  • Anti-TPO antibodies Common cutoff >34–35 IU/mL (assay-specific); marks Hashimoto's risk (ATA)
  • Thyroglobulin antibodies Common cutoff ≤4 IU/mL (Roche) — assay-specific; positive in ~60–80% of Hashimoto's
  • Small LDL-P NMR LipoProfile: ≤527 nmol/L reference
  • LDL particle size NMR: >20.5 nm pattern A, ≤20.5 pattern B
  • sdLDL-C (small dense LDL) Denka assay (Quest Cardio IQ, Boston Heart): <30 mg/dL optimal (lab-specific)
  • Lp-PLA2 activity PLAC Activity test (FDA-cleared): >123 nmol/min/mL higher risk

Key formulas and thresholds

Published clinical cutoffs
  • HOMA-IR = fasting glucose (mg/dL) × fasting insulin (µIU/mL) ÷ 405 — above 2.5 suggests insulin resistance (Matthews 1985).
  • BMI = weight (kg) ÷ height (m)² — 25–29.9 overweight, 30 or more obesity (WHO); lower cutoffs (23/27.5) for many Asian populations.
  • Waist-to-height ratio = waist ÷ height — 0.5 or more signals central adiposity (NICE 2022).
  • TG/HDL ratio = triglycerides ÷ HDL (mg/dL) — above 3 is associated with insulin resistance (observational).
  • HbA1c (%): concern above 5.6, scored 100 at 8 — ADA Standards of Care: 5.7–6.4% prediabetes, ≥6.5% diabetes range
  • Fasting insulin (µIU/mL): concern above 8, scored 100 at 40 — Common functional reference; interpret only with a true fasting sample
  • hs-CRP (mg/L): concern above 1, scored 100 at 10 — AHA/CDC: <1 lower, 1–3 average, >3 higher cardiovascular-inflammatory risk; >10 suggests acute process
  • TSH (mIU/L): concern above 4.5, scored 100 at 20; concern below 0.4, scored 100 at 0.01 — ATA/Endocrine Society: 0.4–4.5 mIU/L; >10 overt range
  • Ferritin (ng/mL): concern below 30, scored 100 at 5; concern above 300, scored 100 at 1000 — AGA 2020: ferritin <45 ng/mL supports iron deficiency; WHO <15 depleted
  • Eosinophils (absolute) (cells/µL): concern above 500, scored 100 at 3000 — >500 cells/µL eosinophilia; ≥1500 hypereosinophilia
  • Total IgE (IU/mL): concern above 100, scored 100 at 1000 — Adult reference typically <100 IU/mL; context-dependent
  • White blood cells (×10³/µL): concern above 11, scored 100 at 20 — Reference ≈ 4.0–11.0 ×10³/µL
  • Free T4 (ng/dL): concern below 0.9, scored 100 at 0.5; concern above 1.8, scored 100 at 3.5 — Typical reference 0.8–1.8 ng/dL (assay-specific); interpret with TSH (ATA)
  • Free T3 (pg/mL): concern below 2.5, scored 100 at 1.8; concern above 4.4, scored 100 at 7 — Typical reference 2.3–4.2 pg/mL; low T3 also occurs in illness and calorie restriction
  • Reverse T3 (ng/dL): concern above 24, scored 100 at 40 — Typical reference 9–24 ng/dL; guidelines (ATA) do not recommend rT3 for routine diagnosis — grade D
  • Anti-TPO antibodies (IU/mL): concern above 34, scored 100 at 500 — Common cutoff >34–35 IU/mL (assay-specific); marks Hashimoto's risk (ATA)
  • Thyroglobulin antibodies (IU/mL): concern above 4, scored 100 at 200 — Common cutoff ≤4 IU/mL (Roche) — assay-specific; positive in ~60–80% of Hashimoto's
  • Small LDL-P (nmol/L): concern above 527, scored 100 at 1000 — NMR LipoProfile: ≤527 nmol/L reference
  • LDL particle size (nm): concern below 20.5, scored 100 at 19.5 — NMR: >20.5 nm pattern A, ≤20.5 pattern B
  • sdLDL-C (small dense LDL) (mg/dL): concern above 30, scored 100 at 60 — Denka assay (Quest Cardio IQ, Boston Heart): <30 mg/dL optimal (lab-specific)
  • Lp-PLA2 activity (nmol/min/mL): concern above 123, scored 100 at 225 — PLAC Activity test (FDA-cleared): >123 nmol/min/mL higher risk

iThese thresholds organize where to look; they do not diagnose. Laboratory ranges, age, sex and pregnancy change interpretation.

Published sources

Guidelines and landmark studies
Protocols for Depressive & Anxiety DisordersCalculate my TOBIN scoresAll reviews