Can Prozac (Fluoxetine) Cause Hyponatremia?
Yes, Prozac (fluoxetine) can cause hyponatremia, particularly in elderly patients, and this risk is highest during the first few weeks of treatment. 1
Mechanism and Clinical Significance
Hyponatremia occurs as a result of SSRI treatment, including fluoxetine, and in many cases appears to be due to the syndrome of inappropriate antidiuretic hormone secretion (SIADH). 1 Cases with serum sodium lower than 110 mmol/L have been reported and are reversible when fluoxetine is discontinued. 1
High-Risk Populations
Elderly patients are at substantially greater risk of developing hyponatremia with SSRIs, including fluoxetine. 1 Specific risk factors include:
- Age over 55-65 years: The reported rate in women over 65 years is 8.5 per thousand, with hyponatremia developing in 15.8% of older patients by the third week of therapy. 2, 3
- Patients taking diuretics or who are volume depleted: These patients face greater risk of SSRI-induced hyponatremia. 1
- Lower body mass index: This is a significant independent risk factor for developing hyponatremia. 4
- Lower baseline plasma sodium level (<138 mEq/L): Patients with baseline sodium in the lower normal range are at increased risk. 4
Time Course and Severity
Hyponatremia typically develops within the first 1-3 weeks of fluoxetine therapy, with most cases occurring within 19 days of initiation. 2, 3 The mean time to development is approximately 9 days (range 1-14 days). 4
In older patients, serum sodium levels decrease significantly by the first week of therapy, whereas younger patients (15-35 years) show decreases only after the third week. 3 The severity is also greater in older patients, with serum sodium levels averaging 135.2±2.06 mmol/L in older patients versus 140.8±2.26 mmol/L in younger patients at week three. 3
Clinical Manifestations
Signs and symptoms of hyponatremia include:
- Headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness (which may lead to falls). 1
- More severe cases: hallucination, syncope, seizure, coma, respiratory arrest, and death. 1
- Case reports document severe presentations with serum sodium as low as 105-114 mmol/L, presenting with generalized seizures, altered mental status, nausea, vomiting, and progressive confusion. 2, 5
Monitoring Recommendations
Monitor serum sodium levels in elderly patients (especially those over 55-65 years) during the first few weeks of fluoxetine therapy. 2, 3 Specific monitoring should include:
- Baseline serum sodium before initiating therapy. 3, 4
- Repeat measurements at 1 week and 3 weeks after initiation, particularly in high-risk patients. 3, 4
- More frequent monitoring in patients with baseline sodium <138 mEq/L, low BMI, concurrent diuretic use, or volume depletion. 1, 4
Management
Discontinuation of fluoxetine should be considered in patients with symptomatic hyponatremia, and appropriate medical intervention should be instituted. 1 Withdrawal of fluoxetine is associated with recovery in all reported cases. 2
Context Among SSRIs
While the American College of Physicians guidelines note that evidence evaluating hyponatremia with second-generation antidepressants is scarce, it should be kept in mind when patients are being treated with SSRIs. 6 This is a class effect of SSRIs, not unique to fluoxetine, with similar risks documented for paroxetine (12% incidence in older adults) and citalopram. 7, 4
Special Considerations in Heart Failure and Liver Disease
In patients with heart failure who develop hyponatremia, alternative causes should be assessed (including SIADH, hypothyroidism, and hypoaldosteronism), and water restriction with maximization of guideline-directed medical therapy should be attempted before attributing hyponatremia solely to SSRI use. 6
In patients with liver cirrhosis, fluoxetine clearance is decreased, increasing elimination half-lives, so a lower or less frequent dose should be used. 1 However, the primary concern in cirrhotic patients with hyponatremia is typically hypervolemic hyponatremia from the underlying liver disease rather than SSRI-induced SIADH. 6