Emorfia Gavrilidis

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.

A prospective cohort study of antipsychotic medications in pregnancy: the first 147 pregnancies and 100 one year old babies.

Background Many women diagnosed with varying psychiatric disorders take antipsychotic medications during pregnancy. The safety of antipsychotic medications in pregnancy is largely unknown. Methods We established the National Register of Antipsychotic Medications in Pregnancy in 2005. Women who are pregnant and taking an antipsychotic medication are interviewed every 6 weeks during pregnancy and then followed until their babies are one year old. The babys progress is closely followed for the first year of life. Findings As of April 18 2012, 147 pregnancies had been followed through to completion. There were 142 live births and data is available for 100 one year old babies. 18% of babies were born preterm, with a higher dose of antipsychotic medication correlating to an increased likelihood of premature delivery; 43% of babies required special care nursery or intensive care after birth; 37% had any degree of respiratory distress and 15% of babies developed withdrawal symptoms. Congenital anomalies were seen in eight babies. Most pregnancies resulted in the birth of live, healthy babies. The use of mood stabilisers or higher doses of antipsychotics during pregnancy increased the likelihood of babies experiencing respiratory distress or admission to Special Care Nursery or Neonatal Intensive Care Units. Conclusion There is a great need for safety and efficacy information about the use of antipsychotic medications in pregnancy. Live, healthy babies are the most common outcome following the use of antipsychotic medication in pregnancy, but clinicians should be particularly mindful of neonatal problems such as respiratory distress.

Role of Estrogen Treatment in the Management of Schizophrenia

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.

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.

The role of oestrogen and other hormones in the pathophysiology and treatment of schizophrenia.

The theory that many serious mental illnesses, in particular psychoses such as schizophrenia, may have a significant hormonal aetiological component is fast gaining popularity and the support of scientific evidence. Oestrogen in particular has been substantially investigated as a potential mediator of brain function in schizophrenia. Epidemiological and life-cycle data point to significant differences in the incidence and course of schizophrenia between men and women suggests a protective role of oestrogen. In vitro and in vivo preclinical research confirms oestradiols interactions with central neurotransmitter systems implicated in the pathogenesis of schizophrenia, while results from randomised controlled trials investigating the antipsychotic potential of oestrogen have been positive. Research into other neuroactive hormones with possible effects on mental state is a rapidly evolving field that may hold new promise. Given that schizophrenia and related psychoses are pervasive and debilitating conditions for which currently available treatments are often only partially effective and entail a high risk of serious side-effects, novel therapeutic strategies are needed. The literature reviewed in this paper suggests that hormones such as oestrogen could be a viable option, and it is hoped that with further research and larger trials, the oestrogen hypothesis can be translated into effective clinical practice.

A four week randomised control trial of adjunctive medroxyprogesterone and tamoxifen in women with mania

Emerging research has suggested that hormone treatments such as selective oestrogen receptor modulators (SERMs) or progestins may be useful in the treatment of mania. The current pilot study compared the use of the SERM tamoxifen and the progestin medroxyprogesterone acetate (MPA), as an adjunct to mood stabiliser medications, for the treatment of mania symptoms in 51 women in a 28-day double blind, placebo controlled study. The primary outcome was the change between baseline and day 28 mania scores as measured by the Clinician Administered Rating Scale for Mania (CARS-M). Adjunctive MPA treatment provided greater and more rapid improvement in mania symptoms compared with adjunctive placebo and tamoxifen treatment. Adjunctive therapy with MPA may be a potentially useful new treatment for persistent mania, leading to a greater and more rapid resolution of symptoms compared with mood stabiliser treatment alone.

Menstrual cycle characteristics in women with persistent schizophrenia.

