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A fully three-dimensional boundary-integral method (BIM) is developed for the interaction of drops, suspended in a uniform far-field flow at small Reynolds number, with arbitrary Lyapunov surfaces. The close approach of fluid interfaces to solid surfaces poses significant challenges for numerical BIM implementations, due to the highly singular behaviour of single- and double-layer boundary integrals. Two new methods are described that generalize the accurate calculation of the highly singular surface integrals used by high-order desingularization techniques. The first method is semi-analytical, and applies to axisymmetric solid obstacles (in an arbitrary three-dimensional configuration). An axisymmetric particle can be divided into a series of characteristic disks along its axis, for which closed-form expressions for single and double layers are derived in terms of elliptic integrals. To accommodate arbitrary smooth surfaces, a multimesh desingularization method is introduced that calculates surface integrals utilizing a hierarchy of embedded mesh resolutions, together with distance-activated mesh interactions. Several particle shapes, including spherocylinders (capsules) and flat plates, are used to represent major classes characteristic of porous media. A droplet approaching a capsule will break up after forming two lobes, connected by a thin filament, on either side of the capsule. The cross-sectional shape of the filament affects lubrication behaviour. A constriction made of two parallel capsules, even of low aspect ratio, significantly retards drop passage compared to two spheres. Trends in drop squeezing between two capsules are summarized over a range of capillary number, viscosity ratio, drop size and capsule length. A constriction of two coplanar plates results in notably different lubrication and squeezing behaviour. Flow rectification is demonstrated for constrictions that are non-symmetrical with respect to flow reversal, for several non-axisymmetric particles.
In this article, we present the results of an analysis of variation, whose main objectives are to ascertain the ethnocultural identities speakers declare and to measure the impact of internal, external and identity factors on the use of the connectors of consequence (ça) fait que vs donc vs alors vs so. Our research emphasizes that while there is no consensus as to the terminology chosen to express these identities, it is important to consider ethnocultural identities as a complementary factor conditioning linguistic variation. It also demonstrates that for communities whose linguistic practices and norms straddle those of minority- and majority-French language communities, the minority/majority dichotomy needs to be nuanced, according to the social and ethnocultural identity dynamics that may characterize specific communities.
Engagement of frontline staff, along with senior leadership, in competition-style healthcare-associated infection reduction efforts, combined with electronic clinical decision support tools, appeared to reduce antibiotic regimen initiations for urinary tract infections (P = .01). Mean monthly standardized infection and device utilization ratios also decreased (P < .003 and P < .0001, respectively).
Archaeologists have struggled to combine remotely sensed datasets with preexisting information for landscape-level analyses. In the American Southeast, for example, analyses of lidar data using automated feature extraction algorithms have led to the identification of over 40 potential new pre-European-contact Native American shell ring deposits in Beaufort County, South Carolina. Such datasets are vital for understanding settlement distributions, yet a comprehensive assessment requires remotely sensed and previously surveyed archaeological data. Here, we use legacy data and airborne lidar-derived information to conduct a series of point pattern analyses using spatial models that we designed to assess the factors that best explain the location of shell rings. The results reveal that ring deposit locations are highly clustered and best explained through a combination of environmental conditions such as distance to water and elevation as well as social factors.
Invasive predators have decimated island biodiversity worldwide. Rats (Rattus spp.) are perhaps the greatest conservation threat to island fauna. The ground nesting Palau Micronesian Scrubfowl Megapodius laperouse senex (Megapodiidae) inhabits many of the islands of Palau’s Rock Island Southern Lagoon Conservation Area (RISL) in the western Pacific. These islands are also heavily visited by tourists and support populations of introduced rats, both of which may act as added stressors for the scrubfowl. Using passive chew-tag and call playback surveys on five tourist-visited and five tourist-free islands, we investigated if rats and tourists negatively affect scrubfowl, and if higher rat activity is associated with tourist presence. Rat detection probability and site occupancy were significantly higher on tourist visited (89% and 99%, respectively) compared to tourist-free islands (52% and 73%). Scrubfowl were detected at significantly more stations on tourist-free (93%) than tourist visited (47%) islands and their relative abundance was higher (2.66 and 1.58 birds per station, respectively), although not statistically significantly. While rat occupancy probability likewise had a non-significant negative effect on scrubfowl numbers across islands, our results show a negative relationship between tourist presence and scrubfowl in the RISL. Our findings also suggest that rat populations may be augmented by tourist visitation in the RISL. Although this situation may not seriously affect the scrubfowl, it may be highly detrimental to populations of other threatened island landbirds.
