Psychiatry & Clinical Pharmacology & Nephrology & Family Medicine
Lithium (lithemia)
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Lithium (Li⁺) is a light alkali metal administered as lithium carbonate (Lithane, Carbolith, Duralith) - the oldest mood stabilizer and one of the best-validated treatments for bipolar disorder (BD), with over 60 years of clinical data. It remains a first-line treatment for the prevention of manic and depressive relapses in type I and II TB (Geddes 2004 - Lancet + Cipriani 2013 - Lancet), and is associated with a 60-80 % reduction in suicide mortality in bipolar patients - a unique antisuicidal effect among mood stabilizers. Its precise mechanism of action remains partially elucidated: inhibition of inositol monophosphatase (IP₃ pathway) + inhibition of GSK-3β (glycogen synthase kinase-3β) + modulation of serotonergic and glutamatergic neurotransmission + neuroprotective effects (increase in BDNF). The therapeutic range of lithium is narrow - the therapeutic target range is 0.6-1.2 mmol/L (measured 12 hours after the last dose), depending on the indication, and toxicity generally begins above 1.5 mmol/L, with severe and potentially fatal complications above 2.0 mmol/L (convulsions + coma + cardiac arrhythmias + acute renal failure). Monitoring of blood lithium levels + renal function (creatinine + eGFR) + TSH (hypothyroidism ++) + blood calcium levels is essential and mandatory throughout treatment - lithium can only be used safely and effectively if this monitoring is rigorously carried out.
Pharmacokinetics, indications and target values
- Lithium pharmacokinetics and mechanisms of action : pharmacokinetics: complete oral absorption (bioavailability quasi-100 %) → no plasma protein binding → volume of distribution: 0.7-1 L/kg → half-life: 20-24h (sustained-release formulations - Duralith) → or 12-16h (immediate-release formulations - Lithane + Carbolith) → steady state reached after 4-5 half-lives (4-7 days) → elimination exclusively renal (glomerular filtration + proximal tubular reabsorption concurrently with sodium - 75-80 % reabsorbed at proximal tubule with sodium) → key factor: lithium follows sodium in tubular reabsorption → any state of sodium depletion or hypovolemia → tubular reabsorption of lithium ↑ → lithemia ↑ → toxicity → mechanisms of action: inhibition of inositol monophosphatase (IMPase) → reduction of second messenger IP₃ (inositol-1,4,5-triphosphate) → reduction of intracellular calcium release + inhibition of GSK-3β → effects on Wnt signaling pathways + neuroprotective effects + serotonergic + dopaminergic + glutamatergic modulation → neuroprotective effects: increase in BDNF (Brain-Derived Neurotrophic Factor) + reduction in neuronal apoptosis → unique neurotropic effects + validated therapeutic indications: bipolar disorder type I and II : prevention of manic + depressive relapses → 1st-line (CANMAT 2018 - Canadian Journal of Psychiatry) + acute treatment of mania (less often - slow titration) + predominantly depressive bipolar disorder + suicide prevention (bipolar disorder + recurrent depression) → reduction in suicide mortality by 60-80 % → Cipriani 2013 - Lancet meta-analysis → schizoaffective disorder (in combination) + severe cyclothymia + antidepressant augmentation in resistant unipolar depression (augmentation with lithium) + neutropenia under clozapine (lithium increases neutrophils) → target values for lithemia (measured 12h after last dose - valle) : maintenance treatment (relapse prevention): 0.6-0.8 mmol/L → young active patients or severe mania: 0.8-1.0 mmol/L → acute mania: 0.8-1.2 mmol/L → elderly + mild CKD: lower target 0.4-0.6 mmol/L → therapeutic zone: 0.6-1.2 mmol/L → probable toxicity: >1.5 mmol/L → severe toxicity: >2.0 mmol/L
