Heather Gilbert

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.

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.

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.

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.

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

Gestational diabetes in women with mental illness.

Information on the safety of antipsychotic medication in pregnancy and breastfeeding is both limited and inconclusive and hence its use during pregnancy has brought about much debate. True prevention of mental illness begins with optimising maternal well-being during pregnancy and ensuring the best possible outcome for the baby. The following case study presents Sally, a participant in the National Register of Antipsychotic Medication in Pregnancy (NRAMP) (Kulkarni et al., 2008). Sally is a 29-year-old woman with schizophrenia and morbid obesity (body mass index of 50). She has a family history of diabetes. Her medications during pregnancy included risperidone (Consta) 37.5 mg intramuscularly fortnightly. Quetiapine (Seroquel XR) 50 mg/day was added at 34 weeks’ gestation. Throughout pregnancy she gained 25 kg, well above the recommended weight gain in pregnancy (Cogswell et al., 1999) (Table 1). Gestational diabetes mellitus (GDM) was diagnosed during routine screening at 28 weeks’ gestation. Dietary management was trialled initially. However, at 32 weeks’ gestation her glycaemic control was suboptimal, requiring the institution of basal-bolus insulin therapy: aspart (NovoRapid) with meals and isophane (Protophane) before bed. Insulin therapy was ceased at the onset of labour. Her postpartum oral glucose tolerance test confirmed that her diabetes had resolved. Sally’s son was born at 36 weeks’ gestation by elective caesarean section (due to maternal obesity, GDM and anxiety). At 4100 g he was large for gestational age (birth weight 99th percentile). He was admitted to the neonatal intensive care unit and then the special care nursery for a total of 8.5 weeks due to neonatal respiratory distress. The baby had neonatal abstinence syndrome and neonatal hypoglycaemia. He was breastfed at birth; however, his poor suckling reflex meant he required nasogastric feeding for 2 weeks. He was noted to be progressing well at 12 months of age. Sally and her son highlight some of the difficulties encountered by women who require antipsychotics in pregnancy. GDM is associated with obesity and excess weight gain in pregnancy. Poorly controlled GDM is also associated with neonatal hypoglycaemia and high birth weight. GDM is noted in 22.1% of NRAMP mothers compared with the Australian population rate of 5.5% (Worsley et al., 2012). It is clear, therefore, that research in this area should be made a priority to achieve better health outcomes for mothers and babies.

Tamoxifen - a potential treatment for women in the manic phase of bipolar affective disorder?

Background: Bipolar affective disorder (BPAD) is an illness with high morbidity and mortality. Lithium and other anticonvulsant drugs are the main treatments for BPAD, despite little being known about their mechanisms of action. Recent attempts to elucidate the biochemical actions of these drugs have focused on the protein kinase C (PKC) pathways. Another PKC inhibitor hypothesized to be effective in the treatment of mania is tamoxifen, a synthetic nonsteroidal antiestrogen. The aim of the current study was to test and compare the effectiveness of two adjunctive antiestrogen agents (tamoxifen or progesterone) in the treatment of acute mania. Methods: A 28-day, three-arm (40 mg/day oral tamoxifen or 20 mg/day oral progesterone or oral placebo), double-blind, placebo-controlled, adjunctive study of 34 women with mania was conducted. All patients also received a mood stabilizer as the baseline treatment. Manic symptoms and psychopathology were measured weekly using the CARS-M and Positive and Negative Syndrome Scale rating scales together with estrogen, progesterone and gonadotropin levels. Cognitive functioning (RBANS) was assessed in a subsample of fi ve participants at baseline and repeated on day 28. Results: Results indicated a decline in the symptoms of mania and psychopathology in the tamoxifen group, and to a lesser extent in the progesterone and control groups. The tamoxifen group also had signifi cant changes in estrogen levels, as well as correlations between estrogen and mania ratings. Conclusion: The results suggest that tamoxifen may be a useful adjunct in the treatment of acute manic symptoms in women with BPAD.

Special Issues for Pregnant Women with Mental Illness

Background: Women who have a mental illness are no less likely to plan for motherhood than any other group in the community. On the contrary, many women with mental illnesses are fully functioning members of society, juggling employment, career, study, family and parenting in conjunction with the ‘normal’ stressors of life. However this is not the case for all. Their burden of illness places extra strain and stress on their lifestyle and family dynamics, often being exacerbated during pregnancy and following the birth. Although some of these effects may be ameliorated using different treatment modalities, they are frequently offered in a disconnected fashion. The introduction of an integrated, holistic approach, as the primary model of care, can successfully incorporate aspects of assessment, prevention and management, thereby strengthening maternal mental health in pregnancy and encouraging healthy mother and infant outcomes. Purpose: This paper will highlight and discuss special issues for pregnant women with mental illnesses, to increase clinical awareness, encourage risk assessment and promote management planning, by using an integrated model of care in support of women during pregnancy and in early motherhood. Conclusion: Pregnancy places extraordinary stress on every conceivable aspect of a woman’s life, including the exponential changes to her own body, intimate relationships, family groupings, career development and lifestyle adjustments. There is true, ongoing, holistic change to the extent that mental health can be compromised. Knowledge of such changes and the opportunity to encourage healthy outcomes must, therefore, be fully supported with an integrated approach by clinicians, consumers and carers.

Special issues for women with mental issues during pregnancy and beyond.

Australian & New Zealand Journal of Psychiatry, 48(9) patients with Pendred syndrome may develop neuropsychiatric symptoms. Various researchers have hypothesized that mood symptoms secondary to thyroid abnormalities may be mediated by changes in neurotransmitters with T3 effectiveness as an antidepressant stemming from augmentation of beta adrenergic activity (Whybrow and Prange, 1981) to modulation of serotonergic, GABA and dopaminergic systems accounting for psychiatric manifestations in patients with thyroid dysfunction (Manzano et al., 2007).