This study investigated metabolic, endocrine, appetite and mood responses to a maximal eating occasion in fourteen men (mean: age 28 (sd 5) years, body mass 77·2 (sd 6·6) kg and BMI 24·2 (sd 2·2) kg/m2) who completed two trials in a randomised crossover design. On each occasion, participants ate a homogenous mixed-macronutrient meal (pizza). On one occasion, they ate until ‘comfortably full’ (ad libitum) and on the other, until they ‘could not eat another bite’ (maximal). Mean energy intake was double in the maximal (13 024 (95 % CI 10 964, 15 084) kJ; 3113 (95 % CI 2620, 3605) kcal) compared with the ad libitum trial (6627 (95 % CI 5708, 7547) kJ; 1584 (95 % CI 1364, 1804) kcal). Serum insulin incremental AUC (iAUC) increased approximately 1·5-fold in the maximal compared with ad libitum trial (mean: ad libitum 43·8 (95 % CI 28·3, 59·3) nmol/l × 240 min and maximal 67·7 (95 % CI 47·0, 88·5) nmol/l × 240 min, P < 0·01), but glucose iAUC did not differ between trials (ad libitum 94·3 (95 % CI 30·3, 158·2) mmol/l × 240 min and maximal 126·5 (95 % CI 76·9, 176·0) mmol/l × 240 min, P = 0·19). TAG iAUC was approximately 1·5-fold greater in the maximal v. ad libitum trial (ad libitum 98·6 (95 % CI 69·9, 127·2) mmol/l × 240 min and maximal 146·4 (95 % CI 88·6, 204·1) mmol/l × 240 min, P < 0·01). Total glucagon-like peptide-1, glucose-dependent insulinotropic peptide and peptide tyrosine–tyrosine iAUC were greater in the maximal compared with ad libitum trial (P < 0·05). Total ghrelin concentrations decreased to a similar extent, but AUC was slightly lower in the maximal v. ad libitum trial (P = 0·02). There were marked differences on appetite and mood between trials, most notably maximal eating caused a prolonged increase in lethargy. Healthy men have the capacity to eat twice the energy content required to achieve comfortable fullness at a single meal. Postprandial glycaemia is well regulated following initial overeating, with elevated postprandial insulinaemia probably contributing.
Lumateperone (lumateperone tosylate, ITI-007) is an investigational drug for the treatment of schizophrenia, bipolar depression, and other disorders. Lumateperone has a unique mechanism of action that simultaneously modulates serotonin, dopamine, and glutamate neurotransmission. This may provide advantages in the treatment of the broad symptoms associated with schizophrenia, including negative and depression symptoms. In 2 previous placebo-controlled trials in patients with acute schizophrenia, lumateperone 42mg (ITI-007 60mg) demonstrated statistically significant improvement in the Positive and Negative Syndrome Scale (PANSS) Total score compared with placebo. In these studies, lumateperone was well tolerated with a safety profile similar to placebo. This open-label long-term study evaluated the safety and effectiveness of lumateperone 42mg in patients with schizophrenia and stable symptoms.
Patients with stable schizophrenia were treated for up to 1 year with lumateperone 42mg. Safety assessments included adverse events (AEs), body weight, laboratory parameters, and extrapyramidal symptoms (EPS)/motor symptom assessments. Efficacy analyses included evaluation of changes in PANSS Total score and in depression symptoms, as measured by the Calgary Depression Scale for Schizophrenia (CDSS).
