Clozapine In Patients Research Articles

Retrospective evaluation of sociodemographic and clinical characteristics of patients with schizophrenia receiving clozapine monotherapy and clozapine combined with different antipsychotics

IntroductionSchizophrenia is a chronic mental disorder and clozapine is an atypical antipsychotic that can be used in treatment-resistant schizophrenia patients. However, treatment-resistant schizophrenia may also include patients with an inadequate response to clozapine.ObjectivesIn our study, we retrospectively analysed the sociodemographic and clinical characteristics of patients receiving clozapine monotherapy and patients receiving clozapine in combination with different antipsychotics. In this way, we aimed to evaluate the factors that influence the response to clozapine.MethodsClozapine monotherapy and clozapine in combination with different antipsychotics were identified by retrospective chart review of patients followed up at the Schizophrenia and Other Psychotic Disorders Outpatient Clinic, Department of Psychiatry, Faculty of Medicine, Selçuk University. Sociodemographic and clinical characteristics were recorded and subjected to statistical analysis. The study was approved by the Ethics Committee of Selçuk University.Results Of the 143 patients whose data were analysed, 60 (42%) were female. The mean age of the patients was 40.2±12.0 years and the mean duration of training was 10.4±4.3 years. 62 patients (43.4%) used long-acting antipsychotics. 90 patients (62.9%) were using clozapine, 52 (36.4%) were using clozapine as monotherapy, 5 (3.5%) were using clozapine together with another oral antipsychotics drug, and 33 (23.1%) were using clozapine together with a long-acting antipsychotic. No statistically significant difference was found when comparing mean age, age at first antipsychotic initiation, age at clozapine initiation and mean clozapine dose between patients using clozapine monotherapy (n=52) and patients using different antipsychotics in combination with clozapine (n=38). When the two groups were compared, a significant difference was found in the mean number of antipsychotics used before starting clozapine and the mean number of hospitalisations, with a lower number in the monotherapy group (3.1±1.4 vs 4.1±2.0, p=0.01 and 2.8±2.2 vs 4.5±3.2, p=0.006, respectively).ConclusionsIt is important to assess the concept of treatment resistance appropriately in the treatment of schizophrenia patients. The results of our study suggest that starting clozapine treatment promptly in treatment-resistant patients may increase the likelihood that patients will benefit from clozapine and reduce the need for additional treatments. Although our data and criteria for evaluating response to treatment are limited, it is important to draw attention to the clinical results of proceeding in accordance with the guidelines in the treatment of schizophrenia. Evaluating the response to clozapine treatment needs studies with stronger data and larger sample sizes.Disclosure of InterestNone Declared

Clozapine clinical toolkit optimizes inpatient clozapine monitoring.

Clozapine is the most effective antipsychotic in the management of treatment-resistant schizophrenia; however, its use is challenging due to the risk of severe adverse effects. Despite the risks associated with clozapine, there is no mandatory monitoring in Canada beyond hematologic testing for agranulocytosis surveillance. This study focuses on the development, implementation, and evaluation of a clozapine clinical toolkit (CTK) targeted at optimizing inpatient clozapine use. A comprehensive literature review was conducted to identify clozapine best practices, experts were consulted, and a comprehensive clozapine CTK was developed and implemented at a large Canadian tertiary hospital in December 2018. To evaluate the CTK, a retrospective chart review was conducted to assess for change in guideline-concordant monitoring pre- and post- CTK implementation. Patients were included if they were > 18 years of age and received clozapine during inpatient admission. Results were analyzed using descriptive and inferential statistics. Among the charts reviewed, 185 and 113 admissions met the pre- and post-CTK inclusion criteria, respectively. Staff used the CTK in the care of 96% of clozapine patients post implementation, and its use resulted in improvements in guideline-concordant monitoring for agranulocytosis and myocarditis. Implementation of the clozapine CTK increased the concordance of clozapine monitoring with best practice recommendations. Future research is necessary to assess the impact of the CTK on clinical outcomes and patient satisfaction.

