How antipsychotics work in schizophrenia: a primer on mechanisms.

Antipsychotics effective for schizophrenia approved prior to 2024 shared the common mechanism of postsynaptic dopamine D receptor antagonism or partial agonism. Positive psychosis symptoms correlate with excessive presynaptic dopamine turnover and release, yet this postsynaptic mechanism improved positive symptoms only in some patients, and with concomitant risk for off-target motor and endocrine adverse effects; moreover, these agents showed no benefit for negative symptoms and cognitive dysfunction. The sole exception was data supporting cariprazine's superiority to risperidone for negative symptoms.

Agonist antibody to guanylate cyclase receptor NPR1 regulates vascular tone.

Heart failure is a leading cause of morbidity and mortality. Elevated intracardiac pressures and myocyte stretch in heart failure trigger the release of counter-regulatory natriuretic peptides, which act through their receptor (NPR1) to affect vasodilation, diuresis and natriuresis, lowering venous pressures and relieving venous congestion. Recombinant natriuretic peptide infusions were developed to treat heart failure but have been limited by a short duration of effect.

Effect of timing of casirivimab and imdevimab administration relative to mRNA-1273 COVID-19 vaccination on vaccine-induced SARS-CoV-2 neutralising antibody responses: a prospective, open-label, phase 2, randomised controlled trial.

Background: Deeper insight is needed on how monoclonal antibodies (mAbs) affect vaccine-mediated immune responses when targeting the same protein. We describe the first prospective randomised trial designed to understand mAb-mediated alterations in vaccine-induced immune responses to SARS-CoV-2 spike protein epitopes.

Methods: This randomised, open-label, parallel-group study assessed the potential interaction of a mAb combination, casirivimab and imdevimab, with a vaccine, Moderna's mRNA-1273, in healthy SARS-CoV-2 immunologically naive, seronegative adults at six centres in the USA.

Mechanistic modeling of twin screw wet granulation for pharmaceutical formulations: Calibration, sensitivity analysis, and model-driven workflow.

Wet granulation, a particle size enlargement process, can significantly enhance the critical quality attributes of powders and improve the ability to form tablets in pharmaceutical manufacturing. In this study, a mechanistic-based population balance model is applied to twin screw wet granulation. This model incorporated a recently developed breakage kernel specifically designed for twin screw granulation, along with nucleation, layering, and consolidation.

Exploring real-world symptom impact and improvement in well-being domains for tardive dyskinesia in VMAT2 inhibitor-treated patients via clinician survey and chart review.

Introduction: Two vesicular monoamine transporter 2 (VMAT2) inhibitors are approved in the United States (US) for the treatment of tardive dyskinesia (TD). There is a paucity of information on the impact of VMAT2 inhibitor treatment on patient social and physical well-being. The study objective was to elucidate clinician-reported improvement in symptoms and any noticeable changes in social or physical well-being in patients receiving VMAT2 inhibitors.

Making sense of norclozapine levels: 3 clinical axioms.

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.

T-shaped partial least squares for high-dosed new active pharmaceutical ingredients in continuous twin-screw wet granulation: Granule size prediction with limited material information.

This work presents a granule size prediction approach applicable to diverse formulations containing new active pharmaceutical ingredients (APIs) in continuous twin-screw wet granulation. The approach consists of a surrogate selection method to identify similar materials with new APIs and a T-shaped partial least squares (T-PLS) model for granule size prediction across varying formulations and process conditions. We devised a surrogate material selection method, employing a combination of linear pre-processing and nonlinear classification algorithms, which effectively identified suitable surrogates for new materials.

Reviewing Non-Dopaminergic Mechanisms for Positive and Negative Schizophrenia Symptom Management.

Schizophrenia is a chronic and debilitating mental health condition that significantly impacts quality of life and can shorten patients' lifetime by decades. It is characterized by symptoms including hallucinations and delusions, apathy, and cognitive impairment, and people with schizophrenia also experience many somatic comorbidities, such as metabolic disturbances, infectious diseases, cardiovascular issues, and respiratory illnesses. For decades, treatment for schizophrenia has focused on antipsychotics (APs) that reduce excess dopamine signaling to the associative striatum, which also blocks dopamine signaling in the dorsal striatum, creating movement disorders.

Increased Metabolic Potential, Efficacy, and Safety of Emerging Treatments in Schizophrenia.

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.

Personalized switching from oral to long-acting injectable second-generation antipsychotics in schizophrenia treatment using pharmacokinetic considerations.

Introduction: Long-acting injectable (LAI) formulations of second-generation antipsychotics (SGA) are a mainstay in the treatment of schizophrenia-spectrum patients, and their use improves adherence and reduces relapse risk. Personalizing LAI-based therapy involves tailoring the transition from oral to LAIs based on individual and drug-related pharmacokinetic peculiarities.

Areas Covered: We discuss pharmacokinetic considerations as a cornerstone of a smooth transition from oral to LAI SGAs based on works identified using an updated search in PubMed and Embase in February 2023.

Olanzapine/samidorphan combination consistently mitigates weight gain across various subgroups of patients.

Objective: A combination of olanzapine and the opioid receptor antagonist samidorphan (OLZ/SAM) has been approved in the United States for the treatment of adults with schizophrenia or adults with bipolar I disorder. In a phase 3 study in adults with schizophrenia (ENLIGHTEN-2), OLZ/SAM treatment was associated with significantly less weight gain compared with olanzapine. Prespecified subgroup analyses explored the consistency of the weight mitigation effect of OLZ/SAM vs olanzapine across demographic subgroups in ENLIGHTEN-2.

