How should lithium be initiated and titrated, including dosing increments, target serum lithium concentrations, monitoring parameters, and adjustments for renal impairment or interacting medications?

Lithium Initiation and Titration

Start lithium at 300 mg twice daily (or 300 mg once daily in elderly/renally impaired patients), increase by 300 mg every 5-7 days based on serum levels drawn 12 hours post-dose, targeting 0.6-1.2 mEq/L for acute mania and 0.6-0.8 mEq/L for maintenance, with mandatory monitoring of renal function, electrolytes, and thyroid function every 3-6 months. 1

Initial Dosing Strategy

Standard Adult Dosing

• Begin with 300 mg twice daily for most adults under age 60 with normal renal function 2
• The typical maintenance dose ranges from 900-1300 mg/day for patients under 40 years, 740-925 mg/day for ages 40-60, and 550-740 mg/day for those over 60 2
• Once-daily evening dosing with sustained-release formulations is equally effective and may improve compliance while reducing renal toxicity compared to divided dosing 3, 2, 4

Special Populations

• Elderly patients or those with renal impairment should start at 150-300 mg once daily (not 150 mg twice daily as sometimes prescribed, which produces subtherapeutic levels of only 0.2-0.6 mEq/L) 1
• For moderate renal impairment (eGFR 30-60 mL/min/1.73 m²), start at 50% of the usual adult dose and extend dosing intervals rather than increasing individual doses 1
• Patients with eGFR <30 mL/min/1.73 m² require monthly monitoring and careful risk-benefit assessment 1

Pediatric Dosing

• Children and adolescents weighing ≥30 kg can start at 300 mg three times daily, with 300 mg increases weekly until response or stopping criteria are met 5
• Those weighing <30 kg should begin at 300 mg twice daily with slower titration 5

Titration Protocol

Dose Adjustments

• Increase by 300 mg every 5-7 days based on clinical response and serum lithium levels 1, 2
• Check serum lithium levels 5-7 days after each dose change, as steady-state is achieved in 7-8 days (approximately 5-7 half-lives with lithium's 18-36 hour elimination half-life) 1, 2
• Draw levels 12 hours post-dose for twice-daily regimens, or 24 hours post-dose for once-daily administration 2

Target Serum Concentrations

• Acute mania: 0.8-1.2 mEq/L (some guidelines support 1.0-1.5 mEq/L for severe acute episodes) 1, 2
• Maintenance therapy: 0.6-0.8 mEq/L to balance efficacy with long-term tolerability 1, 2, 6
• For sustained-release preparations, maintain levels in the upper therapeutic range (0.8-1.0 mEq/L) due to later peak concentrations 2
• Levels up to 0.8 mEq/L appear safe for long-term use in geriatric patients without pre-existing chronic renal failure 6

Monitoring Parameters

Baseline Assessment

• Obtain before initiating lithium: complete blood count, comprehensive metabolic panel (including electrolytes, BUN, creatinine with eGFR), thyroid function tests (TSH, free T4), fasting glucose or HbA1c, urinalysis, and pregnancy test in women of childbearing potential 1
• Baseline ECG is recommended for patients >40 years, those with cardiac risk factors, or when combining lithium with QT-prolonging medications 1
• Correct any baseline electrolyte abnormalities, particularly hypokalemia, before starting lithium 1

Acute Phase Monitoring

• Check serum lithium levels twice weekly until both level and clinical condition stabilize during acute treatment 1
• Monitor renal function and electrolytes 2-4 weeks after initiation to capture early changes 1

Maintenance Monitoring

• Serum lithium levels every 3 months once stable 1
• Renal function (eGFR, BUN, creatinine), electrolytes, thyroid function, and calcium every 6 months 1
• More frequent monitoring (every 1-2 weeks) is required after dose changes, addition of interacting medications, changes in renal function, or significant weight changes 1

High-Risk Situations Requiring Intensified Monitoring

• Patients taking NSAIDs, ACE inhibitors, ARBs, or thiazide diuretics require increased monitoring frequency due to elevated lithium toxicity risk 1
• If eGFR falls to 30-60 mL/min/1.73 m², increase monitoring frequency; if <30 mL/min/1.73 m², monitor at least monthly 1
• Women under 60 are at higher risk for thyroid dysfunction (20-30% develop hypothyroidism) and may warrant more frequent thyroid monitoring 1
• Hypercalcemia occurs in approximately 25% of long-term lithium patients; check parathyroid hormone if calcium is elevated 1

Adjustments for Renal Impairment

Dosing Modifications

• Extend dosing intervals rather than reducing individual doses to maintain adequate peak concentrations while avoiding toxicity 1
• For eGFR 30-60 mL/min/1.73 m²: Consider once-daily or every-other-day dosing at 50% of standard dose 1
• For eGFR <30 mL/min/1.73 m²: Lithium is relatively contraindicated; if continued, use extreme caution with extended intervals and intensive monitoring 1

Creatinine-Based Thresholds

• Up to 30% increase in creatinine from baseline is acceptable and does not require immediate intervention 1
• Creatinine increase >50% or >266 μmol/L: Review other nephrotoxic medications and consider dose reduction 1
• Creatinine increase >100% or >310 μmol/L: Discontinue lithium 1

Drug Interactions Requiring Dose Adjustment

Medications That Increase Lithium Levels

• NSAIDs: Decrease lithium clearance significantly; avoid concomitant use when possible or increase monitoring to weekly 1
• ACE inhibitors and ARBs: Reduce lithium clearance; monitor levels 1-2 weeks after initiation and adjust dose as needed 1
• Thiazide diuretics: Substantially increase lithium levels; consider alternative antihypertensives (calcium channel blockers or losartan preferred) 1

Management Strategy

• When adding interacting medications, check lithium level within 1-2 weeks and anticipate need for 25-50% dose reduction 1
• Temporarily discontinue lithium if patient develops serious intercurrent illness that increases acute kidney injury risk, particularly if eGFR <60 mL/min/1.73 m² 1

Common Pitfalls to Avoid

• Do not abruptly discontinue lithium in long-term users; taper slowly over weeks to avoid life-threatening withdrawal syndrome (seizures, hallucinations, delirium, fever, tachycardia) 1
• Do not rely on standard twice-daily dosing in renal impairment; extending intervals is safer than reducing individual doses 1
• Do not start lithium during pregnancy without documented negative pregnancy test and thorough risk-benefit discussion due to teratogenic risk 1
• Do not prescribe lithium with serum creatinine >2.5 mg/dL in men or >2.0 mg/dL in women (or eGFR <30 mL/min/1.73 m²) without specialist consultation 1
• Do not ignore potassium levels >5.5 mEq/L; this requires lithium dose review and possible temporary discontinuation 1
• Maintain adequate hydration during intercurrent illness and check levels more frequently 1