Change in absolute neutrophil count after COVID-19 infection in patients using clozapine versus other antipsychotics.

It was reported that patients who contracted COVID-19 while taking clozapine exhibited a distinct hematological response. However, the absence of control groups made it difficult to attribute it to clozapine. The changes in absolute neutrophil counts (ANCs) during the 4 weeks after COVID-19 infection were compared between the two groups of patients with severe mental illnesses (SMIs) (49 patients using clozapine and 54 using other antipsychotics) using generalized additive modeling. Although the pattern of a transient drop in ANC followed by gradual recovery could be demonstrated in both groups, it was more pronounced in the clozapine group ( P = 0.00025). Nevertheless, overall ANC remained at a higher level in the clozapine group. The results suggested potential interaction between clozapine and COVID-19 at the level of hematological dynamics. However, it did not necessarily indicate that such interaction is inevitably harmful or dangerous. It was more of a concern that some patients using other antipsychotics exhibited decreased ANC, which did not easily recover. Traditionally, clinicians have been concerned about the worsening of hematological side effects in clozapine patients after COVID-19 infection. However, the obtained result highlighted the necessity of hematological monitoring in patients using any type of antipsychotics for SMIs.

B-335 Rapid Quantitative Clozapine Measurements at the Point-of-Care Using Capillary Blood

Abstract Background Clozapine is the most effective medication for treatment-resistant schizophrenia, and is endorsed in professional guidelines. Therapeutic drug monitoring (TDM) is recommended for Clozapine due to high pharmacokinetic variability and risk of adverse drug reactions. The effectiveness of TDM for managing clozapine patients is limited by the lack of immediate results. Methods A novel immunoassay, the MyCare Insite Clozapine Test (MCI), was developed that uses 20 µL of capillary blood (CP) and delivers 7-minute quantitative results for a portable point-of-care (POC) device. To validate the MCI system, matching CP and serum samples were collected from 113 patients at two sites. CP was tested immediately with MCI and compared to serum immunoassay results on a Beckman-Coulter AU480 analyzer. Precision was evaluated using three whole blood spiked samples and two assay controls over five days with five replicates per day. Results The figure shows a correlation plot evaluated by Passing-Bablok regression of the POC MCI (y-axis) and the Beckman analyzer (x-axis). The regression line was y = 1.05*x + 1.4 ng/L, r = 0.927, indicating good agreement. Precision studies demonstrated that repeatability was ≤11% and within-lab precision was ≤13%. Conclusion Quantitative Clozapine results are available in 7 min using CP in a portable POC device. A rapid POC alternative can achieve timely patient results in many testing environments. Rapid Clozapine testing has the potential for expanding utilization of this important drug by providing actionable POC results.

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

BackgroundUp 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. MethodsThese 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. ResultsThe 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). ConclusionProspective studies should further explore these proposed clozapine indices in average patients, poor metabolizers (3 presented) and ultrarapid metabolizers (2 presented).

Adverse drug reactions and their fatal outcomes in clozapine patients in VigiBase: Comparing the top four reporting countries (US, UK, Canada and Australia)

