Fluoxetine

Fluoxetine is a selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitor (SSRI). Although its mechanism of action in anxiety disorders is unclear, it is thought to act by enhancing serotonergic neurotransmission and down-regulating central receptors. In comparison with other SSRIs, fluoxetine has a long elimination half-life (4 days).

Fluoxetine (usual dosage ≈20 mg/day) for ≥8 weeks was as effective as citalopram, desipramine, imipramine and moclobemide in double-blind trials involving patients with panic disorder; extension studies demonstrated sustained efficacy for up to 12 months. Fluoxetine 20 to 60 mg/day was also significantly better than placebo in the treatment of obsessive-compulsive disorder; response rates were 24 to 54% after 8 to 13 weeks of treatment compared with 7 and 26% for placebo. However, some response rates were significantly lower with fluoxetine than with clomipramine in some studies, although fluvoxamine and sertraline were of similar efficacy to fluoxetine according to a meta-analysis. Sustained or continued improvement was seen with fluoxetine treatment for up to 1 year. Fluoxetine 10 to 80 mg/day for ≥4 weeks significantly improved symptoms of post-traumatic stress disorder from baseline values and, in social anxiety disorder, improved symptoms in the majority of patients studied.

Double-blind studies indicate that fluoxetine is as effective in patients with anxiety symptoms and depression as imipramine, clomipramine and amitriptyline. Preliminary data indicate that fluoxetine, sertraline and paroxetine are similarly effective in patients with depression and high baseline anxiety. However, more research is needed in this area.

Fluoxetine is well tolerated, with similar incidences of adverse events to that seen with sertraline. However, fluoxetine is associated with fewer adverse effects than fluvoxamine and paroxetine. Rates of sexual dysfunction and suicidal ideation with fluoxetine appear similar to those seen with other SSRIs. Withdrawal reactions after discontinuation of medication are less common with fluoxetine than with other SSRIs.

Fluoxetine and its major metabolite norfluoxetine are potent and selective inhibitors of neuronal reuptake of serotonin (5-hydroxytryptamine; 5-HT). In vitro, fluoxetine is much less potent in inhibiting the reuptake of noradrenaline (norepinephrine. Comparative in vitro studies suggest that fluoxetine is less selective in its effects on serotonin uptake than other commonly used selective serotonin reuptake inhibitors (SSRIs), including citalopram and paroxetine. However, in contrast to tricyclic antidepressants (TCAs), fluoxetine has little affinity for neurotransmitter receptors.

The anxiolytic effects of fluoxetine may result from its down-regulation of central serotonin receptors, although it is not clear exactly which receptor subtypes are involved. Evidence suggests that serotonin 5-HT₁ receptors are down-regulated by fluoxetine; observations regarding its effects on 5-HT₂ receptors have been inconsistent.

Fluoxetine reduces food intake and increases resting energy expenditure, which may result in weight loss. Unlike TCAs, fluoxetine has no significant clinical effects on cognitive and psychomotor abilities.

Fluoxetine is well absorbed after oral administration, with mean peak plasma concentrations (C_max) of 15 to 55 μg/L after a single oral dose of 30 or 40mg. Time to C_max (t_max) is 6 to 8 hours; coadministration with food increases t_maxby 3 to 5 hours, but the extent of absorption and C_max are unchanged. Steady-state plasma concentrations are reached after 2 to 4 weeks of treatment. The volume of distribution of fluoxetine ranges from 12 to 43 L/kg.

After extensive first-pass hepatic metabolism involving cytochrome P450 (CYP) 2D6 and 2C isoenzymes, fluoxetine is transformed into its primary metabolite, norfluoxetine, which has similar activity to that of fluoxetine. As fluoxetine is a potent inhibitor of CYP2D6, it is capable of inhibiting its own metabolism. This results in nonlinear pharmacokinetics and high interindividual pharmacokinetic variability. The mean elimination half-life (t1/2β) of fluoxetine is 4 days after multiple doses; norfluoxetine has a t1/2β of 7 to 15 days.

Values for clearance are significantly decreased in patients with hepatic impairment, resulting in significant increases in t1/2β. Fluoxetine and norfluoxetine pharmacokinetics are not significantly affected by impaired renal function. In a multiple dose study, t1/2β values for fluoxetine and norfluoxetine were increased by 28 and 35%, respectively, in elderly compared with adult healthy volunteers.

