Pharmacology · CNS

Tricyclic Antidepressants and Monoamine Oxidase Inhibitors

Module 4 — Chapter 17: Antidepressant Drugs

The TCA receptor map in the infographic shows why this drug class has such a broad adverse effect profile: they block norepinephrine and serotonin transporters but also antagonize muscarinic receptors (anticholinergic toxicity), histamine H1 (sedation and weight gain), and alpha-1 adrenergic receptors (orthostatic hypotension) — each blocked receptor type predicts a specific symptom cluster that helps explain a TCA overdose presentation.
TCA overdose produces a recognizable toxidrome: QRS widening above 100 ms predicts ventricular arrhythmia risk; the R-wave in aVR above 3 mm is a sensitive ECG marker; sodium bicarbonate is the treatment — it alkalinizes the blood (reducing TCA binding to cardiac sodium channels) and increases protein binding, both reducing free drug; physostigmine should be avoided for seizures due to cardiac risk.
Despite being largely superseded for depression, TCAs retain important niche roles the infographic highlights: amitriptyline and nortriptyline for neuropathic pain and migraine prophylaxis (at sub-antidepressant doses), clomipramine as the most potent serotonergic TCA for OCD, and imipramine for childhood enuresis — knowing these keeps TCAs in the prescribing toolkit.
MAOIs are the most efficacious antidepressants for atypical depression (mood reactivity, hypersomnia, hyperphagia, leaden paralysis, rejection sensitivity) but are used last because of the tyramine interaction: dietary tyramine is normally metabolized by intestinal and hepatic MAO-A; with MAO-A inhibited, tyramine enters systemic circulation and displaces norepinephrine from sympathetic terminals, causing a hypertensive crisis.
The serotonin syndrome risk from MAOIs is equally critical: combining any irreversible MAOI with any serotonergic drug — SSRI, SNRI, meperidine, tramadol, linezolid, methylene blue — can be fatal; the 14-day washout in both directions applies to all irreversible MAOIs, and 5 weeks for fluoxetine before starting an MAOI.

Abbreviations: TCA = tricyclic antidepressant · MAOI = monoamine oxidase inhibitor · NET = norepinephrine transporter · SERT = serotonin transporter · MAO-A = monoamine oxidase type A · MAO-B = monoamine oxidase type B · RIMA = reversible inhibitor of MAO-A · OCD = obsessive-compulsive disorder · NE = norepinephrine · aVR = augmented vector right (ECG lead)

Tricyclic Antidepressant Receptor Profile — Mechanism to Adverse Effect

Receptor Blocked	Adverse Effects	Clinical Notes
Norepinephrine + serotonin transporters	Therapeutic antidepressant effect	Primary mechanism; nortriptyline and desipramine more norepinephrine-selective
Muscarinic (M1)	Dry mouth, urinary retention, constipation, blurred vision, cognitive impairment, tachycardia	Avoid in benign prostatic hyperplasia, glaucoma, elderly (Beers Criteria)
Histamine H1	Sedation, weight gain	Amitriptyline most potent H1 blocker; doxepin approved at very low dose for insomnia
Alpha-1 adrenergic	Orthostatic hypotension, dizziness, reflex tachycardia	Major fall risk in elderly; nortriptyline has least alpha-1 blockade
Cardiac sodium channels	QRS widening, arrhythmias (in overdose)	QRS >100 ms predicts arrhythmia; treat with sodium bicarbonate

TCA Overdose Management and Niche Indications

Overdose Toxidrome

TCA Overdose Recognition and Treatment

3 Cs: Coma, Convulsions, Cardiac arrhythmia
QRS >100 ms → arrhythmia risk; QRS >160 ms → ventricular tachycardia
R-wave in aVR >3 mm — sensitive ECG marker
Treatment: sodium bicarbonate IV (alkalinizes serum, reduces free drug, narrows QRS)
Avoid physostigmine (risk of asystole)
Benzodiazepines for seizures

Remaining Clinical Uses

TCA Niche Indications

Neuropathic pain: amitriptyline, nortriptyline (sub-antidepressant doses)
Migraine prophylaxis: amitriptyline, nortriptyline
OCD: clomipramine (most serotonergic TCA; used when SSRIs fail)
Childhood enuresis: imipramine
Insomnia: doxepin 3–6 mg (histamine blockade; approved for this)
Nortriptyline preferred in elderly (least anticholinergic, least orthostasis)

Monoamine Oxidase Inhibitors

Drug Classes and Selectivity

MAOI Classification

Irreversible, non-selective (MAO-A + MAO-B): phenelzine, tranylcypromine, isocarboxazid — most potent; highest dietary restrictions
Irreversible, MAO-B selective: selegiline (low dose for Parkinson disease; transdermal patch bypasses gut MAO-A, requires fewer dietary restrictions)
Reversible MAO-A inhibitor (RIMA): moclobemide (not available in US) — lower tyramine risk; serotonin syndrome risk lower
Best for: atypical depression, treatment-resistant depression

Tyramine Interaction

Hypertensive Crisis Mechanism and Foods

Normally: intestinal/hepatic MAO-A degrades dietary tyramine before systemic absorption
With MAOI: tyramine reaches systemic circulation, enters sympathetic terminals, displaces stored norepinephrine → massive sympathetic surge → hypertensive crisis
High-risk foods: aged cheeses, cured meats, fermented products, red wine, soy sauce, fava beans
Treatment: phentolamine IV (alpha-blocker) or nitroprusside

MAOI Safety Rules

Serotonin syndrome: never combine MAOI with SSRI, SNRI, meperidine, tramadol, linezolid, methylene blue, or dextromethorphan — potentially fatal. Washout rules: wait 14 days after stopping any irreversible MAOI before starting serotonergic drug; wait 14 days after stopping serotonergic drug before starting MAOI (except fluoxetine: wait 5 weeks). Wait 14 days after MAOI before starting any sympathomimetic.

Suggested References

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