Clozapine Plasma Research Articles

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.

Prescribing clozapine in the UK: Quality improvement issues identified by clinical audit.

Introduction:The Prescribing Observatory for Mental Health initiated a quality improvement (QI) programme on clozapine use in UK mental health services.Methods:Clinical audits conducted in 2019 and 2021.Results:Sixty-three participating NHS Trusts/healthcare organisations in 2019, and 61 in 2021, submitted treatment data for 6948 and 8155 patients, respectively. In both audits, high-dose and/or combined antipsychotic medications had been prescribed immediately before initiating clozapine in over a quarter of patients recently started on clozapine. In patients who were tobacco smokers and recently discharged from a smoke-free ward, the impact of the potential change in smoking status had been considered in the care plans of just under one-third in 2019 and just over a half in 2021. For community patients, their Summary Care Records (SCRs) included their clozapine prescriptions in 58% of cases in 2019 and 72% in 2021.Conclusions:Three QI issues were identified. (1) Antipsychotic regimens with limited evidence for efficacy in treatment-resistant schizophrenia were prescribed for over a quarter of cases before starting clozapine. Use of such strategies may delay clozapine treatment, potentially reducing the likelihood of a therapeutic response. (2) While anticipation of the consequences of a change in smoking status on plasma clozapine concentration following discharge from hospital showed improvement over time, even in 2021 it was not evident for nearly a half of relevant cases. (3) While inclusion of clozapine in the SCR also improved over time, even in 2021 it was missing for more than a quarter of community patients.

Plasma Clozapine and Norclozapine After Use of Either Crushed Tablets or Suspension Compared With Tablets.

With clozapine, either crushed tablets suspended in an aqueous medium or proprietary suspension is sometimes prescribed as an alternative to tablets, but bioequivalence data are scant. We compared clozapine dose, and plasma clozapine and N -desmethylclozapine (norclozapine) concentrations after use of either tablets or crushed tablets/suspension in samples submitted for clozapine therapeutic drug monitoring, 1993 to 2017. There were 846 patients (1646 samples) given crushed tablets/suspension and 6065 patients (10,779 samples) given tablets. The median dose (mg d -1 ) was significantly higher in men (500 vs 450) and women (500 vs 400) given crushed tablets/suspension, but the median plasma clozapine and norclozapine concentrations (mg L -1 ) were significantly lower (men: 0.29 and 0.22 vs 0.39 and 0.28; women: 0.35 and 0.26 vs 0.50 and 0.32, respectively). A subgroup of 480 patients was prescribed either crushed tablets/suspension (1016 samples) or tablets (1259 samples) at different times. The median dose was again significantly higher in men (500 vs 500) and women (500 vs 450), but the median plasma clozapine and norclozapine concentrations were significantly lower (men: 0.29 and 0.22 vs 0.32 and 0.24; women: 0.30 and 0.24 vs 0.38 and 0.29, respectively). Poor adherence, sedimentation of suspension before use, and incomplete dosage are potential contributors to the lower median plasma clozapine and norclozapine concentrations observed after use of either crushed clozapine tablets or suspension as compared with tablets. Those administering crushed tablets/suspension should be aware of these factors.

Treatment-resistant schizophrenia : the relationship between clozapine plasma concentration and clinical outcome

IntroductionClozapine is highly effective in patients with treatment-resistant schizophrenia but, to ensure optimal clinical response it is important to optimize its use and this depends on adequate pharmacological monitoring.ObjectivesEvaluate the therapeutic response rate according to clozapine plasma concentration.MethodsIt was a cross-sectional, retrospective and analytical study, carried out over a period of six months, in the F and A psychiatry departments of the Razi hospital in Tunis, including patients followed for treatment-resistant schizophrenia and receiving clozapine. We evaluated the response to clozapine using the Brief Psychiatric Rating Scale (BPRS).Results The average age was 37.7 ± 9.4. The mean age of introduction of clozapine was 31 years and the mean time to its introduction was 9.3 years. Clozapine was administered as a single drug in 85% of cases. The mean dose of clozapine was 373 mg/day. The mean of clozapine plasma concentration was 386.5 ng/ml with a minimum of 89 ng/ml and a maximum of 913 ng/ml. The clinical response rate to clozapine was 25% with a BPRS good response threshold value of less than 35. Patients with clozapine levels above the conventional cut-off of 350 ng/ml (n=34) had a response rate of 34.6%. A response rate of 37% was observed in the group of patients with a clozapine plasma concentration interval of 200-350 ng/ml. There was no statistically significant difference in therapeutic response (p=0186)ConclusionsOur study revealed a therapeutic response variation according to plasma clozapine concentration and showed the existence of a non-negligible and effective response rate.DisclosureNo significant relationships.

