An expert review of clozapine in Eastern European countries: Use, regulations and pharmacovigilance.

OBJECTIVES: To compare the prevalence, regulations, and pharmacovigilance practices of clozapine use in Eastern European countries (except Russia). METHODS: Questionnaires and data from administrative databases (2016 and 2021), package inserts and national guidelines were collected from 21 co-authors from 21 countries. Reports of clozapine adverse drug reactions (ADRs) sent to the global pharmacovigilance database (VigiBase™) were analyzed from introduction to December 31, 2022. RESULTS: Clozapine prescription among antipsychotics in 2021 varied six-fold across countries, from 2.8 % in the Czech Republic to 15.8 % in Montenegro. The utilization of antipsychotics in both 2016 and 2021 was highest in Croatia, and lowest in Serbia in 2016, and Montenegro in 2021, which had half the defined daily dose (DDD)/1000/day compared to the Croatian data. From 2016 to 2021, the prevalence of antipsychotic use increased in almost all countries; the proportion of clozapine use mainly remained unchanged. Differences were detected in hematological monitoring requirements and clozapine approved indications. Only a few national schizophrenia guidelines mention clozapine-induced myocarditis or individual titration schemes. The VigiBase search indicated major underreporting regarding clozapine and its fatal outcomes. By comparison, the United Kingdom had less than half the population of these Eastern European countries but reported to VigiBase more clozapine ADRs by 89-fold and clozapine fatal outcomes by almost 300-fold. CONCLUSION: Clozapine is under-utilized in Eastern European countries. Introducing individualized clozapine treatment schedules may help to maximize clozapine benefits and safety. Major improvement is needed in reporting clozapine ADRs and fatal outcomes in Eastern European countries.

Clozapine prescription rates in Southeast Europe: A cross-sectional study.

Introduction: International reports indicate that clozapine is under prescribed. Yet, this has not been explored in Southeast European (SEE) countries. This cross-sectional study investigates clozapine prescription rates in a sample of 401 outpatients with psychosis from Bosnia and Herzegovina, Kosovo by United Nations resolution, North Macedonia, Montenegro and Serbia. Methods: Descriptive analysis was used to explore clozapine prescription rates; daily antipsychotic dosage was calculated and converted into olanzapine equivalents. Patients receiving clozapine were compared to those not receiving clozapine; next those that were on clozapine monotherapy were compared to those who were on clozapine polytherapy regime. Results: It was showed that clozapine was prescribed to 37.7% of patients (with cross-country variation: from 25% in North Macedonia to 43.8% in Montenegro), with average dose of 130.7 mg/daily. The majority of patients on clozapine (70.5%) were prescribed at least one more antipsychotic (the most frequent combination was with haloperidol). Discussion: Our findings suggested that clozapine prescription rate in SEE outpatients is higher than in Western Europe. The average dose is significantly below the optimal therapeutic dosage recommended by clinical guidelines, and clozapine polytherapy is common. This might indicate that clozapine is prescribed mainly for its sedative effect rather than antipsychotic. We hope that this finding will be taken up by relevant stakeholders to address this non-evidence-based practice.

Corrigendum: Structure of Negative Symptoms in Schizophrenia: An Unresolved Issue.

[This corrects the article DOI: 10.3389/fpsyt.2021.785144.].

Intergeneration Transmission of Violence in Forensic Patients With a Diagnosis of Schizophrenia and Psychosis: Was Parental Alcoholic Abuse a Significant Factor?

