Ever since Kuhn (1958) discovered the antidepressive actions of the archetypal tricyclic antidepressant imipramine, tricyclic antidepressants and related drugs have played an important part in the pharmacotherapy of depression. It was not until the 1980s, with the advent of SSRIs (see Chapter 9) that tricyclic antidepressants and related drugs began to be displaced from their position as the first-line pharmacological treatment for depression. In addition to their use in the treatment of depression, various tricyclic antidepressants are also used in the pharmacotherapy of dysthymia, panic disorder, phobic and obsessional states, childhood nocturnal enuresis, neuralgia, pruritus in eczema, and as an adjunctive treatment of cataplexy associated with narcolepsy.

In general, tricyclic antidepressants have long half-lives. This allows for clinically effective once-daily dosing. It may be best to give more sedating antidepressants, such as amitriptyline, as a once-daily bedtime dose, to aid sleep, and to give less sedating ones, such as imipramine, earlier in the day, perhaps even first thing in the morning.

The elderly are particularly vulnerable to the hypotensive and hyponatraemic actions of tricyclic antidepressants. For these reasons, the initial dosage used in elderly patients should be kept low.

The tricyclic antidepressants include:

Tricyclic antidepressant-related antidepressants include:

Tetracyclic antidepressants include:

The more sedative tricyclic and related antidepressants include:

These are more appropriate for patients suffering from agitation, anxiety, and, if given at bedtime, insomnia.

The less sedative tricyclic and related antidepressants include:

These are more appropriate for patients suffering from withdrawal or apathy.

The British National Formulary (62nd edition) makes the following important comments on these different antidepressants:

Overdosage Limited quantities of tricyclic antidepressants should be prescribed at any one time because their cardiovascular and epileptogenic effects are dangerous in overdosage. In particular, overdosage with dosulepin and amitriptyline is associated with a relatively high rate of fatality. Lofepramine is associated with the lowest risk of fatality in overdosage, in comparison with other tricyclic antidepressant drugs….

Tricyclic and related antidepressants … have varying degrees of antimuscarinic side-effects and cardiotoxicity in overdosage, which may be important in individual patients. Lofepramine has a lower incidence of side-effects and is less dangerous in overdosage but is infrequently associated with
hepatic toxicity. Imipramine is also well established, but has more marked antimuscarinic side-effects than other tricyclic and related antidepressants. Amitriptyline and dosulepin are effective but they are particularly dangerous in overdosage (see ‘Overdosage’, p.138) and are not recommended for the treatment of depression; dosulepin should only be prescribed by specialists.’

Withdrawal of pharmacotherapy of drugs in this group should, as far as is possible, take place gradually.

Most tricyclic antidepressants seriously impair driving performance, even more so than alcohol or benzodiazepines; in contrast SSRIs do not do so (Hale, 1994). Ramaekers (2003) reviewed the major results from studies published between 1983 and 2000 that examined the effects of antidepressants on actual driving performance using a standard test. Adverse changes on that test after acute doses of amitriptyline, imipramine, doxepin, and mianserin were comparable to those seen in drivers conducting this test with a blood alcohol level of at least 0.8mg/mL. Given the potential hazard of these drugs for driving, patients should not drive while taking them. They should also be strongly advised not to operate dangerous machinery.

As mentioned earlier, amitriptyline is particularly dangerous in overdosage and is not recommended for the treatment of depression. Details of its structure and side-effects are given here for comparison with other tricyclic and related antidepressants.