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The role of estrogen in bipolar disorder, a review

Article  in  Nordic Journal of Psychiatry · March 2013

DOI: 10.3109/08039488.2013.775341 · Source: PubMed

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 The role of estrogen in bipolar disorder,
a review
NINJA MEINHARD, LARS VEDEL KESSING, MAJ VINBERG

Meinhard N, Kessing LV, Vinberg M. The role of estrogen in bipolar disorder, a review.
Nord J Psychiatry 2012; Early Online:1–7.
Nord J Psychiatry Downloaded from informahealthcare.com by University of Copenhagen North on 03/19/13

Background: It appears that the female reproductive events and hormonal treatments may
impact the course of bipolar disorder in women. In particular, childbirth is known to be
associated with onset of affective episodes in women with bipolar disorder. During the female
reproductive events the sex hormones, e.g. estrogen, are fluctuating and particularly postpartum
there is a steep fall in the levels of serum estrogen. The role of estrogen in women with bipolar
disorder is, however, not fully understood. Aim: The main objective of this review is to
evaluate the possible relation between serum estrogen levels and women with bipolar disorder
including studies of the anti manic effects of the selective estrogen receptor modulator
tamoxifen. Method: A systematically literature search on PubMed was conducted: two studies
regarding the connection between serum estrogen levels and women with bipolar disorder were
identified. Furthermore, four studies were found concerning the antimanic effects of tamoxifen.
Results: Both studies in the estrogen studies showed very low levels of estrogen in women
with postpartum psychosis and significant improvement of symptoms after treatment with
For personal use only.

estrogen. The four tamoxifen studies found that tamoxifen was effective in producing antimanic
effects. Conclusion: These results indicate that estrogen fluctuations may be an important factor
in the etiology of bipolar disorder and it is obvious that more research on this topic is needed
to clarify the role of estrogen in women with bipolar disorder.
• Bipolar disorder, Estrogen, Mania, Tamoxifen.

Maj Vinberg, M.D., Ph.D., Psychiatric Center Copenhagen, Rigshospitalet, University Hospital
of Copenhagen, Blegdamsvej 9, DK-2100 Copenhagen, Denmark, E-mail: maj.vinberg@regionh.
dk; Accepted 6 February 2013

B ipolar disorder (BD) is a severe, recurrent mood

disorder that affects millions of lives worldwide,
yet the etiology of the illness remains unclear (1, 2).
Unipolar depressions is nearly twice as common in
women than men; in contrast, the lifetime prevalence
of BD is approximately equal in men and women
(3–6). However, it appears that there are some gender
differences in patients with BD even though results are
conflicting. It seems that bipolar subtypes like bipolar
disorder II (BDII) and rapid cycling are more common
in women than men, and that women more often than
men experience depressive and mixed episodes (7–9).
In addition, several studies have indicated that repro-
ductive events, especially childbirth, play a critical role
in the course of the illness (3). In fact, Munk-Olsen
et al. (10) estimated in a large register-based cohort
study that women with BD are more than 23 times
more likely to be admitted with an episode of BD
during the first postpartum month than during their
pregnancy (10).
These gender differences support further investigation
of the possible interaction between BD and reproductive-
related hormonal changes, particularly changes in the
main female sex hormone estrogen. Estrogen regulates
the menstrual cycle and prepares the uterus for preg-
nancy, but estrogen also has a broad spectrum of actions
in the CNS. For example, estrogen appears to function
as an agonist on the serotonergic system, by decreasing
the monoamine oxidase activity (the enzyme catabolizing
serotonin and dopamine) (5), and affecting the interneu-
ronal serotonin transport—both processes increasing the
level of serotonin in the synapse leading to possible
mood enhancement (11). Estrogen also plays a part in
other neurotransmitter systems: it increases the activity
of noradrenaline, acts as a cholinergic agonist and may
decrease dopamine D2 receptor sensitivity (5). Wieck
et al. (12) showed that postpartum psychosis is associ-
ated with increased sensitivity of the dopamine receptors
in the hypothalamus. These changes may be triggered by
the steep fall in estrogen concentrations after delivery.

