Introducing S.C.O.P.E.™ (Schizophrenia Clinical Outcome Scenarios and Patient-Provider Engagement), an Interactive Digital Platform to Educate Healthcare Professionals on Schizophrenia Care.

Despite evidence of benefits beyond those of oral antipsychotics, long-acting injectable antipsychotics (LAIs) are underused in schizophrenia treatment. Underuse may be partially a result of misconceptions held by some healthcare professionals (HCPs) pertaining to LAIs. A panel of four experts convened between January 2022 and May 2022 to identify these misconceptions, and example cases or scenarios were created to illustrate common clinical situations relevant to these beliefs. Ultimately, an online platform and heuristic tool, Schizophrenia Clinical Outcome Scenarios and Patient-Provider Engagement (S.C.O.P.E.™), was developed to help prescribing clinicians and other HCPs better understand common clinical dilemmas, as well as the place for LAIs in schizophrenia treatment. Three main misconceptions related to the use of LAIs to treat schizophrenia were identified and included "physicians/providers know when patients are nonadherent", "patients do not accept/want LAI treatment", and "LAIs are only appropriate for patients who have demonstrated nonadherence". All misconceptions are refuted by current evidence and were used to develop clinical scenarios with questions to consider when patients present to various sites of care for treatment. These cases are presented on the S.C.O.P.E. educational platform. The platform also includes videos designed to help non-prescribing HCPs and mental health professionals address patient/caregiver concerns and to communicate LAI benefits. In addition, S.C.O.P.E. provides a section with information about each LAI that is currently FDA approved in the United States for the treatment of schizophrenia, to help familiarize HCPs with characteristics of LAIs. S.C.O.P.E. is an educational tool designed for HCPs to help improve their understanding of how to manage common clinical dilemmas in the treatment of people with schizophrenia, to clarify the role of LAIs in medication management, and to increase understanding of the characteristics of available LAIs. S.C.O.P.E. also aims to improve care in schizophrenia by facilitating increased awareness to patients and caregivers.

Schizophrenia is a serious, lifelong mental health disorder that affects about 2.8 million adults in the United States and many more worldwide. Symptoms can include hallucinations (ie, hearing "voices"), delusions (ie, convinced something is true when it is not), poor attention, lack of motivation and interest, and cognitive problems. Schizophrenia can have considerable impact on people with the disorder as well as their families, friends, and communities. There are several treatment options available for healthcare professionals (HCPs), patients, and caregivers to consider, with antipsychotic medicines being the cornerstone of the treatment for schizophrenia. Long-acting injectable antipsychotics (LAIs) have shown benefits over antipsychotics taken orally (by mouth), but are underused, and this is likely due to some common misconceptions. Four experts in schizophrenia treatment met repeatedly online to identify some of these misconceptions and created a tool to help HCPs learn about misconceptions, using example cases of patients with schizophrenia who have different types of clinical situations and concerns. On the Schizophrenia Clinical Outcome Scenarios and Patient-Provider Engagement (S.C.O.P.E.™) interactive digital platform, HCPs can choose in which type of case they are interested in and see details of the case, information they should obtain about the case, and appropriate considerations for LAI use. The tool also provides videos about communicating with patients and their families about LAIs, and information about the different LAIs currently available. The goal of providing this tool to HCPs is to improve understanding of how to treat patients with schizophrenia and the role that LAIs can play.

Longevity biotechnology: bridging AI, biomarkers, geroscience and clinical applications for healthy longevity.

The recent unprecedented progress in ageing research and drug discovery brings together fundamental research and clinical applications to advance the goal of promoting healthy longevity in the human population. We, from the gathering at the Aging Research and Drug Discovery Meeting in 2023, summarised the latest developments in healthspan biotechnology, with a particular emphasis on artificial intelligence (AI), biomarkers and clocks, geroscience, and clinical trials and interventions for healthy longevity. Moreover, we provide an overview of academic research and the biotech industry focused on targeting ageing as the root of age-related diseases to combat multimorbidity and extend healthspan. We propose that the integration of generative AI, cutting-edge biological technology, and longevity medicine is essential for extending the productive and healthy human lifespan.

The Collaborative Outcome Study on Health and Functioning during Infection Times (COH-FIT): Results from Cyprus.

Many studies have shown that COVID-19 caused many problems in mental health. This paper presents the results of the Cyprus sample, part of the global initiative named "The Collaborative Outcomes Study on Health and Functioning during Infection Times" (COH-FIT). Methods: The study took place from April 2019 to January 2022, using the Greek version of the online standard COH-FIT questionnaire on 917 Cypriot adults. Weighted t-tests were applied to test the differences between pre-pandemic and intra-pandemic scores using the anesrake package. Results: Participant responses indicated a significant negative impact of the pandemic on measures of mental health (-7.55; 95% CI: -9.01 to -6.07), with worsening in the scores for anxiety (12.05; 95% CI: 9.33 to 14.77), well-being (-11.06; 95% CI: -12.69 to -9.45) and depression (4.60; 95% CI: 2.06 to 7.14). Similar negative effects were observed for feelings of anger (12.92; 95% CI: 10.54 to 15.29), helplessness (9.66; 95% CI: 7.25 to 12.07), fear (22.25; 95% CI: 19.25 to 25.26), and loneliness (12.52; 95% CI: 9.94 to15.11). Increased use of social media (0.89; 95% CI: 0.71 to 1.09), internet (0.86; 95% CI: 0.67 to 1.04), and substance consumption (0.06; 95% CI: 0.00 to 0.11) were reported, along with a significant decrease in physical health (-3.45; 95% CI: -4.59 to -2.32), self-care (-7.10; 95% CI: -9.00 to -5.20), and social function (-11.27; 95% CI: -13.19 to -9.35), including support (-0.72; 95% CI: -1.09 to -0.34) and family function (-7.97; 95% CI: -9.90 to -6.05). Conclusions: The COVID-19 pandemic significantly affected the daily life and emotional well-being of Cypriots. Identifying factors that influence vulnerability and resilience is essential to prioritize mental health support and address the long-term effects of the pandemic.

