Anxiety & Depression: The Functional Medicine Approach

Beyond the Serotonin Myth

For three decades, depression was explained with a cartoon: your brain is low in serotonin, and this pill raises it. Take it and feel better. The “chemical imbalance” theory was elegant, simple, and — as Moncrieff et al. demonstrated in their landmark 2022 umbrella review — not supported by the evidence. There is no consistent finding of serotonin depletion in depressed patients. SSRIs work for some people, but the reason they work is likely not what we were told.

This is not an anti-medication position. Psychiatric medications save lives. But when you tell someone their brain is broken and a pill is the only fix, you close the door on twenty other doors that might actually lead to resolution. Functional medicine opens them.

Depression and anxiety are not serotonin problems. They are multi-system disorders involving inflammation, gut-brain signaling, hormonal disruption, mitochondrial dysfunction, nutrient depletion, methylation errors, and nervous system dysregulation. The IFM approach systematically evaluates each of these nodes.

IFM Root Causes

Inflammation: The Cytokine Theory of Depression

This is perhaps the most important paradigm shift in psychiatry in the last two decades. Pro-inflammatory cytokines — TNF-alpha, IL-6, IL-1-beta — cross the blood-brain barrier and activate microglia (the brain’s resident immune cells). Activated microglia upregulate indoleamine 2,3-dioxygenase (IDO), which shunts tryptophan down the kynurenine pathway instead of the serotonin pathway. The result: less serotonin, more quinolinic acid (a potent excitotoxin that damages neurons via NMDA receptor overactivation).

The clinical implications are concrete: hs-CRP greater than 3 mg/L predicts poor SSRI response (Uher 2014). Inflamed patients do not respond to serotonin drugs because their problem is not serotonin — it is inflammation stealing tryptophan. These patients respond better to anti-inflammatory interventions: omega-3, curcumin, celecoxib (multiple RCTs show antidepressant augmentation), exercise, and addressing the source of inflammation.

Gut-Brain Axis

Ninety-five percent of the body’s serotonin is manufactured in the gut by enterochromaffin cells. The gut microbiome directly modulates this production, produces GABA and dopamine, regulates the vagus nerve, and controls intestinal permeability (which determines how much inflammatory cargo reaches the brain).

Specific microbiome signatures are found in depression: depleted Lactobacillus, Bifidobacterium, and Faecalibacterium prausnitzii (a butyrate producer with anti-inflammatory properties). GI-MAP testing reveals actionable dysbiosis patterns.

Psychobiotics — probiotics with demonstrated mental health effects:

• L. rhamnosus JB-1: Reduced anxiety and depression behaviors in animal studies, modulated GABA receptors via the vagus nerve (Bravo 2011). Human studies ongoing.
• L. helveticus R0052 + B. longum R0175: Messaoudi 2011 — reduced salivary cortisol, reduced anxiety and depression scores in healthy volunteers.
• B. longum 1714: Allen 2016 — reduced cortisol response to stress and improved memory in humans.

Blood Sugar Dysregulation

Reactive hypoglycemia produces symptoms identical to a panic attack: racing heart, trembling, sweating, dizziness, derealization. Many anxiety patients are actually experiencing blood sugar crashes. The mechanism: after a high-glycemic meal, insulin overshoots, glucose plummets, and the adrenal glands dump adrenaline and cortisol to rescue blood sugar. The person interprets this adrenaline surge as anxiety.

Longer-term: insulin resistance leads to brain insulin resistance. The brain becomes energy-starved. Neuroinflammation increases. HbA1c correlates directly with depression incidence in population studies.

Thyroid

Subclinical hypothyroidism is one of the most commonly missed drivers of depression and anxiety. Most physicians check only TSH and maybe total T4. This misses the critical piece: Free T3 — the active thyroid hormone. T3 receptors are densely concentrated in the hippocampus (memory, mood) and amygdala (emotional processing). A person can have a “normal” TSH with low Free T3 and be profoundly depressed.

Many cases of “treatment-resistant depression” are simply missed thyroid dysfunction. A full thyroid panel — TSH, Free T4, Free T3, reverse T3, TPO antibodies, thyroglobulin antibodies — should be standard in every psychiatric evaluation. It rarely is.

