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.

Combination With Long-Acting Injectable Antipsychotics and Utilization of Nonstandard Formulations as Compliance Enhancing Methods for Clozapine Users: A Systematic Review and A Case Series.

BACKGROUND: Combining clozapine with a long-acting injectable antipsychotic (LAI) or using different, nonstandard formulations of the compound may improve treatment outcomes. We aimed to investigate the utility of the clozapine-LAI combination and different formulations of clozapine for compliance problems of clozapine treatment, and to describe a case series on the combined treatment. PROCEDURES: We conducted a PubMed search with no date restriction. The number and length of hospitalizations, the results of clinical scales, and adverse events were recorded. We also present a case series of 18 patients using the clozapine-LAI combination. Data were collected from the medical charts and electronic records. RESULTS: We extracted 9 records describing the use of the clozapine-LAI combination. The case reports and mirror-image studies showed a significant reduction in the number of hospitalizations, length of hospital stays, and number of visits to the emergency department on the combined treatment with no serious adverse events. We included 11 articles for clozapine formulations. The case reports and retrospective data suggested that short-acting intramuscular clozapine was often well tolerated and resulted in an increased acceptance of oral clozapine in the acute phase of illness. In our case series, illness severity and the number of hospitalization per year significantly decreased after the combined treatment, besides a significant improvement in the functioning scores. Hyperprolactinemia and extrapyramidal side effects were reported due to concomitant LAIs. CONCLUSIONS: Despite the encouraging evidence, the present data are preliminary and mostly based on retrospective studies, and oral-dissolving tablets or oral liquid formulations of clozapine have insufficient evidence for clinical practice. Well-designed, controlled, follow-up studies are needed for both clozapine-LAI combination and different formulations of clozapine.

Renal effects of long-term lithium therapy, revisited.

OBJECTIVE: The aim of this study was to investigate the effect of lithium treatment on renal function and to determine influencing factors. In addition, the utility of spot urine protein/creatinine ratio in detection of lithium induced nephropathy was also investigated. METHODS: Serum concentrations of lithium, blood urea nitrogen (BUN), creatinine, estimated glomerular filtration rate (eGFR), and urinalysis including protein/creatinine ratio were measured in 375 patients using lithium. RESULTS: Patients taking lithium for ≥8 years had higher BUN, creatinine levels, percentage of proteinuria, percentages of stage 2 and 3 chronic kidney disease (CKD); lower urine density and eGFR compared to patients taking lithium <8 years. Urine density was lower in groups with >0.8 and 0.6-0.8 mmol/L lithium level than <0.6 mmol/L. Predictors of CKD were serum level of lithium, dose of lithium, cumulative duration of lithium use, age at onset of illness, and caffeine consumption. CONCLUSIONS: Detrimental effects of lithium on renal functions were detected after lithium use for ≥8 years. Proteinuria measured by spot urine protein/creatinine ratio can be detected even when eGFR is >90 ml/min/1.73 m2 . Spot urine protein/creatinine ratio, which is a cost-effective and practical laboratory test, can be used to monitor lithium-treated patients.

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.

A follow-up study of metabolic syndrome in schizophrenia.

The prevalence of metabolic syndrome (MetS) in schizophrenia patients is increasing worldwide. The aim of the current study was to examine the progress of MetS in a schizophrenia cohort we had previously investigated and determine the role of various related factors, including sociodemographic and clinical variables, nutritional status and physical activity. Of the 319 patients investigated in the first study, 149 patients agreed to be included in the follow-up. Physical measurements and laboratory tests were performed in addition to evaluations with the Positive and Negative Syndrome Scale, Udvalg for Kliniske Undersogelser Side Effects Scale, International Physical Activity Questionnaire, 24 h dietary recall method and Nutrition Information Systems Package Program. According to the ATPIII, ATPIIIA and IDF criteria, the MetS prevalences had increased from 35.6 to 44.3%, 38.9 to 53% and 43.6 to 55.7%, respectively. Patients with MetS had a shorter period of hospitalization and a higher UKU total side effects score, and most of them were married or divorced/widowed. Patients with MetS also had a higher daily consumption of added sugar, cholesterol, polyunsaturated fatty acids and omega 3 fatty acid, and the daily added sugar intake was found to be related to the increase in MetS. Unexpectedly, the physical activity level was not found to significantly differ in the patients with and without MetS. In conclusion, the MetS prevalence was found to be increased among schizophrenia patients over time, and the increase in the young age group was particularly striking. Among all of the factors investigated, nutritional status was found to play a major role in this increased prevalence.

Relation of the Allelic Variants of Multidrug Resistance Gene to Agranulocytosis Associated With Clozapine.

