Can Slow Personalized Titration Using C-Reactive Protein Monitoring Decrease the High Rates and Mortality of Clozapine-Associated Myocarditis Seen in Some Countries? A Call for Research.

PURPOSE/BACKGROUND: The hypothesis that slower personalized titration may prevent clozapine-associated myocarditis and decrease the disproportion incidence of 3% found in Australia was not described in a recent Australian article in this journal. METHODS: Six countries in addition to Australia have published information suggesting a similar incidence of clozapine-associated myocarditis. On September 19, 2023, PubMed searches were updated for articles from the United States, Korea, Japan, Canada, New Zealand, and Turkey. FINDINGS/RESULTS: An incidence of 3.5% (4/76) was found in a US hospital, but US experts were the first to propose that clozapine-associated myocarditis may be a hypersensitivity reaction associated with rapid titration and possibly preventable. Koreans and Japanese are of Asian ancestry and need lower minimum therapeutic doses for clozapine than patients of European ancestry. A 0.1% (2/1408) incidence of myocarditis during clozapine titration was found in a Korean hospital, but pneumonia incidence was 3.7% (52/1408). In 7 Japanese hospitals, 34% (37/110) of cases of clozapine-associated inflammation were found during faster titrations (based on the official Japanese titration) versus 13% (17/131) during slower titrations (based on the international titration guideline for average Asian patients). Recent limited studies from Canada, New Zealand, and Turkey suggest that slower personalized titration considering ancestry may help prevent clozapine-associated myocarditis. IMPLICATIONS/CONCLUSIONS: Other countries have very limited published data on clozapine-associated myocarditis. Based on a recent Australian case series and these non-Australian studies, the author proposes that Australia (and other countries) should use slow personalized titration for clozapine based on ancestry and c-reactive protein monitoring.

A Systematic Review of Clozapine Concentration-Dose Ratio from Therapeutic Drug Monitoring Studies in Children and Adolescents Treated with Clozapine for Mental Disorders.

BACKGROUND: Therapeutic drug monitoring of clozapine in children and adolescents has received insufficient attention. Calculation of concentration-to-dose (C/D) ratios from trough steady-state concentrations estimate drug clearance. METHODS: A systematic electronic literature search was conducted in 3 article databases from inception until January 10, 2023, and articles reporting clozapine concentrations in children and adolescents were retrieved. The pharmacokinetic quality of the studies was assessed, and clozapine C/D ratios were calculated using the sample mean clozapine dose and concentration. RESULTS: Of the 37 articles of potential interest, only 7 reported clozapine trough and steady-state concentrations. After excluding case reports and a study confounded by fluvoxamine, 4 studies on psychosis from Europe and the United States were included. The clozapine C/D ratios were similar to published adult values and ranged from 0.82 to 1.24 with a weighted mean of 1.08 ng/mL per mg/d. The weighted means were 334 mg/d for the dose and 380 ng/mL for the concentration. The stratified analysis of the weighted mean clozapine C/D ratios from 2 studies showed lower values in 52 male (1.05 ng/mL per mg/d) than in 46 female (1.46 ng/mL per mg/d) children and adolescents, with values similar to those reported for European adult nonsmokers. Two female adolescents had high clozapine C/D ratios (2.54 ng/mL per mg/d), an Asian American patient with borderline obesity and a patient with intellectual disability with low dosage (mean = 102 mg/d) and concentration (mean = 55 ng/mL). CONCLUSIONS: Reports on clozapine therapeutic drug monitoring in children and adolescents are limited in number and quality. Future studies should focus on basic pharmacokinetic issues, such as stratification by sex, smoking, and relevant comedications with inductive or inhibitory properties.

Will ChatGPT3 Substitute for us as Clozapine Experts?

