Abstract
Several treatment strategies have been proposed for the management of depression in women. The occurrence of depression among females is often associated with periods of intense hormonal fluctuations, as observed in cases of premenstrual dysphoria, perinatal depression and with the development of depressive symptoms during the perimenopause. Various hormones including estrogen, progesterone, testosterone, dehydroepiandrosterone and thyroid hormones may exert modulatory effects on neurotransmitter pathways in the CNS. It has been postulated that abrupt changes in these hormones may negatively affect mood; conversely, hormonal interventions could potentially improve such symptoms. This article reviews the current literature on the impact of hormonal treatments for mood symptoms in women and preventative strategies for depression in women during the reproductive lifecycle.
Hormonal variability & mood disturbance
The influence of sex hormones on brain functioning and behavior have been cited as factors that reinforce gender differences observed in the prevalence and outcome of, and response to, the treatment of mental disorders [1]. Interestingly, these differences become more noticeable after puberty, when the occurrence of depression becomes two to three-times higher for females than males [2,3]. Furthermore, several studies suggest that the vulnerability to depression among subgroups of women increases during times of high hormonal fluctuation (i.e., premenstrual periods, puerperium and perimenopause) [4–6].
The association of dramatic hormonal changes with the onset of mood disturbances is complex. For example, results from the Harvard Study of Moods and Cycles, a prospective, community-based cohort study, have shown significant correlations between the occurrence of depression and ovarian failure. In this study, approximately 1000 premenopausal women (aged 36–44 years) were followed prospectively, with several assessments of serum hormone levels, menstrual characteristics and standardized psychiatric evaluations. Preliminary findings over a 3-year follow-up period suggested that women with a history of depression were more likely to develop a greater fluctuation in serum levels of sex steroids, and reported clinical/menstrual signs of early transition into the menopause [6,7].
Bloch and colleagues explored a putative relationship between hormone fluctuations and mood in a different population. These investigators simulated the hormonal changes commonly observed during pregnancy and after delivery in 16 nonpregnant women [8]. Eight women had a history of postpartum depression (PPD), while eight subjects were enrolled as controls. A hypogonadal state was induced with the use of leuprolide. This procedure was followed by supraphysiological doses of estrogen and progesterone to mimic the levels of hormones observed during pregnancy and then by a subsequent withdrawal of both hormones to simulate the postpartum period. Of the eight women with a history of PPD, five developed significant mood symptoms during the withdrawal phase. In comparison, the eight controls did not develop mood symptoms. This differential response supports the existence of a relationship between the rapid change in hormone levels and higher vulnerability to develop mood symptoms.
If hormonal fluctuations negatively affect mood during certain reproductive cycle-related events, it is not surprising that clinical evidence indicates that sex hormones may in fact prevent or even treat depressive symptoms. This article will examine the impact of hormonal interventions for the treatment of depression or depressive symptoms, particularly related to the menstrual cycle, during the peripartum and in women who are transitioning to menopause. Existing data on the efficacy of hormonal preparations and antidepressant-augmentation strategies will be critically reviewed.
Sex hormones: implications for the treatment of depression
Estrogen
Over the past 10 years, the interactions between estrogens and brain functioning have gained greater understanding [9]. In general, estrogens exert an agonistic effect on serotonergic activity by upregulating serotonergic receptors and increasing the transport of serotonin. Estrogen also decreases the uptake of serotonin by decreasing monoamine oxidase activity [10].
Initial studies investigating the potential antidepressant effect of estrogen in women have produced mixed results, possibly due to differences in the hormone preparations utilized, and the wide range of doses and methods of administration [11]. Estrogens are available in different preparations, including oral tablets, transdermal patches and creams, intranasal or sublingual formulations, injections and subdermal implants [10,12]. Most data on the efficacy and safety of estrogens have been based on studies using oral conjugated estrogens. Therefore, significant differences in the pharmacokinetic aspects of oral versus transdermal estrogens could potentially contribute to the conflicting results found across these studies, particularly in peri- and postmenopausal women [10]. Transdermal administration of estradiol avoids circulation through the liver and gastrointestinal absorption, which provides a rapid rise in the serum concentration of estradiol and nearly consistent serum levels (i.e., constant estradiol:estrone ratios) over the entire application period [12]. Treatment studies of transdermal estradiol for premenstrual syndrome (PMS) [13], puerperal depression [14] and perimenopausal depression [15,16] have shown positive results. Oral estrogens, on the other hand, are metabolized through the hepatic portal system. Consequently, there is a higher conversion rate to the less active metabolite, estrone, which decreases the bioavailability of estradiol [17].
