Continuing Education Activity

Fluoxetine is FDA-approved for major depressive disorder (for patients eight years and older), obsessive-compulsive disorder, panic disorder, bulimia, binge eating disorder, premenstrual dysphoric disorder, and bipolar depression as well as treatment-resistant depression when used in combination with olanzapine. It also has several non-FDA-approved indications. This activity outlines the indications, mechanism of action, dosing, important adverse effects, contraindications, monitoring, and toxicity of fluoxetine, so providers can direct patient therapy to optimal outcomes in combating psychological conditions for which it is indicated.

Objectives:

• Summarize the mechanism of action of fluoxetine.
• Identify the indications for fluoxetine.
• Review the adverse event profile when using fluoxetine.
• Outline interprofessional team strategies for improving care coordination and communication to improve outcomes using fluoxetine when indicated.

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), 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 numbers of serotonin uptake sites are located 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, 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 remember 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 evening, and started at 20 mg daily. It is only available in an oral formulation available in oral solution (20 mg/5 ml), tablet (10 mg, 20 mg, 60 mg), capsule (10 mg, 20 mg, 40 mg), and delayed-release capsule (90 mg). Keeping in mind that the medication can be efficacious at doses of 5 milligrams and weighing 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. When treating bulimia, an efficacious dose is generally 60 mg to 80 mg daily. 

It also comes in a delayed-release capsule formulation with dosing at 90 mg per week. Evidence suggests that the efficacy of the delayed-release formulation (90 mg once weekly) is similar to that of individuals receiving fluoxetine 20 mg daily. Compared to other SSRIs, fluoxetine is not associated with the emergence of abrupt withdrawal symptoms (sleep disturbances, dysphoria, fever, nausea) seen with other antidepressants.[8]

As always, drug-drug interactions require careful monitoring. For example, suppose one is starting a monoamine oxidase inhibitor for treatment-resistant depression. In that case, fluoxetine should be discontinued five weeks before initiating monoamine oxidase inhibitor therapy to avoid precipitating serotonin syndrome. Non-steroid inflammatory agents (e.g., ibuprofen) may impair the effectiveness of fluoxetine.

Pregnancy Considerations

It is categorized as Pregnancy Category C medicine. In the late third trimester, neonates exposed to SSRIs, including fluoxetine, have developed complications requiring prolonged hospitalization, tube feeding, and respiratory support. Complications of temperature instability, feeding difficulty, vomiting, respiratory distress, apnea, cyanosis, hypoglycemia, hypotonia, hypertonia, constant crying, hyperreflexia, tremor, jitteriness, irritability, and seizures are reported. These symptoms could precipitate right at delivery and are consistent with either a drug discontinuation syndrome or a direct toxic effect of SSRIs.The clinician may consider tapering fluoxetine in the third trimester.[9]

Breastfeeding Considerations

As fluoxetine is excreted in human milk, nursing while on fluoxetine is not recommended.[9] If a woman was using fluoxetine during pregnancy, most experts recommend against changing medications while breastfeeding. Otherwise, agents with lower excretion into breastmilk may be preferred, especially while nursing a newborn or preterm infant. In addition, the breastfed infant should be monitored for behavioral side effects such as agitation, colic, irritability, poor feeding, and poor weight gain.[10]

Pediatric Considerations

Fluoxetine is FDA-approved for administration in pediatric patients with MDD and OCD. As with other SSRIs, decreased weight gain is associated with the administration of fluoxetine in children and adolescent patients. There are no studies that evaluate the longer-term effects of fluoxetine on the development, growth, and maturation of children and/or adolescent patients. 

Hepatic Impairment

In patients with liver cirrhosis, the clearance of fluoxetine and its active metabolite (norfluoxetine) decreases, thus increasing the elimination half-lives of these substances. Therefore, a lower/less frequent dose of fluoxetine should be used in patients with cirrhosis. In addition, caution is warranted when using fluoxetine in patients with diseases or conditions that could affect its metabolism.

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.[11][12]

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

Most side effects are immediate and disappear with time. Thus, waiting for the side effects to subside is best before altering treatment. Most side effects are dose-dependent and time-dependent. It is important to exercise caution of the emergence of agitation or activation, which may indicate a bipolar state and 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 the side effects are too distressing for the patient. The patient should be cautioned about side effects; if they persist, switching to a different antidepressant may be indicated after a few weeks.[13]

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 be used to treat anxiety. Bupropion or a phosphodiesterase inhibitor (i.e., sildenafil) may address sexual dysfunction. Bupropion may also be an option for potential cognitive slowing or apathy seen with fluoxetine.

Contraindications

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 fluoxetine in a patient receiving linezolid.[14] Do not give fluoxetine with pimozide, thioridazine, or tamoxifen. Use this agent 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 younger children and 18 to 24-year age range.[15] 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.[16]

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.[17][18] The use of the medication beyond the 20th week is associated with pulmonary hypertension in 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.[15][19]

No routine laboratory testing is necessary for healthy individuals. However, in elderly and population-specific patients, they may order blood glucose and liver function tests. In addition, prescribers may order an ECG assessment for those patients with risk factors for QT prolongation and ventricular arrhythmias. Pediatric patients' height and weight should be monitored periodically when receiving fluoxetine.

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 combined with other agents that increase serotonin levels.[20] 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.[21][22]

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. When treating pregnant women during the third trimester with fluoxetine, the prescriber should consider the potential benefits and risks of treatment. In addition, clinicians should consider that women who stopped antidepressant medication while pregnant were more likely to experience a relapse of MDD than women who continued to use antidepressant medications.

Nursing staff and clinicians should monitor children and adolescent patients for suicidal ideation, especially when starting fluoxetine or increasing doses. Nursing staff, particularly specialty training in psychiatric health, can counsel the patients on proper dosing and administration. For example, it is crucial to educate patients 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, especially check for drug interactions, given fluoxetine's extensive list of interactions, and report these to the prescriber if present. All interprofessional team embers are responsible for monitoring the patient, offering counsel, and noting any changes in patient status. If they note any issues, they should be documented in the patient's health record for all team members to see, and the new information should be communicated to other team members so changes can be made if necessary. With close monitoring from all interprofessional team members, 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]