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A pooled analysis of the efficacy of sertraline in women, with a focus on those of childbearing age

Annals of General Psychiatry volume 23, Article number: 44 (2024) Cite this article

Abstract

Introduction

Gender- and age-specific research on medications is essential for personalizing treatment plans, optimizing dosing, minimizing adverse effects and improving outcomes. Women are twice as likely to be diagnosed with major depressive disorder (MDD), and it is commonly reported during their reproductive years. This post-hoc pooled analysis evaluated the efficacy of sertraline (one of the most studied medications in women) in women of reproductive age (18–44 years).

Methods

Data was pooled from nine clinical trials of sertraline that included 1832 subjects with MDD. The analysis set included 1097 women, 651 of those were of reproductive age. Sertraline was compared with placebo for changes in total HAM-D17 and CGI scores measured over time through MMRM analysis. The change from baseline to the end of study (-week 8) was assessed using ANCOVA.

Results

The changes from baseline in total HAM-D17 and CGI scores were significantly higher for sertraline than for placebo at the end of 8 weeks for all women (LS Mean difference, 95% CI: -1.81(-3.01,-0.62), P = 0.0029; -0.38(-0.55,-0.20), P < 0.0001, respectively). For women of reproductive age these changes (LS Mean difference, 95% CI: -2.08(-3.52,-0.64), P = 0.0047; -0.44(-0.66,-0.22), P < 0.0001, respectively), were significant from week 2 (HAM-D17) and week 1 (CGI) till the end of study.

Limitations

Only sertraline and placebo arms were included in the analysis. The dosing varied between studies, and the effect of dose was not addressed.

Conclusions

Sertraline is an effective option for treatment of MDD in women, including those in the childbearing age.

Introduction

The prevalence of mental disorders is increasing worldwide, as populations grow and more people reach the age at which depression typically manifests [1]. Major depressive disorder (MDD) is a common mental disorder affecting approximately 280–300 million people worldwide, ranking thirteenth among all age groups in 2019 [1,2,3]. Studies suggest that the prevalence of MDD varies between countries, generally being higher in Australasia, tropical Latin America, and high-income North America [2]. In Europe, there is variation between countries and within countries over time [4]. Regardless of geographic and temporal variance, women are about twice as likely as men to develop MDD in their lifetime [2, 5].

Epidemiologic studies report that the most common age of onset for MDD is early adulthood, although it can occur at any age [6]. The sex ratio and age of onset indicate that women are highly susceptible to developing MDD during their reproductive years [7] Throughout their reproductive years and during menopausal transitions, many women experience mood symptoms. These symptoms are well-documented to be influenced by hormonal changes associated with the menstrual cycle, pregnancy, postpartum period, and the stages of perimenopause and menopause. The diverse ways in which depressive disorders can present, along with the challenges in distinguishing between different diagnoses and comorbidities, often contribute to delays in diagnosis and treatment. It’s essential to consider the effects of reproductive stages and hormonal fluctuations when evaluating female patients [8]. In addition, MDD is found in up to 12.7% of pregnant women, potentially affecting both maternal and fetal health. As a result, clinical practice guidelines advocate targeted screening and prompt treatment of MDD in women during pregnancy [9]. Up to 25% of women with depression report that their symptoms began before pregnancy [10]. If a woman with depression becomes pregnant and her condition is not treated, it can result in preterm birth, low birth weight, small-for-gestational-age infants, stillbirth, and increased maternal complications such as perinatal issues, higher rates of operative deliveries, and postpartum depression [11]. Children of parents with depression are at increased risk for anxiety, disruptive behaviours, and depressive disorders [12]. To mitigate these risks, it is crucial to screen, monitor, and manage depression effectively, weighing the potential benefits and risks carefully [11].

To that end, this paper focuses on the importance of evaluating the efficacy and safety of medications based on gender and within specific age groups. We believe that gender- and age-specific research is essential for developing personalized treatment plans, optimizing dosing regimens, minimizing adverse effects, and ultimately improving patient outcomes. In fact, it ensures that both men and women, as well as individuals at different stages of life, receive the most effective and safe medical care tailored to their unique conditions.