In the 1-year open-label study, 602 patients received at least 1 dose of lumateperone 42mg; at the time of this interim analysis, 107 patients had completed 1 year of treatment. Only 4 TEAEs occurred in ≥5% of patients (weight decrease, dry mouth, headache and diarrhea); the majority of AEs were mild or moderate in intensity. Most metabolic parameters and mean prolactin levels decreased from SOC baseline, as did mean body weight and BMI. Based on AE reporting and EPS/motor symptom scales, lumateperone treatment was associated with minimal EPS risk. Lumateperone 42mg treatment was associated with significant reductions in PANSS Total score from baseline, with continuing PANSS improvement throughout the study. In patients with moderate-to-severe depression symptoms at baseline (CDSS>5), mean CDSS scores decreased from 7.4 (baseline) to 3.1 (Day 300); 60% of patients met CDSS response criteria (50% improvement from baseline) by Day 75 and this response rate was maintained through day 300. Similar magnitude of CDSS improvement was seen regardless of concurrent antidepressant therapy.
In long-term treatment, lumateperone was associated with minimal metabolic, EPS, and cardiovascular safety issues relative to current SOC antipsychotic therapy. Lumateperone improved schizophrenia symptoms with continued long-term treatment. In patients with moderate-to-severe depression symptoms at baseline, lumateperone treatment was associated with marked improvement in CDSS scores. These data are consistent with and extend data previously reported in placebo-controlled studies in patients with acute schizophrenia treated with lumateperone.
Supported by funding from Intra-Cellular Therapies, Inc.
Lumateperone (ITI-007) is in late-phase clinical development for schizophrenia. Lumateperone has a unique mechanism of action that modulates serotonin, dopamine, and glutamate neurotransmission. This pooled analysis of lumateperone in 3 randomized, double-blind, placebo-controlled studies was conducted to evaluate the safety and tolerability of lumateperone 42mg (ITI-007 60mg).
Data were pooled from the 3 controlled late-phase studies of lumateperone 42mg in patients with acute exacerbation of schizophrenia. Safety assessments of all patients who received at least one dose of any treatment included treatment-emergent adverse events (TEAEs), changes in laboratory parameters, extrapyramidal symptoms (EPS), and vital signs.
The safety population comprised 1,073 patients (placebo [n=412], lumateperone 42mg [n=406], risperidone [n=255]). TEAEs that occurred in the lumateperone 42mg group at a rate of ≥5% and twice placebo were somnolence/sedation (24.1% vs 10.0%) and dry mouth (5.9% vs 2.2%). Rates of discontinuation due to TEAEs with lumateperone 42mg (0.5%) were similar to placebo (0.5%) and lower than risperidone (4.7%). Mean change in weight and rates of EPS-related TEAEs were less for lumateperone 42mg and placebo patients than risperidone patients. Mean change from baseline in metabolic parameters were similar or smaller for lumateperone 42mg vs placebo. Mean changes were notably higher in risperidone patients vs lumateperone 42mg and placebo for glucose, cholesterol, triglycerides, and prolactin.
In this pooled analysis, lumateperone 42mg showed good tolerability with potential benefits over risperidone for metabolic, prolactin, and EPS risks. The only TEAE that occurred in >10% of lumateperone patients was somnolence/sedation, which was impacted by morning administration; in subsequent studies that administered lumateperone in the evening, somnolence/sedation rates were markedly reduced. These results suggest that lumateperone 42mg may be a promising new treatment for schizophrenia.
Supported by funding from Intra-Cellular Therapies, Inc.
Home care for older people in England is commissioned through local authorities working predominantly with independent providers of care. Commissioners operate in a market model, planning and procuring home care services for local populations. Their role involves ‘managing’ and ‘shaping’ the market to ensure an adequate supply of care providers. Another imperative, emerging from the principles of personalisation, is the drive to achieve user outcomes rather than ‘time and task’ objectives. Little formal research has investigated the way commissioners reconcile these different requirements and organise commissioning. This study investigated commissioning approaches using qualitative telephone interviews with ten commissioners from different local authorities in England. The characteristics of commissioning were analysed thematically. Findings indicated (a) commissioning involved complex systems and processes, uniquely shaped for the local context, but frequently changed, suggesting a constant need for reframing commissioning arrangements; (b) partnerships with providers were mainly transactional, with occasional examples of collaborative models, that were considered to facilitate flexible services more appropriate for commissioning for personalised outcomes; and (c) only a small number of commissioners had attempted to reconcile the competing and incompatible goals of tightly prescribed contracting and working collaboratively with providers. A better understanding of flexible contracting arrangements and the hallmarks of a trusting collaboration is required to move beyond the procedural elements of contracting and commissioning.
