Many women with schizophrenia remain symptomatic despite optimal use of current therapies. While previous studies suggest that adjunctive oestrogen therapy might be effective, large-scale clinical trials are required before clinical applications are possible. This study is the first large-scale randomized-controlled trial in women with treatment-resistant schizophrenia. This Definitive Oestrogen Patch Trial was an 8-week, three-arm, double-blind, randomized-controlled trial conducted between 2006 and 2011. The 183 female participants were aged between 18 and 45 (mean=35 years), with schizophrenia or schizoaffective disorder and ongoing symptoms of psychosis (Positive and Negative Syndrome Scale, PANSS score>60) despite a stable dose of antipsychotic medication for at least 4 weeks. Mean duration of illness was more than 10 years. Participants received transdermal estradiol 200 μg, transdermal estradiol 100 μg or an identical placebo patch. For the 180 women who completed the study, the a priori outcome measure was the change in PANSS score measured at baseline and days 7, 14, 28 and 56. Cognition was assessed at baseline and day 56 using the Repeatable Battery of Neuropsychological Status. Data were analysed using latent growth curve modelling. Both estradiol groups had greater decreases in PANSS positive, general and total symptoms compared with the placebo group (P<0.01), with a greater effect seen for 200 μg than 100 μg estradiol. The largest effect size was for the positive subscale of PANSS in the estradiol 200 μg treatment group (effect size 0.44, P<0.01). This study shows estradiol is an effective and clinically significant adjunctive therapy for women with treatment-resistant schizophrenia, particularly for positive symptoms.
Converging research demonstrates that estrogens have a psychoprotective role in defending against neuronal injury, inflammation, oxidative stress, ischaemia and apoptosis,1, 2, 3, 4 and promoting neurogenesis, plasticity, re-myelination and neural connectivity.5, 6, 7, 8 A link between brain levels of estrogens and the course of schizophrenia has been postulated for many years.9,10 Indeed, the higher incidence of schizophrenia in males,11 coupled with evidence of increased psychosis vulnerability during periods of oestrogen depletion in females,12, 13, 14, 15, 16, 17 has led to the investigation of the role of oestrogen as a mediator of the symptoms of schizophrenia.
Estradiol exerts its action on the central nervous system through genomic and non-genomic mechanisms.18 Genomic mechanisms, requiring hours to days to exert their effects, involve gene transcription mediated by activation of oestrogen receptor alpha and oestrogen receptor beta. Non-genomic mechanisms encompass the rapid effects (within minutes) of estradiol initiated by interaction with membrane ER and/or G protein-coupled receptors. The actions of estradiol in humans and animals are widespread throughout the cortical and subcortical brain\regions, with estradiol exerting its effects on the neural circuitry and neurochemistry implicated in the pathogenesis of the disorder.19, 20, 21, 22, 23, 24 Schizophrenia has long been associated with abnormalities in the synthesis and release of dopamine. Substantial evidence also exists highlighting the importance of serotonergic mechanisms for the antipsychotic (as well as procognitive) effects of atypical antipsychotic medications, which are partly related to the hypoglutamate hypothesis of schizophrenia.25, 26, 27 Estrogens have been shown to modulate the activity of dopamine, serotonin and glutamate. More specifically, animal studies have revealed that estradiol enhances serotonin concentrations28 and stimulates glutamate receptors29 and dopamine synthesis, release and turnover in cortical and striatal regions.19,24,30, 31, 32, 33, 34, 35, 36, 37 Serum levels of estradiol have been associated with heightened wellbeing and improved cognition in people who are healthy38 and those with schizophrenia.16,39, 40, 41 Conversely, there is evidence that many women with schizophrenia have reduced fertility and reduced circulating levels of estradiol, associated with menstrual disorders such as oligomenorrhoea.10,42 It is becoming clear that oestrogen-related neurochemical dysfunction may be critically involved in the aetiology of the disorder.43 Thus, oestrogen supplementation may be a useful method for reducing the symptoms associated with schizophrenia. There is evidence for clinical improvement with oestrogen augmentation in related psychiatric disorders44, 45, 46 and recent clinical trials provide further evidence of an antipsychotic effect of estradiol in women with schizophrenia itself.16,47, 48, 49