BACKGROUND: ChatGPT3 is a new artificial intelligence program released on February 13, 2023. METHOD: The authors tested ChatGPT3 on February 18, 2023, and repeated the test a week later. They used their expertise on the effects of ethnic ancestry in the stratification of clozapine dosing and the new idea that they published in March 2022 that African-Americans need higher clozapine doses because they have higher clozapine clearance. RESULTS: In the first interaction on February 18, ChatGPT3 provided reasonable and very up-to-date information, which included a comment that patients of African ancestry have higher clozapine metabolism. The other 4 interactions became progressively more concerning as we asked ChatGPT3 to provide references to justify the latter statement. ChatGPT3 provided non-existent "references" using articles from real journals, with real authors, false PubMed identifiers, and false titles. Moreover, ChatGPT3 said that the first author wrote in 2003 that African-Americans had higher CYP1A2 activity when that did not happen until 2022. One week later, the second author repeated the same set of questions. This time ChatGPT3 described the opposite, that African-Americans have "lower" CYP1A2 activity and "slower" metabolism. ChatGPT3 provided another set of articles to justify the information; some were real but did not comment on clozapine metabolism in African-Americans while others did not exist. CONCLUSIONS: ChatGPT3 provided a mixture of truth, twisted reality, and non-existent "facts." Within one week it defended opposite positions regarding a clinically relevant issue such as using higher or lower clozapine doses in African-Americans.

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.

Brief report: Revealing the nuance: Examining approaches for research with adolescents who identify with multiple racial/ethnic groups.

INTRODUCTION: Increasing racial/ethnic diversity in the United States calls for methodological approaches that capture participants who identify with multiple racial/ethnic groups. Existing approaches are oriented toward large samples (N > 500); yet, we do not know how effective these approaches are with more common smaller convenience samples. We explored how several approaches were associated with the sample distribution of racial/ethnic groups and ethnic identity using a small convenience sample. METHODS: In 2017, 320 U.S. adolescents (Mage = 16.04 years, SDage = 1.33; 59% female) responded to an open-ended question regarding their racial/ethnic group(s) in a cross-sectional survey. Seventy-five (23%) adolescents identified with multiple racial/ethnic groups. Remaining adolescents identified solely with the Asian/Hawaiian Native/Pacific Islander (19%), Black/African American (3%), European American (21%), Latinx (34%), or Native American/Alaska Native (<1%) group. RESULTS: Three approaches for adolescents with multiple racial/ethnic groups were employed. Findings indicated that the sample distributions differed across the approaches. The greatest differences were shown for Black/African American, Native American/Alaska Native, and Other Race/Ethnicity groups. Descriptively, ethnic identity also differed across the approaches. For example, multiracial/ethnic adolescents reported greater ethnic identity-exploration than their European American counterparts in one approach than in others. CONCLUSIONS: Researchers should carefully consider approaches to research with adolescents who identify with multiple racial/ethnic groups given implications for the literature. This study demonstrates the critical need to further develop approaches for capturing the complexity of race/ethnicity.

The Modernization of Clozapine: A Recapitulation of the Past in the United States and the View Forward.

PURPOSE: Although clozapine was Food and Drug Administration (FDA) approved more than 3 decades ago, major barriers and gaps in knowledge continue to prevent its effective and safe use. We review modern-day problems encountered with clozapine in the United States (US). METHODS: Information surrounding current administrative, clinical, research, and technological gaps or barriers related to clozapine use in the US was reviewed. FINDINGS: The history of how clozapine became FDA approved likely contributes to gaps in knowledge. The frequency of safety warnings added to the FDA prescribing information may add to fears about clozapine, as evidence by numerous published survey studies. The clozapine Risk Evaluation and Mitigation Strategy (REMS) program has been modified several times in the last decade, causing access and safety issues for patients, which are discussed. Evidence may suggest that the FDA REMS requirements for hematologic monitoring are too cumbersome, and there may be ability to safely loosen requirements. The COVID-19 pandemic brought forth the ability for extended interval monitoring but also greater awareness of the clozapine-inflammation interaction. Newer guidelines published describe considerations in personalizing clozapine titration based on principles of ethnopsychopharmacology. Emerging technologies to support the use of clozapine are not widely available. IMPLICATIONS: Clozapine is a unique life-saving drug but it is underused in the US, despite its established efficacy. The 2021 REMS changes led to significant difficulties for providers and patients. We highlight the importance of the clozapine-inflammation interaction, therapeutic drug monitoring, and the ability for individual care based on patient-specific factors. There is an urgent need for advancing technology used for clozapine monitoring, evaluating barriers created by REMS, and establishing consistent practices throughout the US.

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.

Transition from mild cognitive impairment to normal cognition: Determining the predictors of reversion with multi-state Markov models.