UK Biobank is a well-characterised cohort of over 500 000 participants including genetics, environmental data and imaging. An online mental health questionnaire was designed for UK Biobank participants to expand its potential.
Describe the development, implementation and results of this questionnaire.
An expert working group designed the questionnaire, using established measures where possible, and consulting a patient group. Operational criteria were agreed for defining likely disorder and risk states, including lifetime depression, mania/hypomania, generalised anxiety disorder, unusual experiences and self-harm, and current post-traumatic stress and hazardous/harmful alcohol use.
A total of 157 366 completed online questionnaires were available by August 2017. Participants were aged 45–82 (53% were ≥65 years) and 57% women. Comparison of self-reported diagnosed mental disorder with a contemporary study shows a similar prevalence, despite respondents being of higher average socioeconomic status. Lifetime depression was a common finding, with 24% (37 434) of participants meeting criteria and current hazardous/harmful alcohol use criteria were met by 21% (32 602), whereas other criteria were met by less than 8% of the participants. There was extensive comorbidity among the syndromes. Mental disorders were associated with a high neuroticism score, adverse life events and long-term illness; addiction and bipolar affective disorder in particular were associated with measures of deprivation.
The UK Biobank questionnaire represents a very large mental health survey in itself, and the results presented here show high face validity, although caution is needed because of selection bias. Built into UK Biobank, these data intersect with other health data to offer unparalleled potential for crosscutting biomedical research involving mental health.
As life expectancy increases, more people have chronic psychiatric and medical health disorders. Comorbidity may increase the risk of premature mortality, an important challenge for health service delivery.
Population-based cohort study in Ontario, Canada of all 11 246 910 residents aged ⩾16 and <105 on 1 April 2012 and alive on 31 March 2014. Secondary analyses included subjects having common medical disorders in 10 separate cohorts. Exposures were psychiatric morbidity categories identified using aggregated diagnosis groups (ADGs) from Johns Hopkins Adjusted Clinical Groups software® (v10.0); ADG 25: Persistent/Recurrent unstable conditions; e.g. acute schizophrenic episode, major depressive disorder (recurrent episode), ADG 24: Persistent/Recurrent stable conditions; e.g. depressive disorder, paranoid personality disorder, ADG 23: Time-limited/minor conditions; e.g. adjustment reaction with brief depressive reaction. The outcome was all-cause mortality (April 2014–March 2016).
Over 2 years' follow-up, there were 188 014 deaths (1.7%). ADG 25 conferred an almost threefold excess mortality after adjustment compared to having no psychiatric morbidity [adjusted hazard ratio 2.94 (95% CI 2.91–2.98, p < 0.0001)]. Adjusted hazard ratios for ADG 24 and ADG 23 were 1.12 (95% CI 1.11–1.14, p < 0.0001) and 1.31 (95% CI 1.26–1.36, p < 0.0001). In all 10 medical disorder cohorts, ADG 25 carried significantly greater mortality risk compared to no psychiatric comorbidity.
Psychiatric disorders, particularly those graded persistent/recurrent and unstable, were associated with excess mortality in the whole population, and in the medical disorder cohorts examined. Future research should examine whether service design accounting for psychiatric disorder comorbidity improves outcomes across the spectrum of medical disorders.
Rectilinear collisions of three wetted spheres are considered under conditions of high capillary numbers, for which viscous lubrication forces dominate over capillary forces. The viscous forces resist the relative motion, as characterized by the Stokes number (a dimensionless ratio of particle inertia and viscous forces). At high Stokes numbers, the particles penetrate the fluid layers between them with sufficient inertia that they collide and rebound. Both simultaneous and sequential collisions are simulated, and various outcomes are demonstrated: full agglomeration of the three spheres at low Stokes numbers, full separation or Newton’s cradle at large Stokes numbers and even reverse Newton’s cradle at intermediate Stokes numbers when there is a thicker combined fluid layer between the two target spheres than between the striker sphere and the first target sphere. When there is an initial air gap between the two target spheres, even more exotic outcomes are predicted, such as full separation after the initial collisions followed by full agglomeration or reverse Newton’s cradle (intermediate Stokes numbers) or Newton’s cradle (large Stokes numbers) after the subsequent collisions when the striker sphere catches back up to the target spheres. The approach and findings of this work are expected to provide input and guidance to future work on discrete-element modelling of collisions of many wet particles.