Our group’s initial open-label placebo, controlled pilot study revealed that 2 mg of adjunctive oral estradiol valerate conferred rapid recovery from acute symptomatology in women with schizophrenia of child-bearing age.47 We have since conducted two trials in which the efficacy of adjunctive transdermal estradiol has been observed.48,49 The first dose-finding pilot study of 36 women with schizophrenia revealed a significant reduction in positive psychopathology over 4 weeks for those receiving a dose of 100 μg compared with 50 μg or placebo.48 Our second study replicated this effect in a follow-up proof-of-concept investigation of 102 women with schizophrenia. Those receiving a 100 μg dose in adjunct to antipsychotic medication over a 28-day period demonstrated significant improvement in positive and general psychopathological symptoms in comparison with those on antipsychotic medication alone.49 At this dose level, we did not find a significant reduction in negative symptomatology, which is consistent with literature indicating that negative symptoms of schizophrenia are more treatment resistant than other schizophrenia symptomatology.50
It is possible that higher doses and increased time on oestrogen treatment are needed to see improvement in these symptoms, and a recent review concluded that larger and more definitive trials are needed.51 To this end, we conducted an 8-week, dose-finding replication study—a definitive oestrogen patch trial—to investigate the efficacy of a dose of 200 μg adjunctive transdermal estradiol compared with 100 μg or placebo to treat positive, negative and general symptoms in women of child-bearing age with schizophrenia.
Subjects and methods
This study was conducted with approval of the Human Ethics Committee of the Alfred Hospital (202/04). The registration number of this trial (at clinicaltrials.gov) is NCT00357006. The sample size was determined according to the power analyses based on our previous studies.49 Between 2006 and 2011, a total of 1858 women were assessed for eligibility, of which 204 were screened from inpatient and outpatient settings across three Australian sites (Alfred, a tertiary referral centre; Barwon, a rural centre; and Dandenong, an outer metropolitan centre) over a 5-year period and completed a 56-day trial.
Of the 204 women screened, 183 met the inclusion criteria: (a) DSM-IV-TR52 diagnosis of schizophrenia, schizoaffective or schizophreniform disorder; (b) aged between 18–45; (c) physically and endocrinologically healthy; (d) able to give informed consent; (e) mentally unwell as defined by a total Positive and Negative Syndrome Scale (PANSS)53 score of>60; and (f) on a stable dose of antipsychotic medication of 2–12 mg daily ‘risperidone equivalents’ for at least 4 weeks, with residual symptoms as defined by a PANSS-positive score greater than 15 and/or a PANSS-negative score greater than 15. Three patients became unstable following randomization but did not receive medication and were therefore excluded from all analyses. The exclusion criteria were as follows: pregnancy or lactation; postmenopausal women; known severe abnormalities in the hypothalamopituitary gonadal axis; thyroid dysfunction; central nervous system tumours; history of thromboembolic disorders; severe medical conditions and disorders that would contraindicate oestrogen use such as breast cancer, migraine with aura or stroke; current use of oral oestrogen preparations containing greater then 30 mcg estradiol; substance-induced psychotic disorder; schizoaffective disorder in the manic phase. It is particularly important to note that venous thromboembolism, breast cancer, stroke and migraine with aura are strong contraindications for the use of exogenous estrogens.
All participants were individually randomized by the Alfred Clinical Trials Pharmacy to receive adjunctive estradiol 200 μg (administered as two 100 μg Estradot transdermal patches, Novartis, Basel, Switzerland) 62 women), adjunctive estradiol 100 μg (administered as two Estradot 50 μg transdermal patches, 56 women), or adjunctive placebo (administered as two patches, 62 women) according to a computer-generated randomization list (1:1:1 ratio). The estradiol patches delivered 100 μg per day or 200 μg per day of estradiol at a constant rate. Placebo patches were adhesive and identical in appearance but had no active substance. All three types of patches were changed every 3.5 days (for example, on a Monday morning and on a Thursday night) for the trial duration of 56 days. Both researchers and participants remained blind to treatment assignment for the duration of the trial. All participants remained on their stable dose of antipsychotic medication regimen.
