Roisin Worsley

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.

Moderate to severe vasomotor and sexual symptoms remain problematic for women aged 60 to 65 years.

ObjectiveThis study aims to determine the prevalence and severity of menopausal symptoms in older postmenopausal women and, hence, the need for treatment options for women of this age. MethodsThis is a cross-sectional questionnaire-based study conducted between October 2013 and March 2014 among 2,020 women aged 40 to 65 years and living independently across Australia. The main outcome measures were the prevalence of moderate to severe vasomotor symptoms (VMS), as measured by the Menopause-Specific Quality of Life Questionnaire, and the current use of prescription therapy for menopausal symptoms. ResultsThe prevalence of moderate to severe VMS was as follows: 2.8% in premenopausal women, 17.1% in perimenopausal women, 28.5% in postmenopausal women younger than 55 years, 15.1% in postmenopausal women aged 55 to 59 years, and 6.5% in postmenopausal women aged 60 to 65 years. Prescription therapy for menopausal symptoms was used by 135 women: 120 (5.9%) women using hormone therapy and 15 (0.7%) women using nonhormonal medication. The factors positively associated with moderate to severe VMS were smoking (odds ratio, 1.6; 95% CI, 1.1-2.3; P < 0.05) and a body mass index of 25 to 29.9 kg/m2 (odds ratio, 1.7; 95% CI, 1.1-2.5; P < 0.05); education beyond high school was inversely associated (odds ratio, 0.7; 95% CI, 0.5-0.9; P < 0.05). ConclusionsIn this large, representative, community-based sample of women, there is a high prevalence of untreated moderate to severe VMS even in women aged 60 to 65 years. The use of vaginal estrogen and nonhormonal prescription therapy with proven efficacy for treatment of menopausal symptoms is strikingly low, suggesting that menopause remains an undertreated condition.

Androgens and Female Sexual Function and Dysfunction—Findings From the Fourth International Consultation of Sexual Medicine

INTRODUCTION Androgens have been implicated as important for female sexual function and dysfunction. AIM To review the role of androgens in the physiology and pathophysiology of female sexual functioning and the evidence for efficacy of androgen therapy for female sexual dysfunction (FSD). METHODS We searched the literature using online databases for studies pertaining to androgens and female sexual function. Major reviews were included and their findings were summarized to avoid replicating their content. MAIN OUTCOME MEASURES Quality of data published in the literature and recommendations were based on the GRADES system. RESULTS The literature supports an important role for androgens in female sexual function. There is no blood androgen level below which women can be classified as having androgen deficiency. Clinical trials have consistently demonstrated that transdermal testosterone (T) therapy improves sexual function and sexual satisfaction in women who have been assessed as having hypoactive sexual desire disorder. The use of T therapy is limited by the lack of approved formulations for women and long-term safety data. Most studies do not support the use of systemic dehydroepiandrosterone therapy for the treatment of FSD in women with normally functioning adrenals or adrenal insufficiency. Studies evaluating the efficacy and safety of vaginal testosterone and dehydroepiandrosterone for the treatment of vulvovaginal atrophy are ongoing. CONCLUSION Available data support an important role of androgens in female sexual function and dysfunction and efficacy of transdermal T therapy for the treatment of some women with FSD. Approved T formulations for women are generally unavailable. In consequence, the prescribing of T mostly involves off-label use of T products formulated for men and individually compounded T formulations. Long-term studies to determine the safety of T therapy for women and possible benefits beyond that of sexual function are greatly needed.

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.

The association between vasomotor symptoms and depression during perimenopause: A systematic review

There is a high incidence of depression in women presenting to menopause clinics. The aim of this review was to determine if there is an association between depressive symptoms or major depressive disorder (MDD) and vasomotor symptoms (VMS). A systematic review of the literature was conducted according to PRISMA guidelines. 33 relevant publications were found, 12 from three large studies. Overall, we found that there is a bidirectional association between VMS and depressive symptoms. This has been established in well-conducted, large observational studies. There does not appear to be a relationship between VMS and MDD. However, studies examining VMS and MDD were prone to bias making it difficult to draw any conclusions.

