A Textbook of Clinical Pharmacology and Therapeutics

DEPRESSIVEILLNESSES ANDANTIDEPRESSANTS 119

Imipramineandamitriptyline(tertiary amines) have more
powerful anticholinergic and cardiac toxic effects than second-
ary amines (e.g. nortriptyline).

Mechanism of action

The tricyclics block uptake-1 of monoamines into cerebral (and
other) neurones. Thus, the concentration of amines in the
synaptic cleft rises. As discussed above, they may also induce a
slow adaptive decrease in pre- and/or postsynaptic amine
receptor sensitivity.

Adverse effects

Autonomic (anticholinergic)/cardiovascularDry mouth,
constipation (rarely paralytic ileus, gastroparesis),
tachycardia, paralysis of accommodation, aggravation of
narrow-angle glaucoma, retention of urine, dry skin due
to loss of sweating, and (due to α-blockade) postural
hypotension. Rarely, sudden death due to a cardiac
dysrhythmia. In overdose, a range of tachydysrhythmias
and intracardiac blocks may be produced.

Central nervous systemFine tremor and sedation, but also
(paradoxically) sometimes insomnia, decreased rapid eye
movement (REM) sleep, twitching, convulsions, dysarthria,
paraesthesia, ataxia. Increased appetite and weight gain,
particularly with the sedative tricyclics, are common. On
withdrawal of the drug, there may be gastro-intestinal
symptoms such as nausea and vomiting, headache,

giddiness, shivering and insomnia. Sometimes anxiety,

agitation and restlessness follow sudden withdrawal.

Allergic and idiosyncratic reactionsThese include bone marrow

suppression and jaundice (both rare).

HyponatraemiaHyponatraemia is an adverse effect due to

inappropriate ADH secretion, and is more common in the

elderly.

Contraindications

These include the following:

• epilepsy;


• recent myocardial infarction, heart block;


• mania;


• porphyria.

RELATED NON-TRICYCLIC ANTIDEPRESSANT DRUGS

This is a mixed group which includes 1-, 2- and 4-ring struc-

tured drugs with broadly similar properties. Characteristics of

specific drugs are summarized below.

Maprotiline– sedative, with less antimuscarinic effects, but

rashes are more common and fits are a significant risk.

Mianserin– blocks central α 2 -adrenoceptors. It is sedative,

with much fewer anticholinergic effects, but can cause

postural hypotension and blood dyscrasias, particularly in

the elderly. Full blood count must be monitored.

Assess risk factors for

treatment resistance

Assess symptom severity

Partial response to

first-line treatment

Advance dose

as tolerated

Symptoms persist after

6–8 weeks

Ensure safe maximum

tolerated dose

Trial of an alternative

medication

Nonresponders:

mild-to-moderate

symptoms, low risk

All patients:

moderate-to-severe

symptoms, or high risk

No response to

first-line treatment

Persistent symptoms AUGMENTATION* Persistent symptoms

Trial of an alternative

medication

Partial responders:

mild symptoms, low risk

Figure 20.2:General algorithm for

the second phase of treatment of

depression. Augmentation*

involves the use of a combination

of medications to enhance the

efficacy of an antidepressant.

(Redrawn with permission from

Aronson SC and Ayres VE,

‘Depression: A Treatment

Algorithm for the Family

Physician’,Hospital Physician

Vol 36 No 7, 2000. Copyright

2000 Turner White

Communications, Inc.)