Fluoxetine

Abstract

Fluoxetine is a potent and selective inhibitor of neuronal serotonin (5-hydroxytryptamine) reuptake. Fluoxetine reduces food, energy and carbohydrate intake and increases resting energy expenditure, which may account for the moderate and transient bodyweight loss observed with its use. Glucose tolerance and/or hypoglycaemia in patients with type 2 diabetes mellitus improve with fluoxetine therapy. The ability of fluoxetine to inhibit cytochrome P450 (CYP) isoenzymes (CYP2D6, CYP2C and CYP3A4), is potentially important for patients with physical illness who may be taking multiple concomitant medications. Fluoxetine was more effective than placebo in 2 double-blind, randomised trials, and according to limited data appears to be equally effective compared with other SSRIs and tricyclic antidepressants (TCAs), in the treatment of depression in patients with HIV/AIDS. The efficacy of fluoxetine is also superior to that of placebo in the treatment of depression in patients with diabetes mellitus and stroke as shown in double-blind randomised trials, although its efficacy relative to that of nortriptyline in stroke is uncertain. Fluoxetine had similar efficacy to that of desipramine in patients with cancer, with improved Hamilton Depression Rating Scale and quality-of-life scores from baseline; however, the drug was not more effective than placebo in a double-blind randomised trial. Medically healthy individuals tolerate fluoxetine well. Like other SSRIs, fluoxetine lacks the anticholinergic, cardiovascular, sedative and weight-increasing properties of TCAs, and is safer in overdose than TCAs and monoamine oxidase inhibitors. Rates of sexual dysfunction and suicidal ideation with fluoxetine appear similar to those seen with other SSRIs. Conclusion: Fluoxetine has shown superior efficacy compared with placebo in the treatment of depression in patients with HIV/AIDS, diabetes mellitus or stroke; however, it has not significantly improved depressive symptoms versus placebo in patients with cancer. The efficacy of fluoxetine appears similar to that of desipramine in patients with stroke, cancer or HIV, and is similar to that of sertraline or paroxetine in patients with HIV/AIDS; comparisons with nortriptyline give equivocal results. The potential for drug interactions with fluoxetine use should be carefully considered because most patients with comorbid physical illness will be receiving multiple comedications. Although fluoxetine has proved effective as an antidepressant in this population in several clinical trials, its drug interaction profile and long half-life are a potential limitation, and these properties should be carefully considered in relation to the status of each patient. Fluoxetine and its major metabolite, norfluoxetine, are potent and selective inhibitors of neuronal serotonin (5-hydroxytryptamine; 5HT) reuptake. In comparative in vitro studies, fluoxetine shows less selectivity in its effects on serotonin reuptake than most other serotonin reuptake inhibitors (SSRIs), including sertraline and paroxetine. Fluoxetine has little or no affinity for α₁-, α₂- and β-adrenoceptors, muscarinic, serotonin 5-HT₁, 5-HT₂, histamine H₁, opioid, dopamine and γ-aminobutyric acid B receptors. Total daily food intake in healthy volunteers with normal bodyweight, and energy and carbohydrate intake in patients with type 2 diabetes mellitus are reduced with fluoxetine treatment, whereas resting energy expenditure in patients with moderate obesity is increased; these effects may result in bodyweight loss. Treatment with fluoxetine improves glucose tolerance and/or hypoglycaemia in patients with type 2 diabetes mellitus irrespective of the bodyweight-lowering effects of the drug. Discontinuation of fluoxetine treatment may result in hyperglycaemia. Unlike tricyclic antidepressants (TCAs), fluoxetine has no significant clinical effects on cognitive or psychomotor abilities. Fluoxetine treatment does not significantly alter CD4+ counts in patients with HIV/AIDS. Case reports indicate that fluoxetine can decrease the antiemetic efficacy of ondansetron, a 5-HT₃ antagonist; this effect probably results from the accumulation of serotonin, which competes with ondansetron at the receptor. Fluoxetine is well absorbed following oral administration, with mean peak plasma concentrations (C_max) of 15 to 55 μg/L after a single dose of 30 or 40mg. The time to C_max (t_max) is 6 to 8 hours. Coadministration of fluoxetine with food increases the t_max by 3 to 5 hours but does not alter the area under the plasma concentration-time curve or C_max. Steady-state plasma concentrations are reached after 2 to 4 weeks of fluoxetine treatment. The volume of distribution of fluoxetine ranges from 12 to 43 L/kg after single or multiple doses and the drug is highly protein bound. Transformation of fluoxetine into norfluoxetine (the primary active metabolite) occurs after extensive first-pass hepatic metabolism involving cytochrome P450 (CYP) 2C and 2D6 isoenzymes. As a potent inhibitor of CYP2D6, fluoxetine is capable of inhibiting its own metabolism, which results in nonlinear pharmacokinetics and high interindividual pharmacokinetic variability. The elimination half-life (t½β) of fluoxetine is 2 to 7 (mean 4) days after multiple doses; norfluoxetine has a t½β of 7 to 15 days. The clearance of fluoxetine is reduced and t½β increased in patients with hepatic impairment. In contrast, the pharmacokinetics of fluoxetine and norfluoxetine are not significantly altered in patients with renal failure. The t½β values of fluoxetine (40 mg/day for 43 days) and norfluoxetine were increased by 28 and 35%, respectively, in healthy elderly volunteers in a multiple-dose study. Fluoxetine inhibits CYP2D6, CYP2C and CYP3A4, which are involved in...