Risk factors, prevention and treatment of weight gain associated with the use of antidepressants and antipsychotics: a state-of-the-art clinical review.

INTRODUCTION: People with severe mental illness have poor cardiometabolic health. Commonly used antidepressants and antipsychotics frequently lead to weight gain, which may further contribute to adverse cardiovascular outcomes. AREAS COVERED: We searched MEDLINE up to April 2023 for umbrella reviews, (network-)meta-analyses, trials and cohort studies on risk factors, prevention and treatment strategies of weight gain associated with antidepressants/antipsychotics. We developed 10 clinical recommendations. EXPERT OPINION: To prevent, manage, and treat antidepressant/antipsychotic-related weight gain, we recommend i) assessing risk factors for obesity before treatment, ii) monitoring metabolic health at baseline and regularly during follow-up, iii) offering lifestyle interventions including regular exercise and healthy diet based on patient preference to optimize motivation, iv) considering first-line psychotherapy for mild-moderate depression and anxiety disorders, v)choosing medications based on medications' and patient's weight gain risk, vi) choosing medications based on acute vs long-term treatment, vii) using effective, tolerated medications, viii) switching to less weight-inducing antipsychotics/antidepressants where possible, ix) using early weight gain as a predictor of further weight gain to inform the timing of intervention/switch options, and x) considering adding metformin or glucagon-like peptide-1 receptor agonists, or topiramate(second-line due to potential adverse cognitive effects) to antipsychotics, or aripiprazole to clozapine or olanzapine.

Adverse obstetric and neonatal outcomes associated with maternal schizophrenia-spectrum disorders and prenatal antipsychotic use: a meta-analysis of 37,214,330 pregnancy deliveries and propensity-score weighted population-based cohort study assessing confounder dependency of risk estimates.

Studies demonstrated increased obstetric and neonatal complications in women with schizophrenia-spectrum disorder (SSD), but most inadequately addressed confounders and rarely considered antipsychotic effects. We conducted a meta-analysis and a population-based cohort study evaluating associations of adverse obstetric/neonatal outcomes with SSD and prenatal antipsychotic use. In the meta-analysis, we searched four databases from inception to October-31-2023 and generated pooled risk estimates using random-effect models. In the cohort study, we identified women aged 15-50 years with SSD-diagnosis from electronic-heath-record database of public healthcare-services who delivered first/singleton children between 2003 and 2018 in Hong Kong. Propensity-score weighted regression-analyses incorporating important confounders including maternal pre-existing and gestational morbidities, substance/alcohol abuse, and psychotropic use, were performed to assess risk of adverse obstetric/neonatal outcomes in SSD-women versus non-SSD-women, and subsequently treated-SSD and untreated-SSD subgroups to disentangle effects of SSD from antipsychotic exposure. The meta-analysis (studies = 18, women = 37,214,330, including 42,926 SSD-women) found significant associations of SSD with 12 of 17 analyzed negative obstetric/neonatal outcomes (with pooled relative risk ranged:1.12-2.10), including placental complications, induced labor, Caesarean delivery, fetal distress, stillbirth, preterm birth, small-for-gestational-age, low birth weight, low APGAR scores, neonatal and post-neonatal deaths. However, the cohort study (466,358 women, including 804 SSD-women) revealed that elevated risk of most study outcomes in unadjusted-models were markedly-attenuated or became non-significant in propensity-score weighted adjusted-models, except index-delivery hospitalization ≥7 days (odds ratio [OR] = 1.76 [95% CI = 1.33-2.34]), preterm birth (OR = 1.48 [95% CI = 1.09-2.00]) and neonatal special-care admission (OR = 1.65 [95% CI = 1.35-2.01]). Apart from higher neonatal special-care admission in treated-SSD than untreated-SSD women (OR = 1.75 [95% CI = 1.23-2.52]), no significant between-group differences emerged in other outcomes. In sum, elevated risk of most obstetric/neonatal complications reported in SSD-women might largely be explained by maternal physical comorbidities, substance/alcohol use disorders and other confounders. Interventions targeting modifiable maternal risk factors should be incorporated in prenatal care for SSD-women to minimize avoidable adverse outcomes.

The Transdiagnostic Global Impression - Psychopathology scale (TGI-P): Initial development of a novel transdiagnostic tool for assessing, tracking, and visualising psychiatric symptom severity in everyday practice.

