Lithium
lithium carbonate (tablets/capsules) · lithium citrate (oral solution)
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Acute manic and mixed episodes of bipolar I disorder | ≥7 years | Monotherapy | FDA Approved |
| Maintenance treatment of bipolar I disorder | ≥7 years | Monotherapy | FDA Approved |
Lithium remains the gold standard mood stabiliser and was the first medication approved by the FDA for treating bipolar disorder (1970). It is indicated as monotherapy for both the acute treatment of manic and mixed episodes and as maintenance therapy to reduce the frequency and intensity of mood episodes in bipolar I disorder. The 2018 label update extended the approved age range to patients 7 years and older based on a paediatric clinical trial. A sustained-release formulation is approved for patients 12 years and older. Lithium reduces mania, prevents recurrence, and has a unique evidence base for reducing suicide risk in bipolar disorder, an effect not formally in the approved label but consistently supported across observational studies and meta-analyses.
Augmentation of antidepressants in unipolar depression: Robust evidence supports lithium addition when SSRIs or SNRIs provide partial response. Recommended by multiple guidelines including NICE and CANMAT. Evidence quality: High (multiple RCTs).
Cluster headache prophylaxis: Used when verapamil is ineffective or contraindicated; supported by small RCTs. Evidence quality: Moderate.
Neutropenia (chemotherapy or clozapine-induced): Lithium stimulates granulopoiesis. Evidence quality: Low (case series).
Schizoaffective disorder: Commonly prescribed in clinical practice although formal RCT data are limited. Evidence quality: Low.
Dosing
Adults and Paediatric Patients >30 kg
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Acute mania — initial stabilisation | 300 mg TID (900 mg/day) | 600 mg BID–TID (1200–1800 mg/day) | Titrate to serum level 0.8–1.2 mEq/L | Increase by 300 mg every 3 days; check serum level after 3 days from initiation, then regularly until stable Higher doses may be required acutely; reduce as mania resolves |
| Bipolar I maintenance — long-term prophylaxis | 300 mg BID–TID | 300–600 mg BID–TID (900–1200 mg/day) | Titrate to serum level 0.8–1.0 mEq/L | Lower end of therapeutic range preferred to minimise long-term organ effects; monitor levels at least every 2 months once stable |
| Antidepressant augmentation (off-label) | 300 mg daily | 600–900 mg/day | Target serum 0.6–0.8 mEq/L | Lower target levels used; response typically seen within 2–4 weeks Not FDA-approved; supported by NICE, CANMAT guidelines |
Paediatric Patients 20–30 kg
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Acute mania (7–17 years, 20–30 kg) | 300 mg BID (600 mg/day) | 600–1500 mg/day in divided doses | Titrate to serum 0.8–1.2 mEq/L | Increase by 300 mg weekly (slower titration than adults); target same serum range |
| Bipolar I maintenance (7–17 years, 20–30 kg) | 300 mg BID | 600–1200 mg/day in divided doses | Titrate to serum 0.8–1.0 mEq/L | Apparent clearance increases with body weight; dose requirements are weight-based |
Special Populations
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Mild–moderate renal impairment (CrCl 30–89) | Lower than standard | Guided by serum levels | Per serum levels | Titrate slowly; frequent serum lithium monitoring; lithium clearance is directly proportional to renal function |
| Severe renal impairment (CrCl <30) | Avoid use | Risk of lithium accumulation and toxicity greatly increased | ||
| Elderly (≥65 years) | Low end of dosing range | Guided by serum levels | Per serum levels | Age-related decline in renal function reduces clearance; may show toxicity at levels tolerated by younger patients; start low, titrate cautiously |
| Pregnancy | Monitor and adjust per serum levels throughout | Renal clearance increases during pregnancy, requiring dose increases. Reduce or stop 2–3 days before expected delivery. Restart at preconception dose postpartum with close monitoring Fetal echocardiography recommended at 16–20 weeks if first-trimester exposure | ||
Serum lithium levels must be drawn 12 hours after the last dose (trough level) for accurate interpretation. Obtain the first level 3 days after initiation or dose change, then check regularly until stable. During maintenance, levels should be monitored at minimum every 2 months. Additional checks are required after any change in concurrent medications (especially diuretics, NSAIDs, ACE inhibitors), illness with dehydration or fever, or significant changes in sodium or fluid intake. The 8 mEq/5 mL oral solution is equivalent to 300 mg lithium carbonate.