BackgroundPharmacovigilance findings and box warnings in the clozapine package inserts have marked the history of clozapine. ObjectiveThis is the largest review of clozapine adverse drug reactions (ADRs) and their associated fatal outcomes. Reports to the World Health Organization's global pharmacovigilance database, VigiBase™, were analyzed, extending from clozapine's introduction to December 31, 2022. MethodsThe analysis focused on the top four reporting countries: United States (US), United Kingdom (UK), Canada and Australia (83 % of fatal outcomes worldwide). Attempts were made to control for population and clozapine prescription in each country. ResultsClozapine ADRs worldwide accounted for 191,557 reports, with the highest number (53,505) in “blood and lymphatic system disorder”. Of the 22,596 fatal outcomes reported in clozapine patients, 9587 were from the US, 6567 from the UK, 3623 from Canada and 1484 from Australia. The top category worldwide in fatal outcomes was nonspecifically labeled “death” with 46 % (range 22–62 %). “Pneumonia” was second with 30 % (range 17–45 %). Agranulocytosis was numerically only the 35th top clozapine ADR associated with fatal outcomes. On average, 2.3 clozapine ADRs were reported per fatal outcome. Infections were associated with 24.2 % of the UK fatal outcomes (9.4 %–11.9 % in the 3 other countries). ConclusionsThe four countries appeared to report clozapine ADRs in different ways, making comparisons difficult. We estimated higher fatal outcomes in the UK and Canada after controlling for cross-sectional estimations of population and published clozapine use. This last hypothesis is limited by the lack of precise estimation of accumulated clozapine use in each country.

Escaping the Long Shadow Cast by Agranulocytosis: Reflections on Clozapine Pharmacovigilance Focused on the United Kingdom.

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. 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. 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. 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.

The Role of Myeloperoxidase in Clozapine-Induced Inflammation: A Mechanistic Update for Idiosyncratic Drug-Induced Agranulocytosis.

The risk of idiosyncratic drug-induced agranulocytosis (IDIAG) markedly constrains the use of clozapine, a neuroleptic with unparalleled efficacy. Most clozapine patients experience an early inflammatory response, likely a necessary step in IDIAG onset. However, most patients do not progress to IDIAG, presumably because of the requirement of specific human leukocyte antigen (HLA) haplotypes, T cell receptors, and other unknown factors. We established that clozapine activates inflammasomes and that myeloperoxidase bioactivation of clozapine generates neoantigens, but the connection between these early mechanistic events remained unknown and, thus, was the aim of this work. We found that the myeloperoxidase inhibitor PF-1355 attenuated myeloperoxidase activity in phorbol myristate acetate (PMA)-differentiated THP-1 macrophages, and it also attenuated clozapine-induced release of inflammatory mediators (e.g., IL-1β, CXCL1, and C-reactive protein). In vivo, pretreatment of Sprague Dawley rats with PF-1355 significantly attenuated clozapine-induced increases in neutrophil mobilization from the bone marrow to the blood and spleen, as determined using differential blood counts and flow cytometry. Moreover, the clozapine-triggered release of inflammatory mediators (e.g., IL-1β, calprotectin, CXCL1, and α-1-acid glycoprotein) from the liver, spleen, and bone marrow was dampened by myeloperoxidase inhibition. These data support the working hypothesis that oxidation of clozapine to a reactive metabolite by myeloperoxidase is critical for induction of the inflammatory response to clozapine. Ultimately, a better mechanistic understanding of the early events involved in the immune response to clozapine may elucidate ways to prevent IDIAG, enabling safer, more frequent therapeutic use of this and potentially other highly efficacious drugs.

Haematological point of care testing for clozapine monitoring

BackgroundClozapine treatment requires regular full blood counts (FBC) because of the risk of agranulocytosis. Traditionally, FBCs use venous blood samples but the need for frequent venepuncture adversely affects adherence. We investigated the utility of a point of care testing (POCT) finger prick method for clozapine patients. MethodPatients being treated with clozapine, who were having a venous blood sample taken for haematological monitoring, also provided a fingerprick capillary blood sample. The PixCell HemoScreen® POCT analyser was used to test both the capillary and venous samples, and the venous sample was also tested using a standard laboratory method. ResultsWe completed FBCs on 226 patients. We found strong correlations between the results from the standard laboratory venous method and the POCT capillary and venous assays for WBC (R = 0.96 & R = 0.99), neutrophils (R = 0.96 & R = 0.97) and eosinophils (R = 0.94 & R = 0.94). Compared with the standard laboratory venous blood method, mean biases for capillary blood POCT method were −0.56 × 109/L for WBC, −0.39 × 109/L for neutrophils, and −0.01 × 109/L for eosinophils. Mean biases for venous blood POCT method were −0.004 × 109/L for WBC, −0.28 × 109/L for neutrophils, and 0.01 × 109/L for eosinophils. Of the 226 patients tested, 10 (4.4%) had levels below clozapine monitoring thresholds (WBC <3.5 × 109/L and Neutrophils <1.5 × 109/L) by capillary blood, and 4 (1.8%) by venous blood by POCT. The standard laboratory method showed 3 of these to be sub-threshold. All cases of neutropenia were identified by capillary and venous POCT. ConclusionThe PixCell HemoScreen® POCT analyser provided results that were comparable with those from a standard venous blood laboratory method for WBC, neutrophil and eosinophil counts. The availability of an accurate capillary monitoring method may result in increased clozapine uptake and better clozapine adherence.

