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.

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).

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.

Ethnopsychopharmacology study of patients' beliefs regarding concerns about and necessity of taking psychiatric medications.

OBJECTIVE: The aim of this study was to examine whether or not cultural differences influence beliefs about the necessity of taking prescribed psychiatric drugs and concern about their adverse effects in psychiatric outpatients in Spain, Argentina, and Venezuela. METHODS: This cross-sectional study included 1,372 adult psychiatric outpatients using 2,438 psychotropic drugs and was designed to assess outpatients' beliefs about their prescribed medication. Patients completed sociodemographic, clinical questionnaires, and the Beliefs about Medicines Questionnaire Specific Scale and registered scores ranging from 1 to 5 on each of two subscales: concern and necessity. A "necessity-concern differential" was obtained by calculating the difference (range -4 to +4). RESULTS: The global score, including all drugs in the total sample, had a mean necessity score of 3.50 ± 0.95, a mean concern score of 2.97 ± 0.99, and a mean differential score of 0.54 ± 1.42. The concern and necessity mean scores varied significantly across these three culturally Hispanic countries, probably across drug classes, and were associated with treatment duration. On the other hand, age and education played a very limited role. CONCLUSIONS: Understanding the diverse effects of culture and society on these attitudes is highly relevant for the development of responsive mental health services in multicultural societies.

Skepticism and pharmacophobia toward medication may negatively impact adherence to psychiatric medications: a comparison among outpatient samples recruited in Spain, Argentina, and Venezuela.

BACKGROUND: Cultural differences in attitudes toward psychiatric medications influence medication adherence but transcultural studies are missing. The objective of this study was to investigate how attitudes and beliefs toward psychotropic medications influence treatment adherence in psychiatric outpatients in Spain, Argentina, and Venezuela. METHODS: A cross-sectional, cross-cultural psychopharmacology study was designed to assess psychiatric outpatients' attitudes toward their prescribed medication. Patients completed the Drug Attitude Inventory - 10 Item (DAI-10), the Beliefs about Medicines Questionnaire - Specific Scale (BMQ-Specific), the Sidorkiewicz adherence tool, and sociodemographic and clinical questionnaires. The study included 1,291 adult psychiatric outpatients using 2,308 psychotropic drugs from three Spanish-speaking countries, the Canary Islands (Spain) (N=588 patients), Argentina (N=508), and Venezuela (N=195). RESULTS: The univariate analyses showed different mean scores on the DAI-10 and the BMQ - Necessity and Concerns subscales but, on the other hand, the percentages of non-adherent and skeptical patients were relatively similar in three countries. Argentinian patients had a very low level of pharmacophobia. Multivariate analyses (logistic regression and chi-squared automatic interaction detector segmentation) showed that pharmacophobia in general and skepticism about specific medications (high concern about adverse reactions and low belief in their necessity) were associated with non-adherence. Pharmacophobia was the major factor associated with non-adherence (Spain and Venezuela) but when pharmacophobia was rare (Argentina), skepticism was the most important variable associated with non-adherence. CONCLUSION: Psychiatric patients' attitudes and beliefs about their psychiatric treatment varied in these three Spanish-speaking countries, but pharmacophobia and skepticism appeared to play a consistent role in lack of adherence.

[The organo-clinical hiatus today. Some thoughts about Neurosciences, Psychopathology and Clinical Psychiatry in the early twenty-first century]. / El hiato órgano-clínico en la actualidad. Algunas reflexiones acerca de las neurociencias, la psicopatología y la clínica psiquiátrica en el comienzo del Siglo XXI.

The concept of "organo clinical-hiatus" prepared by Henri Ey the mid-twentieth century has transcended the boundaries of time and has an amazing utility if it is considered from the point of view of both epistemological and clinical. Current developments in the field of neuroscience on the one hand and effective in clinical practice of psychopathological concepts born in the nineteenth century on the other, pose a challenge for psychiatrists today. It is important not to take a naive position on the new neuroscientific knowledge adopting a dogmatic stance that keeps us patient and while maintaining a clear position that avoids specialty contempt by those who argue that mental illness is a mere construct sustained by the medical hegemonic power. We believe the best way to protect our psychiatric practice of involuntary biases and attacks blinded by reductionist ideas is having a historical knowledge of our discipline and a solid epistemological basis. That way we will have the largest options to help our patients.