Premenstrual syndrome & estrogen therapy
Although 80–90% of menstruating women experience premenstrual complaints (e.g., bloating, acne, constipation and/or breast pain), only 3–8% of these women will develop severe PMS or premenstrual dysphoric disorder (PMDD). PMS and PMDD are associated with clinically significant symptoms that greatly interfere with everyday activities and interpersonal relationships [18]. Psychiatric symptoms often include markedly depressed mood, anxiety, affective lability, lethargy and decreased interest in usual activities during the premenstrual or luteal phase.
The few studies investigating the efficacy of estradiol for the treatment of severe PMS and PMDD have shown positive results [13,19]. Smith and colleagues examined the effects of Estraderm® (100 and 200 μg twice-weekly) in women with severe PMS [13]. The results indicated that both doses of the transdermal estradiol decreased PMS symptoms, including mood changes, albeit the 100 μg dose was better tolerated and had fewer side effects. Using a crossover design, Watson and colleagues compared 100 μg of transdermal estradiol with placebo in women experiencing premenstrual symptoms [19]. Symptoms improved in women who went from the placebo to the active patch, while symptoms either did not improve or worsened in women who received the placebo patch following active treatment. These studies suggest that estradiol treatment may alleviate mood symptoms in women with severe PMS/PMDD.
Studies investigating the efficacy of the oral contraceptive (OC) pill use to alleviate premenstrual mood symptoms have had mixed results [20,21]. Joffe and colleagues compared premenstrual symptoms in women prior to first OC pill use with symptoms experienced while using an OC pill [20]. Of the 658 women, 12.3% reported an improvement in mood, while 16.3% reported mood deterioration. These results suggest that OC pills do not necessarily influence mood symptoms. It should be noted that OC pill type (i.e., mono-/triphasic, high/low dose) were not factored into the analysis; however, considering the age range in that study (36–44 years of age), it is likely that higher-dose OC pills were being taken. It has been suggested that newer, low-dose OC pills have more positive effects on mood and that monophasic OC pills could help stabilize mood better than triphasics [22,23]. Recent trials using a combination OC pill (drospirenone and ethinylestradiol) have demonstrated improvement of mood symptoms in women with PMDD [19,24,25]. For example, Pearlstein and colleagues examined the effects of a low-dose OC pill (drospirenone 3 mg/ethinyl estradiol 20 μg) for the treatment of PMDD in a double-blind, placebo-controlled, crossover study [24]. Subjects (n = 64) were treated with the monophasic OC pill or placebo for 3 months, with a 1-month washout period before switching treatment regimens. Response to treatment occurred in 62% of the active-treatment group and 32% of the placebo group. Although these results suggest that certain OC pills might improve mood, future studies investigating dose and dose regimen should clarify the role of OC pills for the treatment of PMS/PMDD.
Depression during the peripartum & estrogen treatment
PPD affects 12–16% of women [26]. It can potentially impair the mother's cognitive abilities, functional performance [27] and ability to bond with her infant [28], as well as the child's social and psychological development [29]. Depressed mood, psychomotor agitation or retardation, feelings of worthlessness or inappropriate guilt, frequent thoughts of death or suicide and sleep disturbances (characterized by insomnia or hypersomnia even when the infant is asleep or when the infant is in the care of another person) are some of the symptoms of PPD.
A small body of evidence supports the efficacy of estrogen therapy for the treatment of depressive disorders in women with PPD. It is theorized that by modulating the levels of estrogen and progesterone after the dramatic drop in hormone levels following delivery, PPD can be treated and possibly prevented. Treatment with estrogen has been used with modest success in women suffering from nonpsychotic depressive symptoms during the postpartum period [14,30,31].