The interfacial behaviour of surfactant-laden drops squeezing through tight constrictions in a uniform far-field flow is modelled with respect to capillary number, drop-to-medium viscosity ratio and surfactant contamination. The surfactant is treated as insoluble and non-diffusive, and drop surface tension is related to surfactant concentration by a linear equation of state. The constriction is formed by three solid spheres held rigidly in space. A characteristic aspect of this confined and contaminated multiphase system is the rapid development of steep surfactant-concentration gradients during the onset of drop squeezing. The interplay between two physical effects of surfactant, namely the greater interface deformability due to decreased surface tension and interface immobilization due to Marangoni stresses, results in particularly rich drop-squeezing dynamics. A three-dimensional boundary-integral algorithm is used to describe drop hydrodynamics, and accurate treatment of close squeezing and trapped states is enabled by advanced singularity subtraction techniques. Surfactant transport and hydrodynamics are coupled via the surface convection equation (or convection–diffusion equation, if artificial diffusion is included), the interfacial stress balance and a solid-particle contribution based on the Hebeker representation. For extreme conditions, such as drop-to-medium viscosity ratios significantly less than unity, it is found that upwind-biased methods are the only stable approaches for modelling surfactant transport. Two distinct schemes, upwind finite volume and flow-biased least squares, are found to provide results in close agreement, indicating negligible numerical diffusion. Surfactant transport is enhanced by low drop-to-medium viscosity ratios, at which extremely sharp concentration gradients form during various stages of the squeezing process. The presence of surfactant, even at low degrees of contamination, significantly decreases the critical capillary number for droplet trapping, due to the accumulation of surfactant at the downwind pole of the drop and its subsequent elongation. Increasing the degree of contamination significantly affects surface mobility and further decreases the critical capillary number as well as drop squeezing times, up to a threshold above which the addition of surfactant negligibly affects squeezing dynamics.
This research explores media reporting of Indigenous students’ Programme for International Student Assessment (PISA) results in two national and 11 metropolitan Australian newspapers from 2001 to 2015. Of almost 300 articles on PISA, only 10 focused on reporting of Indigenous PISA results. While general or non-Indigenous PISA results featured in media reports, especially at the time of the publication of PISA results, there was overwhelming neglect of Indigenous results and the performance gap. A thematic analysis of articles showed mainstream PISA reporting had critical commentary which is not found in the Indigenous PISA articles. The three themes identified include: a lack of teacher quality in remote and rural schools; the debate on Gonski funding recommendations and the PISA achievement gap between Indigenous and non-Indigenous students. This study concluded the overwhelming neglect is linked to media bias, which continues to drive mainstream media coverage of Indigenous Australians.
