Exact mechanism unclear; affects second messengers (inositol triphosphate, GSK-3β), modulates serotonergic and dopaminergic transmission. First-line for bipolar disorder, reduces suicide risk. Narrow therapeutic window 0.6–1.2 mmol/L; overdose causes neurotoxicity and nephrotoxicity.
Indications
A
Acute psychomotor agitation
First line
For acute mania, lithium is effective as monotherapy or combined with antipsychotics. 2019 Cochrane review (McKnight) confirmed efficacy with NNT approximately 6 for clinical response. Onset is 5–7 days, so combination with a rapid-acting antipsychotic or benzodiazepine is common in the acute phase.
Lithium is the first-line maintenance therapy for bipolar disorder type I and II. CG185 2023 and RANZCP 2022 list lithium as the drug of choice for long-term mood stabilization in adults. Reduces manic episodes by 60–70% and depressive episodes by 30–40%. For acute mania, comparable to valproate and atypical antipsychotics. Lithium is unique in reducing suicide risk in bipolar disorder (Cipriani 2013 meta-analysis demonstrated all-cause mortality reduction).
Narrow therapeutic range: 0.6–1.2 mmol/L. Regular monitoring of plasma level, renal function, and thyroid is mandatory.
Lithium is used as augmentation in patients with treatment-resistant unipolar depression. and recommend adding lithium to an antidepressant when adequate monotherapy fails. Meta-analyses show NNT approximately 5 for remission. Target blood level 0.4–0.8 mmol/L (lower than for bipolar disorder).
In Russia, the treatment-resistant depression indication is not registered directly in GRLS; use is off-label per clinical guidelines.
The drug is promoted for these uses outside international guidelines. Each entry below is analyzed against AEMPS, FDA, EMA, Cochrane and major RCTs.
F
Behavioral disturbance in dementia
Not recommended
Lithium use without therapeutic drug monitoring is unacceptable. Narrow therapeutic range (0.6–1.2 mmol/L) and toxicity at levels above 1.5 mmol/L require regular monitoring every 3–6 months and with any change in dose, diet, or comedications. Without TDM the drug is not prescribed.
Starting dose 300–600 mg lithium carbonate/day (adults), increase by 300 mg every 5–7 days to target level 0.6–1.2 mmol/L. Maintenance dose typically 600–1200 mg/day in 2–3 divided doses. Extended-release forms (Lithobid) are dosed 1–2 times daily. In patients with eGFR 30–60 mL/min, halve the dose and monitor more frequently.
Monitoring
Plasma lithium level (12 hours after last dose): at 5–7 days post-initiation, with dose changes, and with any suspected toxicity. After stabilization, every 3 months in the first year, then every 6 months. Target range 0.6–1.2 mmol/L (0.4–0.8 mmol/L for elderly). Additionally every 3–6 months: eGFR, TSH, calcium, complete blood count, ECG if cardiac disease. TSH at baseline, 6 months, then annually.
Special situations
Lithium and NSAIDs: ibuprofen, diclofenac, indomethacin raise plasma lithium by 25–60% through reduced renal clearance. Cardioprotective aspirin is safe. Lithium and diuretics: thiazides raise lithium levels (toxicity risk), loop diuretics less pronounced. ACE inhibitors and ARBs also raise levels. Dehydration (vomiting, diarrhea, fever, exertion), salt-restricted diet, or abrupt sodium restriction – risk of acute toxicity; temporarily withhold and check level. Before surgery with dehydration risk, discontinue lithium 24–48 hours prior.
Common myths
Myth: "no need to fear lithium with proper TDM, just take it". Fact: second half is true: with regular TDM, renal and thyroid monitoring, lithium is safe and effective. There really is no need to fear it. But without monitoring, the risk of irreversible toxicity is high.
Drug–nutrient interactions
Sodium
Lithium and sodium compete for reabsorption in proximal renal tubules. Reduced plasma sodium (salt-restricted diet, fluid loss, diuretics) increases lithium reabsorption and plasma concentration, precipitating toxicity. Patients are advised to maintain stable salt intake (about 4–6 g/day) and dietary sodium, increase fluid intake in heat or exertion. With acute diarrhea, vomiting, or fever, temporarily withhold and check level.
For prolonged celecoxib therapy, reduce lithium by 25%; check level at 1 week and then monthly. Alternative analgesic without lithium effect: paracetamol.
FDA boxed warning: lithium toxicity is closely related to serum concentration and can occur at levels close to therapeutic. Regular plasma monitoring is mandatory. Use without TDM capability is not permitted. Administer with caution in patients at risk of dehydration, renal impairment, hyponatremia.
