Continuing Education Activity

Fluoxetine is an FDA-approved medication that has demonstrated efficacy in treating a spectrum of psychological conditions. These indications include major depressive disorder, obsessive-compulsive disorder, panic disorder, bulimia, binge eating disorder, premenstrual dysphoric disorder, and bipolar depression, including cases of treatment-resistant depression when combined with olanzapine. The mechanism of action involves the inhibition of serotonin reuptake in presynaptic neurons, achieved by blocking the reuptake transporter protein. This activity provides insights into fluoxetine's indications, off-label uses, mechanism of action, dosing, adverse effects, contraindications, monitoring, and toxicity.

Objectives:

• Identify potential indications for fluoxetine therapy based on evidence-based guidelines and patient-specific factors.

• Screen patients for contraindications, comorbidities, and potential drug interactions before initiating fluoxetine therapy.

• Apply evidence-based strategies to manage and mitigate common side effects associated with fluoxetine, such as gastrointestinal symptoms, sexual dysfunction, and weight changes.

• Select alternative treatment options or adjust dosages when necessary based on patient response, tolerability, drug interactions, and treatment-resistant symptoms.

Indications

FDA-Approved Indications

Fluoxetine has received FDA approval to treat major depressive disorder (8 and older), obsessive-compulsive disorder (7 and older), panic disorder (with or without agoraphobia), bulimia nervosa, depressive episodes associated with Bipolar I disorder (as an adjunct with olanzapine), and treatment-resistant depression when used in combination with olanzapine.[1][2][3] 

The American Psychiatric Association guidelines recommend fluoxetine as first-line pharmacotherapy (along with CBT) for patients with bulimia nervosa.[4] 

Off-Label Uses

Non-FDA-approved uses for fluoxetine include binge eating disorder, social anxiety disorder, premenstrual dysphoric disorder, borderline personality disorder, Raynaud phenomenon, and selective mutism.[5][6] 

The American Psychological Association endorses fluoxetine for post-traumatic stress disorder (PTSD).[7]

Mechanism of Action

Serotonin and norepinephrine, both biological amines, have been shown to play a role in the treatment of 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 (5-HT1A) receptors are located in the dorsal raphe nucleus, which project to the prefrontal cortex. Fluoxetine exerts its antidepressant effects by blocking the reuptake of serotonin in the presynaptic serotonin neurons by blocking the reuptake transporter protein in the presynaptic terminal. Fluoxetine also has mild activity at the 5-HT2A and 5-HT2C receptors.

Fluoxetine has minimal activity on noradrenergic reuptake. Due to the drug's action on the 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.

Pharmacokinetics

Absorption: Peak plasma concentrations of fluoxetine are attained after 6 to 8 hours. Fluoxetine is well absorbed with a bioavailability of 70% to 90%. Food does not appear to impact the bioavailability of fluoxetine, but it may slow its absorption by 1 to 2 hours, which is not clinically significant. Thus, fluoxetine may be administered with or without food.

Distribution: Fluoxetine has plasma protein binding of approximately 94.5%, bound to albumin and alpha-1 glycoprotein. Fluoxetine readily crosses the blood-brain barrier, with a brain-to-plasma ratio of 2.6:1 in humans. The volume of distribution (Vd) of fluoxetine and its metabolite ranges between 20 to 42 L/kg. Some studies report that fluoxetine has the maximum volume of distribution (Vd) of any SSRI (between 14 and 100 L/kg).[8]

Metabolism: Fluoxetine's active metabolite is norfluoxetine, produced when the cytochrome P450 enzyme (CYP2D6) acts on it. Prescribers must remember that fluoxetine has several drug-drug interactions due to its metabolism through the CYP2D6 isoenzyme. Additionally, norfluoxetine can have an inhibitory effect on CYP3A4. Fluoxetine has a half-life of 2 to 4 days, and its active metabolite norfluoxetine has a half-life of 7 to 9 days.[9][10] Approximately 7% of individuals definitively exhibit poor metabolism of fluoxetine due to reduced activity of CYP2D6.[11]

