Serum Clozapine Levels Research Articles

Clinical and pharmacological factors influencing serum clozapine and norclozapine levels.

Clozapine (CLO) is a very effective antipsychotic, whose use is associated with dose-dependent risk of complications. Due to high interindividual variability in CLO metabolism, there is a need to identify factors affecting the blood concentrations of CLO and its active metabolite, norclozapine (NCLO). A total of 446 blood samples (collected from 233 women and 213 men, aged from 18 to 77 years) were included in this study and analyzed for CLO and NCLO concentrations. The patients were treated at a psychiatric hospital in Warsaw in the years 2016-2021. Serum CLO and NCLO concentrations were determined with high-performance liquid chromatography coupled to UV. The following factors were shown to increase serum CLO and NCLO levels: higher CLO dose (p < 0.001), female sex (p < 0.001), nonsmoker status (p < 0.001), the use of more than two additional psychotropic drugs (only in the case of CLO; p = 0.046), concomitant use of beta-blockers (for CLO p = 0.049; for NCLO p < 0.001), and older age (for CLO p < 0.001; for NCLO p = 0.011). Despite the use of CLO at daily doses within the recommended range (200-450mg), the evaluated serum CLO and NCLO levels were within the therapeutic ranges in only 37% and 75% of cases, respectively, with 5.6% of cases exceeding the CLO toxicity threshold. The use of CLO at recommended doses does not guarantee achieving therapeutic concentrations of CLO or NCLO. Women and nonsmokers were at the highest risk of having toxic CLO levels.

Relationship between C-reactive protein and antipsychotics levels in schizophrenic patients infected with COVID-19

In the context of the COVID-19, inflammation emerges as a prominent characteristic. C-reactive protein (CRP) serves as a commonly employed marker for the evaluation of inflammation. This study aimed to examine the correlation between CRP levels and antipsychotic drug concentrations in patients diagnosed with SCZ during the COVID-19 pandemic. A total of 186 SCZ patients were included in this study, which utilized electronic medical records. The collected data encompassed SCZ diagnoses based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria, respiratory symptoms, and treatments. Laboratory assessments involved the measurement of CRP levels and monitoring of blood drug concentrations. The most prevalent symptoms observed in the patient cohort were fever (59.14%), cough (52.15%), fatigue (45.7%), sore throat (46.24%), runny nose (28.49%), and stuffy nose (25.27%). The levels of CRP during the infection period were significantly higher compared to both the prophase and anaphase of infection (all p < 0.001). The serum levels of clozapine, olanzapine, aripiprazole, quetiapine, and risperidone were elevated during the infection period (all p < 0.001). During the anaphase of infection, patients exhibited higher serum levels of clozapine, olanzapine, and risperidone (all p < 0.001) compared to the infection period, but there was no significant change in serum levels of aripiprazole and quetiapine. Multiple regression analysis revealed a statistically significant positive correlation (P < 0.0001) between CRP and clozapine concentration. In light of the COVID-19 pandemic, it is crucial to adjust the dosage based on drug serum concentration to prevent intoxication or adverse drug reactions.

Inflammatory markers in outpatients with schizophrenia diagnosis in regular use of clozapine: a cross-sectional study.

It is known that inflammation worsen the course of schizophrenia and induce high clozapine serum levels. However, no study evaluated this change in function of clozapine daily dose in schizophrenia. We assessed the correlation between inflammation and severity symptoms in patients with schizophrenia that take and do not take clozapine. We also assessed the correlation between clozapine daily dose and inflammatory markers to patients who take this drug. Patients were recruited from Schizophrenia Ambulatory and Psychosocial Care Center of Clinical Hospital of Porto Alegre and from an association of relatives of patients with schizophrenia. Exam results, and other important clinical exam were assessed in patients record or patients were asked to show their exam in the case of outpatients. We included 104 patients, 90 clozapine users and 14 non-clozapine users. We calculate the systemic inflammatory markers [neutrophil-lymphocyte ratio (NLR), systemic immune inflammation index (SII), and the psychopathology severity by the Brief Psychiatric Rating Scaled anchored (BPRS-a)]. These variables were compared between clozapine users and non-clozapine users. It was used mean/median test according to data distributing, with study factor (SII, MLR, and PLR), the clinical outcome: severity of symptomatology (BPRS score), and clozapine daily dose as adjustment factor. Clozapine users exhibited a significantly higher neutrophil count (mean ± SD: 5.03 ± 2.07) compared to non-clozapine users (mean ± SD: 3.48 ± 1.27; p = 0.031). After controlling for comorbidity, other parameters also showed significant differences. These findings are consistent with previous studies that have demonstrated an inflammatory response following the administration of clozapine.

