An expert review of clozapine in Latin American countries: Use, monitoring, and pharmacovigilance.

There is growing interest in clozapine clinical use, monitoring, and research, particularly adverse drug reactions (ADRs) other than agranulocytosis. In this study we focused on clozapine pharmacovigilance. Hence, we contacted clinicians and researchers in Latin America and requested information about local psychiatric services, clozapine availability, clinical use, and ADR monitoring with the VigiBase system. Only two countries have the minimum recommended number of psychiatric beds (15 per 100,000 residents): Uruguay (N = 34.9) and Argentina (N = 17). Bolivia is the only country where clozapine is unavailable. Nine out of twenty countries (45 %) reported ADRs to VigiBase. Argentina, Brazil, Chile, Colombia, and Mexico published national guidelines for schizophrenia treatment. Chile is the sole country with clozapine clinics with drug serum monitoring. Ethnicity-related drug titration in not described in package inserts in any country. We examined in detail the 9 most frequent and important clozapine ADRs in the worldwide database (pneumonia, sudden death, cardiac arrest, agranulocytosis, myocarditis, constipation, arrhythmia, seizure, and syncope). These 9 ADRs led to 294 reports with fatal outcomes in Argentina (N = 3), Brazil (N = 3), Chile (N = 2), and Peru (N = 1). Agranulocytosis was reported from 7 countries: constipation or seizures from 8 countries. Only two countries reported pneumonia and one country reported myocarditis. The number of clozapine reports in VigiBase has no relationship to the country's population. All Latin American countries underreport clozapine associated ADRs. Latin American governments, along with clinicians, researchers, and educators, should optimize clozapine use and monitoring for the benefit of people with severe mental and some neurological disorders.

Clozapine safety monitoring and related research in psychiatry and neurology in South America: A scoping review.

The quality and quantity of clozapine safety monitoring considerably differs among South American countries and mainly focus on hematological surveillance. Few studies have been conducted on other clozapine-related adverse effects (ADRs) and mainly refer to case reports and literature reviews. We retrieved thirty-nine publications on clozapine related ADRs others than neutropenia. Studies in Brazil and Venezuela accounted for 67 % of all the publications, and 8 out of 12 countries published 2 or less manuscripts. Only Chile offers serum clozapine level measurement in public institutions. Given the recently recognized role of ethnicity, gender, smoking, obesity drug interactions in optimal clozapine administration, modernization of clozapine clinical use and research in psychiatry and neurology most be broadcasted and stimulated in South American countries.

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.

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.

Ego-dystonia: a review in search of definitions.

The ego-dystonic experience refers to the negative assessment that the subject makes of some of their thoughts or emotions, in the context of a conserved state of consciousness, as well as other aspects of their social and intrapersonal life that are relatively intact. Ego-dystonia is a widely used construct, but one that has not been defined in reasonably operational terms. Perhaps this explains why it is no longer used in contemporary classifications of mental disorders such as the ICD-11 and DSM-5. It is related to the awareness of the mental illness, with feelings of guilt and shame, but intuitively we perceive relevant differences between all these experiences. Psychoanalytic theory conceives the ego-dystonic as an alteration in the early structuring of the ego. Cognitive psychology conceives it as a dysfunction of the corrective mechanisms that harmonise the cognitive and the metacognitive. Evolutionary theory has not addressed the issue directly, but through the analysis of guilt, to which it attributes a high adaptive value, since it limits aggression and promotes reparative behaviours. Given the importance of the concept of self-attunement, it is surprising how little theoretical and empirical research there is on the subject, the clarification of which could represent a considerable advance in the field of mental health.

Egodistónico: Una Revisión en Busca de Definiciones / Ego-Dystonia: a Review in Search of Definitions

RESUMEN La vivencia egodistónica se refiere a la valoración negativa del sujeto sobre algunos de sus pensamientos o emociones, en el contexto de un estado de conciencia conservado, al igual que otros aspectos de su vida social e intrapersonal que se encuentran relativamente intactos. La egodistonía es un constructo ampliamente utilizado, pero que no ha sido definido en términos razonablemente operativos. Tal vez ello explica por qué ha dejado de utilizarse en las clasificaciones contemporáneas de los trastornos mentales, como la ICD-11 y el DSM-5. Lo egodistónico se relaciona con la conciencia de enfermedad mental, con los sentimientos de culpa y la vergüenza, pero intuitivamente percibimos diferencias relevantes entre todas estas vivencias. La teoría psicoanalítica concibe lo egodistónico como una alteración en la estructuración temprana del Yo. La psicología cognitiva lo concibe como una disfunción de los mecanismos correctivos que armonizan lo cognitivo y lo metacognitivo. La teoría evolutiva no ha abordado el tema directamente, sino a través del análisis de la culpa, a la cual atribuye un alto valor adaptativo, dado que limita la agresión y promueve conductas reparativas. Dada la importancia del concepto de egosintonía, es sorprendente la escasa investigación teórica y empírica sobre el tema, cuyo esclarecimiento podría representar un avance considerable en el campo de la salud mental.

ABSTRACT The ego-dystonic experience refers to the negative assessment that the subject makes of some of their thoughts or emotions, in the context of a conserved state of consciousness, as well as other aspects of their social and intrapersonal life that are relatively intact. Ego-dystonia is a widely used construct, but one that has not been defined in reasonably operational terms. Perhaps this explains why it is no longer used in contemporary classifications of mental disorders such as the ICD-11 and DSM-5. It is related to the awareness of the mental illness, with feelings of guilt and shame, but intuitively we perceive relevant differences between all these experiences. Psychoanalytic theory conceives the ego-dystonic as an alteration in the early structuring of the ego. Cognitive psychology conceives it as a dysfunction of the corrective mechanisms that harmonise the cognitive and the metacognitive. Evolutionary theory has not addressed the issue directly, but through the analysis of guilt, to which it attributes a high adaptive value, since it limits aggression and promotes reparative behaviours. Given the importance of the concept of self-attunement, it is surprising how little theoretical and empirical research there is on the subject, the clarification of which could represent a considerable advance in the field of mental health.