Pharmacology
Mechanism of Action
The precise mechanism by which lithium stabilises mood is not fully understood, despite more than five decades of clinical use. Lithium is a monovalent cation that alters sodium transport across cell membranes in nerve and muscle tissue and influences intraneuronal catecholamine metabolism. It inhibits glycogen synthase kinase-3 beta (GSK-3β), a key enzyme in multiple signalling cascades including the Wnt pathway and neuroprotective pathways. Lithium also depletes inositol stores by inhibiting inositol monophosphatase, thereby attenuating overactive phosphatidylinositol signalling that may contribute to manic states. Additional proposed mechanisms include enhancement of serotonergic neurotransmission, modulation of glutamate receptor activity, upregulation of neuroprotective proteins such as BDNF and Bcl-2, and stabilisation of circadian rhythms. The convergence of these effects on neuroplasticity and intracellular signalling cascades likely explains its broad efficacy across both poles of bipolar disorder and its unique anti-suicidal properties.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Complete absorption from upper GI tract; Tmax 0.25–3 h (IR), 2–6 h (ER) | Take with food to reduce GI side effects; extended-release produces lower peak levels, potentially fewer peak-related side effects |
| Distribution | Vd 0.7–1.0 L/kg (approximates total body water); negligible protein binding | Distributes throughout body water; brain equilibrium may take up to 24 h (toxicity symptoms can be delayed); not displaced by other protein-bound drugs |
| Metabolism | Not metabolised | No hepatic drug-drug interactions via CYP enzymes; no dose adjustment needed for hepatic impairment |
| Elimination | t½ 18–36 h; 95% excreted renally; 80% reabsorbed in proximal tubule; fecal excretion insignificant | Clearance is directly dependent on GFR; anything reducing renal perfusion (dehydration, NSAIDs, ACE inhibitors) increases levels and toxicity risk; sodium depletion increases proximal tubular lithium reabsorption |
Side Effects
Lithium’s adverse effect profile is well-characterised from decades of clinical use. Adult adverse reaction frequencies below are derived from published cohort studies and systematic reviews (Gitlin 2016; Vestergaard 1988; McKnight 2012), as the FDA PI lists adult adverse reactions from voluntary reports without specific incidence rates. Paediatric data are from the pivotal 8-week placebo-controlled trial (N=53 lithium, N=28 placebo) in the FDA PI.
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Polyuria / polydipsia | 30–60% | Most common complaint; due to renal concentrating defect (nephrogenic DI); may worsen with duration of therapy; amiloride 5 mg BID can be used as antidote (FDA PI Section 5.2) |
| Tremor (fine hand) | 25–50% | Dose- and level-related; usually fine postural tremor; can be managed with propranolol 20–40 mg BID or dose reduction; coarse tremor suggests toxicity |
| Weight gain | 20–47% | Average 4–6 kg in first 2 years; more pronounced in women; multifactorial (increased thirst with caloric beverages, hypothyroidism, insulin effects); may predict later hypothyroidism |
| Nausea / GI discomfort | 10–30% | Most prominent during initiation; usually transient; improves with food or dose splitting; persistent nausea may indicate rising levels |
| Cognitive dulling | 15–30% | Subjective complaints of mental sluggishness, slowed thinking, impaired creativity; major contributor to non-adherence; dose-related; must distinguish from depressive symptoms |
| Hypothyroidism (clinical or subclinical) | 8–27% clinical; up to 40% subclinical | Lithium concentrates in thyroid and inhibits synthesis/release; higher risk in women; treat with levothyroxine — do not discontinue lithium solely for hypothyroidism; monitor TSH regularly |
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Diarrhoea | Up to 10% | More common at levels >0.8 mEq/L and with sustained-release formulations; new-onset diarrhoea should prompt level check (may indicate toxicity) |
