Tricyclic antidepressants

Question 1

Indications

Answer 1

1. As second-line treatment for moderate-to-severe depression where first-line serotonin-specific reuptake inhibitors (SSRIs) are ineffective.
2. As a treatment option for neuropathic pain, although they are not licensed for this indication.

Question 2

Mechanisms of action

Answer 2

Tricyclic antidepressants inhibit neuronal reuptake of serotonin (5-HT) and noradrenaline from the synaptic cleft, thereby increasing their availability for neurotransmission. This appears to be the mechanism by which they improve mood and physical symptoms in moderate-to-severe (but not mild) depression and probably accounts for their effect in modifying neuropathic pain.

Tricyclic antidepressants also block a wide array of receptors, including muscarinic, histamine (H1), α-adrenergic (α1 and α2) and dopamine (D2) receptors. This accounts for the extensive adverse effects profile that limits their clinical utility.

Question 3

Adverse effects

Answer 3

Blockade of antimuscarinic receptors causes dry mouth, constipation, urinary retention and blurred vision. Blockade of H1 and α1 receptors causes sedation and hypotension. Cardiac adverse effects (multiple mechanisms) include arrhythmias and ECG changes (including prolongation of the QT and QRS durations). In the brain, more serious effects include convulsions, hallucinations and mania. Blockade of dopamine receptors can cause breast changes and sexual dysfunction and rarely causes extrapyramidal symptoms (tremor and dyskinesia). Tricyclic antidepressants are extremely dangerous in overdose, causing severe hypotension, arrhythmias, convulsions, coma and respiratory failure, which can be fatal.

Question 4

Warnings

Answer 4

Tricyclic antidepressants should be used with caution in people who are particularly at risk of adverse effects. These include the elderly, people with cardiovascular disease or epilepsy, and people with constipation, prostatic hypertrophy or raised intraocular pressure, which may be worsened by antimuscarinic effects.

Question 5

Interactions

Answer 5

Monoamine oxidase inhibitors

Question 6

Prescribing?

Answer 6

Generally only given to patients who have already tried SSRIs

Much lower doses used in neuropathic pain.

Question 7

Administration

Answer 7

PO

Question 8

Communication

Answer 8

Advise patients that treatment will improve symptoms over a few weeks, particularly sleep and appetite. Discuss referring them for psychological therapy, which may offer more long-term benefits than drug treatment. Explain that they should carry on with drug treatment for at least 6 months after they feel better to stop the depression from coming back (2 years for recurrent depression). Warn them not to stop treatment suddenly as this may cause flu-like withdrawal symptoms and sleeplessnes.

Question 9

Monitoring

Answer 9

Symptoms should be reviewed 1–2 weeks after starting treatment and regularly thereafter. If no effect has been seen at 4 weeks, you should consider changing the dose or drug. Otherwise the dose should not be adjusted until after 6–8 weeks of therapy.