Lithium

Indications for Use

Lithium carbonate is a well-established mood stabiliser primarily used in the management of Bipolar disorder and related conditions. Its main indications include:

• Acute manic or hypomanic episodes: Reduces elevated mood, irritability, overactivity, and other symptoms of mania.

• Depressive episodes resistant to antidepressants: Used as an augmentation strategy and in bipolar depression, with additional anti-suicidal benefits.

• Prophylaxis of bipolar disorder: Long-term treatment to prevent relapse of both manic and depressive episodes.

• Control of aggression or self-harming behaviour: Helps stabilise mood and reduce impulsivity in selected patients.

Lithium remains a cornerstone treatment due to its effectiveness in both acute management and long-term relapse prevention.

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 leads to increased lithium reabsorption, increasing toxicity risk.
• Patients should be counselled to maintain a consistent salt and fluid intake.

Created in BioRender. Boucher, M. (2025) https://BioRender.com/tw0kp4s

Fig 1: Renal reabsorption of lithium

Equivalence:

• Lithium carbonate (tablets) and lithium citrate (liquid) are not bioequivalent; lithium carbonate 200 mg ≈ lithium citrate 509 mg
• When switching formulations or brands, clinicians should 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.

Contraindications

Cardiac disease or insufficiency: lithium can affect cardiac conduction and may worsen underlying heart disease. It is contraindicated in patients with significant cardiac insufficiency or unstable cardiac conditions, as toxicity may precipitate arrhythmias or conduction abnormalities.

Severe renal impairment: lithium is almost entirely excreted by the kidneys. In severe renal impairment, reduced clearance increases the risk of accumulation and toxicity. For this reason, it is contraindicated in patients with significantly compromised renal function.

Untreated hypothyroidism: lithium can interfere with thyroid hormone synthesis and release. In patients with untreated hypothyroidism, it may worsen thyroid dysfunction; thyroid status should therefore be corrected before initiation.

Breastfeeding: lithium passes readily into breast milk and may reach clinically significant levels in the infant.  Its use is contraindicated during breastfeeding because of the risk of toxicity in the neonate.

Low body sodium levels (e.g., dehydration or low-sodium diet): sodium depletion increases renal reabsorption of lithium, raising serum lithium concentrations and the risk of toxicity. Patients who are dehydrated or following strict low-sodium diets should not commence lithium until sodium balance is corrected.

Addison’s disease: In Addison’s disease, disturbances in sodium balance and fluid regulation increase the risk of lithium accumulation and toxicity. Lithium is therefore contraindicated in this condition.

Brugada syndrome or family history of Brugada syndrome: lithium may unmask or exacerbate conduction abnormalities associated with Brugada syndrome. It is contraindicated in patients with known Brugada syndrome or a strong family history of the condition.

Cautions

Epilepsy: lithium may lower the seizure threshold in susceptible individuals. Patients with epilepsy should be monitored closely, particularly during initiation and dose adjustments.

QT interval prolongation: lithium can influence cardiac conduction and may contribute to QT interval prolongation. Caution is advised in patients with known QT prolongation or those taking other QT-prolonging medications.

Avoid abrupt withdrawal: sudden discontinuation of lithium is associated with a high risk of relapse, particularly into mania. Dose reduction should be gradual and carefully supervised to minimise destabilisation.

Psoriasis: lithium may precipitate or worsen psoriasis. In patients with a history of psoriasis, treatment should be undertaken cautiously with monitoring for dermatological exacerbations.

Interactions

Drug interactions can be clinically significant, due to lithium’s narrow therapeutic window and being almost entirely excreted by the kidneys. Many clinically significant interactions occur through effects on renal function or sodium balance. Careful monitoring of lithium levels is essential when interacting medicines are started, stopped, or adjusted.

Increased Lithium Levels (Toxicity Risk)

Decreased Lithium levels (Subtherapeutic Levels Risk)

Caution should be taken with the following interacting drugs if used alongside lithium:

Serotonergic agents (e.g., MAOIs) may increase the risk of serotonin syndrome when combined with lithium, particularly in patients receiving multiple serotonergic drugs.

QT-prolonging medications may have additive effects on cardiac conduction when used with lithium, increasing the risk of arrhythmias in susceptible individuals.

Drugs that lower the seizure threshold, such as quinolone antibiotics, should be used cautiously, as lithium may also increase seizure risk in vulnerable patients.

Adverse Effects

Lithium is generally well tolerated when maintained within its therapeutic range; however, side effects are relatively common, particularly during initiation or dose adjustment. These adverse effects can be broadly divided into early (often transient) reactions and longer-term or persistent complications

Early (Often Transient) Effects:

During the early stages of treatment, patients may experience gastrointestinal symptoms such as nausea and diarrhoea. These effects are usually mild and tend to improve over time or with dose adjustment. Taking lithium with food or using modified-release preparations can help minimise these symptoms.

Neurological effects are also common at the start of therapy. Patients may report vertigo, a sense of muscle weakness, or a fine tremor-typically affecting the hands. This tremor is usually dose-related and may lessen as serum levels stabilise. Some individuals describe feeling drowsy or mildly “dazed,” particularly during the first few weeks of treatment. In most cases, these symptoms are temporary and resolve as the body adapts to the medication.

Long-term lithium therapy is associated with effects on thyroid function. Altered thyroid function is one of the most recognised complications. Patients may develop euthyroid goitre or hypothyroidism, with the risk appearing greatest within the first two years of treatment. Importantly, hypothyroidism often resolves after discontinuation of lithium, though some patients may require ongoing thyroid hormone replacement. Lithium can also cause thyrotoxicosis, because of these potential effects, regular monitoring of thyroid function is recommended throughout treatment.

Lithium may also influence electrolyte balance. Reported abnormalities include hypermagnesaemia and hypercalcaemia. In some cases, elevated calcium levels are accompanied by increased circulating parathyroid hormone (PTH), suggesting lithium-associated primary hyperparathyroidism. Persistent hypercalcaemia requires further evaluation and may necessitate adjustment or discontinuation of therapy.

Nephrotoxicity is a significant long-term concern. A small reduction in glomerular filtration rate (GFR) is observed in approximately 20% of individuals receiving lithium. While often mild, progressive renal impairment can occur in some patients, increasing the risk of lithium toxicity, making regular monitoring of renal function crucial throughout therapy.

Metabolic effects may include weight gain and hyperglycaemia. These changes can contribute to increased cardiovascular risk over time and should be managed proactively with lifestyle advice and metabolic monitoring.

Neurological effects may persist beyond the initiation phase. Tremor can remain problematic, particularly at higher serum concentrations. Rarely, lithium has been associated with benign intracranial hypertension, which presents with persistent headache and visual disturbances and requires urgent medical evaluation.

In summary, although many early adverse effects of lithium are mild and transient, its long-term use requires structured monitoring of renal, thyroid, parathyroid, and metabolic parameters to ensure safe and effective treatment.

Overdose

Signs and symptoms of lithium overdose include the following:

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

1. https://www.medicines.org.uk/emc/product/13162/smpc#gref accessed 22.10.24 
2. https://www.sps.nhs.uk/articles/specific-medicine-switches-for-solid-dose-and-liquid-formulations/ accessed 22.10.24
3. https://bnf.nice.org.uk/drugs/lithium-carbonate/ accessed 22.10.24