Lacking biomarkers in psychiatry calls for a valid and reliable assessment of psychopathology across mental disorders that is easy to use, bridges research and clinical care, and that can capture clinician and patient perspectives. Herein we propose, a novel, brief, transdiagnostic tool to assess and visualize symptom severity in different psychiatric disorders. The Transdiagnostic Global Impression - Psychopathology scale (TGI-P) is based on the Clinical Global Impression - Severity scale (CGI-S), which was originally designed to measure global illness severity in one score. The TGI-P covers 10 transdiagnostic symptom domains and similar to the CGI-S, it is rated on a 7-point Likert-scale from 1 (normal) to 7 (extreme). These ten domains include positive symptoms, negative symptoms, manic symptoms, depressive symptoms, addiction symptoms, cognitive symptoms, anxiety symptoms, sleep symptoms, hostility symptoms, and self-harm symptoms. The results are visually presented, thus simplifying the monitoring of symptoms, and facilitating discussion with patients and caregivers. As part of the development process, the TGI-P was surveyed among 36 psychiatrists from 3 countries. Importantly, over 80 % of them was "very positive" or "positive" about the concept of the tool, and most of them (70 %) reported willingness to use it in their everyday practice. Further psychometric development and testing of the TGI-P is underway alongside future TGI scales covering adverse events, functioning and satisfaction.

Effects of antipsychotic treatment on cardio-cerebrovascular related mortality in schizophrenia: A subanalysis of a systematic review and meta-analysis with meta-regression of moderators.

To further explore the role of different antipsychotic treatments for cardio-cerebrovascular mortality, we performed several subgroup, sensitivity and meta-regression analyses based on a large previous meta-analysis focusing on cohort studies assessing mortality relative risk (RR) for cardio-cerebrovascular disorders in people with schizophrenia, comparing antipsychotic treatment versus no antipsychotic. Quality assessment through the Newcastle-Ottawa Scale (NOS) and publication bias was measured. We meta-analyzed 53 different studies (schizophrenia patients: n = 2,513,359; controls: n = 360,504,484) to highlight the differential effects of antipsychotic treatment regimens on cardio-cerebrovascular-related mortality in incident and prevalent samples of patients with schizophrenia. We found first generation antipsychotics (FGA) to be associated with higher mortality in incident samples of schizophrenia (oral FGA [RR=2.20, 95 %CI=1.29-3.77, k = 1] and any FGA [RR=1.70, 95 %CI=1.20-2.41, k = 1]). Conversely, second generation antipsychotics (SGAs) and clozapine were associated with reduced cardio-cerebrovascular-related mortality, in prevalent samples of schizophrenia. Subgroup analyses with NOS score ≥7 (higher quality) demonstrated a significantly increased cardio-cerebrovascular disorder-related mortality, among those exposed to FGAs vs SGAs. Meta-regression analyses demonstrated a larger association between antipsychotics and decreased risk of mortality with longer follow-up, recent study year, and higher number of adjustment variables. Overall, this subanalysis of a systematic review contributes to the evolving understanding of the complex role of antipsychotic treatment for cardio-cerebrovascular mortality in schizophrenia, paving the way for more targeted interventions and improved patient outcomes.

Efficacy and tolerability of antipsychotic polypharmacy for schizophrenia spectrum disorders. A systematic review and meta-analysis of individual patient data.

BACKGROUND: Antipsychotic polypharmacy (APP) is frequently prescribed for schizophrenia-spectrum disorders. Despite the inconsistent findings on efficacy, APP may be beneficial for subgroups of psychotic patients. This meta-analysis of individual patient data investigated moderators of efficacy and tolerability of APP in adult patients with schizophrenia-spectrum disorders. DESIGN: We searched PubMed, EMBASE, and the Cochrane Central Register of Randomized Trials until September 1, 2022, for randomized controlled trials comparing APP with antipsychotic monotherapy. We estimated the effects with a one-stage approach for patient-level moderators and a two-stage approach for study-level moderators, using (generalized) linear mixed-effects models. Primary outcome was treatment response, defined as a reduction of 25 % or more in the Positive and Negative Syndrome Scale (PANSS) score. Secondary outcomes were study discontinuation, and changes from baseline on the PANSS total score, its positive and negative symptom subscale scores, the Clinical Global Impressions Scale (CGI), and adverse effects. RESULTS: We obtained individual patient data from 10 studies (602 patients; 31 % of all possible patients) and included 599 patients in our analysis. A higher baseline PANSS total score increased the chance of a response to APP (OR = 1.41, 95 % CI 1.02; 1.94, p = 0.037 per 10-point increase in baseline PANSS total), mainly driven by baseline positive symptoms. The same applied to changes on the PANSS positive symptom subscale and the CGI severity scale. Extrapyramidal side effects increased significantly where first and second-generation antipsychotics were co-prescribed. Study discontinuation was comparable between both treatment arms. CONCLUSIONS: APP was effective in severely psychotic patients with high baseline PANSS total scores and predominantly positive symptoms. This effect must be weighed against potential adverse effects.

What Remains to Be Discovered in Schizophrenia Therapeutics: Contributions by Advancing the Molecular Mechanisms of Drugs for Psychosis and Schizophrenia.