Psychopathology was measured using the PANSS,53 a clinician-rated scale comprising a seven-item-positive symptom construct (for example, hallucinations, delusions), a seven-item-negative symptom construct (for example, emotional withdrawal, blunted affect), and a 16-item general symptom construct (for example, anxiety, depression). It is a well-validated, standardized method of evaluating and monitoring psychotic symptoms. For the 180 women who completed the study, the a priori outcome measure was the change in PANSS score measured at baseline and days 7, 14, 28 and 56.
Cognition was assessed at baseline and day 56 using the Repeatable Battery of Neuropsychological Status.54 The Repeatable Battery of Neuropsychological Status is a well-validated and reliable measure of cognition that has been extensively studied in schizophrenia, where it was found to be highly sensitive to the neurocognitive impairments associated with schizophrenias and reliable upon repeat testing. The Repeatable Battery of Neuropsychological Status assesses the broad domains of immediate and delayed memory, attention, language and visuospatial and constructional skills.
Depressive symptoms were assessed at baseline, days 7, 14, 28 and 56 using the Montgomery-Asberg Depression Rating Scale,55 a 10-item clinician-rated scale measuring changes in depression secondary to treatment. It is also a well-validated, standardized method of evaluating and monitoring depressive symptoms.
Adverse reaction monitoring
Side effects were monitored using an Adverse Symptom Checklist that required participants to rate their experience of 18 medication-related adverse effects (for example, nausea, headaches, increased saliva, sexual dysfunction) on a scale of 0–3, where 0 indicates absent; 1, slight; 2, moderate; and 3, severe. The Simpson Angus Rating Scale for Extrapyramidal Side Effects,56 and the Abnormal Involuntary Movement Scale57 were assessed at each time point (days 0, 7, 14, 28 and 56). Hormonal side effects such as breast tenderness and vaginal bleeding were noted at each review.
A single 10 mL blood sample was collected at baseline, day 28 and day 56 of the trial for serum estradiol. Estradiol was measured using a chemiluminescent assay with a coefficient of variation ranging between 2–8 pmol L−1.
Baseline comparisons were made using one-way analysis of variance. A threshold of alpha=0.05 was used to determine a significant effect. All subsequent analyses were done on an intention-to-treat basis. As hormone data was not normally distributed, one-way analysis of variance was performed on the change from baseline to day 56. To evaluate changes in psychological well being as a function of treatment using estrogens, the repeated measures longitudinal data were analysed using latent growth curve modelling.58 Latent growth curve modelling extends on traditional repeated measures analysis of variance by modelling changes in the means and the variance of initial status and the growth rate simultaneously. Muthén and Curran’s59 method was particularly useful for the present study, which involves multiple-group specification and captures the developmental differences between the treatment and control groups. According to Muthén and Curran,59 the control group represents the normative set of individual growth trajectories and the effect of treatments is assessed by comparing the sets of growth trajectories in the treatment groups with those in the control group. By using this method, an additional growth factor is introduced, which represents growth that is specific to the treatment groups while the first two factors (initial status and rate of change) are the same as for the control group. In order to assess the treatment effects, the parameters of the first two growth factors are constrained to be equal between the treatment and control groups. Then, the added growth factor describes the changes in addition to that of the control group.
All models were estimated in the Mplus structural equation modelling programme. Model fit was assessed by examining χ2 statistics, comparative fit index, non-normed fit index (TLI) and root mean square error of approximation. Models are considered reasonably fit if comparative fit index > 0.90, TLI > 0.90 and root mean square error of approximation<0.08, with the χ2 P-value or its scaling correction factor for robust maximum likelihood > 0.05.