INTRODUCTION: The theoretical framework of the Alzheimer's disease continuum considers transition between stages in a unidirectional manner. Here we examine the rate of reversion from mild cognitive impairment (MCI) to normal cognition (NC) and explore a set of potential variables associated with this phenomenon. METHODS: A total of 985 Spanish community-dwelling individuals aged 70 years and over at baseline were monitored for 5 years. During this time, 173 MCI and 36 dementia cases were identified. Multi-state Markov models were performed to characterize transitions between states through the dementia continuum. RESULTS: The rate of reversion from MCI to NC was 11%. There were significant non-modifiable (age, socioeconomic status, or apolipoprotein E) and modifiable factors (cognitive training or absence of affective symptoms) associated with reversion. DISCUSSION: Overall, our results highlight that the likelihood of progression from MCI to dementia is very similar to that of reversion from MCI to NC.

Should we routinely add CRP to clozapine titrations? - Learning from three cases.

Objectives: An international guideline recently provided certain personalized schedules for titrating clozapine in adult inpatients by considering: 1) DNA ancestry group, 2) sexsmoking subgroup, and 3) presence/absence of clozapine poor metabolizer (PM) status. Measuring CRP levels at baseline and during the first 4 weeks is recommended. Titrations too fast for the metabolism of specific patients can lead to clozapine-induced inflammations and CRP elevations. Methods: Three published cases are reinterpreted. Better outcomes might have been obtained by using the guideline. Results: Case 1 was a Chinese male non-smoker, a clozapine PM due to an underlying inflammation. Case 2 was a Turkish female non-smoker who developed clozapine-induced myocarditis in the context of 4 risk factors (undiagnosed infl ammation, obesity, valproate and olanzapine co-prescription). Case 3 was a United States patient of European ancestry with no known risk factors who developed myocarditis after a routine titration and had an unsuccessful rechallenge with 12.5 mg/day. Application of the international clozapine titration guideline may have prevented: 1) Case 1 by recommending against clozapine titration for a patient with an abnormal CRP level, 2) Case 2 by considering 4 risk factors and using a slow titration for clozapine PMs, and 3) Case 3 by using CRP elevations for early identification of a possible genetic PM. Conclusions: When baseline or prior CRPs are normal and then become abnormal during a clozapine titration, this indicates: 1) clozapine-induced inflammation associated with too-rapid titration for that specific patient, and/or 2) co-occurrence of an infection. Prospective studies need to verify this hypothesis.

Four cases of myocarditis in US hospitals possibly associated with clozapine poor metabolism and a comparison with prior published cases.

Objectives: Clozapine-induced myocarditis may be a hypersensitivity reaction due to titration that was too rapid for a patient's clozapine metabolism. Obesity, infections, and inhibitors (e.g., valproate) may lead to clozapine poor metabolizer (PM) status. The hypothesis that 4 patients with clozapine-induced myocarditis from two United States hospitals were clozapine PMs was tested by studying their minimum therapeutic clozapine doses and titrations. Methods: Using methodology from a prior myocarditis case series of 9 Turkish patients, we studied: 1) the concentration-to-dose (C/D) ratio; 2) minimum therapeutic dose required to reach 350 ng/ml (a marker for PM status); and 3) titration speed. Results: All 4 patients were possible clozapine PMs (their respective minimum therapeutic doses were: 134, 84, 119 and 107 mg/day). The identified possible contributors to clozapine PM status were: 1) valproate in Cases 1, 2 and 4; 2) obesity and a urinary tract infection in Case 2; and 3) obesity and very rapid titration in Case 4. Case 3, who was given a normal US titration, appeared to be a genetic clozapine PM. He developed clozapineinduced drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome after rechallenge using 12.5 mg/day > 3 months later. The results were similar to 9 Turkish cases, all of which were PMs (6 on valproate, 4 with obesity, 1 with infection and 1 possibly genetic). Conclusions: Future studies using clozapine levels and considering the role of clozapine PM status should explore whether or not all cases of clozapine-induced myocarditis could be explained by lack of individualized titration. (Neuropsychopharmacol Hung 2022; 24(1): 29-41).

Reflections on the Complex History of the Concept of Clozapine-Induced Inflammation during Titration.

