Optimizing co-prescription of clozapine and antiseizure medications: a systematic review and expert recommendations for clinical practice.

INTRODUCTION: Antiseizure medication (ASM) add-on to clozapine may be efficient to target clozapine-resistant mood or psychotic symptoms or clozapine-related adverse drug reactions (ADR) such as seizures. We aimed to synthesize the information relevant for clinical practice on the risks and benefits of clozapine-ASM co-prescription. AREAS COVERED: Articles were identified with MEDLINE, Web of Sciences and PsycINFO search from inception through October 2023. The review was restricted to ASM with mood-stabilizing properties or with potential efficacy for resistant psychotic symptoms (valproate (VPA), lamotrigine, topiramate, carbamazepine, oxcarbazepine). EXPERT OPINION: VPA add-on to clozapine is associated with a high risk of serious ADR (myocarditis, neutropenia, pneumonia) mostly explained by complex time-dependent drug-drug interactions. The initial inhibitory effects on clozapine metabolism require slow titration to avoid immuno-allergic reactions. After the titration period, VPA has mainly inductive effects on clozapine metabolism that are more marked in smokers requiring therapeutic drug monitoring. Lamotrigine and topiramate add-on may be recommended as the first-line treatment for clozapine-related seizures, but there is limited evidence regarding the efficacy of this strategy for clozapine-resistant psychotic symptoms. Carbamazepine should not be co-prescribed with clozapine because of its potential for agranulocytosis and for inducing clozapine metabolism.

Stigmatization towards electro convulsive therapy: Impact of practical teaching on medical and nursing students.

BACKGROUND: This study explored the impact of theoretical and practical teaching on electro convulsive therapy (ECT) on medical and nursing students' stigmatizing attitudes towards ECT and representations of it. METHOD: Fourth-year medical students and nursing students answered questions from the Questionnaire on Attitudes and Knowledge of ECT (QuAKE) and from the Mental Illness: Clinicians' Attitudes version 2 (MICA v2) scale. The questionnaires were completed before and after observing a 3-hour practical training session in the ECT unit. The endpoint was the impact of practical training as assessed by MICA and QuAKE scores. Multivariate analyses were used to explore the impact of practical training on MICA and QuAKE total scores. RESULTS: Stigmatizing attitudes and representations of both medical and nursing students towards ECT were reduced after practical training (ß=-4.43 [95% CI -6.15; -2.70] p=0.0001). The impact was greater in medical students (ß=-8.03; 95% CI [-10.71; -5.43], P=0.0001) than in nursing students (ß=-2.77; 95% CI [-4.98; to 0.44], P=0.02). Gender, psychiatric history in close persons, and having already followed a psychiatric/ECT course had no independent impact on stigmatizing attitudes towards ECT and representations of it. CONCLUSION: Practical training in ECT should be given to all health professionals to improve access to it.

Revealing the reporting disparity: VigiBase highlights underreporting of clozapine in other Western European countries compared to the UK.

BACKGROUND: Pharmacovigilance studies indicate clozapine history is marked by adverse drug reactions (ADRs). OBJECTIVE: In a 2021 article, the United Kingdom (UK) had >90 % of European clozapine-related fatal outcomes in VigiBase, the World Health Organization's pharmacovigilance database. Two possibly opposing hypotheses could explain this disparity: 1) fewer reported fatal outcomes in other Western European countries mainly reflect underreporting to VigiBase, and 2) the higher number of UK reports reflects higher real relative mortality. METHODS: VigiBase reports from clozapine's introduction to December 31, 2022, were studied for ADRs and the top 10 causes of fatal outcomes. The UK was compared with 11 other top reporting Western countries (Germany, Denmark, France, Finland, Ireland, Italy, Netherlands, Norway, Spain, Sweden and Switzerland). Nine countries (except Ireland and Switzerland) were compared after controlling for population and clozapine prescriptions. RESULTS: The UK accounted for 29 % of worldwide clozapine-related fatal outcomes, Germany 2 % and <1 % in each of the other countries. The nonspecific label "death" was the top cause in the world (46 %) and in the UK (33 %). "Pneumonia" was second in the world (8 %), the UK (12 %), Ireland (8 %) and Finland (14 %). Assuming that our corrections for population and clozapine use are correct, other countries underreported only 1-10 % of the UK clozapine fatal outcome number. CONCLUSIONS: Different Western European countries consistently underreport to VigiBase compared to the UK, but have different reporting/publishing styles for clozapine-related ADRs/fatal outcomes. Three Scandinavian registries suggest lives are saved as clozapine use increases, but this cannot be studied in pharmacovigilance databases.