Baseline characteristics of subjects were not significantly different. The baseline PANSS scores suggest that this sample had marked illness severity.60 Baseline cognitive scores also characterize this sample as having significant cognitive impairment (with total Repeatable Battery of Neuropsychological Status for each group equating to the lowest 5th percentile).54
The progress of subjects through the stages of the trial is shown in Figure 1. To compare the effectiveness of the adjunctive estradiol treatment, we first established the baseline characteristics of all subjects. There were no statistically significant differences among the 62 women in the 200 μg group, the 56 women in the 100 μg group and the 62 women in the placebo group in terms of age, age at illness onset (Table 1) or medication dose at baseline. There were no significant differences between groups on the Montgomery-Asberg Depression Rating Scale, PANSS total score or any of the PANSS subscales at baseline (Table 1).
Estradiol patches increase estradiol serum levels
Hormone results are presented in Table 2. Patients in the estradiol 200 μg group had a significant increase in estradiol serum levels relative to the placebo group (mean increase 164 pmol L−1 compared with a mean decrease of 51.56 pmol L−1 in the placebo group, P=0.01).
Adjunctive estradiol treatment improves psychotic positive, general and total symptoms
To examine the effectiveness of the estradiol treatment, PANSS measures were taken at days 7, 14, 28 and 56 for positive, negative and general and total symptoms.
In general, for 100 μg and 200 μg intervention groups (especially for the 200 μg group), the mean levels of PANSS positive, negative, general and total symptoms showed decreasing trajectories over time compared with the placebo groups (Figure 2). The univariate descriptive statistics showed that absolute values of skewness and kurtosis of the observed variables ranged from 0.06 to 1.50 and 0.01 to 5.17, respectively, suggesting univariate non-normal distribution of the data (Table 3). Robust maximum likelihood estimation was used, which is robust to the non-normality nature of the data.
The two-group latent growth model with an added mean slope in the treatment groups fitted the data reasonably well for each of the PANSS measures (Table 4). In terms of a treatment effect, apart from PANSS-negative measures, significant group differences were observed in all PANSS measures (Table 5). The significant negative slope mean estimate of the growth factor for PANSS positive, general and total (P<0.01) indicated that the treatment groups reported greater decreases in PANSS positive, general and total compared with the placebo group.
The effect size (Table 5), calculated as the difference between the treatment and placebo group observed means at day 56 (termination assessment) scaled by the pooled s.d. at day 56, was small,61 ranging from 0.00 (PANSS positive, 100 μg) to 0.44 (PANSS positive, 200 μg).
There were no between group or interaction effects in relation to cognition at baseline compared with day 56 (see Table 6). The observed improvements across time, noted in several subtests, particularly in relation to immediate memory, were not significantly different between groups and hence, may be attributed to practice effects. Of note, there was no adverse effect on cognition in relation with either estradiol dose.
There were no statistically significant differences in adverse events between groups as measured by the Adverse Symptom Checklist, The Abnormal Involuntary Movement Scale or the Simpson Angus Scale for Extrapyramidal Side Effects. Participants were also monitored for side effects of the oestrogen therapy. There was no increase in the occurrence of breast tenderness, but at day 56, there was a higher rate of irregular menses in the 200 μg estradiol group compared with placebo (68% vs 38% P=0.001).
This is the first large-scale randomized-controlled trial of estradiol for women of child-bearing age with treatment-resistant schizophrenia. Large-scale trials such as this are necessary before recommendations about potential clinical use of adjunctive oestrogen therapy in women with schizophrenia can finally be made. The addition of transdermal estradiol 100 μg or 200 μg to the usual antipsychotic therapy resulted in a clinically meaningful improvement in symptoms of schizophrenia with reductions in the PANSS positive, general and total scores. The 200 μg dose resulted in a greater effect size than the 100 μg dose. The greatest improvement was seen in positive symptoms of schizophrenia with no significant improvement in negative symptoms, which is consistent with our previous work.47,49,62
The treatment effect size is small yet clinically significant. In the 200 μg group, a reduction in total PANSS score of 13 points was seen after 8 weeks, compared with a 5-point reduction in the placebo group. Given that this is a group of women with treatment-resistant disease with a mean duration of more than 10 years, to achieve the therapeutic benefit is a substantial advance. This benefit has occurred in the setting of ongoing antipsychotic use.
