 |
|
Efficacy of Estradiol for the Treatment of Depressive Disorders in Perimenopausal Women
A Double-blind, Randomized, Placebo-Controlled Trial
Cláudio de Novaes Soares, MD, PhD;
Osvaldo P. Almeida, MD, PhD;
Hadine Joffe, MD;
Lee S. Cohen, MD
Arch Gen Psychiatry. 2001;58:529-534.
ABSTRACT
| |
Background Results of previous studies suggest that estrogen improves somatic and
mild depressive symptoms experienced by perimenopausal women. This study investigated
the efficacy of 17ß-estradiol for the treatment of clinically significant
depressive disorders in endocrinologically confirmed perimenopausal women.
Methods Perimenopausal women (aged 40-55 years, with irregular menstrual periods
and serum concentrations of follicle-stimulating hormone >25 IU/L), meeting
criteria for major depressive disorder, dysthymic disorder, or minor depressive
disorder, according to DSM-IV, were randomized to
receive transdermal patches of 17ß-estradiol (100 µg) or placebo
in a 12-week, double-blind, placebo-controlled study. A 4-week washout period
followed the 12-week treatment phase. Outcome measures were the Montgomery-Åsberg
Depression Rating Scale and Blatt-Kupperman Menopausal Index scores.
Results Fifty women were enrolled in the study; 26 met DSM-IV criteria for major depressive disorder, 11 for dysthymic disorder,
and 13 for minor depressive disorder. Remission of depression was observed
in 17 (68%) women treated with 17ß-estradiol compared with 5 (20%) in
the placebo group (P = .001). Subjects responded
similarly to estradiol treatment, regardless of DSM-IV
diagnosis. Patients treated with estradiol sustained antidepressant benefit
of treatment after the 4-week washout period, although somatic complaints
increased in frequency and intensity. Treatment was well tolerated and adverse
events were rare in both groups.
Conclusion Transdermal estradiol replacement is an effective treatment of depression
for perimenopausal women.
INTRODUCTION
DEPRESSIVE symptoms are common during the transition to menopause.1, 2, 3 Cross-sectional surveys
describe high rates of depressive symptoms among women treated in menopause
clinics.4, 5 We recently reported
depressive disorders (major depressive disorder [MDD], dysthymic disorder,
and minor depressive disorder) in 30 of 101 endocrinologically confirmed perimenopausal
women attending a gynecological clinic.6, 7
Unlike clinic-based surveys, community-based studies found that perimenopause
may be a period of risk for mood disturbance for some women but does not necessarily
represent a time of risk for major depression.8, 9, 10
The use of estrogen replacement for the treatment of menopausal symptoms
has been shown to enhance "psychological well-being."11
However, clinical studies using diverse forms of estrogen replacement for
the treatment of depression produced mixed results. Three estrogen treatment
studies in perimenopausal and newly postmenopausal women failed to demonstrate
superiority over placebo for the treatment of mood symptoms.12, 13, 14
In contrast, 2 double-blind, placebo-controlled studies using transdermal
patches of 17ß-estradiol15, 16
and case series in which patients were treated with sublingual estradiol17 suggested that estrogen improves mood in women with
postpartum depression and severe premenstrual syndrome.
More recently, Schmidt and colleagues18
described that perimenopausal women with major (n = 8) or minor depression
(n = 26) with or without hot flushes experience greater relief of depressive
symptoms with estrogen than with placebo. However, data confirming these preliminary
findings are lacking, particularly in a larger group of perimenopausal women
with major depression.
The present study was designed to determine the efficacy of 17ß-estradiol
for the treatment of depressive disorders in endocrinologically confirmed
perimenopausal women. Based on the results of previous reports,15, 16
we hypothesized that the use of transdermal 17ß-estradiol would have
a greater antidepressant benefit than placebo.
PATIENTS AND METHODS
PATIENTS
Subjects were recruited from a sample of 176 consecutive patients seeking
care at the gynecological clinic ("menopause clinic") at the Pérola
Byington Hospital–Brazil (n = 101) and the psychiatric outpatient service
for women at the Institute of Psychiatry of the University of São Paulo
(n = 75) between October 1996 and June 1998. Patients seen at both medical
centers were self-referred or referred by other physicians. Prior to study
entry, all women participated in a 2- to 4-week screening phase (2-4 visits),
during which their mood and perimenopausal somatic symptoms were assessed
and serum levels of follicle-stimulating hormone (FSH) and estradiol were
obtained. Subjects with menses during the screening period had hormone levels
measured in the early follicular phase (days 2-5) of the menstrual cycle.
Those who presented with more prolonged periods of amenorrhea had blood drawn
at the last screening visit.
The entry criteria for the study included (1) age between 40 and 55
years; (2) history of menstrual cycle irregularity or amenorrhea for less
than 12 months; (3) serum level of FSH greater than 25 IU/L (to document the
gonadotropins' attempt to stimulate the declining ovarian function and, therefore,
to confirm the perimenopausal status as the cause of menstrual irregularities);
and (4) diagnoses of MDD, dysthymic disorder, or minor depressive disorder,
according to DSM-IV.19
Diagnostic assessments were performed by the study psychiatrist (C.d.N.S.)
using a clinician-administered diagnostic instrument (Primary Care Evaluation
of Mental Disorders [PRIME-MD] questionnaire,20
supplemented by the specific module of PRIME-MD for Mood Disorders). Exclusion
criteria included medical illness (assessed by general practitioners or gynecologists
at the study entry), use of hormone replacement therapy and/or psychoactive
drugs in the 3 months prior to assessment, contraindication to estrogen therapy,
and presence of psychotic features, suicidality, or severe aggressive behavior.
