Sertraline

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. The mechanisms behind these sex differences may be due to several factors such as differences in neurobiology [2, 3], inflammatory markers, diagnostic tools, or health seeking behavior [4, 5]. Although depression is more prevalent in women, most basic research studies on depression have been focusing on males [2]. However, there are reports of sex differences in response to antidepressant treatment, although no clear consensus exist [3].

Women are two to three times more likely to suffer from an anxiety disorder [1]. Sex differences in symptomology and comorbidity have been reported. These sex differences may be due to several factors such as genetic, neurodevelopmental, environmental, and neurobiological [6].

Pharmacokinetics and dosing

In a study in healthy volunteers (22 men, 22 women), sertraline was titrated from 50 mg daily during 9 days to 200 mg daily for 21 days. The terminal elimination half-life was shorter in young men (18–45 years), (22.4 hours) than in young women, older men, and older women (32.1–36.7 hours). The Cmax, AUC24 and mean trough concentrations of sertraline were 21%, 25% and 33% lower in young men compared to the other groups. For the metabolite N-desmethylsertraline (DSERT) the trough plasma concentrations, Cmax and AUC24 were also lower in young men compared with the other groups [7].

This is in contrast to another study (31 men, 61 women), where the dose-concentration correlation for sertraline and DSERT was approximately 30% higher for women than for men after 12 weeks of treatment (50–150 mg daily). No sex differences in the absolute concentrations for sertraline or DSERT were observed [8]. In a bioavailability study, 100 mg sertraline was given to 24 healthy volunteers (13 men, 11 women). Women had higher Cmax values than men, but the sex difference disappeared when taking the distribution volume into consideration [9]. Differentiation of dosing regimen by patient’s sex is not recommended by the manufacturer [10].

Effects

Depression

Studies analyzing sex differences in sertraline response report contradictory results. Some studies show better effect of sertraline in women than in men [11-13], while other studies show no sex difference [14-16]. The majority of the studies have assessed symptoms according to the HAM-D scale but other scales, such as HAM-A, CGI, and PHQ-9, have also been used.

Treatment response of sertraline has been examined in patients with chronic depression in a 12-week RCT (162 men, 264 women). Women responded better to sertraline treatment than men and premenopausal women responded better than postmenopausal women, suggesting that female sex hormones may enhance treatment response [11]. Also, in another study (59 men, 242 women), menopause was shown to be related to worse treatment response of SSRI in depression compared to non-menopausal women, although no overall sex differences in SSRI treatment response were shown [16]. In contrast, one study showed that acute worsening of chronic depression was more frequent in premenopausal women than in postmenopausal women, and men treated with either sertraline or imipramine (229 men, 267 premenopausal women, 58 postmenopausal women) (8.6%, 4.5% and 5.9%, respectively) [12]. A retrospective cohort analysis of Japanese patients with major depressive disorders treated with sertraline (36 men, 46 women) showed that women were more likely to respond to sertraline treatment than men (74% vs. 44%) [13].

For the treatment of non-melancholic depressive disorder, no sex differences in response to sertraline have been reported, although women responded better to sertraline than imipramine (50 men, 184 women) [14]. No sex differences in sertraline response for treatment of depression were observed in a large German study (1594 men, 3858 women) throughout a 6-month period [15]. According to the original manufacturer of sertraline, no differences between men and women has been recorded in the treatment response of major depressive disorders [10, 17].

Anxiety disorders

Pooled data from four studies (in total 335 men, 338 women), showed a greater improvement of sertraline on panic frequency and Clinical Global Impression-Improvement scale (CGI-I) in women [18]. However, according to the original manufacturer of sertraline, no differences between men and women have been recorded in the treatment response of panic disorders or social anxiety disorders [17]. Efficacy of sertraline in patients with generalized anxiety disorder was similar in men and women in a 12-week RCT trial (167 men, 203 women) [19].

Posttraumatic Stress Disorder (PTSD)

Two RCT trials evaluating the efficacy of sertraline in treatment of PTSD were conducted by the original manufacturer. Post hoc analyses (94 men, 291 women) showed that sertraline-treated women had significant improvements in all efficacy measures compared to placebo-treated women. No significant differences in efficacy measures were shown for  men. Since the two studies included a low number of men (24%), there is insufficient evidence to draw any conclusions about the effect in men [17, 20].

However, pooled data from two studies on PTSD in the general population (184 men, 430 women) found similar response rates in men and women compared to placebo (women 57.2% vs 34.%, men: 53.9% vs 38.2%). Risk factors correlated with decreased effect (such as more substance abuse, longer duration of PTSD, and source of trauma) were more common among men [10].

Alcohol dependence

In a 14-week RCT (52 men, 48 women) men, but not women, with type A alcohol dependence showed an improvement with sertraline treatment [21]. In Sweden, sertraline is not indicated for treatment of alcohol dependence.

Adverse effects

No sex differences in adverse events have been found in pooled data from four RCTs in panic disorder (in total 335 men, 338 women) [18] or in a large observational study (1594 men, 3858 women) [15].

In a study where treatment response after 12 weeks of sertraline treatment was examined in patients with chronic depression (162 men, 264 women), there were no sex difference in overall frequency of adverse events or severe adverse events. However, statistically significant sex differences for some types of adverse events with >10% frequency were shown; women were more likely to report nausea and dizziness, whereas men were more likely to report dyspepsia, sexual dysfunction and urinary frequency [11].

Reproductive health issues

Plasma concentrations of sertraline varies during pregnancy. Furthermore, plasma sertraline concentrations can vary between individuals, probably due to genetic differences in drug metabolic capacity. Therefore, therapeutic drug monitoring of sertraline concentrations during pregnancy and postpartum is recommended [22]. Regarding teratogenic aspects, please consult Janusmed Drugs and Birth Defects (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, 63.6% of the initiators on sertraline were women [23].