Tricyclic Antidepressants (TCAs)

Indications for Use

Depression is associated with low levels of serotonin, dopamine, and noradrenaline in the brain. Tricyclic antidepressants increase the concentration of serotonin and noradrenaline at synaptic clefts, thereby improving mood.

However, due to their higher incidence of side effects, TCAs are not first-line treatments for depression and are generally reserved for cases where newer antidepressants (e.g. SSRIs) are ineffective or contraindicated.

However TCAs, particularly amitriptyline, are widely used for neuropathic pain. Their efficacy in this indication is attributed to their ability to enhance serotonin and noradrenaline activity within descending pain-modulating pathways in the brain and spinal cord.

Mechanism of Action

TCAs work by blocking the reuptake transporters for serotonin (5-HT) and noradrenaline (NA) at presynaptic nerve terminals, by blocking the binding site of the amine transporter. This increases synaptic concentrations of these neurotransmitters, potentiating their antidepressant and analgesic effects. Desipramine and nortriptyline are NA selective whereas amitriptyline, imipramine and clomipramine are non-selective TCAs.

They are termed tricyclic because of their three-ring chemical structure.

Additional Receptor Effects

TCAs are non-selective, and their activity at other receptor sites explains many of their side effects:

• Muscarinic receptor blockade → anticholinergic effects (dry mouth, constipation, blurred vision)
• Histamine (H₁) receptor blockade → sedation and weight gain
• α₁- and α₂-adrenergic receptor blockade → postural hypotension and dizziness

Imipramine and nortriptyline are less sedating compared with amitriptyline, clomipramine, and dosulepin.

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Fig 1: Mechanism of action of antidepressants. Close-up of neurons and synaptic cleft with neurotransmitters, Receptor, Mitochondria and MAO enzyme.

Pharmacokinetics

TCAs undergo rapid absorption and are metabolised in the liver to mostly active metabolites, for instance amitriptyline is converted to nortriptyline. TCAs have a large volume of distribution due to binding to extravascular tissues and high plasma protein binding of 90-95%.

Half lives are shown in the table below:

Cautions

TCAs are associated with QT interval prolongation and arrhythmias, reflecting their significant impact on cardiac conduction. High doses may precipitate hypotension, and particular care is required in individuals with cardiovascular vulnerability. In patients with diabetes, TCAs can unpredictably elevate or lower blood glucose levels, necessitating close monitoring.

Older adults are especially susceptible to anticholinergic and cardiovascular side effects, increasing the risks of confusion, falls, urinary retention, and worsening chronic constipation. TCAs may also lower the seizure threshold, requiring caution in individuals with epilepsy.

As serotonergic agents, they carry a risk of serotonin syndrome, particularly when combined with other serotonergic medications. Abrupt discontinuation can result in a withdrawal syndrome characterized by gastrointestinal disturbance, sleep disruption, and mood changes. Additionally, patients should be counselled that TCAs have a delayed onset of therapeutic effect, often requiring several weeks before clinical improvement is evident.

Contraindications

Tricyclic antidepressants are contraindicated in individuals with a recent myocardial infarction and in those with any degree of heart block or established disorders of cardiac rhythm, given their potential to exacerbate conduction abnormalities and precipitate life-threatening arrhythmias.

Adverse Effects

The adverse effect profile of tricyclic antidepressants reflects their broad pharmacological activity across multiple receptor systems. Antimuscarinic effects are common and include dry mouth, blurred vision, constipation, urinary retention, and tachycardia, resulting from blockade of peripheral cholinergic receptors. Central nervous system effects frequently manifest as sedation and cognitive impairment, with confusion occurring particularly in older adults.

Cardiovascular adverse effects are especially important clinically. Orthostatic hypotension is very common and may predispose patients to falls, while QT interval prolongation can increase the risk of arrhythmias; hypertension is reported more rarely.

Endocrine and metabolic disturbances may also occur, including gynaecomastia, sexual dysfunction, and hyponatraemia. Neurological effects such as seizures, tremor, and behavioural changes including aggression have also been reported, highlighting the need for careful patient selection and monitoring during therapy.

Interactions

Tricyclic antidepressants (TCAs) are associated with numerous clinically significant drug interactions that require careful consideration. Concomitant use with other serotonergic medications increases the risk of serotonin syndrome, a potentially life-threatening condition. Additional caution is warranted when TCAs are prescribed alongside drugs known to prolong the QT interval or cause hyponatraemia, as these combinations may compound cardiovascular and electrolyte-related risks.

Pharmacokinetically, TCAs are primarily metabolised by the cytochrome P450 enzymes CYP2D6 and CYP2C19, with lesser contributions from CYP3A4 and CYP1A2. Inhibitors of CYP2D6, including bupropion, fluoxetine, paroxetine, quinidine, and fluconazole, can increase plasma concentrations of TCAs, thereby raising the risk of toxicity. Similarly, CYP3A4 inhibitors such as ketoconazole, itraconazole, ritonavir, diltiazem, and verapamil may also elevate TCA levels. Conversely, enzyme inducers such as rifampicin, phenytoin, carbamazepine, and St John’s wort can reduce TCA plasma concentrations, potentially diminishing therapeutic efficacy.

Pharmacodynamically, TCAs may antagonise the effects of centrally acting antihypertensive agents such as clonidine, which exert their action through stimulation of α₂-adrenergic receptors, thereby reducing their blood pressure lowering effects. Furthermore TCAs increase the effects of alcohol and anaesthetic agents, which has led to reports of mortality.

References

1. Onset of action of antidepressants | The BMJ
2. Antidepressant drugs | Treatment summaries | BNF | NICE
3. Nortriptyline 10 mg Film-coated Tablets – Summary of Product Characteristics (SmPC) – (emc) (medicines.org.uk)
4. Amitriptyline 10 mg Film-Coated Tablets – Summary of Product Characteristics (SmPC) – (emc) (medicines.org.uk)
5. Ritter JM, Flower RJ, Henderson G, Loke YK, MacEwan DJ. Rang & Dale’s Pharmacology. 9th ed. London: Elsevier; 2019.