Hormonal Drivers

• Low progesterone: Progesterone’s metabolite allopregnanolone is a potent GABA-A receptor modulator — it is essentially a natural benzodiazepine. When progesterone drops premenstrually or during perimenopause, GABA-A activation drops, and anxiety surges. This is why brexanolone (synthetic allopregnanolone) was FDA-approved for postpartum depression.
• Low testosterone: In men, testosterone deficiency drives depression, fatigue, cognitive fog, and loss of motivation. Testosterone replacement in hypogonadal men has antidepressant effects.
• Estrogen fluctuations: Estrogen modulates serotonin receptors. Rapid fluctuations (perimenopause, postpartum) destabilize mood. Stable levels — even low stable levels — are tolerated. It is the volatility that breaks things.
• High cortisol: Chronic stress → sustained cortisol → hippocampal atrophy (the hippocampus is studded with cortisol receptors, and chronic exposure literally shrinks it) → depression and impaired memory.

Nutrient Deficiencies

• B12: Deficiency causes depression, cognitive decline, fatigue. Check MMA (methylmalonic acid) — it elevates before B12 drops below range.
• Folate: Essential for methylation → neurotransmitter synthesis. RBC folate is the better marker.
• Vitamin D: Less than 20 ng/mL doubles depression risk. Vitamin D modulates over 200 genes including those involved in serotonin synthesis.
• Magnesium: NMDA receptor modulation, calming. Tarleton 2017: magnesium supplementation was as effective as imipramine for mild-to-moderate depression.
• Zinc: Drives BDNF (brain-derived neurotrophic factor), anti-inflammatory. Low zinc is consistently associated with depression. Siwek 2009: zinc augments SSRI response.
• Iron: Cofactor for tyrosine hydroxylase — the rate-limiting enzyme in dopamine synthesis. Low ferritin (even with “normal” hemoglobin) → low dopamine → apathy, low motivation.
• Omega-3: EPA is anti-inflammatory (quiets the cytokine-driven kynurenine pathway). DHA maintains neuronal membrane fluidity. Omega-3 index below 4% is associated with increased depression risk.

MTHFR and Methylation

Methylation is the process by which the body attaches methyl groups (-CH3) to DNA, neurotransmitters, hormones, and detox intermediates. S-adenosylmethionine (SAMe) is the universal methyl donor. It is required for the synthesis of serotonin, dopamine, norepinephrine, and melatonin.

William Walsh’s methylation-based approach (from his book “Nutrient Power”) classifies patients as:

• Undermethylators: Low SAMe, low serotonin/dopamine/norepinephrine production. Tend toward depression, OCD, perfectionism, high achievement, seasonal allergies, competitive. Benefit from: SAMe 400-1600mg/day, methionine 1-2g, methylfolate 800-15000mcg, B12 methylcobalamin, zinc.
• Overmethylators: Excess neurotransmitters but also excess anxiety, panic, food/chemical sensitivities. Benefit from: niacinamide 500-1500mg, folic acid (NOT methylfolate), B12, manganese.

Pyrrole Disorder

Elevated urinary hydroxyhemopyrrolin-2-one (HPL) causes obligatory zinc and B6 wasting through the kidneys. The result: low GABA (anxiety), low serotonin (depression), poor stress tolerance, sensitivity to light and sound, poor dream recall, white marks on nails, stretch marks without pregnancy. Testing: urinary kryptopyrroles. Treatment: zinc 30-60mg + B6/P5P 50-100mg + evening primrose oil (GLA replaces the arachidonic acid lost with zinc/B6).

Comprehensive Testing

• CBC, CMP (liver, kidney, electrolytes)
• hs-CRP, ESR (inflammation)
• Homocysteine (methylation)
• Full thyroid panel: TSH, Free T4, Free T3, reverse T3, TPO-Ab, Tg-Ab
• Fasting insulin + glucose, HbA1c
• Vitamin D (25-OH)
• B12 + methylmalonic acid
• RBC folate
• RBC magnesium (serum is inadequate)
• Zinc + copper (ratio matters — high copper/low zinc = anxiety, depression)
• Ferritin, iron panel
• DUTCH Complete (cortisol pattern through the day, sex hormones, metabolites)
• OAT: Neurotransmitter metabolites — HVA (dopamine), VMA (norepinephrine), 5-HIAA (serotonin), quinolinic acid (excitotoxin from kynurenine pathway)
• GI-MAP (gut dysbiosis, pathogens, inflammation)
• Omega-3 index
• Genetic panel: MTHFR, COMT, MAO-A
• Urinary pyrroles (if pyrrole disorder suspected)

Protocol: Address Root Causes

Anti-Inflammatory Layer

• Omega-3 (EPA-dominant): 2-3g/day. Sublette 2011 meta-analysis: EPA must constitute at least 60% of the omega-3 for antidepressant effect. DHA alone is less effective. EPA specifically blocks IDO, protecting the serotonin pathway.
• Curcumin: 1000mg/day (bioavailable form — phytosomal, nano, or with piperine). Lopresti 2014: comparable to fluoxetine for major depression, and the combination of curcumin + fluoxetine was best.
• NAC (N-acetylcysteine): 1200-2400mg/day. Modulates glutamate (reduces excitotoxicity), replenishes glutathione, reduces rumination. Evidence in depression, OCD, bipolar, addiction.

