Tricyclic Antidepressants (TCAs)

Indications For Use

Depression is associated with low levels of serotonin, dopamine, and noradrenaline in the brain. Tricyclic antidepressants increase the concentration of serotonin and noradrenaline at synaptic clefts, thereby improving mood.

However, due to their higher incidence of side effects, TCAs are not first-line treatments for depression and are generally reserved for cases where newer antidepressants (e.g. SSRIs) are ineffective or contraindicated.

Other Uses

TCAs, particularly amitriptyline, are widely used for neuropathic pain. Their efficacy in this indication is attributed to their ability to enhance serotonin and noradrenaline activity within descending pain-modulating pathways in the brain and spinal cord.

Mechanism of Action 

TCAs work by blocking the reuptake transporters for serotonin (5-HT) and noradrenaline (NA) at presynaptic nerve terminals. This increases synaptic concentrations of these neurotransmitters, potentiating their antidepressant and analgesic effects.

They are termed tricyclic because of their three-ring chemical structure.

Examples of TCAs:

• Amitriptyline
  
• Imipramine
  
• Clomipramine
  
• Dosulepin
  
• Nortriptyline

Additional Receptor Effects

TCAs are non-selective, and their activity at other receptor sites explains many of their side effects:

• Muscarinic receptor blockade → anticholinergic effects (dry mouth, constipation, blurred vision)
• Histamine (H₁) receptor blockade → sedation and weight gain
• α₁- and α₂-adrenergic receptor blockade → postural hypotension and dizziness

Imipramine and nortriptyline are less sedating compared with amitriptyline, clomipramine, and dosulepin.

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Fig 1: Mechanism of action of antidepressants. Close-up of neurons and synaptic cleft with neurotransmitters, Receptor, Mitochondria and MAO enzyme.

Cautions and Contraindications

Adverse effects

Interactions 

• Concomitant administration with medications that increase risk of serotonin syndrome 
• Drugs that cause QT prolongation & cause hyponatraemia 
• TCAs are primarily metabolised by CYP2D6 and CYP2C19, lesser extent CYP3A4 and CYP1A2
  • CYP2D6 inhibitors such as bupropion, fluoxetine, paroxetine, quinidine, fluconazole may increase TCA concentrations 
  • CYP3A4 inhibitors ketoconazole, itraconazole, ritonavir, diltiazem and verapamil may increase TCA concentrations
  • Inducers of CYP enzymes such as rifampicin, phenytoin, carbamazepine and St Johns wort may reduce TCA levels and reduce the response 
• TCAs block the action of centrally acting antihypertensives such as clonidine which activate 𝛼2- adrenergic receptors 

References

1. Onset of action of antidepressants | The BMJ
2. Antidepressant drugs | Treatment summaries | BNF | NICE
3. Nortriptyline 10 mg Film-coated Tablets – Summary of Product Characteristics (SmPC) – (emc) (medicines.org.uk)
4. Amitriptyline 10 mg Film-Coated Tablets – Summary of Product Characteristics (SmPC) – (emc) (medicines.org.uk)