Quantitative determination of clozapine in plasma using an environmentally friendly technique

A new method for the determination of clozapine in blood samples, a common antipsychotic drug, has been developed. It is based upon a dispersive liquid–liquid microextraction technique employed as the extraction method together with gas chromatography-mass spectrometry operating in selected ion monitoring (SIM). The method was fully validated including selectivity, sensitivity, accuracy, precision and recovery steps. The limit of quantification was set at 50 ng/mL. Intra and interday accuracy and precision values were lower than 17% at the concentration levels studied. Good recovery results were obtained for all concentrations. The proposed method was satisfactory applied to 10 plasma samples received at the Forensic Toxicology Service of the Forensic Science Institute of Santiago de Compostela, obtaining results within the therapeutic range. The results showed the usefulness of the analysis in any forensic toxicology laboratory and the posibility of determining clozapine in the presence of other drugs or drugs or abuse.

Changes in Plasma Clozapine Levels after Smoking Cessation in Japanese Inpatients with Schizophrenia: A Retrospective Cohort Study.

Although reported for Caucasians, changes in plasma clozapine levels after smoking cessation in East Asians remain unclear. We here investigated plasma clozapine levels before and after smoking cessation in Japanese inpatients with schizophrenia. We conducted a retrospective chart review of 14 inpatients with schizophrenia who were being treated with clozapine between June 1, 2019, and July 31, 2019 and who were smokers as of July 1, 2019, the day on which a smoking ban was instituted in the tertiary public psychiatric hospital. The primary outcome was individual differences in plasma clozapine levels between before and after the smoking ban, which were compared using paired t-tests. The mean plasma clozapine level was significantly increased, by 213.4 ng/mL (95% CI 119.9-306.8; p<0.01) or 53.2%. Four of the 14 inpatients experienced clinically significant side effects, such as myoclonus, drooling, and amnesia, due to the development of high plasma clozapine levels. Our findings indicated that close monitoring of plasma clozapine levels before and after smoking cessation and prior dose adjustment of clozapine may be necessary, to prevent a significant risk of developing high plasma clozapine levels, even in Japanese patients.

Clozapine and COVID-19 Vaccination: Effects on blood levels and leukocytes. An observational cohort study.

ObjectiveTo investigate the safety of COVID‐19 vaccination in patients on clozapine as regards plasma clozapine concentration and haematological parameters.MethodsWe conducted a multicentre observational cohort study from 22 February 2021 to 2 September 2021. Primary outcomes were clinically relevant increase in clozapine blood levels (>100 μg/L increase compared to baseline) and clozapine alert levels (>1000 μg/L). Secondary outcomes were granulocytopenia, leukocytopenia and lymphocytopenia. Outcomes were measured approximately 5 days after the first and (where applicable) second dose of COVID‐19 vaccine.ResultsThis study included 139 patients. Compared to baseline, clozapine blood levels increased significantly (ES = 0.28, p = 0.003) after the second vaccination. Clinically relevant increases in clozapine blood levels occurred in 20/92 patients (22%) and in 16/56 patients (29%) during the first and second phases, respectively. Clozapine alert levels developed in one patient (1%) following the first dose and in three patients (5%) after the second dose. In both phases, changes in white blood cells (WBC) were limited to mild granulocytopenia (3% and 5%), moderate granulocytopenia (1% and 0%) and leukocytopenia (2% and 3%) without cause for extra monitoring according to the guideline.ConclusionIn general, as regards WBC counts COVID‐19 vaccination seems to be safe in patients with SMI. Changes in WBC had no clinical implications. Psychoeducation on the symptoms of clozapine intoxication is recommended, especially in patients with clozapine blood levels approaching the upper limit of the therapeutic range. Increase in the C‐reactive protein (CRP) level can signal inflammation rapidly and help to prevent clozapine intoxication following vaccination.