Gut Layer

Psychobiotics (L. rhamnosus, B. longum, L. helveticus), gut healing 5R protocol, address SIBO and dysbiosis based on testing.

Nutrient Repletion

• Magnesium glycinate: 400mg/day
• Zinc: 25-50mg/day
• Vitamin D: 5000 IU/day (target 50-70 ng/mL)
• B-complex with methylated forms (methylfolate, methylcobalamin, P5P)
• Iron bisglycinate if ferritin below 50

Neurotransmitter Precursors (Based on OAT Testing)

Low serotonin (low 5-HIAA): 5-HTP 100-300mg/day or L-tryptophan 1-3g at bedtime. Always co-administer with B6/P5P (cofactor for decarboxylation). NEVER combine 5-HTP with SSRIs or SNRIs — serotonin syndrome risk is real and potentially fatal.

Low dopamine (low HVA): L-tyrosine 500-2000mg on an empty stomach in the morning. Mucuna pruriens 300mg (natural source of L-DOPA). Ensure adequate B6/P5P and iron — both are cofactors for tyrosine hydroxylase.

Low GABA: L-theanine 200-400mg (promotes alpha brain waves, calming without sedation), taurine 1-2g (GABA-A receptor agonist), pharmaGABA 100-200mg (crosses BBB in small amounts, calms), magnesium, passionflower extract 500mg (increases GABA availability), lemon balm 300-600mg (inhibits GABA transaminase — keeps GABA active longer).

Adaptogens

• Ashwagandha KSM-66: 600mg/day. Chandrasekhar 2012: reduced cortisol by 28%, reduced anxiety scores by 56%. Also modulates GABAergic activity and has thyroid-supporting properties.
• Saffron extract (affron): 30mg/day. Akhondzadeh 2005 and multiple subsequent RCTs: comparable to imipramine and fluoxetine for mild-moderate depression. The mechanism involves serotonin reuptake inhibition (like an SSRI) plus NMDA receptor modulation and anti-inflammatory effects.
• Rhodiola rosea: 400mg AM. Adaptogen for fatigue-related depression. Modulates cortisol, enhances stress resilience.

Targeted Interventions

• SAMe: 400-1600mg/day for undermethylators. Well-studied antidepressant that supports serotonin, dopamine, and norepinephrine synthesis simultaneously. Start low (200mg) and increase gradually.
• St. John’s Wort: 300mg 3x/day standardized to 0.3% hypericin. Linde 2008 Cochrane Review: comparable to SSRIs for mild-to-moderate depression. CRITICAL caution: St. John’s Wort is a potent CYP3A4 inducer with MANY drug interactions. Never combine with SSRIs/SNRIs (serotonin syndrome), birth control pills (reduces efficacy), warfarin, cyclosporine, HIV antiretrovirals, or chemotherapy agents.
• Lithium orotate: 5-20mg/day (this is micro-dose OTC lithium, not prescription lithium carbonate at 300-900mg). Neuroprotective, increases BDNF, increases gray matter volume, anti-suicidal. Regions with naturally higher lithium in drinking water have lower suicide rates.
• Hormonal: Address based on DUTCH — bioidentical progesterone for luteal-phase anxiety, optimize Free T3 for thyroid-driven depression, DHEA if adrenal output is low.

The Critical Safety Note

Never abruptly discontinue psychiatric medications. SSRI/SNRI withdrawal (akathisia, brain zaps, rebound anxiety, emotional instability) can be severe and is frequently misdiagnosed as relapse. Taper slowly — 10% dose reduction every 2-4 weeks is the emerging gold standard — under physician guidance. The functional approach works alongside existing medications and can facilitate gradual, supported tapering when the root causes have been addressed and the brain has been given the raw materials it needs.

The goal is not to replace one prescription with twenty supplements. The goal is to find what is driving the fire — inflammation, gut dysfunction, nutrient depletion, hormonal chaos, nervous system dysregulation — put the fire out, and watch the smoke clear.