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]

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]

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.

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 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.