Exploring the usefulness of plasma level determination and pharmacogenetics for patients treated with clozapine.

Aims: The aims of the present study were to assess the variance of plasma clozapine (CLZ) levels and to identify the influence of sociodemographic and pharmacogenetic factors on it and to introduce these tools in a clinical setting. Patients & methods: CLZ concentration was measured and genetic variants of CLZ pharmacokinetic and pharmacodynamic factors were assessed in 23 patients with psychotic disorders. Results: A significant association between mean concentration/dose ratio (C/D) and smoking status, age and weight were found. There was a significant difference in mean plasma CLZ levels and gender. The rs762551 AA genotype in smokers had a significantly lower C/D. Conclusion: In addition to classical factors, monitoring of plasma concentrations together with pharmacogenetics led to greater individualization of treatment.

Front Cover: Clozapine and norclozapine monitoring in plasma following surfactant assisted dispersive liquid–liquid microextraction

DOI: 10.1002/jssc.202100068 The cover picture shows a surfactant-assisted dispersive liquid-liquid microextraction coupled with HPLC-UV as a fast and simple method for simultaneous determination of clozapine and norclozapine in a small amount of plasma sample. The analytical performance of the method was acceptable with a wide linear dynamic range (6.25-1600 ng/mL) covering the therapeutic range, toxic concentrations, and trace amounts, low limit of quantifications of 0.9 and 0.4 ng/mL for clozapine and norclozapine, respectively, as well as acceptable extraction ratios of 82.9% and 86.2% for clozapine and norclozapine, respectively.

Clozapine and norclozapine monitoring in plasma following surfactant assisted dispersive liquid–liquid microextraction

AbstractClozapine is the drug of choice for treatment‐resistant schizophrenia. However, it is characterized by inter‐ and intraindividual variability in plasma concentrations and complex metabolism requiring drug monitoring. A surfactant‐assisted dispersive liquid–liquid microextraction method followed by high‐performance liquid chromatography–ultraviolet is proposed to determine clozapine and its primary active metabolite, norclozapine, in plasma using haloperidol (400 ng/mL) as an internal standard. The surfactant, cetyl trimethyl ammonium bromide (0.5 mmol/L), and 1‐octanol (extraction solvent) were rapidly injected into the diluted plasma to form a cloudy solution. After centrifugation, 50 μL of the organic phase was injected into high‐performance liquid chromatography for analysis. The procedure was optimized by controlling the extraction solvent type and volume, the surfactant type and concentration, pH, and ionic strength. Furthermore, its suitability was investigated using plasma samples obtained from two healthy volunteers following a 12.5 mg dose of clozapine. The analytical performance of the method was acceptable with a limit of quantification of 0.9 and 0.4 ng/mL for clozapine and norclozapine, respectively (r2 &gt; 0.999) and a wide linear dynamic range 6.25–1600 ng/mL. The optimized method is simple, practical, environmentally friendly, and economically acceptable. It also requires a small amount of the sample.

Metabolic Effects of Clozapine Administration Based on Sex Differences and the Relationships Between Dosage and Prolactin Levels: An Observational Study.

