Tricyclic Antidepressants and Monoamine Oxidase Inhibitors

Module 4 — Chapter 17: Antidepressant Drugs

Tricyclic Antidepressant Receptor Binding and Adverse Effects

Receptor Blocked	Effect	Clinical Consequences
Serotonin reuptake transporter + Norepinephrine reuptake transporter	Primary antidepressant mechanism	Therapeutic effect — same as serotonin-norepinephrine reuptake inhibitors in principle
Muscarinic acetylcholine (anticholinergic)	Parasympathetic blockade	Dry mouth, constipation, urinary retention, blurred vision, tachycardia, confusion/delirium in elderly (Beers Criteria)
Histamine H1 (antihistaminic)	Central sedation, appetite increase	Sedation (especially tertiary amines), weight gain; low-dose doxepin approved for insomnia
Alpha-1 adrenergic	Vasodilation, impaired vasoconstriction reflex	Orthostatic hypotension → syncope and falls; most dangerous during chronic use in elderly
Cardiac sodium channel (in overdose)	Slowed depolarization	Wide QRS, ventricular arrhythmia, death — defines overdose lethality

Overdose Management and Monoamine Oxidase Inhibitor Classification

Tricyclic Antidepressant Overdose

Management Priorities

Sodium bicarbonate for QRS > 100 ms or arrhythmia — do not wait
Target blood pH 7.45 to 7.55 with bicarbonate
Benzodiazepines for seizures
Avoid phenytoin — worsens cardiac toxicity
Hemodialysis is not effective (very large volume of distribution)
Continuous cardiac monitoring mandatory
Clinical deterioration can occur within 1 to 2 hours

Monoamine Oxidase Inhibitors

Classification

Non-selective irreversible: phenelzine, tranylcypromine, isocarboxazid — inhibit monoamine oxidase A and B permanently
Selective monoamine oxidase B (low dose): selegiline oral — Parkinson disease; loses selectivity at antidepressant doses
Selegiline transdermal (Emsam): bypasses gut monoamine oxidase A — reduced dietary restriction at lowest dose
Reversible monoamine oxidase A inhibitor: moclobemide (not available in United States) — reduced dietary risk; 24-hour washout only

Tyramine Pressor Response and Monoamine Oxidase Inhibitor Clinical Niche

Tyramine Interaction

Mechanism and Foods to Avoid

Normal: gut monoamine oxidase A degrades tyramine before it reaches circulation
With monoamine oxidase inhibitor: first-pass monoamine oxidase A inhibited → tyramine enters circulation → displaces norepinephrine from terminals → hypertensive crisis
Avoid: aged cheeses, cured meats, fermented fish, soy sauce, draft beer, Chianti, sauerkraut, fava bean pods
Safe: fresh cheeses, fresh unprocessed meats

Clinical Role

When Monoamine Oxidase Inhibitors Are the Answer

Atypical depression: mood reactivity, hypersomnia, hyperphagia, leaden paralysis, rejection sensitivity — monoamine oxidase inhibitors are superior to tricyclic antidepressants in controlled trials
Treatment-resistant depression: patients who have failed multiple other classes
Efficacy is not inferior — avoidance reflects interaction risk, not lack of effectiveness

Washout Periods — Monoamine Oxidase Inhibitors

After stopping irreversible monoamine oxidase inhibitor → wait 2 weeks before any selective serotonin reuptake inhibitor or serotonin-norepinephrine reuptake inhibitor. After stopping selective serotonin reuptake inhibitor or serotonin-norepinephrine reuptake inhibitor → wait 2 weeks before monoamine oxidase inhibitor. Exception: after stopping fluoxetine → wait 5 weeks (norfluoxetine active metabolite). Violation of washout periods can cause fatal serotonin syndrome.