Optimizing antidepressant and clozapine co-prescription in clinical practice: A systematic review and expert recommendations.

OBJECTIVES: To synthesize the information relevant for clinical practice on clozapine-antidepressant co-prescription concerning pharmacokinetic drug-drug interactions (DDI), adverse drug reactions (ADRs) associated with the co-prescription, antidepressant add-on for clozapine-resistant symptoms and antidepressant add-on for clozapine-induced ADRs. METHODS: Articles were identified with MEDLINE, Web of Sciences and PsycINFO search from inception through April 2023. Data were synthesized narratively. RESULTS: ADRs are most often induced by the co-prescription of antidepressants that inhibit CYP enzymes (fluvoxamine, fluoxetine, paroxetine). Fluvoxamine add-on is hazardous because of its potent inhibition of clozapine metabolism and has few indications (lowering daily number of clozapine tablets, reducing norclozapine-induced metabolic disturbances and other dose-dependent clozapine-induced ADRs). ADR frequency may be reduced by therapeutic drug monitoring and knowledge of other factors impacting clozapine metabolism (pneumonia, inflammation, smoking, etc.). Improvement of negative symptoms is the most documented beneficial effect of antidepressant add-on for clozapine-resistant psychotic symptoms. The add-on antidepressant should be chosen according to its safety profile regarding DDI with clozapine: antidepressants inhibiting clozapine metabolism or increasing the anticholinergic load should be avoided. Other indications of antidepressant add-on (affective or obsessive compulsive symptoms, sialorrhea, and enuresis) are poorly documented. CONCLUSION: Antidepressant add-on to clozapine is associated with potential benefits in clozapine users as this strategy may contribute to reduce the burden of clozapine-resistant symptoms or of clozapine-induced ADRs. Further studies are needed to determine whether antidepressant add-on can reduce the risk of clozapine discontinuation.

"It's possible": reducing the coercion in care for adults living with neurodevelopmental disorders: a mixed-methods study / « C'est possible ¼, réduire la coercition dans les soins pour les personnes adultes vivant avec des troubles neurodéveloppementaux : une étude à devis mixte

Introduction: Adults living with a neurodevelopmental disorder may present episodes of aggression, which may lead to the use of seclusion or restraint. The aim of the study was to assess the effect of an intervention aimed at reducing the use of coercive measures in a long-term care unit for adults suffering from a neurodevelopmental disorder with or without psychiatric co-morbidities. Method: The single-center study used a sequential mixed-methods explanatory design. Retrospective data on periods of seclusion, with and without physical restraint, were collected for the ten-month pre-intervention and post-intervention periods. A qualitative survey was conducted at the end of the intervention period among the health professionals working in the unit to review the implementation and the efficiency of the approach. Results: A significant decrease was observed between the pre- and post-intervention period in the number of seclusion and restraint sequences, the number of patients experiencing seclusion and restraint, and the duration of seclusion and restraint sequences. The efficiency of the approach was confirmed by the health care professionals and was attributed to leadership focused on limiting coercive measures, better adherence to legal obligations, team cohesion, and the implementation of alternative tools and methods. Discussion: Reducing the use of coercive measures with adults with neurodevelopmental disorders is possible. Further studies are needed to confirm the effectiveness of alternative strategies to seclusion and restraint.