The limitations of this study include the heterogeneity of psychotropic drugs used by the participants. We have accounted for this by converting all antipsychotic doses to risperidone equivalents. Interestingly, estradiol was effective regardless of antipsychotic dose, although women with higher PANSS scores benefited the most. Women who received adjunctive 200 μg of estradiol made a more significant improvement than women receiving 100 μg. This clinical symptom difference occurred despite a lack of difference in serum levels, which suggests that peripheral serum assays may not accurately measure brain impacts.
This large-scale trial adds to the growing body of evidence that estradiol has antipsychotic effects, particularly at higher doses, and has a clinically meaningful effect in women with treatment-resistant schizophrenia. However, unopposed estradiol cannot be given for prolonged periods due to the increased risk of endometrial hyperplasia and malignancy. Currently available hormone therapies, such as the oral contraceptive pill and postmenopausal hormone therapy, include a synthetic progestin for endometrial protection. These preparations have not been trialled in randomized-controlled trials in women with treatment-resistant schizophrenia. The estrogens contained in such preparations may not be as effective on psychotic symptoms; synthetic progestins may worsen mood in some women.63,64 Transdermal oestrogen therapies at the doses reported here should be reserved for women with treatment-resistant symptoms and should not be used without specialist advice from an endocrinologist. Oestrogen therapy should not be used in women with a history of thromboembolism, hormone-dependant cancer, stroke or migraine with aura. The long-term risks of high-dose oestrogen therapies include denovo thromboembolism, and in the case of postmenopausal hormone therapy, an apparent increase in breast cancer incidence. Individual patient factors are therefore important to consider before instigating any form of hormone therapy.
Selective oestrogen receptor modulators that cause the activation of oestrogen receptors in a tissue-specific fashion may be the way forward for oestrogen research in schizophrenia. For example, raloxifene has been demonstrated to have central nervous system effects in healthy women and women with schizophrenia,31 but it does not cause endometrial hyperplasia and reduces the risk of breast cancer.
Given the positive outcomes of this study, trials of selective oestrogen receptor modulators represent a hopeful future direction for schizophrenia research. In addition, the impact of estradiol on symptoms of schizophrenia should be expanded to include postmenopausal women and men.
Arevalo MA, Santos-Galindo M, Bellini MJ, Azcoitia I, Garcia-Segura LM . Actions of estrogens on glial cells: Implications for neuroprotection. Biochim Biophys Acta 2010; 1800: 1106–1112.
Behl C . Estrogen can protect neurons: modes of action. J Steroid Biochem Mol Biol 2002; 83: 195–197.
Rao ML, Kölsch H . Effects of estrogen on brain development and neuroprotection—implications for negative symptoms in schizophrenia. Psychoneuroendocrinology 2003; 28:(Suppl 2) 83–96.
Bishop J, Simpkins James W . Role of estrogens in peripheral and cerebral glucose utilization. Rev Neurosci 1992; 3: 121–138.
Garcia-Segura LM, Azcoitia I, DonCarlos LL . Neuroprotection by estradiol. Prog Neurobiol 2001; 63: 29–60.
Li J, Siegel M, Yuan M, Zeng Z, Finnucan L, Persky R et al. Estrogen enhances neurogenesis and behavioral recovery after stroke. J Cereb Blood Flow Metab 2011; 31: 413–425.
Liu M, Kelley MH, Herson PS, Hurn PD . Neuroprotection of sex steroids. Minerva Endocrinol 2010; 35: 127–143.
Yang LC, Zhang QG, Zhou CF, Yang F, Zhang YD, Wang RM et al. Extranuclear estrogen receptors mediate the neuroprotective effects of estrogen in the rat hippocampus. Plos One 2010; 5: 1–13.
Begemann MJH, Dekker CF, van Lunenburg M, Sommer IE . Estrogen augmentation in schizophrenia: a quantitative review of current evidence. Schizophr Res 2012; 141: 179–184.
