Selective serotonin reuptake inhibitors
ATC code: N06AB03 (Fluoxetine)
Selectively blocks serotonin reuptake at the presynaptic membrane. Its distinguishing feature is a long half-life: 1-4 days for fluoxetine itself and 7-15 days for the active metabolite norfluoxetine. A missed dose therefore barely affects plasma levels, and withdrawal syndrome on discontinuation is less common than with other SSRIs.
First line
The only SSRI with approval for bulimia nervosa. Recommended dose is 60 mg daily, higher than the standard antidepressant dose. In RCTs, fluoxetine reduced binge-purge episode frequency by 50-67% versus placebo. The effect is independent of comorbid depression.
First line
First-line treatment for major depressive disorder in adults. Efficacy confirmed in numerous RCTs and meta-analyses. Starting dose is 20 mg daily; therapeutic effect develops over 2-4 weeks. The long half-life allows once-daily dosing. Side-effect profile is comparable to sertraline.
First line
First-line OCD treatment. Doses above the antidepressant range are usually needed – 40-80 mg daily. Response develops more slowly than in depression: efficacy should be assessed no earlier than 8-12 weeks at an adequate dose.
The drug is promoted for these uses outside international guidelines. Each entry below is analyzed against AEMPS, FDA, EMA, Cochrane and major RCTs.
Not recommended
Fluoxetine (Prozac) is an SSRI antidepressant. It is prescribed for depression, anxiety disorders, OCD, bulimia, and PMDD ( 2022 and NG222 guidelines). For energy, weight loss, or productivity in people without a psychiatric diagnosis, fluoxetine does not work: no clinical studies of such use exist. The 1990s Prozac marketing campaigns created the myth of a happiness pill, but no evidence base supports it. The drug has serious risks: sexual dysfunction (often persistent after discontinuation), hyponatremia, nausea, headache, and increased suicide risk in young adults under 24 ( boxed warning). If fluoxetine was prescribed for energy or weight loss, consider seeking a second opinion.
22 pairs found. Sorted from critical to minor.
Mechanism
Fluoxetine (SSRI) raises synaptic serotonin. Linezolid reversibly inhibits MAO. The pair is notable because fluoxetine's active metabolite, norfluoxetine, persists for up to 5 weeks – the serotonergic effect outlasts dosing.
Symptoms
Serotonin syndrome: agitation, confusion, tremor, myoclonus, hyperreflexia, dilated pupils. Autonomic features: profuse sweating, tachycardia, hypertension, fever above 38.5 °C. Severe cases progress to seizures, rhabdomyolysis, disseminated intravascular coagulation, and death. First signs appear within hours of concurrent dosing.
Management
The combination is not prescribed. Stop fluoxetine at least 5 weeks before planned linezolid. For acute antibiotic need, use vancomycin or daptomycin. If linezolid is still required, monitor for serotonin syndrome during therapy plus 5 weeks after fluoxetine discontinuation.
Sources
Mechanism
IV methylene blue inhibits MAO-A. Fluoxetine and its active metabolite norfluoxetine raise synaptic serotonin. Norfluoxetine persists for up to 5 weeks – serotonin syndrome risk outlasts the dose by weeks.
Symptoms
Serotonin syndrome: agitation, confusion, tremor, myoclonus, hyperreflexia, dilated pupils. Autonomic features: profuse sweating, tachycardia, hypertension, fever above 38.5 °C. Severe cases progress to seizures, rhabdomyolysis, disseminated intravascular coagulation, and death. First signs appear within hours of concurrent dosing.
Management
Avoid the combination. Stop fluoxetine 5 weeks before planned methylene blue. In emergencies (methaemoglobinaemia), administer for life-threatening indications under ICU monitoring with cyproheptadine available.
Mechanism
Phenelzine irreversibly inhibits MAO; fluoxetine blocks serotonin reuptake. Combined use causes synaptic serotonin accumulation and serotonin syndrome: hyperthermia, myoclonus, agitation, coma. Nardil Section 4 strict contraindication. A 5-week washout is required between fluoxetine and phenelzine (due to norfluoxetine's long T½).
Symptoms
Within hours: agitation, confusion, tachycardia, hypertension, hyperthermia, tremor, myoclonus, hyperreflexia. Severe cases – seizures, coma, rhabdomyolysis, DIC.
Management
Combination contraindicated. Allow 5-week washout between stopping fluoxetine and starting phenelzine. Allow 2-week washout between stopping phenelzine and starting any SSRI (MAO resynthesis time).