Introduction: Les personnes adultes vivant avec un trouble neurodéveloppemental peuvent présenter des épisodes d'agressivité, susceptibles d'entrainer le recours à l'isolement à la contention. Le but de l'étude a été d'évaluer et d'explorer l'effet d'une démarche de moindre recours aux mesures coercitives dans une unité d'accueil au long cours de personnes adultes souffrant d'un trouble neurodéveloppemental, avec ou sans comorbidités psychiatriques. Méthode: L'étude monocentrique a utilisé un devis mixte séquentiel explicatif. Des données rétrospectives sur les données mensuelles agrégées des séquences d'isolement avec et sans contention ont été recueillies sur une période de 10 mois précédant l'intervention et une période de 10 mois postintervention. Une enquête qualitative a ensuite été réalisée auprès des professionnels de santé intervenant dans l'unité afin d'appréhender la mise en œuvre et l'efficience des interventions de moindre recours. Résultats: La comparaison des périodes pré- et postintervention met en évidence une diminution significative du nombre de séquences d'isolement et de contention, du nombre de patients exposés à une mesure d'isolement et de contention, et de la durée des séquences d'isolement et de contention. L'efficience de la démarche est confirmée par les soignants et expliquée par un leadership tourné vers la limitation des mesures coercitives, l'obligation légale, la cohésion d'équipe, et la mise en place d'outils et de méthodes alternatives. Discussion: La diminution de la coercition auprès des personnes adultes souffrant d'un trouble neurodéveloppemental est possible. D'autres études sont nécessaires pour confirmer l'efficience de stratégies alternatives à l'isolement et à la contention.

"It's possible", reducing the coercion in care for adults living with neurodevelopmental disorders: A mixed-methods study / « C'est possible ¼, réduire la coercition dans les soins pour les personnes adultes vivant avec des troubles neurodéveloppementaux : une étude à devis mixte

INTRODUCTION: Adults living with a neurodevelopmental disorder may present episodes of aggression, which may lead to the use of seclusion or restraint. The aim of the study was to assess the effect of an intervention aimed at reducing the use of coercive measures in a long-term care unit for adults suffering from a neurodevelopmental disorder with or without psychiatric co-morbidities. METHOD: The single-center study used a sequential mixed-methods explanatory design. Retrospective data on periods of seclusion, with and without physical restraint, were collected for the ten-month pre-intervention and post-intervention periods. A qualitative survey was conducted at the end of the intervention period among the health professionals working in the unit to review the implementation and the efficiency of the approach. RESULTS: A significant decrease was observed between the pre- and post-intervention period in the number of seclusion and restraint sequences, the number of patients experiencing seclusion and restraint, and the duration of seclusion and restraint sequences. The efficiency of the approach was confirmed by the health care professionals and was attributed to leadership focused on limiting coercive measures, better adherence to legal obligations, team cohesion, and the implementation of alternative tools and methods. DISCUSSION: Reducing the use of coercive measures with adults with neurodevelopmental disorders is possible. Further studies are needed to confirm the effectiveness of alternative strategies to seclusion and restraint.

Introduction: Les personnes adultes vivant avec un trouble neurodéveloppemental peuvent présenter des épisodes d'agressivité, susceptibles d'entrainer le recours à l'isolement à la contention. Le but de l'étude a été d'évaluer et d'explorer l'effet d'une démarche de moindre recours aux mesures coercitives dans une unité d'accueil au long cours de personnes adultes souffrant d'un trouble neurodéveloppemental, avec ou sans comorbidités psychiatriques. Méthode: L'étude monocentrique a utilisé un devis mixte séquentiel explicatif. Des données rétrospectives sur les données mensuelles agrégées des séquences d'isolement avec et sans contention ont été recueillies sur une période de 10 mois précédant l'intervention et une période de 10 mois postintervention. Une enquête qualitative a ensuite été réalisée auprès des professionnels de santé intervenant dans l'unité afin d'appréhender la mise en œuvre et l'efficience des interventions de moindre recours. Résultats: La comparaison des périodes pré- et postintervention met en évidence une diminution significative du nombre de séquences d'isolement et de contention, du nombre de patients exposés à une mesure d'isolement et de contention, et de la durée des séquences d'isolement et de contention. L'efficience de la démarche est confirmée par les soignants et expliquée par un leadership tourné vers la limitation des mesures coercitives, l'obligation légale, la cohésion d'équipe, et la mise en place d'outils et de méthodes alternatives. Discussion: La diminution de la coercition auprès des personnes adultes souffrant d'un trouble neurodéveloppemental est possible. D'autres études sont nécessaires pour confirmer l'efficience de stratégies alternatives à l'isolement et à la contention.