Clozapine is the second-generation antipsychotic that induces the largest metabolic disorders. However, evidence is limited to the liabilities based on sex differences. This study aimed to investigate the effects of clozapine treatment on metabolic and neuroendocrine parameters, and the relationships between prescribed clozapine dosage and prolactin levels that may be associated with plasma clozapine concentrations, in 24 female and 24 male Japanese schizophrenia inpatients switched to clozapine. Within female and male subjects, sequential changes in 7 items of metabolic parameters, including anthropometric measurements, fasting serum lipid components and glucose levels, and estimated insulin resistance at 2 months were evaluated and analyzed against clozapine dosages and prolactin levels at 2 months. Triglyceride levels, triglyceride to high-density lipoprotein ratios reflecting insulin resistance and glucose levels increased in female and male subjects. High-density lipoprotein cholesterol levels decreased in female and male subjects. High-density lipoprotein cholesterol levels were negatively correlated with prolactin levels in female subjects, and glucose levels were positively correlated with prolactin levels in male subjects, although clozapine doses showed no such correlations. Clozapine administration developed sex-neutral metabolic disorders in the study subjects. Higher prolactin levels seemed to increase the risk of dyslipidemia and hyperglycemia with sex differences, which suggested that serum prolactin levels other than clozapine doses might be useful to predict sex-specific metabolic disorders. Further prospective studies, combining measurement of metabolic hormones and plasma concentrations of clozapine and its metabolites, will help to confirm our findings.

Audit of therapeutic drug monitoring of ‘clozapine plasma levels’

AimsTo re audit the monitoring of Plasma Clozapine levels in Rehabilitation setting in CNTW Trust as per Trust Guidelines PGN on “Safe prescribing of Clozapine”.Objectives:To determine if1. The reason for a clozapine plasma level request is recorded.2. Results are recorded correctly.3. Appropriate action is taken and recorded when results are significant.BackgroundClozapine plasma level monitoring is useful when assessing adherence, adjusting the dose, monitoring the effects of changes in smoking habit, investigating clozapine side effects and when toxicity is suspected.An initial audit was carried out within the Trust in 2015 and the following recommendations were made:Check and record clozapine plasma levelAt baseline (a level should be taken once the patient has been on the target dose for at least a week)Annually.When clinically relevant to optimise therapy.An entry must be made in the patient's progress notes recording the reason of requesting the test.On receipt of results, the paper copy must be scanned &amp; an entry made in progress notes.The clinician should comment on the significance of the results and propose an action plan.We re-audited compliance with the guidance in Rehabilitation (inpatients and community) by reviewing patient notes for a 2 year period of 2017–2018.MethodThe audit work involved a review of 31 case records of patients prescribed Clozapine whose last plasma level was taken between 2017–2018. Patient's details were identified from a randomly generated list by the Trust pharmacy.Result&lt;50% compliance was seen with baseline, annual monitoring, reason for recording and proposed action plan by clinician.&gt;50% compliance was seen with scanned results and levels checked when clinically relevant.No significant improvement from the previous audit except improvement in compliance with documentation of levels.ConclusionDissemination of Clozapine Key cards within teams.

Audit on clozapine dose and plasma level correlation for patients with chronic treatment-resistant psychosis

AimsClozapine is associated with a risk of severe adverse events for which there are current monitoring systems are in place; however, there are no established regimens for monitoring of clozapine plasma levels. Recent Medicines and Healthcare products Regulatory Agency (MHRA) guidance advises clozapine levels should be monitored in certain clinical situations where toxicity may be suspected. This audit aimed to evaluate current practice of clozapine level monitoring within one Local Mental Health Team (LMHT).MethodElectronic (RiO) records of 41 patients (33 male, 8 female; aged from 27 to 76 years; mean age 45 years) registered to the ZTAS system within the Nottingham City Central LMHT were reviewed. 46% had been on clozapine for over 16 years. 73.3% of patients were within clusters 12 and 13; 25.4% of patients were in cluster 11, with one patient in cluster 8. Dates of clozapine plasma level tests for each patient between 2006 and 2020 were found on the electronic NoTIS system, along with clozapine, norclozapine and total clozapine levels. Concurrent clozapine dose and regimens were obtained from pharmacy records from 2018 onwards.Result273 clozapine plasma levels were conducted between 2006 and 2020. The average interval between levels taken was 10 months, 2 weeks but had a wide range, the shortest interval being 2 days, the longest being 13 years. 88 levels taken were &gt;600 ug/L, suggesting increased toxicity risk. 108 levels were &lt;350 ug/L, suggesting possible sub-optimal dosing or non-compliance. Statistical tests on correlation coefficient, although statistically non-significant (R = 0.37), showed a positive trend between total clozapine dose and the plasma level between all 3 parameters (i.e. clozapine, norclozapine and total clozapine).ConclusionThere does not appear to be any routine plasma clozapine level monitoring throughout the LMHT with an average interval between tests of 10 months. There was a non-significant but positive trend between total daily dose of clozapine and clozapine level. 32% of clozapine levels returned were higher than the recommended level. We would recommend as suggested in the guidelines from MHRA, clozapine plasma levels should be monitored in certain clinical situations with increased toxicity risk. Trough levels should be taken with records of time of previous dose taken. Limitations of this study included a small sample size (41 patients) with data collection reliant on electronic systems. It was unclear if these results represent trough levels, making values difficult to interpret. Multifactorial impact on clozapine metabolism causes wide patient variability in plasma levels.

