Caroline Gurvich

Estrogen in Severe Mental Illness: A Potential New Treatment Approach

CONTEXT Accumulating evidence suggests that estrogens may have therapeutic effects in severe mental illnesses, including schizophrenia, via neuromodulatory and neuroprotective activity. OBJECTIVE To compare the efficacy of adjunctive transdermal estradiol with that of adjunctive placebo in the treatment of acute psychotic symptoms. DESIGN Randomized, double-blind study. SETTING Patients were recruited from inpatient acute hospital wards and outpatient clinics of 2 metropolitan Melbourne general hospitals. PARTICIPANTS One hundred two women of childbearing age with schizophrenia. All participants were in an acute or chronic phase of their illness; 73 participants were outpatients and the rest were inpatients. Intervention Patients were randomized to receive 100 microg of transdermal estradiol (n = 56) or transdermal placebo (n = 46) for 28 days. MAIN OUTCOME MEASURES Psychopathological symptoms were assessed weekly with the Positive and Negative Syndrome Scale. RESULTS The addition of 100 microg of transdermal estradiol significantly reduced positive (P < .05) and general psychopathological (P < .05) symptoms during the 28-day trial period compared with women receiving antipsychotic medication alone. CONCLUSION Estradiol appears to be a useful treatment for women with schizophrenia and may provide a new adjunctive therapeutic option for severe mental illness. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00206570.

Piloting the effective therapeutic dose of adjunctive selective estrogen receptor modulator treatment in postmenopausal women with schizophrenia.

Estrogen treatment may enhance the recovery of schizophrenia in women. However, adverse effects on uterine and breast tissue and other physical side effects may limit the long-term therapeutic use of estrogen. Raloxifene hydrochloride is a selective estrogen receptor modulator that acts as an estrogen antagonist in breast tissue and may have agonistic actions in the brain, potentially offering mental health benefits with few estrogenic side effects. To provide an indication of the potential therapeutic dose for raloxifene hydrochloride in postmenopausal women with schizophrenia, this study pools data from an ongoing randomized controlled trial of adjunctive 120 mg/day oral raloxifene hydrochloride (n=13) versus oral placebo (n=13), with data from a previous pilot study administering 60 mg/day raloxifene hydrochloride (n=9). Analysis of variance found significant interaction effects for total (p=.01) and general (p=.02) Positive and Negative Syndrome Scale (PANSS) symptomatology. Participants randomized to receive 120 mg/day raloxifene hydrochloride experienced a significantly more rapid recovery of total and general psychotic symptoms compared to both 60 mg/day raloxifene hydrochloride and placebo. The demonstrated benefit of adjunctive treatment with 120 mg/day raloxifene hydrochloride offers support for the potential role of this selective estrogen receptor modulator in treating postmenopausal women with schizophrenia.

Estradiol for treatment-resistant schizophrenia: a large-scale randomized-controlled trial in women of child-bearing age

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.

Estrogens and men with schizophrenia: Is there a case for adjunctive therapy?

Adjunctive use of estrogen therapy has been shown to be effective in enhancing the treatment of schizophrenia in women. In men, consideration of estrogen therapy has been impacted by concerns of feminising side effects, however, clinical trials of the use of estrogen in treating prostate cancer, bone density loss and even aggression and psychosis in dementia or traumatic brain injury, show this to be a safe and effective therapy. The current 14-day randomised placebo-controlled trial in 53 men with schizophrenia was conducted to evaluate the efficacy of 2 mg oral estradiol valerate as an adjunct to atypical antipsychotic treatment. Results demonstrated for estradiol participants a more rapid reduction in general psychopathology that occurred in the context of greater increases in serum estrogen levels and reductions in FSH and testosterone levels. Approximately 28% of estradiol participants did not achieve an increase (at least a 50% from baseline) in serum estrogen suggesting that further research is needed to refine the type, dose and administration route for estrogen therapy in men. Findings do, however, suggest further exploration of a therapeutic role for adjunctive estradiol treatment in men with schizophrenia is warranted.

Vestibular insights into cognition and psychiatry.

