Laboratories commonly provide norclozapine concentrations when a plasma clozapine level is requested, but the appropriate use of this information for the treatment of individuals with schizophrenia ...is not always clear. Particularly vexing is the fact that norclozapine possesses pharmacological properties that are distinct from its parent compound and which contribute to clozapine's efficacy signal, yet the literature focuses primarily on the association of clozapine levels with symptomatic improvement. The purpose of this brief article is to highlight findings with respect to the need to track norclozapine levels, or the ratio of clozapine/norclozapine plasma levels, to optimize efficacy among inadequate responders to clozapine treatment. In addition, there will be a discussion of the specific type of information provided by the clozapine/norclozapine ratio on clozapine's clearance, and how this ratio is sometimes misinterpreted. There is clinical value from to be derived from norclozapine levels and the clozapine/norclozapine ratio for schizophrenia management, and the principles governing use of this information will be distilled into 3 succinct axioms to aid clinicians in managing their clozapine-treated patients with schizophrenia.
This study investigates how a form of bias correction using linear regression improves the limitations of the community climate system model (CCSM) version 4 when it is dynamically downscaled with ...the Weather Research and Forecasting (WRF) model for the North American monsoon (NAM). Long-term biases in the CCSM dataset were removed using the climate forecast system reanalysis (CFSR) dataset as a baseline, from which a physically consistent set of bias-corrected variables were created. To quantitatively identify the effects of CCSM data on the NAM simulations, three 32-year climatologies were generated with WRF driven by (1) CFSR, (2) original CCSM, and (3) bias-corrected CCSM data. The WRF-CFSR simulations serve as a baseline for comparison. With the bias correction, onset dates simulated by WRF bias-corrected CCSM data were generally within a week of the WRF-CFSR climatology, while WRF using the original CCSM data occur up to 3–4 weeks too early over the core of the NAM. Additionally, bias-correction led to improvements in the mature phase of the NAM, reducing August root-mean-square-error values by 26 % over the core of the NAM and 36 % over the northern periphery. Comparison of the CFSR and the bias-corrected CCSM climatologies showed marked consistency in the general evolution of the NAM system. Dry biases in the NAM precipitation existed in each climatology with the original CCSM performing the poorest when compared to observations. The poor performance of the original CCSM simulations stem from biases in the thermodynamic profile supplied to the model through lateral boundary conditions. Bias-correction improved the excessive capping inversions, and mid-level mixing ratio dry biases (2–3 g kg
−1
) present in the CCSM simulations. Improvements in the bias-corrected CCSM data resulted in greater convective activity and a more representative seasonal distribution of precipitation.
A 20-km regional climate model (RCM) dynamically downscaled the Community Climate System Model version 4 (CCSM4) to compare 32-year historical and future “end-of-the-century” climatologies of the ...North American Monsoon (NAM). CCSM4 and other phase 5 Coupled Model Intercomparison Project models have indicated a delayed NAM and overall general drying trend. Here, we test the suggested mechanism for this drier NAM where increasing atmospheric static stability and reduced early-season evapotranspiration under global warming will limit early-season convection and compress the mature-season of the NAM. Through our higher resolution RCM, we found the role of accelerated evaporation under a warmer climate is likely understated in coarse resolution models such as CCSM4. Improving the representation of mesoscale interactions associated with the Gulf of California and surrounding topography produced additional surface evaporation, which overwhelmed the convection-suppressing effects of a warmer troposphere. Furthermore, the improved land–sea temperature gradient helped drive stronger southerly winds and greater moisture transport. Finally, we addressed limitations from inherent CCSM4 biases through a form of mean bias correction, which resulted in a more accurate seasonality of the atmospheric thermodynamic profile. After bias correction, greater surface evaporation from average peak GoC SSTs of 32 °C compared to 29 °C from the original CCSM4 led to roughly 50 % larger changes to low-level moist static energy compared to that produced by the downscaled original CCSM4. The increasing destabilization of the NAM environment produced onset dates that were one to 2 weeks earlier in the core of the NAM and northern extent, respectively. Furthermore, a significantly more vigorous NAM signal was produced after bias correction, with >50 mm month
−1
increases to the June–September precipitation found along east and west coasts of Mexico and into parts of Texas. A shift towards more extreme daily precipitation was found in both downscaled climatologies, with the bias-corrected climatology containing a much more apparent and extreme shift.
