What can cause elevated lithium levels?

Factors That Can Increase Lithium Levels

Several medications and physiological conditions can significantly increase lithium levels, potentially leading to toxicity, including NSAIDs, diuretics, ACE inhibitors, ARBs, and dehydration. 1, 2

Medication Interactions

NSAIDs (Non-Steroidal Anti-Inflammatory Drugs)

• NSAIDs can significantly increase steady-state plasma lithium concentrations by reducing renal clearance of lithium 2
• Both traditional NSAIDs and selective COX-2 inhibitors have been shown to increase lithium levels 2
• In a study of healthy subjects, celecoxib 200mg BID increased lithium levels by approximately 17% 2
• Indomethacin and piroxicam have been specifically reported to significantly increase steady-state plasma lithium concentrations 2

Diuretics

• Diuretics can reduce sodium reabsorption in the renal tubules, which decreases lithium clearance and increases serum levels 2
• This interaction requires close monitoring of lithium levels and potential dose adjustments 2

ACE Inhibitors and ARBs

• Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) can increase lithium levels by reducing renal clearance 2
• When these combinations are used, lithium dosage may need to be decreased and more frequent monitoring of lithium plasma levels is recommended 2

Antibiotics

• Antibiotics have been associated with elevated lithium serum levels 3
• A case-control study found that starting potentially interacting co-medication, including antibiotics, was significantly associated with elevated lithium levels 3

GLP-1 Receptor Agonists

• Recent evidence suggests that semaglutide and potentially other GLP-1 receptor agonists may increase lithium levels 4
• Mechanisms may include altered kidney function, dehydration from reduced oral intake, gastrointestinal effects, or delayed gastric emptying 4

Physiological Factors

Dehydration and Sodium Depletion

• Decreased fluid intake, excessive sweating, fever, or diarrhea can lead to dehydration and sodium depletion, which reduces lithium excretion 2
• Lithium decreases sodium reabsorption by the renal tubules, which could lead to sodium depletion if not adequately replaced 2
• It is essential for patients to maintain a normal diet, including salt, and adequate fluid intake (2500-3000 mL) during lithium therapy 2

Renal Impairment

• Lithium is primarily excreted by the kidneys, so any decrease in renal function can lead to lithium accumulation 2
• Patients with GFR < 60 ml/min/1.73 m² require lower doses and more frequent monitoring 5
• For patients with GFR < 30 ml/min/1.73 m², dose should be reduced by 50% 5

Age-Related Changes

• Elderly patients have reduced lithium clearance and increased sensitivity to lithium 5
• Lower starting doses (150 mg/day) are recommended for elderly patients 5

Signs of Lithium Toxicity

Early Warning Signs

• Early signs of toxicity include tremor, nausea, diarrhea, polyuria-polydipsia 6
• Fine hand tremor, polyuria, and mild thirst may occur during initial therapy and may persist throughout treatment 2

Moderate to Severe Toxicity

• At lithium levels above 1.5 mEq/L, risk of toxicity increases significantly 2
• Symptoms include diarrhea, vomiting, drowsiness, muscular weakness, and lack of coordination 2
• At higher levels (>2 mEq/L), giddiness, ataxia, blurred vision, tinnitus, and large output of dilute urine may occur 2
• Serum lithium levels above 3 mEq/L can produce a complex clinical picture involving multiple organs and systems 2

Monitoring Recommendations

• Baseline testing should include complete blood count, thyroid function tests, renal function tests, serum calcium, and urinalysis 6
• More frequent monitoring of lithium levels is recommended when starting potentially interacting medications 2
• Patients should be educated about maintaining adequate hydration and salt intake, especially during illness, hot weather, or increased physical activity 2
• Lithium levels should be closely monitored when patients initiate or discontinue NSAID use 2

Prevention Strategies

• Consider alternative medications when possible instead of those known to interact with lithium 2
• If interacting medications must be used, adjust lithium dose preemptively and monitor levels more frequently 2
• Ensure patients maintain adequate hydration and normal salt intake 2
• Educate patients to report signs of early toxicity promptly 2
• Supplemental fluid and salt should be administered if prolonged sweating or diarrhea occurs 2