The Hospital das Clinicas ethics review board approved the research protocol
and written informed consent was obtained from all participants.
MEASURES
The following 2 outcome measures were used: (1) Montgomery-Åsberg
Depression Rating Scale (MADRS), a 10-item clinician-rated scale designed
to assess the severity of depressive symptoms21;
and (2) the 12-item version (0-3 scale) of the Blatt-Kupperman Menopausal
Index (BKMI),22 which was used to quantify
the severity of perimenopausal somatic symptoms, particularly hot flushes
and night sweats, as well as joint pains, headache, vertigo, and sleep disturbance.
We also examined the severity of vasomotor symptoms (hot flushes and night
sweats—items 1 and 2 from the BKMI, respectively) separately. Hot flushes
and night sweats were considered significant if scores were greater than 4
on a 0 to 12 subscale and greater than 2 on a 0 to 6 subscale, respectively.
Improvement of depression was determined by end-of-treatment MADRS scores.
Full remission was achieved if the end-of-treatment MADRS score was less than
10.23 Decline of 50% or more on baseline BKMI
scores was considered indicative of significant improvement of somatic symptoms.
PROCEDURES
The clinical trial comprised 2 phases. Phase 1 was a double-blind, randomized
study comparing the efficacy of 100 µg of transdermal 17ß-estradiol
with placebo. The randomization scheme was externally controlled and based
on a list of random numbers generated by computer. Of 176 subjects initially
screened for the study, 71 (40.3%) met criteria for DSM-IV depressive disorders and for perimenopause. Eight patients were excluded
due to the presence of psychotic symptoms (n = 3), aggressive behavior (n
= 2), significant suicidal thoughts (n = 1), and history of bipolar disorder
with sporadic use of mood stabilizers (n = 2). In addition, 13 subjects declined
enrollment in the clinical trial and/or did not attend all screening visits.
Thus, 50 patients (25 per arm) were randomly assigned to treatment with either
patches of 100 µg of 17ß-estradiol (Systen/Evorel; Janssen-Cilag
Laboratories, São Paulo, Brazil) or identical placebo patches for 12
weeks (phase 1). During phase 1, subjects were evaluated every 4 weeks when
depressive symptoms (MADRS scores) and somatic symptoms (BKMI scores) were
reassessed. After phase 1, subjects underwent a 4-week washout period and
were then reassessed. The evaluation after the washout period was aimed to
examine differences between the course of depressive and somatic symptoms
after treatment discontinuation. Measurements of serum levels of FSH and estradiol
were repeated at week 12.
To avoid compromising the double-blind design, the occurrence of menstrual
bleeding (spontaneous cycling and/or bleeding secondary to estrogen use/withdrawal)
was recorded by an independent gynecologist. The study psychiatrist remained
unaware of these events. In addition, at the study entry, subjects were informed
that menstrual bleeding could occur regardless of the type of treatment received.
Forty-five (90%) of the 50 randomized subjects completed 12 weeks of
treatment (phase 1). Four subjects randomized to placebo patches dropped out
of the study due to patch-related skin irritation (n = 1), "poor response"
(n = 2), and nausea (n = 1). One subject treated with estradiol dropped out
because of adverse effects (headaches and nausea). Two additional subjects
(1 from each arm) dropped out during the washout period due to increased depressive
symptoms.
STATISTICAL ANALYSIS
Data were analyzed with the SPSS statistical software.24
Frequencies of categorical data were analyzed using the Pearson  2 test or Fisher exact test, when appropriate. The independent t test (2-tailed) was used for between-group comparisons.
A paired t test (2-tailed) was used for within-group
comparisons. A preliminary exploratory study showed that the data were fit
for parametric procedures. Of note, nonparametric analyses (Mann-Whitney and
Wilcoxon paired rank tests) produced similar results (data not shown). All
efficacy results reported are on an intent-to-treat basis in which the last
observation was carried forward into all subsequent time points for patients
who dropped out before the end of the study. Statistical significance was
set at the  = .05 level. Data are presented as mean ± SD.
RESULTS
SAMPLE CHARACTERISTICS
Of 50 perimenopausal women with depression enrolled in the study, 36
(72%) reported that they originally had sought medical care due to menopause-related
somatic symptoms. Twenty-six women (52%) met DSM-IV
criteria for MDD, 11 (22%) for dysthymic disorder, and 13 (26%) for minor
depressive disorder. More than half (14 [54%] of 26) of the women with MDD
reported that the index episode was their first experience of depression.
Characteristics of the 2 treatment groups are summarized in Table 1. There were no significant differences between the 2 groups
with respect to demographic characteristics (age, marital status, education,
employment), reproductive history (age at menarche, history of pregnancy,
duration of amenorrhea), current DSM-IV diagnosis,
or previous psychiatric history (as assessed by the study psychiatrist in
a nonstandardized investigation of previous mood, anxiety, psychotic, or substance
abuse episodes).
|
|
|
|
Table 1. Subject Characteristics*
|
|
|
MOOD AND SOMATIC SYMPTOMS
Both groups (estradiol and placebo) had 21 (84%) of 25 subjects with
moderate-to-severe depression (MADRS >17) at baseline. Subjects randomly assigned
to estradiol had higher mean MADRS scores (24.60 ± 6.69; range, 14-38)
than those assigned to the placebo group (21.84 ± 4.43; range, 14-30; t = -2.47, P = .02).