The Role of Estrogen in the Treatment of Men with Schizophrenia

Schizophrenia is a debilitating and pervasive mental illness with devastating effects on many aspects of psychological, cognitive and social wellbeing. Epidemiological and life-cycle data point to significant differences in the incidence and course of schizophrenia between men and women, suggesting that estrogen plays a “protective” role . Adjunctive 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 feminisation, however, clinical trials using estrogen to treat prostate cancer, bone density loss and even aggression in men with dementia or traumatic brain injury, show estrogen to be a safe and effective therapy. Findings do, however, suggest that further exploration of a therapeutic role for adjunctive estradiol treatment in men with schizophrenia is warranted. The development of the new estrogen compounds - Selective Estrogen Receptor Modulators (SERMs) which do not cause feminisation - opens up the possibility of using a different type of estrogen for a longer period of time at higher doses. Estrogen could therefore prove to be an important component in the treatment of psychotic symptoms in men with schizophrenia. This review explains the scientific rationale behind the estrogen hypothesis and how it can be clinically utilised to address concerns unique to the care of men with schizophrenia.

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.

Role of Estrogens and Estrogen-Like Compounds in Female Sexual Function and Dysfunction

INTRODUCTION Sex steroids are important in female sexual function and dysfunction. AIM To review the role of estrogens in the physiology and pathophysiology of female sexual functioning and the evidence for efficacy of estrogen therapy for female sexual dysfunction to update the previously published International Society of Sexual Medicine Consensus on this topic. METHODS Panel members reviewed the published literature using online databases for studies pertaining to estrogen in female sexual function and dysfunction. Attention was specifically given to clinical trials that had reported on sexual function outcomes in women treated with estrogen. MAIN OUTCOME MEASURES Quality of data published in the literature and recommendations were based on the GRADES system. RESULTS Observational studies that have considered relationship factors and physical or mental health have reported that these factors contribute more to sexual functioning than menopausal status or estrogen levels. Few clinical trials have investigated estrogen therapy with sexual function as a primary outcome. The available data do not support systemic estrogen therapy for the treatment of female sexual dysfunction. Topical vaginal estrogen therapy improves sexual function in postmenopausal women with vulvovaginal atrophy (VVA) and is considered first-line treatment of VVA. Oral ospemifene, a selective estrogen receptor modulator, is effective for the treatment of VVA and might have independent systemic effects on female sexual function. CONCLUSION For sexual problems, the treatment of VVA remains the most pertinent indication for estrogen therapy. When systemic symptoms are absent, estrogen therapy ideally can be administered by a vaginal preparation alone. Systemic estrogen therapy with combined estrogen and progestin in non-hysterectomized women is indicated for women who require treatment for vasomotor and/or other systemic estrogen deficiency symptoms. The improvement in well-being achieved by relief of vasomotor and other symptoms might improve libido in some women and abrogate further intervention.

A systematic review of the impact of oral contraceptives on cognition.

Combined oral contraceptives (OCs) are the most commonly prescribed medication in women of reproductive age, but despite widespread use, their effect on cognitive performance remains controversial. Given strong evidence for the neurological impact of reproductive hormones, a clear rationale for investigation exists. This systematic review sought to identify, collate and critically appraise studies assessing the impact of OCs on cognition in healthy premenopausal women. Ovid MEDLINE, PsychINFO and EMBASE were comprehensively searched using relevant keywords for original peer-reviewed observational studies or randomised trials published after 1960. Of 1289 references screened, 22 studies were eligible for inclusion. Assembled evidence supports a cognitive impact of OCs restricted to specific domains; however, the quality of evidence is poor. The most consistent finding is improved verbal memory with OC use. Evidence is also emerging that differing progestin androgenicity may lead diverse OC formulations to differentially impact certain cognitive domains, such as visuospatial ability. At present, evidence is inconclusive, contradictory and limited by methodological inconsistencies. There is scope for further research in this area to definitively determine the cognitive impact of OCs.