Fluoxetine - A review of its use in women's health

The selective serotonin reuptake inhibitor (SSRI) fluoxetine has been investigated for a range of conditions of particular relevance to women. The efficacy of fluoxetine in major depression is well known, but data specific to women are limited. A large retrospective analysis of pooled trial data showed similar efficacy for fluoxetine and tricyclic antidepressants (TCAs) in women. Fluoxetine is the most widely evaluated SSRI regarding use during pregnancy. No significant association has been demonstrated between first-trimester exposure and major fetal malformations. Further data on third-trimester exposure, and on long term developmental outcomes in general, would be beneficial. Fluoxetine showed quantitative benefits over placebo in 1 well controlled trial in postpartum depression, but the difference did not appear to be statistically significant. Data on use during breastfeeding are very limited; most infants had no adverse complications but further data would be beneficial. Fluoxetine, like other SSRIs, has shown efficacy in well controlled trials in women with premenstrual dysphoric disorder (PMDD)/late luteal phase dysphoric disorder. Efficacy in reducing binge-eating and vomiting was demonstrated in 2 randomised double-blind trials in bulimia nervosa. Fluoxetine may be effective in preventing relapse, and in patients failing to respond to, or relapsing after, psychotherapy, although data are limited. No clear advantage was seen for combining fluoxetine with psychological therapy or nutritional counselling in well controlled trials. Fluoxetine was no more effective than placebo when used in addition to supportive/psychological therapy in a single well controlled trial in patients with anorexia nervosa. However, it was more effective than placebo or cognitive-behavioural therapy in preventing relapse after initial weight restoration in 2 randomised double-blind trials. Conclusions: Fluoxetine is an effective treatment for women with general depression, and appears to be a reasonable choice of antidepressant for women of childbearing age. Available data show no association between first-trimester fluoxetine exposure and major fetal malformations. Fluoxetine is an effective treatment for PMDD and is the first drug approved for this condition in the US. Like a number of other antidepressants, it has been used successfully for bulimia nervosa, although comparisons with other agents are not available. Fluoxetine does not appear to be effective in the initial treatment of anorexia nervosa, but may be useful in preventing relapse. Fluoxetine therefore offers a well studied and effective option for many conditions which are particularly relevant to women. Fluoxetine and norfluoxetine (its active metabolite) selectively inhibit neuronal serotonin reuptake in vitro and in vivo, thereby enhancing serotonergic neurotransmission. Serotonin has been implicated, to varying degrees, in the aetiology of depression, premenstrual disorders and eating disorders. Therapeutic effects in patients with eating disorders may be related to drug effects on serotonin in relation to psychiatric comorbidity (depression, anxiety, obsessive-compulsive disorder). Fluoxetine significantly reduced food intake and resting energy expenditure in volunteers, effects which may contribute to weight loss (see Tolerability). It does not appear to have significant effects on cognitive or psychomotor performance, or haemostatic function. Fluoxetine is well absorbed after oral administration. Peak plasma concentrations after a single 30 or 40mg dose were reached within 8 hours. Steady-state plasma concentrations are reached after 2 to 4 weeks' treatment and remained consistent for up to 3 years. The volume of distribution of fluoxetine is high, due to extensive tissue distribution and high plasma protein binding. Fluoxetine undergoes extensive first-pass metabolism in the liver to the primary active metabolite norfluoxetine. Both fluoxetine and norfluoxetine have relatively long elimination half-lives (t1/2 beta) [up to 7 days after multiple doses for fluoxetine and up to 15 for norfluoxetine]. Hepatic impairment significantly reduces fluoxetine clearance and prolongs the t1/2 beta. Fluoxetine is excreted in human breast milk. It has been estimated that breastfed infants receive between 3 and 10.8% of the maternal fluoxetine dose. The drug may accumulate in infants. A range of isozymes involved in the metabolism of a variety of drugs [including tricyclic antidepressants (TCAs), some antiarrhythmics, antipsychotics and benzodiazepines] are inhibited by both fluoxetine and norfluoxetine. Because of the long t1/2 beta of fluoxetine and norfluoxetine, drug interactions may occur some weeks after discontinuation of the drug. Depression: Retrospective analysis of pooled data from 11 randomised, double-blind trials demonstrated similar overall antidepressive efficacy (approximate to 40% improvement from baseline on the Hamilton Rating Scale for Depression at 5 weeks) for fluoxetine and TCAs in women with major depression (n = 850). Fluoxetine (dosage not reported) produced greater improvements from baseline than placebo in women with mild postpartum depression who also received cognitive-behavioural value because of their small size and/or poor design (e.g. case-control comparisons) [section 4.3.2], Preliminary data from 2 randomised double-blind trials suggest that fluoxetine may be useful in preventing relapse tone study showed it to be more effective than psychological therapy) after weight restoration.