A prospective multicenter assessor-blinded randomized controlled study to compare the efficacy of short versus long protocols of electroconvulsive therapy as an augmentation strategy to clozapine in patients with ultra-resistant schizophrenia (SURECT study)

BackgroundAlthough clozapine is the most effective antipsychotic drug for treatment-resistant schizophrenia, it leads to a poor or partial response in 40 to 70% of patients. Augmentation of clozapine with electroconvulsive therapy (ECT) is a highly effective and relatively safe treatment for these clozapine-resistant patients. However, parameters are not yet well specified, such as the optimal number of sessions, their frequency, and the relevance of maintenance ECT. Our objective is to compare the efficacy and tolerance between two protocols of combined ECT and clozapine treatment in patients with ultra-resistant schizophrenia (URS): a 6-month protocol (short protocol with 20 ECT sessions) and a 12-month protocol (long protocol with 40 ECT sessions).MethodsSixty-four patients with schizophrenia with persistent psychotic symptoms despite clozapine treatment will be enrolled in a prospective multicentric assessor-blinded randomized controlled trial. Patients will be randomly assigned to the short or the long protocol. The main outcome is the response rate assessed by the Positive and Negative Symptoms Scale (PANSS) 3 months after the end of the treatment in patients following the long protocol compared to those following the short protocol. The response was defined as a 30% reduction on the PANSS baseline. Clinical assessments (PANSS, BPRS, HAMD-21, YMRS, CGI, GAF, Modified Overt Aggression Scale (MOAS), and Subjective Scale to Investigate Cognition in Schizophrenia (SSTICS)) and plasma clozapine concentration will be performed at baseline and at 2, 4, 6, 9, 12, and 15 months. Neuropsychological measures (MMSE, RL/RI-16, Doors test, D2 Test of Attention, Copy of the Rey-Osterrieth complex figure) will be performed at baseline and at 6 and 15 months.DiscussionThe aims of this research are to optimize protocols of combined ECT with clozapine in patients with URS and to offer specific recommendations for these patients’ care.Trial registrationClinicalTrials.gov NCT03542903. Registered on May 31, 2018. Id RCB: 2017-A02657-46

Risk factors for clozapine-induced central nervous system abnormalities in Japanese patients with treatment-resistant schizophrenia.

The purpose of this study was to assess the risk factors for clozapine-induced central nervous system (CNS) abnormalities (i.e., electroencephalogram [EEG] abnormalities, myoclonus, and seizures). We retrospectively analyzed data from 106 patients with schizophrenia who received clozapine treatment through our hospital. A review of the EEG recordings showed that 71 of these patients (67.0 %) developed CNS abnormalities after initiating clozapine treatment. EEG abnormalities, myoclonus, and seizures occurred in 53.8 %, 38.7 %, and 8.5 % of the patients, respectively. Multivariate logistic regression analysis showed that the risk factors for clozapine-induced CNS abnormalities were concomitant lithium usage (odds ratio, 4.560; 95 % confidence interval, 1.750-11.900) and shorter illness durations before clozapine initiation (odds ratio, 0.796; 95 % confidence interval, 0.649-0.976). However, plasma clozapine levels and the usage of antiepileptics did not exhibit associations with the risks of CNS abnormalities. Clinicians should monitor their patients for incident CNS abnormalities when administering lithium in combination with clozapine regardless of plasma clozapine levels or the usage of antiepileptics. This is especially true for patients with short illness durations.

