Pharmacology

Pharmacodynamics. The actions of fluoxetine are linked to its inhibition of neuronal uptake of serotonin. Serotonergic neurotransmission is enhanced due to increased concentrations of serotonin in the synaptic cleft following serotonin reuptake inhibition by fluoxetine. One neurochemical effect of fluoxetine administration is a decrease of serotonin turnover that is demonstrated by: (1) a decrease in steady-state concentrations of serotonin metabolite 5HIAA, (2) a diminished accumulation of 5HIAA after probenecid is given to block its efflux from the brain, (3) a diminished rate of disappearance of serotonin when p-chlorophenylalanine is given to inhibit its synthesis, and (4) a decreased incorporation of radioactive tryptophan into 5-hydroxyindoles. The decreased turnover of brain serotonin after fluoxetine administration is thought to be due to increased activation of autoreceptors on serotonin neurons, whose physiologic role is sensing the extraneural concentration of serotonin and modulating the further release and synthesis of serotonin. Fluoxetine induces an increase in new neurons by inducing division of progenitor cells and defines a cellular target for antidepressant drug therapies.

Fluoxetine has antiinflammatory and antihyperalgesic effects as well. Spinal 5-HT2 receptors are involved in the antihyperalgesic effect of fluoxetine in experimental models of pain and inflammation (16).

Chronic fluoxetine use can modulate the immune function via a serotonin-dependent pathway as well as through an independent mechanism, and this effect can be beneficial or harmful. For example, it inhibits tumor growth by increasing antitumor T cell activity. Immunomodulator effect of fluoxetine can be exploited for treating several disorders due to immune deficiency, or immune deregulation, or both (08).

A single-photon emission computed tomography study has shown that fluoxetine decreases dopamine transporter binding indicating alleviation of the hyperdopaminergic state and increases concentration of IGF-1 in the CSF, which may also have a neuroprotective effect against dopamine-induced neurotoxicity in autistic children (17).

An fMRI study has shown that fluoxetine normalizes frontal lobe dysfunction via inverse effect by downregulating abnormally increased frontal activation in autism spectrum disorders and upregulating abnormally decreased frontal activation in attention deficit hyperactivity disorder (06). This inverse effect likely reflects differences in baseline levels of serotonin in these two disorders.

A low cortisol response to a single DEX/CRH (dexamethasone/corticotrophic releasing hormone) test is a biomarker of clinical response to treatment.

Pharmacokinetics. The important points are as follows:

Transdermal fluoxetine. A drug-in adhesive patch formulation for the transdermal delivery of fluoxetine is in development for clinical applications to provide a therapeutic plasma level of fluoxetine over an extended period (15).

Pharmacogenetics. A deletion/insertion polymorphism within the 5-HT transporter promoter gene, the site of action of fluoxetine, is also associated with anxiety and depression. Patients with l/l genotype of 5-HT transporter promoter gene have a significantly better response to fluoxetine when compared to s allele carriers (25). Different polymorphisms of CYP2D6 and CYP2C9 may influence the blood concentrations of fluoxetine, whereas polymorphisms of SLC6A4, HTR1A, and MAO-A are involved in the response to fluoxetine (03). Improvement after treatment with fluoxetine in one study on children was associated significantly with two polymorphisms located in genes related to the serotonergic system: the 5-hydroxytryptamine receptor 1B and the tryptophan 5-hydroxylase 2 (19). The polymorphism rs34517220, located in the transcription factor binding site of TPH2, which is one of the most important serotonergic candidate genes, is the crucial functional genetic variant related to the fluoxetine response by higher reduction in depressive symptoms in children and adolescents (11).