Riecher-Rössler A . Oestrogen effects in schizophrenia and their potential therapeutic implications - Review. Archives of Women's Mental Health 2002; 5: 111–118.
Aleman A, Kahn RS, Selten JP . Sex differences in the risk of schizophrenia: evidence from meta-analysis. Arch Gen Psychiatry 2003; 60: 565–571.
Kendell RE, Chalmers JC, Platz . Epidemiology of puerperal psychoses. Br J Psychiatry 1987; 150: 662–673.
Seeman MV . Current outcome in schizophrenia: women vs men. Acta Psychiatr Scand 1986; 73: 609–617.
Bergemann N, Parzer P, Runnebaum B, Resch F, Mundt C . Estrogen, menstrual cycle phases, and psychopathology in women suffering from schizophrenia. Psychol Med 2007; 37: 1427–1436.
Riecher-Rössler A, Häfner H, Stumbaum M, Maurer K, Schmidt R . Can oestradiol modulate schizophrenic symptomatology? Schizophr Bull 1994; 2: 203–214.
Akhondzadeh S, Nejatisafa AA, Amini H, Mohammadi MR, Larijani B, Kashani L et al. Adjunctive estrogen treatment in women with chronic schizophrenia: a double-blind, randomized, and placebo-controlled trial. Prog Neuropsychopharmacol Biol Psychiatry 2003; 27: 1007–1012.
Thompson K, Sergejew A, Kulkarni J . Estrogen affects cognition in women with psychosis. Psychiatry Res 2000; 94: 201–209.
Vasudevan N, Pfaff DW . Non-genomic actions of estrogens and their interaction with genomic actions in the brain. Front Neuroendocrinol 2008; 29: 238–257.
Bethea CL, Mirkes SJ, Shively CA, Adams MR . Steroid regulation of tryptophan hydroxylase protein in the dorsal raphe of macaques. Biol Psychiatry 2000; 47: 562–576.
Fink G, Sumner BE, McQueen JK, Wilson H, Rosie R . Sex steroid control of mood, mental state and memory. Clin Exp Pharmacol Physiol 1998; 25: 764–775.
Fink G, Sumner BH, Rosie R, Grace O, Quinn J . Estrogen control of central neurotransmission: effect on mood, mental state, and memory. Cell Mol Neurobiol 1996; 16: 325–344.
Hafner H, Behrens S, De Vry J, Gattaz WF . An animal model for the effects of estradiol on dopamine-mediated behavior: implications for sex differences in schizophrenia. Psychiatry Res 1991; 38: 125–134.
Hafner H, Behrens S, De Vry J, Gattaz WF . Oestradiol enhances the vulnerability threshold for schizophrenia in women by an early effect on dopaminergic neurotransmission. Evidence from an epidemiological study and from animal experiments. Eur Arch Psychiatry Clin Neurosci 1991; 241: 65–68.
Hiroi R, McDevitt RA, Neumaier JF . Estrogen selectively increases tryptophan hydroxylase-2 mRNA expression in distinct subregions of rat midbrain raphe nucleus: association between gene expression and anxiety behavior in the open field. Biol Psychiatry 2006; 60: 288–295.
Dean B . Neurochemistry of schizophrenia: the contribution of neuroimaging postmortem pathology and nNeurochemistry in schizophrenia. Curr Top Med Chem 2013; 12: 2375–2392.
Meltzer HY, Horiguchi M, Massey BW . The role of serotonin in the NMDA receptor antagonist models of psychosis and cognitive impairment. Psychopharmacology (Berl) 2011; 213: 289–305.
Meltzer HY, Massey BW . The role of serotonin receptors in the action of atypical antipsychotic drugs. Curr Opin Pharmacol 2011; 11: 59–67.
Sanchez MG, Morissette M, Di Paolo T . Oestradiol modulation of serotonin reuptake transporter and serotonin metabolism in the brain of monkeys. J Neuroendocrinol 2013; 25: 560–569.
Meitzen J, Mermelstein PG . Estrogen receptors stimulate brain region specific metabotropic glutamate receptors to rapidly initiate signal transduction pathways. J Chem Neuroanat 2011; 42: 236–241.
