MJA • Volume 190 Number 4 • 16 February 2009
PATHWAYS TO SCHIZOPHRENIA
The Medical Journal of Australia ISSN: 0025-
729X 16 February 2009 190 4 S37-S38
©The Medical Journal of Australia 2009
Randomised controlled trials are providing evidence for the use of
oestradiol to ameliorate the symptoms of schizophrenia.
ne of the most compelling hypotheses to emerge in the
understanding of the possible causes and potential new
treatments for schizophrenia is the oestrogen protection
hypothesis.1,2 The hypothesis is described in two parts:
• In women, oestrogen “protects” women from developing severe
schizophrenia at an early age.
• Fading oestrogen secretion at menopause in vulnerable women
leads to relapse of schizophrenia symptoms or new, late-onset
There are three main areas of support for the oestrogen protec-
tion hypothesis — epidemiological findings, clinical evidence and
animal studies exploring the effects of oestrogens on key neuro-
transmitters that are implicated in producing psychotic symptoms.
Epidemiological sex differences in schizophrenia have been
reported for over a century. In 1910, Kraepelin described a later
age of first admission for women with schizophrenia compared
with men.3 A review of over 50 studies showed the same sex
difference in the age of admission and onset of the first episode of
schizophrenia.4 In a population-based sample of 232 first-episode
schizophrenia presentations, there was a steep early increase in the
age of schizophrenia onset in men between the ages of 15 and 25
years.5 In women, the rates of onset were less steep and had a
broader age of onset between the ages of 15 and 30 years plus a
smaller, second peak between the ages of 45 to 50 years.5 This
pattern of sex differences has been replicated worldwide in
population studies, such as the Danish Case Register.6
A clinical study has shown that perimenopausal women with
schizophrenia required increased antipsychotic drug doses to
maintain remission.2 This study strongly suggested that due to the
declining oestrogen levels during menopause and beyond, the
“protective” or “antipsychotic” effect of oestrogen is diminished,
leading to the patient requiring a greater dose of antipsychotic
medication to treat symptoms of schizophrenia. A small study of
32 women found that psychotic symptoms were worse during the
low-oestrogen phase of their menstrual cycles.7 This suggests that
higher circulating oestradiol levels provide an antipsychotic effect
for women with schizophrenia.8
Many animal studies have demonstrated several neuroprotective
effects of oestrogens. Dopamine and serotonin are key neurotrans-
mitter systems involved in the formation of the main symptoms of
schizophrenia, and oestrogen has a psychoprotective action that
appears to be mediated by central dopaminergic and serotonergic
mechanisms.9 The effects of oestrogen are broadly classified into
the slower, classical, intracellular “genomic” and the more rapid,
direct, non-genomic actions.10 Both the genomic and direct effects
of oestrogen on the central nervous system are thought to contrib-
ute to oestrogen’s antipsychotic properties.
Clinical trials of oestrogen in schizophrenia
Following these epidemiological, clinical, and animal study results,
we conducted a series of clinical trials of oestradiol in women of
child-bearing age with schizophrenia. Beginning with an open-label
pilot study,11 we found that women who received 2mg oral
oestradiol valerate made a significantly more rapid recovery from
acute psychotic symptoms and reported improvement in their
general health status compared with a matched control group who
did not receive oestradiol (P<0.05).
Subsequent to this, we conducted a dose-finding study for the
optimal use of oestradiol in women with schizophrenia.12 This was a
three-arm, double-blind, placebo-controlled 28-day study, in which
12 women received 50μg transdermal oestradiol plus standardised
antipsychotic drug, 12 women received 100μg transdermal oestra-
diol plus standardised antipsychotic drug, and 12 women received
placebo plus standardised antipsychotic drug. All of the women had
a diagnosis of schizophrenia according to the Diagnostic and statisti-
cal manual of mental disorders, fourth revision (DSM-IV). The group
receiving adjunctive 100μg oestradiol showed greatest improvement
across the study compared with the other two groups using the well
validated Positive And Negative Syndrome Scale (PANSS) rating
To extend our findings, we conducted a proof-of-concept study of
102 women with DSM-IV schizophrenia.14 In this double-blind
randomised controlled 28-day study, women received either an
active 100μg oestradiol skin patch treatment (n=56) or an identical
Oestrogen — a new treatment approach for schizophrenia?