In a multidrug regimen, preemptive mitigation of drug-drug interactions requires knowledge of fluoxetine actions on CYP450 enzymes as the major metabolic pathway of fluoxetine leading to the formation of its active metabolite, norfluoxetine, is mediated by CYP2D6. Both fluoxetine and norfluoxetine are strong affinity substrates of CYP2D6 and can inhibit the metabolism of other sensitive CYP2D6 substrates through various mechanisms (07). Long-term inhibition of CYP2D6 is likely a result of competitive inhibition due to strong affinity binding of fluoxetine and norfluoxetine to the enzyme and unbound fluoxetine and norfluoxetine levels circulating in the blood for a long period of time because of their long elimination half-life.

Clinical trials

The efficacy of fluoxetine for the treatment of adult patients with depression has been studied in 5- and 6-week placebo-controlled trials. It was shown to be significantly more effective than placebo as measured by the Hamilton Depression Rating Scale. Two 6-week controlled studies comparing fluoxetine and placebo have shown fluoxetine to be effective in the treatment of elderly patients (older than 60 years of age) with depression. In these studies, fluoxetine produced a significantly higher rate of response and remission as defined respectively by a 50% decrease in the Hamilton Depression Rating Scale score and a total endpoint score of less than 7. The drug was well tolerated, and the rate of treatment discontinuations due to adverse events did not differ much between fluoxetine (12%) and placebo (9%). Clinical trials have also been carried out for other indications such as obsessive-compulsive disorders. In older trials, fluoxetine was compared with tricyclic antidepressants, and now it is used as a comparison drug for clinical trials with other serotonin-modulating drugs.

In a double-blind placebo-controlled trial in adult autism spectrum disorders, fluoxetine produced significantly greater improvement in repetitive behaviors as well as on the Clinical Global Impression overall improvement rating (13).

In a multicenter, randomized, placebo-controlled clinical trial on children as well as adolescents with obsessive compulsive behaviors and autism spectrum disorder, treatment with fluoxetine resulted in significantly lower scores for obsessive-compulsive behaviors compared with placebo at 16 weeks (23).

Indications

Fluoxetine is labeled for use in the United States for the following indications:

Off-label uses

Contraindications

Goals and duration of treatment

For treatment of depression, the aim is control of depression. The achievement of fluoxetine's full antidepressant effect may be delayed until 4 weeks of treatment or longer.

Dosing

For treatment of depression, a morning dose of 20 mg daily is recommended as the initial dose. This may be increased after several weeks if no clinical improvement is observed. Doses above 20 mg daily may be administered on a once-daily (ie, morning) or twice-daily schedule (ie, morning and noon) and should not exceed a maximum dose of 80 mg daily.

Special considerations

Geriatric. In healthy elderly subjects over 65 years of age, the disposition of single doses of fluoxetine does not differ significantly from that in younger normal subjects; however, given the long half-life and nonlinear disposition of the drug, a single-dose study is not adequate to rule out the possibility of altered pharmacokinetics in the elderly, particularly if they have systemic illness or are receiving multiple drugs for concomitant diseases.

Pediatric. Safety and effectiveness in pediatric patients have not been established.

Pregnancy. Fetal development studies in rats and rabbits have shown no evidence of teratogenicity following administration doses equivalent to the maximum recommended human dose throughout organogenesis; however, in rat reproduction studies, an increase in stillborn pups, a decrease in pup weight, and an increase in pup deaths during the first week postpartum occurred following maternal exposure to fluoxetine during gestation and lactation. Symptoms such as irritability, respiratory distress, and muscular hypotonia have been reported in newborns after third trimester exposure.

A meta-analysis indicates that maternal fluoxetine use is associated with a slightly increased risk of cardiovascular malformations in infants, and the risk-benefit must be weighed when making decisions about whether to treat with fluoxetine during pregnancy (10). No significant malformations were reported involving the nervous system, eye, urogenital system, digestive system, respiratory system, or musculoskeletal system. The mean combined dose of fluoxetine and its metabolite norfluoxetine transmitted to infants through breast milk is usually below the 10% level of concern, but it may be greater than 10% in some cases. Adverse effects have been observed in breast-fed infants and, thus, nursing when on fluoxetine treatment is not recommended.

