What are the common side effects of fluoxetine (Selective Serotonin Reuptake Inhibitor - SSRI)?

Fluoxetine Side Effects

Fluoxetine commonly causes gastrointestinal symptoms (nausea, diarrhea), neurological effects (headache, insomnia, dizziness), sexual dysfunction, and anxiety/nervousness, with nausea being the most frequent reason for treatment discontinuation. 1, 2

Most Common Side Effects

Gastrointestinal Effects

• Nausea and vomiting are the most frequently reported adverse effects and the leading cause of discontinuation in clinical trials 1, 2
• Anorexia (decreased appetite) occurs in 11% of patients with major depressive disorder (versus 2% with placebo) and 17% in OCD patients (versus 10% with placebo) 2
• Diarrhea, constipation, dry mouth, and heartburn occur commonly, though fluoxetine has lower rates of diarrhea compared to sertraline 1

Neurological and Psychiatric Effects

• Headache, dizziness, and somnolence are among the most common neurological complaints 1, 2
• Insomnia affects 28% of OCD patients and 33% of bulimia patients treated with fluoxetine 60mg (versus 22% and 13% with placebo, respectively) 2
• Anxiety and nervousness occur in 12-16% of depression patients (versus 7-9% with placebo) and 15% of bulimia patients on 60mg (versus 9% with placebo) 2

Sexual Dysfunction

• Sexual adverse events are common with fluoxetine, though absolute rates are likely underreported in clinical trials 1
• Fluoxetine has lower rates of sexual dysfunction than paroxetine but higher rates than bupropion 1

Weight and Appetite Changes

• Significant weight loss may occur, particularly concerning in underweight depressed or bulimic patients 2
• Weight loss led to discontinuation in only 1.4% of patients (versus 0.5% with placebo) 2
• Fluoxetine causes less weight gain than mirtazapine or paroxetine 1

Serious Adverse Effects Requiring Monitoring

Suicidality

• SSRIs including fluoxetine increase the risk of nonfatal suicide attempts (odds ratio 1.57, CI 0.99-2.55), though not completed suicides 1
• Close monitoring is essential during the first few months of treatment and following dosage adjustments 1

Activation of Mania/Hypomania

• Mania/hypomania occurs in 0.1% of depression patients and 0.8% of OCD patients treated with fluoxetine 2
• This risk is particularly important in patients with bipolar disorder or family history of mania 2

Bleeding Risk

• Fluoxetine increases bleeding risk, ranging from ecchymoses and epistaxis to life-threatening hemorrhages 2
• Concomitant use with NSAIDs, aspirin, warfarin, or other anticoagulants significantly increases this risk 2

Hyponatremia

• Hyponatremia may occur due to SIADH, with cases reported below 110 mmol/L 2
• Elderly patients and those on diuretics are at highest risk 2
• Symptoms include headache, confusion, weakness, unsteadiness, and in severe cases, seizures, coma, or death 2

Serotonin Syndrome

• This rare but potentially life-threatening condition occurs when fluoxetine is combined with other serotonergic medications 1
• Combination with MAOIs is absolutely contraindicated 1
• Caution is required when combining with tramadol, meperidine, fentanyl, dextromethorphan, and other serotonergic agents 1

Seizures

• Seizures occur in approximately 0.1% of patients in controlled trials 2, 3
• Risk increases with higher doses and in overdose situations 3

Drug Interaction Considerations

• Fluoxetine inhibits CYP2D6 and other cytochrome P450 enzymes, increasing potential for drug interactions 1, 4
• Interactions with drugs metabolized by CYP2D6 (including many antidepressants, antipsychotics, and beta-blockers) require dose adjustments 1
• The long half-life of fluoxetine (1-3 days) and its active metabolite (7-15 days) means drug interactions can persist for weeks after discontinuation 4, 5

Clinical Management Pearls

Minimizing Side Effects

• Starting with a subtherapeutic "test" dose can help identify patients who will experience anxiety or agitation as an initial adverse effect 1
• The long half-life of fluoxetine (versus shorter-acting SSRIs) allows for slower dose titration at approximately 3-4 week intervals 1
• Most common side effects (nausea, nervousness, insomnia, headache) can be controlled with careful dose adjustment 6

Discontinuation Considerations

• Fluoxetine has the lowest risk of discontinuation syndrome among SSRIs due to its long half-life, essentially precluding withdrawal phenomena 1, 4
• This contrasts sharply with paroxetine, fluvoxamine, and sertraline, which commonly cause discontinuation syndrome 1

Safety in Overdose

• Fluoxetine has significant relative safety in overdoses compared to tricyclic antidepressants, with no serious cardiovascular effects 2, 5
• It does not affect cardiac conduction or cause orthostatic hypotension at therapeutic doses 5