CNS Drugs 2012

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CNS Drugs 2012; 26 (7): 549-557 1172-7047/12/0007-0549/$49.95/0

LEADING ARTICLE

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Role of Estrogen Treatment in the Management of Schizophrenia Jayashri Kulkarni, Emmy Gavrilidis, Roisin Worsley and Emily Hayes

This material is the copyright of the original publisher. Unauthorised copying and distribution is prohibited. The Monash Alfred Psychiatry Research Centre, The Alfred Hospital and Monash University Faculty of Medicine, Nursing and Health Sciences - Central Clinical School, Melbourne, VIC, Australia

Abstract

Increasing evidence from epidemiological, preclinical and clinical studies suggests that estrogens may exert psychoprotective effects in schizophrenia. Observations of gender differences in the onset and course of schizophrenia have prompted exploration of the effects of estrogen on the CNS. The aim of this paper is to provide an overview of different applications of adjunctive estrogen as a possible treatment for symptoms of schizophrenia in both men and women. Recent trials have suggested that estrogen augmentation therapy may be able to enhance the management of schizophrenia; however, the clinical application of estrogen as a treatment has been limited by potential side effects, the most worrying being breast and uterine cancer in women, and feminization in men. Selective estrogen receptor modulators (SERMs), however, may offer therapeutic benefits for both men and women with schizophrenia without posing threat to breast and uterine tissue and without feminizing effects. The use of estrogen opens up new possibilities for both men and women in the treatment of severe mental illnesses such as schizophrenia. With further preclinical and clinical research, it is hoped that this promising field of hormone modulation can continue to evolve and eventually be translated into real therapeutic potential.

1. Introduction

Evidence from epidemiological work, animal studies, clinical observations and randomized trials have all contributed to our understanding of the effects of estrogen and other gonadal hormones on the CNS and in the regulation of mental state. There is a growing appreciation for the role estrogen may play in the pathophysiology and management of severe mental illnesses such as schizophrenia and depression, in both men and women. In particular, accumulating evidence suggests that estrogen may have a protective effect in

women vulnerable to schizophrenia. An overview of the psychoprotective effects of estrogen will be discussed, as well as the work done using both natural estradiol and new generation selective estrogen receptor modulators (SERMs) to treat symptoms of schizophrenia and aid recovery in women and men with chronic schizophrenia. 2. Epidemiological Findings Epidemiological observations of gender differences in the onset and course of schizophrenia prompted exploration of the role of the female

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sex steroid estrogen in psychotic illnesses.[1,2] For women, the onset of schizophrenia manifests at a later mean age of approximately 5 years than men,[3] with pronounced gender differences in the incidence, prevalence and expression of illness.[4-6] Lifecycle studies have also shown that women are more susceptible to a first episode or relapse of psychosis at two major periods of hormonal change, both characterized by a decrease in estrogen levels: postpartum[7] and menopause.[8-10] Fluctuations in estrogen levels during the menstrual cycle are also associated with changes in psychopathology, with exacerbations of psychosis tending to occur during low-estrogen phases of the menstrual cycle, while improvements in symptomatology, function and therapeutic response are observed during high-estrogen phases.[11-15] Similarly, symptomatology seems to be ameliorated during physiological states such as pregnancy, when estrogen plasma levels are high.[7,16] From these findings collectively, the hypothesis that estrogen may exert a protective effect against schizophrenia was derived.[17]

Second-generation antipsychotic medications are effective both through the traditional antagonism of dopamine D2 receptors and through further interactions with the serotonin 5-HT1A and 5-HT2A receptors.[25] It is probable then, that estrogen shares properties with atypical antipsychotics, and this assertion is supported by extensive preclinical evidence. For example, multiple studies involving ovariectomized rats have noted an estrogen treatmentassociated increase in D2 receptor density in the striatum.[26] It has been suggested that this could be a compensatory response to an estrogeninduced decrease in dopamine levels,[19] most likely due to enhanced actions of the dopamine transporter (DAT). Recent work by Chavez et al.[27] reports considerably reduced DAT density in the nucleus accumbens of ovariectomized rats compared with intact rats, which then increased significantly with estradiol administration. Similarly, in their review of extensive rodent and primate data on the CNS effects of estrogen, Lokuge and associates[28] conclude that estrogen profoundly influences the serotonergic system by reducing the activity of monoamine oxidase, enhancing the activity of tryptophan hydroxylase, manipulating the expression of the serotonin transporter, downregulating 5-HT1A receptors and upregulating 5-HT2A receptors. Estrogen has also been shown to enhance glutamatergic neurotransmission by upregulating NMDA receptors, changing their subunit configuration and increasing NMDA agonist binding in the rat brain.[29] Theoretically, this could help reverse the hypoglutamatergic transmission thought to play a part in the pathology of schizophrenia.[30] Most importantly, these hypotheses regarding dopamine, serotonin and glutamate are supported by recent studies that demonstrate that estradiol can effectively reverse a psychomimetic state in rats induced by the administration of a D2 receptor agonist, a 5-HT1A agonist and an NMDA receptor antagonist, respectively,[31,32] strongly suggesting that the antipsychotic potential of estrogen arises from its interactions with these neurotransmitter systems. Furthermore, Arad and Weiner[33,34] observed that estrogen was as effective as clozapine or haloperidol in ameliorating

