fluoxetine

General Information

Fluoxetine (Prozac) is a long half-life SSRI used for depression, OCD, bulimia nervosa, and bipolar depression (in combination with olanzapine).

Because norfluoxetine persists for weeks, side effects and interaction risk can outlast the last dose; switching plans often require longer washouts than other SSRIs.

The compare view and fluoxetine evidence feed can help weigh activation, discontinuation, and interaction trade-offs when revising maintenance plans.

Its activating profile and low discontinuation risk make it useful in adherence-challenged patients. In patients with bipolar-spectrum risk, mania/hypomania screening and mood-stabiliser coordination are common; the bipolar disorder hub and fluoxetine print page can support shared decision-making.

Potent CYP2D6 inhibition can require dose adjustments for many psychotropics (e.g., risperidone, aripiprazole, TCAs).

Mechanism of Action

Refer to the Glossary entry on Neurotransmitters for background on receptor systems involved in serious mental illness.

Selective serotonin reuptake inhibitor with mild 5-HT2C antagonism that may contribute to activation.

• SERT inhibitor with minimal other receptor affinity.

Metabolism and Pharmacokinetics

• Tmax 6–8 h; half-life 4–6 days at steady state; active metabolite norfluoxetine half-life 7–15 days.
• Metabolized by CYP2D6; eliminated renally as metabolites.
• Hepatic impairment can prolong exposure; dose reductions or alternate-day dosing are sometimes used when tolerability limits continuation.
• Long half-life means steady state takes weeks and missed doses have less immediate impact, but adverse effects may also take longer to resolve.

Dosing and Administration

• Typical adult start is 20 mg once daily (often morning); may increase to 40–60 mg/day after several weeks if needed and tolerated.
• Lower initial doses (10 mg) are often used in anxiety disorders.
• For panic-spectrum presentations where activation is a concern, gradual titration is often used to reduce early jitteriness and insomnia.
• A 5-week washout is required before starting MAOI therapy due to long half-life.
• Once-weekly delayed-release dosing is sometimes used after stabilization on daily therapy; suitability for comorbid hepatic disease is typically confirmed, and labeling is reviewed for transition timing.

Monitoring & Labs

• Suicidality and psychiatric activation (anxiety, agitation, mood elevation) during initiation and dose changes, especially in younger patients.
• Sodium in older adults or patients on diuretics if symptoms suggest hyponatremia (confusion, fatigue, gait change).
• Bleeding/bruising risk when combined with NSAIDs, antiplatelets, or anticoagulants; early symptom reporting is often reinforced.
• Medication reconciliation to avoid serotonergic combinations and to anticipate prolonged interaction windows after stopping.

Fluoxetine’s long half-life lowers discontinuation risk but prolongs both adverse effects and interaction risk after the last dose.

Adverse Effects

Interactions

• Potent CYP2D6 inhibitor—coadministered CYP2D6 substrates (TCAs, antipsychotics, beta-blockers) may require dose adjustment and monitoring.
• Contraindicated with MAOIs; a 5-week washout after stopping fluoxetine is required before initiating an MAOI.
• Reduces tamoxifen efficacy due to CYP2D6 inhibition.
• Caution is common with other serotonergic agents (triptans, tramadol, linezolid) that can raise serotonin syndrome risk; interaction risk can persist for weeks after stopping due to long half-life.
• Other strong CYP2D6 substrates with narrow therapeutic windows (e.g., TCAs) may require dose adjustment and clinical monitoring when combined.

Other Useful Information

• Long half-life reduces discontinuation risk but prolongs adverse effects after stopping.
• Metabolic parameters are commonly assessed when combined with olanzapine (Symbyax).
• When switching therapies (especially to or from MAOIs), washout periods are planned deliberately and a safety-monitoring plan is commonly documented rather than rapid cross-tapers.
• When paired with olanzapine (Symbyax), metabolic monitoring follows the antipsychotic component; baseline weight, lipids, and glucose are typically documented and rechecked during early months.

References

1. PROZAC (fluoxetine) prescribing information — DailyMed (2024)
2. Symbyax Label 2025
3. APA Clinical Practice Guideline for the Treatment of Depression — American Psychiatric Association (2023)Guidelinedepressionclinical
4. CANMAT 2024 Clinical Guidelines for Major Depressive Disorder — Canadian Journal of Psychiatry (2024)
5. Comparative efficacy and acceptability of 21 antidepressant drugs for major depressive disorder — The Lancet (2018)Meta-analysisdepressionefficacy