Clozapine-associated myocarditis in the World Health Organization's pharmacovigilance database: Focus on reports from various countries

IntroductionThe incidence of clozapine-associated myocarditis varies by country. These variations were explored in VigiBase, the World Health Organization's global database which has >25 million spontaneously reported adverse drug reaction (ADR) reports from 145 national drug agencies. MethodsOn January 15, 2021, a search of VigiBase since inception focused on myocarditis in clozapine patients. The 3572 individual reports were studied using the standard VigiBase logarithmic measure of disproportionality called information component (IC). The IC measures the disproportionality between the expected and the reported rates. After duplicates were eliminated there were 3274 different patients with myocarditis studied in logistic regression models. ResultsThe first case was published in 1980 but since 1993 the VigiBase clozapine-myocarditis IC has been significant; moreover, currently it is very strong (IC=6.0, IC005–IC995=5.9–6.1) and statistically significantly different from other antipsychotics. Of the 3274 different patients with myocarditis, 43.4% were non-serious cases, 51.8% were serious but non-fatal, and 4.8% were fatal. More than half (1621/3274) of the reports came from Australia, of which 69.2% were non-serious, 27.7% serious but non-fatal, and 3.1% fatal. Asian countries contributed only 41 cases. ConclusionsIn pharmacovigilance studies, confounding factors may explain statistical associations, but the strength and robustness of these results are compatible with the hypothesis that myocarditis is definitively associated with early clozapine treatment (84% [1309/1560] and 5% [82/1560] in the first and second months). Myocarditis reports from Australia are over-represented to a major degree. Asian countries may be underreporting myocarditis to their drug agencies.

A Covid-19 outbreak in a Spanish long-term psychiatric hospital led to infections in 6 clozapine patients: elevations in their plasma clozapine levels.

A Covid-19 outbreak in a Spanish long-term psychiatric hospital led to infections in 6 clozapine patients: elevations in their plasma clozapine levels.

Distinctive pattern of neutrophil count change in clozapine-associated, life-threatening agranulocytosis

The wider use of clozapine is limited by the risk of agranulocytosis and the associated requirement for monitoring of neutrophil counts. We searched local electronic patient records for cases of agranulocytosis occurring during clozapine treatment during the period 2007–2020. We found 23 episodes recorded as agranulocytosis in clozapine patients. Of these, nine met pre-defined criteria and were considered episodes of life-threatening agranulocytosis (LTA). These episodes of clozapine-induced LTA exhibited a distinct pattern of continuous and rapid neutrophil count decline to zero or near zero. Mean time for neutrophils to fall from ANC > 2 to ANC <0.5 × 109/L was 8.4 days (range 2–15 days). Each event was also characterised by a prolonged nadir and delayed recovery (range 4–16 days). Non-LTA episodes were, in contrast, brief and benign. We conclude that an important proportion of cases of agranulocytosis identified in people prescribed clozapine are not life-threatening and may not even be clozapine-related. Monitoring schemes should aim to identify true clozapine-induced LTA as opposed to threshold-defined nominal agranulocytosis. Genetics studies might benefit from examining associations with clozapine-induced LTA rather than with recorded cases of agranulocytosis or neutropenia.