Prevalence and predictors of QTc prolongation in patients seen in a clozapine clinic in a real-world setting in Australia

BackgroundMany antipsychotic drugs have been associated with QTc prolongation, which is a risk factor for sudden death. We studied the prevalence and predictors of QTc prolongation in treatment-resistant schizophrenia patients who were receiving clozapine in a real-world setting. MethodsData were extracted from the records of all schizophrenia patients aged 18–65 years, enrolled in a clozapine clinic in metropolitan Australia during October 2020 to April 2022, for whom ECG data were available. ResultsThere were 104 eligible patients. The mean age of the sample was 42 years. The sample was 56 % male. About a third of patients were receiving antipsychotic and antidepressant drugs in addition to clozapine. The mean (standard deviation) QTc was 437.0 (24.8) ms in men and 445.8 (28.5) ms in women. QTc prolongation was present in 36.5 % of the sample. In univariate analysis, higher heart rate and higher clozapine levels were significantly associated with QTc prolongation; in multivariable logistic regression analysis, nonsignificant statistical trends were observed for male sex, higher heart rate, and higher serum clozapine level. ConclusionsQTc prolongation may be common in schizophrenia patients who receive clozapine in real world settings; this is a matter of much concern. Potential predictors of QTc prolongation need to be identified and these predictors and their interactions require to be explored in studies with greater statistical power.

Negative symptoms and cognitive impairment are associated with distinct motivational deficits in treatment resistant schizophrenia

BackgroundMotivational deficits are a central feature of the negative syndrome in schizophrenia. They have consistently been associated with reduced willingness to expend physical effort in return for monetary rewards on effort based decision making (EBDM) paradigms. Nevertheless, the mechanisms underlying such altered performance are not well characterised, and it remains unclear if they are driven purely by negative symptoms, or also in part by cognitive impairment, antipsychotic treatment or even positive symptoms. Here we investigated the impact of all these factors using a paradigm that has not previously been used to measure EBDM in schizophrenia.MethodsForty treatment resistant schizophrenia (TRS) patients on clozapine and matched controls (N = 80) completed a well validated EBDM task which offers monetary rewards in return for physical effort. Choice and reaction time data was analysed using logistic regressions, as well as Bayesian hierarchical drift diffusion modelling (HDDM). Behavioural parameters were compared between groups and their association with negative symptoms, cognitive function and serum clozapine levels were assessed.ResultsOverall, TRS patients accepted significantly less offers than controls during effort-based decision making, suggesting they were less motivated. They demonstrated reduced sensitivity to increasing rewards, but surprisingly were also less averse to increasing effort. Despite a positive correlation between negative symptoms and cognitive function in TRS, reward sensitivity was associated only with cognitive performance. In contrast, reduced effort aversion correlated with negative symptom severity. Clozapine levels and positive symptoms were not associated with either behavioural parameter.ConclusionMotivational deficits in TRS are characterised by both diminished reward sensitivity and reduced effort aversion during EBDM. Cognitive dysfunction and negative symptom severity account for distinct aspects of these behavioural changes, despite positive associations between themselves. Overall, these findings demonstrate that negative symptoms and cognitive impairment have significant independent contributions to EBDM in TRS, thereby opening the possibility of individualised treatment targeting these mechanisms to improve motivation.

