Tricyclic and Related Antidepressants

• Depression - moderate to severe forms; especially depression associated with physiological or psychomotor changes
• Panic disorder
• Anxiety disorders - general anxiety disorder, mixed anxiety-depression, phobic disorders
• Post-traumatic stress disorder
• Obsessive-compulsive disorder
• Other possible uses - neuralgia, nocturnal enuresis, chronic fatigue syndrome

• Tricyclic antidepressants
  • Sedating: useful in agitated and anxious depressed patients. Include amitriptyline, clomipramine, dosulepin (dothiepin), doxepin, and trimipramine.
  • Less sedating: useful in withdrawn patients. Includes amoxapine, imipramine, lofepramine, nortriptyline.
• Related antidepressants: have a similar structure to tricyclic antidepressants and consist of maprotiline, mianserin and trazodone.

• Lower doses in elderly patients
• Convenient as long acting therefore, can give once daily
• Imipramine and amitriptyline - marked antimuscarinic and cardiac side-effects
• Doxepin, trazodone and mianserin - less antimuscarinic and more cardiotoxic
• Lofepramine has lower incidence of antimuscarinic side effects and sedation but associated with hepatic toxicity.
• Amoxapine is associated with tardive dyskinesias.

• Arrhythmias
• Recent myocardial infarction
• Liver disease
• Glaucoma
• Mania.

1. Inform patients about side effects especially drowsiness and dangers of suddenly stopping.
2. Check pulse rate, BP, ECG.
3. Monitor liver function tests if patient on lofepramine e.g. every two weeks for the first month and then every month for the first three months then six monthly.³
4. When discontinuing ensure gradual dose reduction and monitoring for relapse (some patients develop symptoms although, not strictly addictive).

1. Cardiotoxicity - arrhythmias and heart block especially with amitriptyline
2. Antimuscarinic effects e.g. drowsiness, dry mouth, blurred vision and constipation. Some tolerance occurs.
3. Convulsions
4. Hypotension - especially in elderly
5. Hyponatraemia - may lead to confusion in the elderly
6. Hepatic dysfunction
7. Haematological abnormalities e.g. leucopenia, thrombocytopenia and agranulocytosis.

TCAs are most toxic of all the antidepressants, particularly amitriptyline and dothiepin, especially when taken in overdose.⁴ 1 in 40 TCA ODs will die - an ingestion of 35mg / kg is the median lethal dose for an adult.

Presentation

• Agitation
• Lethargy
• Hyper / hypothermia and metabolic acidosis
• Anticholinergic effects - muscle twitching, dilated pupils, urinary retention, GIT problems
• Seizures - occurs in up to 20% of patients and associated with severe toxicity, hypoxia and metabolic acidosis.
• Arrhythmias - commonest cause of death. Sinus tachycardia is seen as is prolongation of the QRS complex which predisposes to Torsades de Point which can be fatal.
• Disorientation, confusion, hallucinations and eventual coma
• Cerebellar signs - nystagmus, dysarthria, ataxia
• Other neurological deficits e.g. hyperreflexia, upgoing plantars.

Serious complications tend to occur within 12h of ingestion. Gastric decontamination OK for up to about 8h post ingestion.

Treatment

• Refer urgently to nearest Accident and Emergency department
• Supportive measures e.g. resuscitation, high flow oxygen, cardiac monitor, intravenous cannula and fluids if needed. Control of seizures with benzodiazepines.
• Serial ECGs are required initially e.g. every 15- 20 minutes.
• Arterial blood gases will give information regarding acidosis.
• Activated charcoal - only effective for the first 8 hours after ingestion.
• No antidote is available.
• Patients should be admitted to HDU or ITU for high intensity observation.
• If arrhythmias occur avoid common anti-arrhythmics e.g. beta blockers, calcium channel blockers as these can make the ECG difficult to interpret and some may interact with the TCA leading to worsening of cardiotoxicity.
• Sodium bicarbonate is also used if needed - usually in severe cases of toxicity with either ECG changes such as broad QT interval or severe metabolic acidosis. Toxbase⁵ or the local poisons unit should be contacted for advice.

• Insomnia e.g. sedating TCA - amitriptyline and trazodone. Usually in low doses. Evidence suggests useful in depression related insomnia but data on use in insomnia alone is lacking.⁶
• Anxiety e.g. TCA's like buspirone have been used.
• Pain relief - TCA's, SSRI's and novel antidepressants have been used e.g. venlafaxine. TCA's have been found to be efficacious in the treatment of neuropathic pain in meta-analyses. In some trials SSRIs are less effective.⁷
• Obsessive-compulsive disorder - clomipramine is used.
• Fibromyalgia - TCA's are mildly effective.
• Headaches - a recent meta-analysis revealed that SSRIs are not more useful than placebo in migraines and are less efficacious than TCA's in chronic tension headaches.⁸