Fluoxetine

Additional information

Depression is almost twice as common in women as in men [1]. Women have an earlier age of onset and increased duration of depressive episodes. Differences in neurobiology [2, 3], hormones, inflammatory markers, diagnostic tools, or health seeking behavior [4, 5] may be of importance.  Although depression is more prevalent in women, most preclinical studies on depression have used  male animals [2].

Women are two to three times more likely to suffer from an anxiety disorder [1]. Sex differences in symptomatology and comorbidity  may be due to genetic, hormonal, neurodevelopmental, environmental, and neurobiological factors [6].

Pharmacokinetics and dosing

Studies on differences between healthy adult men and women in fluoxetine pharmacokinetics have not been published. A small study of  elderly individuals (65-85 years; 11 men, 14 women) did not detect any  sex differences  in plasma concentrations, half-life or clearance of fluoxetine. However, women had 17% higher levels and slower elimination of  the active metabolite norfluoxetine [7].

In a study in children and adolescents diagnosed with major depressive disorder, obsessive-compulsive disorder, or generalized anxiety disorder (24 boys, 50 girls; ages 10-17 years), mean doses and mean serum concentrations were higher in girls than boys (week 8: 26.6 vs. 18.5 mg/day; 111.4 vs. 61.7 ng/ml). Sex differences could also be detected at week 12 [8]. However, other studies in children and adolescents using mean doses of 20 mg/day did  not demonstrate sex differences in serum concentrations of fluoxetine and its  active metabolite norfluoxetine [9, 10].

Effects

Major depressive disorder

Studies analyzing sex differences in fluoxetine response report are not consistent. Some studies show higher recurrence rates in fluoxetine-treated women than men [11,12], while other studies show no differences in improvement or recurrence [13-16]. It should be noted that most studies have a short study period and thus the clinically relevance of the results may not be relevant for the long term effect.An open-label 12-week study (266 men, 574 women) found no age- or sex differences in fluoxetine response (20 mg/day) [13,14]. In an cohort study in outpatients receiving fluoxetine 20 mg/day for 8 weeks (153 men, 176 women), rates of remission and reduction of depressive symptoms were similar in men and women and across ages [15]. Fluoxetine 20 mg/day was compared to maprotiline 100-200 mg/day in adult patients with severe unipolar depression in a 6-week randomized trial (in total 42 men, 59 women; on fluoxetine 23 men, 24 women). Men and women taking fluoxetine had equal improvement [16].Long-term studies show higher recurrence rates in women. In a post-hoc analysis of the PREVENT trial (105 men, 161 women on fluoxetine) the recurrence rates during a 12-month maintenance phase (28 men, 51 women on fluoxetine) were approximately 50% in women and 15% in men. However, during another 12 months after the maintenance phase, the recurrence rates were similar for men and women (20 men, 25 women on fluoxetine) [11]. It has to be kept in mind that the statistical power to detect any differences in the second part of this trial might have been too low to draw any conclusion.  Also, a RCT (260 men, 310 women) showed that women were more likely to relapse during the 6-month continuation and 6-month maintenance phases (hazard ratio 1.84) [12].No overall sex differences in SSRI (citalopram, escitalopram, fluoxetin) treatment response were found in a clinical study (59 men, 242 women), but menopausal women had worse outcome that non-menopausal women (95 menopausal women, 147 non-menopausal women) [17].Adolescents randomized to fluoxetine, cognitive behavior therapy, a combination of those or placebo were followed up for 63 months (in total 86 boys, 110 girls; on fluoxetine 48). Recurrence rates were 57% among girls and 33% among boys [18]. Similarly, a small study in children (65 boys, 37 girls, 7-18 years old) reported a higher odds of relapse in girls in the continuation phase (OR 8.86, 95%CI 1.83-42.78) [19]. However, the two studies used different score levels for definition of relapse on the CDRS-R (Children’s Depression Rating Scale). Contrary, the pharmaceutical company report that subgroup analyses did not show any differences in response between boys and girls or between age groups [20].

Obsessive Compulsive Disorder

According to the pharmaceutical company, subgroup analyses on outcome did not show any differences in response between boys and girls, men and women or between age groups [20].

Adverse effects

Data from the UK General Practice Research Database (GPRD) was used to analyze the risk of fatal overdose with SSRI (41 327 men, 93 669 women on fluoxetine). The prevalence of suicidal behavior in patients taking fluoxetine was higher in men than women (0.5% vs. 0.3%) [21].

Reproductive health issues

Sexual dysfunction is common in men and women on SSRI treatment and can affect all phases of the sexual response cycle. It is often underestimated since patients tend to underreport sexual adverse effects if not directly questioned [22, 23]. A meta-analysis consisting of 31 studies (in total 268 men and 801 women on fluoxetine) evaluating sexual dysfunction induced by antidepressants (citalopram, fluoxetine, paroxetine, sertraline, venlafaxine) showed that men treated with fluoxetine had higher odds of having desire dysfunction (OR 2.95) and orgasm dysfunction (OR 6.00) as compared to women [22]. Regarding teratogenic aspects, please consult the Drugs and Birth Defects Database (in Swedish, Janusmed fosterpåverkan).

Other information

Drug utilization of ten commonly prescribed antidepressants during the period 2009-2014 in Sweden, Denmark, Germany, and Spain were analyzed in a large register study (in total 4 833 774 initiators included). Women comprised the majority of initiators for all antidepressants studied. In Sweden, 73.5% of the initiators on fluoxetine were women [24].