There has been increasing recognition that antipsychotic nonadherence is common across all stages of schizophrenia, starting from the first episode. Moreover, numerous meta-analyses of the existing ...literature indicate superiority of long-acting injectable (LAI) over oral antipsychotics when one adjusts for the greater illness severity and duration among patients in LAI antipsychotic trials. The increasing availability of LAI antipsychotic options has raised interest in converting patients from oral medication; however, the successful transition from oral to the comparable LAI antipsychotic requires an understanding of the current extent of antipsychotic exposure, the kinetics of the LAI preparation, and the expected plasma levels achieved by the LAI formulation. The purpose of this article is to provide, in a concise format, the essential information for converting patients to the LAI forms of haloperidol, fluphenazine, risperidone, paliperidone, olanzapine, and aripiprazole from the comparable oral medication, and how the use of plasma antipsychotic levels can be invaluable for this process.
The broad use of atypical antipsychotics was expected to dramatically reduce the prevalence and incidence of tardive dyskinesia (TD), but data show that TD remains an important challenge due the ...persistent nature of its symptoms and resistance to numerous treatment modalities, including antipsychotic discontinuation. Recent insights on genetic risk factors and new concepts surrounding pathophysiology have spurred interest in the possibility of targeted treatment for TD. As will be reviewed in this article, the number of evidence-based strategies for TD treatment is small: only clonazepam, amantadine, ginkgo biloba extract, and the vesicular monoamine transporter 2 (VMAT2) inhibitor tetrabenazine have compelling data. Using new insights into the metabolism of tetrabenazine and the properties of its active metabolites, 2 modifications of tetrabenazine have been synthesized to improve the kinetic profile, and are currently involved in double-blind placebo controlled studies aimed at U.S. Food and Drug Administration (FDA) regulatory approval. The possible availability of these new agents, deuterated tetrabenazine and valbenazine, significantly widens the range of treatment choices for patients with TD. For clinicians with patients at risk for TD due to dopamine antagonist exposure, experience has shown that the problem of TD will be an ongoing issue in modern psychiatry, and that an appreciation of new developments in the pathophysiology of, risk factors for, and treatment of TD is crucial to managing this condition.
Tardive dyskinesia (TD) research is at a crossroads because of renewed interest in this syndrome following the successful development and regulatory approval of two novel vesicular monoamine ...transport 2 (VMAT2) inhibitors. Despite these clinical advances, significant lacunae exist in the knowledge base of TD pathophysiology, prognosis, and epidemiology. Moreover, conflicting definitions of TD as either a syndrome that encompasses a broad array of related phenomena or as a specific subset of tardive syndromes are an impediment to both clinical and basic science research, and to educational efforts targeting nonspecialist clinicians. A unique opportunity is thus presented by the enhanced focus on TD to resolve fundamental issues with regards to nomenclature and clinical criteria, thereby facilitating more sophisticated surveillance and genetic and epidemiological research into tardive movement disorders related to dopamine receptor blocking agents. The widespread use of newer antipsychotics portends that TD will remain a persistent public health issue. This article will present one view of research avenues to be explored for this neuropsychiatric condition, including those that may yield immediate therapeutic benefits by extending expert knowledge into routine clinical care situations.
•Future research demands a consensus TD definition. The Delphi model is proposed as an ideal method to generate consensus.•Important research topics include development of new TD screening tools and use of technology to support clinical assessment.•TD pathophysiology is poorly understood. Clinical marker discovery will require human genetics, imaging and animal data.