The vestibular system has traditionally been thought of as a balance apparatus; however, accumulating research suggests an association between vestibular function and psychiatric and cognitive symptoms, even when balance is measurably unaffected. There are several brain regions that are implicated in both vestibular pathways and psychiatric disorders. The present review examines the anatomical associations between the vestibular system and various psychiatric disorders. Despite the lack of direct evidence for vestibular pathology in the key psychiatric disorders selected for this review, there is a substantial body of literature implicating the vestibular system in each of the selected psychiatric disorders. The second part of this review provides complimentary evidence showing the link between vestibular dysfunction and vestibular stimulation upon cognitive and psychiatric symptoms. In summary, emerging research suggests the vestibular system can be considered a potential window for exploring brain function beyond that of maintenance of balance, and into areas of cognitive, affective and psychiatric symptomology. Given the paucity of biological and diagnostic markers in psychiatry, novel avenues to explore brain function in psychiatric disorders are of particular interest and warrant further exploration.

Inhibitory control and spatial working memory in Parkinson's disease.

Patients with Parkinsons disease (PD) have difficulty performing tasks relying on inhibitory control and working memory, functions of the prefrontal cortex. Eye movement paradigms can be used to investigate basic sensorimotor functions and higher order cognitive aspects of motor control. This study investigated inhibitory control and spatial working memory in the saccadic system of 13 individuals with mild‐moderate PD and 13 age‐matched controls. Tasks explored suppression of reflexive saccades during qualitatively different tasks, generation of express and anticipatory saccades, and the ability to respond to occasional, unpredictable (“oddball”) targets that occurred during a sequence of well‐learned, reciprocating saccades between horizontal targets. Spatial working memory was assessed using single and two‐step (involving a visually guided saccade during the delay period) memory‐guided tasks. Results for the PD group indicated an increased percentage of response selection errors during an oddball task, reduced suppression of inappropriate reflexive saccades during memory‐guided tasks (but not during fixation or saccade‐engagement tasks), and an increased percentage of express and anticipatory saccades. Spatial working memory was preserved in the PD group during single and two‐step memory‐guided tasks. These findings are consistent with dysfunction within fronto‐striatal and prefrontal‐collicular pathways influencing suppression and selection of eye movements.

Preliminary Findings from the National Register of Antipsychotic Medication in Pregnancy

Objective: Following the presentation of a case study and an overview of current data highlighting the need for further research into the use of antipsychotic medication during pregnancy, the aim of the present paper was to outline the establishment of, and present preliminary data from, the National Register of Antipsychotic Medication in Pregnancy (NRAMP). Method: Australian women with a history of psychosis, including schizophrenia, bipolar affective disorder with psychosis, schizoaffective disorder and first-episode psychosis, who are pregnant, are currently being invited to participate. The confluence of speculated national pregnancy rates and epidemiological data regarding child-bearing-age women with psychosis suggested an enrolment target of 100 women over a 24 month period. Details of antipsychotic medication are recorded throughout the pregnancy and for 1 year postnatally. Interviews with the mother are conducted 6 weekly antenatally, and then at 6 and 12 weeks, and 6 and 12 months postnatally, to assess symptoms of psychosis and depression, and attitudes towards parenting. In addition, consultations are conducted with the womens health-care providers to collate information regarding pharmacology and related side-effects, obstetric outcomes, psychiatric diagnoses and symptoms during pregnancy and for 1 year after delivery, and the provision of details on the babys health and well-being. Results: NRAMP was launched in 2005. Ethics approvals have been gained at 14 sites nationally. Thirty women have consented, and 11 have completed. Data including demographics, health-care provision and medication for the first 30 participants are presented. Conclusions: The establishment of NRAMP is an important strategy in improving the management of serious mental illness such as schizophrenia and related disorders, in women who are pregnant. This project involves extensive collaboration between many different clinical groups and industry, and shall culminate in an important resource to improve the quality of life for both patients and future generations.

Hormone Modulation: A Novel Therapeutic Approach for Women with Severe Mental Illness

Objectives: Accumulating evidence describes the effects of oestrogen and other gonadal hormones on the central nervous system and, in particular, on the mental state of women. Evidence supporting the psychotherapeutic effects of exogenous oestrogen has started to emerge only over the past two decades. The purpose of the present paper was to provide an overview of different applications of adjunctive hormones, as treatments for symptoms of severe mental illness in women. Methods: Three case reports are presented: in each case the woman selected had participated in large, double-blind, randomized controlled trials exploring hormone modulation. Case study 1 presents a premenopausal woman with schizophrenia, who received an 8 week trial of daily adjunctive 200 µg transdermal oestradiol. Case study 2 presents a postmenopausal woman with schizophrenia on a 12 week trial of adjunctive raloxifene hydrochloride 120 mg per day−1. Case study 3 presents a woman with schizoaffective disorder, in the manic phase, who received tamoxifen 40 mg per day−1 for 28 days. Results: Adjunctive oestradiol was associated with an improvement in symptoms of psychosis in a premenopausal woman with schizophrenia; adjunctive raloxifene was associated with an improvement in cognitive functioning in a postmenopausal woman with schizophrenia; and adjunctive tamoxifen was associated with an improvement in symptoms of mania in a woman with schizoaffective disorder. Conclusions: These findings are consistent with preliminary research trials suggesting that adjunctive hormone modulation is a promising area of gender-specific treatment for serious mental illness.

