Sertraline vs Fluoxetine
Clinical Comparison
Clinical Context
Both are first-line SSRIs, but sertraline is the most commonly recommended first-choice by NICE for depression and anxiety in adults due to its favourable interaction profile. Fluoxetine is preferred in children/adolescents and where discontinuation syndrome is a concern, thanks to its exceptionally long half-life.
Drug Profiles
Sertraline
Selective serotonin reuptake inhibitor (SSRI)
Mechanism
Selectively inhibits serotonin (5-HT) reuptake at the presynaptic terminal, increasing serotonergic neurotransmission
Indications
- Major depressive disorder
- Generalised anxiety disorder
- Panic disorder
- OCD
- PTSD
- Social anxiety disorder
Common Doses
50 mg OD initially, increased in 50 mg increments to max 200 mg OD
Route
Oral
Onset & Duration
Onset of therapeutic effect 2-4 weeks; half-life 26 hours
Fluoxetine
Selective serotonin reuptake inhibitor (SSRI)
Mechanism
Selectively inhibits serotonin reuptake at the presynaptic terminal, with active metabolite (norfluoxetine) extending activity
Indications
- Major depressive disorder
- OCD
- Bulimia nervosa
- Depression in children and adolescents (age 8+)
Common Doses
20 mg OD, increased to max 60 mg OD (80 mg for OCD/bulimia)
Route
Oral
Onset & Duration
Onset 2-4 weeks; half-life 4-6 days (norfluoxetine: 4-16 days)
Key Differences
| Category | Sertraline | Fluoxetine |
|---|---|---|
| Drug interactions | Fewer CYP interactions — generally safer with polypharmacy | Potent CYP2D6 inhibitor — avoid with tamoxifen, codeine |
| Half-life | 26 hours — needs tapering to avoid discontinuation | 4-16 days (with metabolite) — self-tapering, minimal withdrawal |
| Children/adolescents | Not first-line in under 18s | Only SSRI licensed for depression in children (age 8+) |
| Bulimia nervosa | Not licensed for bulimia | Licensed at 60 mg for bulimia nervosa |
| Cardiac safety | Proven safe post-MI (SADHART trial) | Less cardiac safety data |
| Activation profile | More neutral / mildly sedating | More activating — can worsen anxiety initially |
Drug interactions
Fewer CYP interactions — generally safer with polypharmacy
Potent CYP2D6 inhibitor — avoid with tamoxifen, codeine
Half-life
26 hours — needs tapering to avoid discontinuation
4-16 days (with metabolite) — self-tapering, minimal withdrawal
Children/adolescents
Not first-line in under 18s
Only SSRI licensed for depression in children (age 8+)
Bulimia nervosa
Not licensed for bulimia
Licensed at 60 mg for bulimia nervosa
Cardiac safety
Proven safe post-MI (SADHART trial)
Less cardiac safety data
Activation profile
More neutral / mildly sedating
More activating — can worsen anxiety initially
Key Advantages
Sertraline
- Fewer CYP450 drug interactions than fluoxetine
- NICE first-line SSRI for depression and GAD
- Safe in cardiac patients (SADHART trial)
- Well-tolerated with gradual titration
Fluoxetine
- Very long half-life — minimal discontinuation symptoms
- Only SSRI licensed for depression in children (age 8+)
- Licensed for bulimia nervosa
- Activating profile — may suit patients with lethargy/hypersomnia
Key Cautions
Sertraline
- GI side effects (nausea, diarrhoea) especially initially
- Sexual dysfunction
- Discontinuation syndrome if stopped abruptly
- Hyponatraemia risk in elderly
- Serotonin syndrome risk with MAOIs/triptans
Fluoxetine
- Potent CYP2D6 inhibitor — many drug interactions (tamoxifen, codeine, tramadol)
- Long half-life means interactions persist for weeks after stopping
- More activating — may worsen anxiety/insomnia initially
- Weight loss more common than other SSRIs
Clinical Verdict
Sertraline is the general first-choice SSRI for adult depression and anxiety (fewer drug interactions, cardiac safety). Fluoxetine is preferred in children, bulimia, or when poor medication adherence makes the long half-life advantageous.
Medical Disclaimer: This comparison is for educational purposes only and is not a substitute for professional medical advice. Always consult a qualified healthcare professional before making prescribing decisions. Verify all drug information with current clinical guidelines (BNF, NICE, SmPCs).
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