The efficacy of transdermal 17β-estradiol (E2) (200 μg/day) to treat PPD was demonstrated in a double-blind, placebo-controlled study [14]. A total of 61 women suffering from treatment-resistant PPD were randomized to receive treatment with E2 or placebo for 3 months, followed by E2 plus progesterone or placebo for an additional 3 months. After 4 weeks of treatment, 50% of the women receiving E2 showed a significant response (defined as Edinburgh postnatal depression scale scores <14) compared with 26% receiving placebo. Response to E2 increased progressively during the remaining 5 months of treatment. Although almost half (47%) of women who were treated with E2 were also receiving concomitant treatment with antidepressants, they all met criteria for treatment-resistant depression at study entry. Additional analyses suggested that the efficacy of E2 was not significantly influenced by concomitant use of antidepressants. Although the positive effects may not be the result of estrogen replacement following immediate hormonal withdrawal (women were between 3 and 18 months postpartum), the response due to the potential impact of estrogen in treatment-resistant depression is worth mentioning.
In a second study, an 8-week, open-label trial utilizing sublingual E2 (1 mg 3–8-times daily) also resulted in a rapid antidepressant response (based on Montgomery–Asberg Depression Rating Scale scores) in 23 women with PPD. Within 2 weeks of treatment initiation, clinical recovery was observed in 19 of 23 patients [30]. In an open-label, pilot study, Sichel and colleagues studied the effects of a high dose of oral conjugated estrogens (5 mg/day) [31]. A total of 11 pregnant women with prior episodes of PPD or postpartum psychosis were followed until 12 months postpartum. Almost all the women remained well at the 4-week, 3-, 6- and 12-month follow-up. These studies suggest that estrogen may potentially be an effective antidepressant and may be considered as a prophylactic strategy for women at higher risk of developing PPD.
The efficacy of estradiol as an antidepressant in women with PPD with psychosis is yet to be determined. Ahokas and colleagues treated ten women with sublingual E2 for 6 weeks [32]. Psychotic symptoms significantly improved in the first week of treatment, with symptoms rebounding in the only patient who discontinued treatment. In contrast, Kumar and colleagues investigated various doses of transdermal E2 (200, 400 and 600 μg/day) in 29 women with postpartum psychosis [33]. None of the estradiol regimens reduced the relapse rate in these women. Both of these studies had a small sample size and administered different types of estrogen (i.e., sublingual vs transdermal). In addition, Kumar and colleagues' study included women diagnosed with bipolar type I and II disorder. These limitations should be addressed in future studies to elucidate the putative effects, if any, of estradiol on postpartum psychosis.
Depression in peri- & postmenopausal women & estrogen treatment
The perimenopause or menopausal transition represents the passage from reproductive to non-reproductive life. The initiation of perimenopause is characterized by more frequent anovulatory cycles, and occurrence of vasomotor and other physical symptoms [34,35]. It usually begins in a woman's forties, has a mean age of 47.5 years and has an average duration of 4–8 years. The majority of perimenopausal women experience irregular menstrual periods including shortened cycles or longer periods of amenorrhea.
Perimenopausal women are more likely to report depressive symptoms compared with pre-menopausal (those of the same age who still have regular menstrual periods) or postmenopausal women [36]. A study of more than 500 pre-, peri-and postmenopausal women in a primary care clinic demonstrated that marital disruption and unemployment, as well as somatic symptoms and past history of depression, may influence the likelihood of depressive symptoms in this population, regardless of menopausal status. The presence of severe hot flushes, however, was a risk factor for depression only among perimenopausal women, even though hot flushes occurred in all three menopausal groups [37].
The ‘estrogen withdrawal theory’ proposes that the onset or worsening of mood symptoms in perimenopausal women results from a significant decline in estrogen levels [38]. However, it has been established that estrogen levels may increase during the early perimenopausal period and then drop again, which could be seen as a limitation for the validity of this theory [39]. Nevertheless, the greater incidence of depression observed in women who have undergone bilateral oophorectomy or surgical menopause compared with naturally menopausal women suggest that the abrupt changes in estrogen levels play an important role in the development of depressive symptoms [38].