Exploring low clozapine C/D ratios, inverted clozapine-norclozapine ratios and undetectable concentrations as measures of non-adherence in clozapine patients: A literature review and a case series of 17 patients from 3 studies.

BACKGROUND: Up to 1/2 of outpatients prescribed clozapine may be partially/fully non-adherent, based on therapeutic drug monitoring (TDM). Three indices for measuring partial/full non-adherence are proposed a: 1) clozapine concentration/dose (C/D) ratio which drops to half or more of what is expected in the patient; 2) clozapine/norclozapine ratio that becomes inverted; and 3) clozapine concentration that becomes non-detectable. METHODS: These 3 proposed indices are based on a literature review and 17 cases of possible non-adherence from 3 samples: 1) an inpatient study in a Chinese hospital, 2) an inpatient randomized clinical trial in a United States hospital, and 3) and a Uruguayan outpatient study. RESULTS: The first index of non-adherence is a clozapine C/D ratio which is less than half the ratio corresponding to the patient's specific ancestry group and sex-smoking subgroup. Knowing the minimum therapeutic dose of the patient based on repeated TDM makes it much easier to establish non-adherence. The second index is inverted clozapine/norclozapine ratios in the absence of alternative explanations. The third index is undetectable concentrations. By using half-lives, the chronology of the 3 indices of non-adherence was modeled in two patients: 1) the clozapine C/D ratio dropped to ≥1/2 of what is expected from the patient (around day 2); 2) the clozapine/norclozapine ratio became inverted (around day 3); and 3) the clozapine concentration became undetectable by the laboratory (around days 9-11). CONCLUSION: Prospective studies should further explore these proposed clozapine indices in average patients, poor metabolizers (3 presented) and ultrarapid metabolizers (2 presented).

Clozapine ultrarapid metabolism during weak induction probably exists but requires careful diagnosis. A literature review, five new cases and a proposed definition.

During weak induction (from smoking and/or valproate co-prescription), clozapine ultrarapid metabolizers (UMs) need very high daily doses to reach the minimum therapeutic concentration of 350 ng/ml in plasma; clozapine UMs need clozapine doses higher than: 1) 900 mg/day in patients of European/African ancestry, or 2) 600 mg/day in those of Asian ancestry. Published clozapine UMs include 10 males of European/African ancestry, mainly assessed with single concentrations. Five new clozapine UMs (two of European and three of Asian ancestry) with repeated assessments are described. A US double-blind randomized trial included a 32-year-old male smoking two packages/day with a minimum therapeutic dose of 1,591 mg/day from a single TDM during open treatment of 900 mg/day. In a Turkish inpatient study, a 30-year-old male smoker was a possible clozapine UM needing a minimum therapeutic dose of 1,029 mg/day estimated from two trough steady-state concentrations on 600 mg/day. In a Chinese study, three possible clozapine UMs (all male smokers) were identified. The clozapine minimum therapeutic dose estimated with trough steady-state concentrations >150 ng/ml was: 1) 625 mg/day, based on a mean of 20 concentrations in Case 3; 2) 673 mg/day, based on a mean of 4 concentrations in Case 4; and 3) 648 mg/day, based on a mean of 11 concentrations in Case 5. Based on these limited studies, clozapine UMs during weak induction may account for 1-2% of clozapine-treated patients of European ancestry and <1% of those of Asian ancestry. A clozapine-to-norclozapine ratio <0.5 should not be used to identify clozapine UMs.

Pathways between Risk/Protective Factors and Maternal Postnatal Depressive Symptoms: The ELFE Cohort.

