CNS Drugs

, Volume 14, Issue 4, pp 301–328


A Review of its Use in Women’s Health
Adis Drug Evaluation



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.

Pharmacodynamic Properties

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.

Pharmacokinetic Properties

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 (t1/2β) [up to 7 days after multiple doses for fluoxetine and up to 15 for norfluoxetine]. Hepatic impairment significantly reduces fluoxetine clearance and prolongs the t1/2β.

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 t1/2β of fluoxetine and norfluoxetine, drug interactions may occur some weeks after discontinuation of the drug.

Therapeutic Efficacy

Depression: Retrospective analysis of pooled data from 11 randomised, double-blind trials demonstrated similar overall antidepressive efficacy (≈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 counselling in a 12-week randomised, double-blind trial (n = 87); however, differences versus placebo did not appear to be statistically significant.

Premenstrual Disorders: Several randomised, double-blind, comparative trials have demonstrated that fluoxetine 20 mg/day is effective in the treatment of premenstrual dysphoric disorder (PMDD)/late luteal phase dysphoric disorder (LLPDD). Response rates (defined by various criteria) ranged from 41 to 100% for fluoxetine compared with 0 to 43% for placebo. Fluoxetine was more effective than the non-serotonergic antidepressant amfebutamone (bupropion) in a small randomised, double-blind trial (n = 34). Response rates were similar with fluoxetine administered in a continuous dosing regimen and an intermittent regimen (for 14 days premenstrually) according to a nonrandomised case-control analysis.

Eating Disorders: Fluoxetine monotherapy significantly reduced vomiting and binge-eating in patients with bulimia nervosa in 2 randomised, double-blind studies. Median reductions from baseline with fluoxetine 20 or 60 mg/day were 2.4- to 11.2-fold greater (vomiting) and 1.4- to 2.8-fold greater (binge-eating) than those with placebo. Fluoxetine 60 mg/day was significantly more effective than either placebo (p < 0.001) or fluoxetine 20 mg/day (p < 0.02) in reducing the frequency of vomiting and binge-eating. Long term treatment (up to 52 weeks) with fluoxetine was associated with a significantly lower relapse rate than placebo in a randomised trial in 150 patients. Fluoxetine was effective for patients with bulimia nervosa who had previously failed to respond to or had relapsed after psychotherapy in a small double-blind placebo-controlled trial (n = 22). Studies of fluoxetine in combination with psychological therapy or nutritional counselling have failed to provide clear evidence of any benefit for the combination approach.

Fluoxetine (dosage not reported) was significantly more effective than placebo or cognitive-behavioural therapy in preventing relapse after initial weight restoration in patients with anorexia nervosa, according to preliminary data from 2 randomised double-blind trials (n = 35 and 90). However, fluoxetine (target dosage 60 mg/day) provided no additional benefits to supportive/psychological therapy in a placebo-controlled trial of primary treatment (n = 47).


The tolerability profile of fluoxetine has been well characterised; in general, the most common adverse events are GI dysfunction and CNS-related effects (e.g. anxiety, insomnia, nervousness, somnolence). Although withdrawal reactions, including dizziness, nervousness and anxiety, have been reported after discontinuation of treatment with selective serotonin reuptake inhibitors, the relatively long t1/2β of fluoxetine means that such effects are less common than with paroxetine or sertraline.

Shortening or lengthening of the menstrual cycle during treatment with fluoxetine may occur in some women and appears to be dose related. In common with other antidepressants, fluoxetine may induce non-puerperal lactation in certain susceptible patients. Fluoxetine recipients may experience reduced appetite (anorexia) and modest but transient weight loss.

Data from a number of prospective cohort studies indicate that the rate of major fetal malformations for infants from pregnancies exposed to fluoxetine in the first trimester did not differ significantly from that in control groups or the general population. Meta-analysis of prospective data on first-trimester fluoxetine exposure revealed a weighted risk for major malformations of 2.6%, compared with a cited risk range of 1 to 3% for the general population. According to the manufacturer’s Worldwide fluoxetine pregnancy register, 3.5% of 658 infants from pregnancies with confirmed first-trimester fluoxetine exposure had major malformations, compared with 4% for the general population. Minor fetal malformation occurred in only 0.2% of infants, although a prospective cohort study showed that the incidence of infants with 3 or more minor malformations was significantly higher for infants exposed to fluoxetine in the first trimester (n = 97) than for non-exposed controls (n = 153) [15.5 vs 6.5%, p = 0.03]. In the same analysis, late-exposed infants were significantly more likely than early-exposed or control infants to be born prematurely, to be admitted to a special-care nursery or to have poor neonatal adaptation (p ≤ 0.03). In addition, third-trimester exposure was associated with significantly reduced birthweight and length (p ≤ 0.04).

Data on the use of fluoxetine during breastfeeding are limited. Two published reviews of the literature (with some overlap in data sources) indicate that clinical complications [colic, irritability, seizure-like episodes (n = 1 each) were seen in a small number of infants, but the majority (29 of 30 and 16 of 19) had no significant events. One retrospective analysis has suggested that use of fluoxetine during breastfeeding may be associated with reduced infant growth, although this finding requires confirmation and its clinical significance remains unclear.

Dosage and Administration

An initial fluoxetine dosage of 20 mg/day (up to a maximum of 80 mg/day), administered orally in the morning, is recommended for patients with major depression.

Clinical trials of fluoxetine for the treatment of PMDD/LLPDD have shown an oral dosage of 20 mg/day to be effective, and the drug has recently been approved for PMDD in the US.

Fluoxetine is indicated for the treatment of moderate to severe bulimia nervosa at a dosage of 60 mg/day. For some patients (e.g. those with low bodyweight) it may be advisable to titrate up to this target dose over several days.

A reduced dosage should be used in patients with hepatic impairment, the elderly and patients with concurrent disease or receiving multiple concomitant medications. Dosage adjustment is not normally required in patients who are renally impaired.

Fluoxetine should only be used during pregnancy, labour or delivery if the potential benefit justifies the potential risk to the fetus. Breastfeeding during fluoxetine treatment is not recommended as the drug is excreted in human milk.

Copyright information

© Adis International Limited 2000

Authors and Affiliations

  1. 1.Adis International LimitedMairangi Bay, Auckland 10New Zealand

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