Article Author:
Ahsan Sohel
Article Editor:
Mohammed Molla
10/7/2019 1:39:26 PM
PubMed Link:


Fluoxetine is FDA-approved for major depressive disorder (age 8 and older), obsessive-compulsive disorder (age 7 and older), panic disorder, bulimia, binge eating disorder, premenstrual dysphoric disorder, bipolar depression (as an adjunct with olanzapine also known as Symbyax), and treatment-resistant depression when used in combination with olanzapine.[1][2][3]

Non FDA-approved uses for fluoxetine include social anxiety disorder (social phobia), post-traumatic stress disorder in adults, borderline personality disorder, Raynaud's phenomenon, and selective mutism.[4][5]

Mechanism of Action

Serotonin and norepinephrine, both biological amines, have been shown to play a role in depression. Low concentrations of serotonin have been found in the cerebrospinal fluid of patients with depression. Additionally, lower levels of serotonin uptake sites have been found on platelets of patient’s with depression. Pre-synaptic serotonin (5HT1A) receptors are located in the dorsal raphe nucleus and project to the prefrontal cortex. Fluoxetine exerts its effects by blocking the reuptake of serotonin into presynaptic serotonin neurons by blocking the reuptake transporter protein located in the presynaptic terminal. Fluoxetine also has mild activity at the 5HT2A and 5HT2C receptors. Fluoxetine has minimal activity on noradrenergic re-uptake. Due to its re-uptake of serotonin, fluoxetine produces an activating effect, and due to its long half-life (2 to 4 days), initial antidepressant effect emerges within 2 to 4 weeks. Fluoxetine's active metabolite is norfluoxetine, and it is produced when the cytochrome P450 enzyme (CYP2D6) acts on it. It is important to remember that fluoxetine has several drug-drug interactions due to its metabolism at the CYP2D6 isoenzyme. Additionally, norfluoxetine can have an inhibitory effect on CYP3A4. It is also important to keep in mind that fluoxetine has a half-life of 2 to 4 days and its active metabolite, norfluoxetine has a half-life of 7 to 9 days.[6][7]


Fluoxetine should be administered once a day, either in the morning or the evening. It is only available in an oral formulation available in liquid form, tablet, and capsule and started at a dose of 20 mg per day. Keeping in mind that the medication can be efficacious at doses at 5 milligrams and weigh in on side effect profile, it is important to note that the medication can be administered in smaller doses. For an individual with poorly tolerated side effects, the medication may be administered in 10 mg tablets instead of 20 mg tablet to help minimize any side effect. Generally, 20 mg to 40 mg daily dosing is required to be effective for most individuals. Though, some individuals may require dosing of 60-80 mg daily. There is some evidence, given fluoxetine's long half-life, that the medication also comes in a delayed release formulation that may be dosed at 90 mg per week. Evidence suggests that the efficacy of the delayed-release formulation is similar to the individuals receiving fluoxetine 20 mg per day. As always, drug-drug interactions should be carefully monitored, and if one is starting a monoamine oxidase inhibitor, for treatment-resistant depression, fluoxetine should be discontinued for five weeks before starting a monoamine oxidase inhibitor for fear of precipitating serotonin syndrome. Abrupt discontinuation of the medication, due to its long half-life, compared to other SSRIs, is not associated with the emergence of symptoms (sleep disturbances, dysphoria, fever, nausea) seen with abrupt discontinuation of other antidepressants. When treating Bulimia, generally an efficacious dose is achieved at 60 mg to 80 mg per day. Non-steroid inflammatory agents (e.g., ibuprofen) may impair the effectiveness of fluoxetine.

Adverse Effects

Most common side effects reported by adults include Insomnia, nausea, diarrhea, anorexia, dry mouth, headache, drowsiness, anxiety, nervousness, yawning, decreased libido, decreased arousal (seen as decreased lubrication in women and decreased erectile function in men), bruising, bleeding (rarely), hyperhidrosis, also keep in mind if this may be due to underlying mania/psychosis, seizures (rarely), induction of mania, rare activation of suicidal ideation and behavior (especially in teenagers), weight gain/loss, decreased orgasm (anorgasmia and ejaculation latency), muscle weakness, tremors, and pharyngitis. [8][9]

The 5HT2C antagonism is what is thought to contribute to the anxiety, insomnia, and agitation that patients perceive with fluoxetine. Patient's may even have a panic attack with the administration with fluoxetine. Thus it is the clinician's responsibility to educate patient.

Most side effects are immediate and go away with time. Thus, it is best to wait for the side effects to subside before altering treatment. Most side effects are dose-dependent and time-dependent. It is important to be cautious of emergence of agitation or activation, which may indicate a bipolar state, which may require the addition of a mood stabilizer or an atypical antipsychotic. Fluoxetine can be activating, thus if insomnia is present, consider giving it early in the morning. Additionally, one may reduce dose if side effects are too distressing for the patient. The patient should be cautioned about side effects, if they persist, after a few weeks, switching to a different antidepressant may be indicated. 

