A Textbook of Clinical Pharmacology and Therapeutics

LITHIUM, TRYPTOPHAN AND ST JOHN’S

WORT

LITHIUM

Althoughlithiumis widely used in affective disorders, it has
a low toxic to therapeutic ratio, and serum concentration moni-
toring is essential. Serum is used rather than plasma because
of possible problems due to lithium heparin, which is often
used as an anticoagulant in blood sample tubes. Serum
lithiumlevels fluctuate between doses and serum concentra-
tions should be measured at a standard time, preferably 12
hours after the previous dose. This measurement is made fre-
quently until steady state is attained and is then made every
three months, unless some intercurrent event occurs that
could cause toxicity (e.g. desal-ination or diuretic therapy).

Use

Lithiumis effective in acute mania, but its action is slow (one
to two weeks), so antipsychotic drugs, such as haloperidol,
are preferred in this situation (see Chapter 19). Its main use
is in prophylaxis in unipolar and bipolar affective illness

LITHIUM, TRYPTOPHAN ANDSTJOHN’SWORT 121

(therapeutic serum levels 0.4–1 mmol/L). Lithiumis also

used on its own or with another antidepressant in refractory

depression to terminate a depressive episode or to prevent

recurrences and aggressive or self-mutilating behaviour.

Patients should avoid major dietary changes that alter

sodium intake and maintain an adequate water intake.

Different lithiumpreparations have different bioavailabili-

ties, so the form should not be changed.

Mechanism of action

Lithiumincreases 5HT actions in the CNS. It acts as a 5HT1A

agonist and is also a 5HT 2 antagonist. This may be the basis for

its antidepressant activity and may explain why it increases

the CNS toxicity of selective 5HT uptake inhibitors.

The basic biochemical activity of lithiumis not known. It

has actions on two second messengers.

1. Hormone stimulation of adenylyl cyclase is inhibited,
   so that hormone-stimulated cyclic adenosine
   monophosphate (cAMP) production is reduced. This
   probably underlies some of the adverse effects of lithium,
   such as goitre and nephrogenic diabetes insipidus, since
   thyroid-stimulating hormone (TSH) and antidiuretic
   hormone activate adenylyl cyclase in thyroid and
   collecting duct cells, respectively. The relevance of this
   to its therapeutic effect is uncertain.
   2.Lithiumat a concentration of 1 mmol/L inhibits
   hydrolysis of myoinositol phosphate in the brain, so
   lithiummay reduce the cellular content of phosphatidyl
   inositides, thereby altering the sensitivity of neurones
   to neurotransmitters that work on receptors linked
   to phospholipase C (including muscarinic and
   α-adrenoceptors).

From these actions, it is clear that lithiumcan modify a wide

range of neurotransmitter effects, yet its efficacy both in mania

and in depression indicates a subtlety of action that is cur-

rently unexplained, but may be related to activation of the brain

stem raphe nuclei.

Adverse effects

1. When monitored regularly lithiumis reasonably safe in
   the medium term. However, adverse effects occur even in
   the therapeutic range – in particular, tremor, weight gain,
   oedema, polyuria, nausea and loose bowels.
   2.Above the therapeutic range, tremor coarsens, diarrhoea
   becomes more severe and ataxia and dysarthria appear.
   Higher levels cause gross ataxia, coma, fits, cardiac
   dysrhythmias and death. Serum lithiumconcentrations
   greater than 1.5 mmol/L may be dangerous and if greater
   than 2 mmol/L, are usually associated with serious
   toxicity.
   3.Goitre, hypothyroidism and exacerbation of psoriasis are
   less common.
   4.Renal tubular damage has been described in association
   with prolonged use.

Key points

Antidepressant contraindications

• Tricyclic antidepressants – recent myocardial infarction,
  dysrhythmias, manic phase, severe liver disease.


• SSRIs – manic phase.


• Monamine oxidase inhibitors – acute confused state,
  phaeochromocytoma.


• Caution is needed – cardiac disease, epilepsy, pregnancy
  and breast-feeding, elderly, hepatic and renal
  impairment, thyroid disease, narrow-angle glaucoma,
  urinary retention, prostatism, porphyria, psychoses,
  electroconvulsive therapy (ECT) and anaesthesia.

Key points

Drug treatment of depression

• Initial drug treatment is usually with SSRIs, tricyclic
  antidepressants or related drugs.


• The choice is usually related to the side-effect profile of
  relevance to the particular patient.


• Tricyclic antidepressants are more dangerous in overdose.


• Tricyclic antidepressants commonly cause antimuscarinic
  and cardiac effects.


• Tricyclic antidepressants tend to increase appetite and
  weight, whereas SSRIs more commonly reduce appetite
  and weight.


• SSRIs are associated with nausea, sexual dysfunction
  and sleep disturbance.


• There is a variable delay (between ten days and four
  weeks) before therapeutic benefit is obtained.


• Following remission, antidepressant therapy should be
  continued for at least four to six months.