Background: Child abuse during childhood and the presence of parental alcohol abuse increase the risk of developing mental illness in children, as well as the risk of violent behavior in adulthood. The association of these factors has not been sufficiently investigated when it comes to forensic mental patients. In this study, we examined the impact of traumatic events in childhood and the presence of mental illness and alcohol abuse of parents in subjects with psychosis and schizophrenia who committed serious crimes. Methods: One-hundred and forty-three respondents were included in the current study. Information on childhood abuse was collected by Childhood Trauma Questionnaire (CTQ). The sample included participants diagnosed with psychotic disorders and schizophrenia with a history of violent behavior (PSCH-V, n = 20), patients diagnosed with psychotic disorders and schizophrenia without a history of violent behavior (Non-V-PSCH, n = 51), and healthy control patients (HC, n = 72). Participants were diagnosed according to the ICD 10 classification system. MINI and CAINS scales were used to confirm the diagnosis. Data on sociodemographic and clinical characteristics were collected. Differences between groups in terms of traumatic events in childhood as well as parental alcohol abuse are presented and analyzed, using descriptive statistical values and nonparametric techniques of inferential statistics. Results: Statistically significant differences were obtained for total scores (χ2 = 28.522, p < 0.001) as well as for (1) major upheaval between the parents (χ2 = 20.739, p < 0.001), (2) being victim of violence-other than sexual (χ2 = 12.701, p < 0.01), and (3) other major upheaval that may have shaped life or personality significantly (χ2 = 30.920, p < 0.001). PSCH-V, compared to HC, had greater exposure to all of the three domains of childhood trauma (U = 396.500, 436.500, and 376.000, respectively; p < 0.001). Similar results were obtained when Non V-PSCH were compared with HC (U = 1,223.000, 1,535.000, and 999.000, respectively; p < 0.001). The results indicated statistically insignificant differences between PSCH-V and Non-V-PSCH in having a family history of mental illness. On the other hand, family history of mental illness was less present in HC compared to PSCH-V (χ2 = 24.238, p < 0.001) and Non V-PSCH (χ2 = 14.456, p < 0.001). The presence of parental alcohol abuse was predominantly present in the PSCH-V group (60%) while a significantly lower presence was found in the Non-V PSCH group (35%) and HC (5.5%). Conclusion: Both PSCH-V and Non-V-PSCH groups had a high degree of exposure to traumatic events in childhood compared to the HC. In PSCH-V, the presence of parental alcohol abuse compared to Non-V-PSCH was dominant. Mental illness coupled with a history of violent behavior represents a factor of polyvictimization, which may increase the likelihood of violent behavior of offspring.

Structure of Negative Symptoms in Schizophrenia: An Unresolved Issue.

Background: Negative symptoms are core features of schizophrenia and very challenging to be treated. Identification of their structure is crucial to provide a better treatment. Increasing evidence supports the superiority of a five-factor model (alogia, blunted affect, anhedonia, avolition, and asociality as defined by the NMIH-MATRICS Consensus); however, previous data primarily used the Brief Negative Symptoms Scale (BNSS). This study, including a calibration and a cross-validation sample (n = 268 and 257, respectively) of participants with schizophrenia, used the Clinical Assessment Interview for Negative Symptoms (CAINS) to explore the latent structure of negative symptoms and to test theoretical and data-driven (from this study) models of negative symptoms. Methods: Exploratory factor analysis (EFA) was carried out to investigate the structure of negative symptoms based on the CAINS. Confirmatory factor analysis (CFA) tested in a cross-validation sample four competing theoretical (one-factor, two-factor, five-factor, and hierarchical factor) models and two EFA-derived models. Result: None of the theoretical models was confirmed with the CFA. A CAINS-rated model from EFA consisting of five factors (expression, motivation for recreational activities, social activities, vocational, and close/intimate relationships) was an excellent fit to the data (comparative fix index = 0.97, Tucker-Lewis index = 0.96, and root mean square error of approximation = 0.07). Conclusions: This study cannot support recent data on the superiority of the five-factor model defined by the NMIH-MATRICS consensus and suggests that an alternative model might be a better fit. More research to confirm the structure of negative symptoms in schizophrenia, and careful methodological consideration, should be warranted before a definitive model can put forward and shape diagnosis and treatment of schizophrenia.

Trends in suicide mortality in Montenegro from 2000 to 2018.

