The current report details the first large-scale study to use patients with depression from both primary and specialty care clinics to study sex differences in response to antidepressant treatment with an SSRI, citalopram. This finding was observed on the HRSD17, our a priori specified primary outcome using independent blind research outcome assessors to rate depression symptoms, and persisted after adjustment for baseline differences. The QIDS-SR16 findings were similar but were not significant before or after adjustment. Our findings indicate that women have a better response than men to antidepressant treatment with citalopram. Unlike some other studies, we did not observe a sex difference in frequency, intensity or burden of side effects. This suggests that side effect burden was not a reason for the lower response rate in men. Maximum citalopram dose and dose of citalopram at exit did not significantly differ by sex, which suggests that inadequate dose of citalopram was not an explanation for sex differences in remission. Further, the lower remission rate in men was not due to a difference in time on medication, since 71.7% of men and 72.0% of women had at least eight weeks of treatment with citalopram. The elimination of these potential explanations for the sex differences found in this study increases the likelihood that the explanation is a differential biological response to citalopram in women.
This study has several significant strengths not possessed by previous studies, including a large sample size, the use of well standardized independent raters (ROAs) to judge endpoints for remission, the inclusion of only outpatients who met criteria for unipolar major depression, the inclusion of patients with concurrent Axis I and III disorders or suicidality (not requiring inpatient treatment), and the examination of both response and remission. The only prior study addressing depression that used a general patient population observed no sex differences in response to sertraline (Thiels et al, 2005
). In that study, measurements of depressive symptoms were taken relatively infrequently (baseline, 2 weeks, 1, 3 and 6 months), the study used a depression rating scale unique to the study, raters were not standardized and there was no documentation that participants had major depression. The clinical diagnosis of depressive episode by ICD-10 was made for only 64% of men and 66% of women. Unlike the STAR*D study, in the Thiels et al study women were significantly older then men and had an older age of onset (onset age of 48.2 years in women and 47.1 years in men). Additional differences between the Thiels et al study depressed population and the STAR*D population include the average episode length of three months vs. eight months in STAR*D and only 30% recurrent vs 75% recurrent in the STAR*D population. The Thiels et al study did not use algorithm-based treatment guidelines and thus final mean doses of sertraline were extremely low and sub therapeutic on most patients (average dose =45.5 mg for men and 46.5 mg for women). Despite the low dose of sertraline, the response rate based on the Clinical Global Impression scale was quite high in the Thiels et al study, with 85.5% of participants judged to be responders after one month of treatment. In contrast, the low overall response (46.9%) and remission rates (HRSD17
: 27.5%, QIDS-SR16
: 32.9%) in our sample, the high prevalence of recurrent depression (75%) and the median current episode length of eight months suggest that our participants were more depressed and treatment resistant than those in the Thiels et al study. Thus, the finding of a sex difference in response to citalopram, with a 33% greater likelihood of remission in women than men, has meaning for everyday clinical practice for treatment of major depression.
Although our study sample included a subset of the originally enrolled STAR*D sample (2876 of 4041), the baseline sex differences found were generally similar to those found in our report on the first 1500 participants enrolled (Marcus et al, 2005
) and in our follow-up report on the remaining 2541 participants (Marcus et al, in press
). Of note are the similar findings in women of greater baseline severity of depression by both clinician rating and self rating, younger age of MDD onset, and greater likelihood of past suicide attempt(s). This suggests that the subsample of participants who continued in treatment were representative of the original participants who enrolled seeking treatment for depression, and thus were representative of treatment-seeking patients with depression seen in typical clinical practice.
Our findings are opposite to those of older studies with TCAs, particularly imipramine, which frequently found a better response in men to these predominantly noradrenergic reuptake inhibitors. The sex differences in response to citalopram, an antidepressant that acts predominantly on serotonergic systems, may be related to differences in the biology of men and women, particularly with respect to the role of estrogen on serotonergic systems. Since our study did not address mechanisms by which men and women may differ in responsiveness to citalopram, we can only summarize possible differences that may account for this differential response. Studies in non-human primates (reviewed in Bethea et al, 2002
) have confirmed that estrogen 1) increases tryptophan hydroxylase, the rate-limiting step in serotonin synthesis 2) decreases 5HT1a autoreceptor binding, which would serve to increase serotonin levels at the synapse and 3) modulates the serotonin transporter, which leads to increased transporter expression in the hypothalamus (Bethea et al, 2002
). Furthermore, it is possible that organizational effects of estrogen on the brains of females occurring in utero and post-natally may contribute to changes in serotonin receptors to make women differentially sensitive to SSRIs. Finally the whole context of childhood and adolescent development differs between men and women, so additional cognitive and psychological factors may also contribute to the differential responsiveness to SSRIs in women.
Study limitations include the use of a single agent only (citalopram), the lack of a placebo control, and open-label treatment. Thus it is unclear if the greater responsiveness in women can be entirely ascribed to citalopram. However, a report by Casper et al. (2001)
found no sex differences in depressed patients regarding response to placebo, which suggests that our finding of sex differences for citalopram might be specific to the drug or the drug class. Other limitations include the failure to measure medication adherence as well as the failure to measure concomitant non-depressive psychotherapy (e.g., couples therapy, group therapy, psychodynamic psychotherapy), although psychotherapies with documented efficacy for depression were excluded. Furthermore, psychotherapies that were permitted were those ongoing at the time of referral to the study, so it is unlikely that psychotherapy per se could explain the outcomes in the study. While differential attrition could influence the results, we did not observe sex differences in attrition (Warden et al, 2007
). The study also included a number of patients with psychiatric diagnoses in addition to major depression, which may have influence outcome, particularly comorbid anxiety disorders which were more frequent in women. However, individuals with comorbid anxiety disorders demonstrated a poorer response to citalopram than those without anxiety disorders (Fava et al, 2008
). Furthermore, the increased frequency of anxiety disorders was controlled for in the adjusted analysis.
In conclusion, this large multi-site study of outpatients with nonpsychotic MDD in both primary and specialty care found that women were more likely to achieve remission than men in response to citalopram. These differences occurred despite a greater baseline severity of depression in women and no sex differences in side effect frequency, intensity or burden. Sex differences in response to citalopram could not be accounted for by differences in dose of citalopram or number of treatment visits. Differences in time in treatment were not clinically important either. Such findings suggest that the greater response to SSRIs in women may be due to sex-specific biological differences.