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

ObjectivesTo 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). MethodsThe 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. ResultsThe 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. ConclusionsOur 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 safety monitoring and related research in psychiatry and neurology in South America: A scoping review

The quality and quantity of clozapine safety monitoring considerably differs among South American countries and mainly focus on hematological surveillance. Few studies have been conducted on other clozapine-related adverse effects (ADRs) and mainly refer to case reports and literature reviews. We retrieved thirty-nine publications on clozapine related ADRs others than neutropenia. Studies in Brazil and Venezuela accounted for 67 % of all the publications, and 8 out of 12 countries published 2 or less manuscripts. Only Chile offers serum clozapine level measurement in public institutions. Given the recently recognized role of ethnicity, gender, smoking, obesity drug interactions in optimal clozapine administration, modernization of clozapine clinical use and research in psychiatry and neurology most be broadcasted and stimulated in South American countries.

Development and validation of a risk prediction nomogram for disposition of acute clozapine intoxicated patients to intensive care unit.

Clozapine is an atypical antipsychotic drug used for the treatment of refractory schizophrenia. It is reported as the most toxic in its class. Using serum clozapine level as a severity indicator is doubtful and unfeasible, particularly in low resourced countries. This is an extended two-phase retrospective study that utilized medical records of patients diagnosed with acute clozapine intoxication and admitted to Tanta University Poison Control Center, Egypt during the past 6years. Two hundred and eight medical records were used to establish and validate a nomogram for predicting the need for intensive care unit (ICU) admission in acute clozapine intoxicated patients. A reliable simple bedside nomogram was developed and proved its significant ability to predict the need for ICU admission, with an area under the curve (AUC) of 83.9% and 80.8% accuracy. It encompassed the age of admitted patients (AUC = 64.8%, p = .003), respiratory rate (AUC = 74.7%, p < .001), O2 saturation (AUC = 71.7%, p < .001), and random blood glucose level upon admission (AUC = 70.5%, p < .001). External validation of the proposed nomogram showed a high AUC (99.2%) with an overall accuracy of 96.2%. There is a need to develop a reliable objective tool predicting the severity and need for ICU admission in acute clozapine intoxication. The proposed nomogram is a substantially valuable tool to estimate ICU admission probabilities among patients with acute clozapine intoxication and will help clinical toxicologists make rapid decisions for ICU admission, especially in countries with low resources.

Clozapine levels and therapeutic response: using individual patient meta-analysis data for a ROC Curve analysis

IntroductionClozapine has been well established as the most efficacious medication for treatment refractory schizophrenia. Optimising the benefit during clozapine trial is an important clinical consideration. Therapeutic drug monitoring of clozapine plasma or serum levels has formed a critical part of this. Though there is no agreed standardised therapeutic range, advice traditionally recommends a clozapine level of &gt;350ng/mL in order to effect best response. Most studies analysing the relationship between treatment response and clozapine level are older, have small sample sizes, and do not consider whether additional factors might assist in determining optimal clozapine level for response.ObjectivesWe conducted a systematic review of PubMed, PsycInfo and Embase for studies that provided individual participant level data on clozapine levels and response.MethodsThis data was analysed using Receiver Operating Characteristic (ROC) curves to determine the prediction performance of serum clozapine levels for treatment response.ResultsWe were able to include data on 294 individual participants. ROC analysis yielded an area under the curve (AUC) of 0.612. The clozapine level at the optimal Youden index was 372ng/mL, and at this level there was response sensitivity of 57.3%, and specificity of 65.7%. The interquartile range for treatment response was 223ng/mL – 558ng/mL. There was no improvement in ROC performance with mixed models including patient sex, age or length of trial.ConclusionsClozapine dose should be optimised based on clozapine therapeutic levels. We found that a range between 250 – 550ng/mL could be recommended, while noting that a level of &gt;350ng/mL is most optimal for response.Disclosure of InterestNone Declared

Co-medication with disulfiram markedly increased serum clozapine levels: Two case reports.

Alcohol use disorder (AUD) is a significant co-morbidity in patients with schizophrenia. Clozapine offers some benefits in treating patients with refractory schizophrenia and AUD, but co-medicating with disulfiram is also common. We report two cases where co-medicating with disulfiram led to a significant increase in clozapine serum levels. Clozapine serum levels decreased to one-third in Patient 1 when disulfiram was discontinued and started to increase again when disulfiram was reintroduced. Patient 2 developed toxic serum levels of clozapine during disulfiram treatment combined with heavy coffee drinking and symptoms reminiscent of neuroleptic malignant syndrome. Clozapine and disulfiram are both metabolized by cytochrome P450 CYP1A2 and clinically relevant interaction through this shared pathway is possible.