Schmidt and colleagues administered transdermal estradiol (0.05 mg/day) or placebo to 34 perimenopausal women with major and minor depression [15]. Estradiol improved depressive symptoms in women, regardless of the presence/absence of hot flushes. The authors suggested that the effects of estrogen on mood and vasomotor symptoms were independent. Soares and colleagues examined a larger sample (n = 50) of perimenopausal women suffering from depressive disorders (major [n = 26] and minor [n = 13] depression and dysthymia [n = 11]) [16]. These women received transdermal E2 (100 μg/day) or placebo for 12 weeks. A total of 68% of women in the treatment group experienced full remission of depression after treatment, compared with 20% in the placebo group. Subjects responded similarly to treatment regardless of their subtype of depression. In addition, most women continued to have antidepressant benefits after a 4-week washout period, despite the re-emergence of vasomotor symptoms.
Inan and colleagues reported a significant decrease in depression scores in perimenopausal women receiving either tibolone (2.5 mg/day for 25 days) or conjugated estrogen (0.625 mg for 5 days) plus progestogen therapy (5 mg daily on days 16–25) [40]. In a double-blind, placebo-controlled pilot study, conjugated estrogen (0.625 mg/day) augmentation of antidepressants was also associated with improved mood in perimenopausal women who were in partial remission [41].
The results from studies on postmenopausal women indicate that estrogen may not have a significant antidepressant effect as a monotherapy for these subpopulations. In one study of postmenopausal women receiving conjugated equine estrogens (0.625 mg/day) plus medroxyprogesterone (2.5 mg/day) or raloxifene (60 mg/day), a significant decrease in depression was observed in the raloxifene group only [42]. The use of transdermal estradiol (0.1 mg/day) for the treatment of depressive symptoms in postmenopausal women has also failed to demonstrate significant differences compared with placebo [43]. Studies of estrogen plus progestogen therapies have reported inconclusive findings. On one hand, a comparison between hormone therapy alone (conjugated estrogen 0.625 mg/day plus 5 mg/day of progesterone on days 14–28) or in combination with fluoxetine (40–80 mg/day) showed a greater response in women receiving the combination therapy [44]. Other studies attempting to demonstrate the efficacy of estrogen as an adjunctive therapy for major depressive disorder (MDD) in postmenopausal women had mixed results [45,46].
Positive results have been reported in one study, in which surgically induced menopausal women were given either transdermal estrogen (3.9 mg/week) or tibolone (2.5 mg/day) compared with oral placebo [47]; however, in this study, replacement therapy was initiated immediately following surgery. This may indicate that women experiencing more abrupt hormonal fluctuations are more receptive to estrogenic effects with regard to mood symptoms. In an open-label study, Cohen and colleagues administered transdermal E2 (100 μg/day) to 20 women (9 peri- and 11 postmenopausal women) who met criteria for depressive disorders [48]. Only one postmenopausal woman had full remission of depression after 4 weeks of hormonal intervention, whereas six of the perimenopausal women (67%) showed a satisfactory response to E2. It is possible that postmenopausal women would only benefit from a higher dose and/or prolonged treatment with E2 to obtain a satisfactory antidepressant response to estrogen treatment. In addition, perimenopausal or surgically induced postmenopausal depressed women might be uniquely responsive to the mood-enhancing effects of E2 due to their hormonal fluctuations, which would constitute a window of opportunity for the use of hormone interventions [49].
Progesterone
Premenstrual sydrome & premenstrual dysphoric disorder
Progesterone appears to have hypnotic, anxiolytic and antiepileptic effects, although its use has also been associated with negative effects on mood with increased irritability and dysphoria [50]. The effects of progesterone have been more systematically studied as a treatment for PMS and PMDD. Randomized, placebo-controlled studies utilizing either oral progesterone or progesterone suppositories administered vaginally or rectally have shown negative results. In a study of 168 women with PMS, there was no significant improvement in women receiving progesterone suppositories (400 or 800 mg) compared with women receiving placebo [51].
