Tricyclic antidepressants (TCAs) were among the first classes used in major depression. They are now used less often because of tolerability, interactions and overdose toxicity, but may be selected after better-tolerated options, following a previous response or for specific indications of individual agents; somatic symptoms alone are not a validated preferential indication.
TCAs are divided into tertiary amines and secondary amines. Tertiary amines (e.g. amitriptyline, imipramine, doxepin) generally inhibit both SERT and NET, often with a more pronounced serotonergic component, whereas secondary amines (e.g. nortriptyline, desipramine, protriptyline) are generally more noradrenergic. Hepatic N-demethylation of tertiary amines generates active secondary metabolites, some of which, such as nortriptyline from amitriptyline, are used directly in treatment because of their more favorable tolerability profile.
TCA use includes specific indications of individual agents, such as clomipramine in obsessive-compulsive disorder and some TCAs in neuropathic pain. In depression, they are selected according to previous efficacy, tolerability, comorbidities and risk, not solely because insomnia or somatic symptoms are present.
The antidepressant action of TCAs is mediated mainly by inhibition of presynaptic serotonin (5-HT) and norepinephrine (NE) reuptake, with a consequent increase in the synaptic availability of these neurotransmitters. Their effect on transporters is rapid, whereas clinical improvement may emerge progressively during the first weeks and consolidate later; there is no fixed latency of 2–4 weeks and no single proven neuroadaptive mechanism.
In addition to inhibiting the SERT and NET transporters, TCAs interact with numerous non-monoaminergic receptors, including:
This broad receptor affinity contributes to some clinical effects but is mainly responsible for their multisystem adverse-effect profile, which limits their use in many patients.
TCAs may be considered in major depressive disorder after an insufficient response or intolerance to better-tolerated options. Treatment-resistant depression is assessed on the basis of adequate trials of different treatments, without necessarily requiring them to belong to different classes. Their adverse-effect profile and overdose toxicity limit their use as a first choice.
According to the CANMAT (2023) and NICE (2022) guidelines, TCAs may be indicated:
The use of TCAs requires careful assessment of the patient's profile, because they are contraindicated or should be used with extreme caution in older adults and in patients with cardiovascular disease, angle-closure glaucoma, prostatic hypertrophy, epilepsy and active suicidal ideation.
TCAs are well absorbed orally but undergo first-pass hepatic metabolism, resulting in variable oral bioavailability. Their marked lipophilicity promotes extensive distribution into tissues, including the central nervous system. Their half-life ranges from 12 to more than 30 hours, depending on the agent and the presence of active metabolites.
The dosage should always be titrated gradually to minimize initial adverse effects. Treatment generally begins at 25–50 mg/day, with gradual increases every 3–5 days until the therapeutic dose is reached (usually 75–150 mg/day, and sometimes higher in refractory cases). Plasma drug monitoring is indicated when the response is uncertain, overdose is suspected or complex polypharmacy is present, especially for nortriptyline and imipramine.
In older adults, lower starting doses (10–25 mg/day) are recommended, with very slow increments and careful monitoring of cognitive and cardiac functioning (serial ECGs).
Contemporary guidelines do not recommend tricyclics as a routine first choice for depression, mainly because of tolerability and overdose toxicity; they may be considered when better-tolerated treatments are ineffective, not indicated or have previously proved effective in the individual patient.
In selected patients and under specialist supervision, TCAs may represent a valid, effective and well-established option when previous response, the indication of the individual agent, comorbidities and safety profile justify their use; there is no validated symptom profile that specifically predicts their superiority.
One of the main limitations to using TCAs in the treatment of depression is the high incidence of adverse effects, due to their interaction with non-monoaminergic receptors. Management requires specific strategies, symptom assessment and sometimes dose reduction or switching agents.
Particular caution is required in patients with epilepsy or at risk of seizures, because TCAs can lower the seizure threshold. In such cases, it is preferable to avoid their use or carefully monitor neurological status.
TCAs are substrates of numerous cytochrome P450 enzymes (especially CYP2D6 and CYP1A2) and are therefore subject to clinically relevant pharmacokinetic interactions. Their receptor profile also favors pharmacodynamic synergy or antagonism with other psychoactive agents.
It is essential to review the patient's current treatment carefully before starting a TCA, assess all potential drug interactions and monitor baseline clinical investigations.
Use of TCAs in antidepressant treatment requires regular clinical surveillance, particularly during the first weeks. The principal parameters to monitor include:
In older or multimorbid patients, closer monitoring and use of the minimum effective dose are recommended. Clinical efficacy should be reassessed after 4–6 weeks, with treatment changes considered in the absence of a response.
Tricyclic antidepressants retain a role in selected cases, particularly after an insufficient response to better-tolerated options or when a previous individual response has been documented. Efficacy, overdose toxicity, anticholinergic effects and cardiovascular effects require careful assessment; prominent somatic symptoms alone do not establish a preference for these drugs.
Appropriate patient selection, gradual titration, clinical and laboratory monitoring, and proactive management of adverse effects are the keys to effective and safe use of these drugs. In experienced hands, TCAs remain a valuable therapeutic tool, particularly for treatment-resistant major depression or depression associated with chronic pain.