Fluoxetine inhibits CYP2D6, CYP2C and CYP3A4. These enzymes are involved in the metabolism of a wide range of drugs (including TCAs, antiarrhythmics and antipsychotics). Caution is advised when coadministering fluoxetine with such drugs; however, clinically significant interactions are unlikely if the drugs involved have a wide therapeutic index and/or other elimination pathways are available.

In studies that included a continuation phase for those who responded to initial fluoxetine treatment, most patients with panic disorder who continued to receive fluoxetine remained symptom-free for 6 to 12 months.

Obsessive-Compulsive Disorder: Fluoxetine 20 to 60 mg/day is significantly more effective than placebo in relieving symptoms of obsessive-compulsive disorder (OCD), with response rates of 24 to 54% compared with 7 and 26% for placebo after 8 or 13 weeks of treatment. However, only 1 study reported significantly greater reductions from baseline total Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) scores with fluoxetine than with placebo (19 to 27% vs 3%, respectively, p < 0.001). Extension phases of up to 1 year indicate sustained or continued improvement and lower relapse rates in those patients who continued to receive fluoxetine.

Mixed Anxiety and Depression: Although mixed anxiety and depression has been suggested as a future DSM diagnosis, diagnostic criteria are not yet established and studies have used differing inclusion criteria. Randomised double-blind studies indicate that fluoxetine is as effective as imipramine, clomipramine and amitriptyline in patients with depression and symptoms of anxiety. Fluoxetine 20 mg/day, sertraline 50 mg/day and paroxetine 20 mg/day were all of similar efficacy in a 10-week study in 284 patients with depression; efficacy was not affected by high baseline anxiety (HDRS Anxiety/Somatization Factor score ≥7). After 12 weeks of treatment, significantly more venlafaxine (extended-release formulation) recipients experienced a ≥50% decrease in HARS score than those who received fluoxetine (65 vs 50%, p = 0.037); all patients had depression according to DSM-IV criteria and high baseline anxiety scores. However, response rates did not differ at the final assessment and there were no significant differences between treatments in response rates determined by Clinical Global Impression and HDRS scores.

In a survey of 12 692 fluoxetine recipients, adverse events occurring in ≥5% of patients in the first month of fluoxetine treatment included nausea (16.2%), malaise (10.5%), headache (9.4%), insomnia (7.9%), anxiety (7.4%), dizziness (6.7%), diarrhoea (5.8%) drowsiness/sedation (5.4%), vomiting (5.4%) and agitation (5.0%). Apart from headache, agitation and vomiting, these events were all significantly more common with fluoxetine than with placebo in a smaller survey (n = 1322). Other adverse events that occurred significantly more often with fluoxetine than placebo included nervousness, anorexia, tremor, sweating, asthenia, dyspepsia, decreased libido and weight loss.

Fluoxetine generally displayed a similar tolerability profile to that of sertraline in large cohort studies, although fluvoxamine was associated with higher incidences of adverse events than any of the other SSRIs tested. Paroxetine was associated with a higher incidence of some adverse events than fluoxetine and sertraline. Some adverse effects (including insomnia, dizziness and nervousness) were significantly less common with fluoxetine than with venlafaxine (extended-release formulation) in a randomised double-blind trial in 359 patients with anxiety disorders.

Although 1 large cohort study (n = 172 598) found a higher crude rate of suicide with fluoxetine than with other antidepressants, this rate decreased after adjusting for other risk factors, but remained higher than that of other agents. Other large surveys and prospective trials have failed to demonstrate any association between fluoxetine treatment and suicidal behaviour and have reported incidences similar to those seen with other SSRIs.

Comparative studies indicate that rates of fluoxetine-associated sexual dysfunction are similar to those seen with other SSRIs. Fluoxetine also does not appear to induce serotonin syndrome, although this event has been reported in patients receiving concurrent fluoxetine and monoamine oxidase inhibitors (MAOIs).

The starting dosage recommended for the treatment of OCD is 20 mg/day, which can be increased in 20mg increments to a maximum of 60 mg/day if the patient fails to respond. Although no current dosage recommendations are available for the treatment of other anxiety disorders, similar regimens have been used in clinical trials. Lower dosages (such as 10 mg/day) have also been used in some studies, particularly those involving patients with panic disorder. Dosage reductions are recommended in patients with significant hepatic impairment and should be considered in the elderly.

To decrease the risk of serotonin syndrome, at least 2 weeks should be allowed to elapse between stopping an MAOI and starting fluoxetine. At least 5 weeks should be allowed to elapse between stopping fluoxetine and starting an MAOI. Caution is advised when coadministering fluoxetine with drugs that are active in the CNS, such as lithium, and/or drugs metabolised by CYP2D6.