OBJECTIVE: The risk factors for postnatal depressive symptoms (PNDS) are numerous, but little is known about the protective factors or the interactions between different exposures. The present study explored the pathways between maternal, infant and parenthood vulnerabilities or risk/protective factors and PNDS at 2 months postpartum (PP) in a large sample of women from the general population. METHODS: We used data from the French ELFE cohort, a nationally representative cohort of children followed-up from birth. The available information about vulnerabilities or risk/protective factors for PNDS was collected during the maternity ward stay (mother or medical records) and at 2 months PP (mother by phone). PNDS were evaluated with the Edinburgh Postnatal Depression Scale (EPDS) at 2 months. A measurement model was built based on the psychosocial model for PNDS of Milgrom and colleagues using exploratory factor analysis. The Structural Equation Model was used to investigate the pathways between vulnerability, risk/protective factors and PNDS at 2 months PP. RESULTS: In the study sample (n = 11,583), a lack of a partner's perceived antenatal emotional support, consultation with a mental health specialist before pregnancy, family financial difficulties, prenatal psychological distress and a difficult pregnancy experience were directly associated with the severity of maternal PNDS at 2 months PP, as well as lack of perceived postnatal support. Family financial difficulties and consultation with a mental health specialist before pregnancy were also indirectly associated with the intensity of PNDS through a lack of perceived antenatal emotional support, a difficult pregnancy experience, prenatal psychological distress and a lack of perceived postnatal support. Regarding infant and parenthood characteristics, infant self-regulation difficulties, maternal difficulty in understanding infant crying and infant hospitalisation were directly associated with PNDS severity at 2 months PP, while maternal difficulty in understanding an infant's cries was also indirectly associated with infant self-regulation difficulties. CONCLUSIONS: Perinatal professional support should begin antenatally and target the couple's prenatal functioning, with particular attention to women presenting a history of psychiatric disorders, especially those of low socioeconomic status. After delivery, addressing infant and parenthood characteristics is also recommended.

Escaping the Long Shadow Cast by Agranulocytosis: Reflections on Clozapine Pharmacovigilance Focused on the United Kingdom.

PURPOSE/BACKGROUND: A recent article in this journal presented a US perspective regarding the modernization of clozapine prescription and proposed an escape from the long shadow cast by agranulocytosis. METHODS: Here, an international group of collaborators discusses a point of view complementary to the US view by focusing on worldwide outcomes of clozapine usage that may be uneven in terms of frequency of clozapine adverse drug reactions. FINDINGS/RESULTS: Studies from the Scandinavian national registries (Finland and Denmark) did not find increased mortality in clozapine patients or any clear evidence of the alleged toxicity of clozapine. Data on clozapine-associated fatal outcomes were obtained from 2 recently published pharmacovigilance studies and from the UK pharmacovigilance database. A pharmacovigilance study focused on physician reports to assess worldwide lethality of drugs from 2010 to 2019 found 968 clozapine-associated fatal outcomes in the United Kingdom. Moreover, the United Kingdom accounted for 55% (968 of 1761) of worldwide and 90% (968 of 1073) of European fatal clozapine-associated outcomes. In a pharmacovigilance study from the UK database (from 2008 to 2017), clozapine was associated with 383 fatal outcomes/year including all reports from physicians and nonphysicians. From 2018 to 2021, UK clozapine-associated fatal outcomes increased to 440/year. IMPLICATIONS/CONCLUSIONS: The interpretation of fatal outcomes in each country using pharmacovigilance databases is limited and only allows gross comparisons; even with those limitations, the UK data seem concerning. Pneumonia and myocarditis may be more important than agranulocytosis in explaining the uneven distribution of fatal outcomes in clozapine patients across countries.

Benefits of video games for people with schizophrenia: a literature review.