The prescriber's guide to classic MAO inhibitors (phenelzine, tranylcypromine, isocarboxazid) for treatment-resistant depression.

This article is a clinical guide which discusses the "state-of-the-art" usage of the classic monoamine oxidase inhibitor (MAOI) antidepressants (phenelzine, tranylcypromine, and isocarboxazid) in modern psychiatric practice. The guide is for all clinicians, including those who may not be experienced MAOI prescribers. It discusses indications, drug-drug interactions, side-effect management, and the safety of various augmentation strategies.

Clozapine Use and Forensic Outcomes in Psychiatric Inpatients Deemed Incompetent to Stand Trial.

Referrals for competency restoration increased in the past decade, with the majority of incompetent to stand trial (IST) patients having schizophrenia; 25 percent of schizophrenia patients are treatment resistant. Clozapine is superior to other antipsychotics for treatment resistance but remains underutilized, particularly in forensic settings. Despite the impact of treatment resistance on the legal system, the literature on clozapine for IST patients is limited to two papers comprising 26 patients.

Repeat subcutaneous administration of casirivimab and imdevimab in adults is well-tolerated and prevents the occurrence of COVID-19.

Objectives: A phase 1, double-blind, placebo-controlled trial was conducted to evaluate the safety, tolerability, and exploratory efficacy of repeat monthly doses of subcutaneous (SC) casirivimab and imdevimab (CAS+IMD) in uninfected adult volunteers.

Methods: Participants were randomized (3:1) to SC CAS+IMD 1200 mg or placebo every 4 weeks for up to six doses. Primary and secondary end points evaluated safety, pharmacokinetics, and immunogenicity.

Impact of Transcatheter Aortic Valve Implantation Among Patients With Co-existing Mild to Moderate Mitral Regurgitation.

A subset of patients with severe aortic stenosis (AS) who are who underwent transcatheter aortic valve implantation (TAVI) also has mitral regurgitation (MR). Clinical outcomes in these patients with combined MR and AS have varied. The purpose of this study was to assess clinical outcomes and echocardiographic outcomes after TAVI in patients with preprocedural MR.

Weight gain and comorbidities associated with oral second-generation antipsychotics: analysis of real-world data for patients with schizophrenia or bipolar I disorder.

Background: Many second-generation antipsychotics (SGAs) are associated with weight gain and cardiometabolic effects. Antipsychotic-associated weight gain is linked to treatment interruptions, potentially increasing risk of relapse and hospitalization. This retrospective study assessed clinically significant weight gain (CSWG), treatment interruptions, and development of cardiometabolic conditions in patients with schizophrenia (SZ) or bipolar I disorder (BD-I) following initiation of oral SGAs with moderate to high weight gain risk.

Mn -Acetate Complexes Studied as Single Molecules.

The phenomenon of single molecule magnet (SMM) behavior of mixed valent Mn coordination clusters of general formula [Mn Mn O (RCOO) (H O) ] had been exemplified by bulk samples of the archetypal [Mn Mn O (CH COO) (H O) ] (4) molecule, and the molecular origin of the observed magnetic behavior has found support from extensive studies on the Mn system within crystalline material or on molecules attached to a variety of surfaces. Here we report the magnetic signature of the isolated cationic species [Mn O (CH COO) (CH CN)] (1) by gas phase X-ray Magnetic Circular Dichroism (XMCD) spectroscopy, and we find it closely resembling that of the corresponding bulk samples. Furthermore, we report broken symmetry DFT calculations of spin densities and single ion tensors of the isolated, optimized complexes [Mn O (CH COO) (CH CN)] (1), [Mn O (CH COO) ] (2), [Mn O (CH COO) (H O) ] (3), and the complex in bulk geometry [Mn Mn O (CH COO) (H O) ] (5).

A survey of personnel and services offered in 32 outpatient US clozapine clinics.

Background: Clozapine clinics can facilitate greater access to clozapine, but there is a paucity of data on their structure in the US.

Methods: A 23-item survey was administered to participants recruited from the SMI Adviser Clozapine Center of Excellence listserv to understand characteristics of clozapine clinics.

Results: Clozapine clinics (N = 32) had a median caseload of 45 (IQR = 21-88) patients and utilized a median of 5 (IQR = 4-6) interdisciplinary roles.

Differentiating tardive dyskinesia: a video-based review of antipsychotic-induced movement disorders in clinical practice.

Accurate diagnosis and appropriate treatment of tardive dyskinesia (TD) are imperative, as its symptoms can be highly disruptive to both patients and their caregivers. Misdiagnosis can lead to incorrect interventions with suboptimal or even deleterious results. To aid in the identification and differentiation of TD in the psychiatric practice setting, we review its clinical features and movement phenomenology, as well as those of other antipsychotic-induced movement disorders, with accompanying links to illustrative videos.

The Cal-DSH diversion guidelines.

The Cal-DSH Diversion Guidelines provide 10 general guidelines that jurisdictions should consider when developing diversion programs for individuals with a serious mental illness (SMI) who become involved in the criminal justice system. Screening for SMI in a jail setting is reviewed. In addition, important treatment interventions for SMI and substance use disorders are highlighted with the need to address criminogenic risk factors highlighted.

Pseudohypertriglyceridemia: A Novel Case with Important Clinical Implications.

Pseudohypertriglyceridemia is an overestimation of serum triglyceride levels that may incorrectly lead to a diagnosis of hypertriglyceridemia. Glycerol kinase deficiency is a condition in which glycerol cannot be phosphorylated to glycerol-3-phosphate, resulting in elevated levels of serum glycerol. Laboratory assays that measure triglycerides indirectly may be affected by elevated glyerol levels and incorrectly report serum tryglyceride levels.