Fluoxetine

Depression

Fluoxetine is approved for the treatment of major depression in children and adults.^[7] A meta-analysis of trials in adults concluded that fluoxetine modestly outperforms placebo.^[34] Fluoxetine may be less effective than other antidepressants, but has high acceptability.^[35]

For children and adolescents with moderate-to-severe depressive disorder, fluoxetine seems to be the best treatment (either with or without cognitive behavioural therapy, although fluoxetine alone does not appear to be superior to CBT alone) but more research is needed to be certain, as effect sizes are small and the existing evidence is of dubious quality.^{[36][37][38][39]} A 2022 systematic review and trial restoration of the two original blinded-control trials used to approve the use of fluoxetine in children and adolescents with depression found that both of the trials were severely flawed, and therefore did not demonstrate the safety or efficacy of the medication.^[40]

Obsessive–compulsive disorder

Fluoxetine is effective in the treatment of obsessive–compulsive disorder (OCD) for adults.^[41] It is also effective for treating OCD in children and adolescents.^[42][38][43] The American Academy of Child and Adolescent Psychiatry state that SSRIs, including fluoxetine, should be used as first-line therapy in children, along with cognitive behavioral therapy (CBT), for the treatment of moderate to severe OCD.^[44]

Panic disorder

The efficacy of fluoxetine in the treatment of panic disorder was demonstrated in two 12-week randomized multicenter phase III clinical trials that enrolled patients diagnosed with panic disorder, with or without agoraphobia. In the first trial, 42% of subjects in the fluoxetine-treated arm were free of panic attacks at the end of the study, vs. 28% in the placebo arm. In the second trial, 62% of fluoxetine-treated patients were free of panic attacks at the end of the study, vs. 44% in the placebo arm.^[7]

Bulimia nervosa

A 2011 systematic review discussed seven trials that compared fluoxetine to a placebo in the treatment of bulimia nervosa, six of which found a statistically significant reduction in symptoms such as vomiting and binge eating.^[45] However, no difference was observed between treatment arms when fluoxetine and psychotherapy were compared to psychotherapy alone.

Premenstrual dysphoric disorder

Fluoxetine is used to treat premenstrual dysphoric disorder, a condition where individuals have affective and somatic symptoms monthly during the luteal phase of menstruation.^[8][46] Taking fluoxetine 20 mg/d can be effective in treating PMDD,^[47][48] though doses of 10 mg/d have also been prescribed effectively.^[49][50]

Impulsive aggression

Fluoxetine is considered a first-line medication for the treatment of impulsive aggression of low intensity.^[51] Fluoxetine reduced low-intensity aggressive behavior in patients in intermittent aggressive disorder and borderline personality disorder.^[51][52][53] Fluoxetine also reduced acts of domestic violence in alcoholics with a history of such behavior.^[54]

Obesity and overweight adults

In 2019 a systematic review compared the effects on weight of various doses of fluoxetine (60 mg/d, 40 mg/d, 20 mg/d, 10 mg/d) in obese and overweight adults.^[55] When compared to placebo, all dosages of fluoxetine appeared to contribute to weight loss but lead to increased risk of experiencing side effects, such as dizziness, drowsiness, fatigue, insomnia, and nausea, during the period of treatment. However, these conclusions were from low-certainty evidence.^[55] When comparing, in the same review, the effects of fluoxetine on the weight of obese and overweight adults, to other anti-obesity agents, omega-3 gel capsule and not receiving treatment, the authors could not reach conclusive results due to poor quality of evidence.^[55]

Special populations

In children and adolescents, fluoxetine is the antidepressant of choice due to tentative evidence favoring its efficacy and tolerability.^[56][57] Evidence supporting an increased risk of major fetal malformations resulting from fluoxetine exposure is limited, although the Medicines and Healthcare products Regulatory Agency (MHRA) of the United Kingdom has warned prescribers and patients of the potential for fluoxetine exposure in the first trimester (during organogenesis, formation of the fetal organs) to cause a slight increase in the risk of congenital cardiac malformations in the newborn.^[58][59][60] Furthermore, an association between fluoxetine use during the first trimester and an increased risk of minor fetal malformations was observed in one study.^[59]

However, a systematic review and meta-analysis of 21 studies – published in the Journal of Obstetrics and Gynaecology Canada – concluded, "the apparent increased risk of fetal cardiac malformations associated with maternal use of fluoxetine has recently been shown also in depressed women who deferred SSRI therapy in pregnancy, and therefore most probably reflects an ascertainment bias. Overall, women who are treated with fluoxetine during the first trimester of pregnancy do not appear to have an increased risk of major fetal malformations."^[61]