PURPOSE OF REVIEW: In spite of the overwhelming concerns about the deleterious impact of exposure to video games, a growing body of evidence suggests that it may be of potential interest for therapeutic purposes, particularly in schizophrenia. As literature is rapidly evolving, we carried out a systematic review of recent articles on this issue. RECENT FINDINGS: We identified seven studies published from 2017 to 2022 exploring the benefits of commercial video games in people with schizophrenia and related disorders regarding symptoms, cognition and functional outcome. Six studies used an RCT design. Associations between gaming and better outcomes were found in three main areas: physical condition (walking speed, aerobic fitness), neurocognition (processing speed, memory and executive functions), and social functioning, self-efficacy in daily life activities and quality of life. SUMMARY: Active use of video games is associated with better aerobic fitness and cognitive performances. Video gaming may contribute to better functional outcome and quality of life in patients suffering from cognitive impairments and difficulties in social functioning. Persons with schizophrenia may benefit from using commercial video games because of their potential therapeutic impact on functioning and cognition.

Risks and benefits of clozapine and lithium co-prescribing: A systematic review and expert recommendations.

OBJECTIVES: To identify the risks and benefits of clozapine­lithium co-prescription. METHODS: Articles published in English or French were identified with a MEDLINE, Web of Sciences and PsycINFO search, from inception through January 2023, using the term 'clozapine' in combination with 'lithium'. Data were synthesized narratively. RESULTS: Of the 67 articles included in the review, more than half (n = 38, 56.7 %) were focused on clozapine-related blood dyscrasia. A body of evidence drawn from case reports and retrospective chart studies highlights the potential benefits of lithium prescription for clozapine-related neutropenia, since this strategy may avoid clozapine discontinuation or allow its rechallenge. The most documented adverse drug reactions (ADRs) associated with clozapine­lithium co-prescription are neurotoxic events, which may be prevented or detected early by clinical, electroencephalographic and therapeutic drug monitoring. Causality assessment cannot be established for other reported ADRs occurring during clozapine­lithium co-prescription. The benefits of the combined prescription on psychotic and/or mood symptoms are poorly documented. CONCLUSION: The risks and benefits of clozapine­lithium co-prescription require further exploration as the combination might significantly contribute to reducing underprescription or premature discontinuation of clozapine.

Actionable Predictive Factors of Homelessness in a Psychiatric Population: Results from the REHABase Cohort Using a Machine Learning Approach.

BACKGROUND: There is a lack of knowledge regarding the actionable key predictive factors of homelessness in psychiatric populations. Therefore, we used a machine learning model to explore the REHABase database (for rehabilitation database-n = 3416), which is a cohort of users referred to French psychosocial rehabilitation centers in France. METHODS: First, we analyzed whether the different risk factors previously associated with homelessness in mental health were also significant risk factors in the REHABase. In the second step, we used unbiased classification and regression trees to determine the key predictors of homelessness. Post hoc analyses were performed to examine the importance of the predictors and to explore the impact of cognitive factors among the participants. RESULTS:  First, risk factors that were previously found to be associated with homelessness were also significant risk factors in the REHABase. Among all the variables studied with a machine learning approach, the most robust variable in terms of predictive value was the nature of the psychotropic medication (sex/sex relative mean predictor importance: 22.8, σ = 3.4). Post hoc analyses revealed that first-generation antipsychotics (15.61%; p < 0.05 FDR corrected), loxapine (16.57%; p < 0.05 FWER corrected) and hypnotics (17.56%; p < 0.05 FWER corrected) were significantly associated with homelessness. Antidepressant medication was associated with a protective effect against housing deprivation (9.21%; p < 0.05 FWER corrected). CONCLUSIONS: Psychotropic medication was found to be an important predictor of homelessness in our REHABase cohort, particularly loxapine and hypnotics. On the other hand, the putative protective effect of antidepressants confirms the need for systematic screening of depression and anxiety in the homeless population.

Contrasting the Social Cognitive and Metacognitive Capacities Among Patients With Schizophrenia and Autism Spectrum Disorders Enrolled in Psychiatric Rehabilitation.

