Side Effects of Fluoxetine
Fluoxetine causes common side effects including nausea, insomnia, nervousness, headache, diarrhea, dizziness, sexual dysfunction, and somnolence, with nausea being the most frequent reason for discontinuation, but it has a significantly better safety profile than tricyclic antidepressants with fewer anticholinergic effects and lower risk of discontinuation syndrome compared to other SSRIs. 1, 2
Common Side Effects
The most frequently reported adverse effects with fluoxetine include:
- Gastrointestinal effects: Nausea (most common), diarrhea, anorexia, and dry mouth 1, 2
- Central nervous system effects: Insomnia, nervousness, headache, dizziness, somnolence, and tremor 1, 2
- Sexual dysfunction: Occurs less frequently than with paroxetine but more than with bupropion 1
- Other effects: Constipation, sweating, and vivid dreams 1
Nausea and vomiting are the most common reasons patients discontinue fluoxetine in clinical trials. 1
Serious Adverse Effects
Suicidality Risk
All SSRIs including fluoxetine carry a boxed warning for increased suicidal thinking and behavior in patients through age 24 years. 1 The pooled absolute rate for suicidal ideation is 1% for antidepressant-treated youth versus 0.2% for placebo, with a number needed to harm of 143 1. Meta-analyses show SSRIs increase the risk for nonfatal suicide attempts (odds ratio 1.57-2.25) but not completed suicide 1.
Close monitoring is mandatory during the first months of treatment and following any dosage adjustments. 1
Behavioral Activation/Agitation
Behavioral activation (motor restlessness, insomnia, impulsiveness, disinhibited behavior, aggression) occurs more commonly in younger children than adolescents and in anxiety disorders compared to depressive disorders. 1 This typically emerges early in treatment or with dose increases, supporting the need for slow up-titration and close monitoring, particularly in younger children 1.
Serotonin Syndrome
Serotonin syndrome can occur even at therapeutic doses, characterized by mental status changes, autonomic hyperactivity, and neuromuscular abnormalities. 3 This risk increases when fluoxetine is combined with other serotonergic medications 4.
Seizures
Fluoxetine has minimal epileptogenic potential except at extremely high doses. 5 However, CYP2D6 poor metabolizers have significantly higher plasma concentrations, increasing seizure risk 6. High-dose fluoxetine can produce auto-inhibition of CYP2D6, further compounding toxicity risk 6.
Other Serious Effects
- Hyponatremia: Occurs in 0.5-12% of older adults, typically within the first month 3
- Abnormal bleeding: Increased risk, especially when combined with NSAIDs or antiplatelet medications 1, 3
- Mania/hypomania: Rare but can occur, difficult to distinguish from behavioral activation 1
Comparative Safety Profile
Fluoxetine demonstrates several safety advantages over other antidepressants:
- Fewer anticholinergic effects than tricyclic antidepressants (no significant anticholinergic, hypotensive, or sedative effects) 7, 5, 8
- Lower sexual dysfunction rates than paroxetine 1
- Significantly lower risk of discontinuation syndrome compared to paroxetine, fluvoxamine, sertraline, and venlafaxine due to its long half-life 9
- Safer in overdose than tricyclic antidepressants, with no serious cardiovascular effects 7, 5
Discontinuation Considerations
Fluoxetine has the lowest risk of discontinuation syndrome among SSRIs due to its very long half-life (including its active metabolite norfluoxetine). 9 While tapering over 10-14 days is recommended for most SSRIs, this is less critical for fluoxetine specifically 9.
However, the long half-life means side effects may persist for weeks after stopping, which can be problematic when switching medications or if side effects prompted discontinuation. 9
Pediatric Considerations
In pediatric patients (children and adolescents), the adverse event profile is generally similar to adults, but additional events reported at ≥2% incidence include: thirst, hyperkinesia, agitation, personality disorder, epistaxis, urinary frequency, and menorrhagia 2. The most common reason for discontinuation in pediatric trials was mania/hypomania (1.8% versus 0% for placebo) 2.
Clinical Monitoring
Monitor patients closely during:
- The first 24-48 hours after any dose increase, particularly in those with seizure risk factors 6
- The first months of treatment for suicidality 1
- Early treatment phases for behavioral activation, especially in younger children 1
Consider CYP2D6 genetic testing in patients requiring high doses or those with poor tolerability, as poor metabolizer phenotype significantly increases risk of toxic levels. 6