Reasons for admission to a general medical hospital for patients taking clozapine.

Clozapine is associated with a diverse range of side effects. In addition, patients prescribed clozapine commonly suffer with medical comorbidities. This study aimed to characterise patients prescribed clozapine who required medical admission, understand reasons for admission, identify areas for interventions to prevent future admission and describe clozapine management during the inpatient stay. We conducted a retrospective analysis of patients prescribed clozapine who were admitted to a general medical hospital in a 12-month period. Data were collected using electronic drug charts and notes. In total, 114 clozapine patients were hospitalised. Twenty-eight patients (25%) were admitted because of infection, 12 (11%) were elective admissions and 12 (11%) had gastrointestinal problems. Most patients admitted were Black (54%) and half were female. Few changes were made to clozapine dosing on admission or during the inpatient stay. Most patients had been taking clozapine for many years at the point of admission, the majority were able to continue taking it for the duration of their medical treatment and were discharged on the same dose they were taking prior to admission. Clozapine plasma concentrations were not consistently measured with only 18 (16%) patients having one or more plasma concentrations determined during their admission. The median clozapine plasma concentration on admission was 0.48 mg/L (nor-clozapine 0.21 mg/L), with a range of 0.09 to 3.9 mg/L. Three patients were admitted to the intensive care unit during their admission; all were discharged on clozapine. Four patients died; one from lung adenocarcinoma, one bowel obstruction, one cardiac arrest and one chest sepsis. In total, 27 patients (23%) had their clozapine stopped on admission, 6 (22% of this group) unintentionally. Our study found that the most common reason for admission for patients taking clozapine was infection. Plasma concentrations were not measured routinely despite clozapine having a narrow therapeutic index and enhanced potential for toxicity in the medically unwell patient.

Predictors of functioning and clinical outcomes in inpatient with schizophrenia on clozapine augmented with antipsychotics.

We aimed at exploring predictors of improvement in clinical and functional outcomes of patients on clozapine with chronic treatment-resistant schizophrenia admitted into rehabilitation wards. In a cross-sectional study of 62 patients on clozapine augmented with oral and parenteral antipsychotics, predictors of HoNOS (Health of the Nation Outcome Scales) scores were analysed using ordinal logistic regression. Augmentation with parenteral antipsychotics was associated with lower psychotic symptom scores (OR 0.38 [95%CI 0.15, 0.99]) and activity of daily living scores (OR 0.36 [95%CI, 0.13, 0.96]) compared with oral antipsychotics. Increased age was a predictor of behavioural disturbances, physical illness and cognitive problems for all clozapine patients, and female gender was associated with the increase in depression scores. The addition of parental antipsychotics to clozapine in patients with treatment-resistant schizophrenia might have potential benefits for clinical and functional outcomes and needs a further investigation.

Metabolic profiles differences of overweight patients on olanzapine, clozapine and risperidone