• The oestrogen protection hypothesis proposes that
oestrogen has a protective effect against onset of
schizophrenia. In support of this:
? Epidemiological studies have shown that young women
are less likely to develop schizophrenia than men of the same
age, and women are more likely to develop late-onset
schizophrenia after menopause.
? Clinical studies have shown higher psychotic symptoms in
perimenopausal women, and women at the low oestrogen
phase of the menstrual cycle.
? Animal studies provide further evidence in support of the
oestrogen protection hypothesis.
? Three randomised double-blind placebo-controlled trials
and an open-label study showed that adding oestradiol to
women’s usual antipsychotic medications was associated with
significant abatement of schizophrenia symptoms.
? A small study of men with schizophrenia who received oral
oestradiol valerate also showed a significant abatement in
• Although oestrogen appears to be a useful treatment for
schizophrenia, further research is required to determine the
correct dose and duration of use of oestradiol.
• New types of oestrogen compounds may provide a safer,
non-feminising approach for the treatment of schizophrenia.
MJA 2009; 190: 37–38
S38MJA • Volume 190 Number 4 • 16 February 2009
placebo patch (n=46). All patients received antipsychotic drug
treatment according to a standardised protocol. Psychopathology
was assessed by the PANSS. Serum levels of oestrogen, progesterone,
prolactin, luteinising hormone, and follicle stimulating hormone
were measured. Several cognitive tests was also administered. We
found that patients who received the 100μg oestradiol adjunct made
a significantly better recovery in their total, positive, negative and
general symptoms of schizophrenia than the patients who received
standard antipsychotic medication only (P<0.01). Women who
received the oestradiol patch also showed significant improvement
in cognition (P<0.01).
We are currently undertaking a three-site replication and dose-
finding study of 100μg transdermal oestradiol adjunct compared
with 200μg transdermal oestradiol adjunct versus placebo adjunct
in 180 women of child-bearing age with schizophrenia. Called
ADEPT (A Definitive Estrogen Patch Trial), it is an 8-week trial with
tighter control of the concurrent antipsychotic medication and
comprehensive cognitive testing.
Results from our studies provide strong evidence for the oestrogen
protection hypothesis. We found that the addition of transdermally
delivered oestradiol was associated with significant abatement of
psychotic symptoms in women with DSM-IV schizophrenia when
compared with standardised antipsychotic drug treatment alone
(P<0.01). The impact of administering 100μg of oestradiol
transdermally, as indicated by its effect on the pituitary gland
(measured by luteinising hormone assay), suggests that this dose
and type of unconjugated oestrogen directly affects the hypotha-
lamic–pituitary–gonadal axis, and appears to have an antipsychotic
effect on the dopamine and serotonin systems.
A commonly asked question is whether the addition of oestrogen
to antipsychotic treatment would be useful for men with schizo-
phrenia. As the oestrogen protection hypothesis states that oestrogen
is a potent neuroprotective agent, oestrogen should also have a
protective effect on men with schizophrenia.
We tested the use of adjunctive oestradiol in a small sample of 11
men with schizophrenia.15 We gave 2mg oral oestradiol valerate as
an adjunct to six men who were taking antipsychotic drugs. Five
men received oral placebo plus their standard antipsychotic medica-
tion for 7 days. Our small study was only conducted for 7 days to
avoid feminisation and other side effects in the men. The groups
were matched for age, illness severity and duration. Oral, rather than
transdermal, oestradiol was used to ensure treatment adherence in
men with acute psychosis. Psychopathology was assessed using the
standardised rating scales, PANSS and the Brief Psychiatric Rating
Scale.16 By Day 5, the oestradiol group showed significant abate-
ment of psychotic symptoms compared with the placebo group and,
by Day 7, the oestradiol group made further improvements. This
study, although small in sample size and short in duration, raises the
possibility that non-feminising oestrogen may provide useful treat-
ment possibilities for men with schizophrenia.