© 2013 Informa Healthcare DOI: 10.3109/08039488.2013.775341

 N MEINHARD ET AL.
In 2003, Wieck et al. (13) demonstrated that in women
predisposed to postpartum BD there was increased dop-
aminergic receptor sensitivity in the luteal phase of the
menstrual cycle in the cases where the female sex hor-
mones are relatively increased. Both studies (12, 13)
suggest that the dopaminergic systems in women with
BD have increased sensitivity to changes in female sex
steroids.
Estrogen treatment increases the expression of the
important intracellular messenger, protein kinase C
(PKC) (14). PKC is a family of enzymes that phospho-
rylate neurotransmitter receptors, intracellular signaling
molecules and transcription factors (14). Biochemical
Nord J Psychiatry Downloaded from informahealthcare.com by University of Copenhagen North on 03/19/13
data support the potential involvement of PKC and its
substrates in bipolar patients (2), and mood stabilizers
such as lithium and valproate have been shown to be
inhibitors of PKC (3). Recently, tamoxifen, a selective
estrogen receptor modulator (SERM) and PKC inhibitor
was considered effective in the treatment of acute mania
(1, 2, 14, 15). Tamoxifen is one of several SERMs that
interact with intracellular estrogen receptors in target
organs as estrogen receptor agonists or antagonists (16).
Tamoxifen is widely used in the treatment of hormone-
sensitive breast cancer because of its antagonistic effects
on estrogen receptors in breast tissue. However, it is a
For personal use only.
complex agent with different effects in different tissues
(17). It has been shown that tamoxifen preserves bone
density (18) and lowers cholesterol concentrations, and
that tamoxifen increases the risk of endometrial cancer.
Other SERMs, e.g. raloxifen, also have agonistic and
antagonistic effects on estrogen receptors, but raloxifene
has failed in the treatment of breast cancer and is instead
the only SERM approved internationally for the preven-
tion and treatment of postmenopausal osteoporosis and
vertebral fractures (16). Knowledge concerning the use
of raloxifen in BD is sparse. The effect of tamoxifen in
the CNS is still controversial but Cyr et al. (19) showed
that tamoxifen had estrogenic effects on the serotonin
5HT2A receptor in some parts of the brain. These find-
ings all indicate that tamoxifen shows agonistic effects
on estrogen receptors in several tissues such as the
uterus, bone tissue, the blood and some parts of the
brain, and conversely shows antagonistic effects on estro-
gen receptors in breast tissue. Furthermore, tamoxifen is
also a PKC inhibitor, and is currently the only relatively
selective PKC inhibitor that crosses the blood–brain
barrier available for human use (2).
In summary, these are all findings making estrogen a
subject of major interest in BDs. There is, however, a
lack of literature evaluating the exact role of estrogen in
women with BD. The aim of this review is to evaluate
the role of estrogen in women with BD. Studies investi-
gating the connection between levels of serum estrogen
and women with BD will be in focus together with the
treatment effects of the SERM tamoxifen.
2 NORD J PSYCHIATRY·EARLY ONLINE·2013
Method
A systematic review of original English language studies
concerning estrogen, SERMs and BD, was conducted on
the PubMed database. The key words used were estrogen,
estradiol, bipolar disorder, bipolar depression, mania,
SERM and tamoxifen.
Articles investigating the connection between serum
estrogen concentrations and BD were included, while
studies only concerning estrogen concentrations in
patients with unipolar depression were excluded. Only
two studies were identified with actual measurement of
serum estradiol levels in patients with BD.
In the search for studies concerning the connection
between the MeSH terms bipolar disorder and SERM,
18 studies were identified—all of them concerning the
SERM tamoxifen. Four of the studies were clinical trials
regarding the antimanic effects of tamoxifen in patients
with BD. Animal trials were excluded. Further searches
were made to make sure that all relevant papers were
included.
Results
Studies evaluating the antimanic effect
of tamoxifen in bipolar patients
As can be seen from Table 1, four studies concerning
the treatment of acute mania with tamoxifen were iden-
tified. In total 135 participants were included, 61 men
and 74 women. The participants were all diagnosed with
BD and were in a manic phase at the time of treatment
(1, 2, 14, 15).
All studies were double-blinded, randomized, placebo-
controlled studies with a trial length of 21 days for the
shortest studies, up to 42 days (6 weeks) for the longest.
Three out of four studies used the Young Mania Rating
Scale (YMRS) as the primary outcome measure, but
other scores were also used (Table 1). The participants
all had an entry scores of minimum 14 on the YMRS.
One study used the Clinician Administered Rating Scale
for Mania (CARS-M) as primary outcome measure and
had an entry score of 15. The four studies main objec-
tive was to perform a controlled test of the antimanic
efficacy of the SERM and PKC inhibitor tamoxifen.
In all studies, participants were treated with either
tamoxifen or placebo. One study (1) tested and compared
the use of two hormonal agents, tamoxifen and medroxy-
progesterone (MPA), for the treatment of acute mania
and hypomania. MPA was in this study chosen as a pro-
gesterone agent to compare a hormonal modulator with-
out PKC inhibition with a SERM with potent PKC
inhibition. The same study was the only study that mea-
sured estradiol, progesterone and luteinizing hormone
(LH) assay. In two studies (1, 15) the participants
received lithium and/or valproate as baseline treatment,
and the level of lithium and valproate were monitored
 THE ROLE OF ESTROGEN IN BIPOLAR DISORDER