Contraindications
Hypersensitivity to lithium
Severe renal impairment (eGFR < 30 mL/min)
Severe cardiovascular disease
Addison disease
Severe dehydration
Pregnancy – relative contraindication
Breastfeeding
Low-sodium diet or diuretic use without correction
Polyuria and polydipsia (nephrogenic diabetes insipidus)
Frequently asked
What is Lithium used for?
Lithium is evaluated for the following indications with varying evidence strength: Bipolar disorder (evidence tier A), Acute psychomotor agitation (evidence tier A), Treatment-resistant depression (evidence tier B). See the full indication matrix with dosing and citations above on this page.
What are the side effects of Lithium?
Common side effects of Lithium (≥ 1 in 100): Fine hand tremor, Polyuria and polydipsia (nephrogenic diabetes insipidus), Nausea, diarrhea at initiation, Weight gain, Subclinical hypothyroidism, Metallic taste. See the Safety section for uncommon and serious reactions.
Is Lithium safe during pregnancy?
FDA category D. FDA category D. First-trimester use increases Ebstein anomaly risk (10–20-fold relative risk, absolute risk 0.1–1%). Decision to continue therapy is made jointly with psychiatrist and obstetrician, weighing relapse risk against fetal risk. If continued, fetal echocardiography at 16–20 weeks. Before delivery, lithium dose is reduced by 30–50% to prevent neonatal toxicity.
Is Lithium compatible with breastfeeding?
Passes into breast milk at 40–50% of maternal plasma level. LactMed lists lithium as generally incompatible with breastfeeding: accumulation risk in infant with toxicity (lethargy, hypotonia, cyanosis). If breastfeeding is necessary, monitor infant lithium level.
Who should not take Lithium?
Lithium is contraindicated in: Hypersensitivity to lithium; Severe renal impairment (eGFR < 30 mL/min); Severe cardiovascular disease; Addison disease; Severe dehydration. Full list in the Safety section.
Myth: "lithium permanently damages kidneys". Fact: in most patients, renal function changes are minimal with proper use. Chronic kidney disease develops in some patients after over 15–20 years of therapy, offset by reduced suicide risk and bipolar relapse.
Myth: "lithium is outdated, replaced by atypical antipsychotics". Fact: 2023 and RANZCP 2022 retain lithium as first-line maintenance therapy in BD. The unique suicide-reducing effect has not been replicated by other agents.
Additive serotonergic effect of SSRIs and lithium (lithium enhances synaptic serotonergic transmission). SSRI-related lithium level rises have also been reported.
Symptoms
Serotonin syndrome: agitation, confusion, tremor, myoclonus, hyperreflexia. Autonomic features: sweating, tachycardia, hypertension, fever. First signs appear within hours of co-administration.
Management
The combination is possible with careful monitoring. Check lithium level at 2 and 4 weeks after starting citalopram. If agitation, tremor, or diarrhoea appears, reassess lithium level and serotonergic status.
Avoid prolonged combination. If diclofenac is needed for a short course, reduce lithium by 25–30% and check level at 5–7 days. For chronic analgesia: paracetamol.
Enalapril (ACE-I) lowers glomerular filtration rate and activates sodium reabsorption in the proximal tubules. Lithium follows sodium: its reabsorption rises and serum levels increase by 25–50% over 3–4 weeks.
Symptoms
Tremor, muscle twitching, nausea, diarrhoea, confusion, ataxia. Severe cases include seizures, coma, and nephrogenic diabetes insipidus with dehydration. Symptoms emerge when serum lithium exceeds 1.2 mmol/L.
Management
Reduce lithium dose by 25–30% when starting enalapril; check serum lithium at 1 and 4 weeks. Alternative antihypertensives in bipolar patients: a beta-blocker or a calcium channel blocker (amlodipine).
Furosemide (loop diuretic) lowers circulating volume and, via subclinical volume depletion, increases lithium reabsorption in the proximal tubules. Serum lithium rises by 25–40%.
Symptoms
Tremor, muscle twitching, nausea, diarrhoea, confusion, ataxia. Severe cases include seizures, coma, and nephrogenic diabetes insipidus with dehydration. Symptoms emerge when serum lithium exceeds 1.2 mmol/L.
Management
Reduce lithium dose by 25–30% when starting or escalating furosemide; check serum lithium at 1 week, then monthly. Maintain normal sodium and fluid balance: deficits worsen lithium toxicity.
Thiazide diuretics enhance lithium reabsorption in the proximal tubules via subclinical volume depletion. Serum lithium rises by 25–40% over 1–2 weeks.