| Acne / dermatological effects | 3–10% | Includes folliculitis, psoriasis exacerbation, xerosis, alopecia; dermatology referral may be needed |
| Hyperparathyroidism / hypercalcaemia | 5–10% | Recognised in long-term use; may require surgical intervention if symptomatic; does not always resolve after lithium discontinuation; more often multiglandular |
| ECG changes | 5–10% | T-wave flattening or inversion; QTc prolongation; sinus node dysfunction; typically benign but Brugada syndrome can be unmasked |
| Leukocytosis | Common | Benign WBC elevation (typically 10,000–15,000); granulopoietic effect can be exploited to treat drug-induced neutropenia |
| Oedema | 4–5% | Ankle and wrist swelling; usually mild and sodium-related |
| Dysgeusia | 5% | Metallic or salty taste; may contribute to poor adherence |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Lithium toxicity (mild: 1.5–2.0 mEq/L) | Dose-dependent; risk increases with dehydration, drug interactions | Hours to days; may be delayed up to 24 h due to slow CNS distribution | Stop lithium; check level urgently; IV fluids; monitor neurological and cardiac status; mild symptoms (coarse tremor, ataxia, drowsiness) usually resolve with drug cessation |
| Lithium toxicity (severe: >2.5 mEq/L) | Potentially fatal | Hours | Seizures, coma, cardiovascular collapse possible; haemodialysis is the definitive treatment; ICU admission; activated charcoal is NOT effective; permanent cerebellar damage may result |
| Chronic tubulointerstitial nephropathy | ~26% CKD Stage 3 (eGFR <60) in long-term users | Years of treatment | Monitor eGFR/creatinine regularly; progressive decline warrants nephrology referral and risk-benefit reassessment; end-stage renal disease requiring dialysis is rare but reported |
| Nephrogenic diabetes insipidus | Up to 40% with prolonged use | Weeks to months | May be partially irreversible with long-term exposure; treat with amiloride; avoid dehydration which exacerbates lithium toxicity risk; may require lithium discontinuation if severe |
| Serotonin syndrome | Rare | Hours to days after adding serotonergic drug | Discontinue lithium and serotonergic agent; supportive care; cyproheptadine may be considered; higher risk with MAOIs, SSRIs, SNRIs |
| Encephalopathic syndrome (with antipsychotics) | Rare | Variable | May present as NMS-like picture with weakness, fever, confusion, EPS; may lead to irreversible brain damage; stop both agents immediately if suspected |
| Ebstein anomaly (fetal cardiac malformation) | Absolute risk likely small but elevated vs background | First trimester exposure | Fetal echocardiography at 16–20 weeks; risk-benefit discussion with patient; consider alternatives if possible during organogenesis |
| Brugada syndrome unmasking | Rare (postmarketing) | Any time | ECG if unexplained syncope or palpitations; cardiology consultation; discontinue lithium if confirmed |
Fine postural hand tremor is one of the most common side effects and a leading cause of patient concern. It is dose- and level-related and typically improves at lower serum concentrations. First-line management includes minimising the lithium level within the therapeutic range, ensuring adequate hydration, reducing caffeine intake, and administering lithium as a single bedtime dose (if clinically appropriate) to lower daytime peak levels. If persistent, low-dose propranolol (20–40 mg BID) is effective. Coarse tremor, intention tremor, or sudden worsening of tremor should prompt an urgent serum lithium level as these may indicate toxicity.
Drug Interactions
Lithium is not metabolised by CYP enzymes, so pharmacokinetic interactions occur almost exclusively through changes in renal handling. Since 80% of filtered lithium is reabsorbed in the proximal tubule alongside sodium, any condition or drug that reduces sodium reabsorption, renal blood flow, or GFR will increase lithium levels. Pharmacodynamic interactions involve additive neurotoxicity or serotonergic effects.