For example, women are more susceptible to major depressive disorder (MDD) and experience different pharmacokinetics and pharmacodynamics due to hormonal changes during the reproductive years [13]. By focusing on women of childbearing age, we intend to provide an insight into how sertraline (one of the most studied medications in women of this age group) may treat MDD in this population.

Sertraline is a selective serotonin reuptake inhibitor (SSRI) indicated for MDD, as well as other psychiatric conditions such as social anxiety disorder (SAD), panic disorder (PD), obsessive-compulsive disorder (OCD), and post-traumatic stress disorder (PTSD) [14]. Sertraline is FDA-approved and recommended by various guidelines [15,16,17,18] as a first-line treatment for MDD [19]. Several studies have previously evaluated the safety and efficacy of sertraline in women, including those of reproductive age [20,21,22]. Sertraline is one of the most commonly prescribed antidepressants [14]. Even during pregnancy [8] and lactation [23], sertraline is considered one of the safest therapeutic options. This post-hoc pooled analysis aims to add to the existing body of evidence by evaluating the efficacy of sertraline specifically in women, with a focus on women of reproductive age (18–44 years).

Methods

Data set

Our analysis included women with MDD who were treated with either placebo or sertraline. Placebo-controlled, phase 2 or 3, company-sponsored studies in the short-term treatment of MDD conducted in North America or Europe were considered for inclusion. Data was not available in company records for studies conducted outside of North America and Europe, and were excluded. In all, 17 studies were identified for possible analysis. Of these, 7 studies were excluded as they did not have individual patient data required for the analysis; 1 study was excluded as it was a long-term study. Finally, 9 studies were considered for the analysis, details of which are shown in Table 1 (Supplementary Fig. 1). All nine included studies were short-term, randomized, double-blind (DB), and placebo-controlled (PC). Patients received 50–200 mg/day of sertraline in both fixed-dose (two studies) and dose-ranging (seven studies) trials. Six studies also had additional active comparator (AC) arms, which were excluded, and only the placebo and sertraline arms were included in this analysis. All subjects received once-daily medication. Treatment duration was eight weeks in six studies and six weeks in three studies, with the endpoint considered at week 8 for analysis.

Patients

Women with MDD (> 18 years of age) treated with placebo or sertraline (50–200 mg/day) were included. All included subjects met diagnostic criteria for MDD based on the DSM-III or DSM-III-R classification [24, 25]. Patients who were medically stable and had a primary diagnosis of MDD were selected for the study, and those with other primary diagnoses were excluded. The safety evaluation included all patients who received at least one dose of the double-blind treatment. Discontinuation rates and the most common treatment-emergent adverse events reported by at least 10% of patients in the sertraline group were considered for analysis and compared between the treatment groups.

Outcome measures

Efficacy was assessed using the Hamilton Depression (HAM-D17) and Clinical Global Impression (CGI) rating scales; the primary endpoint was the change from baseline in HAM-D17 and CGI scores at week 8. Seven studies included both HAM-D17 and CGI scores, while 1 study included either HAM-D17 or CGI scores alone. Rates of discontinuation and discontinuation due to adverse effects (AEs) were safety endpoints.

Statistical analysis

The full analysis set (FAS) consisted of all female patients (n = 1097) who received at least one dose of sertraline or placebo, while the women of reproductive age analysis set consisted of women aged 18–44 years with at least one efficacy measure (n = 651). The statistical analyses were conducted on individual patient data and not on summary statistics for each of the studies. Changes in efficacy variables (HAM-D17 and CGI scores) for both treatment and placebo groups were measured and plotted over time (baseline, weeks 1, 2, 3, 4, 5, 6, 7, and 8). A mixed-effects model for repeated measures (MMRM) was used to analyze the continuous efficacy variables over time (weeks 1, 2, 3, 4, 6, and 8) with terms for study, visit, treatment group, interaction between visit and treatment group, and baseline score as a covariate. Analysis of covariance (ANCOVA) was used to assess change from baseline at week 8, with last observation carried forward (LOCF) used to manage missing data. Week 8 was considered the end of the study period. Statistical significance was set at P < 0.05 two-sided. Full details are shown in Supplementary Table 1.