Elimination: Fluoxetine and norfluoxetine have long elimination half-lives, leading to the presence of the drug in the body for several weeks, even after stopping its use. This has important implications when discontinuing fluoxetine and prescribing medications that may interact with fluoxetine and norfluoxetine after discontinuation. The metabolism of fluoxetine is extensive, resulting in approximately 2.5% of the administered dose being excreted unchanged in the urine.[12]

Administration

Available Dosage Forms and Strengths

Fluoxetine should be administered once a day, either in the morning or evening and started at 20 mg daily. Fluoxetine is only available in an oral formulation as an 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).

Fluoxetine is also available in a fixed-dose combination with olanzapine (6 mg olanzapine with 25 mg fluoxetine). Considering that the medication can be efficacious at doses of 5 mg and weighing in on the adverse effect profile, it is essential to note that the drug can be administered in a smaller dosage. For an individual with poorly tolerated adverse effects, the fluoxetine may be dosed in 10 mg tablets instead of 20 mg to help minimize any adverse effects. Generally, 20 mg to 40 mg daily dosing is required to be effective for most individuals.

It also comes in a delayed-release capsule formulation with a dosage of 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 (eg, sleep disturbances, dysphoria, fever, nausea) seen with other antidepressants due to prolonged half-life.[13][14]

Adult Dosing

Major depressive disorder: The typical starting dose of fluoxetine for major depressive disorder (MDD) is 20 mg daily. The maximum recommended dose of fluoxetine for MDD is 80 mg daily.[15] 

Obsessive-compulsive disorder: The starting dose of fluoxetine for obsessive-compulsive disorder (OCD) is 20 mg daily. The typical maintenance dose for OCD is 20 to 60 mg.

Bulimia nervosa: The American Psychiatric Association guidelines recommend cognitive-behavioral therapy as the primary treatment for adults with bulimia nervosa. If there is minimal or no response to psychotherapy alone within 6 weeks, prescribing 60 mg of fluoxetine daily is recommended.[4]

Panic disorder: The typical starting dose of fluoxetine for panic disorder is 10 mg daily. After 1 week, consider increasing the fluoxetine to 20 mg daily. The maximum recommended dose of fluoxetine for panic disorder is 60 mg daily.

Special Patient Populations

Hepatic impairment: In patients with liver cirrhosis, the clearance of fluoxetine and its active metabolite (norfluoxetine) decreases, thus increasing the elimination of 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.

Renal impairment: No dose adjustment of fluoxetine is required in patients with renal impairment. A study suggests that directly observed, once-weekly fluoxetine could be a feasible and well-tolerated treatment option for hemodialysis patients.[16]

Pregnancy considerations: Fluoxetine 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.[17]

Breastfeeding considerations: As fluoxetine is excreted in human milk, nursing while on fluoxetine is not recommended.[17] If a woman used fluoxetine during pregnancy, most experts recommend against changing medications while breastfeeding. Otherwise, agents with lower excretion into breast milk may be preferred, especially while nursing a newborn or preterm infant. In addition, the breastfed infant should be monitored for behavioral adverse effects such as agitation, colic, irritability, poor feeding, and poor weight gain.[18]

Pediatric patients: Fluoxetine is FDA-approved for administration in pediatric patients with MDD and OCD. As with other SSRIs, decreased weight gain is associated with administering fluoxetine in children and adolescent patients. The dose for children with MDD and OCD is 10 mg once daily. According to the AACAP (American Academy of Child and Adolescent Psychiatry), it is recommended to offer selective serotonin reuptake inhibitor (SSRI) medication, particularly fluoxetine, to children and adolescents diagnosed with major depressive disorder. For those who respond positively to acute treatment with fluoxetine, AACAP suggests continuing with fluoxetine alone or combining it with cognitive-behavioral therapy to prevent the relapse or recurrence of major depressive disorder.[19] 

Extensive metareview study results show that fluoxetine offers a strong risk-benefit ratio compared to other antidepressants in youth. This finding suggests that fluoxetine could be recommended as the initial treatment of choice for depressive disorders in children and adolescents.[20]

Older patients: Fluoxetine is effective for major depressive disorder in older patients.[21] The usual starting dose of fluoxetine is 10 mg once daily; it can be increased to 20 mg as tolerated.