MPA, medroxyprogesterone acetate (progesterone); YMRS, Young Mania Rating Scale, a diagnostic questionnaire to measure the severity of manic symptoms; PANSS, Positive and Negative Syndrome
Scale, an interview to rate the severity of psychotic symptoms; CARS-M, Clinician-Administered Rating Scale for Mania, rating scale to measure the manic symptoms; HAMD-17, Hamilton Depression
Estrogen
weekly. In the two other studies (2, 14), all psychotropic

(pmol/l)

⫹ 392.2

⫺ 266.7
⫺ 74.5

NA
NA
NA
NA
NA
NA
medications, with the exception of benzodiazepines, were
discontinued at least 48 h before randomization. Three of
the studies (2, 14, 15) allowed concomitant use of lora-

HAMD-175

⫺ 0.97
zepam, a benzodiazepine agonist. Lorazepam was allowed

⫺ 2.1
⫺ 0.8

⫺ 1.1
NA
NA
NA
NA
NA
in doses of 2–5 mg/24 h in the first 10–12 days of the
trial. After the initial 10–12 days, lorazepam was avoided
whenever possible.
CARS-M4

⫺ 22.2
⫺ 8.50
⫺ 13.0 Participants treated with tamoxifen showed a signifi-
NA
NA
NA
NA
NA
NA
cant improvement in manic symptoms compared with the
placebo groups. In one study, the tamoxifen group
showed significant improvement from baseline as early
PANSS3

⫺ 20.4
⫹ 10.4

⫺ 17.6
(total)

⫺ 4.7
NA
NA
⫺ 20

⫺ 30
as day 5, continuing throughout the trial. In comparison,
⫺2
Nord J Psychiatry Downloaded from informahealthcare.com by University of Copenhagen North on 03/19/13

the placebo group showed no significant change from

baseline at any point (2). The group treated with MPA
YMRS2

⫺ 23.05
⫺ 18.3

⫺ 18.3

⫺ 29.8
NA
NA
NA

⫹ 4.7

⫹ 2.9

(1) also showed a significant improvement in manic

symptoms and decrease in positive symptoms of psycho-
sis compared with the placebo group. The within-group
Study length

improvement in mania, though, was only significant in

(days)

28

21

21

42

the tamoxifen group, not in the MPA group. In addition,

this study showed that participants receiving tamoxifen
had a considerable increase in estradiol level while the
1–1.2 mEq/l 40–80

women receiving MPA and placebo had decreases in

Dose, mg/day

1–1.2 mEq/l

estradiol level (Table 2).

20–140

40–80
40

20

The two studies using lithium as a baseline treatment

Table 1. Results and characteristics of bipolar patients randomized to receive tamoxifen vs. placebo.
For personal use only.