This material is the copyright of the original publisher. Unauthorised copying and distribution is prohibited. 3. Estrogen: A Modulator and Protector of the CNS

Estrogen has been found to have substantial positive effects in the CNS above and beyond its primary endocrine and reproductive functions, to the extent that it has been considered as ‘nature’s psychoprotectant’.[18] Indeed, brain-imaging modalities have mapped the widespread distribution of estrogen receptors throughout many extrahypothalamic regions of the brain including the limbic system, basal ganglia, cerebellum and multiple areas of cerebral cortex.[19,20] Through classical genomic and rapid non-genomic interactions with these receptors, estrogen influences central signalling pathways and neurodegenerative processes and may even permanently modify neural circuits.[21,22] Consequently, estrogen is able to modulate multiple neurotransmitter systems, including the dopaminergic, serotonergic and glutamatergic pathways.[19,23] This is important given that, in addition to dopamine, other neurotransmitters such as serotonin and glutamate are likely involved in the pathophysiology of schizophrenia.[24] Adis ª 2012 Springer International Publishing AG. All rights reserved.

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Estrogen Treatment in the Management of Schizophrenia

amphetamine-induced psychotic behaviours in female and male rats. Finally, in vitro and in vivo research also provides substantial evidence for the diverse neuroprotective properties of estrogen. This could be of particular relevance to estrogen’s potential efficacy as a treatment for psychotic illness, as the pathogenesis of schizophrenia is believed by many to involve a progressive neurodegenerative component.[35,36] Widespread anatomical abnormalities have been reported in the brains of schizophrenia patients, including grey matter volume reductions, enlarged ventricles and medial temporal lobe and prefrontal cortex changes,[36,37] in addition to the neuropathological finding of grossly abnormal cytoarchitecture.[35,38] It is possible that estrogen could have a positive influence on such changes by protecting brain cells against injury from excitotoxicity, oxidative stress, inflammation, ischaemia and apoptosis,[39-43] as well as promoting neurogenesis, angiogenesis, synaptic density, plasticity and connectivity, axonal sprouting and remyelination, and expression of neurotrophic factors.[44-47]

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in this higher-dose group: mean score reduced from 18.25 (standard deviation 8.8) at baseline to 14.45 (7.4) at the endpoint, whereas in the placebo group mean positive symptom score reduced only from 17.17 (6.8) to 15.37 (5.5).[48,49] Similar findings were observed by Akhondzadeh and colleagues[50] in a double-blind, placebocontrolled study in 32 women of child-bearing age with schizophrenia: they also report significant reductions in total, positive symptom and general psychopathology PANSS scores for women treated with haloperidol plus ethinyl estradiol compared with the group who received haloperidol plus a placebo. Reductions in PANSS scores were clinically substantial in the estradiol group, with decreases of over 40% in all of total, positive symptom and general psychopathology PANSS scores, and statistically, these reductions were significantly more pronounced than in the placebo group (p < 0.001).[50] A case study by Korhonen and colleagues[51] reported that estradiol therapy alone alleviated psychotic symptoms during the premenstrual phase of a woman with schizoaffective disorder. This patient received 3 mg of percutaneous estradiol for 5 months and was able to discontinue regular medications 1 month after starting estradiol treatment. All these findings seem to suggest that exogenous estrogen may be beneficial in potentiating the effects of traditional antipsychotic medications, most likely via its interactions with neurotransmitter systems as discussed above, but also possibly by affecting the hepatic metabolism of antipsychotic drugs,[52] although this is yet to be quantified. To further extend our findings we conducted a proof-of-concept double-blind, randomized controlled trial that compared 100 mg of transdermal estradiol with placebo.[53] 102 women of childbearing age with a diagnosis of schizophrenia or schizoaffective disorder, who were not taking any other hormonal treatment, participated in this 28-day trial. Results showed that the addition of 100 mg estradiol to standard antipsychotic treatment significantly reduced total (p = 0.002), positive (p = 0.005) and general psychopathological (p = 0.01) PANSS scores, and improved cognition (p < 0.01), compared with placebo. Once again,

This material is the copyright of the original publisher. Unauthorised copying and distribution is prohibited. 4. Clinical Trials Using Estrogen in Women with Schizophrenia

