Psycholeptics. Lithium
ATC code: N05AN01 (Lithium)
Brand names
Lithobid, Eskalith, Lithonate, Lithotabs, Cibalith-S
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.
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.
First line
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.
Sources
Adjunct
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.
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.
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.
Source: FDA: Lithobid (lithium carbonate) prescribing information (2021)
12 pairs found. Sorted from critical to minor.
Mechanism
NSAIDs (including selective COX-2 inhibitors like celecoxib) reduce renal lithium clearance. Lithium plasma levels rise.
Symptoms
Tremor, muscle twitching, nausea, diarrhoea, confusion, ataxia. Symptoms emerge when serum lithium exceeds 1.2 mmol/L.
Management
For prolonged celecoxib therapy, reduce lithium by 25%; check level at 1 week and then monthly. Alternative analgesic without lithium effect: paracetamol.
Opens the checker prefilled with this drug. Pick the second one from your regimen.
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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.
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.
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.
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.
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.
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.
Mechanism
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.
Mechanism
Similar to naproxen + lithium. NSAIDs reduce renal lithium clearance via prostaglandin blockade.
Symptoms
Tremor, muscle twitching, nausea, diarrhoea, confusion, ataxia. Symptoms emerge when serum lithium exceeds 1.2 mmol/L.
Management
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.
Mechanism
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).
Mechanism
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.
Mechanism
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.
Mechanism
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.
Mechanism
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.
Mechanism
The ARB (losartan) reduces glomerular filtration rate and renal lithium clearance by 25–40%. Serum lithium rises with toxicity risk.
Symptoms
Tremor, muscle twitching, nausea, diarrhoea, confusion, ataxia. Symptoms emerge when serum lithium exceeds 1.2 mmol/L.
Management
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).
Mechanism
NSAIDs reduce renal lithium clearance via prostaglandin-dependent renal blood flow blockade. Lithium plasma levels rise 1.5- to 2-fold with toxicity risk.
Symptoms
Tremor, muscle twitching, nausea, diarrhoea, confusion, ataxia. Symptoms emerge when serum lithium exceeds 1.2 mmol/L.
Management
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).
Mechanism
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.
Mechanism
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.
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.
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.
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.
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.
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.