Monitoring
-
Serum Lithium Level
3 days after initiation, then regularly until stable; ≥every 2 months in maintenance
Routine Draw 12 hours post-dose (trough). Recheck after any dose change, new interacting medication, illness with dehydration, or change in sodium intake. Acute target 0.8–1.2 mEq/L; maintenance 0.8–1.0 mEq/L. Toxicity ≥1.5 mEq/L. -
Renal Function
Baseline, then every 6–12 months
Routine Serum creatinine and eGFR. Also consider urine osmolality or 24-hour urine volume to assess concentrating ability. Progressive decline warrants nephrology referral. CKD Stage 3 occurs in ~26% of long-term users. -
Thyroid Function
Baseline, 3 months, then every 6–12 months
Routine TSH and free T4. Hypothyroidism occurs in 8–27% of patients; treat with levothyroxine without necessarily stopping lithium. Rare hyperthyroidism also reported. -
Serum Calcium
Baseline, then annually
Routine Long-term lithium causes hyperparathyroidism with hypercalcaemia in 5–10% of patients. Check PTH if calcium is elevated. May require surgical intervention; does not always reverse after lithium cessation. -
Electrolytes
Baseline and periodically
Routine Sodium and potassium. Lithium can cause hyponatraemia via renal sodium wasting. Instruct patients to maintain normal salt and fluid intake (2500–3000 mL/day initially). Supplement salt during excessive sweating or diarrhoea. -
ECG
Baseline (especially >40 years or cardiac history)
Trigger-based Assess for baseline conduction abnormalities and Brugada pattern. T-wave changes are common and usually benign. Repeat if syncope or palpitations occur during treatment. -
Weight / BMI
Baseline and every visit
Routine Monitor for clinically significant weight gain; counsel on dietary strategies; weight gain in the first year may predict subsequent hypothyroidism development. -
Pregnancy Test
Before initiation in women of childbearing potential
Trigger-based Lithium is associated with cardiac malformations (Ebstein anomaly) with first-trimester exposure. Discuss contraception. If pregnancy occurs, consider fetal echocardiography at 16–20 weeks.
Contraindications & Cautions
Absolute Contraindications
- Severe renal impairment (CrCl <30 mL/min) — inability to reliably excrete lithium; very high toxicity risk
- Known hypersensitivity — to any inactive ingredient in lithium carbonate or lithium citrate products
Relative Contraindications (Specialist Input Recommended)
- Brugada syndrome or suspected Brugada — lithium may unmask this arrhythmia syndrome; cardiology consultation required before initiating
- Significant cardiovascular disease — sick sinus syndrome, AV block; risk of lithium-induced conduction disturbances
- Severe dehydration or sodium depletion — must be corrected before lithium initiation; concurrent low-sodium diets are hazardous
- Addison disease or other sodium-wasting conditions — compromised sodium homeostasis makes lithium-sodium balance precarious and increases toxicity risk
- First trimester of pregnancy — risk of cardiac malformations; use only if benefits clearly outweigh risks after specialist discussion
Use with Caution
- Mild–moderate renal impairment — start lower, titrate slower, monitor more frequently
- Elderly patients — reduced renal clearance; may show toxicity at levels tolerated by younger adults
- Concurrent diuretics, NSAIDs, or ACE inhibitors — all raise lithium levels substantially
- Hypothyroidism (pre-existing) — lithium will exacerbate; ensure thyroid replacement is optimised
- Psoriasis — lithium may trigger or exacerbate psoriasis; dermatology co-management may be needed
Lithium toxicity is closely related to serum lithium concentrations and can occur at doses close to therapeutic levels. Facilities for prompt and accurate serum lithium determinations should be available before initiating therapy. Some patients may exhibit toxic signs at serum concentrations considered within the therapeutic range. The toxic range (≥1.5 mEq/L) is perilously close to the therapeutic range (0.8–1.2 mEq/L). Risk factors for toxicity include renal impairment, dehydration, sodium depletion, febrile illness, and concurrent medications that reduce lithium clearance. No specific antidote exists; haemodialysis is the treatment of choice for severe toxicity.
Patient Counselling
Purpose of Therapy
Lithium is a mood-stabilising medication that helps prevent the extreme mood swings of bipolar disorder. It is most effective at reducing manic episodes and preventing future episodes of both mania and depression. It works best when taken consistently every day at the same times. Unlike many medications, lithium requires regular blood tests to ensure the dose is right for you, because the difference between an effective dose and a harmful one is very small.
