Symptoms and management of TCA overdose is covered under Tricyclic Antidepressant Overdose.

Antidepressant drugs include:

  • Tricyclic Antidepressants (TCAs)
    Mechanism of action by multiple effects, including:
    • Competitively inhibit reuptake of NA and 5-HT
    • Muscarinic antagonism
      Leads to anticholinergic side effects (dry mouth, blurred vision, constipation, urinary retention).
    • H1 and H2 antagonism
    • α1 antagonism
    • NMDA antagonism
  • Selective Serotonin Reuptake Inhibitors (SSRIs)
    • Inhibit neural reuptake of 5-HT
    • Preferred over TCAs as:
      • Similar effectiveness
      • Better side effect profile
  • Monoamine Oxidase Inhibitors (MAO-Is)
    • Inhibit monoamine oxidase on external mitochondrial membrane, increasing the level of amine neurotransmitters in the CNS and PNS
      Two enzymes exist:
      • MAO-A
        • Dominant enzyme in CNS
        • Acts on serotonin, noradrenaline, adrenaline
      • MAO-B
        • Dominant in GIT and platelets
        • Responsible for 75% of MAO activity
        • Preferential metabolism of non-polar amines
    • MAO-Is classified by their mechanism and selectivity
      • Non-selective, irreversible
        Bind covalently to the enzyme, permanently inactivating it.
        • May lead to hypertensive crisis when catecholamine levels increased
          • Tyramine in food
            Metabolised by MAO-B.
          • Indirectly acting sympathomimetics
            Absolutely contraindicated.
        • Risk of serotonin syndrome with serotonin reuptake inhibitors
        • Include:
          • Phenelzine
          • Isocarboxazid
          • Tranylcypromine
        • Enzyme levels will take 2-3 weeks to recover following cessation
      • MAO-A selective, reversible
        • Hypertensive crisis is less common
          • MAO-B unaffected - tyramine is metabolised
          • Short acting
            Enzyme levels normalise after 24 hours of cessation.
        • Include:
          • Moclobemide
      • MAO-B selective
        • Much lower risk of hypertensive crisis
        • Include:
          • Selegiline
    • Discontinuation syndrome may occur if abruptly ceased
Property Tricyclic Antidepressants Selective Serotonin Reuptake Inhibitors Monoamine Oxidase Inhibitors
Example Amitriptyline Fluoxetine
Uses Depression, treatment of chronic pain and trigeminal neuralgia Depression, anxiety Treatment resistant depression. Now largely superseded due to side-effect profile
Absorption High PO bioavailability High PO bioavailability
Distribution Highly lipid soluble with High VD. Very highly protein bound - leads to interactions with warfarin, digoxin, and aspirin Highly protein bound, high VD
Metabolism Hepatic with active metabolites. Large interpatient variability Hepatic with non-linear kinetics

Venlafaxine does not affect CYP450 enzymes.
Elimination Unaffected by renal impairment
Resp Dry mouth
CVS Postural hypotension, ↑ HR.
QT prolongation and widening QRS in overdose, with arrhythmia more likely when QRS exceeds 0.16s.
Less cardiotoxic than TCAs, may precipitate serotonin syndrome
CNS Sedation, blurred vision, lowered seizure threshold. Excitation, followed by seizures and depression in overdose. Identical antidepressant effect to TCAs. Less sedation
Renal Urinary retention
GU Sexual dysfunction Greater incidence of sexual dysfunction compared with TCAs
GIT Constipation Greater incidence of N/V compared with TCAs
Other Multiple complex drug interactions, including arrhythmias and variable BP with sympathomimetics, central anticholinergic syndrome, serotonin syndrome, and seizures.

↑ Sensitivity to catecholamines - suggest avoiding:
-Indirectly acting sympathomimetics
-Surgical stress
Continue during perioperative period to avoid risk of discontinuation syndrome.

Serotonin Syndrome

Serotonin syndrome is excessive serotonin in the CNS, typically as a consequence of drug interactions. The syndrome may be mild, moderate, or severe, and presents with some or all of:

  • Altered mental state
    • Confusion
  • Motor changes
    • Myoclonus
    • Hyperreflexia
    • Tremor
  • Autonomic instability
    • Diaphoresis
    • Shivering
    • Fever

Serotonin syndrome is typically self-limiting and resolves with cessation of the drug.


  1. Petkov V. Essential Pharmacology For The ANZCA Primary Examination. Vesselin Petkov. 2012.
  2. Altamura AC, Moro AR, Percudani M. Clinical pharmacokinetics of fluoxetine. 1994 Mar;26(3):201-14.
  3. Bromhead H, Feeney A. Anaesthesia & Psychiatric Drugs - Antidepressants. Anaesthesia Tutorial of the Week (164). 2009.
Last updated 2019-07-18

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