Clozapine was synthesized in 1958. The Food and Drug Administration approved it in 1989 when comprehensive pharmacokinetic studies were not required and it was not known that clozapine was metabolized by the cytochrome P450 1A2 (CYP1A2). Currently it is known that clozapine personalized dosing may be influenced by one's DNA ancestry (African, European and/or Asian/Indigenous American), sex/smoking subgroup, and the presence/absence of genetic/non-genetic poor metabolizer (PM) status. The literature does not properly reflect the concept of "clozapine-induced inflammation" during rapid titration. Elaborating upon this concept, this historical review discusses: 1) clozapine-induced fever, 2) the effects of inflammation on clozapine metabolism, 3) clozapine-induced myocarditis, 4) other clozapine-induced inflammations, 4) current support for "clozapine-induced inflammation" as a hypersensitivity reaction, 5) the difficulty in addressing such a concept to a readership with diverse beliefs about it and 6) the limitations of this review in convincing skeptics. Clozapine-induced fever in the absence of any concomitant infection was first described in 1972 and is a mild form of "clozapine-induced inflammation" during rapid titration, which also includes myocarditis and other localized inflammations. They may be part of a hypersensitivity reaction that has 3 phases. In the first phase, the titration is too fast for a specific patient; either the psychiatrist was too aggressive in titrating, and/or the patient is a clozapine PM. This situation leads to a release of cytokines. In the second phase, a positive feedback loop develops; the cytokines inhibit CYP1A2, which further increases plasma clozapine concentrations. In the third phase, if the titration continues, the inflammation becomes complicated by the development of an auto-immune phenomenon leading to localized inflammation. Skeptical readers are challenged to try: 1) 6 titrations proposed for stratified dosing and 2) c-reactive protein (CRP) monitoring for personalized dosing in the absence of genetic testing for clozapine PM status.

The UPPS model of impulsivity in the abuse of Information and Communication Technologies (ICT). / El modelo UPPS de impulsividad en el abuso de las Tecnologías de la Información y la Comunicación (TIC).

The UPPS model of impulsivity has recently been proposed, has been widely applied to substance abuse and is one of those recommended in the context of Research Domain Criteria, RDoC. However, its application to the abuse of information and communication technologies (ICTs) has been very limited. In the present work, a sample of n = 748 (67% females) was recruited through the Internet, and the reduced version of the UPPS-P was administered, in addition to the MULTICAGE-TIC and the Prefrontal Symptoms Inventory (PSI-20). The psychometric properties of UPPS-P were satisfactory in terms of internal consistency (0.87 > ω > 0.75) and structural validity. Impulsivity measured by UPPS-P correlated with all MULTICAGE-TIC scales, although with a very small effect size, and with greater magnitude with prefrontal dysfunction symptoms. The impulsivity dimension most related to ICT abuse was Urgency (0.3 > r > 0.2). A structural analysis of all the variables was carried out, with impulsivity appearing as a product of the prefrontal malfunction that predicted, through Positive Urgency, the abuse of ICTs. Impulsivity does not seem to be the central nucleus of ICT abuse, but rather failures in the superior control of behavior, of which impulsivity would be a consequence, but not the most important. This makes it advisable to design cognitive rehabilitation interventions that improve the functioning of superior behavior control mechanisms in the prevention and treatment of ICT abuse.

El modelo UPPS de impulsividad se ha propuesto recientemente, ha sido ampliamente aplicado al abuso de sustancias y es uno de los recomendados en el contexto de investigación Research Domain Criteria, RDoC. Sin embargo, su aplicación al abuso de tecnologías de la información y la comunicación (TIC) ha sido muy limitado. En el presente trabajo se reclutó a través de Internet una muestra de n = 748 (67% mujeres) y se administró la versión reducida de la UPPS-P, además del MULTICAGE-TIC y el Inventario de Síntomas Prefrontales (ISP-20). Las propiedades psicométricas de la UPPS-P resultaron satisfactorias en consistencia interna (0,87 > ω >0,75) y validez estructural. La impulsividad medida por la UPPS-P correlacionó con todas las escalas del MULTICAGE-TIC, aunque con un tamaño del efecto muy pequeño, y con mayor magnitud con las de síntomas de mal funcionamiento prefrontal. Las dimensiones de impulsividad más relacionadas con el abuso de las TIC fueron las de Urgencia (0,3 > r > 0,2). Se realizó un análisis estructural de todas las variables apareciendo la impulsividad como un producto del mal funcionamiento prefrontal que predecía, a través de la Urgencia Positiva, el abuso de las TIC. La impulsividad no parece ser el núcleo central del abuso de las TIC, sino los fallos en el control superior de la conducta, de los que la impulsividad sería una consecuencia, pero no la más importante. Ello hace recomendable el diseño de intervenciones de rehabilitación cognitiva que mejoren el funcionamiento de los mecanismos de control superior de la conducta en la prevención y tratamiento del abuso de las TIC.