Intervention studies using estrogen as a therapeutic agent have provided further support for the estrogen protection hypothesis. One of our research group’s earlier studies was a dose-finding, double-blind, placebo-controlled trial of 50 mg or 100 mg adjunctive transdermal estradiol versus placebo for 28 days in a comparable cohort of 36 women with schizophrenia.[48,49] The 12 participants who received 100 mg of adjunctive transdermal estradiol showed significant abatement of psychopathology compared with the 50 mg and placebo groups (p < 0.01). Estradiol 100 mg was particularly effective against placebo, with significant comparative reductions in total (p = 0.001), positive symptom (p = 0.002), negative symptom (p = 0.03) and general psychopathology (p = 0.002) Positive and Negative Syndrome Scale (PANSS) scores, respectively. The reduction from baseline in positive symptom scores was even clinically significant at 21% for women Adis ª 2012 Springer International Publishing AG. All rights reserved.

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positive symptoms improved the most in the estradiol group, with a 19% reduction from baseline.[53] In comparison, positive, general psychopathology and total PANSS scores in the placebo group all changed by less than 2% over the course of the trial. Despite the positive results of these studies, two relatively recent reviews[54,55] on the use of estrogen in the treatment of schizophrenia failed to conclude that estrogen offers any benefit over placebo, as a number of the trials reviewed report negative or non-significant findings.[56-59] For example, two recent high-quality, double-blind randomized controlled trials by Bergemann et al.[56] and Louza et al.[59] did not find adjunctive estrogen to be efficacious in the treatment of women with schizophrenia. Neither group observed any significant improvements in psychopathology or relapse rates for estrogen treatment compared with placebo. Similarly, no significant treatment effect of estrogen on psychological symptoms in women with schizophrenia was found in two early randomized controlled studies by Glazer et al.[57] and Good et al.[58] However, it would be prudent to interpret these findings with caution. First, the trials of Good et al.[58] and Glazer et al.[57] included only ten participants each, and with such small sample sizes generalizing results is problematic. Second despite the high-quality design and larger sample size (n = 40) of Louza and colleagues’[59] investigation, women in their estrogen treatment arm failed to respond with an increase in serum estradiol levels, which could explain why these women did not improve significantly over the placebo arm. Furthermore, Louza et al.[59] and Glazer et al.[57] both utilized conjugated estrogens in their studies, as opposed to 17b-estradiol, while Bergemann et al.[56] and Good et al.[58] administered estradiol in combination with a synthetic progestin. These factors are of note given that conjugated estrogens do not have the same potency as 17b-estradiol in the brain, and the administration of a synthetic progestin in conjunction with estradiol is often observed to attenuate any positive actions of estradiol on mental state.[60,61] Such differences in hormonal preparations between studies could thus help explain the positive results of some, but

negative results of others. Nonetheless, it was highlighted in both reviews[54,55] that adequately powered, well designed randomized controlled trials are needed before recommendation for broad clinical application can be made. We have addressed this by undertaking a three-site replication and 8-week dose-finding study of 100 mg adjunctive transdermal estradiol, 200 mg adjunctive transdermal estradiol and placebo, in women of child-bearing age with schizophrenia, titled ‘ADEPT’ (A Definitive Estrogen Patch Trial), which is current and ongoing.

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Adis ª 2012 Springer International Publishing AG. All rights reserved.

5. Clinical Trials Using Estrogen in Men with Schizophrenia

Although the estrogen protection hypothesis postulates that estrogen is a potent neuroprotective agent, the use of estrogen supplementation in men with schizophrenia is somewhat controversial. This has arisen from the possibility of feminizing effects such as gynecomastia and decreased libido; however, these are not reported in studies that use less than 2.5 mg of estrogen daily for the duration of less than 4 weeks.[62-64] Estrogen has in fact been used effectively to prevent bone loss and enhance cardiovascular function in men with prostate cancer.[65] Other studies have also highlighted that estrogen can be used to good effect in elderly men with dementia by enhancing the management of aggression[66] and psychosis,[64] as well as in young men following traumatic brain injury by reducing aggression.[67] Furthermore, a small study of 16 young healthy men by Kirschbaum and colleagues[63] suggests that administering just 0.1 mg transdermal estradiol in short-term treatment can blunt the functions of the hypothalamic-pituitary-adrenal axis (HPA), resulting in a decrease in sympathetic responsiveness to psychosocial stress. Most recently, our research group has piloted the use of adjunctive 2 mg oral estradiol valerate in a 2-week randomized, placebo-controlled trial in 53 men with schizophrenia.[68] Results of this preliminary study indicate that although there were no significant treatment effects for total, positive or negative PANSS scores, men in the estradiol group actually displayed a significantly more CNS Drugs 2012; 26 (7)

Estrogen Treatment in the Management of Schizophrenia

rapid improvement in general psychopathology than the placebo group (p