Schizophrenia is a frequently debilitating and complex mental disorder affecting approximately 1% of the global population, characterized by symptoms such as hallucinations, delusions, disorganized thoughts and behaviors, cognitive dysfunction, and negative symptoms. Traditional treatment has centered on postsynaptic dopamine antagonists, commonly known as antipsychotic drugs, which aim to alleviate symptoms and improve functioning and the quality of life. Despite the availability of these medications, significant challenges remain in schizophrenia therapeutics, including incomplete symptom relief, treatment resistance, and medication side effects. This opinion article explores advancements in schizophrenia treatment, emphasizing molecular mechanisms, novel drug targets, and innovative delivery methods. One promising approach is novel strategies that target neural networks and circuits rather than single neurotransmitters, acknowledging the complexity of brain region interconnections involved in schizophrenia. Another promising approach is the development of biased agonists, which selectively activate specific signaling pathways downstream of receptors, offering potential for more precise pharmacological interventions with fewer side effects. The concept of molecular polypharmacy, where a single drug targets multiple molecular pathways, is exemplified by KarXT, a novel drug combining xanomeline and trospium to address both psychosis and cognitive dysfunction. This approach represents a comprehensive strategy for schizophrenia treatment, potentially improving outcomes for patients. In conclusion, advancing the molecular understanding of schizophrenia and exploring innovative therapeutic strategies hold promise for addressing the unmet needs in schizophrenia treatment, aiming for more effective and tailored interventions. Future research should focus on these novel approaches to achieve better clinical outcomes and improve the functional level and quality of life for individuals with schizophrenia.

Systematic Review and Network Meta-Analysis: Efficacy and Safety of Antipsychotics vs Antiepileptics or Lithium for Acute Mania in Children and Adolescents.

OBJECTIVE: To compare second-generation antipsychotics (SGAs) and mood stabilizers (MSs) in youth with a bipolar disorder type I (BD-I) manic/mixed episode. METHOD: A systematic PubMed/Embase/PsycInfo literature search until December 31, 2023, for randomized trials of SGAs or MSs in patients ≤18 years of age with BD-I manic/mixed episode was conducted. The study included a network meta-analysis comparing treatments regarding mania symptoms and mania response (co-primary outcomes), and secondary efficacy and tolerability outcomes. RESULTS: Eighteen studies (n = 2844, mean age = 11.74, female participants = 48.0%, mean study duration = 5.4 weeks) comparing 6 SGAs (aripiprazole, asenapine, olanzapine, quetiapine, risperidone, and ziprasidone) and 4 MSs (lithium, oxcarbazepine, topiramate, and valproate) were meta-analyzed. All 6 SGAs outperformed placebo in reducing manic symptomatology, including risperidone (standardized mean difference [SMD] = -1.18, 95% CI = -0.92, -1.45, Confidence in Network Meta-Analysis [CINeMA] = moderate confidence), olanzapine (SMD = -0.77, 95% CI = -0.36, -1.18, low confidence), aripiprazole (SMD = -0.67, 95% CI = -0.33, -1.01, moderate confidence), quetiapine (SMD = -0.60, 95% CI = -0.32, -0.87, high confidence), asenapine (SMD = -0.54, 95% CI = -0.19, -0.89, moderate confidence), and ziprasidone (SMD = -0.43, 95% CI = -0.17, 0.70, low confidence), whereas no mood stabilizer outperformed placebo. Concerning mania response, risperidone (Risk ratio [RR] = 2.58, 95% CI = 1.88, 3.54, low confidence), olanzapine (RR = 2.42, 95% CI = 1.33, 3.54, very low confidence), aripiprazole (RR = 2.05, 95% CI = 1.44, 2.92, low confidence), quetiapine (RR = 1.89, 95% CI = 1.45n 2.47, moderate confidence), asenapine (RR = 1.81, 95% CI = 1.28, 2.55, very low confidence) and lithium (RR = 1.35, 95% CI = 1.00, 1.83, p = .049, very low confidence) outperformed placebo, without superiority of other MSs vs placebo. Individually, risperidone was more efficacious in reducing manic symptomatology than all other comparators, except olanzapine and topiramate, yet with low/very low confidence, and was associated with increased prolactin and glucose. Pooled together, SGAs outperformed both placebo and MSs for mania symptom reduction (SMD = -0.68, 95% CI = -0.86, -0.51 and SMD = -0.61, 95% CI = -0.82, -0.40, moderate confidence), and mania response (RR = 1.85, 95% CI = 1.53, 2.24 and RR = 1.65, 95% CI = 1.33, 2.04, moderate confidence) without differences between MSs and placebo. There were no significant treatment-placebo differences for all-cause discontinuation, whereas lithium, ziprasidone, and oxcarbazepine were associated with more adverse event-related drop-outs than placebo. Most SGAs were associated with more sedation, weight gain, and metabolic issues vs placebo and MSs. CONCLUSION: SGAs were more efficacious than placebo and MSs in treating acute mania symptoms, however, their use must be carefully weighed against important side effects.

Efficacy and acceptability of long-acting antipsychotics in acutely ill individuals with schizophrenia-spectrum disorders: A systematic review and network meta-analysis.