Adverse Effects

The most common adverse effects reported by adults include insomnia, nausea, diarrhea, anorexia, dry mouth, headache, drowsiness, anxiety, nervousness, yawning, bruising, seizures, bleeding (rarely), hyperhidrosis, 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.[22][23]

The 5-HT2C 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, the clinician's responsibility is to educate patients.

Most adverse effects are immediate and disappear with time. Thus, waiting for the side effects to subside is best before altering treatment. Most adverse effects are dose-dependent and time-dependent. Clinicians must exercise caution against 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; if insomnia is present, consider dosing early in the morning. Additionally, the dose may be reduced if the side effects are too distressing. The patient should be cautioned about adverse effects; if they persist, switching to a different antidepressant may be indicated after a few weeks.[24]

Reversible cerebral vasoconstriction syndrome presenting with a severe headache has been associated with fluoxetine.[25] A rare case report describes chorea induced by fluoxetine.[26] Rabbit syndrome is distinguished by rapid, fine, and rhythmic movements along the vertical axis of the mouth, usually due to antipsychotics. A case report of rabbit syndrome due to fluoxetine in a child with obsessive-compulsive disorder has been reported.[27]

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 adverse effects. Benzodiazepines may be used to treat anxiety. Bupropion or a phosphodiesterase inhibitor (such as sildenafil) may address sexual dysfunction. Bupropion may also be an option for potential cognitive slowing or apathy seen with fluoxetine.

Drug-Drug Interactions

Fluoxetine inhibits CYP2D6, an enzyme responsible for metabolizing drugs like TCAs, antipsychotics, and antiarrhythmics, and increases the serum concentration of the drugs.[12]

Tricyclic antidepressants: Using fluoxetine concurrently with tricyclic antidepressants (TCAs) can increase levels of TCAs. This may require adjusting the TCA dosage.

Antipsychotics: SSRIs, including fluoxetine, can increase the concentration of haloperidol and clozapine.[28] Coingestion of aripiprazole and fluoxetine can predispose to prolongation of the QT interval.[29]

Antiarrhythmic medications: Simultaneous use of fluoxetine with Class 1A antiarrhythmic medications like quinidine, procainamide, and Class III antiarrhythmics like amiodarone and sotalol can increase the QT interval.[30]

Benzodiazepines: Fluoxetine can increase the plasma concentration of alprazolam and diazepam. Signs of sedation and impaired psychomotor function should be monitored.[31]

Warfarin: Among SSRIs, fluoxetine has one of the highest drug-drug interaction risks with warfarin. Use with caution due to the increased risk of bleeding. Clinicians should monitor the PT/INR.[32]

NSAIDs: Concurrent use of fluoxetine with NSAIDs/aspirin increases the risk of upper gastrointestinal bleeding.[33]

Warfarin: The concurrent use of fluoxetine with SNRIs or SSRIs and warfarin can increase the anticoagulant effects of warfarin, leading to increased bleeding risk. Warfarin should be used cautiously, and the PT/INR should be monitored.[32]

Anticonvulsants: The simultaneous administration of fluoxetine with anticonvulsants like phenytoin or carbamazepine can increase plasma concentration, requiring therapeutic drug monitoring (TDM).[34] 

Serotonergic agents: Fluoxetine, especially in combination with other serotonergic medications, can lead to serotonin syndrome. These drugs include triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, and St. John's Wort. If any symptoms of serotonin syndrome occur, discontinuing fluoxetine and providing supportive treatment is recommended.[35]

Contraindications

Contraindications to fluoxetine include hypersensitivity to fluoxetine or any component in its formulation. This drug is also contraindicated with the concurrent use of monoamine oxidase inhibitors (current use of MAOI or within 2 weeks of discontinuing the MAOI) due to the risk of serotonin syndrome.