Astrophysics Telescope for Large Area Spectroscopy Probe is a concept for a National Aeronautics and Space Administration probe-class space mission that will achieve ground-breaking science in the fields of galaxy evolution, cosmology, Milky Way, and the Solar System. It is the follow-up space mission to Wide Field Infrared Survey Telescope (WFIRST), boosting its scientific return by obtaining deep 1–4 μm slit spectroscopy for ∼70% of all galaxies imaged by the ∼2 000 deg2 WFIRST High Latitude Survey at z > 0.5. Astrophysics Telescope for Large Area Spectroscopy will measure accurate and precise redshifts for ∼200 M galaxies out to z < 7, and deliver spectra that enable a wide range of diagnostic studies of the physical properties of galaxies over most of cosmic history. Astrophysics Telescope for Large Area Spectroscopy Probe and WFIRST together will produce a 3D map of the Universe over 2 000 deg2, the definitive data sets for studying galaxy evolution, probing dark matter, dark energy and modifications of General Relativity, and quantifying the 3D structure and stellar content of the Milky Way. Astrophysics Telescope for Large Area Spectroscopy Probe science spans four broad categories: (1) Revolutionising galaxy evolution studies by tracing the relation between galaxies and dark matter from galaxy groups to cosmic voids and filaments, from the epoch of reionisation through the peak era of galaxy assembly; (2) Opening a new window into the dark Universe by weighing the dark matter filaments using 3D weak lensing with spectroscopic redshifts, and obtaining definitive measurements of dark energy and modification of General Relativity using galaxy clustering; (3) Probing the Milky Way’s dust-enshrouded regions, reaching the far side of our Galaxy; and (4) Exploring the formation history of the outer Solar System by characterising Kuiper Belt Objects. Astrophysics Telescope for Large Area Spectroscopy Probe is a 1.5 m telescope with a field of view of 0.4 deg2, and uses digital micro-mirror devices as slit selectors. It has a spectroscopic resolution of R = 1 000, and a wavelength range of 1–4 μm. The lack of slit spectroscopy from space over a wide field of view is the obvious gap in current and planned future space missions; Astrophysics Telescope for Large Area Spectroscopy fills this big gap with an unprecedented spectroscopic capability based on digital micro-mirror devices (with an estimated spectroscopic multiplex factor greater than 5 000). Astrophysics Telescope for Large Area Spectroscopy is designed to fit within the National Aeronautics and Space Administration probe-class space mission cost envelope; it has a single instrument, a telescope aperture that allows for a lighter launch vehicle, and mature technology (we have identified a path for digital micro-mirror devices to reach Technology Readiness Level 6 within 2 yr). Astrophysics Telescope for Large Area Spectroscopy Probe will lead to transformative science over the entire range of astrophysics: from galaxy evolution to the dark Universe, from Solar System objects to the dusty regions of the Milky Way.
Translocation of species to areas of former habitat after threats have been mitigated is a common conservation action. However, the long-term success of reintroduction relies on identification of currently available habitat and areas that will remain, or become, habitat in the future. Commonly, a short-term view is taken, focusing on obvious and assumed threats such as predators and habitat degradation. However, in areas subject to significant climate change, challenges include correctly identifying variables that define habitat, and considering probable changes over time. This poses challenges with species such as the western ground parrot Pezoporus flaviventris, which was once relatively common in near-coastal south-western Australia, an area subject to major climate change. This species has declined to one small population, estimated to comprise < 150 individuals. Reasons for the decline include altered fire regimes, introduced predators and habitat clearing. The establishment of new populations is a high priority, but the extent to which a rapidly changing climate has affected, and will continue to affect, this species remains largely conjecture, and understanding probable climate change impacts is essential to the prioritization of potential reintroduction sites. We developed high-resolution species distribution models and used these to investigate climate change impacts on current and historical distributions, and identify locations that will remain, or become, bioclimatically suitable habitat in the future. This information has been given to an expert panel to identify and prioritize areas suitable for site-specific management and/or translocation.
Lumateperone is a first-in-class agent in development for schizophrenia that acts synergistically through serotonergic, dopaminergic and glutamatergic systems. Lumateperone is a potent 5-HT2A antagonist, a mesolimbic/mesocortical dopamine phosphoprotein modulator (DPPM) with pre-synaptic partial agonist and post-synaptic antagonist activity at D2, a glutamate GluN2B receptor phosphoprotein modulator with D1-dependent enhancement of both NMDA and AMPA currents via the mTOR protein pathway and an inhibitor of serotonin reuptake.
Lumateperone was evaluated in 3 controlled clinical trials to evaluate efficacy in patients with acute schizophrenia. The primary endpoint was change from baseline on the PANSS total score compared to placebo. In Study ‘005, 335 patients were randomized to receive ITI-007 60mg or 120mg , risperidone 4mg (active control) or placebo QAM for 4weeks. In Study ‘301, 450 patients were randomized to receive ITI-007 60mg or 40mg , or placebo QAM for 4weeks. In Study ‘302, 696 patients were randomized to receive ITI-007 60mg or 20mg , risperidone 4mg (active control) or placebo QAM for 6weeks. Also, an open-label safety switching study was conducted in which 302 patients with stable schizophrenia were switched from standard-of-care (SOC) antipsychotics and treated for 6weeks with lumateperone QPM and then switched back to SOC.