The potential anxiolytic benefit of progesterone was investigated in 170 women with documented PMS [52]. Subjects received either oral micronized progesterone (OMP) 300 mg), alprazolam (0.25 mg four-times/day) or placebo during the luteal phase of their menstrual cycle. There was no significant improvement in PMS symptoms in women receiving OMP compared with those receiving placebo. Girdler and colleagues investigated the relationship between levels of allopregnanolone, a progesterone metabolite that acts as a γ-aminobutyric acid (GABA) agonist, and symptom severity in 24 women with documented PMDD and 12 healthy women [53]. In women with PMDD, allopregnanolone levels were lower among those with higher premenstrual anxiety and irritability. In addition, there was a greater allopregnanolone:progesterone ratio in women with PMDD compared with controls, which indicates that progesterone metabolism dysregulation may be in involved. The few studies demonstrating a positive and significant effect of progesterone on symptoms of PMS have used vaginal or rectal suppositories [54,55]. Less is known regarding the effects of synthetic progestins on brain function. However, it has been speculated that their metabolites have a lower potency than allopregnanolone [56].
Peripartum
During the peripartum period, progesterone parallels estrogen with a drastic decrease following delivery. Early case studies investigating the prophylactic qualities of progesterone use have shown some promising results [57]. In contrast, Lawrie and colleagues randomized 180 women at risk of PPD to receive either an injection of depot norethisterone enanthate (a long-acting synthetic progesterone contraceptive agent) or a saline placebo [58]. Women receiving the synthetic progesterone had significantly higher depression scores at 6-weeks postpartum than the control group. Although these results may not be applicable to naturally occurring progesterone, evidence to date does not support the use of progesterone as an effective treatment or prophylactic strategy for perinatal depression.
Peri- & postmenopausal
DeWit and colleagues administered weekly intramuscular injections of progesterone (25, 50 or 100 mg) to postmenopausal women for 1 month [59]. Treatment effects were compared with those obtained in premenopausal women with regular menstrual cycles who received 100 mg of intramuscular progesterone weekly. Progesterone caused slight sedation in postmenopausal women who received the highest dose of progesterone, while premenopausal women experienced mild sedative effects, despite receiving supraphysiological doses of progesterone. Serum levels of allopregnanolone did not correlate with mood symptoms.
Studies of the contraceptive depot medroxyprogesterone acetate (MPA) and mood have shown either no effect on mood or a minimal increase in negative mood symptoms [60,61]. Civic and colleagues compared depressive symptoms in users and nonusers of depot-MPA and found that women who continually used depot-MPA reported more depressive symptoms than nonusers [62]. Overall, existing studies are still inconclusive regarding the relationship between mood and progesterone (or synthetic progestin) use, as well as with respect to the possible effects on mood of the metabolites pregnanolone and allopregnenolone.
Androgens
The neuroprotective properties of androgens [63] and their role in the organization of brain circuitry [64] are supported by animal studies and considerable clinical evidence. In women, androgens are produced by the adrenal glands and ovaries, and include testosterone, androstenedione, dehydroepiandrosterone (DHEA), and DHEA sulfate (DHEA-S). Due to a decreased adrenal production and a reduction in the mid-cycle ovarian secretion, circulating levels of androgens decrease significantly with aging [65]. Interestingly, both low and elevated levels of androgens are associated with depressive symptoms in women [66].
Testosterone
The impact of testosterone on mood and behavior in women has been well described. Data indicate an association between serum levels of testosterone and aggression [66]. Premenopausal women produce approximately 300 μg of testosterone/day from adrenal and ovarian secretions. This amount is reduced by 50% following bilateral oophorectomy and is associated with increased depressive symptoms [67].
During the peripartum, results from a study by Hohlagschwandtner and colleagues have demonstrated that higher maternal testosterone levels correlated with anger during pregnancy (38–40 weeks gestation) and at postpartum days 1 and 2 [68]. In contrast, Buckwalter and colleagues demonstrated that an increased rate of negative mood states within 2 months postpartum was associated with lower levels of testosterone [69].
