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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.
A patient in a medium secure psychiatric unit with a 19-year history of treatment-resistant schizophrenia and violence whose mental illness only responded to clozapine, was noted to have a sustained tachycardia. Echocardiography revealed mild biventricular cardiomyopathy. The patient was not significantly affected by this. Initial recommendation from Cardiology was to consider discontinuation of clozapine. It was decided, however, that the risk of worsening psychosis and resultant violence outweighed the risk of the patient’s relatively mild cardiomyopathy. The patient was commenced on ramipril, and later bisoprolol. The patient no longer requires treatment in a medium secure unit and has remained on clozapine with follow-up from cardiology.
Volumetric atrophy and microstructural alterations in diffusion tensor imaging (DTI) measures of the hippocampus have been reported in people with Alzheimer's disease (AD) and mild cognitive impairment (MCI). However, no study to date has jointly investigated concomitant microstructural and volumetric changes of the hippocampus in dementia with Lewy bodies (DLB).
A total of 84 subjects (23 MCI, 17 DLB, 14 AD, and 30 healthy controls) were recruited for a multi-modal imaging (3T MRI and DTI) study that included neuropsychological evaluation. Freesurfer was used to segment the total hippocampus and delineate its subfields. The hippocampal segmentations were co-registered to the mean diffusivity (MD) and fractional anisotropy (FA) maps obtained from the DTI images.
Both AD and MCI groups showed significantly smaller hippocampal volumes compared to DLB and controls, predominantly in the CA1 and subiculum subfields. Compared to controls, hippocampal MD was elevated in AD, but not in MCI. DLB was characterized by both volumetric and microstructural preservation of the hippocampus. In MCI, higher hippocampal MD was associated with greater atrophy of the hippocampus and CA1 region. Hippocampal volume was a stronger predictor of memory scores compared to MD within the MCI group.
Through a multi-modal integration, we report novel evidence that the hippocampus in DLB is characterized by both macrostructural and microstructural preservation. Contrary to recent suggestions, our findings do not support the view that DTI measurements of the hippocampus are superior to volumetric changes in characterizing group differences, particularly between MCI and controls.
We studied neuroinflammation in individuals with late-life, depression, as a
risk factor for dementia, using [11C]PK11195 positron emission
tomography (PET). Five older participants with major depression and 13
controls underwent PET and multimodal 3T magnetic resonance imaging (MRI),
with blood taken to measure C-reactive protein (CRP). We found significantly
higher CRP levels in those with late-life depression and raised
[11C]PK11195 binding compared with controls in brain regions
associated with depression, including subgenual anterior cingulate cortex,
and significant hippocampal subfield atrophy in cornu ammonis 1 and
subiculum. Our findings suggest neuroinflammation requires further
investigation in late-life depression, both as a possible aetiological
factor and a potential therapeutic target.
I am what Chinese would call a waihang (outsider to the guild) in this discussion, neither a specialist in European urban history nor up-to-date on the body of critical social theory that informs much of the discussion in the roundtable. Therefore, I see my role here as primarily presenting a comparative case – China – and only incidentally engaging with the theoretical aspects of the discussion.
The Australian Imaging, Biomarkers and Lifestyle (AIBL) Flagship Study of Ageing is a prospective study of 1,112 individuals (211 with Alzheimer's disease (AD), 133 with mild cognitive impairment (MCI), and 768 healthy controls (HCs)). Here we report diagnostic and cognitive findings at the first (18-month) follow-up of the cohort. The first aim was to compute rates of transition from HC to MCI, and MCI to AD. The second aim was to characterize the cognitive profiles of individuals who transitioned to a more severe disease stage compared with those who did not.
Eighteen months after baseline, participants underwent comprehensive cognitive testing and diagnostic review, provided an 80 ml blood sample, and completed health and lifestyle questionnaires. A subgroup also underwent amyloid PET and MRI neuroimaging.
The diagnostic status of 89.9% of the cohorts was determined (972 were reassessed, 28 had died, and 112 did not return for reassessment). The 18-month cohort comprised 692 HCs, 82 MCI cases, 197 AD patients, and one Parkinson's disease dementia case. The transition rate from HC to MCI was 2.5%, and cognitive decline in HCs who transitioned to MCI was greatest in memory and naming domains compared to HCs who remained stable. The transition rate from MCI to AD was 30.5%.
There was a high retention rate after 18 months. Rates of transition from healthy aging to MCI, and MCI to AD, were consistent with established estimates. Follow-up of this cohort over longer periods will elucidate robust predictors of future cognitive decline.
Of 120 specimens of garden fertilizers of animal origin purchased in retail shops, 40 (33·3%) were found to be contaminated with salmonella organisms. Untreated bone meal (53·1%) was the most heavily contaminated but 25% of specimens of this product classed as heat-treated or sterilized were positive. In all, 32 serotypes were identified.
