Results
This is the first multicenter, randomized, controlled trial that evaluated the efficacy of fluoxetine vs. venlafaxine in women with postmenopausal MDD. The symptoms of depression significantly improved in both groups; however, venlafaxine was superior to fluoxetine in controlling depression symptoms. Our results showed that menopause affected SSRI’s antidepressant effect, which is consistent with other studies comparing the effect of SNRIs and SSRIs in menopausal depression [
11]. SNRIs may have a consistent antidepressant effect in women across different ages and menopausal staging. In their study on sleep-related issues, Davari-Tanha et al suggested that venlafaxine is more efficacious than citalopram in the treatment of depression in postmenopausal women [
21]. The results from the present study confirm and extend these findings. On the other hand, Soares et al found no significant differences in the efficacy of SNRIs and SSRIs in their study on the treatment of postmenopausal women with MDD [
22]. The main reason for these inconsistencies might be the high doses of desvenlafaxine (100–200 mg/d) that did not necessarily confer a greater magnitude of efficacy but were associated with greater TEAEs. By contrast, the doses in our study, which were prescribed according to the physicians’ decision, all fell within the recommended doses, i.e., 75–225 mg/d for venlafaxine and 20–60 mg/d for fluoxetine.
There are other possible explanations for the differences in drug efficiency. First, the pharmacological profiles of the drugs could explain the clinical differences between them. Venlafaxine is an antidepressant with a mechanism of action that is believed to involve the inhibition of the uptake pumps for 5-HT and NE with inhibition of NE uptake, which is particularly relevant at high doses [
23]. Fluoxetine is an antidepressant of the SSRI class [
24] that mainly inhibits 5-HT. Second, estrogens decline in postmenopausal women [
25], and augments the response to SSRIs in female patients with MDD [
26,
27]. Animal studies support the notion that estrogens increase serotonergic activity, which could explain why postmenopausal patients have a poor response to SSRIs. Estrogen can increase 5-HT by decreasing the expression of monoamine oxidases-A (MAO-A) activity, the enzymes responsible for the degradation of 5-HT [
28,
29]. Estrogens increase the activity of tryptophan hydroxylase, the rate-limiting enzyme involved in the synthesis of 5-HT, resulting in an increase in overall 5-HT availability [
30,
31]. Estrogens also decrease the serotonin reuptake transporter; this transporter, located presynaptically, is very important in the elimination pathway of 5-HT from the synaptic cleft [
32]. Taken together, these points could explain why menopausal depressed women were less responsive to SSRIs.
In the present study, the venlafaxine-treated group displayed a statistically significant earlier improvement of MDD symptoms compared with fluoxetine, which is consistent with a previous study [
33]. Venlafaxine has an acute onset of down-regulation of β-adrenergic receptors, which might be a mechanism underlying the early onset of action [
34]. It will be necessary to determine the exact mechanisms of the early improvement of depressive symptoms in menopausal women when using venlafaxine.
The present study also showed that venlafaxine significantly improved anxiety and somatization compared with fluoxetine. These findings are in line with a previous study in which venlafaxine was superior to fluoxetine in improving anxiety symptoms [
33]. Similarly, a pooled analysis from five double-blind, randomized studies showed that venlafaxine is superior to fluoxetine in improving anxious symptoms [
35]. The AEs and TEAEs of venlafaxine and fluoxetine were similar. Treatment discontinuation due to AEs occurred at low incidence, thus suggesting that the two drugs were well tolerated. Also, all TEAEs in the present study were mild or moderate in severity, which is again consistent with previous studies [
35].
Clinical implications
The overall health and well-being of middle-aged women have become a major public health concern around the world. According to the current life expectancy, women spend almost a third of their life being menopausal and estrogen-deficient [
36]. More than 80% of the women experience physical or psychological symptoms in the years when they approach menopause, with various distress and disturbances in their lives, leading to a decreased quality of life [
37]. Women are about twice as likely as men to develop depression during their lifetime, and the postmenopausal period is associated with a higher vulnerability to depression among female patients [
38‐
40]. Postmenopausal women are more likely to have suicidal ideation and poorer physical functioning than premenopausal and perimenopausal women [
41]. Hence, it is essential to optimize pharmacologic options for the treatment of patients with postmenopausal MDD. This study suggests that women with postmenopausal major depressive disorder might benefit more from an SNRI than from an SSRI, with a more rapid and better response to treatment. The results provide some clues to optimize antidepressant pharmacotherapy for postmenopausal MDD.
Strengths and limitations
This was a prospective trial, and it was finally adequately powered to verify the hypothesis; however, there are still some limitations. First, we did not measure estrogen levels at baseline. Future studies should measure estrogens, which could provide a new perspective towards understanding estrogen’s influence on antidepressants. Second, 8 weeks of antidepressant treatment were insufficient to evaluate the long-term effects, and a longer follow-up period is required. Third, we only compared two active treatments without a placebo. Fourth, Menopause-Related Symptoms were not used to evaluate hot flashes, night sweats, and other menopausal symptoms in this study. Fifth, this study did not include treatment-resistant depression (TRD) in postmenopausal depression; research in this area will be strengthened in the future. Sixth, the drop-out rate was high in this study. Finally, we did not recruit 200 patients as per the sample size calculation This non-significant finding might be due to a type II error, underlining the need for replication. Only 189 were included due to time limit and economic resources.