European Whites May Need Lower Minimum Therapeutic Clozapine Doses Than Those Customarily Proposed.

PURPOSE/BACKGROUND: A nomogram from a British naturalistic study proposed that the clozapine dosing needed to reach a serum concentration of 350 ng/mL ranged from 265 mg/d (female nonsmokers) to 525 mg/d (male smokers). Some European reviews have used these dosing recommendations, which seem greater than what we found in an Italian White sample ranging from 245 mg/d (female nonsmokers) to 299 mg/d (male smokers). Five other published samples of European Whites were added to the Italian sample to estimate clozapine doses recommended for reaching 350 ng/mL. METHODS/PROCEDURES: Average clozapine metabolizers were obtained by eliminating outliers with confounding variables: (1) psychiatric inducers and inhibitors; (2) doses less than 100 mg/d; and (3) when possible, patients with inflammation, obesity, or using oral contraceptives. The study included 1363 average metabolizer European Whites: the Italian sample and 5 new samples. Mean averages that reached serum concentration levels of 350 ng/mL were calculated after stratification by sex and smoking status in each sample. Then, weighted mean averages were obtained by combining the 6 samples. FINDINGS/RESULTS: The estimated weighted mean clozapine dosages ranged from 236 to 368 mg/d (236 mg/d in 218 female nonsmokers, 256 mg/d in 340 male nonsmokers, 357 mg/d in 269 female smokers, and 368 mg/d in 546 male smokers). IMPLICATIONS/CONCLUSIONS: Our recommended dosages are less than those recommended in Europe. Future studies in European Whites need to replicate these recommended doses for average metabolizer patients after sex and smoking stratification and further explore clozapine dosing for those with relevant clinical confounders.

Clinimetric Criteria for Patient-Reported Outcome Measures.

Patient-reported outcome measures (PROMs) are self-rated scales and indices developed to improve the detection of the patients' subjective experience. Given that a considerable number of PROMs are available, it is important to evaluate their validity and usefulness in a specific research or clinical setting. Published guidelines, based on psychometric criteria, do not fit in with the complexity of clinical challenges, because of their quest for homogeneity of components and inadequate attention to sensitivity. Psychometric theory has stifled the field and led to the routine use of scales widely accepted yet with a history of poor performance. Clinimetrics, the science of clinical measurements, may provide a more suitable conceptual and methodological framework. The aims of this paper are to outline the major limitations of the psychometric model and to provide criteria for clinimetric patient-reported outcome measures (CLIPROMs). The characteristics related to reliability, sensitivity, validity, and clinical utility of instruments are critically reviewed, with particular reference to the differences between clinimetric and psychometric approaches. Of note is the fact that PROMs, rating scales, and indices developed according to psychometric criteria may display relevant clinimetric properties. The present paper underpins the importance of the clini-metric methodology in choosing the appropriate PROMs. CLIPROM criteria may also guide the development of new indices and the validation of existing PROMs to be employed in clinical settings.

Effect of necessity-concern framework and polypharmacy on treatment adherence in psychiatric patients. Comparing an Argentinian with a Spanish sample.