BACKGROUND: This is an ecological study that analyzes suicides committed in Montenegro during the 2000-2018 period, taking into account gender, age and methods of suicide. METHODS: Suicide rates and trends up until 2009 were obtained from the official registers of Bureau of Statistics of Montenegro (MONSTAT) while the later data were obtained from the Department of Interior's. MONSTAT also provided data on unemployment and average salary. As per statistical methods, descriptive and correlations were calculated. RESULTS: The average crude suicide rate was 21.06, for males 29.93 and for females 12.42. Crude suicide rates were not associated with unemployment rate or average salary. However, the unemployment rate was significantly correlated with lethal methods of suicide, namely suicide by firearm and by hanging. Average net salary was negatively correlated with suicide by firearm. CONCLUSIONS: The ratio of males and females who committed suicide was 2.41. In the last three years, this ratio continues to rise in favor of males (reaching 4.29 in 2018). This could be explained by specific cultural features where males are expected to be the main financial contributors to the households. The labor market of Montenegro does not offer adequate opportunities to set and maintain a stable economic situation which puts additional pressure and stress on males.

Staging of Schizophrenia With the Use of PANSS: An International Multi-Center Study.

INTRODUCTION: A specific clinically relevant staging model for schizophrenia has not yet been developed. The aim of the current study was to evaluate the factor structure of the PANSS and develop such a staging method. METHODS: Twenty-nine centers from 25 countries contributed 2358 patients aged 37.21 ± 11.87 years with schizophrenia. Analysis of covariance, Exploratory Factor Analysis, Discriminant Function Analysis, and inspection of resultant plots were performed. RESULTS: Exploratory Factor Analysis returned 5 factors explaining 59% of the variance (positive, negative, excitement/hostility, depression/anxiety, and neurocognition). The staging model included 4 main stages with substages that were predominantly characterized by a single domain of symptoms (stage 1: positive; stages 2a and 2b: excitement/hostility; stage 3a and 3b: depression/anxiety; stage 4a and 4b: neurocognition). There were no differences between sexes. The Discriminant Function Analysis developed an algorithm that correctly classified >85% of patients. DISCUSSION: This study elaborates a 5-factor solution and a clinical staging method for patients with schizophrenia. It is the largest study to address these issues among patients who are more likely to remain affiliated with mental health services for prolonged periods of time.

Psychiatric comorbidities among patients with epilepsy in Montenegro.

The aim of this study was to evaluate the prevalence of psychiatric comorbidities, depression and anxiety, among patients with epilepsy in the outpatient Clinic for Epilepsy, Clinical Centre of Montenegro. Patients aged 18 and above with a diagnosis of epilepsy for at least one year were consecutively enrolled during a six-month period. Patients anonymously filled out a questionnaire which included data on the gender, age, education, marital status and degree of seizure control. The Hamilton Depression Rating Scale (HAM-D) and Hamilton Anxiety Rating Scale (HAM-A) were used to evaluate the presence or absence of anxiety and depression. Total number of study patients was 70, including 52 patients with partial seizures and 18 patients with generalized tonic-clonic seizures. The mean patient age was 37 ± 7.92 years. The prevalence of depression in our sample was 32.8%, whereas the prevalence of anxiety was 21.4%. Patients with partial seizures were more depressed, while those with idiopathic generalized seizures were more anxious (p < 0.01). Depression was associated with a lower educational level, unemployment and poor seizure control (p < 0.05). The number of antiepileptic drugs showed a trend towards negative association with depression (p = 0.005). Anxiety was associated with the level of education and uncontrolled seizures (p < 0.01). Neither depression nor anxiety was associated with age, gender, marital status, age at onset and duration of epilepsy. Psychiatric disorders among patients with epilepsy are quite common but yet under-recognized. Therefore, appropriate recognition and efficient treatment of these disorders in patients with epilepsy might improve their quality of life and could consequently lead to better treatment success.