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Tardive dyskinesia (TD) is a persistent and potentially disabling movement disorder associated with prolonged exposure to antipsychotics and other dopamine receptor blocking agents. Long-term safety of the approved TD medication, valbenazine, was demonstrated in 2 clinical trials (KINECT 3 [NCT02274558], KINECT 4 [NCT02405091]). Data from these trials were analyzed post hoc to evaluate the onset and resolution of adverse events (AEs).
Participants in KINECT 3 and KINECT 4 received up to 48 weeks of once-daily valbenazine (40 or 80 mg). Data from these studies were pooled and analyzed to assess the incidence, time to first occurrence, and resolution for the following AEs of potential clinical interest: akathisia, balance disorder, dizziness, parkinsonism, somnolence/sedation, suicidal behavior/ideation, and tremor.
In the pooled population (N=314), all AEs of potential clinical interest occurred in <10% of participants, with somnolence (9.6%), suicidal behavior/ideation (6.4%), and dizziness (5.7%) being the most common AEs. Mean time to first occurrence ranged from 36 days (akathisia [n=9]) to 224 days (parkinsonism [n=2]). By end of study (or last study visit), resolution of AEs was as follows: 100% (suicidal ideation/behavior, parkinsonism); >85% (somnolence/sedation, dizziness); >70% (akathisia, balance disorder, tremor).
In long-term clinical trials, the incidence of AEs of potential clinical interest was low (<10%) and most were resolved by end of treatment (>70–100%). All patients taking valbenazine should be routinely monitored for AEs, particularly those that may exacerbate the motor symptoms associated with TD.
Little is known about the determinants of community integration (i.e. recovery) for individuals with a history of homelessness, yet such information is essential to develop targeted interventions.
We recruited homeless Veterans with a history of psychotic disorders and evaluated four domains of correlates of community integration: perception, non-social cognition, social cognition, and motivation. Baseline assessments occurred after participants were engaged in supported housing services but before they received housing, and again after 12 months. Ninety-five homeless Veterans with a history of psychosis were assessed at baseline and 53 returned after 12 months. We examined both cross-sectional and longitudinal relationships with 12-month community integration.
The strongest longitudinal association was between a baseline motivational measure and social integration at 12 months. We also observed cross-sectional associations at baseline between motivational measures and community integration, including social, work, and independent living. Cross-lagged panel analyses did not suggest causal associations for the motivational measures. Correlations with perception and non-social cognition were weak. One social cognition measure showed a significant longitudinal correlation with independent living at 12 months that was significant for cross-lagged analysis, consistent with a causal relationship and potential treatment target.
The relatively selective associations for motivational measures differ from what is typically seen in psychosis, in which all domains are associated with community integration. These findings are presented along with a partner paper (Study 2) to compare findings from this study to an independent sample without a history of psychotic disorders to evaluate the consistency in findings regarding community integration across projects.
In an initial study (Study 1), we found that motivation predicted community integration (i.e. functional recovery) 12 months after receiving housing in formerly homeless Veterans with a psychotic disorder. The current study examined whether the same pattern would be found in a broader, more clinically diverse, homeless Veteran sample without psychosis.
We examined four categories of variables as potential predictors of community integration in non-psychotic Veterans: perception, non-social cognition, social cognition, and motivation at baseline (after participants were engaged in a permanent supported housing program but before receiving housing) and a 12-month follow-up. A total of 82 Veterans had a baseline assessment and 41 returned for testing after 12 months.
The strongest longitudinal association was between an interview-based measure of motivation (the motivation and pleasure subscale from the Clinical Assessment Interview for Negative Symptoms) at baseline and measures of social integration at 12 months. In addition, cross-lagged panel analyses were consistent with a causal influence of general psychiatric symptoms at baseline driving social integration at 12 months, and reduced expressiveness at baseline driving independent living at 12 months, but there were no significant causal associations with measures of motivation.
The findings from this study complement and reinforce those in Veterans with psychosis. Across these two studies, our findings suggest that motivational factors are associated at baseline and at 12 months and are particularly important for understanding and improving community integration in recently-housed Veterans across psychiatric diagnoses.
Individuals with tardive dyskinesia (TD) who completed a long-term study (KINECT 3 or KINECT 4) of valbenazine (40 or 80 mg/day, once-daily for up to 48 weeks followed by 4-week washout) were enrolled in a subsequent study (NCT02736955) that was primarily designed to further evaluate the long-term safety of valbenazine.
Participants were initiated at 40 mg/day (following prior valbenazine washout). At week 4, dosing was escalated to 80 mg/day based on tolerability and clinical assessment of TD; reduction to 40 mg/day was allowed for tolerability. The study was planned for 72 weeks or until termination due to commercial availability of valbenazine. Assessments included the Clinical Global Impression of Severity-TD (CGIS-TD), Patient Satisfaction Questionnaire (PSQ), and treatment-emergent adverse events (TEAEs).