Metabolite Profiling of Clozapine in Patients Switching Versus Maintaining Treatment: A Retrospective Pilot Study.

Purpose/BackgroundPharmacokinetics may be of relevance for the risk of clozapine discontinuation. We compared metabolite profiles, accounting for smoking habits, in patients switching versus maintaining clozapine treatment at therapeutic concentrations.Methods/ProceduresAdult patients with clozapine serum levels above 1070 nmol/L (350 ng/mL) were retrospectively included from a Norwegian therapeutic drug monitoring service during 2018–2020. Inclusion criteria were (1) known smoking habits, (2) blood sample drawn within 10 to 30 hours after last clozapine intake, and (3) detectable levels of N-desmethylclozapine, clozapine-N-oxide, clozapine-5N-glucuronide, or clozapine-N+-glucuronide. Patients comedicated with cytochrome P450 enzyme inducers, inhibitors, or valproic acid were excluded. The high-resolution mass spectrometry assay enabled detection of 21 clozapine metabolites. Metabolite profiles were compared between patients switching treatment (switchers), measured as clozapine being replaced by another antipsychotic drug in blood samples, versus maintaining clozapine treatment (nonswitchers) during the study period.Findings/ResultsOf the 84 patients fulfilling the study criteria, 7 patients (8.3%) were identified as clozapine switchers. After correcting for smoking habits, the clozapine-5N-glucuronide/clozapine ratio was 69% lower (P < 0.001), while the clozapine-N+-glucuronide/clozapine-5N-glucuronide ratio was 143% higher (P = 0.026), respectively, in switchers versus nonswitchers. The other metabolite ratios did not significantly differ between switchers and nonswitchers.Implications/ConclusionsThe present study found a significantly reduced 5N-glucuronidation phenotype in patients switching from clozapine at therapeutic serum concentrations (>1070 nmol/L) to other antipsychotic drugs. This may indicate that glucuronidation, as a potential detoxification mechanism, is related to clozapine tolerability. However, the causality of this observation needs to be investigated in future studies with larger patient populations.

Successful clozapine rechallenge after neutropenia using lithium carbonate : a case report

IntroductionClozapine is widely known as the drug of choice in treating refractory schizophrenia. However, clozapine prescription requires close clinical and biological monitoring to prevent harmful side effects like agranulocytosis, neutropenia and myocarditis.ObjectivesTo show the benefits of lithium carbonate in the clozapine rechallenge of a patient with neutropenia under clozapine.MethodsWe present the clinical case of a patient who developed neutropenia under clozapine, we rechallenged with clozapine after lithium treatment to stimulate hematopoietic functions.ResultsA 42-year-old man diagnosed with refractory schizophrenia, under clozapine for 11 years with a good clinical response at a dosage of 500mg per day (clozapine serum level 328ng/ml), developed a neutropenia (BCC at 840/mm3) within an interval of 2 months. Clozapine treatment was suspended and the patient presented a severe psychotic relapse requiring hospitalization. During hospitalization the patient remained symptomatic under haloperidol 15mg daily. At week 3 of clozapine cessation, neutrophil count reached 1510/mm3. After week 4 we introduced lithium carbonate and while reaching 500mg per day we observed an increase in the neutrophil count to 4850/mm3. We rechallenged with clozapine at week 12 after a poor clinical response, with incremental dosage to 150mg per day in 17 weeks. The blood cell count did not show any abnormalities and the patient had a good clinical response up to 11 months after the clozapine rechallenge.ConclusionsDespite the lack of guidelines assessing clozapine rechallenge after neutropenia, the use of lithium carbonate may be considered to stimulate hematopoietic functions.DisclosureNo significant relationships.