Per the FDA, infants exposed to SSRIs in late pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn. Limited data support this risk, but the FDA recommends physicians consider tapering SSRIs such as fluoxetine during the third trimester.^[7] A 2009 review recommended against fluoxetine as a first-line SSRI during lactation, stating, "Fluoxetine should be viewed as a less-preferred SSRI for breastfeeding mothers, particularly with newborn infants, and in those mothers who consumed fluoxetine during gestation."^[62] Sertraline is often the preferred SSRI during pregnancy due to the relatively minimal fetal exposure observed and its safety profile while breastfeeding.^[63]

Sexual dysfunction

Sexual dysfunction, including loss of libido, erectile dysfunction, lack of vaginal lubrication, and anorgasmia, are some of the most commonly encountered adverse effects of treatment with fluoxetine and other SSRIs. While early clinical trials suggested a relatively low rate of sexual dysfunction, more recent studies in which the investigator actively inquires about sexual problems suggest that the incidence is >70%.^[66]

In 2019, the Pharmacovigilance Risk Assessment Committee of the European Medicines Agency recommended that packaging leaflets of selected SSRIs and SNRIs should be amended to include information regarding a possible risk of persistent sexual dysfunction.^[67] Following on the European assessment, a safety review by Health Canada "could neither confirm nor rule out a causal link ... which was long lasting in rare cases", but recommended that "healthcare professionals inform patients about the potential risk of long-lasting sexual dysfunction despite discontinuation of treatment".^[68]

Antidepressant discontinuation syndrome

Fluoxetine's longer half-life makes it less common to develop antidepressant discontinuation syndrome following cessation of therapy, especially when compared with antidepressants with shorter half-lives such as paroxetine.^[69][70] Although gradual dose reductions are recommended with antidepressants with shorter half-lives, tapering may not be necessary with fluoxetine.^[71]

Pregnancy

Antidepressant exposure (including fluoxetine) is associated with shorter average duration of pregnancy (by three days), increased risk of preterm delivery (by 55%), lower birth weight (by 75 g), and lower Apgar scores (by <0.4 points).^[72][73] There is 30–36% increase in congenital heart defects among children whose mothers were prescribed fluoxetine during pregnancy,^[12][13] with fluoxetine use in the first trimester associated with 38–65% increase in septal heart defects.^[74][12]

Suicide

This section needs to be updated. (March 2022)

On 14 September 1989, Joseph T. Wesbecker killed eight people and injured twelve before committing suicide.^[75] His relatives and victims blamed his actions on the Fluoxetine he had begun taking 11 days previously. Eli Lilly settled the case. The incident set off a chain of lawsuits and public outcries, resulting in Eli Lilly paying out $50 million across 300 claims.^[76] Eli Lilly was accused of not doing enough to warn patients and doctors about the adverse effects, which it had described as "activation", years before the incident.^[77] It was revealed in a lawsuit by the family of Bill Forsyth Sr, who killed his wife and then himself on 11 March 1993,^[78] that the Federal Health Agency (BGA) in the Federal Republic of Germany had refused to license Fluoxetine after examination of internal Eli Lilly documents there had been 16 suicide attempts, two of which had been successful, during clinical trials. The BGA considered that Fluoxetine administration was causative because those considered to be at risk of suicide were not allowed to participate in the trial.^[79] On the basis of the internal statistical evidence engathered by Eli Lilly that emerged in this lawsuit, it was estimated by 1999 that there would have been 250,000 suicide attempts and 25,000 suicides globally.^[78]

In October 2004, the FDA added its most serious warning, a black box warning, to all antidepressant drugs regarding use in children.^[80] In 2006, the FDA included adults aged 25 or younger.^[81] Statistical analyses conducted by two independent groups of FDA experts found a 2-fold increase of the suicidal ideation and behavior in children and adolescents, and 1.5-fold increase of suicidality in the 18–24 age group. The suicidality was slightly decreased for those older than 24, and statistically significantly lower in the 65 and older group.^[82][83][84] In February 2018, the Food and Drug Administration (FDA) ordered an update to the warnings based on statistical evidence from twenty-four trials in which the risk of such events increased from two percent to four percent relative to the placebo trials.^[85]

A study published in May 2009 found that fluoxetine was more likely to increase overall suicidal behavior. 14.7% of the patients (n=44) on Fluoxetine had suicidal events, compared to 6.3% in the psychotherapy group and 8.4% from the combined treatment group.^[86] Similarly, the analysis conducted by the UK MHRA found a 50% increase in suicide-related events, not reaching statistical significance, in the children and adolescents on fluoxetine as compared to the ones on placebo. According to the MHRA data, fluoxetine did not change the rate of self-harm in adults and statistically significantly decreased suicidal ideation by 50%.^[87][88]