No significant differences between the 2 groups were observed with respect
to the prevalence of menopausal somatic symptoms (BKMI scores, Table 2), particularly the prevalence of moderate-to-severe hot
flushes (estradiol group, 64%, vs placebo group, 56%; 2 =
0.33, P = .56) and night sweats (36% vs 32%, respectively; 2 = 0.09, P = .76).
|
|
|
|
Table 2. Depressive Symptoms (MADRS Scores) and Perimenopausal Symptoms
(BKMI Scores) in Women Who Received Estradiol or Placebo for 12 Weeks, and
After 4 Weeks of Washout (Week 16): Intent-to-Treat Analysis*
|
|
|
HORMONE LEVELS
No difference was observed between mean estradiol levels at baseline
(estradiol group = 44.03 ± 2.88 pmol/L [12 ± 0.8 pg/mL]; placebo
group = 52.01 ± 8.59 pmol/L [14 ± 2.3 pg/mL]; t = 0.69, P = .48). Mean serum FSH levels
obtained at study entry were significantly higher in patients randomly assigned
to receive 17ß-estradiol (58.08 ± 21.03 IU/L) compared with those
having placebo (43.00 ± 20.01 IU/L) (t = -2.59; P = .01). When the analysis was limited to subjects whose
hormonal assessment was obtained during the early follicular phase of the
menstrual cycle (estradiol group, n = 12; placebo group, n = 17), there were
no significant differences between estradiol and placebo groups, with respect
to mean levels of FSH (48.33 ± 15.88 IU/L vs 37.49 ± 18.14 IU/L,
respectively; t = -1.66, P = .11) or estradiol (59.58 ± 15.06 pmol/L [16 ± 4.1
pg/mL] vs 45.21 ± 6.9 pmol/L [12 ± 1.9 pg/mL], respectively; t = -0.97, P = .34) at baseline.
OUTCOME ASSESSMENTS
Phase 1
Effect of 17ß-Estradiol on Mood.
The end-of-treatment mean MADRS scores among women treated with estradiol
were significantly lower than the mean MADRS scores in the placebo group (8.60
± 5.02 vs 16.84 ± 5.12, respectively; t
= 5.28, P<.001). The MADRS scores decreased significantly
more from baseline in the estradiol group (-16.36 ± 8.04) than
in the placebo group (-4.16 ± 5.09; t
= - 6.41, P<.001).
Remission of depression (week 12, MADRS score <10) was observed in
17 (68%) of 25 subjects treated with estradiol during 12 weeks compared with
5 (20%) of 25 women who received placebo (2 = 11.69, P = .001). The efficacy of estradiol treatment was similar
across DSM-IV diagnostic subgroups; remission of
depression was observed in 12 of 26 subjects with MDD, 6 of 11 subjects with
dysthymic disorder, and 5 of 13 subjects with minor depressive disorder (2 = 0.62, P = .73).
There was no statistical association between response to treatment (remission
of depression) and recruitment site, sociodemographic variables, reproductive
history, psychiatric history, severity of depression, or hormonal conditions
at baseline (P>.05 for all comparisons; 2 tests).
Effect of 17ß-Estradiol on Somatic Symptoms.
As shown in Table 2, at
the end of 12 weeks of treatment, women who received estradiol had a significant
decrease in their BKMI scores compared with their baseline scores (P< .001) and lower BKMI scores compared with women treated with
placebo (P<.01). A greater than 50% decrease in
mean BKMI scores occurred in 17 (68%) of 25 subjects treated with estradiol
compared with 7 (28%) of 25 who received placebo (2 = 8.11, P = .005). When we analyzed vasomotor symptoms separately,
only 1 (4%) of 25 subjects who received estradiol was still reporting significant
hot flushes at week 12 compared with 9 (36%) of 25 treated with placebo (2 = 8.0, P = .005). No patients treated with
estradiol reported moderate-to-severe night sweats, whereas 5 (20%) of 25
of those who received placebo still had these symptoms (Fisher exact test, P = .05).
Hormone Levels.
As expected, mean serum levels of estradiol obtained during the last
week of phase 1 (week 12) were significantly higher (256.57 ± 57.52
pmol/L [70 ± 15.6 pg/mL]) than those obtained at baseline in subjects
treated with 17ß-estradiol (t = -4.05, P<.001). In contrast, there were no significant changes
(t = -1.48, P = .15)
in the placebo group (end-of-treatment mean estradiol level, 85.52 ±
20.12 pmol/L [23 ± 5.5 pg/mL]). There was a significant difference
in end-of-treatment mean estradiol levels between the 2 treatment groups (P<.001).
Adverse Events.
Adverse events were spontaneously reported by 8 (32%) of 25 subjects
receiving estradiol and 9 (36%) of 25 patients receiving placebo. With the
exception of the 2 placebo dropouts (1 due to skin irritation and 1 due to
nausea) and 1 estradiol-treated dropout (due to headaches and nausea) mentioned
previously, most adverse events were considered mild and well tolerated and
included local skin irritation (10%; 2 placebo and 3 estradiol), breast tenderness
(12%; 2 placebo and 4 estradiol), headaches (6%; 3 placebo), and nausea (6%;
2 placebo and 1 estradiol). Spontaneous bleeding was reported by 4 (16%) of
25 subjects receiving estradiol and by 2 (8%) of 25 subjects receiving placebo,
during the treatment phase (12 weeks).
