Clinically, there have been case reports of psychotic symptoms occurring cyclically in women with schizophrenia during the late luteal phase when estrogen levels are at their lowest (Endo et al., 1978; Riecher-Rossler et al., 1992). Seeman (1983) reported that neuroleptic dose requirements in women who are psychotic rise as they approach menopause and described premenopausal women as "already neuroleptized by their antidopaminergic estrogens(Drug information on estrogens)." The psychiatric literature contains case reports of women suffering from psychotic symptoms around the time of menopause (Berlin et al., 1982). There are also reports of improvement in psychotic symptoms with the addition of a combined estrogen-progesterone oral contraceptive (Dennerstein et al.,1983; Felthous et al., 1980). Following these clues, it appears that estrogen has inherent protective aspects that may prove to be clinically important in considering hormone treatments for women with schizophrenia. As a clinical trial, my colleagues and I conducted an open-label pilot study in which 11 women of childbearing age with schizophrenia were given 0.02 mg oral ethynyl estradiol(Drug information on estradiol) as an adjunct to antipsychotic drug treatment for eight weeks. Their progress was compared to a similar group who received antipsychotic drugs only (Kulkarni et al., 1996). The group receiving estrogen made a significantly more rapid recovery from acute psychosis symptoms. Subsequently, we conducted a dose-finding study for the optimal use of estradiol in women with DSM-IV schizophrenia (Kulkarni et al., 2001). In this three-arm, double-blind, placebo-controlled, 28-day study, 12 women received 50 mcg transdermal estradiol plus antipsychotic medication; 12 women received 100 mcg transdermal estradiol plus antipsychotic medication; and 12 women received transdermal placebo plus antipsychotic medication. The main finding was that the women who received 100 mcg estradiol adjunct made a more rapid and greater recovery in their psychotic symptoms (positive, negative and general symptoms as measured by the Positive and Negative Syndrome Scale [PANSS]). To confirm this finding, we are continuing a two-arm, 28-day, double-blind, placebo-controlled study comparing symptom resolution in women with schizophrenia receiving transdermal 100 mcg estradiol plus antipsychotic medication, with women receiving transdermal placebo plus antipsychotic medication. This is an ongoing study, and interim data are included below.
The sample size reported here is 36 (18 women in each group). Women were excluded if they were taking any synthetic steroids (including the oral contraceptive) or illicit drugs; they were also excluded if they were pregnant, lactating or postmenopausal. All patients gave written informed consent, and the Alfred Hospital Ethics Committee approved the study. Each subject was enrolled for 28 days (one menstrual cycle) and received baseline psychopathology and hormone assessment, followed by assessments at days 4, 7, 14, 21 and 28. Psychopathology was measured with PANSS. Hormone assays for serum estrogen, progesterone(Drug information on progesterone), prolactin, luteinizing hormone, follicle stimulating hormone and testosterone were performed.
There were no statistically significant differences between the women receiving the 100 mcg transdermal estradiol adjunct and the women who received the placebo adjunct, in terms of age, menstrual cycle phase, race, illness duration, diagnosis or antipsychotic drug dose. The mean baseline PANSS was 86.3±12.3 for the estrogen group and 73.3±12.3 for the placebo group. The difference is statistically significant (p<0.05). To allow for correction of this difference in baseline scores, the change from baseline across time was used to compare the effect of adding estradiol to treatment with placebo adjunct (Figure).
These interim results show that the women who received the 100 mcg transdermal estradiol adjunct made a greater improvement in their psychotic symptoms as measured by the PANSS. The hormone analysis showed that the administration of 100 mcg estradiol had a significant impact on the pituitary as evidenced by significant luteinizing hormone suppression. This suggests that the dose (100 mcg) and type (unconjugated estradiol) of estrogen is affecting psychotic symptoms positively and is consistent with the estrogen hypothesis. It must be stressed that the area of hormone treatments for women with schizophrenia is still in research phase and further clinical trials are needed to confirm the usefulness of such an approach. However, adjunctive hormone replacement therapy (HRT) for postmenopausal women with schizophrenia is a new treatment area well worth considering.
The biological advent of declining estrogen levels and/or the preceding elevation in pituitary gonadotrophin levels may be a major contributing factor in the well-observed and documented deterioration in psychosis in women with schizophrenia as they approach menopause (Seeman and Lang, 1990). Hormone replacement therapy is currently an option for assisting women who experience hot flashes and other troubling symptoms of menopause, as well as assisting in the prevention of osteoporosis. More recently, menopause has been noted to be associated with changes in cognition and mood (Meyer et al., 2003). Following the results we have described from our clinical trials in women of childbearing age with schizophrenia, it can be hypothesized that menopausal women with schizophrenia may benefit from HRT in terms of their psychotic symptoms.
A further reason to consider short-term HRT in menopausal women with schizophrenia is to counter unwanted hyperprolactinemic effects that may accompany a lifetime of treatment with some antipsychotic medications. Adverse effects of HRT have been documented in studies such as the Women's Health Initiative Study (Wassertheil-Smoller et al., 2003). However, many of the putative adverse effects were reported in elderly women who received long-term HRT. In shorter term use with adequate general health measures, such as regular breast examinations and assessment of cardiovascular illness risk, HRT may be a useful adjunct in the prevention or treatment of psychosis relapse in perimenopausal women with a history of schizophrenia. In the future, a useful adjunct may be with the use of the selective estrogen receptor modulators (SERMs) or the so-called "brain estrogens."
Currently, my colleagues and I are conducting a clinical trial assessing the effectiveness of adjunctive HRT compared with an adjunctive SERM (raloxifene [Evista]) and adjunctive placebo in peri and postmenopausal women with schizophrenia. Early results from this ongoing study (n=15) suggest that both the adjunctive HRT and SERM arms are more effective in treating psychosis symptoms than placebo adjuncts to antipsychotic medication (Kulkarni et al., 2003). More definitive clinical data are required.
Progesterone and Women
Progesterone and related steroids are thought to exert a sedative effect (Cone et al., 1981; Hackmann et al., 1973). Estrogen induces brain progesterone receptors (Alves et al., 1998; McEwen et al., 1981); hence, the action of estrogen could also be partly mediated by progesterone. Estrogen may potentiate the sedative action of progesterone by stimulating an increase in progesterone receptors during the luteal phase of the menstrual cycle and during pregnancy. The drop in plasma progesterone concentrations at the end of the luteal phase may account for anxiety symptoms in women with premenstrual syndrome (Fink et al., 1998). The role of progesterone-only preparations as a treatment in postpartum depression has been advocated (Dalton, 1980; Solthau and Taylor, 1982), but its therapeutic success in the puerperium has not been substantiated by controlled clinical trials.
Many women with schizophrenia describe subjective observations of correlations between changes in menstrual cycle and the onset of, or relapse in, psychotic symptoms. "It's my hormones causing the illness" is an often made observation, but sadly an often ignored comment. Hormone research in women with schizophrenia is still in its infancy, but early indications suggest that there may be promising new treatments in this area. Listening to our patients and researching their subjective observations may provide new answers and treatments.