An international guideline with six personalised titration schedules for preventing myocarditis and pneumonia associated with clozapine.

White blood cell (WBC) monitoring has reduced clozapine-treated patient deaths associated with agranulocytosis to a rarity. However, clozapine protocols and package inserts worldwide provide no instructions for preventing myocarditis or pneumonia during clozapine titrations. Prescribers worldwide are largely unaware of that. Meanwhile, as they worry about agranulocytosis, their clozapine-treated patients are at risk of dying from pneumonia or myocarditis. Consequently, an international guideline with 104 authors from 50 countries/regions was recently published to provide personalised clozapine titration schedules for adult inpatients. This forum article reviews pneumonia and myocarditis occurring during clozapine titration, as well as the three most innovative aspects of this new guideline: (1) personalised titration, (2) C reactive protein (CRP) measures, and (3) dose predictions based on blood levels. Clozapine metabolism is influenced by 3 levels of complexity: (1) ancestry groups, (2) sex-smoking subgroups, and (3) presence/absence of poor metabolizer status. These 3 groups of variables should determine the maintenance dose and speed of clozapine titration; they are summarised in a table in the full-text. The international clozapine titration guideline recommends measuring CRP levels simultaneously with WBC, at baseline and weekly at least for the first 4 weeks of titration, the highest risk period for clozapine-induced myocarditis.

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.

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).

Poor Adherence to Oral Psychiatric Medication in Adults with Depression: Psychological Reactance May Have Specific Effects in Depression.

Objective: Medication adherence in psychiatric disorders, including depression, may be influenced by 6 self-reported dimensions: 1) high/low doctor health locus of control (HLOC), 2) high/low internal HLOC, 3) high/low psychological reactance, 4) pharmacophilia, 5) pharmacophobia, and 6) skepticism about a specific medication. This study in Spain, Argentina, and Venezuela included 521 outpatients with depression prescribed 920 psychiatric medications and 851 other psychiatric outpatients prescribed 1534 medications. Methods: Logistic regression models were completed in patients with depression and psychiatric controls. The dependent variable was adherence for each psychiatric medication (Sidorkiewicz Adherence Tool). The models provided adjusted odds ratios (ORs) of dichotomous independent variables: clinical variables, and 6 self-reported dimensions. Results: ORs significant in both diagnostic groups were: 1) pharmacophobia (OR=0.500 in depression, OR=0.599 in other patients), 2) pharmacophilia (respectively OR=1.51, OR=1.65), 3) treatment for 1 year (respectively OR=0.731, OR=0.608), 4) geriatric age (respectively OR=2.28, OR=3.02), and 5) skepticism about a specific medication (respectively OR=0.443, OR=0.569). Two ORs were significant in the depression group, but not in the controls: the country of Spain (OR=0.744), and high psychological reactance (OR=0.685). The study included 470 depression patients prescribed 510 antidepressants and 348 other patients prescribed 370 antidepressants. One OR was significant for antidepressant adherence in both groups: high psychological reactance (respectively OR=0.597, OR=0.561). Conclusions: All clinical studies using self-report include biases but the most important is lack of access to patients not coming for treatment. Future studies should further explore the specificity/commonality of these dimensions, particularly psychological reactance, in depression versus other psychiatric disorders. (Neuropsychopharmacol Hung 2021; 23(4): 374-387).

Poor Adherence to Oral Psychiatric Medication in Adults with Schizophrenia May Be Influenced by Pharmacophobia, High Internal Health Locus of Control and Treatment Duration.

Objective: This study in Spain, Argentina, and Venezuela included 212 schizophrenia outpatients prescribed 387 psychiatric medications and 1,160 other psychiatric outpatients prescribed 2,067 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: 1) clinical variables, 2) subscales from the Patient Health Beliefs Questionnaire on Psychiatric Treatment (presence/absence of pharmacophobia and pharmacophilia and high/low psychological reactance, internal health locus of control [HLOC] and doctor's HLOC) and 3) presence/absence of skepticism toward each medication measured by the Beliefs about Medicines Questionnaire (BMQ). Results: ORs significant in both groups were: 1) pharmacophobia (OR=0.389 in schizophrenia, OR=0.591 in other patients and not significantly different) and 2) pharmacophilia (respectively OR=2.18, OR=1.59 and significantly higher in schizophrenia: p=0.012). Prescribing the medication for >1 year increased adherence in schizophrenia (OR=1.92) while decreasing it in others (OR=0.687). Four ORs were significant in the schizophrenia group but not in the controls: treatment for >1 year (OR=0.161), high internal LOC (OR=0.389), extreme polypharmacy (OR=1.92) and the country of Spain (OR=0.575). Regarding antipsychotics, the study included 204 schizophrenia patients prescribed 240 antipsychotic medications and 301 other patients prescribed 315 antipsychotic drugs. Three ORs were significant for antipsychotic adherence in the schizophrenia group: pharmacophobia (OR=0.324), treatment for >1 year (OR=0.362), and skepticism about specific antipsychotics (OR=0.535). Conclusions: Future adherence studies for antipsychotic/all medications should further explore the specificity/commonality of these dimensions in schizophrenia versus other psychiatric patients. (Neuropsychopharmacol Hung 2021; 23(4): 388-404).