Depressive symptoms and anxiety, as well as decreased libido, have been described among postmenopausal women who present with decreased testosterone, particularly after oophorectomy. Shifren and colleagues examined the impact of transdermal testosterone (150 or 300 μg) for 12 weeks in 75 women (aged 31–56 years) who underwent hysterectomy and oophorectomy [70]. All subjects received concomitant treatment with oral conjugated estrogens. When compared with placebo, women receiving testosterone reported greater psychological well-being and a significant improvement in mood and anxiety, as well as an improvement in their sexual life.
Dehydroepiandrosterone & dehydroepiandrosterone sulfate
DHEA and its sulfate may have a modulatory effect on mood. Barrett-Connor and colleagues examined 699 women (aged 50–89 years) in a community-based sample, and tried to establish a significant association between depressive symptoms and serum concentrations of gonadal steroids [71]. DHEA and DHEA-S levels had a negative correlation with depressive symptoms. Another study of 394 older women (over 65 years of age) showed similar results. DHEAs effect on mood may be explained by several mechanisms: its partial aromatization into estrogens, its effects on GABA receptors and an increase in serotonergic activity in the brain [72]. DHEAs antidepressant benefit has been documented in placebo-controlled trials. Wolkowitz and colleagues administered oral DHEA (30–90 mg/day) or placebo to 22 patients (10 women) for 6 weeks [73]. Both men and women who were given DHEA experienced a significant improvement in mood compared with those receiving placebo. In a second study, Schmidt and colleagues administered oral DHEA (90 mg/day for 3 weeks; 450 mg/day for 3 weeks) or placebo for 6 weeks to 46 patients (23 women) who had midlife onset of mild or major depression [74]. A 50% reduction from baseline depression scores was observed in 23 patients who received DHEA compared with 13 who received placebo.
Gonadotropin-releasing hormone analogs
Several studies have investigated the effects of danazol, a synthetic androgen that suppresses ovulation, for the treatment of PMS [75–77]. Two placebo-controlled, crossover studies found that danazol (100 mg twice-daily [75] and 200 mg twice-daily [76] for three cycles) was more effective than placebo in alleviating PMS symptoms. In contrast, O'Brien and Abukhalil randomized subjects to receive placebo or danazol (200 mg daily) for three cycles, during the luteal phase, and did not find any difference between groups [77]. The negative results could be related to the timing of the treatment; in addition, most participants had PMS symptoms along with significant premenstrual mastalgia. Although continuous treatment seems to be more effective than an intermittent regime, the long-term effects of danazol use for the treatment of PMS have not been examined.
Triiodothyronine & thyroxine
The mechanism by which thyroid dysfunction is associated with mood symptoms is unclear; serotonin levels appear to be positively correlated with triiodothyonine (T3) levels, and low central serotonin activity is associated with low thyroid activity [78]. In addition, reduced thyroid activity may result in decreased β-adrenergic receptor activity, in which catecholamine transmission is functionally decreased [79]. Ever since antidepressant effects were reported for T3 in 1958 [80], several case studies and clinical trials have examined the treatment of depressive disorders with the use of adjunctive T3 [81–95]. Three case reports described the use of T3 augmentation of trazodone [81], phenelzine [82] and fluoxetine [83], in which the addition of T3 potentiated the effects of the respective antidepressants. Open-label trials examined the use of adjunctive T3 (25–50 μg) in selective serotonin-reuptake inhibitor (SSRI)- [84–86] and tricyclic antidepressent (TCA)-resistant [87] MDD (Table 1). Two recent double-blind, placebo-controlled studies of adjunct T3 treatment for depression have shown the reverse with regard to the antidepressants [88,89]. Joffe and colleagues compared the addition of T3 to TCAs [88]. Of the 17 patients receiving T3 augmentation, ten responded (responder defined as a 50% reduction in depression), whereas only three patients responded to placebo. In contrast, Appelhof and colleagues did not find a significant difference in response when a SSRI, paroxetine, was augmented with T3 (doses of either 25 or 50 μg/day) for 8 weeks in 106 depressed patients [89]. The effectiveness of T3 augmentation may be dependent on the type of depression being treated (i.e., with or without melancholic features) or the antidepressant being used. Finally, a double-blind study by Stern and colleagues included 12 depressed patients who underwent treatment with T3 (compared with placebo) along with electroconvulsive therapy (ECT) [90]. Patients treated with T3 required fewer ECT treatments than placebo-treated patients.