Clozapine use is associated with leukopenia and more rarely agranulocytosis, which may be lethal. The drug and its metabolites are proposed to interact with the multidrug resistance transporter (ABCB1/MDR1) gene product, P-glycoprotein (P-gp). Among various P-glycoprotein genetic polymorphisms, nucleotide changes in exons 26 (C3435T), 21 (G2677T), and 12 (C1236T) have been implicated for changes in pharmacokinetics and pharmacodynamics of many substrate drugs. In this study, we aimed to investigate the association between these specific ABCB1 polymorphisms and clozapine-associated agranulocytosis (CAA). Ten patients with a history of CAA and 91 control patients without a history of CAA, despite 10 years of continuous clozapine use, were included. Patient recruitment and blood sample collection were conducted at the Hacettepe University Faculty of Medicine, Department of Psychiatry, in collaboration with the members of the Schizophrenia and Other Psychotic Disorders Section of the Psychiatric Association of Turkey, working in various psychiatry clinics. After DNA extraction from peripheral blood lymphocytes, genotyping was performed using polymerase chain reaction and endonuclease digestion. Patients with CAA had shorter duration of clozapine use but did not show any significant difference in other clinical, sociodemographic characteristics and in genotypic or allelic distributions of ABCB1 variants and haplotypes compared with control patients. Among the 10 patients with CAA, none carried the ABCB1 all-variant haplotype (TT-TT-TT), whereas the frequency of this haplotype was approximately 12% among the controls. Larger sample size studies and thorough genetic analyses may reveal both genetic risk and protective factors for this serious adverse event.

A systematic chart review of pharmacological interventions in patients with clozapine-induced hypersalivation.

OBJECTIVES: To investigate the efficacy and tolerability of medications, such as mouthwash use of 1 % atropine sulfate and tropicamide drops, oral amitriptyline and amisulpride used for clozapine-induced hypersalivation (CIH). METHODS: The medical charts of inpatients with psychotic disorders between 2010 and 2022 were reviewed retrospectively. We detected 161 patients with eligible data who received or commenced clozapine. Primary outcome was defined as the percentage change in the diameter of a wet patch on the pillow (DWP) for improvements in CIH. RESULTS: The frequency of CIH was 42 % (n = 68). The first step medications for CIH were tropicamide drops (49 %), atropine drops (43 %) and amitriptyline (3 %). After the first step, the median DWP significantly decreased by -33 %. During the index hospitalization, in 18 patients with persistent CIH, the median DWP significantly decreased by -42 % with the second step medications which also included amisulpride. There were no reported serious adverse events. The change in DWP was significantly correlated with the duration of clozapine treatment (r = 306) and clozapine serum level at discharge (r = 0.294). A linear regression model showed a link between the change in DWP and reduced Positive and Negative Syndrome Scale scores. CONCLUSIONS: Our findings emphasize that mouthwash use of atropine or tropicamide drops has a satisfying and tolerable effect in treating CIH. Switching medications for CIH seems to be effective when CIH persists despite a first step agent. Controlled follow-up studies are needed to understand the relationship between CIH, clozapine serum levels, illness severity, and functioning.

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.

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).

Valproate, obesity and other causes of clozapine poor metabolism in the context of rapid titration may explain clozapine-induced myocarditis: A re-analysis of a Turkish case series.

INTRODUCTION: Clozapine-induced myocarditis or any clozapine-induced inflammation may be a hypersensitivity reaction due to titration that was too rapid for the patient's clozapine metabolism. Clozapine metabolism is influenced by ancestry, sex, smoking and the presence of confounders including obesity, infections, and inhibitors (e.g., valproate) causing the patient to behave as a clozapine poor metabolizer (PM). A published study in a Turkish hospital identified 1 case of clozapine-induced pancreatitis and hepatitis and 9 cases of clozapine-induced myocarditis. To explore the hypothesis that the 10 patients were clozapine PMs, their serum clozapine concentrations were investigated using concentration-to-dose (C/D) ratios and their titrations carefully reviewed. METHODS: Dividing the trough serum concentration by the dose produces the clozapine C/D ratio. The dose required to reach 350ng/ml was considered the minimum therapeutic dosage and was used to classify patients according to clozapine PM status. Titration speed was assessed. RESULTS: All 10 patients were possibly clozapine PMs (3 of them had as minimum therapeutic doses: 72, 82 or 83mg/day). Nine of the 10 patients may have behaved as clozapine PMs due to obesity and/or valproate co-prescription during titration. One also had an undiagnosed infection. Of the 10 patients, 9 had at least 1 of 3 factors: too-rapid titration in the first or second weeks, or a final dosage that was too high. CONCLUSIONS: Future studies using clozapine levels and considering the role of clozapine PM status should explore whether or not all cases of clozapine-induced inflammation could be explained by lack of individualized titration.