(1, 15) demonstrated that the combination of tamoxifen

with lithium was superior to lithium solely concerning
the rapid reduction of manic symptoms. In one of these
(mean)
Age

30,2

30.4
30.9

studies (15), the patients were defined as responders if

36
41
36
34
29
36

they demonstrated an at least 50% improvement in

YMRS scores from baseline, and as remitters if they had
female (%)

5 (100%)
4 (100%)
4 (100%)
Gender,

2 (25%)
18 (51%)
16 (52%)
12 (60%)
13 (65%)

an YMRS score of 7 or less at endpoint. In this study,

0

both groups showed a significant change on the YMRS

compared with baseline at day 7 and at the end of trial.
In terms of percentage of responders at week 1 and at
Number who
finished trial

endpoint, there was a significant difference between the

5
4
4
4
5
29
21
19
18

two treatments (Table 1).

In three studies, the total score of the Positive and
Negative Syndrome Scale (PANSS) also showed a signif-
randomized

icant improvement in the tamoxifen group compared with

Number

NA
NA
NA
8
8
35
31
20
20

placebo (1, 14, 15). The negative subscales, however,

scale, a rating scale to measure depressive symptoms.

showed no significant changes with either treatment (14).

Two studies used the Hamilton Depression scale
Tamoxifen ⫹ lithium

Lithium ⫹ tamoxifen
Medication group

(HAMD-17) to monitor depressive symptoms (14, 15).

Lithium ⫹ placebo
Placebo ⫹ lithium

In one study there was a trend towards a lower depres-

MPA ⫹ lithium

sion score (14) in the tamoxifen group but in none

Tamoxifen

Tamoxifen

of the studies was the difference statistically significant

Placebo

Placebo

(14, 15). Furthermore, in one study (14) the participants

in the tamoxifen group showed a higher reduction in
their use of lorazepam per week than the placebo group.
Amrollahi et al. (15)
Kulkarni et al. (1)

Yildiz et al. (14)

Zarate et al. (2)

Studies evaluating the treatment effect of estradiol

in postpartum psychosis
As can be seen from Table 2, two studies investigating
Study

the relation between low estrogen levels in women with

NORD J PSYCHIATRY·EARLY ONLINE·2013 3

 N MEINHARD ET AL.

postpartum psychosis and clinical response to treatment

Mean duration of
symptoms before
baseline measure

73.0 ⫾ 65.2 days

with sublingual 17β estradiol were identified. In total, 12
women with BD were included and both studies showed

2 months
very low levels of estrogen in women with postpartum

7 days
psychosis (20, 21). Both studies were open-label trials
delivery to onset
measuring serum concentration of estradiol before and
after treatment with 17β estradiol in women with post-

12.3 ⫾ 8.3 days

of symptoms
Time from

partum psychosis. One study (20) was a case study

2 months
1 months
including only two participants; the other study included
10 participants (21). Both studies used the Brief Psychi-
atric Rating Scale (BPRS) to evaluate the psychotic
symptoms and none of the studies used control groups.
30.6 ⫾ 5.3
Age

Results and characteristics of the participants are shown

31
22
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in all the studies in which serum estradiol levels at base-

BPRS, Brief Psychiatric Rating Scale, a rating scale to measure psychiatric symptoms such as depression, anxiety, hallucination and unusual behavior.

line were lower than the threshold for gonadal failure

Week 6

(⬍ 110 pmol/l) in all patients. All patients were treated

692
NA
NA

0.2

with 17β estradiol, 1 mg sublingually three to six times

daily according to the serum concentration. The goal was
Week 5

to reach about one third of the peak level during a nor-

NA
NA
NA
NA

mal menses rhythm: approximately 400 pmol/l.

In one study (21), 10 women meeting the ICD-10 cri-
teria of psychosis with postpartum onset were recruited.
Week 4

0.9

Patients with long duration of symptoms had mild symp-

410
610
615

toms at the beginning of their illness, which progressed

until the patients were floridly psychotic. Within 2 weeks
Week 3
For personal use only.

