What can cause a low lithium level in a patient with a history of psychiatric illness, such as bipolar disorder?

Causes of Low Lithium Levels

Low lithium levels in patients with bipolar disorder are most commonly caused by medication non-adherence, but can also result from increased renal clearance due to drug interactions (especially NSAIDs, diuretics, and ACE inhibitors), dehydration, sodium depletion, or reduced renal function requiring dose adjustments. 1, 2

Primary Causes of Subtherapeutic Lithium Levels

Non-Adherence to Medication

• Medication non-adherence is the most common cause of low lithium levels, with studies showing that more than 90% of adolescents who were noncompliant with lithium treatment relapsed, compared to 37.5% of those who were compliant 3
• Therapeutic drug monitoring should be used to confirm whether subtherapeutic concentrations explain treatment failure, as noncompliance is a common cause of apparent treatment failure 3

Drug Interactions That Increase Lithium Clearance

• Sodium loss from diuretics or ACE inhibitors can paradoxically reduce lithium levels initially by increasing renal clearance, though chronic use typically increases lithium levels and toxicity risk 1, 2
• When diuretics or ACE inhibitors are used concomitantly with lithium, sodium loss may reduce the renal clearance of lithium, requiring careful monitoring and potential dose adjustments 2
• The lithium dosage may need adjustment when these combinations are used, with more frequent monitoring of lithium plasma levels recommended 2

Physiological Factors Affecting Lithium Excretion

Renal Function Changes

• Lithium is primarily excreted in urine with renal excretion proportional to plasma concentration, and the half-life of elimination is approximately 24 hours 2
• Improved renal function can increase lithium clearance and lower serum levels, particularly relevant in patients recovering from acute illness 1, 4
• For patients with GFR < 60 ml/min/1.73 m², lower doses and more frequent monitoring are recommended, but improved renal function would have the opposite effect 1

Sodium and Fluid Balance

• Lithium decreases sodium reabsorption by the renal tubules which could lead to sodium depletion, making it essential for patients to maintain a normal diet including salt and adequate fluid intake (2500-3000 mL) at least during initial stabilization 2
• Increased sodium intake can increase lithium excretion and lower serum levels, as lithium and sodium compete for renal reabsorption 2
• Adequate hydration is crucial, and changes in fluid intake can affect lithium levels 1, 2

Phase-Specific Tolerance Changes

• The ability to tolerate lithium is greater during the acute manic phase and decreases when manic symptoms subside, which may necessitate dose adjustments during different phases of illness 2
• This means that as patients transition from mania to euthymia or depression, the same dose may result in higher serum levels, but conversely, during acute mania, higher doses may be needed to achieve therapeutic levels 2

Clinical Algorithm for Evaluating Low Lithium Levels

Step 1: Verify Medication Adherence

• Check serum lithium levels to confirm subtherapeutic concentrations (therapeutic range for acute treatment is 0.8-1.2 mEq/L, maintenance is 0.6-1.0 mEq/L) 3, 1
• Assess adherence through patient interview, pill counts, and pharmacy refill records 3

Step 2: Review Concomitant Medications

• Identify any recent additions or discontinuations of NSAIDs, diuretics, or ACE inhibitors that could affect lithium clearance 1, 2
• NSAIDs should be avoided as they can increase lithium levels, but their discontinuation could lower levels 1, 2
• Diuretics and ACE inhibitors typically increase lithium levels, but their initiation may transiently increase clearance 1, 2

Step 3: Assess Dietary and Fluid Intake

• Evaluate recent changes in sodium intake or fluid consumption that could affect lithium excretion 2
• Patients must maintain a normal diet including salt and adequate fluid intake of 2500-3000 mL daily 2
• Increased sodium intake or excessive fluid intake can increase lithium clearance 2

Step 4: Evaluate Renal Function

• Monitor renal function with serum creatinine and calculate creatinine clearance to assess for changes that could affect lithium excretion 1, 4
• Baseline and ongoing monitoring should include BUN, creatinine, GFR, and urinalysis every 3-6 months 3, 1
• Improved renal function can increase lithium clearance and lower serum levels 1, 4

Step 5: Consider Clinical Phase of Illness

• Assess whether the patient is in an acute manic phase, as tolerance to lithium is greater during mania and may require higher doses to achieve therapeutic levels 2
• As manic symptoms subside, the same dose may result in higher serum levels, but during acute mania, higher doses are often needed 2

Critical Monitoring Requirements

Frequency of Lithium Level Monitoring

• During the acute phase, serum concentrations should be checked twice per week until levels and clinical condition stabilize 1
• Once stable, lithium levels should be monitored every 3-6 months along with renal and thyroid function 3, 1
• More frequent monitoring is required when medications are added or discontinued, or when clinical status changes 1, 2

Baseline and Ongoing Laboratory Assessment

• Baseline tests should include complete blood count, thyroid function tests (TSH, free T4), renal function (BUN, creatinine, GFR), serum electrolytes including calcium, and urinalysis 1
• Ongoing monitoring should include lithium levels, renal and thyroid function, and urinalysis every 3-6 months 3, 1

Common Pitfalls to Avoid

• Never assume low lithium levels are solely due to non-adherence without checking for drug interactions and physiological factors 1, 2, 4
• Avoid making dose adjustments without first verifying the cause of low levels, as increasing the dose in a patient with improved renal clearance may lead to toxicity when renal function normalizes 1, 4
• Do not overlook the impact of dietary sodium changes, as patients may inadvertently increase sodium intake (e.g., during holidays or dietary changes) leading to increased lithium excretion 2
• Remember that protracted sweating or diarrhea can lead to sodium depletion and require supplemental fluid and salt, but resolution of these conditions could increase lithium clearance 2