Pharmacology
The majority of the TCAs act primarily as serotonin-norepinephrine reuptake inhibitors (SNRIs) by blocking the serotonin transporter (SERT) and the norepinephrine transporter (NET), respectively, which results in an elevation of the synaptic concentrations of these neurotransmitters, and therefore an enhancement of neurotransmission. Notably, the TCAs have negligible affinity for the dopamine transporter (DAT), and therefore have no efficacy as dopamine reuptake inhibitors (DRIs). Both serotonin and norepinephrine have been highly implicated in depression and anxiety, and it has been shown that facilitation of their activity has beneficial effects on these mental disorders.
In addition to their reuptake inhibition, many TCAs also have high affinity as antagonists at the 5-HT2 (5-HT2A and 5-HT2C), 5-HT6, 5-HT7, α1-adrenergic, and NMDA receptors, and as agonists at the sigma receptors (σ1 and σ2), some of which may contribute to their therapeutic efficacy, as well as their side effects. The TCAs also have varying but typically high affinity for antagonising the H1 and H2 histamine receptors, as well as the muscarinic acetylcholine receptors. As a result, they also act as potent antihistamines and anticholinergics. These properties are generally undesirable in antidepressants, however, and likely contribute to their large side effect profiles.
Most, if not all, of the TCAs also potently inhibit sodium channels and -type calcium channels, and therefore act as sodium channel blockers and calcium channel blockers, respectively. The former property is responsible for the high mortality rate upon overdose seen with the TCAs via cardiotoxicity.
Read more about this topic: Tricyclic Antidepressant