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.
Extra info: Although amitriptyline has its strongest affinity for the M1-receptor, this does not lead to antidepressant effects. The principle mechanism of antidepressant action is blockade of the 5HT and NE transporters.
In contrast to the SSRI’s, TCA’s block the 5-HT and or NE transporter only at the neuronal synapse.
Extra info: The antidepressant action of TCA's start at the presynaptic dedritic area, not the synapse.
The most harmful action in an overdose from TCA’s is due to the blockade of the 5-HT transporter.
Extra info: The dangerous effects of overdose arise from the blockade of other receptors such as the M1 or fast sodium channels.
TCA’s are typically very sedating due to histamine1 antagonism and thus, should be taken at night.
Extra info: This is true, however, sometimes clinicians spread out the dosage over 3 times a day also to minimize side effects.