What are the guidelines for taking lithium (a mood stabilizer) and furosemide (a loop diuretic) together in patients with bipolar disorder and hypertension or heart failure, considering potential risks of lithium toxicity and impaired renal function?

Lithium and Furosemide Co-Administration Guidelines

Critical FDA Contraindication

Lithium should generally not be given to patients receiving diuretics, as the FDA explicitly states that "the risk of lithium toxicity is very high in such patients." 1 If the psychiatric indication is life-threatening and the patient fails other measures, lithium may be used with extreme caution, including daily serum lithium determinations, adjustment to unusually low doses, and mandatory hospitalization. 1

Furosemide specifically reduces lithium's renal clearance and adds a high risk of lithium toxicity, and the FDA states that "lithium generally should not be given with diuretics." 2

Mechanism of Interaction

Loop diuretics like furosemide cause volume depletion and sodium loss, which triggers compensatory increased proximal tubular reabsorption of both sodium and lithium, dramatically reducing lithium clearance and elevating serum levels by 25-40%. 3 This interaction occurs because lithium is handled by the kidney similarly to sodium—when sodium is depleted by diuretics, the kidney avidly reabsorbs both ions to maintain homeostasis. 3

Mandatory Monitoring Protocol When Combination Cannot Be Avoided

If this combination must be used due to life-threatening psychiatric illness:

Initial Phase (First Week)

• Check serum lithium levels daily until stable, as mandated by the FDA for high-risk patients. 1
• Measure serum electrolytes (sodium, potassium, magnesium), creatinine, and BUN within 2-3 days of initiating the combination. 2, 4
• Assess volume status and blood pressure daily to detect early dehydration. 1

Stabilization Phase (Weeks 2-12)

• Check lithium levels twice weekly for the first month, then weekly for months 2-3. 5
• Monitor creatinine clearance, as values <50 mL/min significantly predict lithium toxicity risk even at therapeutic doses. 5
• Measure serum electrolytes weekly, as furosemide causes hypokalemia and hypomagnesemia that can exacerbate lithium neurotoxicity. 2, 6

Maintenance Phase (After 3 Months)

• Check lithium levels every 1-2 weeks indefinitely, as this combination remains high-risk chronically. 5
• Monitor renal function (creatinine, eGFR) monthly for the first 6 months, then every 3 months. 2, 5
• Check electrolytes monthly, correcting any abnormalities aggressively. 2

Dosing Adjustments Required

Reduce lithium dose by 50% when initiating furosemide, then titrate based on daily serum levels to achieve therapeutic range (0.6-1.0 mEq/L for maintenance). 1, 7 The FDA explicitly recommends "adjustment to the usually low doses ordinarily tolerated" in patients on diuretics. 1

Use the lowest effective furosemide dose (typically 20-40 mg daily) to minimize sodium depletion and lithium retention. 8 Higher furosemide doses (>80 mg daily) dramatically increase toxicity risk. 2

Electrolyte Management

Maintain potassium levels at 4.0-5.0 mEq/L through supplementation or addition of potassium-sparing diuretics like spironolactone 25-50 mg daily. 4, 6 Hypokalemia potentiates lithium neurotoxicity and cardiac effects. 6

Correct hypomagnesemia aggressively (target >0.6 mmol/L), as magnesium depletion from furosemide makes hypokalemia refractory to correction and increases arrhythmia risk. 4, 6 Loop diuretics enhance magnesium losses through increased distal tubular sodium delivery. 6

Avoid severe sodium restriction (<2,300 mg daily), as this exacerbates lithium retention. 8 Moderate sodium restriction (2,300-3,000 mg daily) is acceptable but requires closer lithium monitoring. 8

Warning Signs of Lithium Toxicity

Patients and caregivers must be educated to recognize early toxicity symptoms:

• Neurological: Coarse tremor (distinct from fine physiologic tremor), dysarthria, ataxia, confusion, drowsiness. 5, 9
• Gastrointestinal: Severe nausea, vomiting, diarrhea (beyond typical lithium side effects). 9
• Renal: Oliguria, marked increase in thirst/urination. 9

Not overdose-related lithium toxicity (from drug interactions and renal impairment) causes more severe neurological symptoms and longer hospitalizations than overdose-related toxicity. 5

Absolute Contraindications to This Combination

• Creatinine clearance <50 mL/min, as this dramatically increases toxicity risk even at therapeutic lithium doses. 5
• Significant cardiovascular disease with hemodynamic instability. 1
• Severe dehydration or sodium depletion. 1
• Concurrent use of thiazide diuretics, NSAIDs, or ACE inhibitors, as these create additive lithium retention. 2, 3
• Inability to perform frequent laboratory monitoring. 1

Alternative Strategies to Consider

If heart failure management permits, substitute furosemide with a potassium-sparing diuretic alone (spironolactone 25-100 mg daily), which has minimal effects on lithium clearance and provides dual benefit of potassium conservation. 8, 3 Loop diuretics have "minor variable effects" on lithium levels compared to thiazides' 25-40% increase, but still carry significant risk. 3

Consider alternative mood stabilizers (valproate, lamotrigine, second-generation antipsychotics) if the psychiatric indication is not absolutely refractory to other agents, as the FDA contraindication reflects genuine life-threatening risk. 1

Common Pitfalls to Avoid

• Never assume therapeutic lithium levels are safe in patients on furosemide—toxicity occurs at lower levels when diuretics are present. 5
• Do not wait for symptoms to check lithium levels—neurological damage from toxicity may be irreversible. 5, 9
• Avoid combining two diuretics (e.g., furosemide plus metolazone), as this markedly enhances electrolyte depletion and lithium retention risk. 8, 10
• Never discontinue furosemide abruptly without adjusting lithium dose downward, as sodium repletion will cause lithium levels to drop precipitously. 7
• Do not rely solely on serum creatinine—calculate creatinine clearance, as elderly patients may have normal creatinine despite significant renal impairment. 5