Objective: Oestradiol has been implicated in the pathogenesis of schizophrenia. Women with schizophrenia often suffer with menstrual dysfunction, usually associated with low oestradiol levels, but whether menstrual dysfunction has an effect on their psychiatric symptoms is not well researched. The aim of this study is to document the menstrual characteristics of women with chronic schizophrenia with focus upon menstrual regularity, menstrual cycle length and menstrual symptoms. To determine which patient characteristics are associated with irregular menses and whether irregular menses are associated with the severity of psychotic symptoms, menstrual symptoms or depressive symptoms. Method: Cross-sectional analyses using baseline data of women enrolled in a clinical trial. Inclusion criteria include Diagnostic and Statistical Manual of Mental Disorders–Fourth Edition, Text Revision diagnosis of schizophrenia, schizoaffective or schizophreniform disorder; aged between 18 and 51 years; residual symptoms of psychosis despite treatment with a stable dose of antipsychotic medication for at least 4 weeks. Menstrual cycle characteristics including regularity, cycle length and menstrual associated symptoms were documented. Symptoms of schizophrenia were measured using Positive and Negative Syndrome Scale, cognition was measured using Repeatable Battery for the Assessment of Neuropsychological Status and depression was assessed using the Montgomery–Asberg Depression Rating Scale. Blood samples were collected at baseline for hormone assays. Results: Of the 139 women, 77 (55.4%) had regular menses, 57 (41%) had irregular menses and 5 (3.6%) women had missing data on their menstrual cycle. Use of atypical antipsychotics associated with hyperprolactinaemia was positively associated with irregular menses (odds ratio = 4.4, 95% confidence interval = [1.8, 10.9], p = 0.001), while age more than 30 years was negatively associated (odds ratio = 0.3, 95% confidence interval = [0.1, 0.6], p = 0.004). Women with irregular cycles had significantly lower oestradiol levels than women with regular cycles (213.2 ± 25.0 vs 299.0 ± 27.3, p = 0.03), but there was no difference in Positive and Negative Syndrome Scale, Montgomery–Asberg Depression Rating Scale or Repeatable Battery for the Assessment of Neuropsychological Status between those with regular and irregular cycles. The most common menstrual associated symptoms were decrease in mood with the menstrual cycle (64.8%), bloating (64.8%), cramps (59.7%), back pain (37.6%) and worsening of psychosis symptoms (32.4%). Conclusion: Regular menses are associated with higher oestradiol levels and higher rates of cyclical mood symptoms but are not associated with Positive and Negative Syndrome Scale scores. Understanding the effect the menstrual cycle can have on psychiatric illness, such as premenstrual exacerbations, is important for the holistic care of women with schizophrenia.

Do mental health clinicians elicit a history of previous trauma in female psychiatric inpatients

Abstract Background: A history of trauma is linked to the development of a wide range of mental health problems, and has long-lasting physiological and psychological consequences. The importance of clinicians directly questioning trauma history has been consistently emphasised in the literature. Aims: To investigate whether a trauma history is obtained from female psychiatry inpatients during an inpatient admission. Methods: The study was a retrospective file audit of 100 female patients admitted to the psychiatric ward of a major metropolitan Melbourne Hospital between December 2013 and November 2014. Results: In the files of 51% of patients there was no mention of whether or not the patient had a trauma-abuse history. Eight percent of patients had documentation stating there was no trauma-abuse history. Forty-one percent of the patients had documented evidence of a trauma-abuse history, although only 3% of these patients had a specific description provided. The presence of current illicit drug use and the diagnosis of borderline personality disorder were the only variables associated with an increase in the likelihood of having a documented trauma-abuse history. Conclusion: There is a need for clinician retraining, a trauma-informed care model and the incorporation of mandatory inquiry in best practice guidelines to generate a shift in culture in the delivery of mental health care services.

Breastfeeding and psychotropic medications

In an Editorial (Oct 20, p 1359), you recommend the initiation of a Global Commission on Tuberculosis Elimination. We advocate for the inclusion of more clear and consistent methods for generating and communicating estimates of country progress on its list of priorities. WHO incidence and mortality fi gures for several African countries in its Global Tuberculosis Reports of 2011 and 2012 diff er by more than an order of magnitude. Some countries’ status for the tuberculosis indicators of Millennium Develop ment Goal 6 (MDG-6) seem to oscillate from report to report (fi gure)—owing not necessarily to changes in programme eff ectiveness, but to poorly communicated changes in the reports’ methods. Although both reports cite the same epidemio logical assessment guide lines, precisely why certain Breastfeeding and psychotropic medications

Menstrual cycle irregularity and menopause status influence cognition in women with schizophrenia

Cognitive impairments are a core feature of schizophrenia and contribute significantly to functional complications. Current pharmacological treatments do not ameliorate cognitive dysfunction and the aetiology of cognitive impairments are poorly understood. Hormones of the hypothalamic-pituitary-gonadal (HPG) axis that regulate reproductive function have multiple effects on the development, maintenance and function of the brain and have been suggested to also influence cognition. The aim of the current study was to investigate how HPG axis hormones effect cognition, specifically exploring the influence of menopause status and menstrual cycle irregularity on cognitive performance in women with schizophrenia. The data for the present study represents pooled baseline data from three clinical trials. Two hundred and forty female participants with a diagnosis of schizophrenia or schizoaffective disorder were included in the analysis. Cognition was assessed using the Repeatable Battery for the Assessment of Neuropsychological Status. Hormone assays for serum sex steroids and pituitary hormones (including estradiol, progesterone, luteinising hormone and follicle-stimulating hormone) were conducted and women were classified as postmenopausal; perimenopausal; premenopausal/reproductive, further classified into regular and irregular menstrual cycles. To model a comparison of cognitive performance for i) perimenopausal; ii) post-menopausal women and iii) reproductive aged women with irregular cycles to reproductive aged women with regular cycles a semiparametric regression model (generalised additive mode) was fitted. The results revealed that in females with schizophrenia, menstrual cycle irregularity predicted significantly poorer cognitive performance in the areas of psychomotor speed, verbal fluency and verbal memory. Perimenopause was not associated with cognitive changes and the post-menopausal period was associated with poorer visuospatial performance. This study provides evidence to associate reproductive hormones with cognitive dysfunction in schizophrenia.