Lithium Pharmacology

Lithium carbonate is the first-line maintenance treatment for bipolar disorder, an effective treatment for acute mania, and an augmentation agent for resistant depression. It reduces suicide and relapse rates. Its therapeutic index is narrow, and serum level monitoring is essential.

Mechanism. Lithium inhibits inositol monophosphatase and glycogen synthase kinase 3, and modulates neuroplasticity and signalling.

Pharmacokinetics. It is fully absorbed, not protein bound, not metabolised, and cleared by the kidney, with a half-life of 18 to 36 hours (longer in older adults and renal impairment). Proximal tubule reabsorption competes with sodium, so sodium depletion, dehydration and drugs that reduce renal sodium clearance raise lithium levels.

Preparations. Modified-release lithium carbonate tablets (usually 400 mg) and lithium citrate liquid. Preparations are not interchangeable, so levels are rechecked on any switch.

Starting. 400 mg once daily at night (200 mg in older adults), adjusted by level.

Target serum level. 0.6 to 0.8 mmol/L for maintenance (0.8 to 1.0 mmol/L after relapse on a lower level, 0.4 to 0.6 mmol/L in older adults); 0.8 to 1.2 mmol/L in acute mania. Levels are taken 12 hours after the last dose.

Differences. Other mood stabilisers carry fewer renal and thyroid effects but weaker evidence for maintenance and suicide prevention.

• Bipolar maintenance and acute mania: first-line where monitoring is available.
• Augmentation in depression: 0.6 to 0.8 mmol/L added to an antidepressant after 2 failed courses.
• Monitoring schedule: level 5 to 7 days after starting or any dose change, weekly until stable, then every 3 months for the first year and every 6 months afterwards (every 3 months in older adults, those with renal impairment or on interacting drugs).
• Baseline: urea and electrolytes, eGFR, calcium, thyroid function, ECG in those over 50 or with cardiac disease, weight, and pregnancy test.
• Stopping: taper over at least 4 weeks, preferably 3 months, to reduce rebound mania.
• Sick day rule: stop lithium during vomiting, diarrhoea, fever with dehydration or poor intake, and restart when eating and drinking normally.

Special groups. Pregnancy: avoid in the first trimester where possible (small excess of cardiac malformations including Ebstein anomaly, absolute risk under 1%); if continued, check levels monthly then weekly in the final month, as clearance rises by up to 50% and falls after delivery. Breastfeeding: infant levels are 30 to 50% of maternal, so avoid unless the infant can be monitored. Children: from 12 years under specialist care.

Older adults: lower target and more frequent levels. Kidney impairment: avoid with eGFR under 30 mL/min. Liver impairment: no change. Regional: heat, heavy sweating, gastroenteritis and fasting cause dehydration and lithium toxicity; unrestricted NSAID use is common; where level testing is not available, lithium should not be started.

Adverse effects. Fine tremor, nausea, diarrhoea, thirst and polyuria (nephrogenic diabetes insipidus), weight gain, hypothyroidism (about 20%), hyperparathyroidism and hypercalcaemia, leucocytosis, acne and psoriasis flares, ECG changes, and chronic kidney disease with long-term use.

Toxicity. Mild (1.5 to 2.0 mmol/L): coarse tremor, nausea, diarrhoea, ataxia. Moderate (2.0 to 2.5 mmol/L): confusion, hyperreflexia, myoclonus, seizures. Severe (over 2.5 mmol/L): coma, arrhythmia. Management: stop lithium, give 0.9% sodium chloride, monitor levels every 6 hours, and consider haemodialysis for a level over 4.0 mmol/L with impaired kidney function, any level with reduced consciousness, seizures or arrhythmia, or when the level is expected to stay high. Activated charcoal does not bind lithium.

Contraindications. Severe renal impairment, Addison disease, untreated hypothyroidism, Brugada syndrome, and sodium depletion.

Interactions. NSAIDs (levels rise 20 to 60%), ACE inhibitors and angiotensin receptor blockers, thiazides (levels rise 25 to 40%), loop and potassium-sparing diuretics, metronidazole, and carbamazepine or antipsychotics (neurotoxicity).

Monitoring. Lithium level, eGFR, calcium and thyroid function every 6 months.

Referral and escalation. Toxicity, eGFR fall, hypercalcaemia, hypothyroidism, or pregnancy.