Table 1 Sertraline clinical studies considered for the pooled analysis
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Table 2 Demographic characteristics, all randomized patients/safety population
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Results

In this post-hoc pooled analysis of nine clinical trials of sertraline, we evaluated the change from baseline in total HAM-D17 and CGI scores.

Patients

The analysis set included 1832 adult participants from nine studies, of whom 1097 (59.8%) were women. In the pooled female subgroup, 92.5% were white with a mean (SD) age of 43.5 (14.88) years. The mean (SD) HAM-D17 total score at baseline was 23.8 (3.49) for all women and 23.6 (3.29) for women of reproductive age (18–44 years). The mean (SD) CGI total score at baseline for all women was 4.3 (0.59) and for women of reproductive age (18–44 years) was 4.3 (0.59). Demographic and baseline details of the placebo and sertraline groups are described in Table 2.

Efficacy

Women across all age groups

HAM-D17

The analysis set for all women included 947 subjects (placebo, 335; sertraline, 612) who had at least one efficacy measure in addition to baseline. Overall, the least squares mean (SE) change from baseline in the HAM-D17 total score, analyzed by ANCOVA, was significantly higher in female patients receiving sertraline than in those receiving placebo at the end of 8 weeks, with a least squares mean difference (95% CI) of -1.81 [-3.01, -0.62], p = 0.0029, Fig. 1A. MMRM analysis of the change from baseline in HAM-D17 score over time showed that a statistically significant separation between the placebo and sertraline groups began at week 2 (P = 0.0253) and remained significant through the end of week 8 (P = < 0.0001), Fig. 1B.

CGI

The analysis set for all women included 982 subjects (placebo, 390; sertraline, 592). Overall, the least squares mean (SE) change from baseline in the CGI total score, analyzed by ANCOVA, was significantly higher for female patients on sertraline than for those on placebo at the end of 8 weeks, with the least squares mean difference (95% CI) being − 0.38 [-0.55, -0.20], P < 0.0001, Fig. 1C. MMRM analysis of change from baseline in CGI scores over time showed that a statistically significant separation between the placebo and sertraline groups began at week 2 (P = 0.0051), and the separation remained significant through the end of week 8 (P = < 0.0001), Fig. 1D.

Women in reproductive age group (18–44 years)

HAM-D17

The analysis set for women of reproductive age (18–44 years) included 572 subjects (placebo, 213; sertraline, 359) who had at least one efficacy measure in addition to baseline. Overall, the least squares mean (SE) change from baseline in HAM-D17 total score analyzed by ANCOVA was significantly higher in the subset of female patients of reproductive age receiving sertraline than in those receiving placebo at the end of 8 weeks, with a least squares mean difference (95% CI) of -2.08 [-3.52, -0.64], p = 0.0047, Fig. 2A. MMRM analysis of the change from baseline in HAM-D17 scores over time showed that a statistically significant separation between the placebo and sertraline groups began at week 2 (P = 0.0010) and remained significant through the end of week 8 (P = 0.0011), Fig. 2B.

CGI

The analysis set for women of reproductive age-FAS (18–44 years) included 594 subjects (placebo, 237; sertraline, 357). Overall, the least squares mean (SE) change from baseline in the CGI total score was significantly higher in the subset of reproductive-age female patients receiving sertraline than in those receiving placebo at the end of 8 weeks, with a least squares mean difference (95% CI) of -0.44 [-0.66, -0.22], P < 0.0001, Fig. 2C. MMRM analysis of change from baseline in CGI scores over time showed that a statistically significant separation between the placebo and sertraline groups began at week 1 (P = 0.0486) and remained significant through the end of week 8 (P = 0.0011), Fig. 2D.