Mechanical property anisotropy is one of the issues that are limiting the industrial adoption of additive manufacturing (AM) Ti-6Al-4V components. To improve the deposits’ microstructure, the effect ...of high-pressure interpass rolling was evaluated, and a flat and a profiled roller were compared. The microstructure was changed from large columnar prior
β
grains that traversed the component to equiaxed grains that were between 56 and 139
μ
m in size. The repetitive variation in Widmanstätten
α
lamellae size was retained; however, with rolling, the overall size was reduced. A “fundamental study” was used to gain insight into the microstructural changes that occurred due to the combination of deformation and deposition. High-pressure interpass rolling can overcome many of the shortcomings of AM, potentially aiding industrial implementation of the process.
Patients with schizophrenia experience a broad range of detrimental health outcomes resulting from illness severity, heterogeneity of disease, lifestyle behaviors, and adverse effects of ...antipsychotics. Because of these various factors, patients with schizophrenia have a much higher risk of cardiometabolic abnormalities than people without psychiatric illness. Although exposure to many antipsychotics increases cardiometabolic risk factors, mortality is higher in patients who are not treated versus those who are treated with antipsychotics. This indicates both direct and indirect benefits of adequately treated illness, as well as the need for beneficial medications that result in fewer cardiometabolic risk factors and comorbidities. The aim of the current narrative review was to outline the association between cardiometabolic dysfunction and schizophrenia, as well as discuss the confluence of factors that increase cardiometabolic risk in this patient population. An increased understanding of the pathophysiology of schizophrenia has guided discovery of novel treatments that do not directly target dopamine and that not only do not add, but may potentially minimize relevant cardiometabolic burden for these patients. Key discoveries that have advanced the understanding of the neural circuitry and pathophysiology of schizophrenia now provide possible pathways toward the development of new and effective treatments that may mitigate the risk of metabolic dysfunction in these patients. Novel targets and preclinical and clinical data on emerging treatments, such as glycine transport inhibitors, nicotinic and muscarinic receptor agonists, and trace amine-associated receptor-1 agonists, offer promise toward relevant therapeutic advancements. Numerous areas of investigation currently exist with the potential to considerably progress our knowledge and treatment of schizophrenia.
Constipation is a known side effect of psychotropics that possess high affinity for muscarinic cholinergic receptors. In severe cases, constipation progresses to ileus and bowel ischemia, with ...multiple fatalities related to sepsis and perforation described in the literature, primarily among patients with schizophrenia. A historical prospective database study was performed using registry data from psychiatric and somatic hospitals, combined with the prescription database to examine associations between medications and ileus. Only cases with an ICD-10 diagnosis of schizophrenia (F20) and a concurrent diagnosis of ileus in the years 1996-2007 were included in the study. A total of 26,720 patients with schizophrenia were identified with 123 cases of ileus noted in the study period. Increasing age (OR: 1.03 CI: 1.01-1.04) and female sex (OR: 1.60 CI: 1.10-2.31) were associated with an increased risk of ileus. Treatment with clozapine (OR: 1.99 CI: 1.21-3.29), high-potency first-generation antipsychotics (OR: 1.81 CI: 1.01-3.23), tricyclic antidepressants (OR: 2.29 CI: 1.29-4.09), anticholinergics (OR: 1.48 CI: 1.00-2.19), and opioids (OR: 2.14 CI: 1.36-3.36) were associated with an increased risk of ileus. The onset of ileus occurred on average more than 3 years after the first prescription of the offending drug. Aripiprazole and amisulpride were not associated with ileus. Nine of the ileus cases (7.3%) had a fatal course. Treatment with clozapine (OR: 6.73 CI: 1.55-29.17) or anticholinergics (OR: 5.88 CI: 1.47-23.58) were associated with increased risk of fatal ileus. Patients receiving psychotropics associated with significant anticholinergic properties should undergo proper monitoring and interventions in order to minimize the burden of constipation and the risk of ileus.
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