QT prolongation

Fluoxetine can affect the electrical currents that heart muscle cells use to coordinate their contraction, specifically the potassium currents I_to and I_Ks that repolarise the cardiac action potential.^[89] Under certain circumstances, this can lead to prolongation of the QT interval, a measurement made on an electrocardiogram reflecting how long it takes for the heart to electrically recharge after each heartbeat. When fluoxetine is taken alongside other drugs that prolong the QT interval, or by those with a susceptibility to long QT syndrome, there is a small risk of potentially lethal abnormal heart rhythms such as torsades de pointes.^[90] A study completed in 2011 found that fluoxetine does not alter the QT interval and has no clinically meaningful effects on the cardiac action potential.^[91]

Pharmacodynamics

Fluoxetine is a selective serotonin reuptake inhibitor (SSRI) and does not appreciably inhibit norepinephrine and dopamine reuptake at therapeutic doses. It does, however, delay the reuptake of serotonin, resulting in serotonin persisting longer when it is released. Large doses in rats have been shown to induce a significant increase in synaptic norepinephrine and dopamine.^{[113][114][115][116]} Thus, dopamine and norepinephrine may contribute to the antidepressant action of fluoxetine in humans at supratherapeutic doses (60–80 mg).^[115][117] This effect may be mediated by 5HT_2C receptors, which are inhibited by higher concentrations of fluoxetine.^[118]

Fluoxetine increases the concentration of circulating allopregnanolone, a potent GABA_A receptor positive allosteric modulator, in the brain.^[116][119] Norfluoxetine, a primary active metabolite of fluoxetine, produces a similar effect on allopregnanolone levels in the brains of mice.^[116] Additionally, both fluoxetine and norfluoxetine are such modulators themselves, actions which may be clinically relevant.^[120]

In addition, fluoxetine has been found to act as an agonist of the σ₁-receptor, with a potency greater than that of citalopram but less than that of fluvoxamine. However, the significance of this property is not fully clear.^[121][122] Fluoxetine also functions as a channel blocker of anoctamin 1, a calcium-activated chloride channel.^[123][124] A number of other ion channels, including nicotinic acetylcholine receptors and 5-HT₃ receptors, are also known to be inhibited at similar concentrations.^[120]

Fluoxetine has been shown to inhibit acid sphingomyelinase, a key regulator of ceramide levels which derives ceramide from sphingomyelin.^[125][126]

Mechanism of action

While it is unclear how fluoxetine exerts its effect on mood, it has been suggested that fluoxetine elicits an antidepressant effect by inhibiting serotonin reuptake in the synapse by binding to the reuptake pump on the neuronal membrane^[127] to increase serotonin availability and enhance neurotransmission.^[128] Over time, this leads to a downregulation of pre-synaptic 5-HT1A receptors, which is associated with an improvement in passive stress tolerance, and delayed downstream increase in expression of brain-derived neurotrophic factor, which may contribute to a reduction in negative affective biases.^[129][130] Norfluoxetine and desmethylfluoxetine are metabolites of fluoxetine and also act as serotonin reuptake inhibitors, increasing the duration of action of the drug.^[131][127]

Prolonged exposure to fluoxetine changes the expression of genes involved in myelination, a process that shapes brain connectivity and contributes to symptoms of psychiatric disorders. The regulation of genes involved with myelination is partially responsible for the long-term therapeutic benefits of chronic SSRI exposure.^[132]

Pharmacokinetics

The bioavailability of fluoxetine is relatively high (72%), and peak plasma concentrations are reached in 6–8 hours. It is highly bound to plasma proteins, mostly albumin and α₁-glycoprotein.^[9] Fluoxetine is metabolized in the liver by isoenzymes of the cytochrome P450 system, including CYP2D6.^[133] The role of CYP2D6 in the metabolism of fluoxetine may be clinically important, as there is great genetic variability in the function of this enzyme among people. CYP2D6 is responsible for converting fluoxetine to its only active metabolite, norfluoxetine.^[134] Both drugs are also potent inhibitors of CYP2D6.^[135]

The extremely slow elimination of fluoxetine and its active metabolite norfluoxetine from the body distinguishes it from other antidepressants. With time, fluoxetine and norfluoxetine inhibit their own metabolism, so fluoxetine elimination half-life increases from 1 to 3 days, after a single dose, to 4 to 6 days, after long-term use.^[9] Similarly, the half-life of norfluoxetine is longer (16 days) after long-term use.^{[133][136][137]} Therefore, the concentration of the drug and its active metabolite in the blood continues to grow through the first few weeks of treatment, and their steady concentration in the blood is achieved only after four weeks.^[138][139] Moreover, the brain concentration of fluoxetine and its metabolites keeps increasing through at least the first five weeks of treatment.^[140] For major depressive disorder, while onset of antidepressant action may be felt as early as 1–2 weeks,^[141] the full benefit of the current dose a patient receives is not realized for at least a month following ingestion. For example, in one 6-week study, the median time to achieving consistent response was 29 days.^[138] Likewise, complete excretion of the drug may take several weeks. During the first week after treatment discontinuation, the brain concentration of fluoxetine decreases by only 50%,^[140] The blood level of norfluoxetine four weeks after treatment discontinuation is about 80% of the level registered by the end of the first treatment week, and, seven weeks after discontinuation, norfluoxetine is still detectable in the blood.^[136]

