Tricyclic Antidepressants (TCAs)

Tricyclic antidepressants (TCAs) are one of the first classes of drugs used in the treatment of major depressive disorder, introduced into clinical practice in the 1950s. Their name derives from their molecular structure, which consists of three rings (two benzene rings and a central cyclic ring), hence the term "tricyclic." Although they are now less commonly used than second-generation antidepressants due to a less favorable tolerability profile, TCAs still play a significant role in specific subgroups of depressed patients, particularly in treatment-resistant cases or those with prominent somatic symptoms.

Chemical Structure and Classification

TCAs are classified as tertiary amines and secondary amines. The former (e.g., amitriptyline, imipramine, doxepin) tend to act in a balanced manner on both serotonin and norepinephrine, whereas the latter (e.g., nortriptyline, desipramine, protriptyline) are generally more selective for norepinephrine. Hepatic methylation of tertiary amines produces active secondary metabolites, which are sometimes used directly in therapy due to their improved tolerability profiles (e.g., nortriptyline from amitriptyline).

The use of TCAs extends beyond depression: they are also used in obsessive-compulsive disorder (clomipramine), chronic non-cancer pain, neuralgias, and certain sleep disorders. However, their primary psychiatric indication remains the treatment of major depressive disorder, especially in the presence of insomnia, painful somatic symptoms, or poor response to second-generation antidepressants.

Mechanism of Action

The antidepressant effect of TCAs is primarily mediated by inhibition of the presynaptic reuptake of serotonin (5-HT) and norepinephrine (NE), resulting in increased synaptic availability of these neurotransmitters. While the biochemical effect is rapid, the clinical response generally requires 2–4 weeks, reflecting the role of neuroadaptive mechanisms.

In addition to inhibiting SERT and NET transporters, TCAs interact with various non-monoaminergic receptors, including:

• Muscarinic receptors (anticholinergic effects: dry mouth, urinary retention, constipation);
• Histaminergic H1 receptors (sedation, weight gain);
• Alpha1-adrenergic receptors (orthostatic hypotension);
• 5-HT2 receptors (involved in the regulation of mood, anxiety, and sleep);
• Ion channels and membrane stabilization (antiarrhythmic effects and risk of cardiac toxicity).

This broad receptor affinity contributes to the potent antidepressant activity of TCAs but also underlies their multisystemic side effect profile, which limits their use in many patients.

Clinical Indications in Depression

TCAs are indicated in various subtypes of depression, particularly in cases of treatment-resistant major depression, defined as failure to respond to at least two antidepressants from different classes, administered at adequate doses and durations. Their efficacy is comparable to that of SSRIs and SNRIs, but their side effect profile has led to a gradual decline in their use as first-line treatments.

According to the CANMAT (2016) and NICE (2022) guidelines, TCAs are recommended:

• for melancholic or somatic forms, characterized by psychomotor retardation, insomnia, weight loss, and marked anhedonia;
• in patients with a previous favorable response to TCAs in earlier depressive episodes;
• in the presence of comorbid chronic pain (e.g., fibromyalgia, neuropathies) or treatment-resistant sleep disorders;
• in cases of failure or intolerance to other first-line antidepressants.

The use of TCAs requires careful patient profiling, as they are contraindicated or should be used with extreme caution in the elderly, in patients with cardiovascular disease, narrow-angle glaucoma, benign prostatic hyperplasia, epilepsy, or active suicidal ideation.

Pharmacokinetics and Dosage

TCAs are well absorbed orally but undergo significant first-pass hepatic metabolism, resulting in variable oral bioavailability. Their high lipophilicity allows for widespread tissue distribution, including the central nervous system. Half-life ranges from 12 to over 30 hours, depending on the specific compound and presence of active metabolites.

Dosing should always be titrated gradually to minimize initial side effects. Treatment usually starts at 25–50 mg/day, with incremental increases every 3–5 days until reaching a therapeutic dose (typically 75–150 mg/day, and higher in refractory cases). Plasma level monitoring is indicated when response is uncertain, in suspected overdose, or in complex polypharmacy—especially for nortriptyline and imipramine.

In the elderly, lower starting doses (10–25 mg/day) are recommended, with very slow titration and close monitoring of cognitive function and cardiac status (serial ECGs).