Washout Period
The estradiol group showed a significant (P<.01)
and the placebo group similar (P = .30) increases
in MADRS scores 4 weeks after treatment was discontinued (estradiol group,
+3.64 ± 3.82; placebo group, +2.52 ± 3.74). At week 16, subjects
previously treated with estradiol still showed mean MADRS scores significantly
lower (12.24 ± 5.31) than those obtained at baseline (24.60 ±
6.69) (t = 8.15, P<.001).
In contrast, patients who discontinued placebo reported mean MADRS scores
(19.36 ± 5.12) almost as severe as those observed at baseline (21.84
± 4.43) (t = 1.92, P
= .07) and significantly higher compared with subjects who discontinued estradiol
treatment (t = 5.03, P<.001).
When the analysis was limited to patients who had shown remission of
depression at week 12, we observed that 10 (59%) of 17 subjects treated with
estradiol remained well after treatment discontinuation, whereas none of the
5 subjects who previously responded to placebo sustained MADRS scores less
than 10 (Fisher exact test, P = .04). Of note, sustained
remission of depression was observed similarly across DSM-IV diagnoses (2 = 1.72, P =
.42).
With respect to somatic symptoms, subjects who discontinued estradiol
treatment showed a significant increase in mean BKMI scores (+13.12 ±
9.89; t = 4.44, P<.001),
whereas women who discontinued placebo patches had a nonsignificant increase
in their mean BKMI scores (+2.36 ± 6.99) (t
= -1.69, P = .10). Seven of 10 subjects who
discontinued estradiol treatment and remained well (MADRS <10) reported
moderate-to-severe hot flushes.
COMMENT
The results of this study indicate that estradiol is an effective antidepressant
treatment for women in perimenopause. Previous reports had already shown that
estrogen replacement therapy improves menopausal somatic symptoms, subjective
well-being, and quality of life during perimenopause.11, 12, 25
Recently, in a 6-week study, Schmidt and colleagues18
found that the use of 50 µg of 17ß-estradiol improves mood in perimenopausal
women who meet standardized criteria for major and minor depression. Our results
support these findings, as estradiol improved mood in subjects with depressive
disorders. Estradiol therapy was efficacious in treating depressive symptoms
in a larger sample of women who met criteria for MDD (n = 26)—67% of
those receiving estradiol had full remission of depression. In addition, we
were able to demonstrate the occurrence of continued mood improvement throughout
the 12-week treatment phase (decreasing MADRS scores consecutively observed
at weeks 4, 8, and 12). Our findings obtained with 100 µg of estradiol
contrast with the aforementioned study,18 which
used a lower dose of estradiol, and in which increasing improvement in mood
occurred only during the first 3 weeks of treatment.
The present investigation focused on treatment of endocrinologically
confirmed perimenopausal women with depression. Reproductive endocrine criteria
were used to obtain a relatively homogeneous group with respect to endocrine
status26 and to exclude women with other causes
of irregular menstrual cycles and amenorrhea (eg, polycystic ovarian syndrome,
hypothalamic amenorrhea). Previous investigations of the antidepressant effect
of estrogen in perimenopausal women have been confounded by multiple factors,
including the heterogeneity of methods to define and assess menopausal and
hormonal status, lack of standardized diagnostic and outcome measures, differences
in hormone preparations, and a wide range of doses and methods of administration.1, 26, 27
In the present study, we opted for using transdermal 17ß-estradiol
because of its demonstrated safety and efficacy.16, 17
Other estrogen trials that failed to detect an antidepressant efficacy in
comparison with placebo used either oral preparations of conjugated equine
estrogen28, 29 or estropipate.30 Existing data suggest that the transdermal administration
of estradiol (matrix-type system) to postmenopausal women provides a rapid
rise in the serum concentration of estradiol and nearly constant serum levels
(ie, constant estradiol-estrone ratios) over the entire application period.31, 32 Oral administration, on the other
hand, results in highly variable serum levels of estradiol, and lower bioavailability
compared with estrone.33 It is unclear, however,
whether a more constant estradiol level could be expected in our sample, which
consists exclusively of perimenopausal women, given the endogenous hormone
fluctuation this subpopulation may exhibit and the lack of serial hormone
measures in our study.
Some authors have suggested that relief of vasomotor symptoms associated
with estradiol treatment risks unblinding clinical trials designed to evaluate
the efficacy of estradiol for the treatment of perimenopausal depression.27 Others have speculated that the capacity of estrogen
to improve mood is secondary to the relief of menopausal symptoms (nocturnal
hot flushes and sleep disturbance).1, 13
However, Schmidt and colleagues18 demonstrated
that estradiol reduces symptoms of depression in perimenopausal women who
do not have hot flushes. This reinforces the concept that the effects of estrogen
on mood and vasomotor symptoms may be independent. Recently, Bloch and colleagues34 examined the effects of gonadal steroids in 16 euthymic
women aged 22 to 45 years (half of whom had a history of postpartum depression)
by simulating hormonal conditions related to pregnancy and parturition. Women
with a history of postpartum depression (but not the comparison group) showed
increased mood symptoms during the hypogonadal phase, produced by the administration
of a gonadotropin-releasing hormone analog (leuprolide acetate). More important,
the emergence of mood symptoms during the hormone withdrawal phase preceded
the occurrence of hot flushes.
