Twice-Daily Dosing of Lithium Extended-Release During Titration is NOT Contraindicated
Twice-daily dosing of lithium extended-release is an acceptable and well-established administration schedule during titration, with no absolute contraindication against this approach. 1
Evidence Supporting Twice-Daily Dosing
The available evidence demonstrates that multiple dosing schedules are clinically appropriate for lithium:
The twice-daily schedule for sustained-release lithium preparations is well established and has been used successfully in clinical practice, though once-daily evening dosing is increasingly recommended by expert panels 1
Sustained-release formulations result in 30-50% reductions in peak plasma concentrations without major changes in overall drug exposure, making them suitable for divided dosing 1
A comparative study found that twice-daily dosing was of similar efficacy to once-daily dosing for treating mania, though the twice-daily group experienced higher urinary frequency and required higher total daily doses 2
Practical Dosing Considerations
Initial Titration Approach
Start with 12-24 mmol (450-900 mg) per day depending on age and body weight 1
- Patients <40 years: target maintenance 25-35 mmol daily (925-1300 mg)
- Patients 40-60 years: target 20-25 mmol daily (740-925 mg)
- Patients >60 years: target 15-20 mmol daily (550-740 mg) 1
For sustained-release preparations specifically, maintain serum concentrations in the upper therapeutic range (0.8-1.0 mmol/L) rather than 0.6-0.8 mmol/L used for standard formulations, due to the later peak concentration 1
Monitoring Requirements During Titration
Serum concentrations should be determined twice per week during the acute phase and until levels and clinical condition stabilize 3
Draw levels 12 hours after the last dose for twice-daily dosing; for once-daily administration, the 24-hour level serves as the control value 1
Lithium toxicity is closely related to serum concentrations and can occur at doses close to therapeutic levels, necessitating careful monitoring 3, 4
Critical Safety Warnings
Renal Function Monitoring
Monitor GFR, electrolytes, and lithium levels every 6 months or more frequently if dose changes or patient becomes acutely unwell 3
Lithium is nephrotoxic and may cause renal tubular dysfunction with prolonged use even at therapeutic levels 3
Drug Interactions to Avoid
Avoid concomitant NSAIDs, which can decrease lithium clearance and increase toxicity risk 3
Exercise caution with ACE inhibitors, ARBs, and AT1 blockers, which can increase serum lithium levels—monitor closely not only during introduction but also if the temporal pattern of administration is modified 5
Special Populations
Elderly patients are prone to develop neurotoxicity at higher lithium dosages 3
During pregnancy, lithium clearance increases by 30-50% in the last months, requiring dose adjustments 1
Based on animal studies, lithium may cause fetal harm; human studies suggest fetal harm but are insufficient to determine full risk 3
Clinical Bottom Line
The classical administration schedule allows for both twice-daily and three-times-daily dosing, though compliance with midday doses is questionable 1. With modern sustained-release preparations, the twice-daily schedule is well established, making it a reasonable choice during titration 1. The key is not avoiding twice-daily dosing but rather ensuring appropriate monitoring, maintaining hydration during intercurrent illness, and weighing the risk-benefit in each specific clinical situation 3.