With the advent of SSRI's, tricyclic antidepressants are now considered a second-line treatment for depression. This is largely because of their side effect profile and the high potential for death after overdose. Most of the side effects that patients experience with tricyclic antidepressants reflects their antagonism of histamine H1, adrenergic alpha1, and muscarinic receptors. The common side effects of tricyclic antidepressants are compared in this table.
Side effects
Since the side effects are enumerated in the table, there isn't much purpose in repeating them here. The primary side effects include sedation, dry mouth, and postural hypotension. Typically people develop some tolerance to these side effects over time. Tricyclic antidepressants at therapeutic levels can prolong the QTc interval, but this rarely leads to any clinically appreciable effects in patients without pre-existing conduction abnormalities.
Interactions
One concern arises when the tricyclic antidepressants or combined with other medications that have significant anticholinergic activity. Such combinations can result in increased anticholinergic side effects, as well as anti-cholinergic delirium. Although the risk isn't great, the combination of certain tricyclic antidepressants and SSRIs may increase the likelihood of serotonin syndrome.
Tricyclic antidepressants have a narrow therapeutic window and most are metabolized predominantly by 2D6 or 3A4. Thus, inhibitors of these enzymes can increase tricyclic serum levels which can lead to toxicity.
Toxicity
Overdoses of tricyclic antidepressants carry a significant risk of death as result of cardiac conduction abnormalities. Typically the conduction abnormalities result and the like in its ventricular arrhythmias. However, the initial symptoms of overdose usually reflect the central nervous system alterations as a result of anticholinergic effects of the medications. This is typically seen as initial central nervous system stimulation (which includes delirium, hypertension, hallucinations, seizure, agitation, hyperreflexia, and Parkinsonian symptoms). the initial phase of stimulation and subsequently followed by central nervous system depression, which is reflected as drowsiness, hyporeflexia, hypothermia, respiratory depression, hypotension, and coma. The risk of toxicity is high if the total tricyclic antidepressant concentration is greater than 1000 ng/ml; concentrations greater than 2500 ng/ml are generally fatal.