What baseline assessments, laboratory evaluations, and follow‑up schedule should be used to monitor a patient initiating fluoxetine, including considerations for bipolar disorder, seizure disorder, hepatic or renal impairment, hyponatremia risk (especially in older adults), and potential adverse effects?

Monitoring for Fluoxetine

Monitor serum sodium at baseline and within 2-4 weeks of initiating fluoxetine in high-risk patients (elderly, low body weight, history of hyponatremia), and obtain baseline ECG in patients with personal/family history of QT prolongation or sudden cardiac death, particularly those with CYP2D6 poor metabolizer status. 1, 2

Baseline Assessments

Cardiac Evaluation

• Obtain baseline ECG in patients with congenital long QT syndrome, previous QT prolongation history, family history of long QT syndrome or sudden cardiac death, as fluoxetine requires caution in these conditions per FDA safety labeling 2
• Consider CYP2D6 genotyping in patients with cardiac risk factors, as poor metabolizers have significantly elevated drug levels (AUC 3.9-fold higher at 20mg, 11.5-fold higher at 60mg) and increased risk of QT prolongation 2

Electrolyte and Metabolic Assessment

• Check serum sodium at baseline in all high-risk patients: elderly (particularly females), low body weight, history of SIADH or hyponatremia 1, 3
• Hyponatremia typically develops within the first month and is not dose-dependent 1

Bipolar Disorder Screening

• Screen for bipolar disorder history before initiating fluoxetine, as up to 45% of patients with major depression may have bipolar II disorder 4
• Document any history of manic/hypomanic episodes, rapid cycling, or family history of bipolar disorder 2

Seizure History

• Document seizure history and risk factors, though fluoxetine is not specifically highlighted for increased seizure risk compared to other antidepressants 5
• Note that high-dose fluoxetine (80-100mg/day) in CYP2D6 poor metabolizers has been associated with fatal metabolic toxicity and seizures 2

Hepatic and Renal Function

• Assess baseline hepatic function, as fluoxetine undergoes extensive hepatic metabolism via CYP2D6 to active metabolite norfluoxetine 6
• Both parent compound and metabolite have elimination half-lives of several days, requiring dose adjustment in hepatic impairment 6

Follow-Up Monitoring Schedule

First Month (Critical Period)

• Recheck serum sodium at 2-4 weeks in high-risk patients, as hyponatremia risk is highest during initial treatment 1, 3
• Sodium <135 mmol/L is clinically significant; <130 mmol/L requires immediate intervention 1
• Monitor for adverse effects weekly during first 4 weeks, particularly nausea, nervousness, and insomnia (most common side effects) 6
• Assess for hypomanic/manic symptoms in patients with known or suspected bipolar disorder, though manic switch rate is relatively low (3.8% in bipolar II patients) 4, 7

Weeks 6-8

• Evaluate therapeutic response using standardized depression rating scales, as adequate trial duration is 6-8 weeks 2
• Monitor tolerability, as higher dropout rates occur with higher doses due to adverse effects 2

Long-Term Monitoring (Beyond 3 Months)

• Monitor serum sodium every 3-6 months in patients with ongoing risk factors 1
• Periodic assessment of therapeutic response and side effects to justify continued treatment 2
• Consider that long-term fluoxetine at 20mg/day converts approximately 43% of extensive metabolizers to poor metabolizer phenotype through auto-inhibition of CYP2D6 2

Special Population Considerations

Elderly Patients

• Intensify sodium monitoring: check at baseline, 2 weeks, 4 weeks, then every 3-6 months 1, 3
• Elderly females with lower body weight are at highest risk for hyponatremia 3
• Case reports demonstrate severe symptomatic hyponatremia with seizures occurring within 2 weeks of starting treatment 3

Bipolar Disorder Patients

• Monitor for manic switch during first 8 weeks, though risk is low (7.3% showed hypomanic symptoms in one study) 7
• Consider mood stabilizer co-administration in bipolar I disorder; fluoxetine monotherapy may be appropriate for bipolar II depression 4, 7

High-Dose Therapy (>20mg/day)

• Enhanced monitoring for toxicity in patients requiring doses above 20mg, particularly for OCD treatment 2
• Consider CYP2D6 genotyping before escalating doses, as poor metabolizers have dramatically elevated drug levels 2
• Monitor for serious adverse events including blood pressure changes, QT prolongation, and seizures 2

Management of Hyponatremia

• If sodium <135 mmol/L develops: immediately switch to mirtazapine or bupropion, discontinue fluoxetine, implement fluid restriction, and ensure adequate oral salt intake 1
• For persistent severe hyponatremia with cognitive symptoms despite water restriction, consider vasopressin antagonists 1

Critical Safety Considerations

• Avoid unnecessary polypharmacy with CYP2D6 inhibitors, as this further increases fluoxetine levels and toxicity risk 2
• Fatal cases have been reported with high-dose fluoxetine in CYP2D6 poor metabolizers, including metabolic toxicity, seizures, status epilepticus, and cardiac arrest 2
• Fluoxetine does not affect cardiac conduction intervals in patients without pre-existing cardiovascular disease at therapeutic doses 6