Paul Tillich (1886–1965) was born and raised in Germany. He received his PhD in 1910 and in 1912 was ordained in the ministry. From 1914 to 1918 he served as a chaplain in the First World War. Returning from the war, he taught both philosophy and theology at several universities. In 1933 the Nazi government suspended Tillich's position at the University of Frankfurt. He then went to the United States where, until 1937, he was Visiting Professor of Philosophy of Religion and Systematic Theology at Union Theological Seminary. He served at Union as Associate Professor of Philosophical Theology (1937–40) and Professor (1941–55). From 1955 to 1962, he was a University Professor at Harvard, and during his last three years he was the Nuveen Professor of Theology in the Divinity School of the University of Chicago. He was buried in New Harmony, Indiana. Tillich wrote a number of books among which are the following: Systematic Theology (3 vols, 1951–63), The Courage to Be (1952), Biblical Religion and the Search for Ultimate Reality (1955) and Dynamics of Faith (1957).
In his writings Tillich describes certain basic questions (he calls them ‘existential questions’) that arise out of the human situation. These questions cannot be answered within that situation. Their answers, he claims, are found in the great symbols of the Christian message. In his writings he endeavours to analyse the human situation and to interpret the traditional Christian symbols as answers to this situation.
The Kepler Mission is a space-based mission whose primary goal is to determine the frequency of Earth-size and larger planets in the habitable zone of solar-like stars. The mission will monitor more than 100,000 stars for patterns of transits with a differential photometric precision of 20 ppm at V = 12 for a 6.5 hour transit. It will also provide asteroseismic results on several thousand dwarf stars. It is specifically designed to continuously observe a single field of view of greater than 100 square degrees for 3.5 or more years.
This paper provides a short overview of the mission, a brief history of the mission development, expected results, new investigations by the recently chosen Participating Scientists, and the plans for the Guest Observer and Astrophysical Data Programs.
Perhaps best known today as a pioneering scholar of Inner Asia and a victim of the McCarthy witch hunts of the 1950s, Owen Lattimore was more basically, like his friend Arnold Toynbee, a major player in the vogue of comparative history that captured wide public attention in the second quarter of the twentieth century. His lifelong intellectual project was to develop a “scientific” model of the way human societies form, evolve, grow, decline, mutate, and interact with one another along “frontiers.” In the process of working out this model, Lattimore appropriated for his own purposes, and often later discarded, some of the analytic devices most popular in his day, including ecological determinism, biological racism, economic geography and location theory, and Marxist modes of production. At every stage in his thinking, he sought to confound complacent teleologies, both those of Western “progress” and those of Chinese “civilization” of its pastoralist neighbors.
The issue between my view and Hasker's concerns a certain principle that he takes to be true, but I hold to be false. The principle in question asserts that failing to do better than one did is a defect only if doing the best one can is possible for one to do. I claim that this principle is false because if an all-knowing, all-powerful being were confronted with an unending series of increasingly better creatable worlds and deliberately chose to create the least good world, that being would thereby show itself to be something less than a supremely perfect world-creator. In fact, I argue that if a supremely perfect world-creator were to exist and create a world, it would have to be a world than which there is no better creatable world.
To find a ground for poetry which is not an inheritance from the past, however prestigious, nor a programme for social change, however necessary, has been a recurrent preoccupation for Latin American poets. Pablo Neruda's long poem 'Alturas de Macchu Picchu' ('Heights of Macchu Picchu') is one of the key poems where those concerns are worked out: 'Alturas' is itself part of Canto general (1950; Canto general), an epic presentation of the land, prehistory, history and politics of Latin America up until the middle of the twentieth century. Canto general celebrates Latin America as an alternative to already-known histories, a new world and a new definition of the possible. But in 'Alturas', that epic narrative reaches a point of collapse: the magnificence of the native Inca city, whose architecture makes it seem to grow out of the extraordinary subtropical landscape, is not enough. A terrible grief for the nameless, forgotten dead and the hunger and slavery they suffered floods into the poem and extends outwards into a wider need to mourn the unburied and unmourned of later history, from the Spanish Conquest to the dictatorships of the twentieth century. And with that the language itself breaks, and reveals its architecture of unresolved pain and violence, the long burden of conquest, colonialism, hunger and early death secreted in the language spoken by Latin Americans through into the twentieth century and beyond.
It is fitting that one of the last pieces of philosophical writing to come from Reid's hand should bear the title “Of Power.” For the concept “power” lies at the foundation of Reid's account of agent-causation, which in turn is the central idea in his account of human freedom and responsibility. In this final piece of philosophizing on this subject, Reid begins by pointing out that: “Every voluntary exertion to produce an event implies a conception of the event, and some belief or hope that the exertion will be followed by it” (OP: 3). Accordingly, our willing (deciding) to take a walk in the woods implies our having a conception of our taking a walk in the woods and some belief or hope that an exertion of ours intended to bring that about will be followed by our taking a walk in the woods. Reid takes this claim of his to imply that a conception of power is antecedent to every deliberate act.
Does he think that the earliest exertions by an infant involve a conception of power? No. Reid thinks that our earliest exertions are instinctive, unaccompanied by a conception of some goal to be accomplished. It is only when experience teaches us that certain exertions are followed by certain events that we learn to make these exertions voluntarily and deliberately in order to produce such an event. And once we believe that the event depends upon our exertion, we then have “the conception of power in ourselves to produce the event” (ibid.). Reid therefore concludes that our conception of power “is the fruit of experience and not innate” (ibid.).