ABSTRACT: Unique deficits in synthetic metacognition have been found in schizophrenia when compared with other psychiatric conditions and community controls. Although persons with autism spectrum disorders (ASD) display similar deficits in social cognition relative to those with schizophrenia, to date no study has compared metacognitive function between these groups. We aimed to compare the metacognitive capacities of persons with schizophrenia and ASD and their associations with other outcomes (neurocognition, social cognition, depression, and quality of life). Fifty-six outpatients with schizophrenia or ASD (mean age, 32.50 [9.05]; 67.9% male) were recruited from two French Centers of Reference for Psychiatric Rehabilitation of the REHABase cohort. Evaluation included the Indiana Psychiatric Illness Interview, Metacognition Assessment Scale-Abbreviated, Movie for the Assessment of Social Cognition, and a large cognitive battery. Compared with those with schizophrenia, participants with ASD had higher self-reflectivity ( p = 0.025; odds ratio, 1.38 [1.05-1.86]) in univariable analyses. Metacognitive deficits may be found in ASD with a profile that varies from what is found in schizophrenia. It is possible that methods for enhancing metacognitive abilities during psychiatric rehabilitation may be refined to assist adults with ASD to better manage their own recovery.

The central role of self-esteem in the quality of life of patients with mental disorders.

In psychiatry, recent years have seen a change of focus from a clinician- to a patient-centered perspective that emphasizes quality of life as a treatment target. As a complex construct, quality of life is composed of multiple dimensions that interact with one-another (e.g. physical and psychological well-being, relationships, autonomy, self-esteem). Here, we used data from the REHABase cohort, which includes N = 2180 patients from 15 psychosocial rehabilitation centers in France, to explore networks of quality-of-life dimensions among six psychiatric disorders: schizophrenia, neurodevelopmental, bipolar, depressive, anxiety, and personality disorders. Stronger connections (edges) involved the Self-Esteem dimension, such as Self-Esteem-Physical Well-Being, Self-Esteem-Autonomy, Self-Esteem-Psychological Well-Being, and Self-Esteem-Resilience. Self-esteem was also consistently retrieved as the most central node (the dimension with the most connections within each network). Between-group tests did not reveal any differences regarding network structure, overall connectivity, edge-weights, and nodes' centrality. Despite presenting with different symptom profiles, various psychiatric disorders may demonstrate similar inter-relationships among quality-of-life dimensions. In particular, self-esteem may have a crucial inter-connecting role in patients' quality of life. Our findings could support treatment programmes that specifically target self-esteem to improve patients' quality of life in a cost-effective way.

Trauma and resistance to antipsychotic treatment in schizophrenia: A narrative review.

This review explored whether trauma exposure is associated with poorer response to antipsychotic treatment in schizophrenia patients. A systematic search identified eight studies, of which five reported an association between trauma and non-remission of psychotic symptoms (n = 4) or treatment-resistant schizophrenia (TRS, n = 1). Although evidence supporting the link between trauma and resistance to antipsychotic treatment is scarce, trauma history should be systematically investigated in all persons with TRS, as there is a growing body of evidence showing that schizophrenia patients benefit from therapies for post-traumatic symptoms.

Comparing psychotic experiences in low-and-middle-income-countries and high-income-countries with a focus on measurement invariance.

BACKGROUND: The prevalence of psychotic experiences (PEs) is higher in low-and-middle-income-countries (LAMIC) than in high-income countries (HIC). Here, we examine whether this effect is explicable by measurement bias. METHODS: A community sample from 13 countries (N = 7141) was used to examine the measurement invariance (MI) of a frequently used self-report measure of PEs, the Community Assessment of Psychic Experiences (CAPE), in LAMIC (n = 2472) and HIC (n = 4669). The CAPE measures positive (e.g. hallucinations), negative (e.g. avolition) and depressive symptoms. MI analyses were conducted with multiple-group confirmatory factor analyses. RESULTS: MI analyses showed similarities in the structure and understanding of the CAPE factors between LAMIC and HIC. Partial scalar invariance was found, allowing for latent score comparisons. Residual invariance was not found, indicating that sum score comparisons are biased. A comparison of latent scores before and after MI adjustment showed both overestimation (e.g. avolition, d = 0.03 into d = -0.42) and underestimation (e.g. magical thinking, d = -0.03 into d = 0.33) of PE in LAMIC relative to HIC. After adjusting the CAPE for MI, participants from LAMIC reported significantly higher levels on most CAPE factors but a significantly lower level of avolition. CONCLUSION: Previous studies using sum scores to compare differences across countries are likely to be biased. The direction of the bias involves both over- and underestimation of PEs in LAMIC compared to HIC. Nevertheless, the study confirms the basic finding that PEs are more frequent in LAMIC than in HIC.

