Lithium

What is lithium?

The anti-manic properties of lithium were first discovered by Australian psychiatrist John Cade in 1949.¹ 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 years.²

Indications³⁴⁵

The summary of product characteristics says that use in the paediatric population is not recommended, but it is listed in the BNF for the following indications, in children aged 12-17 and in adults:

• Treatment and prophylaxis of mania.

• Treatment and prophylaxis of bipolar disorder.

• Treatment and prophylaxis of recurrent depression.

• Treatment and prophylaxis of aggressive or self-harming behaviour.

There are reports of its use in other areas, which are not listed in the BNF or the summary of product characteristics, and are therefore unlicensed:

• Schizophrenia or schizoaffective disorder as an addition to antipsychotics - a 2015 Cochrane review noted that the available evidence is of low quality, but that further trials were justified. ⁶

• Augmentation of the antidepressant effect when it is co-prescribed with antidepressants in treatment resistant depression.⁷

• Prophylaxis of cluster headache.⁸⁹

• Control of aggressive behaviour or intentional self-harm and possibly suicidal behaviour. ¹⁰

Before starting lithium

Lithium should never be started in primary care - the decision to start should rest with a consultant psychiatrist or a suitably qualified member of their team, and the drug should be prescribed in secondary care until the patient is stable. The following actions are therefore only relevant to those in secondary care, who should arrange their own tests rather than asking the GP to do this on their behalf:

• If the patient is dangerously manic, consider admission, either on a voluntary basis or using the Mental Health Act.

• 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).

  • 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

There is a long list of medications that interact with lithium - electronic prescribing software should be used when available, and the BNF consulted, to avoid dangerous interactions.

Contra-indications

• Cardiac disease associated with rhythm disorder.

• Cardiac insufficiency.

• Dehydration.

• Personal or family history of Brugada syndrome.

• Addison's disease.

• Low sodium diet.

• Untreated hypothyroidism.

Pregnancy and breastfeeding ¹¹¹²¹³

• Pregnancy: ideally avoid in the first trimester (teratogenic). Only use in the second and third trimester if the benefits of control of mental health outweigh the possible risks to the fetus, and monitor levels every four weeks, and every week after 36 weeks gestation.

• Breastfeeding: ideally avoid, as present in milk and there is risk of toxicity in an infant. Bottle-feeding is advisable. If breastfeeding is seen as essential then this must be done very cautiously, under specialist supervision and with close monitoring of the infant.

Beginning lithium 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 blood levels during the early days of prescribing may vary by indication and should be set by the patient's specialist.

Monitoring lithium treatment ¹⁴

This may be done in general practice, if there is an agreed and resourced shared care protocol. Shared care can only be done if consent is freely given by the GP, who feels that it is safe. Otherwise, prescribing and monitoring responsibilities rest with the specialist, on a long-term basis.

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

• Target therapeutic lithium levels will vary with indication and previous experiences such as a relapse while taking lithium, or ongoing sub-threshold symptoms while taking lithium. They should be set by the patient's specialist.

• 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 toxicity¹⁵

• Lithium levels >1.5 mmol/L (>2.0 mmol/L may be associated with serious toxicity); toxicity can also occur with normal levels, and the diagnosis should not be excluded because levels are not high.

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 hypercalcaemia.

• Hypermagnesaemia.

• Nephrogenic diabetes insipidus.

• Neurological symptoms such as tremor and ataxia.

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 noticed.¹⁷ 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.

Lithium withdrawal

Abrupt withdrawal (both because of poor adherence or rapid change in dose) can precipitate relapse. If a decision is made to stop lithium, withdraw it slowly over several weeks, with regular specialist monitoring for relapse.