To assess the effect of Long-acting injectable (LAI) antipsychotics in acutely ill patients, we systematically searched major databases for randomized controlled trials (RCTs) comparing LAIs with other LAIs, oral antipsychotics, or placebo in acutely symptomatic adults with schizophrenia-spectrum disorders. Data were analyzed with a random-effects network meta-analysis. Co-primary outcomes were efficacy (mean change in psychopathology rating scales) and acceptability (all-cause discontinuations) at study endpoint. Of 25 RCTs, 19 studies tested second-generation LAIs (SGA-LAIs) and six first-generation LAIs (FGA-LAIs). Due to a disconnected network, FGA-LAIs were analyzed separately, with poor data quality. The SGA-LAIs network included 8,418 individuals (males=63%, mean age=39.3 years). All SGA-LAIs outperformed placebo in reducing acute symptoms at study endpoint (median follow-up=13 weeks). They were more acceptable than placebo with the only exception of olanzapine, for which no differences with placebo emerged. Additionally, we distinguished between different LAI formulations of the same antipsychotic to explore potential pharmacokinetic differences. Most formulations outperformed placebo in the very short-term (2 weeks or less), regardless of the need for initial oral supplementation. SGA-LAIs are evidence-based treatments in acutely ill individuals with schizophrenia-spectrum disorders. Findings support the use of SGA-LAIs to manage psychopathology and improve adherence right from the acute phases of illness.

Predictors of COVID-19 vaccine uptake among youth with bipolar disorder spectrum disorders and their caregivers.

BACKGROUND: Little is known about rates of COVID-19 vaccine uptake among youth with bipolar spectrum disorders (BSD). As such, the aim of this study is to assess rates and predictors of COVID-19 vaccine uptake among youth with BSD and their caregivers in the United States. METHODS: Youth and their main caregiver were recruited from a large pragmatic study cohort. Youth who were aged 8-22 at the time of this data collection, had a bipolar-spectrum disorder diagnosis, had overweight or obesity, and were treated with a second-generation antipsychotic were invited to participate in an online survey and interview assessing the impact of the COVID-19 pandemic. RESULTS: A total of 453 surveys and 341 interviews were completed 07/2021-05/2022 by youth and their caregivers. Sixty-seven percent of caregivers and 63 % of youth reported receiving the COVID-19 vaccine. Vaccine uptake rates among youth and caregivers were highly correlated. Predictors of vaccine uptake among youth were older age and living in the Northeast Region of the United States. Predictors of caregiver vaccine uptake were male sex, higher annual household income and not having to quarantine due to COVID-19. LIMITATIONS: The sample was small and not a full representation of a population with bipolar-spectrum disorders therefore, the results may not be generalizable. The study design and statistical method do not allow for causal inferences to be made. CONCLUSIONS: These findings may aid in targeting interventions to maximize COVID-19 and other vaccine uptake in youth with bipolar disorders and their families.

Hypomania-Checklist-33: risk stratification and factor structure in a mixed psychiatric adolescent sample.

BACKGROUND: The 33-item Hypomania Checklist (HCL-33) has been shown to distinguish between adolescent bipolar disorder (BD) and unipolar depression. To investigate the utility of the HCL-33 as a screening tool in routine diagnostics, the frequency and psychopathological characteristics of detected individuals in a mixed psychiatric sample necessitate more examination. METHODS: The HCL-33, Children's Depression Inventory, Beck's Anxiety Inventory, and Strengths and Difficulties Questionnaire were completed by 285 children and adolescents (12-18 years) in a mixed psychiatric sample. Applying the proposed HCL-33 cut-off score of ≥ 18, individuals with depressive symptoms were divided into at-risk or not at-risk for BD groups. The factorial structure, sum and factor score correlations with psychopathology, and impact on daily functioning were assessed. RESULTS: 20.6% of the sample met at-risk criteria for BD. These individuals (n = 55) were older, more anxious, and showed more conduct problems vs the not at-risk group (n = 107). A two- and a three-factor model were pursued with the same Factor 1 ("active-elated"). Factor 2 ("risk-taking/irritable") was separated into 2a ("irritable-erratic") and 2b ("outgoing-disinhibited") in the three-factor model. Whereas higher Factor 2 and 2a scores correlated with a broad range of more severe symptomatology (i.e., depression, anxiety, hyperactivity), higher Factor 1 and 2b scores correlated with more emotional and conduct problems, respectively. 51.7% of the sample reported a negative impact from hypomanic symptoms on daily functioning. LIMITATIONS: Cross-sectional design and data collection in a single mental health service. CONCLUSIONS: The HCL-33 may be a useful tool to improve diagnostics, especially in adolescents with depressive symptoms additionally presenting with anxious symptoms and conduct problems.

The Economic Impact of Cognitive Impairment and Negative Symptoms in Schizophrenia: A Targeted Literature Review With a Focus on Outcomes Relevant to Health Care Decision-Makers in the United States.

Abstract.Objective: To conduct a targeted literature review to examine the impact of cognitive impairment and negative symptoms among patients with schizophrenia treated in the United States across a range of outcomes pertinent to the US health care system decision-makers, such as payers and policy-makers.Data Sources: The authors searched EMBASE and PubMed from January 2012 to January 2024. Search terms included schizophrenia, cognitive impairment and negative symptoms, and direct medical and nonmedical, indirect, and societal outcomes.Study Selection: Considered for inclusion were US-based studies reporting on the relationship between cognitive impairment or negative symptoms and direct medical and nonmedical, indirect, and societal outcomes in patients with schizophrenia. A total of 4,212 articles were initially identified for screening.Data Extraction: One reviewer extracted data and another reviewer ensured studies met Population, Intervention, Comparison, Outcomes, Study Design-Time Period (PICOS-T) criteria for inclusion and exclusion.Results: Eight studies (n = 262,683) were included that reported specifically on associations between cognitive impairment or negative symptoms and targeted outcomes. Patients with schizophrenia and moderate/severe cognitive impairment had a 100% increase in relapse-related hospitalizations (0.6 vs 0.3, adjusted incidence rate ratio = 1.85, P < .05) and ER visits (0.4 vs 0.2, adjusted odds ratio = 1.77, P < .05) vs patients with no/mild cognitive impairment. Additionally, there was an almost 50% increase in outpatient visits (8.4 vs 5.5, P < .001) and inpatient admissions (6.8 vs 4.5, P < .001) over the study period (2014 Q1-2017 Q4) for patients with negative symptoms vs without negative symptoms. Direct nonmedical, indirect, and societal outcomes are described.Conclusions: This review highlights the economic burden of cognitive impairment and negative symptoms by focusing on outcomes relevant to health care decision-makers in the United States.