Never initiate fluoxetine in a patient receiving linezolid.[36]

Do not give fluoxetine with pimozide or thioridazine due to the risk of QT prolongation.[37]

Use this agent with caution in those with a history of seizures or older patients. 

Boxed Warnings

There is a warning for suicidal ideations in those treated with fluoxetine, especially in younger children and adults 18 to 24 years old.[38] Parents and caregivers should be advised to closely monitor patients for any changes in behavior within the first 2 months after initiating warfarin therapy.[39]

Warning and Precautions

Pregnancy: 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.[40][41] 

The use of the medication beyond 20 weeks is associated with pulmonary hypertension in the newborn, although this is definitively not proven. 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.

Electroconvulsive therapy: Case reports of seizures have been reported in patients administered electroconvulsive therapy (ECT) while on fluoxetine treatment. Caution should be exercised when prescribing fluoxetine to individuals with a history of seizures.[42][43]

Allergic reactions and rash: If patients develop a rash or any signs of an allergic reaction appear, fluoxetine should be stopped. Fluoxetine-induced Stevens-Johnson syndrome has been reported.[44]

Activation of mania/hypomania: Patients should be evaluated for bipolar disorder before starting fluoxetine, as it can trigger manic or hypomanic episodes. Close monitoring for any mood changes is necessary during treatment.[45]

Anxiety and insomnia: Some patients may experience increased anxiety and insomnia while taking fluoxetine.[24]

Angle-closure glaucoma: Fluoxetine may cause angle-closure glaucoma. Monitor IOP in patients with a history of glaucoma.[46]

Hyponatremia: In rare cases, fluoxetine has been associated with low sodium levels (hyponatremia) due to the syndrome of inappropriate antidiuretic hormone (SIADH).[47][48]

QT prolongation: Fluoxetine can prolong the QT interval, possibly leading to torsade de pointes. The drug should be used cautiously in patients with an increased risk of QT prolongation.[37]

Cognitive impairment: Fluoxetine can potentially impair cognitive function and motor skills. Per manufacturer labeling, caution should be exercised when performing tasks requiring alertness, such as operating machinery. On the contrary, some studies suggest that fluoxetine may enhance cognitive function in patients with dementia. Individual patient assessment and MMSE may be required if there is doubt regarding deteriorating cognition.[49]

Sexual dysfunction: SSRIs, including fluoxetine, can lead to sexual side effects in both males and females. In males, these may include delayed ejaculation, decreased libido, and erectile dysfunction. This ADR can be utilized for patients with from premature ejaculation. Females may experience decreased libido or anorgasmia.[50][51]

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.[38][52] The PHQ-9 (Patient Health Questionnaire-9) and HAM-D/HDRS (Hamilton Depression Rating Scale) should be monitored.[53][54][55]

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

The American Society of Regional Anesthesia (ASRA) suggests a washout period of approximately 5 weeks before interventional spine and pain procedures due to the long half-life of fluoxetine to decrease the risk of bleeding.[56]

Toxicity

Fluoxetine is rarely lethal in monotherapy overdose. However, when taken 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.[57][58] 

Management of Overdose

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.[59][60]

Enhancing Healthcare Team Outcomes

Fluoxetine is a commonly prescribed antidepressant by physicians and advanced practice 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 drugs.

Nursing staff and prescribers should monitor children and adolescent patients for suicidal ideation, especially when starting fluoxetine or increasing doses. Nursing staff, particularly those with specialty training in psychiatric health, can counsel 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 follow-ups 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 members are responsible for monitoring the patient, offering counsel, and noting any patient status changes. If they observe any issues, they should be documented in the patient's health record for all team members to follow, and the new information should be communicated to other team members so changes can be made if necessary. With close monitoring from all team members, fluoxetine can be an effective drug for numerous psychiatric conditions, including major depression. An interprofessional approach involving open communication between clinicians, specialists, and pharmacists can achieve optimal outcomes related to fluoxetine therapy while mitigating adverse effects.