600
530
NA
NA

of treatment with 17β estradiol, the serum estradiol lev-

els increased in nearly all patients to about the levels
normally found during the follicular phase (Table 2). One
Week 2

4.1

patient discontinued estradiol treatment after 5 weeks,

320
330
431

and 1 week later, her estradiol concentration had

Table 2. Results and characteristics of the participants treated with 17β estradiol.

decreased to near the pretreatment level (from 1000 to

Week 1

18.8

46 pmol/l). After a week of treatment, the total scores of

470
160
362

psychosis symptoms were significantly decreased. After

2 weeks of treatment, all patients were almost free of
Week 0

psychiatric symptoms, but the patient who stopped estra-

49.5
78.3
79
54

diol treatment developed florid psychotic symptoms by

the end of the following week.
Measure of outcome (mean)

The other study (20) presented two cases with women

Serum estradiol (pmol/l)
Serum estradiol (pmol/l)
Serum estradiol (pmol/l)

having a postpartum psychosis. Both patients had docu-

mented estrogen deficiency and were refractory to neuro-
leptic medication.
Case 1 described a 31-year-old woman who after her
second childbirth was included in the trial just described
BPRS

above (21) because of a postpartum psychosis. She was

at that time successfully treated with estradiol. This
time, 2 months after her third childbirth, she became
Case A1
Case B1

psychotic again (Table 2). She began treatment with

n

sublingual 17β as monotherapy and 1 week later the

10

symptoms had diminished significantly. After 2 weeks

she was almost recovered (BPRS ⫽ 2). The estradiol
Ahokas & Aito (20)

Ahokas et al. (21)

treatment continued for 5 months and was gradually

reduced after her first spontaneous menstruation. Case 2
involved a 22-year-old woman with no personal or fam-
ily history of psychiatric disorders (Table 3). She began
Study

