Lithium

The anti-manic properties of lithium were first discovered by Australian psychiatrist John Cade in 1949¹. It is a mood stabiliser and has numerous effects on biological systems. It can substitute for sodium, potassium, calcium and magnesium in biological systems and enters the cells and interferes with transmitter release and second messenger systems. Hence, it can block release of certain transmitters and hormones.

It has been effective in the prevention and treatment of bipolar disorder for over sixty years².

Indications³

NB: unsuitable for children.

• Management of acute manic or hypomanic episodes.

• Prophylaxis of bipolar (manic-depressive) illness (co-administration of antidepressants may be needed in a depressive phase)⁴. Lithium is highly effective at reducing both relapses (particularly manic episodes) and suicide rate .

• Prophylaxis of recurrent depression and schizoaffective disorder.

• Augmentation of the antidepressant effect when it is co-prescribed with antidepressants in treatment resistant depression⁵.

• Prophylaxis of cluster headache (unlicensed indication)⁶.

• Control of aggressive behaviour or intentional self-harm and possibly suicidal behaviour. Lithium has been used successfully to reduce aggression in patients with learning disabilities who are unmanageable by environmental factors, and in patients with aggressive self-mutilating behaviour.

There is no conclusive evidence to support the use of lithium to augment antipsychotic medication in schizophrenia (compared with antipsychotic medication alone)⁷.

Before starting lithium

• Discuss with a psychiatrist - lithium should only be started under specialist supervision, weighing up the risks and benefits.

• If the patient is dangerously manic, refer for urgent admission.

• Lithium has a slow onset of action (7-14 days) so an antipsychotic may be needed initially - eg, haloperidol.

• Perform the following baseline tests:
  

  • Measure weight, blood pressure and pulse.

  • Ensure renal function is normal, as lithium is primarily excreted by the kidney. Measure serum creatinine, eGFR and possibly urine albumin:creatinine ratio (see SPC reference below for a good algorithm to follow).

  • Check FBC, U&E, creatinine, TFT, calcium. NB: plasma lithium levels are increased by sodium depletion (competitive reabsorption at the renal level)³.

  • Check there is no goitre; take blood for thyroid autoantibodies where there is a family history of thyroid disorders.

  • It may be worth measuring baseline parathyroid hormone and magnesium.

  • Perform baseline ECG.

Important drug interactions

Avoid any medicines that can impair renal function or induce hyponatraemia (see monograph). Seek specialist advice:

• Angiotensin-converting enzyme (ACE) inhibitors.

• Diuretics (particularly thiazides).

• Non-steroidal anti-inflammatory drugs (NSAIDs).

• Selective serotonin reuptake inhibitors (SSRIs) - sometimes co-prescribed.

Contra-indications

• Cardiac disease³.

• Significant renal impairment.

• Addison's disease and patients with low body sodium levels.

• Untreated hypothyroidism.

Pregnancy and breastfeeding⁸

• Pregnancy: avoid in the first trimester (teratogenic). Only use in the second and third trimester if considered essential (ie a severe risk to the patient) and monitor levels closely, as dose requirements may alter.

• Breastfeeding: avoid, as present in milk and there is risk of toxicity in an infant. Bottle-feeding is advisable.

Beginning treatment³

• Always prescribe non-generically by brand name - preparations may vary widely in bioavailability.

• Inform patients:
  

  • Of potential toxicity and symptoms of this (see 'Side-effects and toxicity', below).

  • That they should ensure they have a regular fluid intake.

  • Of the need for compliance in taking medication - reinforce this and that they should not stop or omit doses.

  • Of the dangers of crash diets.

  • To avoid NSAIDs.

  • Not to exceed more than 1-2 units of alcohol per day.

  • That it takes 3-6 months to be established on lithium.

  • That lithium cards are available from pharmacists.

• The initial dose will depend on weight - use a lower dose in elderly patients.

• Check lithium levels (12 hours following dose):
  

  • Five days following starting therapy or changing a dose.

  • Then check levels weekly until levels have been stable for four weeks.

  • Once levels have stabilised, check lithium levels every three months.

  • Consider more frequent monitoring (eg, every two months) in the elderly, in those on interacting medication or in those with renal, thyroid or cardiac disease.

• Target concentrations:
  

  • Acute episode (mania, hypomania, depression) 0.6-1.0 mmol/L (elderly 0.4-0.8 mmol/L).

  • Prophylaxis of bipolar affective disorder 0.4-0.8 mmol/L.

  • Toxic range usually >1.5 mmol/L; however, may begin at >1.0 mmol/L (levels >2 mmol/L need urgent treatment).

Monitoring lithium treatment

Many PCTs have agreed shared care protocols:

• Check lithium levels (12 hours post-dose) at least every three months and during any intercurrent illness (can increase and cause toxicity).

• Therapeutic lithium levels: 0.4 to 1.0 mmol/L (may vary from laboratory to laboratory).

• At each consultation, ask about any signs of toxicity or signs of hypothyroidism.

• Check thyroid function, U&Es, calcium and creatinine (and possibly urine dipstick for protein) every 6-12 months.

Side-effects and toxicity

• Lithium levels >1.5 mmol/L (>2.0 mmol/L may be associated with serious toxicity).

• Lithium toxicity should also be suspected at 'therapeutic' levels in compromised patients with relevant symptoms⁹.

Common side-effects
These can usually be reduced or eliminated by lowering the lithium dose or changing the dosage schedule:

• Abdominal pain.

• Nausea.

• Metallic taste in the mouth (usually wears off).

• Fine tremor.

• Thirst, polyuria, impaired urinary concentration - avoid fluid restriction.

• Weight gain and oedema.

Less commonly

• Acne.

• Cognitive impairment - presents as memory deficits, mild drowsiness.

• Hypothyroidism.

• Hyperparathyroidism and hypercalcaemia⁹.

• Hypermagnesaemia.

• Nephrogenic diabetes insipidus.

Toxicity

Toxicity may be due to intentional overdose but it usually occurs during chronic treatment because of reduced drug excretion (dehydration, worsening renal function, concurrent infections, and drug interactions).

Stop lithium, check level and refer for urgent assessment (encourage fluids, stop diuretics, monitor electrolytes and monitor renal function).

• Anorexia, diarrhoea and vomiting.

• Drowsiness, apathy, restlessness.

• Dysarthria.

• Dizziness, ataxia, inco-ordination, muscle twitching, coarse tremor.

Severe toxicity
Admit as an emergency (whole bowel irrigation may be considered if large quantities have been ingested).

• Hyperreflexia, convulsions.

• Collapse, coma.

• Renal failure, dehydration, circulatory collapse (may need haemodialysis).

• Hypokalaemia.

• Death.

Additionally ECG changes are noticed¹¹. T wave inversion was the most frequently reported ECG finding but other findings include sinus node dysfunction, sinoatrial blocks, PR prolongation, QT prolongation/dispersion, and ventricular tachyarrhythmias. Other cases have shown lithium-treated patients experiencing serious cardiac outcomes, such as ST elevation myocardial infarction and heart blocks. Electrical changes from lithium were found to be dependent on both duration of treatment and the serum lithium level.

Withdrawal

Abrupt withdrawal (both because of poor compliance or rapid change in dose) can precipitate relapse. Withdraw lithium slowly over several weeks, watching for relapse.