Schizophrenia: Impact of Estradiol on Psychosis Symptoms Interview with:
Professor Jayashri Kulkarni MBBS, MPM, FRANZCP, PhD
Monash University What are the main findings of the study?

Professor Kulkarni: Persistent schizophrenia is difficult and unfortunately common, despite advances over the past years in antipsychotic drug development. New treatment approaches are urgently needed. Also, a specific focus for women with schizophrenia is still somewhat lacking and there is a need to consider the special issues facing women with schizophrenia.

Over many years, we have been conducting clinical trials to develop the role of adjunctive estradiol use to treat symptoms of schizophrenia. This study is the largest clinical trial in the world of this type and we found that in an 8 week, three arm, double blind, placebo-controlled, adjunctive trial of transdermal estradiol (200mcg v 100mcg v placebo) in 183 women with schizophrenia, that the women who received either 200mcg or 100mcg transdermal estradiol made a better recovery. The women who received 200mcg transdermal estradiol made a slightly better recovery than women receiving 100mcg transdermal estradiol. Both estradiol groups were significantly better than the group who received adjunctive transdermal placebo. Were any of the findings unexpected?

Professor Kulkarni: Since we are the pioneers in this area, the optimal safe dose and delivery mode of estradiol has been explored by our group in earlier trials and now also in this one – with the 200mcg transdermal estradiol arm. It was a surprise that the 200mcg arm yielded slightly better results than the 100mcg – although not that much better. What should clinicians and patients take away from your report?

Professor Kulkarni: First and foremost, we suggest that adjunctive estradiol treatment has practical use for women who have not responded well to antipsychotic drug treatment. There are many types of estradiol available in general clinical practice, so it is possible to use estradiol in a longer-term way – of course with careful physical health monitoring and using intermittent progesterone in women who have an intact uterus. While it is not advisable to use the high dose of estradiol for a very long time, it is possible to use other forms such as in the oral contraceptive pill that have good clinical use.

Secondly – we urge clinicians to take a careful history from their women patients about natural reproductive hormone shifts such as premenstrual exacerbation of symptoms, onset of psychosis in the postpartum period or approaching menopause. All of these turbulent times with respect to estrogen fluctuation, may impact adversely on the woman’s psychosis. Hence- consideration of estradiol adjunctive treatment is an important option. If psychiatrists are not comfortable prescribing hormone treatment, then they should work with a primary care doctor or endocrinologist or gynecologist. A team approach with the woman patient being a collaborative member of the team is vital for the best outcomes – which involves both health and mental health care.

Thirdly – we urge our basic science researcher colleagues to follow up this important clue about the positive impact of estradiol on psychosis symptoms – to research the underlying mechanisms for this now well replicated and established finding. What recommendations do you have for future research as a result of this study?

Professor Kulkarni: We have already published a study involving a clinical trial developing the role of the next generation of estrogen treatments – the SERMs (Selective Estrogen Receptor Modulators). These estrogens target the brain estrogen receptors more specifically, with less agonism of estrogen receptors in breast, uterus and ovaries – hence we think this will be a safer option in the long term for adjunctive hormone treatment in schizophrenia – for both women and men with schizophrenia. We have conducted a recent clinical trial of the SERM, raloxifene hydrochloride and will publish this soon.

There are many promising newer forms of hormone treatment that offer great hope in the much-needed area of new, effective treatments for people with persistent schizophrenia.


Estradiol for treatment-resistant schizophrenia: a large-scale randomized-controlled trial in women of child-bearing age

J Kulkarni, E Gavrilidis, W Wang, R Worsley, PB Fitzgerald, C Gurvich, T Van Rheenen, M Berk and H Burger.
The Monash Alfred Psychiatry research centre
Published Molecular Psychiatry advance online publication, 15 April 2014; doi:10.1038/mp.2014.33