Factors predicting serum clozapine levels in Middle Eastern patients: an observational study

BackgroundDespite its superiority over other drugs for psychosis, clozapine remains underused and is associated with many clinical challenges, including difficulties in predicting therapeutic serum levels (350-600 ng/mL). We found no large or recent study that investigated the determinants of serum clozapine levels in Middle Eastern patients. Therefore, we investigated the association between clozapine dose and serum level, and the clinical predictors of the clozapine serum level, in Middle Eastern patients.MethodsThis cross-sectional study included 94 patients of Middle Eastern ethnicity who attended the Clozapine Clinic in King Saud University Medical City in Riyadh, Saudi Arabia. We used a single measure of the serum clozapine level, which was collected 12 h after the last oral dose of clozapine under steady-state conditions.ResultsThe average clozapine dose and serum level were 400 mg/daily and 705 ng/mL, respectively. The majority of patients (59.8%) had serum levels higher than 600 ng/mL. Clozapine dose and serum level were positively correlated (rs [94] = 0.32, p = 0.002). We generated a predictive model of the serum clozapine level, which revealed that the daily dose, smoking status, use of fluvoxamine or lamotrigine, and body mass index (BMI) predicted 43.6% of the variance in the serum level (p < 0.001). Using this model, we calculated that patients with a BMI of 25 kg/m2 would require a clozapine dose between 50 to 275 mg/daily if they were non-smokers, and a dose of 200 to 450 mg/daily if they were smokers, in order to reach a serum clozapine level between 350 to 600 ng/mL. Patients with higher BMI and those receiving fluvoxamine would require lower doses.ConclusionsThis was a naturalistic study of the clozapine dose-level relationship and the clinical predictors of the serum clozapine level in a sample of Middle Eastern patients. The ratios of clozapine level to dose in our patients more closely resembled those reported in Asian samples than in European samples. These findings do not reduce the value of individualised therapeutic drug monitoring, but may assist clinicians when prescribing clozapine to Middle Eastern patients. Further psychopharmacological studies are needed on this demographic population.

Da li je klozapin odgovoran za odloženi Ogilvie sindrom i gastrointestinalno krvarenje u uslovima predoziranja?

Introduction: Ogilvie syndrome and gastrointestinal bleeding as complications after reversal of typical clinical picture of acute Clozapine overdose is described. Case Report: A previously healthy 31-year-old man was found unconscious with Glasgow Coma Score of 6, non-reactive miotic pupils, hypersalivation and heart rate of 115 bpm. In the blood, the presence of Clozapine, Diazepam, haloperidol and biperiden were confirmed. The patient was referred to the intensive care unit for symptomatic and supportive treatment. Clinical signs registered on admission, except for sinus tachycardia, were completely resolved by the day 3. The patient began to eat and had regular bowel movements. From the seventh day, gastrointestinal complications were noticed. Nonobstructive dilatation of the stomach and intestine was confirmed on computed tomography scan. Nasogastric suction, the usage of laxatives and prostigmin injections as well as colonic irrigation was performed with a good clinical response. Conclusion: Clinicians should be aware of the potential of atypical antipsychotics to cause ileus, particulary in combination with other drugs with antimuscarinic properties, and ready to rapidly detect and treat intestinal atony thus preventing life-threatening complications. Serum Clozapine levels may not equate to clinical toxicity and the drug-näive patient require more careful observation for complications in Clozapine toxicity settings.

Relationship of clozapine serum levels with gender, smoking and symptom severity (tur)

Relationship of clozapine serum levels with gender, smoking and symptom severity (tur)

Clinical Use of Clozapine Serum Level and Management of Adverse Effects in an Adolescent with Difficult to Treat Schizophrenia.

Clinical Use of Clozapine Serum Level and Management of Adverse Effects in an Adolescent with Difficult to Treat Schizophrenia.

Clozapine point of care testing in acute psychiatry: A precision approach to treatment resistant psychosis