Symptoms
Tremor, muscle twitching, nausea, diarrhoea, confusion, ataxia. Severe cases include seizures, coma, and nephrogenic diabetes insipidus with dehydration. Symptoms emerge when serum lithium exceeds 1.2 mmol/L.
Management
Reduce lithium dose by 25–30% when starting hydrochlorothiazide; check serum lithium at 1 week, then monthly. Alternative antihypertensive in bipolar patients: a calcium channel blocker (amlodipine), which does not affect lithium.
Ibuprofen (NSAID) reduces renal prostaglandin synthesis, lowers lithium glomerular clearance, and concurrently increases sodium and lithium reabsorption in the proximal tubules. Serum lithium rises by 20–60% within a week.
Symptoms
Tremor, muscle twitching, nausea, diarrhoea, confusion, ataxia. Severe cases include seizures, coma, and nephrogenic diabetes insipidus with dehydration. Symptoms emerge when serum lithium exceeds 1.2 mmol/L.
Management
Avoid chronic ibuprofen on lithium. For short-term analgesia, use paracetamol, celecoxib, or an opioid. If a short ibuprofen course is needed, reduce lithium by 25–30% and check serum levels at 5–7 days.
Indapamide is a thiazide-like diuretic. The lithium-raising mechanism is the same as hydrochlorothiazide: enhanced lithium reabsorption in the proximal tubules via subclinical volume depletion. Serum lithium rises.
Symptoms
Tremor, muscle twitching, nausea, diarrhoea, confusion, ataxia. Severe cases include seizures, coma, and nephrogenic diabetes insipidus with dehydration. Symptoms emerge when serum lithium exceeds 1.2 mmol/L.
Management
Reduce lithium dose by 25–30% when starting indapamide; check serum lithium at 1 week, then monthly. Alternatives: amlodipine or a beta-blocker without lithium effects.
Reduce lithium dose by 25% when starting losartan; check serum lithium at 1 and 4 weeks. Alternative antihypertensives in bipolar patients: a beta-blocker or calcium channel blocker (amlodipine).
Avoid prolonged combination. If naproxen is needed for a short course, reduce lithium by 25–30% and check lithium level at 5–7 days. For chronic analgesia: paracetamol or celecoxib (with lithium monitoring).
Calcium carbonate as an antacid mildly reduces lithium intestinal absorption, but no clinically significant drop in blood concentration has been documented.
Symptoms
The combination usually causes no specific symptoms. Each drug's individual side effects remain.
Management
No dose adjustment needed. Check lithium levels on the usual schedule (every 3 months on stable dose). With significant clinical changes (return of manic or depressive symptoms), check off-schedule.
Magnesium theoretically antagonises lithium-driven neuronal excitability, but no clinical cases of efficacy loss at standard magnesium doses (up to 400 mg/day) have been described.
Symptoms
The combination usually causes no specific symptoms. Each drug's individual side effects remain.
Management
No dose adjustment needed. On stable lithium dose, monitor levels on the usual schedule. Higher magnesium doses (over 1 g/day) are discussed separately — hypermagnesaemia risk in chronic kidney disease.
FDA category D. First-trimester use increases Ebstein anomaly risk (10–20-fold relative risk, absolute risk 0.1–1%). Decision to continue therapy is made jointly with psychiatrist and obstetrician, weighing relapse risk against fetal risk. If continued, fetal echocardiography at 16–20 weeks. Before delivery, lithium dose is reduced by 30–50% to prevent neonatal toxicity.
Breastfeeding
Passes into breast milk at 40–50% of maternal plasma level. LactMed lists lithium as generally incompatible with breastfeeding: accumulation risk in infant with toxicity (lethargy, hypotonia, cyanosis). If breastfeeding is necessary, monitor infant lithium level.
Reference information, not a clinical decision. Discuss feeding pauses or changes with your physician or an IBCLC.
Does Lithium carry an FDA boxed warning?
FDA boxed warning: lithium toxicity is closely related to serum concentration and can occur at levels close to therapeutic. Regular plasma monitoring is mandatory. Use without TDM capability is not permitted. Administer with caution in patients at risk of dehydration, renal impairment, hyponatremia.
no need to fear lithium with proper TDM, just take it
second half is true: with regular TDM, renal and thyroid monitoring, lithium is safe and effective. There really is no need to fear it. But without monitoring, the risk of irreversible toxicity is high.
lithium permanently damages kidneys
in most patients, renal function changes are minimal with proper use. Chronic kidney disease develops in some patients after over 15–20 years of therapy, offset by reduced suicide risk and bipolar relapse.
lithium is outdated, replaced by atypical antipsychotics
NICE 2023 and RANZCP 2022 retain lithium as first-line maintenance therapy in BD. The unique suicide-reducing effect has not been replicated by other agents.