Mechanism
Tranylcypromine is an irreversible MAOI. Combined with fluoxetine causes serotonin syndrome. AEMPS Parnate Section 4.3.
Symptoms
Hyperthermia, myoclonus, tachycardia, hypertension.
Management
Combination contraindicated. 5-week washout from fluoxetine.
Mechanism
Fluoxetine (SSRI) depletes the platelet serotonin pool, impairing primary haemostasis. Aspirin irreversibly blocks platelet cyclooxygenase. Combined, GI bleeding risk roughly doubles.
Symptoms
Gum bleeding, epistaxis, bruising without trauma, black stools, blood in urine. Severe cases include gastrointestinal or intracranial haemorrhage.
Management
The combination is acceptable at low aspirin doses (75–100 mg as cardioprotection). PPI cover with pantoprazole is mandatory. Alternative antidepressants with minimal platelet effect: mirtazapine or agomelatine.
Sources
Mechanism
Fluoxetine and its active metabolite norfluoxetine moderately block CYP3A4. Alprazolam plasma levels rise by 30–50%; deep sedation and fall risk in older patients emerge.
Symptoms
Deep sedation, drowsiness, ataxia. Older patients: fall and fracture risk. Symptoms appear within 1–2 weeks of combination.
Management
Reduce alprazolam by 30–50% when combined. Alternative benzodiazepines without CYP3A4 dependence: lorazepam or oxazepam.
Mechanism
Fluoxetine blocks CYP2D6 (a minor amiodarone clearance route) and modestly prolongs QT. Amiodarone plasma levels rise and QT effects add up. The long half-life of fluoxetine and norfluoxetine (up to 5 weeks) is relevant.
Symptoms
QT prolongation on ECG. Clinically: dizziness, syncope, palpitations. Severe cases progress to polymorphic ventricular tachycardia (torsades de pointes) with risk of ventricular fibrillation and sudden cardiac death. Risk is higher with hypokalaemia, hypomagnesaemia, bradycardia, and ischaemic heart disease.
Management
Avoid the combination. Alternative antidepressants with minimal QT effect and no CYP2D6 inhibition: mirtazapine or agomelatine. Interaction potential persists up to 5 weeks after fluoxetine discontinuation.
Mechanism
Dual mechanism. Fluoxetine raises synaptic serotonin and strongly blocks CYP2D6 – the amitriptyline metabolic route. Amitriptyline plasma levels rise 2- to 4-fold while serotonergic activity adds up.
Symptoms
Serotonin syndrome (agitation, tremor, tachycardia, hyperthermia). Amitriptyline anticholinergic effects intensify (dry mouth, constipation, urinary retention, confusion in older patients). QT prolongation.
Management
Avoid the combination. If combined for augmentation, halve amitriptyline and check ECG at 2 weeks. Alternative antidepressant: mirtazapine or agomelatine (no CYP2D6 dependence).
Mechanism
Fluoxetine is a potent CYP2D6 inhibitor. Levels of bupropion's active metabolite (hydroxybupropion) rise. Both drugs lower the seizure threshold.
Symptoms
Seizures (generalised tonic-clonic or focal), agitation, tremor, insomnia. Patients with prior epilepsy or eating disorders are at particular risk.
Management
The combination is possible for augmentation with careful monitoring. Keep doses low: fluoxetine 20 mg, bupropion 300 mg/day. Avoid with prior epilepsy or eating disorders.
Mechanism
Fluoxetine is a potent CYP2D6 inhibitor, the main carvedilol metabolic route. Carvedilol plasma levels rise 2- to 3-fold. Marked hypotension and bradycardia emerge.
Symptoms
Bradycardia (heart rate below 50/min), dizziness, syncope. ECG: first- to second-degree AV block. Older patients: fall risk.
Management
Halve the carvedilol dose when combined; monitor blood pressure and pulse. Alternative beta-blockers without CYP2D6 dependence: bisoprolol or nebivolol. Alternative antidepressants without CYP2D6 inhibition: sertraline or escitalopram.
Sources
Mechanism
Two SSRIs simultaneously. Fluoxetine is a potent CYP2D6 inhibitor and weak CYP2C19 inhibitor, so citalopram levels may rise. Additive serotonin syndrome and QT prolongation risk.