Our findings also suggest independent effects of estrogen on mood and
vasomotor symptoms. Specifically, we observed a sustained antidepressant benefit
after discontinuation of estradiol treatment despite recrudescence of somatic
symptoms. Seven of 10 patients who remained well (MADRS <10) after estradiol
discontinuation reported reemergence of moderate-to-severe hot flushes.
The good treatment tolerability, scarcity of significant adverse events,
and placebo response rates observed in our study are consistent with previous
reports using transdermal matrix patches of estradiol.18, 35, 36
Although mounting evidence indicates that estrogen influences neuronal
function via serotonergic-, noradrenergic-, dopaminergic-, and  -aminobutyric–mediated
systems,37, 38, 39
a mechanism by which estradiol may have an antidepressant effect remains unclear.
Our investigation has some methodological limitations. First, subjects
were recruited from 2 specialized outpatient services and presented with different
types of depressive disorder and menopause-related physical symptoms. It is
unclear how well this relatively small sample represents the population of
perimenopausal women with depression living in the community and/or seeking
treatment for mood symptoms. The recruitment of subjects with depression who
primarily sought treatment for physical symptoms in a gynecological outpatient
clinic appears to be appropriate and consistent with previous reports showing
that depressive disorders are frequently encountered in medical care settings.40, 41 In addition, their first appearance
may be dominated by the physical symptoms of the syndrome, and minor depressive
episodes are particularly common.24, 42
The second limitation that might be considered is the maintenance of
the double-blind design. We attempted to maintain the blind by keeping the
psychiatric rater unaware of possible adverse events associated with drug
assignment—6 women had bleeding episodes during the trial (2 of whom
were treated with placebo) and another 6 during the washout period (all treated
with estradiol). We also estimated the degree to which the blind was maintained
by asking the subjects and the psychiatric rater to guess to which group the
patient was assigned. Twelve (57%) of the 21 subjects treated with placebo
and 12 (50%) of 24 women who received estradiol guessed their treatment correctly,
while the psychiatrist rater correctly identified the treatment assignment
for 64.5% of placebo-treated women and 62.5% of estradiol-treated women. Although
we acknowledge that the blinding of placebo-controlled trials of estradiol
is problematic, the assessment of blindness in this case suggested that it
was acceptable.43
To date, this is the largest study examining the impact of estradiol
on MDD. The results of this investigation indicate that transdermal estradiol
has a clinically significant antidepressant effect in perimenopausal women.
This finding may support a potential role of estrogen replacement therapy
for the treatment of perimenopausal mood disturbance, complementing other
established benefits of this compound. Larger clinical trials, which use a
longer treatment follow-up and evaluate the potential alteration of antidepressant
benefit with concomitant progesterone, are needed. Further investigation also
will be crucial to delineate the putative role for estrogen in other subgroups
of patients who have a spectrum of depressive illnesses.
AUTHOR INFORMATION
Accepted for publication December 21, 2000.
This research was supported by grant 96/05105-8 from Fundação
de Amparo à Pesquisa do Estado de São Paulo (FAPESP)–São
Paulo Research Foundation, São Paulo, Brazil.
Dr Soares is the recipient of an FAPESP scholarship 99/08459-3 from
Fundação de Amparo à Pesquisa do Estado de São
Paulo–São Paulo Research Foundation.
We thank César E. Fernandes, MD, PhD, Nilson R. Melo, MD, PhD,
the study gynecologists, and the staff at the Pérola Byington Menopause
Clinic and at Women's Outpatient Clinic (Institute of Psychiatry–University
of São Paulo Medical School) for their helpful assistance. We thank
Janssen-Cilag Laboratories for supplying the estradiol and placebo patches.
From the Institute of Psychiatry, University of São Paulo Medical
School, São Paulo, Brazil (Dr Soares); the Department of Psychiatry
and Behavioral Science, University of Western Australia, Perth (Dr Almeida);
and Perinatal and Reproductive Psychiatry Clinical Research Program, Massachusetts
General Hospital, Harvard Medical School, Boston (Drs Soares, Joffe, and Cohen).
Corresponding author: Cláudio de Novaes Soares, MD, PhD, Perinatal
and Reproductive Psychiatry Clinical Research Program, Massachusetts General
Hospital, Harvard Medical School, 15 Parkman St, WACC 812, Boston, MA 02114
(e-mail: csoares{at}partners.org).
REFERENCES
| |
1. Ballinger CB. Psychiatric morbidity and the menopause: screening of general population
sample. BMJ. 1975;3:344-346.
2. Schmidt PJ, Rubinow DR. Menopause-related affective disorders: a justification for further
study. Am J Psychiatry. 1991;148:844-852.
FREE FULL TEXT
3. Kaufert PA, Gilbert P, Tate R. The Manitoba Project: a re-examination of the link between menopause
and depression. Maturitas. 1992;14:143-155.
FULL TEXT
|
ISI
| PUBMED
4. Hay AG, Bancroft J, Johnstone EC. Affective symptoms in women attending a menopause clinic. Br J Psychiatry. 1994;164:513-516.