- Clinical and biological monitoring on lithium : mandatory lithium monitoring - prior to initiation: basal blood lithium level + creatinine + eGFR + ionogram + TSH + T4L + blood calcium level + CBC + liver function tests + ECG (if age >50 or known heart disease) + pregnancy test if woman of childbearing age (teratogenic - Ebstein's anomaly) → monitoring during treatment: blood lithium level : weekly during titration + then monthly for the first 3 months + then every 3-6 months at steady state + at each dose change + if symptoms of toxicity + if an interfering drug is introduced + if intercurrent episode (dehydration + infection + fever) → creatinine + eGFR: every 6 months → lithium is nephrotoxic in the long term (chronic tubulointerstitial nephropathy → progressive reduction of eGFR → CKD → in advanced forms → nephrogenic diabetes insipidus - polydipsia + polyuria - as an early symptom of nephropathy) → TSH: every 6 months → lithium-induced hypothyroidism in 20-40 % of patients → sometimes hyperthyroidism + hypercalcemia → calcemia every 6 months → lithium-induced hyperparathyroidism (asymptomatic or symptomatic hypercalcemia) + annual ECG (QT prolongation + T-wave changes - cardiac effects of lithium) → weight and signs of renal lithiasis → prevention of toxicity: maintain adequate hydration ++ → stable sodium intake → educate patient on signs of toxicity + risk situations (vomiting + diarrhea + heat + intense exercise + low-sodium diet + interfering medications)
Toxicity, interactions and management
| Aspect / situation | Data, signs and protocols | Key studies and recommendations |
|---|---|---|
| Lithium toxicity - clinical signs and management Lutemia >1.5 mmol/L - mild moderate severe toxicity - tremor - ataxia - confusion - convulsions - coma - arrhythmias - ARF - dialysis - lithium discontinuation - IV rehydration - emergency - activated charcoal useless |
Lithium toxicity - signs according to lithemia level: mild toxicity (lithemia 1.5-2.0 mmol/L): nausea + vomiting + diarrhea + fine hand tremor (aggravated) + fatigue + muscle weakness + dizziness + mild somnolence → moderate toxicity (lithemia 2.0-2.5 mmol/L): ataxia (unsteady gait + lack of coordination) + dysarthria (slow + garbled speech) + coarse tremor + confusion + disorientation + marked somnolence + nystagmus + myoclonus + increased osteotendinous reflexes → severe toxicity (lithemia >2.5-3.0 mmol/L): convulsions + coma + muscular rigidity + hyperthermia + acute renal failure (oliguria) + cardiac arrhythmias (bradycardia + BAV + ventricular tachycardia) → life-threatening emergency + CAUTION: lithemia may be normal at the start of acute on chronic intoxication (lithium redistributes from cells) → clinical symptoms take precedence over lithemia → always treat symptomatically + SILENT (Syndrome of Irreversible Lithium-Effected Neurotoxicity): ataxia + dysarthria + cognitive deficits persisting after resolution of acute toxicity → SILENT can occur at moderately high lithemias → treatment of lithium toxicity: immediate lithium discontinuation + medical emergencies → DO NOT give activated charcoal (lithium not adsorbed by charcoal) → IV hydration (NaCl 0.9 %): vigorous rehydration → restores natraemia → reduces tubular reabsorption of lithium → promotes its excretion → electrolyte + renal balance + lithemia every 4-6h → hemodialysis: indications → lithemia >4.0 mmol/L + or lithemia >2.5 mmol/L + severe neurological symptoms (convulsions + coma) + or oliguric ARF + or persistent lithemia despite hydration → hemodialysis rapidly depletes lithium → but beware of rebound (redistribution from tissues after hemodialysis) → monitor and repeat if lithemia rises → continuous cardiac monitoring | Waring 2006 - Journal of Toxicology: lithium + toxicity + hemodialysis → reference + Timmer 2006 - Nephrology Dialysis Transplantation: hemodialysis + lithium + indications → Gitlin 1999 - Psychiatric Clinics of North America: lithium + adverse effects + toxicity → reference + Duffy 2009 - Acta Psychiatrica Scandinavica: lithium + monitoring + Kessing 2010 - JAMA Psychiatry: lithium + suicide mortality → reference + SPIBI (Saskatchewan Prevention Intervention for Bipolar Initiative) + CANMAT 2018 (Canadian Journal of Psychiatry): TB + lithium + monitoring → Canadian recommendations → INESSS Québec + RAMQ: lithium (Carbolith + Duralith) reimbursed + lithemia dosage reimbursed + toxicology emergencies Québec: 1-800-463-5060 |