Usual doses of fluoxetine result in relatively low concentrations of fluoxetine during pregnancy, which are partly due to increased demethylation of fluoxetine by cytochrome P450 2D6, which may explain undertreatment of depression in pregnancy and therapeutic failure. The positive effects of treatment of depression during pregnancy and the perinatal period generally outweigh the risks of possible adverse effects of fluoxetine.

Liver disease. Liver impairment can affect the elimination of fluoxetine. The elimination half-life of fluoxetine was prolonged in cirrhotic patients, with a mean of 7.6 days compared to the range of 2 to 3 days seen in subjects without liver disease; norfluoxetine elimination is also delayed, with a mean duration of 12 days for cirrhotic patients compared to the range of 7 to 9 days in normal subjects. This suggests that the use of fluoxetine in patients with liver disease must be approached with caution. If fluoxetine is administered to patients with liver disease, then a lower or less frequent dose should be used.

Renal disease. In depressed patients on dialysis, fluoxetine administered 20 mg once daily for 2 months produced steady-state fluoxetine and norfluoxetine plasma concentrations comparable to those seen in patients with normal renal function. Although the possibility exists that renally excreted metabolites of fluoxetine may accumulate to higher levels in patients with severe renal dysfunction, use of a lower or less frequent dose is not routinely necessary in renally impaired patients.

Interactions

The metabolism of fluoxetine (like that of several other compounds including tricyclic and other selective serotonin antidepressants) involves the P4502D6 enzyme system; therefore, concomitant therapy with drugs also metabolized by this enzyme system may lead to drug interactions as follows:

Anticonvulsants. Patients on stable doses of phenytoin and carbamazepine can develop elevated plasma anticonvulsant concentrations and clinical anticonvulsant toxicity following initiation of concomitant fluoxetine treatment.

Antipsychotics. A pharmacodynamic interaction, pharmacokinetic interaction, or both is possible between selective serotonin reuptake inhibitors and antipsychotics. Elevations of blood levels of haloperidol and clozapine have been observed in patients receiving concomitant fluoxetine.

Benzodiazepines. The half-life of concurrently administered diazepam may be prolonged in some patients. Coadministration of alprazolam and fluoxetine has resulted in increased alprazolam plasma concentrations and in further psychomotor performance decrement due to increased alprazolam levels.

Lithium. There have been reports of both increased and decreased lithium levels when lithium was used concomitantly with fluoxetine. Cases of lithium toxicity and increased serotonergic effects have been reported. Lithium levels should be monitored when these drugs are administered concomitantly.

Tryptophan. Patients receiving fluoxetine in combination with tryptophan can experience adverse reactions that include agitation, restlessness, and gastrointestinal distress.

Monoamine oxidase inhibitors. Monoamine oxidase inhibitors present a contraindication because of risk of developing serotonin syndrome.

Tricyclic antidepressants. Stable plasma levels of imipramine and desipramine can increase several-fold when fluoxetine has been administered in combination. This influence may persist for 3 weeks or longer after fluoxetine is discontinued; thus, the dose of tricyclic antidepressants may need to be reduced and plasma tricyclic antidepressant concentrations monitored temporarily when fluoxetine is coadministered or has been discontinued.

Drugs tightly bound to plasma proteins. Fluoxetine is tightly bound to plasma protein and, therefore, the administration of fluoxetine to a patient taking another drug that is tightly bound to protein (eg, warfarin, digitoxin) may cause a shift in plasma concentrations, potentially resulting in an adverse effect. Altered anticoagulant effects, including increased bleeding, have been reported when fluoxetine is coadministered with warfarin. Patients receiving warfarin therapy should receive careful coagulation monitoring when fluoxetine is initiated or stopped.

Adverse effects

Management. The adverse effects of fluoxetine are shared with other selective serotonin reuptake inhibitors.

Reversible cerebral vasoconstriction syndrome. This syndrome is a rare iatrogenic complication of fluoxetine in patients presenting with headache and ischemia (18). Identification of safe alternative treatments for patients with psychiatric illness who would otherwise be candidates for serotonergic medications is an important consideration for individuals affected by this disorder.