Symptoms
Serotonin syndrome: agitation, confusion, tremor, myoclonus, hyperreflexia. Autonomic features: sweating, tachycardia, hypertension, fever. First signs appear within hours of co-administration.
Management
The combination is not prescribed. When switching from fluoxetine to citalopram, allow at least 5 weeks of washout (due to norfluoxetine). From citalopram to fluoxetine, 2 weeks suffice.
Mechanism
Fluoxetine inhibits CYP2C19, the enzyme converting clopidogrel into its active metabolite. Active levels fall and antiplatelet effect weakens. Fluoxetine also depletes the platelet serotonin pool, impairing primary haemostasis.
Symptoms
Dual risk: weakened antiplatelet effect (raising thrombosis risk) alongside increased upper GI bleeding risk.
Management
Alternative antidepressants: sertraline or escitalopram (weaker CYP2C19 inhibitors), or mirtazapine/agomelatine (minimal platelet effect). Alternative antiplatelet: ticagrelor (not CYP2C19-dependent). PPI cover with pantoprazole is mandatory.
Mechanism
Fluoxetine blocks CYP2D6 (strongly) and CYP3A4 (moderately). Dronedarone plasma levels may rise. Additive QT risk.
Symptoms
QT prolongation on ECG. Dizziness, syncope, palpitations. Severe cases: polymorphic ventricular tachycardia (torsades de pointes). Risk is higher with hypokalaemia and hypomagnesaemia.
Management
Avoid the combination. Alternative antidepressants without CYP3A4/CYP2D6 inhibition: sertraline or escitalopram. Alternative antiarrhythmic: a beta-blocker for rate control.
Mechanism
Fluoxetine is a potent CYP2D6 inhibitor; duloxetine is minorly metabolised by CYP2D6. Additive serotonergic load with dual SSRI/SNRI dosing.
Symptoms
Serotonin syndrome: agitation, confusion, tremor, myoclonus, hyperreflexia. Autonomic features: sweating, tachycardia, hypertension, fever. First signs appear within hours of co-administration.
Management
The combination is not prescribed. When switching from fluoxetine to duloxetine, allow a 5-week washout (due to norfluoxetine); from duloxetine to fluoxetine, 1 week.
Mechanism
Two SSRIs simultaneously raise synaptic serotonin activity. Fluoxetine's active metabolite (norfluoxetine) persists in plasma for up to 5 weeks, so serotonin syndrome risk outlasts fluoxetine discontinuation.
Symptoms
Serotonin syndrome: agitation, confusion, tremor, myoclonus, hyperreflexia, dilated pupils. Autonomic features: sweating, tachycardia, hypertension, fever. First signs appear within hours of co-administration.
Management
The combination is not prescribed. When switching from fluoxetine to escitalopram, allow at least a 5-week washout. From escitalopram to fluoxetine, 2 weeks suffice.
Mechanism
Fluoxetine is a potent CYP2D6 inhibitor, the main metoprolol metabolic route. Metoprolol plasma levels rise 4- to 5-fold. Risk of marked bradycardia, hypotension, and AV block emerges.
Symptoms
Bradycardia (heart rate below 50/min), dizziness, syncope, orthostatic hypotension. In heart failure: worsening dyspnoea and oedema.
Management
Reduce metoprolol 2- to 3-fold when combined; monitor pulse and blood pressure. Alternative beta-blockers without CYP2D6 dependence: bisoprolol or carvedilol. Alternative antidepressants without CYP2D6 inhibition: sertraline or escitalopram.
Mechanism
Additive serotonergic effect. Mirtazapine blocks 5-HT2/3 but activates 5-HT1A. Combined with a potent SSRI, serotonin syndrome has been reported, especially at high doses.
Symptoms
Serotonin syndrome: agitation, confusion, tremor, myoclonus, hyperreflexia. Autonomic features: sweating, tachycardia, fever.
Management
The combination is used for augmentation in resistant depression ('California rocket fuel'). Keep doses low: fluoxetine 20 mg, mirtazapine 30 mg/day. Monitor mental status in the early weeks.
Mechanism
Dual mechanism. Fluoxetine (SSRI) raises synaptic serotonin; tramadol weakly inhibits serotonin reuptake – combined serotonergic activity adds up. Fluoxetine also blocks CYP2D6 – the route activating tramadol to O-desmethyltramadol – so analgesia weakens.
Symptoms
Serotonin syndrome: agitation, confusion, tremor, myoclonus, hyperreflexia, dilated pupils. Autonomic features: sweating, tachycardia, hypertension, fever. First signs appear within hours of co-administration.
