Estradiol for treatment-resistant schizophrenia

Researchers from Australia have conducted the first controlled trial of estrogen in premenopausal women with treatment-resistant psychosis (1). They recruited 183 women with schizophrenia or schizoaffective disorder who were not pregnant, lactating, or postmenopausal; and who had no history of breast cancer, endocrine disorders, migraine with aura, or thromboembolism. Patients with acute mania were excluded. Patients were randomly assigned to receive either transdermal estradiol 100 mcg daily, transdermal estradiol 200 mcg daily, or placebo patch. The primary outcome measure during the 56-day trial was the Positive and Negative Syndrome Scale (PANSS). Other measures included the Montgomery-Asberg Depression Rating Scale (MADRS), the Repeatable Battery of Neuropsychological Status, adverse-effects monitoring, and serum estradiol concentration at the baseline and during treatment.

The baseline demographic, illness, and treatment characteristics did not differ among the placebo, 100 mcg-estradiol, and 200-mcg estradiol groups. Most subjects were outpatients, and the three groups had mean PANSS total scores of 72-75. Compared with the placebo group, both treatment groups had significant increases in serum estradiol concentration; and greater decreases in mean PANSS positive, general, and total scores. The effect size for positive symptoms, however, was 0.0 for the 100 mcg group and 0.44 for the 200 mcg group, which reflected a mean 3.3-point reduction in PANSS-positive score with the higher dose. No significant treatment effect was found for negative symptoms or cognition. The only significant adverse effect was an increase of irregular menses in the 200 mcg group compared with the placebo group.

The investigators acknowledge that this trial was short-term and that the risks of thromboembolism and endometrial carcinoma may accumulate during longer-duration therapy. Raloxifene, a selective estrogen receptor modulator, entails a lower risk of these adverse effects. In 2011, investigators from Spain reported on a randomized trial of 16 postmenopausal women who had significant mean reduction of positive, negative, and general symptoms compared with a comparable placebo group (2). Case reports exist of raloxifene use in premenopausal women with treatment-resistant schizophrenia (3,4), but controlled trials in this population have not been published.


1. Kulkarni J, Gavrilidis E, Wang W. Estradiol for treatment-resistant schizophrenia: a large-scale randomized-controlled trial in women of child-bearing age. Molecular Psychiatry. Published online 15 Apr 2014. Abstract

2. Usall J, Huerta-Ramos E, et al. Raloxifene as an adjunctive treatment for postmenopausal women with schizophrenia: a double-blind, randomized, placebo-controlled trial. J Clin Psychiatry. 2011;72(11):1552-1557. Abstract

3. Raveendranathan D, Shivakumar V, Jayaram N, Rao NP, Venkatasubramanian G. Beneficial effects of add-on raloxifene in schizophrenia. Arch Womens Ment Health. 2012;15(2):147-148. Abstract

4. Shivakumar V, Venkatasubramanian G. Successful use of adjuvant raloxifene treatment in clozapine-resistant schizophrenia. Indian J Psychiatry. 2012;54(4):394. Full text

One thought on “Estradiol for treatment-resistant schizophrenia

  1. Although, I was initially excited to see that some researchers are finally acknowledging that “psychosis” has several etiological factors, I do find it bizarre, from a treatment perspective, that they would choose to use a SERM (Raloxifan), rather than the NATURAL COMPLEMENT to estrogen, PROGESTERONE (which is not to be confused with toxic progestins), to mitigate “the risks of thromboembolism and endometrial carcinoma.” Interestingly enough, “at neuronal synapses, estrogen INCREASES the concentration of neurotransmitters such as serotonin, DOPAMINE, and norepinephrine.[4] It affects their release, re-uptake, and enzymatic inactivation. It also increases the number of RECEPTORS for these neurotransmitters[2]” (Shepherd, J.E.).
    Isn’t it time we stopped banging the drum of the “excess dopamine” hypothesis of psychosis and forcibly medicating people with drugs that REDUCE FUNCTIONAL CAPACITY at ALL levels within ALL systems plus, further sensitize people to future psychotic episodes? Moreover, isn’t it time medical professionals were able to differentiate between psychosis, dementia, and delirium, then treat appropriately? It is well-established that dementia is a dopamine-DEFICIENT state and, that estrogen protects against dementia. As for delirium, it is easily the end result of estrogen deficiency, since this deficiency causes the pelvic organs to painfully prolapse, as well as non-stop bladder voiding, which then results in dehydration. Of course, both pain and dehydration are KNOWN CAUSES of delirium.

    Shepherd, J.E., “The effects of estrogen on cognition, mood, and degenerative brain diseases.” J Am Pharm Assoc 2001;41(2)

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