Memory disturbance. Postmarketing studies and isolated case reports suggest that fluoxetine may cause impairment of memory in some patients. Memory impairment that results from fluoxetine treatment usually disappears after switching to another selective serotonin reuptake inhibitor.

Skin rash. In fluoxetine clinical trials performed in the United States, 7% of the patients developed various types of rashes and urticaria. Among the cases of rash and urticaria reported in premarketing clinical trials, almost one third were withdrawn from treatment because of the rash or systemic signs or symptoms associated with the rash. Most patients improved promptly with discontinuation of fluoxetine and adjunctive treatment with antihistamines or steroids, and all patients experiencing these events were reported to recover completely.

Gastrointestinal adverse effects. The most common adverse effect is nausea, which occurs in up to 20% of patients receiving fluoxetine. It is usually mild and transient; vomiting is rare. A tendency to develop diarrhea is possible, which is dose-related and transient. Loss of appetite may occur, resulting in possible weight loss. The weight loss is usually mild and may even be beneficial in overweight patients.

Anxiety and nervousness. In some patients, selective serotonin reuptake inhibitors have been associated with increased anxiety, nervousness, and insomnia. This can be alleviated by dosage reduction or by using benzodiazepines.

Movement disorders. Selective serotonin reuptake inhibitor use has been associated with the development of movement disorders, either due to the drug or due to exacerbation of the underlying condition. Akathisia, dystonia, and bruxism have been reported. Some of these movement disorders were due to the use of neuroleptic comedications in psychiatric patients. Rarely, tremor has been reported with selective serotonin reuptake inhibitors; though, if it persists, it may respond to dose reduction or the addition of beta-blockers. Discontinuation of selective serotonin reuptake inhibitors usually leads to improvement of other movement disorders. Dystonia can be treated with botulinum toxin type A.

The mechanism of these adverse reactions is not fully understood. One explanation is that selective serotonin reuptake inhibitors increase the activity of the serotonergic neural pathways that are diffusely interconnected with dopaminergic nuclei. The serotonergic input to the dopaminergic system appears to be inhibitory; therefore, the net effect of selective serotonin reuptake inhibitors would be movement disorders like those induced by the dopamine antagonist effect of neuroleptic medications. Dopamine depletion can manifest as nocturnal bruxism, which may be prevented by using buspirone, a 5-HT1A agonist that reduces serotonergic activity and increases dopaminergic activity (24).

Hyponatremia. This is due to inappropriate secretion of antidiuretic hormone and may occur with the use of selective serotonin reuptake inhibitors in elderly patients. It usually resolves after discontinuation of the selective serotonin reuptake inhibitor.

Seizures. In United States fluoxetine clinical trials, 0.2% of the patients reported convulsions. This rate is lower than that of seizures associated with tricyclic antidepressants. These can be controlled by usual anticonvulsants.

Disorders of sexual function. Depression is a common cause of sexual dysfunction, and antidepressant medications have also been associated with sexual side effects. Selective serotonin reuptake inhibitors have been associated with delayed ejaculation and inability to ejaculate in men and anorgasmia in women. Sexual dysfunction following selective serotonin reuptake inhibitor therapy is considered likely to be due to stimulation of 5-HT2A postsynaptic receptors. This adverse effect has been exploited for therapeutic effect in erectile dysfunction. A prospective, randomized, double-blind, placebo-controlled study showed that fluoxetine plus tadalafil significantly increased the intravaginal ejaculatory latency time in men with lifelong premature ejaculation when compared to placebo, phosphodiesterase-5 inhibitor tadalafil, or fluoxetine alone (20).

Withdrawal effects. Withdrawal effects of serotonin reuptake inhibitors include anxiety, crying spells, psychomotor agitation, irritability, memory disturbances, confusion, and decreased concentration. These are usually mild following fluoxetine cessation; a patient was reported to develop delirium after abrupt discontinuation of fluoxetine (04).