Lithium is a mood-stabilising agent used to treat a range of affective and behavioural disorders. It remains one of the most effective long-term therapies for bipolar disorder. Clinical Indications Acute manic or hypomanic episodes Depressive episodes resistant to antidepressants Prophylaxis of bipolar disorder (prevention of relapse) Control of aggression or self-harming behaviour The following article will describe the mechanism of action of lithium, key pharmacokinetic parameters, monitoring, contraindications and caution for use, side effects and clinically significant interactions. Mechanism of Action and Key Pharmacokinetic Parameters Although the exact mechanism is not fully understood, lithium is thought to: Modulate neurotransmitter production and turnover, particularly serotonin Block dopamine receptors Lithium is excreted via renal route and the elimination half-life ranges from 18 to 36 hours. Effect of Sodium on Lithium Levels Lithium and sodium compete for renal reabsorption (the kidneys treat lithium ions and sodium ions similarly) Lithium is largely absorbed in the proximal convoluted tubule (PCT), also in the distal tubule and collecting duct Sodium depletion → increased lithium reabsorption → toxicity risk. Patients should maintain a consistent salt and fluid intake. Created in BioRender. Boucher, M. (2025) https://BioRender.com/tw0kp4s Fig 1: Renal reabsorption of lithium Form Example Notes Lithium carbonate Tablets (e.g. Priadel®, Camcolit®) Modified-release formulations; doses not equivalent to liquid form Lithium citrate Oral liquid Used when tablets unsuitable Equivalence: Lithium carbonate 200 mg ≈ lithium citrate 509 mg When switching formulations or brands, re-monitor lithium levels due to potential bioavailability differences Monitoring Lithium possesses a narrow therapeutic window, so small differences in dose or blood concentration may lead to serious therapeutic failures or adverse drug reactions. Due to this, lithium requires therapeutic drug monitoring. Monitoring Parameter Timing / Frequency Target Range / Notes Lithium level 4–7 days after initiation or dose change Sample taken as a trough level, i.e. 24 hours after the last dose Target: 0.6–1.0 mmol/L Levels > 1.5 mmol/L indicate toxicity Renal function (U&E, eGFR) Baseline, then regularly Monitor for nephrotoxicity Thyroid function (TSH, T4) Baseline, then regularly Risk of hypothyroidism or goitre Cardiac function (ECG) Baseline, then regularly QT prolongation, bradyarrhythmia risk Contraindications Cardiac disease or insufficiency. Severe renal impairment. Untreated hypothyroidism. Breastfeeding Patients with low body sodium levels, including for example dehydrated patients or those on low sodium diets. Addison’s disease. Brugada syndrome or family history of Brugada syndrome. Cautions Epilepsy QT interval prolongation Avoid abrupt withdrawal due to risk of relapse May exacerbate psoriasis Interactions Increased Lithium Levels (Toxicity Risk) Drug Class Example Mechanism NSAIDs Ibuprofen, naproxen ↓ renal clearance ↑ nephrotoxicity risk ACE inhibitors / ARBs Ramipril, losartan ↓ renal clearance Thiazide diuretics Chlorthalidone, indapamide, metolazone ↓ renal clearance Metronidazole Metronidazole ↓ renal clearance Decreased Lithium levels Drug Class Example Mechanism SGLT2 inhibitors Empagliflozin, dapagliflozin ↑ renal excretion Caution with: Serotonergic agents → risk of serotonin syndrome QT-prolonging drugs → additive cardiac risk Drugs that lower seizure threshold Adverse effects Early (Often Transient) Nausea, diarrhoea Vertigo, muscle weakness Fine tremor Drowsiness or “dazed” feeling Long term/persistent effects Altered thyroid function Euthyroid goitre and/or hypothyroidism (risk appears to be greatest in the first 2 years of treatment and resolves upon stopping lithium) Thyrotoxicosis Electrolyte abnormalities Hypermagnesaemia Hypercalcaemia accompanied by elevations in circulating parathyroid hormone (PTH) suggesting primary hyperparathyroidism Nephrotoxicity A small reduction in glomerular filtration rate is seen in 20% of people taking lithium. Metabolic effects Weight increase Hyperglycaemia Neurological effects Tremor Benign intracranial hypertension (presents as a persistent headache and visual disturbance) Overdose Signs and symptoms of lithium overdose include the following: Mild Moderate Severe Nausea, diarrhoea, blurred vision, polyuria, lightheadedness, fine resting tremor, muscular weakness, drowsiness Increasing confusion, blackouts, fasciculation and increased deep tendon reflexes, myoclonic twitches and jerks, choreoathetoid movements, urinary or faecal incontinence, increasing restlessness followed by stupor. Hypernatraemia. Coma, convulsions, cerebellar signs, cardiac dysrhythmia (SA block, bradycardia, AV block), hypotension or rarely hypertension, circulatory collapse and renal failure. There is no antidote in lithium toxicity; patients electrolytes should be managed and monitoring should continue, gastric lavage for non-sustained-release preparations can be considered in certain situations and haemodialysis is the treatment of choice for severe lithium intoxication References https://www.medicines.org.uk/emc/product/13162/smpc#gref accessed 22.10.24 https://www.sps.nhs.uk/articles/specific-medicine-switches-for-solid-dose-and-liquid-formulations/ accessed 22.10.24 https://bnf.nice.org.uk/drugs/lithium-carbonate/ accessed 22.10.24 Do you think you’re ready? Take the quiz below Pro Feature - Quiz Lithium Question 1 of 3 Submitting... Skip Next Rate question: You scored 0% Skipped: 0/3 More Questions Available Upgrade to TeachMePharmacy Pro Challenge yourself with over 2100 multiple-choice questions to reinforce learning Learn More Rate This Article