At study termination, 85.7% (138/161) of participants were still active. Four participants had reached week 60, and none reached week 72. The percentage of participants with a CGIS-TD score ≤2 (normal/not ill or borderline ill) increased from study baseline (14.5% [23/159]) to week 48 (64.3% [36/56]). At baseline, 98.8% (158/160) of participants rated their prior valbenazine experience with a PSQ score ≤2 (very satisfied or somewhat satisfied). At week 48, 98.2% (55/56) remained satisfied. Before week 4 (dose escalation), 9.4% of participants had ≥1 TEAE. After week 4, the TEAE incidence was 49.0%. No TEAE occurred in ≥5% of participants during treatment (before or after week 4).
Valbenazine was well-tolerated and persistent improvements in TD were found in adults who received once-daily treatment for >1 year.
Oxidative stress is implicated in the aetiology of schizophrenia, and the antioxidant defence system (AODS) may be protective in this illness. We examined the major antioxidant glutathione (GSH) in prefrontal brain and its correlates with clinical and demographic variables in schizophrenia.
GSH levels were measured in the dorsolateral prefrontal region of 28 patients with chronic schizophrenia using a magnetic resonance spectroscopy sequence specifically adapted for GSH. We examined correlations of GSH levels with age, age at onset of illness, duration of illness, and clinical symptoms.
We found a negative correlation between GSH levels and age at onset (r = −0.46, p = 0.015), and a trend-level positive relationship between GSH and duration of illness (r = 0.34, p = 0.076).
Our findings are consistent with a possible compensatory upregulation of the AODS with longer duration of illness and suggest that the AODS may play a role in schizophrenia.
Mismatch negativity (MMN) is an event-related potential (ERP) component reflecting auditory predictive coding. Repeated standard tones evoke increasing positivity (‘repetition positivity’; RP), reflecting strengthening of the standard's memory trace and the prediction it will recur. Likewise, deviant tones preceded by more standard repetitions evoke greater negativity (‘deviant negativity’; DN), reflecting stronger prediction error signaling. These memory trace effects are also evident in MMN difference wave. Here, we assess group differences and test-retest reliability of these indices in schizophrenia patients (SZ) and healthy controls (HC).
Electroencephalography was recorded twice, 2 weeks apart, from 43 SZ and 30 HC, during a roving standard paradigm. We examined ERPs to the third, eighth, and 33rd standards (RP), immediately subsequent deviants (DN), and the corresponding MMN. Memory trace effects were assessed by comparing amplitudes associated with the three standard repetition trains.
Compared with controls, SZ showed reduced MMNs and DNs, but normal RPs. Both groups showed memory trace effects for RP, MMN, and DN, with a trend for attenuated DNs in SZ. Intraclass correlations obtained via this paradigm indicated good-to-moderate reliabilities for overall MMN, DN and RP, but moderate to poor reliabilities for components associated with short, intermediate, and long standard trains, and poor reliability of their memory trace effects.
MMN deficits in SZ reflected attenuated prediction error signaling (DN), with relatively intact predictive code formation (RP) and memory trace effects. This roving standard MMN paradigm requires additional development/validation to obtain suitable levels of reliability for use in clinical trials.
Childhood adversity is associated with cognitive impairments in schizophrenia. However, findings to date are inconsistent and little is known about the relationship between social cognition and childhood trauma. We investigated the relationship between childhood abuse and neglect and cognitive function in patients with a first-episode of schizophrenia or schizophreniform disorder (n = 56) and matched healthy controls (n = 52). To the best of our knowledge, this is the first study assessing this relationship in patients and controls exposed to similarly high levels of trauma.
Pearson correlational coefficients were used to assess correlations between Childhood Trauma Questionnaire abuse and neglect scores and cognition. For the MCCB domains displaying significant (p < 0.05) correlations, within group hierarchical linear regression, was done to assess whether abuse and neglect were significant predictors of cognition after controlling for the effect of education.
Patients and controls reported similarly high levels of abuse and neglect. Cognitive performance was poorer for patients compared with controls for all cognitive domains except working memory and social cognition. After controlling for education, exposure to childhood neglect remained a significant predictor of impairment in social cognition in both patients and controls. Neglect was also a significant predictor of poorer verbal learning in patients and of attention/vigilance in controls. However, childhood abuse did not significantly predict cognitive impairments in either patients or controls.
These findings are cross sectional and do not infer causality. Nonetheless, they indicate that associations between one type of childhood adversity (i.e. neglect) and social cognition are present and are not illness-specific.
