Dr. Kulkarni also said that she has seen "dramatic turnarounds" in some postmenopausal patients and among women with whose psychosis onset was post partum, in the intervention arms of her studies. But there have also been slow responders and nonresponders, she said. Predictors of response "will hopefully get clearer as our sample sizes increase. We think there may be an inherited sensitivity to the hormonal milieu."
The Australian team also is conducting a small trial of raloxifene in men with schizophrenia, designed to enroll 30. Dr. Kulkarni previously had worked with estradiol in men with schizophrenia (Schizophr. Res. 2011;125:278-83), but found that its feminizing effects necessitated that the trial be stopped. The investigators hope that raloxifene, which is more selective, will deliver improvement without the feminizing effects.
Raloxifene is a long way from being a standard of care for schizophrenia in patients of any age or sex, but it is increasingly being used as an adjunct treatment for postmenopausal women with schizophrenia in Australia, Dr. Kulkarni said. Some researchers have begun to recommend it as a supplementary treatment for younger women, too.
In a recent literature review on treating hormone-linked disease exacerbations among women with schizophrenia, Dr. Mary V. Seeman of the University of Toronto concluded that raloxifene could be considered among treatment options for premenstrual symptom aggravation (Acta. Psychiatr. Scand. 2012;125:363-71).
Dr. Mary V. Seeman
Dr. Seeman said in an e-mail interview that although SERMs for schizophrenic symptoms have been used mainly in research studies and not in general practice, "individual clinicians may prescribe them for individual patients."
Dr. Kulkarni said that awareness is growing of the potential to add estrogens or SERMs when standard treatment is not enough.
"We’re in a transition phase at the moment, because we’ve gone from [SERMs’] being used purely in research to their being a product that’s out there to be tried; it’s a question of getting the information to practicing clinicians." A 2012 paper by the Stanley Research Foundation, which has helped fund Dr. Kulkarni’s and Dr. Usall’s clinical trials, recommended several adjunct treatments for schizophrenia, among which were estrogen and raloxifene.
Still, "psychiatry tends to operate in a silo," Dr. Kulkarni said. "Most psychiatrists are happy to prescribe antidepressants or antipsychotics but may not want to prescribe a hormone because it opens up a whole new clinical area. I think that’s to the profession’s detriment." Dr. Kulkarni added that as the results of more ongoing trials come in, "we can begin to think about creating clinical guidelines" for adjunctive treatment with SERMs.
Dr. Usall commented that "unfortunately, the issue of gender-sensitive mental health is not sufficiently introduced into clinical practice." However, she said, clinicians can nonetheless incorporate aspects of the estrogen hypothesis into the management of female schizophrenia patients even without prescribing SERMs.
Exacerbations of disease activity often will coincide with menstrual changes, Dr. Usall said, and symptoms should "always be evaluated with regard to the menstrual cycle." Clinicians might choose to add estrogen/progesterone combinations, or increase dosage of antipsychotic drugs during the luteal phase, she said.
Dr. Kulkarni said she felt that raloxifene represented "a whole new avenue" of adjunctive treatment, with many drugs like it currently in the pipeline. Dr. Seeman, meanwhile, cautioned that SERMs might represent only the first stage of a new treatment paradigm.
"While SERMs like raloxifene are thought to be safe for breast and uterus, they still have difficulty in crossing the blood-brain barrier," she said. "I suspect that, with time, safe estrogenlike compounds that enter the brain more efficiently will be developed – maybe they already exist – and will be useful for neuropsychiatric disease, including schizophrenia. It’s still early days but very promising."
Dr. Usall, Dr. Seeman, and Dr. Kulkarni declared no conflicts of interest related to their research. Dr. Seeman is medical adviser to Clera Inc.