Fluoxetine (Prozac)
SSRI • Last reviewed 2025-09-23
General information
Fluoxetine is an SSRI approved for major depressive disorder, OCD, panic disorder, bulimia nervosa, and PMDD; it is frequently combined with antipsychotics or mood stabilisers to manage depressive symptoms in serious mental illness (fluoxetine_label_2024, thase2015).
Multiple formulations exist: capsules (10, 20, 40 mg), tablets (10, 20, 60 mg), oral solution (20 mg/5 mL), and 90 mg delayed-release capsules for once-weekly maintenance after acute response (fluoxetine_label_2024).
Fluoxetine selectively inhibits the serotonin transporter while weakly antagonising 5-HT2C receptors, conferring activating properties and relatively low weight gain risk. It is also a potent CYP2D6 inhibitor, necessitating consideration of interactions with antipsychotics and beta-blockers (domino2018, tacconi2020).
Fluoxetine and its active metabolite norfluoxetine have elimination half-lives of approximately 2–4 days and 7–15 days, respectively, buffering missed doses yet requiring extended washout before initiating MAOIs (fluoxetine_label_2024, domino2018).
Dosing & administration
MDD: 20 mg once daily in the morning; increase after 3–4 weeks to 40–60 mg/day if needed.
OCD: initiate 20 mg/day; titrate to 40–60 mg/day (maximum 80 mg/day).
Bulimia nervosa: 60 mg once daily produces the greatest reduction in binge/purge frequency.
PMDD: 20 mg/day continuously or 20 mg/day during the luteal phase beginning 14 days before menses.
Dose adjustments
- Hepatic impairment
- Reduce dose or administer every other day; clearance declines significantly.
- Elderly
- Start 10 mg/day; monitor sodium and gait.
- Concomitant CYP2D6 substrates
- Reduce substrate dose (e.g., risperidone, metoprolol) and monitor plasma levels.
- Transition to MAOI
- Observe a 5-week washout after discontinuing fluoxetine.
Mechanism of action
Fluoxetine increases synaptic serotonin by inhibiting SERT, normalising activity within limbic and cortical circuits implicated in depression and anxiety (thase2015).
Norfluoxetine sustains receptor occupancy, while 5-HT2C antagonism disinhibits norepinephrine and dopamine release in prefrontal cortex, contributing to activation and weight neutrality (domino2018).
- SERT Ki ≈ 1 nM.
- Weak NET inhibition (Ki ≈ 500 nM) and 5-HT2C antagonism.
- Potent CYP2D6 inhibitor—key consideration for polypharmacy.
Metabolism & pharmacokinetics
Peak plasma concentrations occur 6–8 hours post-dose; oral bioavailability exceeds 70% with minimal food effect (fluoxetine_label_2024).
Fluoxetine is >94% protein bound and extensively metabolised by CYP2D6/CYP2C9 pathways. Apparent clearance averages ~10 mL/min/kg; norfluoxetine contributes to pharmacologic activity long after discontinuation (domino2018).
Drug interactions
CYP2D6 inhibition elevates concentrations of risperidone, aripiprazole, metoprolol, and TCAs—dose adjustments are often necessary.
Serotonergic agents (MAOIs, linezolid, triptans) increase serotonin syndrome risk; adhere to recommended washouts.
Consider ECG monitoring when combined with QT-prolonging medications in patients with cardiac risk factors.
| Mechanism | Agents / factors | Management |
|---|---|---|
| CYP2D6 inhibition | Risperidone, aripiprazole, metoprolol | Reduce substrate dose; monitor for toxicity. |
| Serotonergic toxicity | MAOIs, linezolid, triptans | Avoid or monitor closely; educate on symptoms. |
| QT prolongation | Ziprasidone, methadone | Baseline ECG and electrolytes in high-risk patients. |
Monitoring & safety checks
Mood, suicidality, activation
Baseline and each follow-up • Detect manic switch or emergent suicidality.
Serum sodium
Baseline and if hyponatremia symptoms occur • SSRIs can cause SIADH, especially in older adults.
Weight and appetite
During titration and quarterly • Monitor for anorexia or weight changes.
Set expectations for 2–4 week onset of benefit and potential early activation; consider evening dosing if insomnia occurs.
When used with antipsychotics, re-evaluate antipsychotic dosing after 2–3 weeks because fluoxetine can increase serum levels.
Discontinuation guidance
Gradual taper (e.g., decrease by 10 mg every 1–2 weeks) is prudent for sensitive patients despite low withdrawal risk.
Ensure a 5-week washout before initiating MAOIs to prevent hypertensive crises or serotonin syndrome.
Special populations
Pregnancy: large observational datasets indicate minimal teratogenic risk; monitor neonates for adaptation syndrome with third-trimester exposure (apa_depression_2020).
Breastfeeding: fluoxetine is present in breast milk; monitor infants for irritability or poor feeding.
Hepatic impairment: reduce dose or extend dosing interval due to reduced clearance.
Common adverse effects
Common: nausea, insomnia, nervousness, sexual dysfunction, sweating.
Less common: tremor, rash, bruxism; consider adjunctive management or dose adjustment if persistent.
Serious: serotonin syndrome, QT prolongation, SIADH—monitor high-risk patients closely.
References
- PROZAC (fluoxetine) prescribing information — DailyMed (2024)
- APA practice guideline for the treatment of patients with major depressive disorder — American Psychiatric Association (2020) DOI: 10.1176/appi.books.9780890426814
- Efficacy of fluoxetine revisited: meta-analytic perspectives — Focus (2015) DOI: 10.1176/appi.focus.20150011
- Fluoxetine pharmacokinetics and pharmacogenomics: current insights — Clinical Pharmacokinetics (2018) DOI: 10.1080/14656566.2018.1470968
- Drug-drug interaction profile of fluoxetine — Expert Opinion on Drug Metabolism & Toxicology (2020) DOI: 10.1080/17512433.2020.1736936
Educational use only — verify details in current prescribing information and authoritative clinical guidelines before making prescribing decisions.