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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.

BackgroundMany women diagnosed with varying psychiatric disorders take antipsychotic medications during pregnancy. The safety of antipsychotic medications in pregnancy is largely unknown.MethodsWe 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 baby's progress is closely followed for the first year of life.FindingsAs 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.ConclusionThere 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.

Aims/hypothesis The aims of the study were to examine whether type 2 diabetes mellitus is associated with greater brain atrophy and cognitive decline, and whether brain atrophy mediates associations between type 2 diabetes and cognitive decline. Methods Participants without dementia aged 55-90 years from the Cognition and Diabetes in Older Tasmanians (CDOT) study underwent brain MRI (ventricular and total brain volume) and neuropsychological measures (global function and seven cognitive domains) at three time points over 4.6 years. Mixed models were used to examine longitudinal associations of type 2 diabetes with cognitive and MRI measures, adjusting for covariates. A test of mediation was used to determine whether brain atrophy explained associations between type 2 diabetes and cognitive decline. Results A total of 705 participants (diabetes: n = 348, mean age 68.2 years [SD 7.0]; no diabetes: n = 357, mean age 72.5 years [SD 7.1]) were available at baseline. Adjusting for age, sex, education and vascular risk factors, there were significant diabetes × time interactions for verbal memory (β −0.06; 95% CI −0.09, −0.02) and verbal fluency (β −0.03; 95% CI −0.06, −0.00). Although people with diabetes had lower brain (β −14.273; 95% CI −21.197, −6.580) and greater ventricular (β 2.672; 95% CI 0.152, 5.193) volumes at baseline, there were no significant diabetes × time interactions (p > 0.05) or evidence of mediation of the diabetes-cognition relationship by brain atrophy. Conclusions/interpretation In older community-dwelling people, type 2 diabetes is associated with decline in verbal memory and fluency over~5 years. The effect of diabetes on brain atrophy may begin earlier (midlife). KeywordsBrain atrophy . Brain imaging . Cognition . Dementia . Longitudinal study . Type 2 diabetes mellitus Abbreviations DBP Diastolic blood pressure SBP Systolic blood pressure WMH White matter hyperintensityElectronic supplementary material The online version of this article (https://doi.org/10.1007/s00125-018-4778-9) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

ObjectiveTo study longitudinal relationships between type 2 diabetes mellitus (T2DM), cortical thickness, and cognitive function in older people with normal cognition, mild cognitive impairment, and Alzheimer disease (AD).MethodsThe sample was derived from the Alzheimer's Disease Neuroimaging Initiative cohort who underwent brain MRI and cognitive tests annually for 5 years. Presence of T2DM was based on fasting blood glucose ≥7.0mml/L or the use of glucose-lowering agents. We used latent growth curve modeling to explore longitudinal relationships between T2DM, cortical thickness, and cognitive function, adjusting for relevant covariates and testing for interactions.ResultsThere were 124 people with T2DM (mean age 75.5 years, SD 6.2) and 693 without T2DM (mean age 75.1 years, SD 6.9) with at least 1 MRI available. AD and lower cortical thickness at study entry was associated with a lower chance of having a MRI available at each follow-up phase (all p < 0.001). T2DM was associated with lower baseline cortical thickness (p = 0.01). We found no direct effect of T2DM on decline in cortical thickness or cognitive function, but there was an indirect pathway linking T2DM and cognitive decline via baseline cortical thickness (β = −0.17, p = 0.022). There was an interaction between T2DM and education whereby the negative effect of T2DM on baseline cortical thickness was reduced in those with greater education (β = 0.34, p = 0.037). These associations changed minimally when adjusted for baseline cognitive diagnosis.ConclusionsIn an older cohort with low cerebrovascular disease burden, T2DM contributes to cognitive decline via neurodegeneration. Prior brain and cognitive reserve may protect against this effect.

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Summary Motor responses of varying intensities rely on descending commands to heterogeneous pools of motoneurons. In vertebrates, numerous sources of descending excitatory input provide systematically more drive to progressively less excitable spinal motoneurons. While this presumably facilitates simultaneous activation of motor pools, it is unclear how selective patterns of recruitment could emerge from inputs weighted this way. Here, using in vivo electrophysiological and imaging approaches in larval zebrafish, we find that, despite weighted excitation, more excitable motoneurons are preferentially activated by a midbrain reticulospinal nucleus, by virtue of longer membrane time constants that facilitate temporal summation of tonic drive. We confirm the utility of this phenomenon by assessing the activity of the midbrain and motoneuron populations during a light-driven behavior. Our findings demonstrate that weighted descending commands can generate selective motor responses by exploiting systematic differences in the biophysical properties of target motoneurons and their relative sensitivity to tonic input.

BackgroundDiscretionary salt use varies according to socio-demographic factors. However, it is unknown whether salt knowledge and beliefs mediate this relationship. This study examined the direct and indirect effect of socio-demographic factors on salt knowledge and discretionary salt use in a sample of 530 Australian adults.MethodsAn internet based cross-sectional survey was used to collect data for this study. Participants completed an online questionnaire which assessed their salt knowledge, beliefs and salt use behaviour. Mplus was used to conduct structural equation modelling to estimate direct and indirect effects.ResultsThe mean age of the participants was 49.2 years, and about a third had tertiary education. Discretionary salt use was inversely related to age (r=-0.11; p<0.05), and declarative salt knowledge (knowledge of factual information) scores (r = -0.17; p<0.01), but was positively correlated with misconceptions about salt (r = 0.09; p<0.05) and beliefs about the taste of salt (r = 0.51; p<0.001). Structural equation modelling showed age, education and gender were indirectly associated with the use of discretionary salt through three mediating pathways; declarative salt knowledge, misconceptions about salt and salt taste beliefs.ConclusionsInequalities observed between socio-demographic groups in their use of discretionary salt use can potentially be reduced through targeted salt knowledge and awareness campaigns.