How can we better address the pharmacokinetics of antipsychotics in children and adolescents?

INTRODUCTION: Despite a steady increase of antipsychotic prescriptions in children and adolescents, knowledge about pharmacokinetics and dosing of antipsychotics in children and adolescents remains limited. AREAS COVERED: We discuss seven issues with major impact on the pharmacokinetics of antipsychotics in youth: estrogens, ii) obesity, iii) ethnicity, iv) smoking, v) inflammation, vi) drug-drug interactions (DDIs), and vii) pharmacogenetics. Despite their major impact, these issues have not been adequately considered in the context of dosing algorithms for antipsychotics in youth. A simple tool to quantify the impact of these pharmacokinetics issues on antipsychotics is therapeutic drug monitoring (TDM), which refers to the quantification of the prescribed medication in the blood of the patients, as a surrogate for the peripheral antipsychotic exposure. We also provide summary tables extrapolated from the adult literature on metabolism, therapeutic reference ranges (TRRs) and DDIs. EXPERT OPINION: Despite considerable experience with TDM for antipsychotics in the management of other patient subgroups, TDM use for antipsychotics in children and adolescents may be limited with TRRs invariably being extrapolated from adult patients. Advancing TDM knowledge is expected to help clinicians address the special properties of pharmacokinetics of antipsychotics and ultimately enable antipsychotic dose individualization in youth.

A Long-Term Safety and Tolerability Study of TV-46000 for Subcutaneous Use in Patients with Schizophrenia: A Phase 3, Randomized, Double-Blinded Clinical Trial.

BACKGROUND: TV-46000 is a long-acting subcutaneous antipsychotic (LASCA) formulation of risperidone that is approved by the United States Food and Drug Administration for the treatment of schizophrenia in adults. In the phase 3, randomized, double-blind RIsperidone Subcutaneous Extended-release (RISE) study, TV-46000 once monthly (q1m) and once every 2 months (q2m) significantly prolonged time to impending relapse compared with placebo [5.0-fold (q1m) and 2.7-fold (q2m)]. This phase 3, randomized, double-blind Safety in Humans of TV-46000 subcutaneous INjection Evaluation (SHINE) study was designed to evaluate the long-term safety, tolerability, and exposure of TV-46000 in schizophrenia. METHODS: Patients who completed RISE without relapse (rollover) or who were newly recruited (de novo) were eligible for the SHINE study. Patients were initially stabilized on oral risperidone for 12 weeks (completed in RISE for rollover, or in SHINE for de novo). Patients in the de novo cohort and patients who received placebo in RISE were randomized 1:1 in SHINE to receive TV-46000 q1m or q2m for up to 56 weeks. Primary endpoint for SHINE was frequency of reported adverse events (AEs); event rates [ER; events per 100 patient-years (PYs)] were calculated for each AE by patients upon general questioning. RESULTS: Overall, 336 patients were randomized in SHINE [TV-46000 q1m, n = 174; TV-46000 q2m, n = 162; of these, de novo, n = 109 and rollover, n = 227 (n = 172 patients were treated and n = 55 received placebo)]. A total of 334 patients were evaluated for safety [q1m, n = 172 (PY = 97.8); q2m, n = 162 (PY = 104.5)]. Proportions of patients (ER) with ≥ 1 AE and ≥ 1 treatment-related AE were 37% (180.0) and 21% (84.9) for TV-46000 q1m and 46% (157.9) and 20% (70.8) for TV-46000 q2m, respectively. Frequent treatment-related AEs [≥ 3% of patients in either group; proportion of patients (ER)] were injection site pain [q1m, 5% (24.5); q2m, 4% (22.0)] and injection site nodule [q1m, 2% (9.2); q2m, 6% (12.4)]. The proportions of patients with serious AEs was 5% for TV-46000 q1m and 7% for TV-46000 q2m; serious AEs reported for ≥ 2 patients overall were worsening schizophrenia [q1m, n = 1 (< 1%; ER, 1.02); q2m, n = 2 (1%; ER, 1.91)] and hyperglycemia [q1m, n = 1 (< 1%; ER, 1.02); q2m, n = 1 (< 1%; ER, 0.96)]. Of three reported deaths, none were related to treatment. Overall, eight patients discontinued treatment because of AEs. Similar or somewhat lower rates of AEs were reported for patients who rolled over from TV-46000 treatment compared with those who had no prior TV-46000 treatment (de novo and placebo rollover). Most AEs related to injection site reactions were mild; no patient had a severe reaction. CONCLUSION: Results from this long-term safety study add to the favorable safety profiles of TV-46000 q1m and q2m, consistent with other formulations of risperidone and previous studies with TV-46000. REGISTRATION: ClinicalTrials.gov, NCT03893825; 27 March 2019.