How to Take
Take lithium exactly as prescribed, at the same times each day. Swallow tablets or capsules whole with a full glass of water, preferably with food to reduce stomach upset. Drink plenty of fluids daily (at least 8–10 glasses) and maintain a normal salt intake in your diet. Do not suddenly change the amount of salt in your diet without discussing it with your prescriber. Never double a missed dose. Extended-release tablets should not be crushed or chewed.
Sources
- Lithium (oral solution) / Lithium Carbonate (tablets, capsules). Full Prescribing Information. West-Ward Pharmaceuticals Corp. Revised 12/2018. FDA LabelPrimary regulatory source for all dosing, contraindications, warnings, paediatric trial data, and drug interactions.
- Lithium Carbonate Extended-Release Tablets, USP. DailyMed label. DailyMedExtended-release formulation label; describes different PK profile with lower peak concentrations.
- Findling RL, Robb A, McNamara NK, et al. Lithium in the acute treatment of bipolar I disorder: a double-blind, placebo-controlled study. Pediatrics. 2015;136(5):885–894. DOIPivotal paediatric RCT (NCT01166425) that led to the 2018 label expansion to age ≥7 years.
- Bowden CL, Brugger AM, Swann AC, et al. Efficacy of divalproex vs lithium and placebo in the treatment of mania. JAMA. 1994;271(12):918–924. DOILandmark RCT comparing lithium, valproate, and placebo for acute mania in adults.
- BALANCE investigators. Lithium plus valproate combination therapy versus monotherapy for relapse prevention in bipolar I disorder (BALANCE): a randomised open-label trial. Lancet. 2010;375(9712):385–395. DOIMajor maintenance trial demonstrating superiority of lithium-containing regimens over valproate monotherapy.
- Yatham LN, Kennedy SH, Parikh SV, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder. Bipolar Disord. 2018;20(2):97–170. DOIComprehensive guideline recommending lithium as first-line for acute mania and maintenance in bipolar I.
- National Institute for Health and Care Excellence (NICE). Bipolar disorder: assessment and management. Clinical guideline CG185. Updated 2020. NICEUK guideline positioning lithium as first-line maintenance for bipolar disorder and first-line antidepressant augmentation strategy.
- Malhi GS, Tanious M, Das P, Coulston CM, Berk M. Potential mechanisms of action of lithium in bipolar disorder: current understanding. CNS Drugs. 2013;27(2):135–153. DOIReview of GSK-3β inhibition, inositol depletion, and neuroprotective mechanisms underlying lithium’s therapeutic effects.
- Gitlin M. Lithium side effects and toxicity: prevalence and management strategies. Int J Bipolar Disord. 2016;4(1):27. DOIComprehensive review of lithium side effect prevalence and evidence-based management strategies for tremor, polyuria, and renal/thyroid effects.
- McKnight RF, Adida M, Budge K, et al. Lithium toxicity profile: a systematic review and meta-analysis. Lancet. 2012;379(9817):721–728. DOISystematic review of lithium’s effects on renal function, thyroid, and parathyroid across 385 studies.
- Shine B, McKnight RF, Leaver L, Geddes JR. Long-term effects of lithium on renal, thyroid, and parathyroid function: a retrospective analysis of laboratory data. Lancet. 2015;386(9992):461–468. DOILarge retrospective cohort (500,000+ individuals) establishing hazard ratios for CKD, hypothyroidism, and hypercalcaemia with lithium use.
- Cipriani A, Hawton K, Stockton S, Geddes JR. Lithium in the prevention of suicide in mood disorders: updated systematic review and meta-analysis. BMJ. 2013;346:f3646. DOIMeta-analysis providing evidence for lithium’s unique anti-suicidal effect in mood disorder patients.
- Gitlin M, Bauer M. Current state of lithium therapy. Chapter in: Pharmacotherapy for Bipolar Disorders. 2023. PMCMost recent comprehensive review of lithium efficacy, side effects, renal outcomes, and clinical monitoring recommendations.