Is it appropriate to give lithium extended‑release (ER) tablets twice daily?

Lithium Extended-Release Twice Daily Dosing

Yes, it is appropriate and often preferable to dose lithium extended-release (ER) formulations twice daily, particularly for patients experiencing gastrointestinal side effects or those requiring divided doses due to poor absorption or rapid elimination. 1

Dosing Schedule Considerations

Standard ER Dosing Approaches

• Twice-daily (BID) dosing is well-established for modern sustained-release lithium preparations and represents a clinically validated administration schedule. 2

• Once-daily (OD) evening dosing is also recommended by expert panels and may improve compliance while reducing side effects in some patients. 2

• The classical administration schedule historically involved two or three times daily dosing, though there is no strong evidence favoring three-times-daily schedules, and compliance with midday doses is questionable. 2

When to Choose BID Over OD Dosing

Specific clinical scenarios favor twice-daily dosing:

• Patients experiencing gastrointestinal side effects (nausea, diarrhea, abdominal discomfort) with once-daily dosing should be switched to BID administration. 1

• Patients with documented poor absorption or rapid elimination requiring divided doses to maintain therapeutic levels. 1

• Patients requiring higher total daily doses may benefit from divided dosing to minimize peak-related side effects. 3

Pharmacokinetic Rationale

Peak Concentration Differences

• Sustained-release formulations produce 30-50% reductions in peak plasma concentrations compared to immediate-release forms, without major changes in total drug exposure (area under the curve). 2

• Peak plasma concentration occurs at 4-5 hours for sustained-release forms versus 1-2 hours for standard-release preparations. 2

Therapeutic Level Monitoring

Critical monitoring differences based on dosing schedule:

• For once-daily dosing: Draw serum lithium levels at 24 hours post-dose (not 12 hours), as 12-hour levels are approximately 1.3 times higher than true trough levels and may lead to underdosing. 4

• For twice-daily dosing: Draw levels at the standard 12 hours post-dose (before the morning dose if dosing BID). 5

• With sustained-release preparations, 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. 2

Comparative Efficacy and Tolerability

Clinical Outcomes

Recent evidence demonstrates:

• Prolonged-release formulations show equivalent clinical efficacy to immediate-release preparations over 2-year follow-up periods. 6

• PR lithium is associated with fewer side effects, particularly tremors and gastrointestinal issues, leading to better adherence. 6

• PR administration results in more stable blood lithium levels compared to immediate-release formulations. 6

Side Effect Profile

Twice-daily dosing may produce higher renal adverse effects:

• Patients receiving twice-daily lithium experienced significantly higher urinary frequency at Day 21 (P=0.008) and Day 42 (P=0.035) compared to once-daily dosing. 3

• Twice-daily dosing required significantly higher total daily doses (P=0.017) and resulted in lower serum lithium levels (P<0.001). 3

• There was a significant positive correlation between urinary frequency and lithium dose at Day 42. 3

Renal Considerations

Potential Renal Protection with Once-Daily Dosing

Emerging evidence suggests once-daily dosing may be nephroprotective:

• Renal structural and functional changes were most pronounced in patients given lithium in divided doses during the day compared to single evening doses. 7

• Lithium may be more harmful to the kidney when administration produces relatively constant serum levels rather than greater variations including peak and low minimum levels. 7

• Regenerative kidney processes may only occur during periods with low lithium concentrations, suggesting potential benefit of allowing daily lithium-free intervals. 7

Practical Clinical Algorithm

Decision-making framework for ER lithium dosing frequency:

1. Start with once-daily evening dosing as the default approach for most patients to optimize compliance and potentially reduce renal toxicity. 2, 7

2. Switch to twice-daily dosing if:

   • Gastrointestinal side effects (nausea, diarrhea) develop with OD dosing 1
   • Therapeutic levels cannot be achieved despite adequate total daily dose 1
   • Patient has documented rapid elimination or poor absorption 1

3. Monitor appropriately based on schedule:

   • OD dosing: Check levels at 24 hours post-dose 4
   • BID dosing: Check levels at 12 hours post-dose 5

4. Maintain hydration and avoid nephrotoxic medications (NSAIDs, ACE inhibitors, ARBs, thiazide diuretics) regardless of dosing schedule. 5, 1

Common Pitfalls to Avoid

• Do not check 12-hour lithium levels in patients on once-daily dosing, as this will overestimate true trough levels by approximately 30% and may lead to underdosing. 4

• Do not assume twice-daily dosing is always superior—it may increase urinary frequency and require higher total daily doses without improving efficacy. 3

• Be cautious with drug interactions that increase lithium levels (NSAIDs, diuretics) regardless of dosing schedule. 1

• Avoid divided dosing in patients with impaired renal function (eGFR <60 mL/min/1.73 m²) unless absolutely necessary, as these patients benefit from extended dosing intervals, not increased frequency. 8