It is best to try another antidepressant before relying on augmentation strategies to minimize polypharmacy and encourage adherence to psychotropic medications. Trazodone, mirtazapine, or a hypnotic may be used for insomnia. Mirtazapine may also be used for agitation or gastrointestinal side effects. Benzodiazepines may be used for anxiety. Bupropion or a phosphodiesterase inhibitor (i.e., Sildenafil) may be used for sexual dysfunction. Bupropion may also be indicated for cognitive slowing or apathy seen with fluoxetine.


Contraindications include:

Hypersensitivity to fluoxetine or any component in its formulation

Use of monoamine oxidase inhibitors (MAOI) used to treat psychiatric disorders (fluoxetine use should be avoided within 2 weeks of discontinuing the MAOI)

Initiation of fluoxetine in a patient receiving linezolid. Do not give with pimozide, thioridazine, or tamoxifen. Use with caution in those with a history of seizures.

Use caution when dosing in elderly. Additionally, there is a warning for suicidal ideations in those treated with fluoxetine, especially in the 18 to 24 year age range. Parents and caregivers should be advised to closely monitor patients for any changes in behaviors within the first one to 2 months of initiating the medication. 

Not recommended for use during pregnancy. However, depending on the scenario, treatment may be necessary during pregnancy. A risk/benefit analysis should carefully be considered during treatment with fluoxetine in pregnancy. Fluoxetine exposure early in pregnancy may be associated with increased risk of septal heart defects. Use of the medication beyond the 20th week is associated with pulmonary hypertension of the newborn, although this is not proven entirely. Exposure to fluoxetine late in pregnancy may be associated with risk of gestational hypertension and preeclampsia. Additionally, trace amounts of the drug may be found in breast milk.


A thorough assessment of depression and suicidal risk, particularly in the beginning of therapy or when doses are changed, anxiety/panic attacks, social functioning, mania/mood lability, and features of serotonin syndrome.[10]

No routine laboratory testing is required for healthy individuals. However, for elderly and population-specific patients, may order blood glucose and liver function tests. May order ECG assessment for those patients with risk factors for QT prolongation and ventricular arrhythmias.


Rarely lethal in monotherapy overdose. However, when taken in conjunction with alcohol, may cause ataxia and respiratory depression. May cause serotonin syndrome (clinical constellation of changes in mental status, autonomic instability, and neuromuscular abnormalities).

Enhancing Healthcare Team Outcomes

Fluoxetine is a commonly prescribed anti depressant by the primary care provider, nurse practitioner, psychiastrist and the internist. However, it is important to educate the patient that it should not be combined with alcohol or other antidepressants. The patient should be regularly questioned about depression and suicidal thoughts. With close monitoring, fluoxetine is an effective drug for depression and can be administered for long periods.


[1] Mikocka-Walus A,Prady SL,Pollok J,Esterman AJ,Gordon AL,Knowles S,Andrews JM, Adjuvant therapy with antidepressants for the management of inflammatory bowel disease. The Cochrane database of systematic reviews. 2019 Apr 12;     [PubMed PMID: 30977111]
[2] Dhenain T,Côté F,Coman T, Serotonin and orthodontic tooth movement. Biochimie. 2019 Apr 3;     [PubMed PMID: 30953672]
[3] Burch R, Antidepressants for Preventive Treatment of Migraine. Current treatment options in neurology. 2019 Mar 21;     [PubMed PMID: 30895388]
[4] Li X,Li J,Li X,Wang J,Dai H,Wang J, Effectiveness and safety of fluoxetine for premature ejaculation: Protocol for a systematic review. Medicine. 2019 Feb;     [PubMed PMID: 30762772]
[5] Slee A,Nazareth I,Bondaronek P,Liu Y,Cheng Z,Freemantle N, Pharmacological treatments for generalised anxiety disorder: a systematic review and network meta-analysis. Lancet (London, England). 2019 Feb 23;     [PubMed PMID: 30712879]
[6] Robertson OD,Coronado NG,Sethi R,Berk M,Dodd S, Putative neuroprotective pharmacotherapies to target the staged progression of mental illness. Early intervention in psychiatry. 2019 Jan 28;     [PubMed PMID: 30690898]
[7] Cao B,Zhu J,Zuckerman H,Rosenblat JD,Brietzke E,Pan Z,Subramanieapillai M,Park C,Lee Y,McIntyre RS, Pharmacological interventions targeting anhedonia in patients with major depressive disorder: A systematic review. Progress in neuro-psychopharmacology     [PubMed PMID: 30611836]
[8] Mullen S, Major depressive disorder in children and adolescents. The mental health clinician. 2018 Nov;     [PubMed PMID: 30397569]
[9] Bahar MA,Kamp J,Borgsteede SD,Hak E,Wilffert B, The impact of CYP2D6 mediated drug-drug interaction: a systematic review on a combination of metoprolol and paroxetine/fluoxetine. British journal of clinical pharmacology. 2018 Dec;     [PubMed PMID: 30248178]
[10] Lee-Kelland R,Zehra S,Mappa P, Fluoxetine overdose in a teenager resulting in serotonin syndrome, seizure and delayed onset rhabdomyolysis. BMJ case reports. 2018 Oct 8;     [PubMed PMID: 30301727]