OBJECTIVE: We aimed to replicate a prior Spanish study of medication adherence where logistic regression models provided highly significant odds ratios (ORs) for three continuous scores: necessity, concern and the necessity-concern differential, and a dichotomous variable: skeptical attitude. Adherence ORs in the necessity-concern framework were very strong in patients taking five or six medications. METHODS: The sample comprised consecutive adult psychiatric outpatients in Mendoza, Argentina. The necessity-concerns framework was assessed using a subscale of the Beliefs about Medicines Questionnaire. Adherence (yes/no) to prescribed psychiatric medications was assessed by the Sidorkiewicz adherence tool. RESULTS: When compared with the Spanish sample, the Argentinian group (508 patients with 875 medications) was characterized by: (1) significantly stronger adherence ORs with the necessity-concern framework, (2) significantly lower number of medications per patient and percentage of patients with marked psychiatric polypharmacy (≥4 medications), (3) though a higher number of medications still was significantly associated with poor adherence. CONCLUSIONS: The Argentinian sample replicated the previous finding that patient beliefs regarding necessity and concern were associated with poor adherence to prescribed medications. Polypharmacy had an additive role decreasing adherence in both samples. In both samples, when prescribed ≥4 psychiatric medications, patients reported adherence to only two-third of the medications.

Reflections on US Psychiatry: How the Baton Was Passed From European Psychiatry and the Contributions of US Psychiatry.

ABSTRACT: The medical model in psychiatry and descriptive psychopathology were established in Germany by Krapelin's textbook and Jaspers' General Psychopathology. In the United Kingdom, Mayer-Gross' textbook synthesized both books, influencing US psychiatry. US psychiatrists from the World War II generation defeated the US academic psychoanalytic establishment by building three pillars: biological psychiatry (brought by Wortis), the psychopharmacology revolution, and the Diagnostic and Statistical Manual of Mental Disorders, 3rd Edition (DSM-III). The psychopharmacology revolution included immigrants (e.g., Gershon), Cole's marketing, and textbooks by Klein and Fink. The "neo-Kraepelinians" introduced the medical model in US psychiatry and defined 15 valid psychiatric disorders. Spitzer supervised DSM-III's development. Its 1980 publication started the world dominance of US psychiatry and the multiplication of diagnoses. Major contributions by US psychiatrists include a) McHugh's update of the Jaspersian approach, b) Fink's inclusion of catatonia as a syndrome in DSM-5 (following Abrams and Taylor's studies), and c) DSM-III's departure from the Jaspersian hierarchy of schizophrenia and affective symptoms.

Automated ELISA On-Chip for the Detection of Anti-SARS-CoV-2 Antibodies.

The COVID-19 pandemic has been the most critical public health issue in modern history due to its highly infectious and deathly potential, and the limited access to massive, low-cost, and reliable testing has significantly worsened the crisis. The recovery and the vaccination of millions of people against COVID-19 have made serological tests highly relevant to identify the presence and levels of SARS-CoV-2 antibodies. Due to its advantages, microfluidic-based technologies represent an attractive alternative to the conventional testing methodologies used for these purposes. In this work, we described the development of an automated ELISA on-chip capable of detecting anti-SARS-CoV-2 antibodies in serum samples from COVID-19 patients and vaccinated individuals. The colorimetric reactions were analyzed with a microplate reader. No statistically significant differences were observed when comparing the results of our automated ELISA on-chip against the ones obtained from a traditional ELISA on a microplate. Moreover, we demonstrated that it is possible to carry out the analysis of the colorimetric reaction by performing basic image analysis of photos taken with a smartphone, which constitutes a useful alternative when lacking specialized equipment or a laboratory setting. Our automated ELISA on-chip has the potential to be used in a clinical setting and mitigates some of the burden caused by testing deficiencies.

Practical Approach to Measuring and Predicting Medication Adherence by Outpatient's SelfReport After More than 10 Years of Research in Psychopharmacology.

Schizophrenia, bipolar disorder and major depression are associated with nonadherence registered mean figures of around 50%, highlighting the relevance of having simple adherence tools to incorporate into daily clinical practice. For 10 years we have focused on self-report as an assessment method and have studied thousands of outpatients taking thousands of psychiatric medications in three countries. Measurement of treatment adherence during use of polypharmacy is a really complex task as patients could adhere differently to the various medications prescribed, making it essential to assess adherence to each individual medication. This was not possible until the introduction of the Sidorkiewicz Adherence Tool that allows one to separate adherence to each medication, whether poor or not. Health psychologists have developed the Health Belief Model which has not received enough attention by psychiatrists. Based on this model, we have focused on personality styles and specific beliefs concerning specific medications as possible predictors of poor adherence. We developed the Patient Health Beliefs Questionnaire on Psychiatric Treatment which provides 5 self-reported personality dimensions: negative aspects of medication (pharmacophobia), positive aspects of medication (pharmacophilia), high/low psychological reactance, high/low doctor health locus of control (HLOC) and high/low internal HLOC. Based on the Beliefs about Medicines Questionnaire we have developed a measure of skepticism, defined as a patient's high concern about adverse reaction to an individual medication and a low belief in its necessity. Our research experience based on the tools for assessing and predicting adherence is presented in a practical manner by using seven boxes and examples. (Neuropsychopharmacol Hung 2021; 23(4): 336-346).