A key obstacle to the development of new drugs to treat the cognitive deficits of schizophrenia was the absence of a standard by which to measure their efficacy. Before granting approval for any new drug for this condition, the US Food and Drug Administration wanted a standard cognitive endpoint based on a broad consensus-based method. To address this obstacle, the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) intiative oversaw a process to develop a consensus neurocognitive battery. Its development included a ten-step process that is described in this article.
Se analizaron los datos de seis estudios comparativos controlados distribuidos al azar de risperidona y neuroleptics convencionales (haloperidol, zuclopentixol y perfenazina) en el tratamiento de 911 pacientes con esquizofrenia crónica para estimar los beneficios y riesgos del tratamiento. Se evaluó la eficacia y el riesgo del tratamiento por medio de la Escala del Síndrome Positivo y Negativo (PANSS) y la Escala de Evaluación de Síntomas Extrapiramidales (ESRS). A partir de las puntuaciones de la PANSS y la ESRS, se calculó la eficacia del efecto (la diferencia entre los tratamientos). La eficacia del efecto antipsicótica fue favorable a la risperidona (iba de 0,22 a 0,37 en las subescalas de la PANSS), y el nivel de la seguridad también (iba de 0,18 a 0,36 en la ESRS). Un análisis de la proporción de pacientes que precisaron medicación antiparkinsoniana produjo un nivel del efecto de 0,37 (precisaron medicación anti-Jarkinsoniana el 20% de los pacientes con risperidona y el 38% de los pacientes que recibían un neuroléptico convencional). Estos datos indican que la risperidona es un antipsicótico más efectivo que los agentes convencionales y causa síntomas extrapiramidales menos graves.
The dynamic fracture (spallation) of ductile metals is known to initiate through the nucleation and growth of microscopic voids. Here, we apply atomistic molecular dynamics modeling to the early growth of nanoscale (2nm radius) voids in face centered cubic metals using embedded atom potential models. The voids grow through anisotropic dislocation nucleation and emission into a cuboidal shape in agreement with experiment. The mechanism of this nucleation process is presented. The resulting viscous growth exponent at late times is about three times larger than expected from experiment for microscale voids, suggesting either a length scale dependence or a inadequacy of the molecular dynamics model such as the perfect crystal surrounding the void.
In the present work, we analyze the behaviour of graphite-reinforced composite materials under periodic loading. We reconstruct the phase space of these physical systems by means of the tools of nonlinear system theory. Experimental measurements are used to calculate chaotic parameters as fractal and embedding dimensions. We use these quantities to characterize differences in the physical samples and modifications in their internal structure. This analysis can provide useful indications about the fracture process.
We have numerically studied various models for crack formation in the slow dynamical regime. Two different aspects are presented herein: (i) sputtering with reconstruction and (ii) internal destruction of a porous medium through the invasion of a secondary phase.
Recent work on the phenomenon of diffusion-controlled quasi-static brittle fracture, known as dynamic embrittlement, is reviewed here with reference to sulfur-induced embrittlement of steel, tin-induced embrittlement of Cu-Sn alloys, and oxygen-induced embrittlement of copper-based and nickel-based alloys. The mechanisms of this generic form of intergranular brittle fracture are discussed.
The mechanical behavior of Fe-Cr-Al-alloys was investigated at different temperatures and after several heat-treatments in order to determine critical conditions for the ductility of the material. It was found that a significant embrittlement takes place during deformation at higher temperatures around 400 °C as well as after heat-treatments at temperatures above 1000 °C in combination with very high or very low cooling rates. Possible reasons for this behavior are discussed with respect to the results of transmission electron microscopy (TEM), Auger spectroscopy (AES), positron annihilation spectroscopy (PAS) and measurements of the electrical resistivity.
An investigation of the brittle-to-ductile transition (BDT) in silicon has been conducted on essentially dislocation-free silicon test specimens made by photolithography. No pre-cracks or additional dislocation sources were introduced into the samples. Three-point bending tests of the samples reveals a well defined transition from brittle fracture of the specimens to complete yielding near 732°C at a crosshead displacement rate of 0.1 mm/min. Limited plasticity is observed below 732°C but is insufficient to prevent crack propagation suggesting that yielding is not dislocation mobility limited. Instead the transition may be controlled by the nucleation of a sufficient density of dislocations. Further support comes from the results of experiments conducted at temperatures below 732°C in which samples were rapidly pre-loaded within the linearly elastic regime, then immediately retested. This rapid pre-loading results in a lower transition temperature. This would not be expected if dislocation mobility controlled the BDT. Instead, it is believed that the transition only occurs when a sufficient density of dislocations has nucleated within the sample. In these experiments, the pre-loading event may increase the dislocation nucleation rate. The source of the dislocations in these defect free samples is still under investigation.