AimsWe set out to examine the differences in metabolic profiles of at risk (overweight) patients across commonly used atypical antipsychotics (Olanzapine, Risperidone, Clozapine). We hypothesized that Olanzapine and Clozapine group will have more metabolic abnormalities compared to Risperidone.BackgroundCardiovascular diseases remain the leading cause of morbidity and mortality among people with schizophrenia. Since the introduction of atypical antipsychotics, there is cumulative evidence of their association with metabolic abnormalities. Clozapine and Olanzapine are known to constitute the highest metabolic risks amongst atypical antipsychotics.MethodThis study is based on the data of 67 subjects recruited into a 12-week open-labelled trial looking at the effects of adjunctive Aripiprazole in atypical antipsychotics for weight reduction and improvement in metabolic profile. Metabolic profiles including weight, waist circumference, fasting blood glucose, HbA1c, serum total, HDL and LDL cholesterol levels and triglycerides were measured at baseline. The measurements were then compared across the different subgroups of atypical antipsychotics. The definition of metabolic syndrome proposed by the Third Report of the National Cholesterol Education Program Expert Panel (Adults Treatment Panel III) was used.ResultThe atypical antipsychotics were grouped into Olanzapine (n = 27), Risperidone (n = 24) and Clozapine (n = 16). More than 50% of clozapine-treated and Olanzapine-treated overweight patients were demonstrated to have metabolic syndrome at baseline. There was a statistically significant difference in serum triglycerides (p = 0.012), LDL (p = 0.046) and HbA1c (p = 0.045) across the three groups as demonstrated by one-way ANOVA. A Tukey post hoc test showed that both the Olanzapine (p = 0.032) and Risperidone (p = 0.013) groups demonstrated statistically significant lower serum triglycerides when compared to Clozapine. Interestingly, the mean serum HbA1c was significantly lower in Clozapine when compared to Olanzapine group (p = 0.045), perhaps reflecting the closer monitoring of fasting blood sugar in clozapine patients. When controlled for age and BMI, the significant differences in serum triglycerides remain between Clozapine and Risperidone groups [but not for serum HbA1c]. There were no statistically significant differences across the groups with respect to other metabolic parameters.ConclusionAt baseline, metabolic dysregulation was demonstrated in all subgroups of overweight patients. As hypothesized, patients on Olanzapine and Clozapine groups fared worse than Risperidone. Further studies examining long term effects of atypical antipsychotics in a larger sample of patients are warranted to confirm these findings. These findings have clinical significance in terms of choosing the first antipsychotic for drug naïve patients or where there is no clinically significant difference in efficacy.

Metabolic profiles differences of overweight patients on olanzapine, clozapine and risperidone

AimsWe set out to examine the differences in metabolic profiles of at risk (overweight) patients across commonly used atypical antipsychotics (Olanzapine, Risperidone, Clozapine). We hypothesized that Olanzapine and Clozapine group will have more metabolic abnormalities compared to Risperidone.BackgroundCardiovascular diseases remain the leading cause of morbidity and mortality among people with schizophrenia. Since the introduction of atypical antipsychotics, there is cumulative evidence of their association with metabolic abnormalities. Clozapine and Olanzapine are known to constitute the highest metabolic risks amongst atypical antipsychotics.MethodThis study is based on the data of 67 subjects recruited into a 12-week open-labelled trial looking at the effects of adjunctive Aripiprazole in atypical antipsychotics for weight reduction and improvement in metabolic profile. Metabolic profiles including weight, waist circumference, fasting blood glucose, HbA1c, serum total, HDL and LDL cholesterol levels and triglycerides were measured at baseline. The measurements were then compared across the different subgroups of atypical antipsychotics. The definition of metabolic syndrome proposed by the Third Report of the National Cholesterol Education Program Expert Panel (Adults Treatment Panel III) was used.ResultThe atypical antipsychotics were grouped into Olanzapine (n = 27), Risperidone (n = 24) and Clozapine (n = 16). More than 50% of clozapine-treated and Olanzapine-treated overweight patients were demonstrated to have metabolic syndrome at baseline. There was a statistically significant difference in serum triglycerides (p = 0.012), LDL (p = 0.046) and HbA1c (p = 0.045) across the three groups as demonstrated by one-way ANOVA. A Tukey post hoc test showed that both the Olanzapine (p = 0.032) and Risperidone (p = 0.013) groups demonstrated statistically significant lower serum triglycerides when compared to Clozapine. Interestingly, the mean serum HbA1c was significantly lower in Clozapine when compared to Olanzapine group (p = 0.045), perhaps reflecting the closer monitoring of fasting blood sugar in clozapine patients. When controlled for age and BMI, the significant differences in serum triglycerides remain between Clozapine and Risperidone groups [but not for serum HbA1c]. There were no statistically significant differences across the groups with respect to other metabolic parameters.ConclusionAt baseline, metabolic dysregulation was demonstrated in all subgroups of overweight patients. As hypothesized, patients on Olanzapine and Clozapine groups fared worse than Risperidone. Further studies examining long term effects of atypical antipsychotics in a larger sample of patients are warranted to confirm these findings. These findings have clinical significance in terms of choosing the first antipsychotic for drug naïve patients or where there is no clinically significant difference in efficacy.

