ESTROGEN AND RALOXIFENE (EVISTA)

Background

Estrogen is a naturally occurring hormone that has been widely used in women to ameliorate postmenopausal symptoms. Raloxifene (Evista) is a selective estrogen receptor modulator (SERM) that has estrogen-like effects and is marketed to decrease postmenopausal osteoporosis. Both estrogen and raloxifene have been used in trials for women with schizophrenia, based on the theory that estrogens are protective and are the reason women generally develop schizophrenia later and less severely than men. One study using estrogen in men has also been published.

Mechanism of Action

Estrogen is thought to modulate dopamine receptors and to also affect the serotonin and GABAergic systems. There is some evidence that estrogen is also neuroprotective.20

Use in Schizophrenia

A variety of trials have been carried out, with conflicting findings. All trials were as adjunct medication except for a single case study in which estrogen alone was successfully used to treat a 51-year-old woman who refused antipsychotics for her late-onset schizophrenia.21 One open and six double-blind, placebo-controlled trials have been published using estrogen to treat women of childbearing age with schizophrenia. The open trial treated 11 women with oral 0.02mg ethinylestradiol for 8 weeks; it reported that “the patients who received adjunctive estradiol made a much quicker recovery.”22 The first double-blind trial treated 36 women: 12 received 50mcg of transdermal estradiol given by patch for 4 weeks, 12 received 100mcg, and 12 received a placebo patch. Those receiving 100mcg compared to the placebo group had a significant improvement in PANSS positive (P=0.002), negative (P=0.039), and general (P=0.002) symptoms, with the 50mcg group having intermediate values.23 The same research group replicated their findings with a trial of 102 women randomized to 100mcg transdermal estradiol or placebo for 4 weeks; those on estradiol had a significant reduction in positive (P<0.04) and general (P<0.05), but not negative symptoms24

Two other research groups reported positive results of double-blind studies using oral ethinylestradiol 0.05mg/day for 8 weeks. In one (n=32), the women on estradiol had a significant improvement in PANSS positive and total and general psychopathological symptoms.25 In the other (n=64), a significant improvement was reported for these same symptoms and negative symptoms as well.26 In contrast to these positive results, a double-blind study with 17-beta estradiol given to 46 women over 8 months, using the women as their own controls in a crossover design, reported no improvement.27 In addition, a study of 52 postmenopausal women with schizophrenia showed no clinical difference between those who did, and did not, receive hormone replacement therapy.28 Another study randomized 44 women to conjugated estrogens 0.625mg/day or placebo for 4 weeks; the women on estrogen had a trend (P<0.10) toward improvement, but it was not statistically significant.29 Finally, one study using estrogen in men with schizophrenia was published; 53 men were randomized to 2mg/day estradiol valerate or placebo for 2 weeks without any significant improvement in symptoms.30 SMRI is supporting an ongoing 8-week, placebo-controlled study in which 100mcg and 200mcg transdermal estradiol patches are being compared to placebo in 180 women; an interim analysis presented at a research meeting reported that both doses produced significant improvement in PANSS positive, but not negative symptoms.

Raloxifene has been used in two small trials for postmenopausal women with schizophrenia. In one study, 35 women were randomized to raloxifene 120mg/day (n=13), raloxifene 60mg/day (n=9), or placebo (n=13) for 12 weeks. Those on 120mg, but not 60mg, had a significant improvement in the PANSS total score.31 In the other study, 33 women were randomized to raloxifene 60mg/day or placebo for 12 weeks; those on raloxifene showed significant reduction in PANSS positive, negative, and general symptoms.32 SMRI is supporting two large (n=80 and 200) raloxifene trials in progress.

Use in Bipolar Disorder

There are case reports of two women with bipolar disorder who were resistant to lithium, but who responded to a combination of estrogen and progesterone.33

Assessment

Given the known side effects of long-term estrogen on breast and uterine cancer as well as thromboembolism, these drugs should be used very cautiously, with a careful risk-benefit calculation. Raloxifene is thought to not have thesame effects on breast and uterine tissue and so may be the drug of choice. If these drugs are effective, it appears more likely that it will be for positive, rather than negative,symptoms.