Elevated clozapine levels in patients with COVID-19 infection

IntroductionClozapine is the most effective antipsychotic for treatment resistant schizophrenia. In patients treated with clozapine, COVID-19 infection may result in complications including an increased risk of pneumonia, clozapine toxicity, and disruption to clozapine treatment by COVID-19 induced lymphopenia.ObjectivesWe report 5 cases of elevated clozapine levels occurring in patients with COVID-19 infection who had been previously managed for several years on stable doses.MethodsSubjects: 48 admitted patients to a long-stay psychiatric unit. COVID-19 infection confirmed by positive nasopharyngeal swab for viral ribonucleic acid of SARS-CoV-2. Hematological controls between March and April 2020.Results16 patients (33%) treated with clozapine.18 patients (37’5%) had COVID-19 infection, of which 5 (10’4%) were treated with clozapine. Results are presented in table 1. Increases in plasma clozapine levels were observed in all cases (49’38 to 307.5%). We don’t have the clozapine levels of a patient who presented a pneumonia requiring admission and treatment in the general hospital. Two cases of neutropenia were observed, of which one had to discontinue treatment with clozapine. In the other three patients the dose of clozapine was reduced and they did not present haematological or intoxication complications that required further adjustments.ConclusionsCovid-19 infection is associated with increased serum clozapine levels by probably multifactorial mechanisms (systemic infection, reduced smoking). Importance of full clinical assessment of suspected COVID-19 infection in clozapine treated patients, including assessment clozapine level, and full blood count. The general recommendation is to reduce the dose of clozapine in this patients.

Comprehensive assessment of exposure to clozapine in association with side effects among patients with treatment-resistant schizophrenia: a population pharmacokinetic study.

Background:There have been scarce data on the distribution of clozapine concentrations in comparison with the recommended range (350–600 ng/ml) or their relationship with side effects among patients with treatment-resistant schizophrenia. Furthermore, no studies have assessed the association between side effects and overall exposure to the drug by calculating the 24-h area-under-curve (AUC).Methods:In- and outpatients with schizophrenia or schizoaffective disorder (ICD-10) who were receiving a stable dose of clozapine for ⩾2 weeks were included. Side effects were assessed using the Glasgow antipsychotic side-effects scale for clozapine (GASS-C). Using two collected plasma samples, plasma clozapine and norclozapine concentrations at peak and trough and their 24-h AUC were estimated using population pharmacokinetic models.Results:A total of 108 patients completed the study (mean ± SD age, 43.0 ± 10.1 years; clozapine dose, 357.5 ± 136.9 mg/day); 33 patients (30.6%) showed estimated trough concentrations of clozapine within the recommended range (350–600 ng/ml) whereas the concentrations were higher and lower than this range among 37 (43.5%) and 28 (25.9%) patients (%), respectively. There were no significant correlations between estimated peak or trough concentrations or 24-h AUC of both clozapine or norclozapine, and GASS-C total or individual scores. No significant differences were found between GASS-C total or individual item scores between the patients with estimated trough concentrations of clozapine of >600 ng/ml and the other subjects.Conclusion:The results suggest that clozapine or norclozapine concentrations are not linked directly to the extent of side effects experienced in clozapine-treated patients with treatment-resistant schizophrenia while the cross-sectional study design limits the interpretation of any causal relationships. These findings indicate that side effects associated with clozapine may occur at any dose or concentration.