Summary of open trials with triiodothyonine augmentation of an antidepressant.
SSRI: Selective serotonin-reuptake inhibitor; TCA: Tricyclic antidepressant; T3: Triiodothyonine; T4: Thyroxine.
Only two studies have investigated the effects of T4 (1.6 μg L-thyroxine [L-T4]/kg) as a treatment for PMS [96,97], in which there were no significant differences between the treatment groups. Studies comparing T4 and placebo for the treatment of depression have not been published. However, open trials suggest that T4 may have potential benefits as an adjunctive strategy in treatment-resistant depression (Table 2) [91–93]. It should be noted that the sample sizes of these studies were small and that various medications were utilized during the T4 augmentation treatments. Finally, the results of a double-blind study (n = 40) indicate that T3 (37.5 μg) has superior efficacy compared with T4 (150 μg) as an adjunct to TCAs in TCA-resistant MDD [94].
Summary of open-label trials with T4 augmentation of an antidepressant.
T3: Triiodothyonine; T4: Thyroxine.
Conclusions
Existing evidence suggests that the interactions between sex hormones and brain functioning are quite complex. There are many other factors that might play an important role in the development of depressive symptoms in women, such as history of depression, medical conditions, lack of social support and lifestyle. Nonetheless, existing data support the potential impact of hormone changes for their occurrence, as well as the promising use of various sex hormones as an antidepressant strategy (either monotherapy or augmentation). To date, existing studies are encouraging for a potential use of estradiol in women who experience depression during periods of fluctuating hormone levels, particularly during the menopausal transition – this may represent the best window of opportunity to observe the antidepressant benefits of estrogen. However, further studies are needed to determine the extent to which augmenting treatments with estrogen, testosterone or DHEA may help to improve mood symptoms in women who do not respond to antidepressants.
Healthcare providers involved in psychiatric care should be aware of the accumulating data on the effects of sex hormones in order to better treat depressed women during various stages of the reproductive cycle. Further investigation should help to identify strategies to effectively improve depressive symptoms and quality of life for female patients.
Future perspective
The complexity involving the neuroendocrine system and its impact on mood and behavior represents a challenge for clinicians and researchers. Epidemiological and clinical studies are still needed to detect critical periods or windows of opportunity in which hormonal treatments or preventative strategies could be used more effectively and safely. Although some results with estrogen therapies for the management of menopause-related mood changes are encouraging, antidepressants are still the first line of treatment for these patients. In light of recent controversies involving long-term use of hormone therapies, it is expected that more emphasis will be placed on a search for more brief hormonal augmentation strategies, as well as on the efficacy and safety of selective estrogen receptor modulator agents.
Executive summary
Low-dose, monophasic oral contraceptive preparations may ameliorate mood symptoms and physical complaints associated with premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PMDD) more effectively than high-dose or triphasic preparations.
Evidence suggests that some estradiol plus progesterone combinations contained in oral contraceptives may positively affect mood symptoms in women with PMS.
Progesterone treatments do not appear to have a positive impact on mood in women with PMS or in women at risk for postpartum depression.
Continuous treatment with the gonadotropin-releasing hormone analog danazol may improve PMS mood symptoms via ovulation suppression.
Clinical trials demonstrate that transdermal estradiol may be particularly helpful for the management of depressive symptoms during periods of great hormonal fluctuation (i.e., postpartum and during the menopausal transition).
Hormone therapy alone does not appear to improve depression in postmenopausal women.
Clinical evidence is mixed regarding the efficacy of triiodothyonine as an adjunctive strategy to antidepressants. Small or no effects have been shown as an adjunct to TCA, whereas worsening of symptoms was described when triiodothyonine was given in combination with selective serotonin-reuptake inhibitors.
Thyroxine treatment does not appear to be an effective treatment of PMS symptoms. Further studies with thyroxine treatment for depression in women are required.