Depression has a biochemical signature. So do thyroid disease, iron deficiency, and cortisol dysregulation. Those signatures overlap in ways that are clinically meaningful and frequently missed - not because clinicians aren't careful, but because the standard depression workup doesn't include the labs that would catch them.
This is not an argument against antidepressants. It is an argument for biological completeness before treatment. A woman presenting with fatigue, low mood, anhedonia, and disrupted sleep could have major depressive disorder, hypothyroidism, ferritin below 20 ng/mL, or elevated evening cortisol. The treatment for each is different. Running the labs first costs less than a mismatched prescription and a year of wondering why it isn't working.
Mimic 1: Thyroid - especially Free T3
Hypothyroidism is the closest biochemical analogue to depression. Slowed metabolism produces exactly the constellation that fills DSM criteria: low energy, slowed thinking, reduced motivation, flat affect, impaired concentration, weight gain, disturbed sleep. When subclinical - normal TSH, low-normal Free T3 - it is often invisible on a standard workup.
The symptom profile that distinguishes thyroid from primary depression: cold intolerance, constipation, hair thinning at the outer third of the eyebrows, dry skin, slow pulse, and hoarseness. These aren't always present, but their clustering alongside mood symptoms should prompt a full thyroid cascade, not just TSH.
Mimic 2: Cortisol dysregulation
The HPA axis and the mood regulatory system are not separate circuits - they are deeply intertwined. Elevated evening cortisol suppresses melatonin, fragments sleep, and increases amygdala reactivity (emotional hyperarousal). Blunted morning cortisol, the hallmark of HPA exhaustion, produces anhedonia and motivational flatness that is phenomenologically indistinguishable from melancholic depression.
Critically, standard depression screening - PHQ-9, HAM-D - does not distinguish between primary mood disorder and HPA dysregulation. Both produce the same scores. A four-point diurnal cortisol test is the only way to characterise the underlying pattern. Treatment implications diverge: HPA dysregulation responds to circadian anchoring, adaptogenic support, and stress-load reduction; primary depression requires psychiatric intervention.
Mimic 3: Iron - specifically ferritin
Dopamine and serotonin synthesis both require iron as a cofactor - specifically in the hydroxylase enzymes that produce these neurotransmitters. Iron deficiency impairs monoamine metabolism at the root. The result is a neurochemical environment that resembles what antidepressants are designed to correct - but one that won't respond to SSRIs because the substrate problem is upstream of the serotonin transporter.
A 2003 study found that depression scores in women with ferritin below 20 ng/mL were statistically indistinguishable from those with clinical depression on the Beck Depression Inventory. Correcting ferritin to functional levels (above 50 ng/mL) improved mood scores significantly in some trials - not as a cure for depression, but as a resolution of the biochemical floor that prevented recovery.
The full workup before escalating treatment
- TSH + Free T3 - screen for hypothyroidism and low-T3 syndrome.
- Ferritin - target >50 ng/mL; below 20 is significant in a mood context.
- 4-point salivary cortisol - characterise the diurnal pattern before attributing to primary depression.
- Vitamin D (25-OH) - deficiency strongly associated with SAD and contributes to low mood year-round.
- Vitamin B12 - deficiency produces neuropsychiatric symptoms including depression and cognitive impairment.
This is not either/or
Biological mimics and primary psychiatric depression coexist. Hashimoto's and depression co-occur more frequently than chance. Low ferritin and PMDD frequently overlap. Correcting the biochemical substrate doesn't cure depression - but missing it means every antidepressant trial runs with one hand tied. The baseline labs are not an alternative to psychiatric care; they are the floor it rests on.