Medicine & USMLE

Tricyclic Antidepressants (TCAs)

Psych Pharm
  1. Lithium
  2. Typical Antipsychotics
  3. Atypical Antipsychotics
  4. SSRIs
  5. SNRIs
  6. Tricyclic Antidepressants (TCAs)
  7. Monoamine Oxidase Inhibitors (MAOIs)
  8. Bupropion
  9. Mirtazapine
  10. Trazadone
  11. Vilazodone
  12. Vortioxetine
  13. Buspirone
  14. Varenicline


TCAs are a class of medications that commonly end in -ipramine and -triptyline, including imipramine, clomipramine, amitriptyline, and nortriptyline. These drugs increase levels of serotonin and norepinephrine signaling in the brain by blocking the reuptake of these neurotransmitters from neuronal synapses. Clinically, TCAs are the second-line treatment for depression, and are also used to treat neuropathic pain and are used as a prophylaxis for migraines and tension headaches. These drugs are classically associated with anticholinergic effects and cardiotoxicity, especially in the case of overdose. Remember that overdose symptoms can be reversed with sodium bicarbonate.

Key Points

  • Tricyclic Antidepressants (TCAs)
    • Drug Names (-ipramine, -triptyline):
      • Secondary amine TCAs
        • Nortriptyline
        • Desipramine
        • Amoxapine
      • Tertiary amine TCAs
        • Amitriptyline
        • Clomipramine
        • Imipramine
        • Doxepin
    • Mechanism
      • Block serotonin (5-HT) and norepinephrine reuptake
        • Therefore increases serotonin and norepinephrine levels in the synaptic cleft
      • Block alpha-1 adrenergic receptors
      • Anticholinergic
      • Antihistaminic
    • Indications:
      • Major depressive disorder
        • Now second-line after SSRIs and SNRIs due to side effects
      • Neuropathic pain
        • Peripheral neuropathy
        • Diabetic neuropathy
        • Chronic neuropathic pain
          • E.g. for fibromyalgia, multiple sclerosis
      • Headache prophylaxis
        • Amitriptyline is often used for migraine and tension headache prophylaxis
      • OCD (clomipramine)
      • Nocturnal enuresis (imipramine)
    • Adverse effects
      • Treat acute overdose with NaHCO3
        • Acute overdose presents with severe anticholinergic symptoms, arrhythmias, seizures, and hypotension (same as side effects below)
        • Theorized that the Na+ helps to relieve Na+ channel blockade
      • Anticholinergic effects
        • More likely with tertiary amines
        • Eg. tachycardia, confusion, constipation, urinary retention, dry mouth, increase in pupil size (mydriasis), dry skin
        • Avoid in elderly (may induce delirium) or in patients with BPH (due to urinary retention)
      • Cardiotoxicity
        • Cardinal sign of acute intoxication
        • Generally occur due to Na+ channel inhibition
        • May present as prolonged QT, prolonged QRS, torsades de pointes
      • Seizures (convulsions)
        • Often seen in acute intoxication
        • TCAs lower seizure threshold
        • Avoid in patients with seizure hx
      • Orthostatic hypotension
        • From blockade of alpha-1 adrenergic receptors
      • Sedation
        • Thought to be from antihistaminic effects
      • Serotonin syndrome
        • Due to anti-serotonergic effects
      • Antidepressant discontinuation syndrome