A Textbook of Clinical Pharmacology and Therapeutics

ST JOHN’S WORT

St John’s wort (Hypericum perforatum) is an unlicensed herbal

remedy in popular use for treating depression (Chapter 17).

However, it can induce drug-metabolizing enzymes, and many

important drug interactions have been identified, including

with antidepressant drugs, with which St John’s wort should

therefore not be given. The amount of active ingredient can

vary between different preparations, thus changing the prepa-

ration can alter the degree of such interactions. Importantly,

when St John’s wort is discontinued, the concentrations of

interacting drugs may increase.

SPECIAL GROUPS

THE ELDERLY

Depression is common in the elderly, in whom it tends to be

chronic and has a high rate of recurrence. Treatment with drugs

is made more difficult because of slow metabolism and sensi-

tivity to anticholinergic effects. Lower doses are therefore needed

than in younger patients.

Lack of response may indicate true refractoriness of the

depression, or sadness due to social isolation or bereavement.

The possibility of underlying disease, such as hypothyroidism

(the incidence of which increases with age), should be

considered.

Lofepramineand SSRIs cause fewer problems in patients

with prostatism or glaucoma than do the tricyclic antidepres-

sants because they have less antimuscarinic action. Dizziness

and falls due to orthostatic hypotension are less common with

nortriptylinethan with imipramine.Mianserinhas fewer

anticholinergic effects, but blood dyscrasias occur in about one

in 4000 patients and postural hypotension can be severe.

EPILEPSY

No currently used antidepressive is entirely safe in epilepsy,

but SSRIs are less likely to cause fits than the amitriptyline

group, mianserinormaprotiline.

Contraindications

These include the following:

• renal disease;


• cardiac disease;


• sodium-losing states (e.g. Addison’s disease, diarrhoea,
  vomiting);


• myasthenia gravis;


• during surgical operations;


• avoid when possible during pregnancy and breast-feeding.

Pharmacokinetics

Lithiumis readily absorbed after oral administration and
injectable preparations are not available. Peak serum concen-
trations occur three to five hours after dosing. The t1/2varies
with age because of the progressive decline in glomerular fil-
tration rate, being 18–20 hours in young adults and up to 36
hours in healthy elderly people. Sustained-release prepar-
ations are available, but in view of the long t1/2they are not
kinetically justified. Lithiumtakes several days to reach steady
state and the first samples for serum level monitoring should
be taken after about one week unless loading doses are given.
Lithiumelimination is almost entirely renal. Like sodium,
lithiumdoes not bind to plasma protein, and it readily passes
into the glomerular filtrate; 70–80% is reabsorbed in the proxi-
mal tubules but, unlike sodium, there is no distal tubular reab-
sorption and its elimination is not directly altered by diuretics
acting on the distal tubule. However, states such as sodium
deficiency and sodium diuresis increase lithiumretention (and
cause toxicity) by stimulating proximal tubular sodium and
lithiumreabsorption. An important implication of the renal
handling of lithiumis that neither loop diuretics, thiazides nor
potassium-sparing diuretics can enhance lithiumloss in a toxic
patient, but all of them do enhance its toxicity. Dialysis reduces
elevated serum lithiumconcentration effectively.

Drug interactions

• Lithiumconcentration in the serum is increased by
  diuretics and non-steroidal anti-inflammatory drugs.


• Lithiumtoxicity is increased by concomitant
  administration of haloperidol, serotonin uptake
  inhibitors, calcium antagonists (e.g. diltiazem) and
  anticonvulsants (phenytoinandcarbamazepine) without
  a change in serum concentration.


• Lithiumincreases the incidence of extrapyramidal effects
  of antipsychotics.

L-TRYPTOPHAN

Tryptophan is the amino acid precursor of 5HT. On its own
or with other antidepressants or lithiumit sometimes bene-
fits refractory forms of depression. However, L-tryptophan
should only be initiated under specialist supervision because
of its association with an eosinophilic myalgic syndrome char-
acterized by intense and incapacitating fatigue, myalgia and
eosinophilia. Arthralgia, fever, cough, dyspnoea and rash may
also develop over several weeks. A few patients develop
myocarditis.

122 MOOD DISORDERS

Case history

A 75-year-old woman with endogenous depression is

treated with amitriptyline. After three weeks, she appears

to be responding, but then seems to become increasingly

drowsy and confused. She is brought to the Accident

and Emergency Department following a series of

convulsions.

Question

What is the likely cause of her drowsiness, confusion and

convulsions?

Answer

Hyponatraemia.

Comment

Hyponatraemia (usually in the elderly) has been associated

with all types of antidepressant but most frequently with

SSRIs.