Management
Avoid the combination. For analgesia on fluoxetine, use paracetamol, an NSAID, or pure opioid agonists such as morphine/oxycodone. Alternative antidepressant: mirtazapine or agomelatine.
Mechanism
SSRI + SNRI – serotonin syndrome. Fluoxetine is also a potent CYP2D6 inhibitor and raises venlafaxine levels.
Symptoms
Serotonin syndrome: agitation, confusion, tremor, myoclonus, hyperreflexia. Autonomic features: sweating, tachycardia, fever.
Management
The combination is not prescribed. When switching from fluoxetine to venlafaxine, allow at least 5 weeks of washout (due to norfluoxetine). From venlafaxine to fluoxetine, 1 week.
Mechanism
Fluoxetine and its active metabolite norfluoxetine moderately block CYP3A4 – the main amlodipine metabolic route. Amlodipine plasma levels may rise modestly. In older patients: additive hypotension.
Symptoms
Lower blood pressure, postural dizziness, fatigue. Older patients: fall risk.
Management
The combination is acceptable in most patients without dose change. In older patients, monitor blood pressure and hypotension symptoms 2 weeks after start.
Mechanism
Fluoxetine, like other SSRIs, impairs primary haemostasis by inhibiting platelet serotonin reuptake. Additively with apixaban, GI bleeding risk rises.
Symptoms
Gum bleeding, epistaxis, bruising without trauma, black or tarry stools, haematuria. Higher risk in older patients, prior peptic ulcer disease, and chronic kidney disease.
Management
The combination is acceptable. In patients over 65 or with prior peptic ulcer: pantoprazole 20 mg/day. The long half-life of fluoxetine and its active metabolite norfluoxetine (4–6 days) prolongs bleeding risk for another 4–6 weeks after discontinuation.
Mechanism
Additive QT prolongation (fluoxetine weakly prolongs QT at high doses).
Symptoms
QT prolongation on ECG. Dizziness, syncope, palpitations. Rarely: polymorphic ventricular tachycardia (torsades de pointes). Risk is higher with hypokalaemia, hypomagnesaemia, bradycardia, and ischaemic heart disease.
Management
For short azithromycin courses (3–5 days) with normal potassium and magnesium, the combination is acceptable. In cardiovascular disease or fluoxetine doses above 40 mg: ECG before start or alternative antibiotics (doxycycline, a cephalosporin).
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Boxed warning
Antidepressants increase the risk of suicidal thoughts and behavior in children, adolescents, and young adults under 25. Suicidality monitoring is mandatory during the first weeks of treatment and after dose changes.
FDA category C. Third-trimester use is associated with neonatal adaptation syndrome – respiratory distress, irritability, tremor. The decision to continue during pregnancy balances the risk of untreated maternal depression.
Passes into breast milk. Fluoxetine and norfluoxetine are detectable in infant serum. Per LactMed, SSRIs with shorter half-lives (sertraline, paroxetine) are preferred during breastfeeding.
Reference information, not a clinical decision. Discuss feeding pauses or changes with your physician or an IBCLC.
Fluoxetine is evaluated for the following indications with varying evidence strength: Obsessive-compulsive disorder (evidence tier A), Bulimia nervosa (evidence tier A), Major depressive disorder (evidence tier A). See the full indication matrix with dosing and citations above on this page.
Common side effects of Fluoxetine (≥ 1 in 100): Nausea, diarrhea, Headache, Insomnia, anxiety, Sexual dysfunction – decreased libido, anorgasmia, Decreased appetite, Tremor. See the Safety section for uncommon and serious reactions.
FDA category C. FDA category C. Third-trimester use is associated with neonatal adaptation syndrome – respiratory distress, irritability, tremor. The decision to continue during pregnancy balances the risk of untreated maternal depression.
Passes into breast milk. Fluoxetine and norfluoxetine are detectable in infant serum. Per LactMed, SSRIs with shorter half-lives (sertraline, paroxetine) are preferred during breastfeeding.
Fluoxetine is contraindicated in: Concurrent MAOI use or within 14 days of MAOI discontinuation; Concurrent use of thioridazine or pimozide; Hypersensitivity to fluoxetine. Full list in the Safety section.
Antidepressants increase the risk of suicidal thoughts and behavior in children, adolescents, and young adults under 25. Suicidality monitoring is mandatory during the first weeks of treatment and after dose changes.