FREE FULL TEXT
5. Stewart DE, Boydell K, Derzko C, Marshall V. Psychologic distress during the menopausal years in women attending
a menopause clinic. Int J Psychiatry Med. 1992;22:213-220.
ISI
| PUBMED
6. Novaes C, Almeida OP, Melo NR. Mental health among perimenopausal women attending a menopause clinic:
possible association with premenstrual syndrome? Climacteric. 1998;1:264-270.
PUBMED
7. Soares CN, Almeida OP. Depression during the perimenopause [letter]. Arch Gen Psychiatry. 2001;58:306.
FREE FULL TEXT
8. Hunter M. The south-east England longitudinal study of the climacteric and postmenopause. Maturitas. 1992;14:117-126.
FULL TEXT
|
ISI
| PUBMED
9. Avis NE, Brambilla D, McKinlay SM, Vass K. A longitudinal analysis of the association between menopause and depression:
results from the Massachusetts Women's Health Study. Ann Epidemiol. 1994;4:214-220.
PUBMED
10. Weissman MM, Myers JK. Rates and risks of depressive symptoms in a United States urban community. Acta Psychiatr Scand. 1978;57:219-231.
ISI
| PUBMED
11. Montgomery JC, Appleby L, Brincat M, Versi E, Tapp A, Fenwick PB, Studd JW. Effect of oestrogen and testosterone implants on psychological disorders
in the climacteric. Lancet. 1987;1:297-299.
FULL TEXT
|
ISI
| PUBMED
12. Coope J. Is oestrogen therapy effective in the treatment of menopausal depression? J R Coll Gen Pract. 1981;31:134-140.
PUBMED
13. Campbell S, Whitehead M. Oestrogen therapy and the menopause syndrome. Clin Obstet Gynaecol. 1977;4:31-47.
ISI
| PUBMED
14. Pearce J, Hawton K, Blake F, Barlow D, Rees M, Fagg J, Keenan J. Psychological effects of continuation versus discontinuation of hormone
replacement therapy by estrogen implants: a placebo-controlled study. J Psychosom Res. 1997;42:177-186.
FULL TEXT
| PUBMED
15. Gregoire AJ, Kumar R, Everitt B, Henderson AF, Studd JW. Transdermal oestrogen for treatment of severe postnatal depression. Lancet. 1996;347:930-933.
FULL TEXT
|
ISI
| PUBMED
16. Smith RN, Studd JW, Zamblera D, Holland EF. A randomised comparison over 8 months of 100 micrograms and 200 micrograms
twice weekly doses of transdermal oestradiol in the treatment of severe premenstrual
syndrome. Br J Obstet Gynaecol. 1995;102:475-484.
PUBMED
17. Ahokas A, Kaukoranta J, Aito M. Effect of oestradiol on postpartum depression. Psychopharmacology. 1999;146:108-110.
PUBMED
18. Schmidt PJ, Nieman L, Danaceau MA, Tobin MB, Roca CA, Murphy JH, Rubinow DR. Estrogen replacement in perimenopause-related depression: a preliminary
report. Am J Obstet Gynecol. 2000;183:414-420.
FULL TEXT
|
ISI
| PUBMED
19. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders,
Fourth Edition. Washington, DC: American Psychiatric Association; 1995.
20. Spitzer RL, Williams JB, Kroenke K, Linzer M, de Gruy III FV, Hahn SR, Brody D, Johnson JG. Utility of a new procedure for diagnosing mental disorders in primary
care: the PRIME-MD 1000 Study. JAMA. 1994;272:1749-1756.
FREE FULL TEXT
21. Montgomery SA, Åsberg M. A new depression scale designed to be sensitive to change. Br J Psychiatry. 1979;134:382-389.
FREE FULL TEXT
22. Blatt MH, Weisbader H, Kupperman HS. Vitamin E and climacteric syndrome. Arch Intern Med. 1953;91:792-799.
FREE FULL TEXT
23. Mittmann N, Mitter S, Borden EK, Herrmann N, Naranjo CA, Shear NH. Montgomery-Åsberg severity gradations. Am J Psychiatry. 1997;159:1320-1321.
24. SPSS Statistical Package for Social Sciences, Version 8.0 for
Windows [computer program]. Chicago, Ill: SPSS Inc; 1997.
25. Karlberg J, Mattsson LA, Wiklund I. A quality of life perspective on who benefits from estradiol replacement
therapy. Acta Obstet Gynecol Scand. 1995;74:367-372.
ISI
| PUBMED
26. Joffe H, Cohen LS. Estrogen, serotonin, and mood disturbance: where is the therapeutic
bridge? Biol Psychiatry. 1998;44:798-811.
FULL TEXT
|
ISI
| PUBMED
27. Holte A. Menopause, mood and hormone replacement therapy: methodological issues. Maturitas. 1998;29:5-18.
PUBMED
28. Coope J, Thomson JM, Poller L. Effects of "natural oestrogen" replacement therapy on menopausal symptoms
and blood clotting. BMJ. 1975;4:139-143.
29. Strickler RC, Borth R, Cecutti A, Cookson BA, Harper JA, Potvin R, Riffel P, Sorbara VJ, Woolever CA. The role of oestrogen replacement in the climacteric syndrome. Psychol Med. 1977;7:631-639.
PUBMED
30. Thompson J, Oswald I. Effect of oestrogen on the sleep, mood, and anxiety of menopausal women. BMJ. 1977;2:1317-1319.
