What could be the reason for a subtherapeutic lithium level of 0.5 in a patient taking Lithium (lithium carbonate) 900mg in the morning and 600mg at night for over 3 weeks?

Reasons for Subtherapeutic Lithium Level Despite Adequate Dosing

The most likely causes for a subtherapeutic lithium level of 0.5 mEq/L despite taking 1500mg daily for over 3 weeks include medication non-adherence, drug interactions, increased renal clearance, or individual pharmacokinetic variations.

Primary Causes to Consider

1. Medication Non-Adherence

• Partial or inconsistent adherence to the prescribed regimen
• Taking medication with food when it should be taken on an empty stomach
• Vomiting after taking medication

2. Drug Interactions

• Concurrent medications that increase lithium clearance:
  • Caffeine
  • Theophylline
  • Sodium-containing medications
  • Diuretics (especially loop diuretics)
  • NSAIDs (can have variable effects on lithium levels)

3. Physiological Factors

• Increased renal clearance of lithium:

  • High sodium intake (dietary or IV fluids)
  • Pregnancy
  • Hyperthyroidism
  • Increased physical activity with excessive sweating

• Individual pharmacokinetic variations:

  • Faster metabolism in some individuals
  • Higher volume of distribution
  • Enhanced renal clearance due to individual variation

4. Formulation Issues

• Using immediate-release rather than extended-release formulations
• Improper storage of medication affecting potency
• Manufacturing variability

Clinical Approach to Management

1. Verify medication adherence:

   • Ask about timing of doses, missed doses, and administration method
   • Consider pill counts or medication event monitoring

2. Review concurrent medications and supplements:

   • Check for interactions that might increase lithium clearance
   • Assess caffeine intake and sodium consumption

3. Evaluate renal function:

   • Check creatinine, BUN, and eGFR
   • Assess for polyuria (a sign of nephrogenic diabetes insipidus)

4. Consider timing of blood draws:

   • Lithium levels should be drawn 12 hours after the last dose
   • Morning trough levels are standard for monitoring

5. Adjust dosing strategy:

   • Consider increasing dose if no contraindications exist
   • Evaluate splitting the dose differently (e.g., 750mg twice daily)
   • Consider changing to extended-release formulation if using immediate-release

Important Considerations

While the therapeutic range for lithium in bipolar disorder is typically 0.6-1.2 mEq/L, it's important to note that some patients may respond to lower levels. The guideline indicates that for certain conditions, blood levels of 0.2 to 0.6 mEq/L may be adequate 1.

However, a level of 0.5 mEq/L is generally considered subtherapeutic for bipolar disorder management, and dose adjustment would typically be recommended to achieve therapeutic levels.

Caution

Even at seemingly subtherapeutic levels, lithium toxicity can occasionally occur. There are documented cases of lithium neurotoxicity at serum levels of 0.5 mEq/L 2. Therefore, when adjusting doses, careful monitoring for signs of toxicity remains important, particularly in patients with risk factors such as advanced age, reduced renal function, dehydration, or fever 3.