| Drug interactions and risk situations NSAIDs increased lithemia - ACEI ARB II reduced clearance lithium - thiazide diuretics - dehydration - infections - heat - diarrhea - salt - pregnancy teratogenic Ebstein anomaly - aging kidney - methotrexate - carbamazepine neurotoxicity |
Drug interactions and situations increasing the risk of lithium toxicity: critical drug interactions: NSAIDs (ibuprofen + naproxen + diclofenac + indomethacin + ketorolac): reduction of prostaglandin → renal vasoconstriction → reduction of lithium clearance → blood levels may increase by 30-60 % in a few days → AVOID NSAIDs in patients on lithium + or monitor blood levels 5-7 days after introduction + ACEI (ramipril + lisinopril + enalapril) + ARB II (losartan + valsartan): reduction in glomerular filtration → reduction in lithium clearance → increase in lithium levels by 20-40 % → if introduction unavoidable → reduce lithium dose + monitor lithium levels at 5-7 days + thiazide diuretics (hydrochlorothiazide + chlorthalidone): sodium depletion → compensatory tubular reabsorption of lithium → increase in lithium levels by 30-50 % → AVOID + or reduce lithium dose + monitor → loop diuretics (furosemide): less effect on lithium (moderate sodium depletion) → monitoring recommended → carbamazepine: association with lithium → risk of neurotoxicity (cerebellar syndrome) even at lithemias in therapeutic range → monitor for signs of neurological toxicity → clinical situations increasing lithemia (by sodium depletion + hypovolemia): dehydration (gastroenteritis + vomiting + diarrhea + intense heat + intense exercise + excessive diuresis) → strict low-sodium diet → NSAID + any drug reducing renal function → instructions to patient: maintain adequate hydration ++ → do not start low-sodium diet without adjusting dose → consult if severe vomiting or diarrhea → do not self-medicate with NSAID → pregnancy and lithium: teratogenic risk: Ebstein's anomaly (cardiac malformation - displacement of tricuspid valve) → small but present absolute risk (× 2-3 vs general population) → risk of bipolar relapse if stopped → individualized decision in collaboration with psychiatrist + obstetrician → if maintained → fetal echocardiographic monitoring → lower target lithemia + adjustment during pregnancy (lithium clearance increases in 2nd trimester → increase dose to maintain lithemia) + reduce or stop before delivery (neonatal risk) → neonatal toxicity + breastfeeding : CONTRAINDICATION (concentration in breast milk of 30-50 % of maternal lithemia → neonatal toxicity) | |
| Chronic side effects - kidney, thyroid and others Tubulointerstitial nephropathy - nephrogenic diabetes insipidus - eGFR monitoring - hypothyroidism TSH - hyperparathyroidism calcemia - chronic tremor - weight gain - acne - psoriasis - benign leukocytosis - lithium relapse - biphosphonates DIN |
Chronic adverse effects of lithium - monitoring and management: renal effects (most important long-term): nephrogenic diabetes insipidus (DIN): 20-40 % of patients on lithium → polydipsia + polyuria (isosthenuric dilute urine - urinary osmolality 10-15 years → raise concern to minimum effective lithemia + monitor eGFR every 6 months → if eGFR <60 → discussion with nephrologist + psychiatrist → reduce target lithemia + if eGFR 10 mUI/L → DO NOT discontinue lithium for hypothyroidism unless severe → hyperthyroidism (less common - autoimmune mechanism) + goiter → lithium-induced primary hyperparathyroidism: hypercalcemia → calcemia monitoring + dermatological effects: acne (20 %) + aggravation of psoriasis + alopecia → reversible on discontinuation + metabolic effects: weight gain (2-10 kg in 1st year) → metabolic obesity → dietary counseling + physical activity → essential-like tremor: propranolol 10-20 mg × 2-3/d if troublesome + benign leukocytosis: lithium stimulates leukopoiesis → WBC 10-14 × 10⁹/L without infection → benign + lithium