IntroductionClozapine, the antipsychotic of choice for treatment-resistant schizophrenia, has a narrow therapeutic range and high interpatient variability in the dose-response relationship. Serum clozapine levels are essential both for therapeutic dosing and to monitor adherence. Use of venepuncture and prolonged result turnaround times with standard laboratory based methods for drug monitoring together contribute to the suboptimal use of clozapine.ObjectivesA novel portable point-of-care (POC) device has been developed to measure whole blood clozapine concentrations using an automated homogenous immunoassay. It is as accurate and reliable as standard laboratory methods but only requires a drop of blood obtained by finger prick and can produce a result in minutes. We pioneered clozapine POC testing in the acute inpatient setting during the outbreak of the COVID-19 pandemic.MethodsWe report on the use of POC clozapine testing in the management of 4 acutely psychotic patients with treatment resistant schizophrenia.ResultsPOC testing offered a more practical, less invasive and quicker alternative to conventional methods for monitoring of clozapine levels. Near immediate availability of clozapine levels expedited clinical decisions and helped ensure safe clozapine prescribing to severely unwell patients in a time of crisis. By facilitating patients’ early safe discharge from hospital, clozapine point of care testing also reduced length of hospitalisation.ConclusionsPoint of care monitoring of other psychotropic medications in addition to clozapine brings about the prospect of personalised precision medicine for patients with severe mental illness, both in the acute setting and in the community.

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.

Measurement of the Antipsychotic Clozapine Using Reduced Graphene Oxide Nanocomposites‐Au/Pd/Pt Electrodes

AbstractEnhanced methods of drug monitoring are required to support the individualization of therapeutic drug dosing. Clozapine is one of the most important medications for managing schizophrenia, and timely measurement of serum clozapine levels has been identified as a barrier to the broader use of clozapine. For the first time, reduced graphene oxide nanocomposites were used to construct an electrochemical clozapine (Clz) sensor. The Reduced graphene oxide (Rego) nanocomposites were synthesized and characterized by using X‐Ray Diffraction (XRD), Fourier‐Transform Infrared Spectroscopy (FTIR), Scanning Electron Microscopy (SEM), and Transmission Electron Microscopy (TEM) techniques. The Clz sensing electrode was fabricated by drop coating of Rego nanocomposites suspension and Nafion solution on the pencil graphite electrode, respectively. The electrochemical behavior and influence of various physicochemical parameters of sensing electrodes were investigated by using cyclic voltammetry (CV) and differential voltammetry (DPV) techniques. The designed sensor displayed decent linear range, detection limit, reproducibility, and reusability results. Under optimum experimental parameters a linear dynamic range of 0.05–10 μM clozapine was observed with actual detection limit of 50 nM. Furthermore, the designed sensing electrode was used to measure the amount of Clz in real samples.

A systematic review and meta-analysis of the association between clozapine and norclozapine serum levels and peripheral adverse drug reactions.

Clozapine is the most effective antipsychotic for treatment-refractory schizophrenia for reducing positive psychotic symptoms. It is associated with a reduction in hospitalisation and overall mortality. In spite of this, clozapine remains underutilised due to its complex adverse drug reaction (ADR) profile. This systematic review aims to investigate the association of clozapine and norclozapine serum levels, and peripheral ADRs. Studies were searched from four electronic databases (PubMed, EMBASE, PsycINFO and CINAHL) from inception to 12 June 2020. Studies were included if they had adult patients, provided data on steady-state trough clozapine or norclozapine levels and reported on clozapine-associated ADRs. Pregnant women, case reports and series were excluded. A statistically significant correlation was found for clozapine serum levels and triglycerides (n = 70; r = 0.303, 95% CI 0.0119-0.546, p = 0.042), heart rate (n = 137; r = 0.269, 95% CI 0.0918-0.486, p = 0.035), and overall combined ADRs (n = 160; r = 0.264, 95% CI 0.110-0.405, p = 0.001), but not for absolute neutrophil count (n = 223; r = - 0.164, 95% CI - 0.529-0.253, p = 0.444) or total white cell count (n = 18; r = 0.0176, 95% CI - 0.203-0.237, p = 0.878). Interestingly, norclozapine serum levels were found to be statistically correlated to triglycerides (n = 120; r = 0.211, 95% CI 0.0305-0.378, p = 0.022), total cholesterol (n = 120; r = 0.272, 95% CI 0.0948-0.432, p = 0.003) and weight gain (n = 118; r = 0.208, 95% CI 0.0261-0.377, p = 0.025). Heart rate, triglycerides and combined ADRs are significantly correlated with clozapine levels, and triglycerides, total cholesterol and weight gain with norclozapine levels. Future prospective, randomised controlled studies are needed to identify the cause-effect relationship between clozapine levels and peripheral ADRs.