[Augmentation of Clozapine Due to Inadequate Treatment Response in Schizophrenia: Comparison of Patients with Augmented and Non-augmented Treatments]. / Sizofrenide Klozapine Yetersiz Yanit Nedeniyle Tedavi Güçlendirme: Güçlendirme Yapilan ve Yapilmayan Hastalarin Karsilastirilmasi.

OBJECTIVE: Clozapine is considered to be a gold standard antipsychotic in treatment resistant schizophrenia. This study aims to investigate clozapine augmentation METHODS utilized in schizophrenia and compare the sociodemographic characteristics, clinical features and remission states of patients whose treatments are augmented and not. METHOD: This study included 122 outpatients diagnosed with DSMIV schizophrenia. Patients were assessed with the Structured Clinical Interview for DSM-IV Axis I Disorders, Positive and Negative Syndrome Scale, Clinical Global Impression Scale, Global Assessment of Functioning, Calgary Depression Scale for Schizophrenia, Panic Agoraphobia Scale, Yale-Brown Obsessive Compulsive Scale and the World Health Organization Disability Assessment Schedule II. The remission state of the patients was assessed utilizing the Remission in Schizophrenia Working Group criteria for schizophrenia. RESULTS: Combined antipsychotic drug use was the most prevalent method utilized for clozapine augmentation. Patients on augmentation treatment were on higher daily clozapine doses and their remission rates were lower. In addition, the severity of psychopathology related with schizophrenia and comorbid symptoms, the level of functioning and disability were worse in this particular patient group. History of antipsychotic combination use prior to clozapine was found to predict the future use of clozapine augmentation. CONCLUSION: Adding a second antipsychotic seems to be the most common method of augmenting clozapine treatment in schizophrenia. The group of patients whose clozapine treatment is augmented appears to represent a "more difficult to treat" patient group before clozapine is initiated.

Common Side Effects and Metabolic Syndrome due to Clozapine: Relationship with the Clinical Variables and Disability. / Klozapine Bagli Sik Görülen Yan Etkiler ve Metabolik Sendrom: Klinik Degiskenlerle ve Yetiyitimiyle Iliskisi.

OBJECTIVE: Common side effects of clozapine may affect the treatment process negatively. In this study, we aimed to assess the common side effects and the prevalence of metabolic syndrome in schizophrenia patients treated with clozapine, and to study their relationship with clinical variables and disability. METHOD: One hundred and twenty two patients who met DSM-IV criteria for schizophrenia, and were on clozapine treatment were included in the study. Clinical status was evaluated through a clinical interview and review of the medical records, and physical measures and laboratory tests were recorded. Patients were assessed with the Structured Clinical Interview for DSM-IV Axis I Disorders, UKU (Udvalg for Kliniske Undersogelser) Side Effect Rating Scale, World Health Organization (WHO)-Disability Assessment Schedule II, Positive and Negative Syndrome Scale, Global Assessment Scale, Clinical Global Impression Scale. RESULTS: Common side effects of clozapine were hypersalivation, fatigue, sedation and constipation. The relationship between constipation and clozapine dose, and dizziness and norclozapine plasma levels were significant. The prevalence of metabolic syndrome was 50%, and patients with metabolic syndrome had higher means of age and lifetime cigarette consumption. Disability was positively correlated with the severity of psychopathology and the number of side effects, and negatively correlated with the age at onset of illness. Severity of the psychopathology and the number of side effects predicted the severity of the disability. CONCLUSION: Clozapine was associated with various side effects and half of the patients had metabolic syndrome. Assessment of common side effects due to clozapine is important for reducing disability.

The Effect of Life Skills Training on Functioning in Schizophrenia: A Randomized Controlled Trial. / Sizofrenide Yasam Becerileri Egitiminin Islevsellige Olan Etkisi: Seçkisiz Kontrollü Bir Çalisma.

OBJECTIVE: Psychosocial approaches including occupational therapeutic interventions constitute an important part of mental health treatments. This research was planned to investigate the effects of individualized life skills training on the functionality of individuals diagnosed with schizophrenia. METHOD: A total of 32 individuals diagnosed with schizophrenia were assigned randomly to the study (n=15) and the control groups (n=17). The participants were evaluated with the Positive and Negative Syndrome Scale for symptom severity, the Clinical Global Impression Scale for illness severity and improvement and response to treatment, the Katz Index of Independence in Activities of Daily Living and the Lawton - Brody Instrumental Activities of Daily Living Scale for adequacy of performance of basic activities and tasks of daily living, the Functioning Assessment Short Test and Social Functioning Scale for assessing the level of functionality before and after the scheduled interventions for both groups. The control group received a singlesession awareness training to increase independence in daily living activities and the study group received individualized life skills training in 2 sessions per week for 8 weeks (=16 sessions). RESULTS: At the end of the research program, improvements were observed in the negative symptoms, general psychopathology, severity of illness and independence in basic and instrumental activities of daily living and functioning in the study group as compared to the control group. CONCLUSION: On the basis of the obtained results, we believe that the individualized life skills training may be an effective therapeutic method for the rehabilitation of individuals diagnosed with schizophrenia. The results of our study should be supported by long-term follow-up studies.