Pasqualini C, Olivier V, Guibert B, Frain O, Leviel V . Acute stimulatory effect of estradiol on striatal dopamine synthesis. J Neurochem 1995; 65: 1651–1657.
Becker JB . Oestrogen effects on dopaminergic function in striatum. Novartis Found Symp 2000; 230: 134–145, discussion 145-154.
Becker JB . Estrogen rapidly potentiates amphetamine-induced striatal dopamine release and rotational behavior during microdialysis. Neurosci Lett 1990; 118: 169–171.
Pecins-Thompson M, Brown NA, Kohama SG, Bethea CL . Ovarian Steroid Regulation of Tryptophan Hydroxylase mRNA Expression in Rhesus Macaques. J Neurosci 1996; 16: 7021–7029.
Häfner H, Behrens S, Vry J, Gattaz W . Oestradiol enhances the vulnerability threshold for schizophrenia in women by an early effect on dopaminergic neurotransmission. Eur Arch Psychiatry Clin Neurosci 1991; 241: 65–68.
Seeman P . Dopamine receptors and the dopamine hypothesis of schizophrenia. Synapse 1987; 1: 133–152.
Adams MM, Fink SE, Janssen WGM, Shah RA, Morrison JH . Estrogen modulates synaptic N-methyl-D-aspartate receptor subunit distribution in the aged hippocampus. J Comp Neurol 2004; 474: 419–426.
Xiao L, Becker JB . Quantitative microdialysis determination of extracellular striatal dopamine concentration in male and female rats: effects of estrous cycle and gonadectomy. Neurosci Lett 1994; 180: 155–158.
Hampson E . Estrogen-related variations in human spatial and articulatory-motor skills. Psychoneuroendocrinology 1990; 15: 97–111.
Riecher-Rossler A, Hafner H, Stumbaum M, Maurer K, Schmidt R . Can estradiol modulate schizophrenic symptomatology? Schizophr Bull 1994; 20: 203–214.
Ko YH, Joe SH, Cho W, Park JH, Lee JJ, Jung IK et al. Estrogen, cognitive function and negative symptoms in female schizophrenia. Neuropsychobiology 2006; 53: 169–175.
Hoff AL, Kremen WS, Wieneke MH, Lauriello J, Blankfeld HM, Faustman WO et al. Association of estrogen levels with neuropsychological performance in women with schizophrenia. Am J Psychiatry 2001; 158: 1134–1139.
Riecher-Rossler A, Kulkarni J . Estrogens and gonadal function in schizophrenia and related psychoses. Curr Top Behav Neurosci 2011; 8: 155–171.
Goff DC, Coyle JT . The emerging role of glutamate in the pathophysiology and treatment of schizophrenia. Am J Psychiatry 2001; 158: 1367–1377.
Carranza-Lira S, Valentino-Figueroa ML . Estrogen therapy for depression in postmenopausal women. Int J Gynecol Obstet 1999; 65: 35–38.
Schmidt PJ, Nieman L, Danaceau MA, Tobin MB, Roca CA, Murphy JH et al. Estrogen replacement in perimenopause-related depression: a preliminary report. Am J Obstet Gynecol 2000; 183: 414–420.
Ghafari E, Fararouie M, Shirazi HG, Farhangfar A, Ghaderi F, Mohammadi A . Combination of estrogen and antipsychotics in the treatment of women with chronic schizophrenia: a double-blind, randomized, placebo-controlled clinical trial. Clin Schizophr Relat Psychoses 2013; 6: 172–176.
Kulkarni J, de Castella A, Smith D, Taffe J, Keks N, Copolov D . A clinical trial of the effects of estrogen in acutely psychotic women. Schizophr Res 1996; 20: 247–252.
Kulkarni J, Riedel A, de Castella AR, Fitzgerald PB, Rolfe TJ, Taffe J et al. Estrogen - a potential treatment for schizophrenia. Schizophr Res 2001; 48: 137–144.