The United States Food and Drug Administration approved TV-46000 in April 2023 for the treatment of schizophrenia in adults. TV-46000 is a long-acting subcutaneous antipsychotic (LASCA) that uses technology that allows for the slow release of risperidone. TV-46000 is injected under the skin once monthly or once every 2 months. When people start taking TV-46000, they do not need an additional injection or oral risperidone. The Safety in Humans of TV-46000 subcutaneous INjection Evaluation (SHINE) was a clinical study in which patients with schizophrenia received TV-46000. SHINE was conducted in patients who completed the RIsperidone Subcutaneous Extended-release (RISE) study and new patients. All patients (TV-46000 once monthly, n = 162; TV-46000 once every 2 months, n = 172) received TV-46000 in SHINE to see whether safety results were the same long term compared with RISE. The proportions with more than one adverse event were 37% for TV-46000 once monthly and 46% for TV-46000 once every 2 months. The proportions with more than one adverse event related to treatment were 21% for TV-46000 once monthly and 20% for TV-46000 once every 2 months. Common adverse events related to treatment were injection site pain and small swelling. Serious adverse events were rare. None of the three reported deaths were related to treatment. Similar or lower rates of adverse events were reported for those who received TV-46000 in RISE compared with those with no prior TV-46000 treatment. The long-term safety results in SHINE were consistent with other forms of risperidone and previous studies with TV-46000.

Three-Year Outcomes of 6-Month Paliperidone Palmitate in Adults With Schizophrenia: An Open-Label Extension Study of a Randomized Clinical Trial.

Importance: Long-acting injectable (LAI) antipsychotics have the potential to improve adherence and symptom control in patients with schizophrenia, promoting long-term recovery. Paliperidone palmitate (PP) once every 6 months is the first and currently only LAI antipsychotic with an extended dosing interval of 6 months. Objective: To assess long-term outcomes of PP received once every 6 months in adults with schizophrenia. Design, Setting, and Participants: In a 2-year open-label extension (OLE) study of a 1-year randomized clinical trial (RCT), eligible adults with schizophrenia could choose to continue PP every 6 months if they had not experienced relapse after receiving PP once every 3 or 6 months in the 1-year, international, multicenter, double-blind, randomized noninferiority trial. The present analysis focused on patients receiving PP every 6 months in the double-blind trial through the OLE study (November 20, 2017, to May 3, 2022). Intervention: Patients received a dorsogluteal injection of PP on day 1 and once every 6 months up to month 30. Main Outcomes and Measures: End points included assessment of relapse and change from the double-blind trial baseline to the OLE end point in Positive and Negative Syndrome Scale (PANSS) total and subscale, Clinical Global Impression-Severity (CGI-S) Scale, and Personal Social Performance (PSP) Scale scores. Treatment-emergent adverse events (TEAEs), injection site evaluations, and laboratory tests were also assessed. Results: Among 121 patients (83 [68.6%] male), mean (SD) age at baseline was 38.6 (11.24) years and mean (SD) duration of illness was 11.0 (9.45) years. At screening of the double-blind study, 101 patients (83.5%) were taking an oral antipsychotic and 20 (16.5%) were taking an LAI antipsychotic. Altogether, 5 of 121 patients (4.1%) experienced relapse during the 3-year follow-up; reasons for relapse were psychiatric hospitalization (2 [1.7%]), suicidal or homicidal ideation (2 [1.7%]), and deliberate self-injury (1 [0.8%]). Patients treated with PP every 6 months were clinically and functionally stable, and outcomes were well maintained, evidenced by stable scores on the PANSS (mean [SD] change, -2.6 [9.96] points), CGI-S (mean [SD] change, -0.2 [0.57] points), and PSP (mean [SD] change, 3.1 [9.14] points) scales over the 3-year period. In total, 101 patients (83.5%) completed the 2-year OLE. At least 1 TEAE was reported in 97 of 121 patients (80.2%) overall; no new safety or tolerability concerns were identified. Conclusions and Relevance: In a 2-year OLE study of a 1-year RCT, results supported favorable long-term outcomes of PP once every 6 months for up to 3 years in adults with schizophrenia.

Identifying differential predictors for treatment response to amisulpride and olanzapine combination treatment versus each monotherapy in acutely ill patients with schizophrenia: Results of the COMBINE-study.

BACKGROUND: Extensive research has been undertaken to predict treatment response (TR) to antipsychotics. Most studies address TR to antipsychotics in general and as monotherapy, however, it is unknown whether patients might respond favourably to a combination of antipsychotics. AIMS: This study aimed to identify differential predictors for TR to monotherapy with amisulpride or olanzapine compared to a combination of antipsychotics. METHODS: Post-hoc analysis was conducted of data collected from the COMBINE-study, a double-blind, randomized, controlled trial. Demographic and disease-related measures were gathered at baseline to predict TR after eight weeks defined by the Positive and Negative Syndrome Scale. Missing values were accounted for by a random replacement procedure. Attrition effects and multicollinearity were analysed and sets of logistic regression models were calculated for different treatment groups. RESULTS: Of the 321 randomized patients, 201 completed procedures until week eight and 197 were included in the analyses. For all treatment groups, early TR after two weeks and high subjective well-being under antipsychotics at baseline were robust predictors for TR. The propensity for early side effects also indicated a higher risk of later non-response. Specific parameter estimates were rather similar between treatment groups. CONCLUSION: Early TR, drug-related subjective well-being, and early side effect propensity evolved as predictors for later TR whether to monotherapy or combination strategy. Accordingly, due to a lack of differential predictors, early and close monitoring of targeted and unwanted effects is indicated to guide respective treatment decisions.