The muscarinic system, cognition and schizophrenia

An increasing body of evidence has implicated the central muscarinic system as contributing to a number of symptoms of schizophrenia and serving as a potential target for pharmaceutical interventions. A theoretical review is presented that focuses on the central muscarinic systems contribution to the cognitive symptoms of schizophrenia. The aim is to bridge the void between pertinent neuropsychological and neurobiological research to provide an explanatory account of the role that the central muscarinic system plays in the symptoms of schizophrenia. First, there will be a brief overview of the relevant neuropsychological schizophrenia literature, followed by a concise introduction to the central muscarinic system. Subsequently, we will draw from animal, neuropsychological and pharmacological literature, and discuss the findings in relation to cognition, schizophrenia and the muscarinic system. Whilst unifying the multiple domains of research into a concise review will act as a useful line of enquiry into the central muscarinic systems contribution to the symptoms of schizophrenia, it will be made apparent that more research is needed in this field.

Effect of Adjunctive Raloxifene Therapy on Severity of Refractory Schizophrenia in Women: A Randomized Clinical Trial

IMPORTANCE A substantial proportion of women with schizophrenia experience debilitating treatment-refractory symptoms. The efficacy of estrogen in modulating brain function in schizophrenia has to be balanced against excess exposure of peripheral tissue. Raloxifene hydrochloride is a selective estrogen receptor modulator (mixed estrogen agonist/antagonist) with potential psychoprotective effects and fewer estrogenic adverse effects. OBJECTIVE To determine whether adjunctive raloxifene therapy reduces illness severity in women with refractory schizophrenia. DESIGN, SETTING, AND PARTICIPANTS This 12-week, double-blind, placebo-controlled, randomized clinical trial with fortnightly assessments was performed at an urban tertiary referral center and a regional center from January 1, 2006, to December 31, 2014. Participants included 56 women with schizophrenia or schizoaffective disorder and marked symptom severity despite substantial and stable antipsychotic doses. Data were analyzed using intention to treat as the basis. INTERVENTIONS Adjunctive raloxifene hydrochloride, 120 mg/d, or placebo for 12 weeks. MAIN OUTCOMES AND MEASURES The primary outcome was the change in the Positive and Negative Syndrome Scale (PANSS) total score. Clinical response (defined as a ≥20% decrease in PANSS total score from baseline) and change in PANSS subscale scores, mood, cognition, reproductive hormone levels, and adverse events were also assessed. RESULTS Of the 56 participants (mean [SD] age, 53 [7.7] years; age range, 40-70 years; mean [SD] duration of psychotic illness, 24 [11] years), 26 were randomized to raloxifene and 30 were randomized to placebo. Raloxifene produced a greater reduction in the PANSS total score relative to placebo (β = -6.37; 95% CI, -11.64 to -1.10; P = .02) and resulted in an increased probability of a clinical response (hazard ratio, 5.79; 95% CI, 1.46 to 22.97; P = .01). A significant reduction was found in the PANSS general symptom scores for the raloxifene compared with the placebo (β = -3.72; 95% CI, -6.83 to -0.61; P = .02) groups. For patients who completed the full 12-week trial, there was not a statistically significant treatment effect on PANSS positive symptom scores (β for change in raloxifene vs placebo, -1.92; 95% CI, -3.83 to 0.00; P = .05). Change in mood, cognition, and reproductive hormone levels and the rate of adverse events did not differ between groups. CONCLUSIONS AND RELEVANCE Raloxifene hydrochloride, 120 mg/d, reduces illness severity and increases the probability of a clinical response in women with refractory schizophrenia. This large trial of raloxifene in this patient population offers a promising, well-tolerated agent that has potential application in clinical practice. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00361543.