Non-attendance at psychiatric outpatient clinics: comparison of clinical, risk and demographic factors between attenders and non-attenders

AimsWith an overarching aim of decreasing the incidence of non-attendance in psychiatric outpatient clinics, this service evaluation was intended to explore the profile of non-attenders. Specifically, the clinical, risk and demographic features of patients who did not attend their psychiatric outpatient appointments were compared with those of attenders. The outcome of patients who did not attend was also studied.MethodAll the consecutive non-attenders (n = 32) in November 2020 in a psychiatric outpatient clinic were compared with 32 consecutive attenders. The groups were compared based on clinical features (diagnosis, medical treatment, psychological treatment, care programme approach, first contact), risk profile (self or others) and demographic features (age, gender, ethnicity, accommodation, occupation, benefits). The non-attender sample was also analysed to consider the outcome after their missed appointment, following local Trust protocols.ResultThe overall rate of patients who did not attend their appointment was 22%. There was a statistically significant difference between the age and gender of non-attenders. Males were less likely to attend their appointment than females (p = 0.024). The mean age of patients who did not attend their appointment was 36.4 compared with 44.8 years in the attenders (p = 0.005). There were a few clinically relevant findings. Around one third (34%) of patients who did not attend their appointments had a history of risk of self-harm noted in previous appointments. The results also showed that 75% of individuals who did not attend their outpatient appointments were unemployed. There were no significant differences based on the type of treatments (depot injections, lithium, clozapine, antipsychotics or antidepressants) patients received. Patients who did not attend were more likely to have a mood disorder (59% compared with 40%), and less likely to have a psychotic disorder (25% compared with 44%). Of the patients who did not attend, all were appropriately contacted as per the local Trust guidelines via a letter, and were provided with appointments where appropriate; 34% of non-attenders were discharged from services.ConclusionNon-attendance at psychiatric outpatient appointments is a concern, particularly for younger and male patients. Considering the clinical risks associated with this patient population, efforts need to be taken to improve their engagement with mental health services. Future studies may explore patients’ perspectives of non-attendance and how to ameliorate any hindrances to attending.

Clozapine in epilepsy and psychosis: effects on seizures and metabolic profile

Clozapine (CZP) is an antipsychotic used in resistant psychosis, but has adverse metabolic effects and is associated with new onset or worsening of epileptic seizures (ES). There is not enough information available regarding its effect on metabolic variables and on ES in patients with epilepsy. To describe the effect of CZP on the metabolic and hematologic profiles, and on ES in patients with epilepsy and with psychosis and/or aggressive behavior. A case series of patients with epilepsy and psychosis and/or aggressive behavior that received CZP with an 18-week follow-up. Clinical records were assessed from 2008-2018. 30 patients with epilepsy that received CZP were included. A paired analysis (Student’s t-test or Wilcoxon signed rank test) was performed with metabolic variables (glucose, cholesterol, and triglycerides), hematologic variables, weight, body mass index (BMI), and monthly ES before and after CZP administration. The median age to CZP initiation was 31.9 ± 16.07 years. Median CZP dosage was 193 mg/day. There were changes on BMI (p = 0.001; 3.2 kg/m2 increase, median = 3.08), triglycerides (p = 0.002) and glucose (p = 0.030). Weight increase was 7 kg (p = 0.292; median = 4 kg). Monthly ES mean was decreased from 4.9 (median = 2) to 2.04 (median = 1; p = 0.001). This study provide information regarding the security profile of CZP in patients with epilepsy with psychosis and/or aggressive behavior. A decrease on monthly ES was observed, as well as moderate increases in triglycerides, glucose and BMI, which coincide with that described by other authors.