Nutraceuticals and phytoceuticals in the treatment of schizophrenia: a systematic review and network meta-analysis "Nutra NMA SCZ".

Sub-optimal response in schizophrenia is frequent, warranting augmentation strategies over treatment-as-usual (TAU). We assessed nutraceuticals/phytoceutical augmentation strategies via network meta-analysis. Randomized controlled trials in schizophrenia/schizoaffective disorder were identified via the following databases: PubMed, MEDLINE, EMBASE, Scopus, PsycINFO, CENTRAL, and ClinicalTrials.gov. Change (Standardized Mean Difference = SMD) in total symptomatology and acceptability (Risk Ratio = RR) were co-primary outcomes. Secondary outcomes were positive, negative, cognitive, and depressive symptom changes, general psychopathology, tolerability, and response rates. We conducted subset analyses by disease phase and sensitivity analyses by risk of bias and assessed global/local inconsistency, publication bias, risk of bias, and confidence in the evidence. The systematic review included 49 records documenting 50 studies (n = 2384) documenting 22 interventions. Citicoline (SMD =-1.05,95%CI = -1.85; -0.24), L-lysine (SMD = -1.04,95%CI = -1.84; -0.25), N-acetylcysteine (SMD = -0.87, 95%CI = -1.27; -0.47) and sarcosine (SMD = -0.5,95%CI = -0.87-0.13) outperformed placebo for total symptomatology. High heterogeneity (tau2 = 0.10, I2 = 55.9%) and global inconsistency (Q = 40.79, df = 18, p = 0.002) emerged without publication bias (Egger's test, p = 0.42). Sarcosine improved negative symptoms (SMD = -0.65, 95%CI = -1.10; -0.19). N-acetylcysteine improved negative symptoms (SMD = -0.90, 95%CI = -1.42; -0.39)/general psychopathology (SMD = -0.76, 95%CI = -1.39; -0.13). No compound improved total symptomatology within acute phase studies (k = 7, n = 422). Sarcosine (SMD = -1.26,95%CI = -1.91; -0.60), citicoline (SMD = -1.05,95%CI = -1.65;-0.44), and N-acetylcysteine (SMD = -0.55,95%CI = -0.92,-0.19) outperformed placebo augmentation in clinically stable participants. Sensitivity analyses removing high-risk-of-bias studies confirmed overall findings in all phases and clinically stable samples. In contrast, the acute phase analysis restricted to low risk-of-bias studies showed a superior effect vs. placebo for N-acetylcysteine (SMD = -1.10, 95%CI = -1.75,-0.45), L-lysine (SMD = -1.05,95%CI = -1.55, -0.19), omega-3 fatty acids (SMD = -0.83,95%CI = -1.31, -0.34) and withania somnifera (SMD = -0.71,95%CI = -1.21,-0.22). Citicoline (SMD = -1.05,95%CI = -1.86,-0.23), L-lysine (SMD = -1.04,95%CI = -1.84,-0.24), N-acetylcysteine (SMD = -0.89,95%CI = -1.35,-0.43) and sarcosine (SMD = -0.61,95%CI = -1.02,-0.21) outperformed placebo augmentation of TAU ("any phase"). Drop-out due to any cause or adverse events did not differ between nutraceutical/phytoceutical vs. placebo+TAU. Sarcosine, citicoline, and N-acetylcysteine are promising augmentation interventions in stable patients with schizophrenia, yet the quality of evidence is low to very low. Further high-quality trials in acute phases/specific outcomes/difficult-to-treat schizophrenia are warranted.

The impact of the COVID-19 pandemic on administrative eating disorder prevalence in the outpatient sector and on severity of anorexia nervosa.

The COVID-19 pandemic appears to have had a considerable impact on the mental health of children and adolescents, particularly regarding eating disorders. However, it remains unclear whether the pandemic affected only the frequency or also the severity of eating disorders. We examined potential pandemic-related changes in the administrative prevalence of eating disorders in the outpatient sector compared with other mental disorders using German statutory health insurance data for the age group 10 to 16 years. We also examined disorder severity of anorexia nervosa using data from the multicenter German Registry of Children and Adolescents with Anorexia Nervosa in the same age group. Our results showed a marked increase in the administrative prevalence of eating disorders (based on documented diagnoses) in the outpatient sector among girls but not among boys. A similar pattern was found for internalizing disorders, whereas the administrative prevalences of externalizing disorders decreased. Regarding the severity of anorexia nervosa among inpatients, we found no pandemic-related changes in body mass index standard deviation score at admission, body weight loss before admission, psychiatric comorbidities and psychopharmacological medication. Given the administrative prevalence increase in the outpatient sector, the lack of impact of the pandemic on the inpatient sector may also be partly due to a shift in healthcare utilization towards outpatient services during the pandemic. Thus, the higher number of children and adolescents requiring specialized and timely outpatient care may be a major concern under pandemic conditions.