The risk of dementia in patients using psychotropic drugs: Antidepressants, mood stabilizers or antipsychotics.

OBJECTIVE: The risk of dementia associated with the use of psychotropic drugs is not fully understood. A nested case-control study was carried out to assess the risk of dementia broadly defined or Alzheimer's disease associated with antidepressants, mood stabilizers or antipsychotics. METHODS: A cohort was formed from healthcare claim databases including all patients aged 50 and over with a first dispensing of the psychotropic drugs concerned between 2006 and 2017. Patients who developed dementia over the study period were considered as cases. The association between drug exposure prior to a five-year lag time and diagnosis of dementia was assessed by conditional logistic regression models. RESULTS: No association was found between dementia, either broadly defined or Alzheimer disease, and antidepressant or mood stabilizers. Findings were conflicting with regard to antipsychotics. First- and second-generation antipsychotics (FGA and SGA) were not associated with Alzheimer disease. SGA treatments of more than 3 months were associated with a higher risk of dementia broadly defined than no use of antipsychotics (Odds ratio [OR] 2.00; 95%CI 1.06-3.79; p = 0.03). In a sensitivity analysis using a lag time of 3 years, ever use of SGA and SGA treatments of more than 3 months were associated with a higher risk of dementia broadly defined than no use of antipsychotics (OR 1.71; 1.10-2.67; p = 0.02 and OR 1.84; 1.03-3.32; p = 0.04, respectively). CONCLUSION: The association between antipsychotics and dementia should be further investigated to establish patients, specific drugs, and patterns of treatment at risk. Prescribers should remain cautious when prescribing them.

An International Adult Guideline for Making Clozapine Titration Safer by Using Six Ancestry-Based Personalized Dosing Titrations, CRP, and Clozapine Levels.

This international guideline proposes improving clozapine package inserts worldwide by using ancestry-based dosing and titration. Adverse drug reaction (ADR) databases suggest that clozapine is the third most toxic drug in the United States (US), and it produces four times higher worldwide pneumonia mortality than that by agranulocytosis or myocarditis. For trough steady-state clozapine serum concentrations, the therapeutic reference range is narrow, from 350 to 600 ng/mL with the potential for toxicity and ADRs as concentrations increase. Clozapine is mainly metabolized by CYP1A2 (female non-smokers, the lowest dose; male smokers, the highest dose). Poor metabolizer status through phenotypic conversion is associated with co-prescription of inhibitors (including oral contraceptives and valproate), obesity, or inflammation with C-reactive protein (CRP) elevations. The Asian population (Pakistan to Japan) or the Americas' original inhabitants have lower CYP1A2 activity and require lower clozapine doses to reach concentrations of 350 ng/mL. In the US, daily doses of 300-600 mg/day are recommended. Slow personalized titration may prevent early ADRs (including syncope, myocarditis, and pneumonia). This guideline defines six personalized titration schedules for inpatients: 1) ancestry from Asia or the original people from the Americas with lower metabolism (obesity or valproate) needing minimum therapeutic dosages of 75-150 mg/day, 2) ancestry from Asia or the original people from the Americas with average metabolism needing 175-300 mg/day, 3) European/Western Asian ancestry with lower metabolism (obesity or valproate) needing 100-200 mg/day, 4) European/Western Asian ancestry with average metabolism needing 250-400 mg/day, 5) in the US with ancestries other than from Asia or the original people from the Americas with lower clozapine metabolism (obesity or valproate) needing 150-300 mg/day, and 6) in the US with ancestries other than from Asia or the original people from the Americas with average clozapine metabolism needing 300-600 mg/day. Baseline and weekly CRP monitoring for at least four weeks is required to identify any inflammation, including inflammation secondary to clozapine rapid titration.