Tricyclic antidepressants

Tricyclic antidepressants

This graphic shows the pharmacological activity of many of the tricyclic antidepressants (TCA). Like the SSRI's, the tricyclic's mechanism of action seems to work in stages (stage 1-4). However, the difference is that the tricyclic antidepressants can block either the serotonin or norepinephrine transporter, or both.

The receptor affinity profile of amitriptyline (shown in the pie chart) is used as a representative of this class of agents. Amitriptyline was chosen as it demonstrates the lack of specificity that the SSRI's provide. Other tricyclic antidepressants include clomipramine, imipramine, nortriptyline.

Due to this lack of specificity, the clinician should monitor the patient for the emergence of side effects from the blockade of muscarinic, histaminergic and alpha-adrenergic receptors. Anti-cholinergic side effects include e.g. dry mouth, dizziness, constipation, tachycardia, excessive perspiration and miction problems.


Orthostatic hypotension and dizziness are caused by the anti-α1 adrenergic effects of TCAs. The anti-histaminergic effects result in sedation.

The strong affinity that tricyclic antidepressants have for various receptors is also a cause for concern for safety as large or multiple doses can lead to significant toxic effects (i.e. muscarinic blockade: confusion and blockade of fast sodium channels (via a quinidine-like effect): cardiac arrhythmias).

Antidepressants in general may produce a discontinuation syndrome (characterised by restlessness, sleeping problems, GI-complaints, and flu-like symptoms), which can be managed by a gradual reduction in dosage over a period of weeks or months.


The principle mechanism of antidepressant action for TCA’s is the blockade of muscarinic1 receptors. 


In contrast to the SSRI’s, TCA’s block the 5-HT and or NE transporter only at the neuronal synapse. 


The most harmful action in an overdose from TCA’s is due to the blockade of the 5-HT transporter. 


TCA’s are typically very sedating due to histamine1 antagonism and thus, should be taken at night.