Prozac (Fluoxetine): Clinical Overview
FDA-Approved Indications
Fluoxetine is FDA-approved for major depressive disorder, OCD, panic disorder, bulimia nervosa, premenstrual dysphoric disorder, and bipolar disorder (in combination with olanzapine), and is the only antidepressant FDA-approved for pediatric depression (ages 8 years and older). 1
Pediatric Use
- Fluoxetine is the sole antidepressant with FDA approval for children and adolescents aged 8 years and older with major depression 2, 1
- All other antidepressants used in pediatric populations are prescribed off-label 2
Dosing Guidelines
Adults
For major depressive disorder and most anxiety disorders, start fluoxetine at 20 mg once daily; the optimal therapeutic range is 20–40 mg daily, though doses up to 80 mg/day may be used for specific indications. 3, 4
- Standard depression/anxiety dosing: 20 mg once daily, may increase to 40 mg after several weeks if needed 3, 4
- OCD requires substantially higher doses: 60–80 mg daily demonstrates superior efficacy compared to lower doses 1
- Time to effect: Allow 6–8 weeks at therapeutic doses before assessing adequacy of response; approximately 38% of patients do not achieve response and 54% do not achieve remission during initial 6–12 weeks 1
Pediatric Patients
- Start at lower doses (5–10 mg daily) and titrate gradually, particularly in patients with anxiety or panic symptoms 5
- Approximately 28% of patients cannot tolerate the standard 20 mg dose but may benefit from lower doses (5–15 mg daily) 5
- Patients with comorbid panic disorder are especially likely to require lower starting doses 5
Special Populations
CYP2D6 poor metabolizers have 3.9-fold higher drug exposure at 20 mg and 11.5-fold higher exposure at 60 mg compared to extensive metabolizers, substantially increasing toxicity risk including QT prolongation and arrhythmias. 1
- Fluoxetine itself inhibits CYP2D6, converting approximately 43% of normal metabolizers to poor metabolizer phenotype with chronic use 1
- Consider genetic testing before prescribing high doses (≥60 mg) 1
Mechanism of Action and Pharmacokinetics
Fluoxetine is a bicyclic antidepressant that potently and selectively inhibits presynaptic serotonin reuptake with negligible effects on norepinephrine or other neurotransmitters. 3, 4
Key Pharmacokinetic Properties
- Bioavailability: Approximately 72% after oral administration 3
- Time to peak concentration: 4–8 hours 3
- Protein binding: ~94% 3
- Half-life: 1–3 days after single dose; averages 4 days after long-term administration 3
- Active metabolite: Norfluoxetine (desmethylfluoxetine) also inhibits serotonin reuptake with a half-life averaging 7 days after chronic dosing 3, 4
- Unique advantage: The long half-life of fluoxetine and norfluoxetine essentially precludes withdrawal syndrome, unlike shorter-acting SSRIs 6
Absolute Contraindications
- Current or recent MAOI use (within 14 days of discontinuation) due to serotonin syndrome risk 1
- Concurrent tamoxifen therapy due to CYP2D6 inhibition 1
- Known hypersensitivity to fluoxetine 6
Common Adverse Effects
The most common adverse effects are nausea, anxiety, insomnia, anorexia, diarrhea, nervousness, and headache; these are dose-related and generally mild. 3, 6
Frequency and Tolerability
- Adverse effects are more common at higher doses (>20 mg/day) 6
- Gastrointestinal and nervous system effects predominate at the recommended 20 mg/day dose 6
- Fluoxetine causes significantly fewer anticholinergic effects than tricyclic antidepressants 4
- Sexual dysfunction occurs but at lower rates than with paroxetine 1
- Weight effects: Fluoxetine is associated with less weight gain compared to paroxetine 1
Cardiovascular Safety
- Therapeutic doses do not affect cardiac conduction intervals in patients without pre-existing cardiovascular disease 4
- Fluoxetine has been relatively safe in overdose situations 4, 6
- Eight reports of intentional overdose with fluoxetine alone resulted in no deaths and only mild adverse effects 3
Critical Safety Warnings
Black Box Warning: Suicidality
All SSRIs, including fluoxetine, carry FDA black box warnings for increased risk of suicidal thoughts and behaviors in patients younger than 24 years, with the greatest risk during the first 1–2 months of treatment. 1
- Pooled risk shows 14 additional cases per 1,000 patients treated compared to placebo 1
- Monitor weekly during the first month, especially in the first 1–2 weeks after initiation or dose changes 1
- Risk is particularly elevated in adolescents and young adults under age 24 1
Drug Interactions
Fluoxetine is a potent inhibitor of CYP2D6 and other CYP enzymes, increasing the potential for drug interactions, though most are not clinically important. 6
- Dangerous interactions: Tamoxifen (reduced efficacy), codeine/tramadol (reduced analgesic effect), and other CYP2D6 substrates 1
- Serotonin syndrome risk: Avoid combining with MAOIs, tramadol, triptans, other antidepressants, and St. John's wort 1
- Allow at least 2 weeks washout when switching to/from MAOIs 1
Treatment Duration
Continue fluoxetine for a minimum of 4–9 months after satisfactory response for first-episode depression; longer duration (≥1 year) is recommended for patients with recurrent episodes. 1
- Meta-analysis of 31 trials supports continuation therapy to reduce relapse risk 1
- After two episodes, recurrence probability increases to 70%; after three episodes it reaches 90% 1
Comparative Efficacy
All second-generation antidepressants (SSRIs and SNRIs) demonstrate equivalent efficacy for treating major depression and anxiety symptoms, with no significant differences in overall response rates. 1
- Fluoxetine has comparable efficacy to imipramine, amitriptyline, and doxepin in unipolar depression 4
- One trial showed venlafaxine had statistically better response rates than fluoxetine for depression with prominent anxiety, though evidence is limited 1
- Fluoxetine may be less effective than tricyclics in relieving sleep disorders in depressed patients 4
Common Pitfalls to Avoid
- Do not discontinue prematurely: Full response may take 6–8 weeks; partial response at 4 weeks warrants continued treatment, not switching 1
- Do not exceed maximum doses without genetic testing: High doses (≥60 mg) in CYP2D6 poor metabolizers carry substantial toxicity risk 1
- Do not combine with MAOIs: Serotonin syndrome can be fatal 1
- Do not use as monotherapy in bipolar disorder: Risk of mood destabilization and rapid cycling 1
- Do not start at full dose in anxious patients: Consider 5–10 mg starting dose and titrate gradually 5
Special Clinical Considerations
Obsessive-Compulsive Disorder
For OCD, fluoxetine requires doses of 40–60 mg daily, with optimal efficacy at 60–80 mg daily; efficacy should not be evaluated before 8 weeks of treatment. 7, 1
- Minimum treatment duration of 1–2 years is recommended 7
- Efficacy is comparable to clomipramine with superior safety profile (fewer anticholinergic effects, lower cardiotoxicity) 7
- Predictors of good response: presence of remissions, absence of prior pharmacologic therapy, nervousness/insomnia at treatment start 7
Combination with Behavioral Therapy
- Combining fluoxetine with cognitive-behavioral therapy yields superior outcomes for anxiety disorders and OCD compared to either modality alone 1