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Fluoxetine

; ; .

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Last Update: June 27, 2020.

Indications

Fluoxetine has FDA-approval for major depressive disorder (age eight and older), obsessive-compulsive disorder (age seven 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 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 appear in the cerebrospinal fluid of patients with depression. Additionally, lower levels of serotonin uptake sites have are also present on the platelets of patients with depression. Presynaptic serotonin (5HT1A) receptors are 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 reuptake. Due to its reuptake of serotonin, fluoxetine produces an activating effect, and due to its long half-life (2 to 4 days), the initial antidepressant effect emerges within 2 to 4 weeks. Fluoxetine's active metabolite is norfluoxetine, which gets 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]

Administration

Fluoxetine should be administered once a day, either in the morning or in 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 the side effect profile, it is essential to note that the drug can be administered in smaller doses. For an individual with poorly tolerated side effects, the drug may be dosed in 10 mg tablets instead of 20 mg tablets to help minimize any side effects. Generally, 20 mg to 40 mg daily dosing is required to be effective for most individuals.

Some individuals may require dosing of 60 to 80 mg daily. There is some evidence, given fluoxetine's long half-life, that the medication also comes in a delayed-release formulation with dosing 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 require careful monitoring, and if one is starting a monoamine oxidase inhibitor, for treatment-resistant depression, fluoxetine should be discontinued for five weeks before initiating monoamine oxidase inhibitor therapy, 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 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. Patients may even have a panic attack with the administration with fluoxetine. Thus it is the clinician's responsibility to educate patients.

Most side effects are immediate and disappear 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 the 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 dosing early in the morning. Additionally, one may reduce the 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. This approach can minimize polypharmacy and encourage adherence to psychotropic medications. Trazodone, mirtazapine, or a hypnotic may be options for insomnia. Mirtazapine may also help with agitation or gastrointestinal side effects. Benzodiazepines may treat for anxiety. Bupropion or a phosphodiesterase inhibitor (i.e., sildenafil) may address for sexual dysfunction. Bupropion may also be an option for potential cognitive slowing or apathy seen with fluoxetine.

Contraindications

Contraindications include:

Hypersensitivity to fluoxetine or any component in its formulation

Use of monoamine oxidase inhibitors (MAOI) used to treat psychiatric disorders (clinicians should avoid initiating fluoxetine within two weeks of discontinuing the MAOI)

Never initiate of fluoxetine in a patient receiving linezolid. Do not give fluoxetine with pimozide, thioridazine, or tamoxifen. Use with caution in those with a history of seizures.

Use caution when dosing in the 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 behavior within the first one to 2 months of initiating the medication. 

Fluoxetine is not recommended for use during pregnancy. However, depending on the scenario, treatment may be necessary during pregnancy. A risk/benefit analysis merits careful consideration during therapy with fluoxetine in pregnancy. Fluoxetine exposure early in pregnancy may be associated with an increased risk of septal heart defects. The 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 correlate with the risk of gestational hypertension and preeclampsia. Additionally, trace amounts of the drug may appear in breast milk.

Monitoring

A thorough assessment of depression and suicidal risk, particularly at 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 necessary for healthy individuals. However, for elderly and population-specific patients, they may order blood glucose and liver function tests. Prescribers may order ECG assessment for those patients with risk factors for QT prolongation and ventricular arrhythmias.

Toxicity

FLuoxetine is rarely lethal in monotherapy overdose. However, when taken in conjunction with alcohol, it may cause ataxia and respiratory depression. The drug may cause serotonin syndrome (clinical constellation of changes in mental status, autonomic instability, and neuromuscular abnormalities) when taken in excessive amounts or if combined with other agents that also increase serotonin levels.

In the case of SSRI overdose, the goal is to provide supportive therapy. This support can be in the form of airway protection, serial ECGs to monitor for cardiotoxicity, administration of benzodiazepines for sedation, and GI decontamination with activated charcoal. 

Serotonin syndrome is treatable with the administration of cyproheptadine.[11][12][13]

Enhancing Healthcare Team Outcomes

Fluoxetine is a commonly prescribed antidepressant by primary care providers, nurse practitioners, psychiatrists, and internists, but effective therapy requires the effort of an interprofessional team. Nursing staff, particularly with specialty training in psychiatric health, can counsel the patients on proper dosing and administration. For example, it is crucial to educate the patient that they should not combine the drug with alcohol or other antidepressants. The patient should have regular followup regarding depression and suicidal thoughts. The pharmacist should verify dosing, and especially check for drug interactions, given fluoxetine's extensive list of interactions, and report these to the prescriber if present. With close monitoring from all members of the interprofessional team, fluoxetine can be an effective drug for numerous psychiatric conditions, including major depression. It can also be administered for long periods, leading to optimal patient results. [Level 5]

Questions

To access free multiple choice questions on this topic, click here.

References

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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. Cochrane Database Syst Rev. 2019 Apr 12;4:CD012680. [PMC free article: PMC6459769] [PubMed: 30977111]
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Dhenain T, Côté F, Coman T. Serotonin and orthodontic tooth movement. Biochimie. 2019 Jun;161:73-79. [PubMed: 30953672]
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Burch R. Antidepressants for Preventive Treatment of Migraine. Curr Treat Options Neurol. 2019 Mar 21;21(4):18. [PubMed: 30895388]
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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 (Baltimore). 2019 Feb;98(7):e14481. [PMC free article: PMC6407935] [PubMed: 30762772]
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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. 2019 Feb 23;393(10173):768-777. [PubMed: 30712879]
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Robertson OD, Coronado NG, Sethi R, Berk M, Dodd S. Putative neuroprotective pharmacotherapies to target the staged progression of mental illness. Early Interv Psychiatry. 2019 Oct;13(5):1032-1049. [PubMed: 30690898]
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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. Prog. Neuropsychopharmacol. Biol. Psychiatry. 2019 Jun 08;92:109-117. [PubMed: 30611836]
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Mullen S. Major depressive disorder in children and adolescents. Ment Health Clin. 2018 Nov;8(6):275-283. [PMC free article: PMC6213890] [PubMed: 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. Br J Clin Pharmacol. 2018 Dec;84(12):2704-2715. [PMC free article: PMC6255988] [PubMed: 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 Rep. 2018 Oct 08;2018 [PMC free article: PMC6194370] [PubMed: 30301727]
11.
Bruggeman C, O'Day CS. StatPearls [Internet]. StatPearls Publishing; Treasure Island (FL): Dec 3, 2019. Selective Serotonin Reuptake Inhibitor (SSRI) Toxicity. [PubMed: 30521236]
12.
Nelson LS, Erdman AR, Booze LL, Cobaugh DJ, Chyka PA, Woolf AD, Scharman EJ, Wax PM, Manoguerra AS, Christianson G, Caravati EM, Troutman WG. Selective serotonin reuptake inhibitor poisoning: An evidence-based consensus guideline for out-of-hospital management. Clin Toxicol (Phila). 2007 May;45(4):315-32. [PubMed: 17486478]
13.
Barbey JT, Roose SP. SSRI safety in overdose. J Clin Psychiatry. 1998;59 Suppl 15:42-8. [PubMed: 9786310]
Copyright © 2020, StatPearls Publishing LLC.

This book is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, duplication, adaptation, distribution, and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, a link is provided to the Creative Commons license, and any changes made are indicated.

Bookshelf ID: NBK459223PMID: 29083803

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