to have broken sleep and anxiety symptoms 1 month

4 NORD J PSYCHIATRY·EARLY ONLINE·2013


after childbirth, which progressed until 3 months postpar-
tum where she became psychotic with paranoid delusions
and audible hallucinations. For 2 weeks she was treated
with chlorpromazine, but the effect was unsatisfactory.
When she came to the psychiatric consultation, she had a
high BPRS score and a low serum estradiol level. Treat-
ment with sublingual 17β estradiol was given as mono-
therapy. Two weeks later she was almost free of symptoms
(for results, see Table 2). Six months later, she was still
free of symptoms but 2 weeks after she discontinued the
medication she had a recurrence of florid psychotic symp-
toms. The serum estradiol level after discontinuation of
medication was not determined in the hospital.
Nord J Psychiatry Downloaded from informahealthcare.com by University of Copenhagen North on 03/19/13
Discussion
The tamoxifen trails all demonstrated significant anti-
manic effects. In addition, one study showed that MPA,
with no PKC inhibitor effect, also had antimanic effects.
Furthermore, one study (1) showed a significant increase
in serum estradiol levels in the tamoxifen group. Both
estrogen trials showed a significant improvement of
symptoms after treatment with estrogen in women with
postpartum psychosis (20, 21). The studies also showed
a recurrence of psychotic symptoms and a decline in
For personal use only.
serum estradiol in the patients who discontinued the
estradiol treatment.
These findings indicate that hormonal changes, e.g.
estrogen, could be an important factor in the etiology
of the disease. This is in concordance with two other
naturalistic studies. The first study following 47 women
with BD for 17.0 ⫾ 14.0 months (22). It was concluded
that women with BD experience a high frequency of
depressive episodes during perimenopausal years and
this frequency appears greater than during prior repro-
ductive years. The second study, from the same group
as the first but including a large sample of 748 women
followed over 19.8 ⫾ 15.5 months, showed that a pro-
gression in female reproductive stages was associated
with bipolar illness exacerbation (23).
The tamoxifen trials
The results regarding the treatment of acute manic epi-
sodes with tamoxifen seem very promising. Whether
tamoxifen has a potential as a maintenance treatment or
antidepressive in patients with BD remains unclear and
studies with longer duration are needed to clarify this.
There are still many patients who respond poorly to the
main mood stabilizing agents, e.g. lithium and valproate
(1), and especially women have shown poorer adherence
to lithium than men (24). This makes the investigation of
other treatment possibilities important.
The described studies were all performed as double-
blinded, randomized, placebo-controlled studies, therefore
making the level of evidence high. However, there are
NORD J PSYCHIATRY·EARLY ONLINE·2013
THE ROLE OF ESTROGEN IN BIPOLAR DISORDER
some limitations to the studies. Firstly, the small sample
sizes are a problem; although all studies show significant
results, more and larger studies are needed before con-
sidering the implementation of tamoxifen in the treat-
ment of acute mania. Secondly, most of the studies were
short-term trials that may demonstrate greater symptom-
atic improvement than placebo, but the study durations
are too brief to quantify, e.g. functional recovery, side-
effects in the long term (14).
The mechanisms of tamoxifen
All articles concerning tamoxifen lean towards the
conclusion that the PKC inhibitor effect of tamoxifen
is essential in the treatment of acute mania. At the same
time, none of the articles can rule out the potential
contributory agonistic/antagonistic effect of tamoxifen
on estrogen receptors (1, 2, 14, 15). They all refer to
tamoxifen as an “anti-estrogen” compound and only one
study (1) mentions that tamoxifen may have a direct
estrogenic effect in some tissues.
Kulkarni et al. (1) included women only and found
that the participants in their tamoxifen group showed
a substantial increase in estradiol level compared with
the participants in the placebo and MPA groups that
showed a decrease in estradiol levels. These results are
not discussed and no plausible explanation is suggested
in the article. It is possible that tamoxifen stimulates
ovarian steroid genesis and consequently increases
estradiol levels. Cohen et al. (25) showed that treatment
with tamoxifen induced significantly higher levels of
serum 17β estradiol in premenopausal women with
breast cancer compared with non-treated breast cancer
patients. Furthermore, this group showed that tamoxifen
increased the incidence of ovarian cysts. The follicular-
stimulating hormone (FSH) and LH remained unchanged
that may indicate that tamoxifen acts directly on the
ovary to increase steroid genesis (25). Consequently, it
is of interest to identify which component of tamoxifen
is responsible for the antimanic properties. It could
be the PKC inhibition as suggested in all studies con-
cerning tamoxifen or it may be the effects on estrgen
receptors in some tissues, which none of the studies
can rule out (1, 2, 14, 15). Another possibility is that it
actually is the higher level of serum estradiol that
exhibits antimanic properties. The latter might be sup-
ported by the antipsychotic effects of estrogen treatment
in women with postpartum psychosis (20, 21).
Kulkarni et al. (1) suggests that MPA may play a role
in the treatment of manic symptoms. As MPA is not a
PKC inhibitor, this indicates that its PKC inhibitor effects
may not cause the antimanic effect of tamoxifen only.
Conversely, both men and women are successfully treated
with tamoxifen and other well known antimanic agents
such as lithium and valproate also have PKC inhibitor
effects (2).
5
 N MEINHARD ET AL.
The estrogen trials
The trials concerning treatment of women with postpar-
tum psychosis with estrogen are interesting because they
