Fluoxetine

Fluoxetine is a psychoactive drug of the selective serotonin reuptake inhibitor (SSRI) class. It was the first SSRI approved for medical use in the United States, where it was sold as Prozac, and it is widely used to treat depressive disorders, obsessive-compulsive disorder, and several other conditions. Because it is easy to administer and patients tend to take it consistently, fluoxetine has become one of the most commonly prescribed medications in psychiatry.

History and development

The research that produced fluoxetine began at pharmaceutical company Eli Lilly around 1970, in a collaboration between Bryan Molloy and Ray Fuller. The work that eventually led to the discovery of fluoxetine began at Eli Lilly and Company in 1970 as a collaboration between Bryan Molloy and Ray Fuller. The compound was first synthesized in 1971 and first disclosed in 1974 under the code LY110140. Fluoxetine was first synthesized in 1971, first disclosed in 1974 as LY110140. Clinical testing in humans began in 1976, and a phase II and III trial programme later demonstrated efficacy in major depression without the cardiovascular problems and anticholinergic effects associated with older tricyclic antidepressants.

Approval required placebo-controlled evidence. At the time, FDA regulations changed, stating that new compounds must be tested against a placebo to prove their effectiveness. Regulators in Belgium approved the drug for depression in 1986, and the US approval followed on December 29, 1987, with the drug reaching the American market in early 1988. The success of the product was commercially large: by 1999 Prozac was reported to generate about $2.5 billion a year, roughly a quarter of Eli Lilly's revenue.

Pharmacology

Mechanism of action

Fluoxetine acts on the serotonin system. It blocks the serotonin transporter on presynaptic neurons, so less serotonin is taken back into the nerve terminal and more remains in the synaptic cleft to act on postsynaptic receptors. The drug's effects in animals and humans are considered to arise almost entirely from this uptake inhibition. Its affinity for the transporters of dopamine and noradrenaline is low, and it has little effect on histaminergic, cholinergic, or noradrenergic receptors, which accounts for a side-effect profile that differs from older tricyclic drugs.

The therapeutic action develops slowly, even though serotonin levels rise soon after dosing. Antidepressant benefit is usually seen only after several weeks of treatment. Research on the mechanism has also examined neurotrophic signalling: one review notes that the antidepressant effect involves serotonin reuptake inhibition together with activation of TrkB receptors, which are linked to brain-derived neurotrophic factor (BDNF) signalling. Animal studies have reported increased adult hippocampal neurogenesis during chronic treatment.

Metabolism and pharmacokinetics

Fluoxetine is extensively metabolized in the liver to norfluoxetine, an active metabolite that retains selectivity for the serotonin transporter. Both compounds have long elimination half-lives, which means that drug levels change slowly and that a missed dose has little immediate effect. The prescribing information notes that dose changes take several weeks to be fully reflected in plasma concentrations. The molecule is a racemate, and its para-trifluoromethyl group is considered important for its binding to the serotonin transporter.

Therapeutic uses

In the United States, fluoxetine is indicated for major depressive disorder, obsessive-compulsive disorder, bulimia nervosa, panic disorder, premenstrual dysphoric disorder, and bipolar I disorder in certain combinations. It is also approved for pediatric use in some indications: PROZAC is approved for use in pediatric patients with MDD and OCD. A combination of fluoxetine and olanzapine is approved as a treatment for bipolar depression, a use that is separate from fluoxetine alone. Other uses, including anxiety disorders and eating-related conditions, are supported by clinical trials but are not all covered by the approved labelling.

Fluoxetine has also been studied in obesity, and controlled trials have examined its role in bulimia. Its use in psychiatric practice has extended beyond depression, but the evidence strength varies by condition.

Adverse effects

The most common side effects are gastrointestinal, central nervous system, and sexual. These include nausea, vomiting, diarrhoea, insomnia, restlessness, tremor, headache, and sexual dysfunction. Changes in appetite and body weight occur in about one in ten adult patients. Mania has been reported in roughly 1% of patients, a risk common to antidepressants. Long-term effects on cognition have been studied with mixed results, and one review describes the findings as inconsistent.

Cardiovascular effects have drawn attention in older patients. Research has suggested that drug concentrations may rise with age, and that fluoxetine and other SSRIs may affect vascular smooth-muscle function, which raises the question of cardiovascular risks in elderly patients.

Warnings and safety

Suicidality boxed warning

Fluoxetine carries the FDA boxed warning shared by all antidepressants: increased risk of suicidal thinking and behavior in children, adolescents, and young adults taking antidepressants. The warning is the most severe the FDA can place on a labelled drug short of a ban. The warning has been debated. A 2017 analysis found that a claimed link between falling antidepressant prescriptions and rising youth suicide was methodologically weak, and it argued that a study questioning the drug's pediatric risk had an invalid measure of suicidality. A later meta-analysis found that fluoxetine in paediatric major depression neither increased nor significantly decreased the risk of suicidality. Clinicians and regulators therefore continue to monitor patients for worsening mood and emerging suicidal thoughts, especially early in treatment and after dose changes.

Other warnings

• QT prolongation: Post-marketing reports include QT interval prolongation and ventricular arrhythmia, including torsades de pointes.
• Bleeding: Serotonergic drugs can increase bleeding risk, particularly when combined with NSAIDs, aspirin, warfarin, or other drugs that affect coagulation.
• Serotonin syndrome: Combining fluoxetine with other serotonergic agents, such as monoamine oxidase inhibitors, triptans, or tramadol, can cause serotonin syndrome, a potentially life-threatening condition.
• Contraindicated combinations: The label prohibits use with certain drugs such as pimozide, and with thioridazine within five weeks of stopping fluoxetine.

Regulatory and clinical significance

In 2003, a UK regulatory review of SSRIs for adolescents judged that, with the exception of fluoxetine, SSRIs had not been shown to be effective in randomized trials for this age group. Fluoxetine's pediatric record is therefore distinct from other antidepressants of its class, although it too carries the boxed warning.

Fluoxetine's clinical importance also lies in its role as a pharmacological tool. Its selectivity for the serotonin transporter and lack of affinity for other neurotransmitter receptors have made it a standard probe for studying serotonergic function in the brain and in mental health research. The development of fluoxetine also helped establish the SSRI class, which replaced many older antidepressants in first-line psychiatric treatment, and the drug is now available as a generic medicine in many countries.

References

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