August 7, 2008 — In women with severe schizophrenia, adding 100 µg a day of transdermal estradiol significantly reduced symptoms compared with antipsychotic medication alone.
The 28-day double-blind, placebo-controlled study extends and confirms previous findings by investigators led by psychiatrist Jayashri ulkarni, PhD, at the Alfred and Monash University in Melbourne, Australia.
"There is a lot to be done, but I believe that we have opened up a new and promising area of treatment for a debilitating illness in both men and women," said Dr. Kulkarni.
These findings also validate the observation by many women that exacerbation or recurrence of psychosis is observed during low-estrogen phases of the menstrual cycle, and symptoms improve during high estrogen phases, she told Medscape Psychiatry.
In the current study, compared with women in the placebo group, those in the estradiol group exhibited a significantly greater improvement in positive and in general psychopathologic symptoms, as measured by the Positive and Negative Syndrome Scale (PANSS), she noted.
A subgroup of approximately 12 women made a "truly dramatic" recovery, going from a PANSS score of approximately 80 to a score of 10, she added.
The study is published in the August issue of the Archives of General Psychiatry.
Therapeutic Role for Estrogen?
In the early 1990s, 3 lines of evidence suggested that estrogen might be a potential therapy for severe mental illness, Dr. Kulkarni said.
First, animal studies showed that estradiol profoundly affected dopamine and serotonin, key neurotransmitters in schizophrenia.
Second, epidemiologic studies suggest that estrogen might have a protective effect that accounts for the later onset of schizophrenia in women. Researchers found that the peak onset of schizophrenia in men is between ages 16 and 49 years. In women, a first peak of onset occurs at approximately 25 to 30 years of age (which includes postpartum onset), and a second peak occurs at approximately 45 to 50 years of age (which includes perimenopausal onset), said Dr. Kulkarni.
Third, clinical studies found that women with schizophrenia relapsed in the low estrogen phase of their menstrual cycles, whereas other women relapsed when they were perimenopausal, and others had postpartum psychosis coinciding with a sudden decrease in estradiol levels.
This initial research led to a small pilot study in women by the current investigators, which suggested that 100 µg a day of adjunctive transdermal estradiol led to significant improvement in psychotic symptoms vs placebo.
The current study was designed to provide adequate power to compare the efficacy of adjunctive transdermal estradiol with that of adjunctive placebo in the treatment of acute psychotic symptoms.
The researchers recruited 102 women of childbearing age from a Melbourne hospital. Of these subjects, 83 had schizophrenia, 18 had schizoaffective disorder, and 1 had schizophreniform disorder. The participants included outpatients and had a mean age of approximately 34 years.
All participants scored 60 or higher in total baseline PANSS score, indicating severe schizophrenia.
The women were randomly assigned to receive their regular medications plus a skin patch that delivered 100 µg a day of estradiol or placebo.
The main outcome measures were psychopathologic symptoms, as measured by PANSS scores, which were monitored weekly for 4 weeks.
The PANSS includes subscales for positive symptoms such as hallucinations and delusions, negative symptoms such as loss of pleasure and energy, and general psychopathologic symptoms such as depression and anxiety, said Dr. ulkarni.
The women who received adjunctive estradiol had significantly reduced positive and general pathopsychologic symptoms during the 28-day trials the women who received antipsychotic medication alone (P < .05 =or both). No significant differences were observed for negative symptoms, possibly because longer-term treatment might be required for these symptoms.
A subgroup of women who responded exceptionally well and who largely had postpartum onset of schizophrenia showed a dramatic improvement in negative symptoms as well as in positive and general symptoms.
For all participants, adverse effects were significantly reduced from baseline.
Following this proof-of-concept study, the researchers performed a -week pilot study in men with schizophrenia that showed an improvement in psychotic symptoms with the use of oral estradiol.
They also conducted a pilot study in women using a selective estrogen-receptor modulator, which has different tissue-dependent effects on estrogen receptors, and showed promise in improvement of symptoms.
"There is a lot of reason to think that estrogen can be a useful modulator of dopamine and serotonin neurotransmitter systems that are implicated in other disorders such as depression, anxiety, or OCD [obsessive-compulsive disorder]" said Dr. Kulkarni.
"Provided that general health measures such as mammograms, PAP =Papanicolaou] smears, regular blood pressure tests, and tests for clotting disorders are maintained, then estrogen could be a useful adjunct for a number of mental illnesses in women," she said.
This study was supported by the Stanley Medical Research Institute and the National Health and Medical Research Council of Australia. One of the study authors is supported by a National Health and Medical Research Council Practitioner Fellowship and NARSAD Young Investigator award. The other study authors have disclosed no relevant financial relationships.
Arch Gen Psychiatry. 2008;65:955-960.
Learning Objectives for This Educational Activity
Upon =ompletion of this activity, participants will be able to:
- Describe the effect of transdermal estradiol on symptoms of schizophrenia in women.
- Identify potential mechanisms for a therapeutic effect of estradiol for schizophrenia.
There is growing appreciation for the role of estrogen in the treatment of severe mental illness including schizophrenia. Women present with schizophrenia with their first episode approximately 5 years later than men and are more vulnerable during the postpartum and menopausal periods. Estrogen is noted to be neuroprotective and psychoprotective and acts via a variety of pathways, including antioxidant effects, enhancement of cerebral blood flow and glucose utilization, genomic mechanisms, and modulation of neurotransmitters such as dopamine and serotonin.
This is a placebo-controlled, double-blind, randomized clinical trial comparing the effect of transdermal estradiol with placebo as adjunctive treatment of severe schizophrenia in women.