Safety

A total of 142/404 (35.2%) women in the placebo group and 265/693 (38.2%) women in the sertraline group discontinued the study. Discontinuation due to adverse events was reported in 16/404 (4%) in the placebo group and 115/693 (16.6%) in the sertraline group. Details of AEs in the overall cohort are shown in Table 3.

Fig. 1
figure 1

Least square mean (95% CI) changes from baseline HAM-D17 (1 A and 1B) and CGI (1 C and 1D) scores in women of all age groups. *P < 0.05, **P < 0.01, ***P < 0.0001 A) Least square mean (95% CI) change from baseline HAM-D17 score over time (MMRM analysis); 1B.) Least square mean (95% CI) change from baseline HAM-D17 score at the end of week 8 (ANCOVA analysis); 1 C.) Least square mean (95% CI) change from baseline CGI score over time (MMRM analysis); 1D.) Least square mean (95% CI) change from baseline CGI score at the end of week 8 (ANCOVA analysis). CI: confidence interval; HAM-D17: Hamilton Rating Scale for Depression; CGI: Clinical Global Impression; MMRM: Mixed Models for Repeated Measures; ANCOVA: Analysis of covariance.

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Fig. 2
figure 2

Least square mean (95% CI) changes from baseline HAM-D17(2 A and 2B) and CGI (2 C and 2D) scores in women of reproductive age (18–44 years). *P < 0.05, **P < 0.01, ***P < 0.0001. 2 A.) Least square mean (95% CI) change from baseline HAM-D17 score over time (MMRM analysis); 2B.) Least square mean (95% CI) change from baseline HAM-D17 score at the end of week 8 (ANCOVA analysis); 2 C.) Least square mean (95% CI) change from baseline CGI score over time (MMRM analysis); 2D.) Least square mean (95% CI) change from baseline CGI score at the end of week 8 (ANCOVA analysis). CI: confidence interval; HAM-D17: Hamilton Rating Scale for Depression; CGI: Clinical Global Impression; MMRM: Mixed Models for Repeated Measures; ANCOVA: Analysis of covariance

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Table 3 Most common (≥ 10% in sertraline group) treatment-emergent adverse events
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Discussion

Meta-analyses have shown that sertraline can be considered one of the safest antidepressants and the preferred first antidepressant for breastfeeding mothers. Infants generally have low or undetectable sertraline levels regardless of maternal dose [20,21,22].

In this analysis, HAM-D17 and CGI scores recorded at baseline and at the end of week 8 were compared using ANCOVA; the analysis showed that the magnitude of the reduction in HAM-D17 and CGI scores from baseline to week 8 was significantly greater in all women, as well as women in the reproductive age group treated with sertraline, than in those treated with placebo. HAM-D17 and CGI scores were recorded at baseline and each week. In women, a significant separation between the placebo and sertraline-treated groups began at week 2 for both HAM-D17 and CGI scores. Similarly, in women of reproductive age, a significant separation between the two groups started at week 2 for HAM-D17 score, and at week 1 for the CGI score. This significant reduction continued till the end of week 8 for all measures across both the groups.

A pharmacotherapeutic approach is recommended for patients with moderate to severe symptoms of MDD, especially if their ability to function and care for themselves is impaired [26]. Drug labels and dosing guidelines often overlook sex and physiological differences, despite the impact of sex steroid level variations on drug effects [13]. Physiological differences between the sexes have an impact on drug activity, both pharmacokinetic (lower body weight, slower gastrointestinal motility, reduced intestinal enzyme activity, and lower glomerular filtration rate in women compared to men) and pharmacodynamic (women have increased sensitivity to and greater efficacy of drugs such as SSRIs) elements. Women are also more likely than men to experience drug reactions [27]. The variations in sex steroid levels in women at different stages of life may have direct and indirect effects on the absorption, distribution, metabolism, and excretion of drugs. In addition, there is a paucity of scientific literature examining how circulating levels of sex steroids affect drug efficacy or the occurrence of adverse effects. Consequently, there is a critical need for studies that focus on women to gain a better understanding of the effects of sex hormones on pharmacological therapies [28].