In Studies ‘005 and ‘301, lumateperone (60mg ITI-007) met the primary endpoint with statistically significant superior efficacy over placebo at Day 28. In Study ‘302, neither dose of lumateperone separated from placebo on the primary endpoint; a high placebo response was observed in this study. Across all 3 efficacy trials, lumateperone improved symptoms of schizophrenia with the same trajectory and same magnitude of improvement from baseline to endpoint on the PANSS total score.
Lumateperone was well-tolerated with a favorable safety profile in all studies. In the two studies with risperidone included as an active control, lumateperone was statistically significantly better than risperidone on key safety and tolerability measures. In the open-label safety switching study statistically significant improvements from SOC were observed in body weight, cardiometabolic and endocrine parameters worsened again when switched back to SOC medication. In this study, symptoms of schizophrenia generally remained stable or improved. Greater improvements were observed in subgroups of patients with elevated symptomatology (comorbid symptoms of depression and those with prominent negative symptoms).
Lumateperone represents a novel approach to the treatment of schizophrenia with a favorable safety profile in clinical trials. The lack of cardiometabolic and motor safety issues presents a safety profile differentiated from standard-of-care antipsychotic therapy.
Funding Acknowledgements: Intra-Cellular Therapies, Inc.
Tardive dyskinesia (TD) results from exposure to dopamine-receptor antagonists (DRAs), such as typical and atypical antipsychotics. Clinicians commonly manage TD by reducing the dose of or stopping the causative agent; however, this may cause psychiatric relapse and worsen quality of life. In the 12-week ARM-TD and AIM-TD trials, deutetrabenazine demonstrated statistically significant improvements in Abnormal Involuntary Movement Scale (AIMS) scores versus placebo and was generally well tolerated, regardless of baseline DRA use or comorbidities.
To evaluate the impact of underlying disease and current DRA use on efficacy and safety of long-term therapy of deutetrabenazine in patients with TD.
Patients with TD who completed ARM-TD or AIM-TD were eligible to enter this open-label, single-arm, long-term extension after completing the 1-week washout period and final evaluation in the blinded portion of the trial. Change in AIMS scores from baseline to Week 54 and patients “Much Improved” or “Very Much Improved” (treatment success) on the Clinical Global Impression of Change (CGIC) and Patient Global Impression of Change (PGIC) at Week 54 were analyzed by baseline psychiatric illness type, including mood disorders (bipolar disorder/depression/other) or psychotic disorders (schizophrenia/schizoaffective disorder), and presence or absence of current DRA use.
At Week 54, meaningful improvements from baseline in mean (standard error) AIMS scores were observed for patients with baseline mood disorders (–5.2[0.93]) and psychotic disorders (–5.0[0.63]), and in patients currently using DRAs (–4.6[0.54]) or not using DRAs (–6.4[1.27]). Most patients with mood disorders (73%) and psychotic disorders (71%) were “Much Improved” or “Very Much Improved” on CGIC at Week 54, similar to patients currently using (71%) or not using (74%) DRAs. The majority of patients with mood disorders (62%) and psychotic disorders (57%), as well as patients currently using (58%) or not using (63%) DRAs, were also “Much Improved” or “Very Much Improved” on PGIC at Week 54. Prior treatment in ARM-TD and AIM-TD did not impact the long-term treatment response. Underlying psychiatric disorder and concomitant DRA use did not impact the occurrence of adverse events (AEs). The frequencies of dose reductions, dose suspensions, and withdrawals due to AEs were low, regardless of baseline psychiatric comorbidities and DRAuse.
Long-term deutetrabenazine treatment demonstrated meaningful improvements in abnormal movements in TD patients, which were recognized by clinicians and patients, regardless of underlying psychiatric illness or DRAuse.
Presented at: American Psychiatric Association Annual Meeting; May 5–9, 2018, New York, New York, USA
Funding Acknowledgements: This study was supported by Teva Pharmaceuticals, Petach Tikva, Israel.