Adherence to psychiatric medications: Comparing patients with schizophrenia, bipolar disorder and major depression.

Findings of three articles reporting results in 1372 stabilized outpatients taking 2454 medications in Spain, Argentina, and Venezuela were combined. Prevalence of good adherence was not obviously different across diagnoses: 69.5% (N=212) for schizophrenia, 66.3% (N=142) for bipolar disorder, and 69.8% (N=521) for depression. Besides the focus on stabilized outpatients, other study biases included use of a research sample; limited to oral medications, ignoring long-acting injectable antipsychotics; and lack of data on active substance abuse, clinical severity, and insight. Logistic regression models explored predictors of good vs. poor adherence. The six self-reported variables studied were pharmacophobia, pharmacophilia, high psychological reactance, high internal health locus of control (LOC), high doctor LOC, and skepticism concerning specific medications. ORs were significant in 56% (47/84) of the statistical tests vs. 24% (23/98) of ORs significant in case of 7 demographic/clinical variables (p=0.001). At least 2/3 of the ORs for pharmacophobia, pharmacophilia and skepticism were significantly associated with adherence in cases and controls, indicating their independence from diagnoses. In need of replication, three other self-reported measures had differential effects on adherence across diagnoses. High psychological reactance was associated with decreased adherence to antidepressant medications in general, or for patients with mood disorders. High internal LOC as associated with poor adherence may reflect the distrust patients with schizophrenia or severe bipolar disorder have of other people. High doctor LOC was significantly associated with increased adherence only in patients with bipolar disorder, but was significant for all medications, mood stabilizers and antipsychotics, indicating the relevance of the patient-psychiatrist relationship in these patients. (Neuropsychopharmacol Hung 2021; 23(4): 363-373).

Poor Adherence to Oral Psychiatric Medication in Adults with Bipolar Disorder: The Psychiatrist May have More Influence than in Other Severe Mental Illnesses.

Objective: Medication adherence in bipolar disorder (BD) may be influenced by 6 selfreported dimensions: 1) high/low psychological reactance, 2) high/low internal healthlocus of control (HLOC), 3) high/low doctor HLOC, 4) pharmacophobia, 5) pharmacophilia, and 6) skepticism about a specific medication. This study in Spain, Argentina, and Venezuela included 142 outpatients with BD prescribed 320 psychiatric medications and 1230 other psychiatric outpatients prescribed 2134 medications. Methods: Logistic regression models included adherence for each psychiatric medication, measured by the Sidorkiewicz Adherence Tool as the dependent variable. The models provided adjusted odds ratios (ORs) of dichotomous independent variables: clinical variables and 6 self-reported dimensions. Results: ORs significant in both groups were: 1) high doctor HLOC (OR=1.87 in BD, OR=1.25 in other patients), 2) high psychological reactance (respectively OR=0.572, OR=0.798), 3) pharmacophobia (respectively OR=0.361, OR=0.614), and 4) skepticism about a specific medication (respectively OR=0.300, OR=0.556). Two ORs were only significant in BD patients: medication duration > 1 year (OR=0.449), and extreme polypharmacy (OR=2.49). The study included 104 BD patients prescribed 122 mood stabilizers and 136 other patients prescribed 140 mood stabilizers. Two ORs were significant for mood stabilizer adherence only in BD patients: high doctor HLOC and skepticism (respective ORs=2.38, OR=0.390). The study included 87 BD patients prescribed 97 antipsychotics and 417 other patients prescribed 458 antipsychotics. Four ORs were significant for antipsychotic adherence only in the BD group. Conclusions: Future studies of adherence to all/specific medications should explore the specific city/commonality of these dimensions, particularly doctor HLOC, in BD versus other psychiatric patients. (Neuropsychopharmacol Hung 2021; 23(4): 347-362).