The use of oestrogen as a potential treatment for schizophrenia
opens up exciting new possibilities for both the preventive and acute
treatment of schizophrenia in men and women. There is still
considerable research to be done to determine the correct dose and
duration of use of oestradiol, its safe use in women and men with
schizophrenia with respect to the known side effects, and whether it
may be used eventually as a standalone medication rather than as an
We are currently conducting clinical trials of new types of
oestrogen compounds — the selective oestrogen receptor modu-
lators, or “brain oestrogens”. This rapidly developing area of hor-
mone treatments may be a potentially safer, non-feminising new
approach for the treatment of schizophrenia and other mental
illnesses in women and men. Studying the mechanisms by which
oestrogen potentially ameliorates psychotic symptoms may also
further our understanding of the aetiology of schizophrenia. We are,
of course, mindful of the potential adverse effects of oestrogen
treatments as highlighted by the Women’s Health Initiative Study.17
It is important to monitor patients’ general health while using short-
term oestradiol adjuncts.
We need new treatments, such as oestrogen, to help people with
schizophrenia achieve symptom remission and significantly improve
their quality of life.
Jayashri Kulkarni, MBBS, FRANZCP, PhD, Professor and Director
Alfred Psychiatry Research Centre, Monash University and Alfred
Hospital, Melbourne, VIC.
1 Häfner H. The epidemiology of beginning schizophrenia. In: WPA section of
Epidemiology and Community Psychiatry Symposium; 1991 Jun 14–16; Oslo.
2 Seeman MV, Lang M. The role of estrogens in schizophrenia gender
differences. Schizophr Bull 1990; 16: 185-195.
3 Kraepelin E. Dementia praecox and paraphrenia (translated by Barclay RM,
Robertson GM). Extracted from: Psychiatrie. Vol 3. 8th ed (1910). Edin-
burgh: Livingstone, 1919.
4 Angermeyer MC, Kühn L. Gender differences in age at onset of schizophre-
nia. Eur Arch Psychiatry Neurol Sci 1988; 237: 351-364.
5 Häfner H. Gender differences in schizophrenia. In: Bergemann N, Riecher-
Rössler A, editors. Estrogen effects in psychiatric disorders. Vienna:
Springer-Verlag, 2005: 53-94.
6 Loffler W, Häfner H, Fatkenheuer B, et al. Validation of Danish case register
for schizophrenia. Acta Psychiatr Scand 1994; 90: 196-203.
7 Riecher-Rössler A, Häfner H, Stumbaum M, et al. Can estradiol modulate
schizophrenic symptomatology? Schizophr Bull 1994; 20: 203-214.
8 Riecher-Rössler A. Estrogens and schizophrenia. In: Bergemann N, Riecher-
Rössler A, editors. Estrogen effects in psychiatric disorders. Vienna:
Springer-Verlag, 2005: 31-52.
9 Fink G. The psychoprotective action of estrogen is mediated by central
serotonergic as well as dopaminergic mechanisms. In: Takada A, Curzon G,
editors. Serotonin in the central nervous system and periphery. Amster-
dam: Elsevier Science BV, 1995: 175-187.
10 Mosselman S, Polman J, Dukema R. ER beta: identification and characteri-
zation of a novel human estrogen receptor. FEBS Lett 1996; 392: 49-53.
11 Kulkarni J, de Castella A, Smith D, et al. A clinical trial of the effects of
estrogen in acutely psychotic women. Schizoph Res 1996; 20: 247-252.
12 Kulkarni J, de Castella A, Riedel A, et al. Estrogen — a potential new
treatment in schizophrenia. Schizophr Res 2001; 48: 137-144.
13 Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale
(PANSS) for schizophrenia. Schizophr Bull 1987; 13: 261-276.
14 Kulkarni J, de Castella A, Fitzgerald P, et al. Estrogen in severe mental illness.
A potential new treatment approach. Arch Gen Psychiatry 2008; 65: 955-960.
15 Kulkarni J. Clinical estrogen trials in patients with schizophrenia. In:
Bergemann N, Riecher-Rössler A, editors. Estrogen effects in psychiatric
disorders. Vienna: Springer-Verlag, 2005: 107-123.
16 Overall JE, Gorham DR. The Brief Psychiatric Rating Scale. Psychol Rep
1962; 10: 799-812.
17 Chlebowski RT, Hendrix SL, Langer RD, et al; WHI Investigators. Influence
of estrogen plus progestin on breast cancer and mammography in healthy
postmenopausal women: the Women’s Health Initiative Randomized Trial.
JAMA 2003; 289: 3243-3253.
(Received 9 Jun 2008, accepted 26 Oct 2008)