The relationship between plasma clozapine concentration and clinical outcome: a cross‐sectional study

There is no report that statistically evaluates the therapeutic reference (350-600ng/ml) and adverse drug reaction (ADR) range (>1000ng/ml) of clozapine (CLZ) recommended by the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) consensus guidelines in an isolated and large sampling study. We administered CLZ to 131 Japanese patients with treatment-resistant schizophrenia in a multicenter cross-sectional study. Plasma CLZ concentrations were assayed by high-performance liquid chromatography using trough sampling. The Brief Psychiatric Rating Scale (BPRS) and severe dose-dependent ADR (sedation, myoclonus, and seizures) were analyzed statistically after adjusting for possible confounders. The daily CLZ dosage showed a moderately positive relationship with the plasma concentration (r=0.49, p<0.001). Every 100ng/ml increase in plasma CLZ concentration improved the total BPRS score 1.95% (95% CI: 0.89-3.01, p<0.001) and the odds ratio (OR) 1.38 (95% CI: 1.14-1.66, p=0.001) for BPRS response. Compared with concentrations below 350ng/ml CLZ, 350-600ng/ml (11.12%; 95% CI: 2.52-19.72, p=0.012) and 600-1000ng/ml (11.05%; 95% CI: 2.40-19.71, p=0.013) showed significant improvement in the total BPRS score. Dosages above 1000ng/ml showed greater improvement (25.36%; 95% CI: 13.08-37.64, p<0.001) of the total BPRS score but more severe ADRs than dosages below 1000ng/ml (OR: 31.72; 95% CI: 1.04-968.81, p=0.048). The AGNP therapeutic reference range (350-600ng/ml) is useful, and a dose above 1000ng/ml is potentially more effective but carries the risk of severe ADRs in the central nervous system.

Clozapine prescribing: comparison of clozapine dosage and plasma levels between White British and Bangladeshi patients.

To compare differences in clozapine doses and plasma levels between Bangladeshi and White British patients. Following ethical approval we identified all current Bangladeshi and White British patients on clozapine maintenance in an east London clinic. We carried out univariate and multivariate regression analyses to examine associations between clozapine doses and ethnicity, age, gender, smoking status and weight. We also compared plasma clozapine levels of the two groups. On univariate analysis White British patients had on average 85 mg higher doses than Bangladeshi patients (P = 0.004). Older age, male gender and smoking were also associated with higher dose. On multivariate analysis only age and smoking status remained significant. A greater proportion of Bangladeshi patients had high plasma clozapine levels compared with White British (30.76% v. 20.75%), although the difference was not statistically significant. Our findings point to the need for the broadening of data collection on ethnic differences in clozapine prescribing within big data-sets such as Prescribing Observatory for Mental Health (POM-UK). Ethnopharmacological variations can inform more person-centred guidance on prescribing.

The relationship between plasma levels of clozapine and N-desmethyclozapine as well as M1 receptor polymorphism with cognitive functioning and associated cortical activity in schizophrenia

Studies that examined the effect of clozapine on cognitive functions in schizophrenia provided contradictory results. N-desmethylclozapine (NDMC) is the major metabolite of clozapine and have procognitive effects via agonistic activity in the M1 cholinergic receptors. The rs2067477 polymorphism in the M1 receptors may play role in cognitive profile in schizophrenia. We investigated the association of plasma clozapine (PClz), NDMC (PNdmc) levels and the rs2067477 polymorphism with cognitive functions and cortical activity measured by functional near infrared spectroscopy during the N-Back task in subjects with schizophrenia (N = 50) who are under antipsychotic monotherapy with clozapine. We found that PClz and PNdmc levels were negatively, PNdmc/PClz ratio was positively correlated with immediate recall score in the Rey Auditory Verbal Learning Test. PNdmc/PClz ratio was positively correlated with cortical activity during the N-back task. M1 wild-type group (CC: wild-type) produced higher cortical activity than M1 non wild-type group (CA: heterozygote / AA: mutant) in cortical regions associated with working memory (WM). These results suggest that individual differences in clozapine's effect on short term episodic memory may be associated with PClz and PNdmc. Higher activity in the M1 wild-type group may indicate inefficient use of cortical resources and/or excessive use of certain cognitive strategies during WM performance.