Kulkarni J, de Castella A, Fitzgerald PB, Gurvich CT, Bailey M, Bartholomeusz C et al. Estrogen in severe mental illness: a potential new treatment approach. Arch Gen Psychiatry 2008; 65: 955–960.
Erhart SM, Marder SR, Carpenter WT . Treatment of schizophrenia negative symptoms: future prospects. Schizophr Bull 2006; 32: 234–237.
Begemann MJ, Dekker CF, van Lunenburg M, Sommer IE . Estrogen augmentation in schizophrenia: a quantitative review of current evidence. Schizophr Res 2012; 141: 179–184.
First MB . Diagnostic and Statistical Manual of Mental Disorders – Fourth Edition (DSM-IV-TR™). American Psychiatric Association: Washington, DC, USA, 2000.
Kay SR, Fiszbein A, Opler LA . The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull 1987; 13: 261–276.
Randolph C . RBANS Repeatable Battery for the Assessment of Neuropsychological Status: Manual. Ncs Pearson Incorporated: San Antonio, TX, USA, 1999.
Montgomery SA, Asberg M . A new depression scale designed to be sensitive to change. Br J Psychiatry 1979; 134: 382–389.
Simpson GM, Angus JW . A rating scale for extrapyramidal side effects. Acta Psychiatr Scand Suppl 1970; 212: 11–19.
Branch NIoMHPR. Abnormal Involuntary Movement Scale (AIMS). Psychopharmacol Bull 1988; 24: 781–783.
Duncan TE, Duncan SC . An introduction to latent growth curve modeling. Behav Ther 2004; 35: 333–363.
Muthén B, Curran PJ . General longitudinal modeling of individual differences in experimental designs: a latent variable framework for analysis and power estimation. Psychol Methods 1997; 2: 371–402.
Leucht S, Kane JM, Kissling W, Hamann J, Etschel E, Engel RR . What does the PANSS mean? Schizophr Res 2005; 79: 231–238.
Cohen J . A power primer. Psychol Bull 1992; 112: 155–159.
Kulkarni J, Gurvich C, Gilbert H, Mehmedbegovic F, Mu L, Marston N et al. Hormone modulation: a novel therapeutic approach for women with severe mental illness. Aust N Z J Psychiatry 2008; 42: 83–88.
Lawrie TA, Hofmeyr GJ, De Jager M, Berk M, Paiker J, Viljoen E . A double-blind randomised placebo controlled trial of postnatal norethisterone enanthate: the effect on postnatal depression and serum hormones. Br J Obstet Gynaecol 1998; 105: 1082–1090.
Backstrom T, Haage D, Lofgren M, Johansson IM, Stromberg J, Nyberg S et al. Paradoxical effects of GABA-A modulators may explain sex steroid induced negative mood symptoms in some persons. Neuroscience 2011; 191: 46–54.
Professor Kulkarni is the Principal Investigator and Dr Wei Wang performed the statistical analysis. This trial was funded by The Stanley Medical Research Institute, Washington USA. Grant ID: 05 T-742. The design and conduct of the study; collection, management, analysis and interpretation of the data; preparation, review and approval of the manuscript; and decision to submit the manuscript for publication were performed by the authors without interference from the funder.
The authors declare no conflict of interest.
About this article
Cite this article
Kulkarni, J., Gavrilidis, E., Wang, W. et al. Estradiol for treatment-resistant schizophrenia: a large-scale randomized-controlled trial in women of child-bearing age. Mol Psychiatry 20, 695–702 (2015). https://doi.org/10.1038/mp.2014.33
Exacerbation of Psychosis During the Perimenstrual Phase of the Menstrual Cycle: Systematic Review and Meta-analysis
Schizophrenia Bulletin (2020)
Translating ENIGMA schizophrenia findings using the regional vulnerability index: Association with cognition, symptoms, and disease trajectory
Human Brain Mapping (2020)
Frontiers in Neuroscience (2020)
The effect of 17β-estradiol on maternal immune activation-induced changes in prepulse inhibition and dopamine receptor and transporter binding in female rats
Schizophrenia Research (2020)