verify a treatment that may have etiological relevance to
postpartum psychiatric disorders (20, 21). It seems that
treatment with estrogen is effective in women with both
early and late onset of psychosis and especially in women
with documented estradiol deficiency. Furthermore, the
women who stopped the estradiol treatment too early had
a drop in their estrogen levels and relapsed with psy-
chotic symptoms within a week (20, 21).
There are, however, several limitations in the two
estrogen trials. Firstly, the studies have very small sam-
Nord J Psychiatry Downloaded from informahealthcare.com by University of Copenhagen North on 03/19/13
ple sizes. Secondly, in the first study (21), four out of
10 patients received psychotropic medication before
estradiol treatment. This was, however, without ade-
quate effect and the treatment was stopped during the
first week of estradiol treatment. Thirdly, the trials were
performed as open-label clinical trials with no control
group, thus it was not possible to compare the serum
estradiol levels with mentally well women. Childbirth
is an event of drastic endocrinological alterations in a
woman’s body. Serum estradiol is very high at the end
of pregnancy, and declines sharply after parturition
(26). In these studies, however, we cannot see whether
For personal use only.
the serum estradiol is even lower than normal or
whether the psychosis is maybe a consequence of
greater susceptibility to the estradiol fluctuation. Finally,
it should be noted that the same group of scientists
performed both studies.
Safety and tolerability
The participants treated with tamoxifen all seemed to tol-
erate tamoxifen rather well. Only loss of appetite (2) and
fatigue (15) had a statistically significant more frequent
occurrence in the tamoxifen group compared with the
placebo group. One study (14) reported complaints
including dermatological changes and other non-specific
somatic symptoms (14). The estrogen trials had no reports
of side-effects. However, although tamoxifen have many
benefits, it is known that it also have some potentially
serious adverse effects, such as thromboembolic disorders
and, because of its agonistic effect in the uterus, uterine
cancer (26). These adverse effects represent a major con-
cern if long-term treatment of patients with BD is con-
sidered. Another SERM, i.e. raloxifen, has not yet to our
knowledge been used in correlation with BD probably as
tamoxifen is the only known centrally active PKC inhibi-
tor available for human use (14). The ideal SERM with
antiestrogenic effects on breast tissue, estrogenic effects
on bone and serum lipids, and neutral effects on the
uterus should be under development (26), but whether
this SERM will have antimanic effects we can only pre-
dict. Concerning estradiol as supplementation therapy, the
6 NORD J PSYCHIATRY·EARLY ONLINE·2013
side-effects are known to be nausea, headache, breast
tenderness, hypertension, an increased probability of
developing a thromboembolic event, and risk of breast or
endometrial cancer (27). The risk of endometrial and
breast cancer restricts its use as a long-term treatment as
antidepressant.
Limitations
The present findings should be interpreted with caution
because of the heterogeneity among studies, the low
study numbers and few participants, the results thus
being more influenced by selection bias and confound-
ing factors (age, prior course of illness, tobacco use,
sex hormone changes due to natural menstrual cycle).
Furthermore, other clinical parameters like physical
activity, alcohol intake and medication (in particular
antipsychotic medication and mood stabilizers) can
potentially alter the estrogen level.
Conclusion
The knowledge of the relation between estrogen and
patients with BD are still limited. This review, however,
supports the hypothesis that estrogen plays a role in the
course of BD. All four studies concerning tamoxifen
demonstrated that tamoxifen has significant antimanic
effects. In addition, it was showed that MPA, with
no PKC inhibitor effect, also had antimanic effects.
Furthermore, a study exhibited a significant increase in
serum estradiol levels in the tamoxifen group (1). The
estradiol studies demonstrated a significant improvement
of symptoms after treatment with estrogen in women
with postpartum psychosis (20, 21). The studies also
showed a recurrence of psychotic symptoms and a
decline in serum estradiol in the patients who discontin-
ued the estradiol treatment.
In summary, these findings indicate that hormonal
changes, e.g. estrogen, could be an important factor in
the etiology of the disease. Although it seems likely that
estrogen plays a role in the course of BD, it is clear that
more research in this area is needed. In future studies, it
is important to determine whether estrogen levels are
abnormal in women with BD or whether women with
BD are especially vulnerable to changes in hormone
levels. Furthermore, studies estimating the estrogen
levels and the PKC activity would be of great use for
clarifying the mechanisms of tamoxifen.
Declaration of interest: LVK has been a consultant for
Bristol-Myers Squibb, Eli Lilly, Lundbeck, AstraZeneca,
Pfizer, Wyeth and Servier. MV has been a consultant for
Eli Lilly, Lundbeck, AstraZeneca and Servier. NM
declares no conflicts of interest. The authors alone are
responsible for the content and writing of the paper.

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Ninja Meinhard, MD, Psychiatric Center Copenhagen, Rigshospitalet,
University Hospital of Copenhagen, Blegdamsvej 9, DK-2100
Copenhagen, Denmark.
Lars V. Kessing, Professor, MD, DMSc. Psychiatric Center
Copenhagen, Rigshospitalet, University Hospital of Copenhagen,
Blegdamsvej 9, DK-2100 Copenhagen, Denmark.
Maj Vinberg MD, Ph.d. Psychiatric Center Copenhagen, Rigshospitalet,
University Hospital of Copenhagen, Blegdamsvej 9, DK-2100
Copenhagen, Denmark.
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