discontinuation - major risk: severe bipolar relapse → hypomania rebound + mania → abrupt discontinuation is not recommended → gradual discontinuation over at least 4 weeks → educate patient about risk of relapse on discontinuation | Geddes 2004 - Lancet: lithium + TB relapse prevention → reference + Cipriani 2013 - Lancet meta-analysis: lithium + suicide prevention → -60-80 % suicide mortality + Bendz 1994 - NEJM: lithium + chronic kidney disease → longitudinal data + Gitlin 1999 - Psychiatric Clinics of North America: lithium + adverse effects + Duffy 2009 - Acta Psychiatrica Scandinavica: lithium + renal monitoring + CANMAT 2018 (Yatham - Canadian Journal of Psychiatry): TB + lithium → Canadian guidelines → targets lithemia + monitoring → Canadian reference + Kessing 2010 - JAMA Psychiatry: lithium + eGFR + CKD + longitudinal follow-up + INESSS Quebec + RAMQ: levothyroxine + lithium + eGFR monitoring → reimbursed + Canadian Psychiatric Society: lithium + TB + monitoring |
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Lithaemia must be measured exactly 12 hours after the last dose (valle) - sampling at any other time gives uninterpretable results: the therapeutic range is narrow (0.6-1.2 mmol/L) - above 1.5 mmol/L, toxicity begins. Any episode of vomiting, diarrhea, dehydration, fever or new medication (NSAIDs ++ + ACE inhibitors + thiazides) can cause lithemia to rise dangerously. Activated charcoal is useless in cases of lithium intoxication - management relies on IV rehydration (NaCl 0.9 %) and hemodialysis if necessary. Lithium reduces suicide mortality by 60 to 80 % - abrupt discontinuation is dangerous.
Situations requiring an urgent call to the Poison Control Centre (1-800-463-5060) or 911
Patient on lithium with gross tremor + ataxia + dysarthria + confusion + myoclonus + nystagmus - OR lithemia >2.0 mmol/L even if not very symptomatic → moderate to severe lithium toxicity → call Quebec Poison Control Center (1-800-463-5060) → or 911 if severe symptoms → medical emergencies → lithium discontinuation + NaCl 0.9 % IV → cardiac monitoring + lithemia every 4-6h → discussion of hemodialysis if lithemia >2.5 mmol/L + neurological symptoms.
Patient on lithium + recent prescription of an NSAID (ibuprofen + naproxen) by another doctor + or initiation of an ACEI + ARB II + or thiazide → without lithium adjustment → potentially serious interaction → lithemia control within 5-7 days + patient education → if symptoms of toxicity → call Poison Control Center → if asymptomatic but lithemia high → NSAID discontinuation + rehydration + lithemia control.
Patient on lithium for 10+ years + polyuria + polydipsia + progressively decreasing eGFR + last eGFR 45 → 38 → 31 mL/min/1.73m² → advanced lithium nephropathy → urgent nephropathy consultation + psychiatry → discussion of dose reduction + mood stabilizer change + if eGFR <30 → lithium contraindicated → transition plan to another agent (valproate + lamotrigine + aripiprazole) in collaboration with psychiatrist.
Consult at Clinique Omicron
Les médecins de Clinique Omicron assurent le suivi des patients sous lithium (lithémie à 12h + créatinine + DFGe + TSH + calcémie tous les 6 mois), éduquent les patients sur les signes de toxicité et les situations à risque, identifient et gèrent les interactions médicamenteuses (AINS + IECA + diurétiques thiazidiques), traitent les effets indésirables (hypothyroïdie + diabète insipide + tremblement), et coordonnent avec le psychiatre et le néphrologue pour les cas complexes. Des consultations sont disponibles dans plusieurs points de service au Québec et en télémédecine. Pour prendre rendez-vous, Choose your online service.
The contents of this page are provided for information purposes only and do not replace the advice of a doctor, psychiatrist or pharmacist. Lithium has a narrow therapeutic range and requires regular biological monitoring. In case of suspected toxicity, contact the Quebec Poison Control Centre at 1-800-463-5060 or call 911.
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