Semantic memory deficits based on category fluency performance in schizophrenia: similar impairment patterns of semantic organization across Turkish and Japanese patients.

Patients with schizophrenia exhibit a wide range of cognitive dysfunction, including impairments in semantic memory and verbal fluency. Previous studies report that semantic memory, i.e. associated meaning of words or knowledge, is specifically disorganized in patients who use the English or Japanese language. The purpose of the present study was to determine if semantic memory, as evaluated by verbal fluency data, shows similar patterns of semantic disorganization in non-English-speaking patients who do (Turkish) or do not (Japanese) use an alphabetical language. Turkish (N=20) and Japanese (N=22) patients with schizophrenia, as well as Japanese normal controls (N=22), entered the study. As a measure of semantic memory organization, two types of cluster analyses, i.e. ADDTREE and hierarchical cluster analysis, were performed on category fluency task data. The cluster analyses revealed a greater similarity between the Turkish patients vs. Japanese patients comparison than the Japanese patients vs. Japanese controls comparison. The results provide further support to the concept that impaired semantic memory organization is one of the core features of schizophrenia, and is independent of the language system or cultural backgrounds.

Augmentation of Antipsychotic Treatment with Memantine in Patients with Schizophrenia: A Systematic Review and Meta-Analysis. / Sizofreni Hastalarinda Antipsikotik Tedavinin Memantin ile Güçlendirilmesi: Bir Sistematik Gözden Geçirme ve Metaanaliz.

OBJECTIVE: Many patients with schizophrenia respond partially to treatment with antipsychotic medications. A wide range of pharmaceutical agents are utilized as augmentation therapy in order to increase the efficacy of antipsychotic medication treatment. Memantine which is a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist is one such agent among these. In this study, by conducting a systematic review and meta-analysis we aimed to assess the efficacy of memantine augmentation on psychopathology in patients with schizophrenia receiving antipsychotic medication. METHOD: We analyzed double-blind, randomized, placebo-controlled trials of memantine add-on treatment in schizophrenia patients receiving antipsychotic medications. The primary outcome measure was amelioration of negative symptoms and the secondary outcome measures were amelioration of positive, total and general psychopathology symptoms. Publication bias was evaluated by Funnel plot and Egger test. RESULTS: Eleven studies (n=570) were included. Although memantine add-on treatment was superior to placebo for ameliorating negative symptoms (SMD=0.596, 95% CI=0.075-1.118, p=0.025), there were no statistically significant differences in the amelioration of general psychopathology (SMD=0.034, 95% CI=0.419-0.488, p=0.883), positive (SMD=-0.041, 95% CI=0.217-0.135, p=0.650) and overall (SMD=0.315, 95% CI=0.256-0.887, p=0.280) symptoms. No publication bias was observed between studies according to Funnel plots and Egger test results. CONCLUSION: Memantine augmentation treatment seems to be beneficial for particularly treating negative symptoms in schizophrenia patients. Further studies with larger sample size and longer follow-up durations are needed.

A comparative study of detection of myocarditis induced by clozapine: With and without cardiac monitoring.

The aim of this study was to investigate and compare the incidence of suspected or definite cases of clozapine induced myocarditis (SDM) and clinical factors which could influence its onset in two different time periods, defined by pre- and post-cardiac monitoring at an inpatient setting, during the initiation phase of clozapine treatment. Hospital records of patients started on clozapine in the inpatient unit between 2011 and 2018 were investigated. Eight in 38 patients (11.3%) were classified as SDM after the initiation of the monitoring protocol, whereas only 1 in 33 patients (1.4%) was classified as SDM, before. Monitored and non-monitored patient groups were similar with regard to demographic and clinical variables. Diagnosis of schizoaffective disorder and use of concominant lithium, valproic acid and atypical antipsychotics were higher in patients with SDM, while clozapine dose titration was similar compared to the rest of the patients. Cardiac monitoring seems to be the main factor leading to the increase in the detection of clozapine induced myocarditis (CIM). If not monitored, the outcome of CIM can be fatal without any warning signs and symptoms. Concominant use of mood stabilizers including valproic acid and lithium, are important risk factors for the development of CIM.