31. Scott RT Jr, Ross B, Anderson C, Archer DF. Pharmacokinetics of percutaneous estradiol: a crossover study using
a gel and a transdermal system in comparison with oral micronized estradiol. Obstet Gynecol. 1991;77:758-764.
PUBMED
32. Ramachandran C, Fleisher D. Transdermal delivery of drugs for the treatment of bone diseases. Adv Drug Deliv Rev. 2000;42:197-223.
PUBMED
33. Fraser IS, Wang Y. New delivery systems for hormone replacement therapy. In: Studd JWW, ed. The Management of the Menopause—Annual
Review. London, England: Parthenon Publishing Group Inc; 1998:101-110.
34. Bloch M, Schmidt PJ, Danaceau M, Murphy J, Nieman L, Rubinow DR. Effects of gonadal steroids in women with a history of postpartum depression. Am J Psychiatry. 2000;157:924-930.
FREE FULL TEXT
35. Muller P, Botta L, Ezzet F. Bioavailability of estradiol from a new matrix and a conventional reservoir-type
transdermal therapeutic system. Eur J Clin Pharmacol. 1996;51:327-330.
PUBMED
36. Delmas PD, Pornel B, Felsenberg D, Garnero P, Hardy P, Pilate C, Dain MP. A dose-ranging trial of a matrix transdermal 17ß-estradiol for
the prevention of bone loss in early postmenopausal women: International Study
Group. Bone. 1999;24:517-523.
PUBMED
37. McEwen BS, Alves SE, Bulloch K, Weiland NG. Ovarian steroids and the brain: implications for cognition and aging. Neurology. 1997;48:S8-S15.
38. Kendall DA, Stancel GM, Enna SJ. The influence of sex hormones on antidepressant-induced alterations
in neurotransmitter receptor binding. J Neurosci. 1982;2:354-360.
ABSTRACT
39. DeBattista C, Smith DL, Schatzberg AF. Modulation of monoamine neurotransmitters by estrogen: clinical implications. In: Leibenluft E, ed. Gender Differences in Mood
and Anxiety Disorders. Washington, DC: American Psychiatric Press;
1999:137-154.
40. Spitzer RL, Williams JB, Kroenke K, Hornyak R, McMurray J. Validity and utility of the PRIME-MD patient health questionnaire in
assessment of 3000 obstetric-gynecologic patients: the PRIME-MD Patient Health
Questionnaire Obstetrics-Gynecology Study. Am J Obstet Gynecol. 2000;183:759-769.
FULL TEXT
|
ISI
| PUBMED
41. Higgins ES. A review of unrecognized mental illness in primary care: prevalence,
natural history, and efforts to change the course. Arch Fam Med. 1994;3:908-917.
FREE FULL TEXT
42. Schuyler D. Depression comes in many disguises to the providers of primary care:
recognition and management. J S C Med Assoc. 2000;96:267-275.
PUBMED
43. Friedman LM, Furberg CD, DeMets DLF. Blindness. In: Friedman LM, Furberg CD, DeMets DL, eds. Fundamentals
of Clinical Trials. 3rd ed. New York, NY: Springer-Verlag NY Inc; 1998:82-93.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati  Twitter
What's this?
THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES
|
Moderation of antidepressant response by the serotonin transporter gene
Huezo-Diaz et al.
Br. J. Psychiatry 2009;195:30-38.
ABSTRACT
| FULL TEXT
Adult female wildtype, but not oestrogen receptor {beta} knockout, mice have decreased depression-like behaviour during pro-oestrus and following administration of oestradiol or diarylpropionitrile
Walf et al.
J Psychopharmacol 2009;23:442-450.
ABSTRACT
Presence of depressive symptoms during early pregnancy and the risk of preterm delivery: a prospective cohort study
Li et al.
Hum Reprod 2009;24:146-153.
ABSTRACT
| FULL TEXT
Approach to the Patient with Menopausal Symptoms
Martin and Manson
J. Clin. Endocrinol. Metab. 2008;93:4567-4575.
ABSTRACT
| FULL TEXT
Depression during menopausal transition: a review of treatment strategies and pathophysiological correlates
Frey et al.
Menopause Int 2008;14:123-128.
ABSTRACT
| FULL TEXT
Health related quality of life after combined hormone replacement therapy: randomised controlled trial
Welton et al.
BMJ 2008;337:a1190-a1190.
ABSTRACT
| FULL TEXT
Estrogen in Severe Mental Illness: A Potential New Treatment Approach
Kulkarni et al.
Arch Gen Psychiatry 2008;65:955-960.
ABSTRACT
| FULL TEXT
Low Free Testosterone Concentration as a Potentially Treatable Cause of Depressive Symptoms in Older Men
Almeida et al.
Arch Gen Psychiatry 2008;65:283-289.
ABSTRACT
| FULL TEXT
The Effects of Estradiol on Central Serotonergic Systems and Its Relationship to Mood in Women
Lasiuk and Hegadoren
Biol Res Nurs 2007;9:147-160.
ABSTRACT
Depressive Disorders Related to Female Reproductive Transitions
Serrano and Warnock
Journal of Pharmacy Practice 2007;20:385-391.
ABSTRACT
The resistance to depressive relapse in menopausal women undergoing tryptophan depletion: preliminary findings
Epperson et al.
J Psychopharmacol 2007;21:414-420.
