Why do mood and anxiety symptoms so often have a physiological cause that gets missed?

What physiological systems affect mood and anxiety?

Several systems shape mood and anxiety symptoms:

• Hormonal. Progesterone is the body's natural calming hormone, acting on GABA receptors (the same receptors that anti-anxiety medications target). Its decline in perimenopause can produce sudden-onset anxiety in women with no prior history. Estrogen affects serotonin; declining estrogen contributes to depression and irritability. Low testosterone in men is strongly associated with depression. Thyroid dysfunction commonly presents as mood disorder
• Metabolic. Blood sugar instability produces panic-attack-like symptoms. Reactive hypoglycemia causes shakiness, palpitations, anxiety, irritability, and rapid heart rate, often misdiagnosed as anxiety disorder when the trigger is actually glucose volatility
• Gut-brain axis. 90% of serotonin and 50% of dopamine are produced in the gut. Gut dysbiosis, inflammation, and intestinal permeability directly affect neurotransmitter availability and mood
• Inflammatory. Chronic inflammation produces depressive symptoms through cytokine effects on neurotransmitter production and metabolism. The "inflammatory hypothesis" of depression has substantial supporting evidence
• Nutritional. B12 deficiency causes depression, anxiety, and cognitive symptoms. Magnesium deficiency contributes to anxiety and insomnia. Iron deficiency reduces dopamine production and contributes to depression. Vitamin D deficiency is associated with depression. Omega-3 inadequacy correlates with depression and anxiety
• Sleep. Sleep deprivation is one of the strongest mood destabilizers. Untreated sleep apnea commonly presents as depression, anxiety, or both
• Cortisol patterns. Both chronically elevated cortisol and the later-stage low cortisol patterns produce mood symptoms

What labs are useful for evaluating mood and anxiety physiologically?

A useful workup typically includes:

• Full thyroid panel with antibodies and reverse T3
• Sex hormones, especially relevant in perimenopause and andropause
• Fasting insulin and HOMA-IR, or CGM data for blood sugar patterns
• hs-CRP (a general inflammation marker)
• Vitamin D, B12 with methylmalonic acid
• Ferritin (the iron storage marker), RBC magnesium, omega-3 index
• Four-point cortisol or comprehensive cortisol metabolite assessment
• Depending on history: organic acids for neurotransmitter metabolism (specifically the kynurenine pathway and tryptophan metabolites), food sensitivities, gut health assessment

Many patients with mood symptoms have multiple drivers showing up simultaneously, and the pattern across markers tells a story that any single value couldn't.

How does the gut affect mood?

The gut-brain axis operates through multiple mechanisms:

• Neurotransmitter production. 90% of serotonin and 50% of dopamine are produced in the gut. Gut bacteria produce and metabolize these neurotransmitters and their precursors
• Inflammatory signaling. Inflammatory cytokines from gut tissue cross the blood-brain barrier and trigger neuroinflammation, which can present as depression, anxiety, or brain fog
• Vagal tone. The vagus nerve (the main communication highway between gut and brain) carries roughly 80% of its signals from gut to brain. Vagal tone affects digestion, heart rate variability, inflammation, and stress response
• Microbial metabolites. Short-chain fatty acids produced by gut bacteria affect brain function. Butyrate has direct neuroprotective effects

This is why patients with treatment-resistant mood disorders often benefit from gut evaluation alongside or before psychiatric treatment, particularly when symptoms are accompanied by gut symptoms.

Why are SSRIs and SNRIs not always the right first step?

SSRIs (selective serotonin reuptake inhibitors, like sertraline or escitalopram) and SNRIs (serotonin-norepinephrine reuptake inhibitors, like venlafaxine) have a legitimate role in treating mood and anxiety. They're not always the wrong choice.

The issue is when they're the first and only intervention without physiological investigation. Treating subclinical hypothyroidism, addressing hormonal shifts, restoring nutrient sufficiency, or resolving sleep apnea often produces meaningful mood improvement that medications alone wouldn't achieve. When medications are needed, they work better in a body whose underlying physiology is also being addressed.

The category of "treatment-resistant" depression often turns out to be physiologically-driven depression that hasn't been investigated. Patients who have failed multiple antidepressants frequently respond to interventions that address thyroid, hormones, inflammation, or metabolic dysfunction.

Could perimenopause be causing my new anxiety?

Women in their 40s presenting with new-onset anxiety or panic symptoms are often experiencing perimenopausal hormonal shifts, particularly progesterone decline. This isn't a primary anxiety disorder.

Progesterone has direct effects on GABA receptors, the brain's main calming system. As progesterone declines (often beginning in the mid-30s), the calming signal weakens, and anxiety can emerge in women who never had it before. Hormonal evaluation and appropriate treatment (often progesterone support) can resolve symptoms in ways that anti-anxiety medications cannot.

This pattern is genuinely common and frequently misdiagnosed as a primary psychiatric condition.

Could this be a thyroid problem?

Thyroid dysfunction commonly presents as mood disorder:

• Hypothyroidism (low thyroid function): depression, low motivation, brain fog, fatigue
• Hyperthyroidism (excess thyroid function): anxiety, panic, irritability, palpitations, insomnia

Both are misdiagnosed as primary psychiatric conditions. A full thyroid panel including TSH, free T4, free T3, reverse T3, and antibodies is essential when mood symptoms are prominent.

What's the right framework for mood and anxiety care?

Functional mental health care doesn't reject the role of psychiatry or psychotherapy. Both have value. The framework that works best:

1. Comprehensive physiological workup, especially when symptoms are new, when they accompany physical symptoms, or when standard treatments haven't worked
2. Address identifiable drivers (hormones, thyroid, nutrients, inflammation, sleep, gut, blood sugar) systematically
3. Use psychiatric medication when clinically appropriate, in coordination with psychiatric care
4. Combine with therapy when indicated
5. Monitor response and adjust

Skipping straight to medication without physiological investigation is what often leads to the "treatment-resistant" pattern.

The deeper picture

Mood and anxiety symptoms deserve a physiological workup, particularly when they're new, when they accompany other symptoms, or when standard treatments haven't produced sustained results. The drivers are often identifiable and responsive to intervention. Working with a physician who investigates the upstream causes alongside considering psychiatric care typically produces better outcomes than either approach alone. Extend takes this comprehensive view of mental health.