The estrogen hypothesis of schizophrenia holds that estrogen has a protective, mitigating effect on schizophrenia in women, and that this helps explain why women tend to present with first episodes later in life, present less frequently than men, and, some studies have found, have better prognosis and treatment response.
A growing scientific and clinical literature on estrogen and the brain has added heft to what was once a contentious theory. Estrogen has been found to modulate dopamine and serotonin transmission. Estrogen levels in women with schizophrenia have been shown to be lower than those seen in healthy women, with illness onset or relapses most often occurring during the phase of the menstrual cycle when estrogen drops. Women also see a higher rate of late life–onset schizophrenia than do men, which might be related to estrogen decreases at menopause (Schizophr. Res. Treatment 2012 [doi:10.1155/2012/916198]).
A handful of studies has explored whether estrogen replacement therapy, in the form of oral or transdermal estrogen, is helpful in patients with schizophrenia. Recent research has begun to investigate whether agents with estrogenlike effects, such as the selective estrogen receptor modulator (SERM) raloxifene, also could be helpful when added to conventional treatment with antipsychotics. Raloxifene, manufactured by Eli Lilly & Co. as Evista, is licensed as a preventive therapy for osteoporosis, and – unlike estrogens – does not affect breast or uterine tissue.
Dr. Jayashri Kulkarni
At the fourth International Congress of Medicine and Women’s Mental Health, held in April in Medellin, Colombia, schizophrenia researcher Dr. Judith Usall of Parc Sanitari Sant Joan de Déu, in Barcelona, presented her ongoing work exploring the estrogen hypothesis and raloxifene. Dr. Usall is one of a small group of researchers working with raloxifene in schizophrenia patients; another leader in the field, Dr. Jayashri Kulkarni of Australia’s Alfred Hospital in Melbourne and Monash University in Clayton, Victoria, previously had tested raloxifene in a pilot study – a small, randomized, controlled trial enrolling postmenopausal women with schizophrenia (n = 26) – and found it to be effective (Psychoneuroendocrinology 2010;335:1142-7).
Last year, in a randomized, placebo-controlled trial enrolling 33 postmenopausal women with schizophrenia, Dr. Usall and colleagues found that adding 60 mg daily of raloxifene – the standard dosage indicated for osteoporosis prevention – to regular antipsychotic treatment improved psychotic symptoms at 12 weeks, compared with antipsychotics alone, with reduction in negative (P = .044), positive (P = .031), and general psychopathological (P = .045) symptoms, and without significant adverse effects (J. Clin. Psychiatry 2011;72:1552-7).
A new trial of similar design, also led by Dr. Usall, began enrolling in January, and will recruit a cohort of 80 postmenopausal women with schizophrenia to determine whether they see a benefit after 6 months of adjunctive treatment with 60 mg of raloxifene.
"My main objective is to improve the treatment of patients with schizophrenia, as well as to improve our knowledge of the etiology of schizophrenia," Dr. Udall said in an interview. "If our trial and others confirm and expand upon our positive results, I think that the use of raloxifene could be recommended in postmenopausal patients."
The Australian researchers are taking a somewhat bolder approach, using higher doses of raloxifene and recruiting younger women and men as well as postmenopausal women to their randomized, controlled trials. Dr. Kulkarni and colleagues are close to wrapping up a larger trial in postmenopausal women with schizophrenia (n = 180) using 120 mg daily of raloxifene in the intervention arm. Their pilot study of raloxifene in postmenopausal women had used the lower dose, but "while the 60-mg [dose] gave some cognitive improvement, it didn’t really touch the psychotic symptoms," Dr. Kulkarni said in an interview.
Dr. Usall said she thought that raloxifene also might be useful in premenopausal women with schizophrenia, particularly those with symptom exacerbations coinciding with their menstrual cycles, but noted that safety information was lacking for both the higher dose and for younger women. "My trial addresses the possible efficacy of raloxifene only in postmenopausal women with schizophrenia," Dr. Usall said.
The Barcelona researchers also are focusing on the negative symptoms of schizophrenia, setting their primary clinical end point at a 20% or more improvement in negative symptoms. Their reasoning, Dr. Usall said, is that "antipsychotics are not as effective in negative symptoms as in positive ones, and because there are different neurobiological and clinical data that point to the possible efficacy of estrogen in negative symptoms."
Dr. Kulkarni said that although no formal analysis has yet been conducted for her team’s raloxifene trial in younger women (n = 120), "it’s already looking even better than in the older women. We’re getting positive symptom response plus cognitive improvement."