Guidelines and Recommendations

The APA (2020) and NICE (2022) guidelines do not recommend TCAs as first-line treatment due to their poor tolerability and high overdose risk. However, they acknowledge their role as second- or third-line options, especially in treatment-resistant depression, in cases with coexisting chronic pain, or when other medications are ineffective or poorly tolerated.

In carefully selected patients and under specialist supervision, TCAs remain a valid, effective, and well-established option for treating depression, particularly when the symptom profile aligns with their pharmacological actions.

Managing Side Effects

One of the main limitations of TCAs in depression treatment is the high incidence of side effects due to interactions with non-monoaminergic receptors. Management requires specific strategies, symptom-based assessment, and sometimes dose reduction or switching agents.

• Anticholinergic effects (dry mouth, constipation, blurred vision): encourage hydration, use of artificial saliva, osmotic laxatives; avoid co-administration with other anticholinergics (e.g., typical antipsychotics, antiparkinsonians).
• Sedation and drowsiness: may be beneficial in cases of insomnia; otherwise consider evening dosing or switching to a less sedating TCA (e.g., nortriptyline).
• Orthostatic hypotension: monitor blood pressure in supine and standing positions; reduce dose, avoid sudden postural changes; consider switching in elderly patients or those at risk of falls.
• Sexual dysfunction: often related to hyperprolactinemia; consider dose reduction, switching to a compound with lower serotonergic impact, or a drug holiday strategy.
• Cognitive disturbances and confusion: common in frail patients or those with neurological comorbidities; evaluate the need for discontinuation or therapeutic switch.

Particular caution is advised in epileptic patients or those at risk of seizures, as TCAs may lower the seizure threshold. In such cases, TCAs should be avoided or used only with close neurological monitoring.

Drug Interactions

TCAs are substrates of several cytochrome P450 enzymes (especially CYP2D6 and CYP1A2) and are therefore subject to significant pharmacokinetic interactions. Additionally, their receptor profile may lead to pharmacodynamic synergy or antagonism with other psychoactive agents.

• Alcohol: enhances sedative and anticholinergic effects, increasing the risk of central toxicity.
• Benzodiazepines: increase sedation and the risk of cognitive and respiratory impairment.
• SSRIs (e.g., fluoxetine, paroxetine): inhibit TCA metabolism (especially nortriptyline), increasing the risk of overdose and cardiotoxicity.
• Antiarrhythmics, antipsychotics, macrolides: increased risk of QT prolongation and ventricular arrhythmias.
• MAO inhibitors: contraindicated due to the risk of hypertensive crises and serotonin syndrome; a washout period of at least 14 days is required.

It is essential to thoroughly review the patient’s current medications before starting a TCA, assessing all potential drug interactions and monitoring baseline clinical parameters.

Monitoring and Follow-up

The use of TCAs in depression therapy requires regular clinical monitoring, particularly during the first weeks of treatment. Key monitoring elements include:

• Electrocardiogram (ECG): perform before and during therapy, especially in patients >50 years old or with cardiovascular conditions;
• Blood pressure: assess for orthostatic hypotension;
• Liver and kidney function: to evaluate metabolism and excretion;
• Plasma drug levels: useful for nortriptyline, imipramine, and desipramine in case of poor response, suspected toxicity, or polypharmacy;
• Mental status and suicide risk: critical especially during the first 10–14 days, when there is a paradoxical activation risk.

In elderly or comorbid patients, closer monitoring and use of the lowest effective dose are recommended. Clinical efficacy should be reassessed after 4–6 weeks, and therapeutic adjustments considered if no improvement is observed.

Final Considerations

Although an older pharmacological class, tricyclic antidepressants still play an active role in modern depression treatment, particularly in resistant forms, in presentations with prominent somatic symptoms, or where there is a documented history of individual efficacy. Their strong clinical efficacy is tempered by a less favorable tolerability profile compared to second-generation antidepressants, positioning them as second- or third-line agents to be prescribed in carefully selected cases under close clinical supervision.

Proper patient selection, gradual dose titration, clinical and laboratory monitoring, and proactive management of side effects are the keys to safe and effective use of these medications. In expert hands, TCAs remain a valuable therapeutic tool, especially in treatment-resistant major depression or depression associated with chronic pain.

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