ABSTRACT
Blinded trials taken to the test: an analysis of randomized clinical trials that report tests for the success of blinding
Hrobjartsson et al.
Int J Epidemiol 2007;36:654-663.
ABSTRACT
| FULL TEXT
Body Mass Index and Risk of Suicide Among Men
Mukamal et al.
Arch Intern Med 2007;167:468-475.
ABSTRACT
| FULL TEXT
Estrogen, Menopause, and the Aging Brain: How Basic Neuroscience Can Inform Hormone Therapy in Women
Morrison et al.
J. Neurosci. 2006;26:10332-10348.
FULL TEXT
Augmentation and combination strategies for depression
DeBattista
J Psychopharmacol 2006;20:11-18.
ABSTRACT
Associations of hormones and menopausal status with depressed mood in women with no history of depression.
Freeman et al.
Arch Gen Psychiatry 2006;63:375-382.
ABSTRACT
| FULL TEXT
Risk for new onset of depression during the menopausal transition: the Harvard study of moods and cycles.
Cohen et al.
Arch Gen Psychiatry 2006;63:385-390.
ABSTRACT
| FULL TEXT
Premenstrual Symptoms and Perimenopausal Depression
Richards et al.
Am. J. Psychiatry 2006;163:133-137.
ABSTRACT
| FULL TEXT
Duloxetine for the Treatment of Major Depressive Disorder in Women Ages 40 to 55 Years
Burt et al.
Psychosomatics 2005;46:345-354.
ABSTRACT
| FULL TEXT
Perimenopause and Sexual Functioning: Implications for Therapists
Cobia and Harper
The Family Journal 2005;13:226-231.
ABSTRACT
Effect of Estrogen-Serotonin Interactions on Mood and Cognition
Amin et al.
Behav Cogn Neurosci Rev 2005;4:43-58.
ABSTRACT
Hormone replacement therapy and antidepressant prescription patterns: a reciprocal relationship
McIntyre et al.
CMAJ 2005;172:57-59.
FULL TEXT
Guideline Watch: Practice Guideline for the Treatment of Patients With Major Depressive Disorder, 2nd Edition
Fochtmann and Gelenberg
Focus 2005;3:34-42.
FULL TEXT
A Longitudinal Evaluation of the Relationship Between Reproductive Status and Mood in Perimenopausal Women
Schmidt et al.
Am. J. Psychiatry 2004;161:2238-2244.
ABSTRACT
| FULL TEXT
Depression, Estrogen, and the Women's Health Initiative
Stewart et al.
Psychosomatics 2004;45:445-447.
ABSTRACT
| FULL TEXT
Depression increases in women during early to late menopause but decreases after menopause
Bosworth
Evid. Based Ment. Health 2004;7:90-90.
FULL TEXT
Postmenopausal Estrogen for Treatment of Hot Flashes: Clinical Applications
Nelson
JAMA 2004;291:1621-1625.
ABSTRACT
| FULL TEXT
Hormones and Menopausal Status as Predictors of Depression in Women in Transition to Menopause
Freeman et al.
Arch Gen Psychiatry 2004;61:62-70.
ABSTRACT
| FULL TEXT
Concordant Restoration of Ovarian Function and Mood in Perimenopausal Depression
Daly et al.
Am. J. Psychiatry 2003;160:1842-1846.
ABSTRACT
| FULL TEXT
Short-Term Use of Estradiol for Depression in Perimenopausal and Postmenopausal Women: A Preliminary Report
Cohen et al.
Am. J. Psychiatry 2003;160:1519-1522.
ABSTRACT
| FULL TEXT
Oestrogen, brain function, and neuropsychiatric disorders
Cutter et al.
J. Neurol. Neurosurg. Psychiatry 2003;74:837-840.
FULL TEXT
An Integrative Approach to Depression: Part 2--Assessment and Treatment
Zuess
Complementary Health Practice Review 2003;8:99-115.
ABSTRACT
Update in Women's Health
Freund et al.
ANN INTERN MED 2003;138:119-127.
FULL TEXT
OTHER ARTICLES NOTED (Nov 01 to 18 Oct 02)
Evid. Based Nurs. 2003;6:e1-1.
FULL TEXT
Combination Therapy in the Treatment of Major Depressive Disorder Complicated by Fibromyalgia and Menopause
Clayton and Kaltsounis-Puckett
Psychosomatics 2002;43:491-493.
FULL TEXT
Update in Psychiatry
Schneider and Levenson
ANN INTERN MED 2002;137:671-677.
FULL TEXT
Other Articles Noted
Evid. Based Ment. Health 2002;5:8-8.
FULL TEXT
17{beta}-estradiol reduced depressive and somatic symptoms in perimenopausal women
Thacker
Evid. Based Med. 2002;7:21-21.
FULL TEXT
Perspectives on Neuroscience and Behavior
Neuroscientist 2001;7:356-357.
Estradiol for Depression?
JWatch Women's Health 2001;2001:6-6.
FULL TEXT
Is Estrogen an Antidepressant?
JWatch Psychiatry 2001;2001:2-2.
FULL TEXT
Estrogen for Depression in Menopausal Women
JWatch General 2001;2001:6-6.
FULL TEXT
Increased anxiety and synaptic plasticity in estrogen receptor beta -deficient mice
Krezel et al.
Proc. Natl. Acad. Sci. USA 2001;98:12278-12282.
ABSTRACT
| FULL TEXT
|