Alcohol intake potentiates clozapine adverse effects associated to CYP1A2*1C in patients with refractory psychosis.

Clozapine (CLZ) is an atypical antipsychotic and the gold standard for refractory psychosis treatment. However, there is little information regarding pharmacogenetics of CLZ in patients with refractory psychosis and its clinical correlation with alcohol intake. Although neurological effects of CLZ in patients with concomitant alcohol intake are documented, its use is very common in patients with psychosis. We explored the impact of CYP1A2, CYP2D6, CYP2C19, and CYP3A4 genetic variants on CLZ pharmacokinetics and side effects, along with coffee/alcohol/tobacco consumption habits and clinical data of 48 adult patients with refractory psychosis on CLZ antipsychotic monotherapy. Relevant CYP variants in CLZ metabolism were evaluated by targeted genotyping and multiplex ligation-dependent probe amplification. CLZ and its main metabolite plasma concentrations were determined by high performance liquid chromatography. Biochemical and molecular data, along with other potential confounders, were included in the analysis by linear regression. Overall, CYP variants showed no effect on CLZ pharmacokinetics. The rs2069514 variant in homozygous genotype (also known as CYP1A2*1C/*1C) was associated with CLZ adverse reactions in Mexican patients with refractory psychosis (OR=3.55 CI95 = 1.041-12.269, p=.043) and demonstrated that this effect is doubled by concomitant alcohol consumption (OR=7.9 CI95 =1.473-42.369, p=.016). Clinicians should be aware of this information before starting CLZ use, when treating patients with refractory psychosis, who are alcohol drinkers and carriers of this genetic variant in order to prevent CLZ-related adverse reactions. Nevertheless, our findings should be replicated in larger samples.

Clozapine Use in Patients with Early-Stage Schizophrenia in a Chinese Psychiatric Hospital.

ObjectivePrevious studies suggest that clozapine is commonly underutilized and that its initiation is delayed in patients with first-episode schizophrenia. Knowledge regarding clozapine use among Chinese patients with early-stage schizophrenia is limited. The aim of the present study was to investigate the point prevalence of and patterns and factors associated with clozapine use in patients with early-stage schizophrenia discharged from a psychiatric hospital in China.MethodsA retrospective study was conducted to analyze the prescriptions of 867 consecutive patients with early-stage schizophrenia who were admitted to the Affiliated Brain Hospital of Guangzhou Medical University between Jan 1, 2011 and Dec 31, 2016.ResultsAt discharge from the hospital, 114 (13.1%) patients were prescribed clozapine. Among the patients taking clozapine, 93 patients (81.6%) were prescribed clozapine polypharmacy, and only 21 patients (18.4%) were prescribed clozapine monotherapy. None of the patients were prescribed an overdose of clozapine. The mean daily dosage of clozapine was 160.97 mg, 149.05 mg and 213.69 mg among all patients taking clozapine, patients taking clozapine polypharmacy and patients taking clozapine monotherapy, respectively. The antipsychotic most frequently combined with clozapine was risperidone. Logistic regression suggested that the length of hospital stay, high school education, lower benzodiazepine use and antipsychotic polypharmacy were independently and significantly associated with clozapine use (P<0.05).ConclusionAlthough clozapine has been commonly used in China in recent years, the present study found that clozapine was not commonly used in patients with early-stage schizophrenia. An underutilization and delayed initiation of clozapine may exist in a portion of patients with early-stage schizophrenia. Given the unfavorable outcomes of underutilized and delayed clozapine use, future studies may be needed to assess and increase clozapine use in this population.