19.01.5 Tricyclic Antidepressants

The tricyclic antidepressants (TCAs) are so named for their characteristic three-ringed molecular core. These drugs do not produce euphoria or dependence, and in depressed individuals they elevate mood, improve physical activity, appetite and sleep, and reduce rumination. The short term mechanism of action of all TCAs is blockade of presynaptic noradrenaline and serotonin high affinity reuptake transporters, which effectively increases availability of noradrenaline and serotonin in the synapse to act on pre- and post-synaptic noradrenergic and serotoninergic receptors. After many weeks of administration, tricyclic antidepressants downregulate -adrenoceptors and 5-HT₂ receptors, reducing the number and activity of these receptors. The time-course of this decrease in -adrenoceptors is in keeping with the delayed therapeutic effect. Postsynaptic 5-HT₁ receptors in the hippocampus are also increased with long-term tricyclic antidepressant use. Further, presynaptic ₂-adrenoceptors and 5-HT₁ autoreceptors, which control noradrenaline and serotonin release, are downregulated, facilitating release of these neurotransmitters.

TCAs also block muscarinic acetylcholine, histamine and serotonin (5-HT₂, 5-HT₃) receptors at therapeutic doses, leading to a number of side/adverse effects. These side effects include blurred vision, dry mouth, constipation, urinary retention, drowsiness, restlessness, insomnia, nausea, anorexia, diarrhoea, and disturbances of libido and potency. Most importantly, TCAs may cause adverse cardiovascular effects including hypotension, tachycardia and arrhythmias. These may become fatal in overdose through cardiotoxicity, and make the use of TCAs dangerous since the narrow therapeutic index allows for a relatively easy overdose.