A few studies have focused on the efficacy of different antidepressants in subgroups of women. Short-term studies have shown that the SSRI citalopram, as well as serotonin and norepinephrine reuptake inhibitors (SNRI) desvenlafaxine and duloxetine have antidepressant efficacy in women with MDD in both perimenopausal and postmenopausal subcategories [29,30,31,32,33]. A comparison of the efficacy of fluoxetine (SSRI) and venlafaxine (SNRI) in postmenopausal women with MDD showed that venlafaxine was well tolerated and resulted in greater improvement in MDD symptoms [34]. Results from a similar comparitive study between escitalopram (SSRI) and desvenlafaxine (SNRI) showed that escitalopram was more effective in the short-term treatment of depression, while both were equally safe and well tolerated in postmenopausal women [35]. Women of reproductive age (18–43 years) with depression have been shown to respond better to SSRIs (fluoxetine) than to norepinephrine tetracyclic antidepressants (maprotiline) [36].

SSRIs are the most commonly prescribed medications used for the treatment of depression [37]. Originator or generic formulations of sertraline are available globally including in low-income and lower-middle income countries [38,39,40]. Similar prescription patterns are seen even in women, including those in the reproductive age group; SSRIs are most commonly prescribed, followed by other antidepressants (such as venlafaxine and mirtazapine) and tricyclic antidepressants (such as amitriptyline and dosulepin) [41, 42]. The efficacy of sertraline has also been extensively studied in these populations [43]. Research conducted on South Asian populations has shown that sertraline was more efficacious than escitalopram in reducing depression [44].While this study does not include patients from low- and middle-income countries, the findings could still be relevant to these regions and could be a subject for future research.

During pregnancy, SNRIs and SSRIs are the most commonly prescribed antidepressants [45]. SSRIs, such as citalopram, escitalopram, paroxetine and fluoxetine, and duloxetine, an SNRI, are associated with maternal comorbidities and certain risks to the embryo [46,47,48,49]. In contrast, studies have demonstrated the efficacy of sertraline in these patients with relatively low associated risks [19, 48, 50].

Unlike tricyclic antidepressants, sertraline does not have anticholinergic effects. In particular, the advantages of sertraline extend to the avoidance of dose adjustments in elderly patients, unlike paroxetine and citalopram, and to superior cognitive function parameters compared with fluoxetine. In addition, its lower potential for drug-drug interactions is particularly important for elderly patients who are treated with multiple medications due to comorbidities [51]. Despite the modest efficacy advantage of sertraline over placebo in the treatment of MDD in older patients (over 60 years), sertraline is effective [52] and well tolerated [51].

Women in the reproductive age group, especially those with a history of depression, may experience a recurrence of the disorder during pregnancy and the postpartum period. Untreated depression may have serious consequences, including an increased risk of suicide, inadequate maternal and fetal nutrition, and unfavorable neonatal and obstetric outcomes, in addition to its effects on mother-child bonding [53]. Women with a history of depression, including depression during pregnancy, are at increased risk of developing postpartum depression [54], postpartum PTSD [55, 56], postpartum obsessive-compulsive disorder [57] and postpartum anxiety [58]. Therefore, prompt management of MDD is important in women of child-bearing age to prevent its associated comorbidities that may occur during the postpartum period.

Conclusion

This post-hoc pooled analysis examined the efficacy of sertraline in women of reproductive age across the spectrum of MDD severity and confirmed its status as an effective antidepressant in this population. More studies are needed for each of the different medications commonly prescribed to patients with MDD to evaluate better the efficacy and safety of these medications in people of different sexes and ages.

Limitations

This analysis is constrained by several factors. First, the number of trials that met the inclusion criteria was relatively small. Additionally, the trials included in the analysis featured multiple treatment arms, meaning they did not exclusively compare sertraline to a placebo. Variations in dosage design across the trials were not examined in this analysis, which means the impact of different dosages on the results was not considered. Furthermore, the baseline characteristics analyzed were restricted to those available in the database; other potentially relevant baseline characteristics were not included and may have influenced the outcomes. Lastly, the generalizability of the findings might be limited, as the studies included in this analysis were exclusively from North America and Europe.