Measurement in body fluids

Fluoxetine and norfluoxetine may be quantitated in blood, plasma, or serum to monitor therapy, confirm a diagnosis of poisoning in hospitalized persons, or assist in a medicolegal death investigation. Blood or plasma fluoxetine concentrations are usually in a range of 50–500 μg/L in persons taking the drug for its antidepressant effects, 900–3000 μg/L in survivors of acute overdosage, and 1000–7000 μg/L in victims of fatal overdosage. Norfluoxetine concentrations are approximately equal to those of the parent drug during chronic therapy but may be substantially less following acute overdosage since it requires at least 1–2 weeks for the metabolite to achieve equilibrium.^{[142][143][144]}

Prescription trends

In 2010, over 24.4 million prescriptions for generic fluoxetine were filled in the United States,^[165] making it the third-most prescribed antidepressant after sertraline and citalopram.^[165]

In 2011, 6 million prescriptions for fluoxetine were filled in the United Kingdom.^[166] Between 1998 and 2017, along with amitriptyline, it was the most commonly prescribed first antidepressant for adolescents aged 12–17 years in England.^[167]

Environmental effects

Fluoxetine has been detected in aquatic ecosystems, especially in North America.^[168] There is a growing body of research addressing the effects of fluoxetine (among other SSRIs) exposure on non-target aquatic species.^{[169][170][171][172]}

In 2003, one of the first studies addressed in detail the potential effects of fluoxetine on aquatic wildlife; this research concluded that exposure at environmental concentrations was of little risk to aquatic systems if a hazard quotient approach was applied to risk assessment.^[171] However, they also stated the need for further research addressing sub-lethal consequences of fluoxetine, specifically focusing on study species' sensitivity, behavioural responses, and endpoints modulated by the serotonin system.^[171]

Fluoxetine – similar to several other SSRIs – induces reproductive behavior in some shellfish at concentrations as low as 10^-10 M, or 30 parts per trillion.^[173]: 21

Since 2003, several studies have reported fluoxetine-induced impacts on many behavioural and physiological endpoints, inducing antipredator behaviour,^{[174][175][176]} reproduction,^[177][178] and foraging^[179][180] at or below field-detected concentrations. However, a 2014 review on the ecotoxicology of fluoxetine concluded that, at that time, a consensus on the ability of environmentally realistic dosages to affect the behaviour of wildlife could not be reached.^[170] At environmentally realistic concentrations, fluoxetine alters insect emergence timing.^[181] Richmond et al., 2019 find that at low concentrations it accelerates emergence of Diptera, while at unusually high concentrations it has no discernable effect.^[181]

Several common plants are known to absorb fluoxetine.^[182] Several crops have been tested, and Redshaw et al. 2008 find that cauliflower absorbs large amounts into the stem and leaf but not the head or root.^[182] Wu et al. 2012 find that lettuce and spinach also absorb detectable amounts, while Carter et al. 2014 find that radish (Raphanus sativus), ryegrass (Lolium perenne) – and Wu et al. 2010 find that soybean (Glycine max) – absorb little.^[182] Wu tested all tissues of soybean and all showed only low concentrations.^[182] By contrast various Reinhold et al. 2010 find duckweeds have a high uptake of fluoxetine and show promise for bioremediation of contaminated water, especially Lemna minor and Landoltia punctata.^[182] Ecotoxicity for organisms involved in aquaculture is well documented.^{[183]: 275–276} Fluoxetine affects both aquacultured invertebrates and vertebrates, and inhibits soil microbes including a large antibacterial effect.^[183] For applications of this see § Other uses.

Politics

During the 1990 campaign for governor of Florida, it was disclosed that one of the candidates, Lawton Chiles, had depression and had resumed taking fluoxetine, leading his political opponents to question his fitness to serve as governor.^[184]

American aircraft pilots

Beginning in April 2010, fluoxetine became one of four antidepressant drugs that the FAA permitted for pilots with authorization from an aviation medical examiner. The other permitted antidepressants are sertraline (Zoloft), citalopram (Celexa), and escitalopram (Lexapro).^[185] These four remain the only antidepressants permitted by FAA as of 2 December 2016.^[ref][186]

Sertraline, citalopram, and escitalopram are the only antidepressants permitted for EASA medical certification, as of January 2019.^[187][188]