Data availability

The data that support the findings of this study are not openly available due to reasons of sensitivity and are available from the corresponding author upon reasonable request.

Abbreviations

AC:

Active Comparator

AEs:

Adverse Effects

ANCOVA:

Analysis of Covariance

BMI:

Body Mass Index

CGI:

Clinical Global Impression

CI:

Confidence Interval

DB:

Double-Blind

DSM-III:

Diagnostic and Statistical Manual of Mental Disorders-III

DSM-III-R:

Diagnostic and Statistical Manual of Mental Disorders-III-Revised

et. al:

‘et alia’’ or ‘and others’

FAS:

Full Analysis Set

FDA:

Food and Drug Administration

HAM-D17:

Hamilton Rating Scale for Depression

LOCF:

Last Observation Carried Forward

MDD:

Major Depressive Disorder

MMRM:

Mixed Models for Repeated Measures

OCD:

Obsessive-Compulsive Disorder

PC:

Placebo-Controlled

PD:

Panic Disorder

PTSD:

Post-Traumatic Stress Disorder

SAD:

Social Anxiety Disorder

SD:

Standard Deviation

SE:

Standard Error

SNRI:

Serotonin and Norepinephrine Reuptake Inhibitors

SSRI:

Selective Serotonin Reuptake Inhibitor

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Acknowledgements

Medical writing and editorial support was provided by Pramod Mallikarjuna, Viatris Inc.

Funding

This manuscript has been supported by Viatris.

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Authors and Affiliations

  1. Department of Molecular Medicine, University of Siena School of Medicine, Siena, Italy

    Andrea Fagiolini

  2. Department of Psychiatry, University of the East Ramon Magsaysay Memorial Medical Centre, Quezon City, Philippines

    Melissa Paulita Mariano

  3. Biometrics, Viatris Inc, Amstelveen, Netherlands

    Egbert Biesheuvel

  4. Global Medical Affairs, Viatris Inc, Bangalore, India

    Pradeep Purushottamahanti

Authors
  1. Andrea Fagiolini
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  2. Melissa Paulita Mariano
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  3. Egbert Biesheuvel
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Contributions

A.F.: Validation, Writing - review & editing. M.P.M.: Validation, Writing - review & editing. E.B.: Data curation and Formal analysis, Methodology, Writing – review and editing. P.P.: Conceptualization, Methodology, Writing – review and editing.

Corresponding author

Correspondence to Andrea Fagiolini.

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Ethics approval

Primary data from research on human or animal subjects were not used in the analyses for this paper. Secondary, deidentified and anonymized data from previously conducted clinical trials were utilized in this paper. Hence ethics approval has been deemed not required. Not all studies have been previously published. This post-hoc pooled analysis considered data from other clinical studies, therefore ethical considerations, including the Helsinki declaration on ethical considerations are not applicable.

Competing interests

Andrea Fagiolini has received research grants and/or a paid consultant and/or a paid speaker of Angelini, Boehringer Ingelheim, Janssen, Biogen, Lundbeck, Mylan, Neuraxpharm, Otsuka, Pfizer, Recordati, Rovi, Sanofi Aventis, Viatris, Apsen, Glaxo Smith Kline, and Vifor. Melissa P Mariano is a paid consultant and/or a paid speaker of Johnson & Johnson, Otsuka Pharmaceutical, Viatris, and H. Lundbeck. Egbert Biesheuvel is a shareholder and an employee of Viatris, and a former employee of MSD. Pradeep Purushottamahanti is an employee of Viatris.

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Fagiolini, A., Mariano, M.P., Biesheuvel, E. et al. A pooled analysis of the efficacy of sertraline in women, with a focus on those of childbearing age. Ann Gen Psychiatry 23, 44 (2024). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12991-024-00519-9

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Keywords

Annals of General Psychiatry

ISSN: 1744-859X