Plasma Clozapine and N -Desmethylclozapine (Norclozapine) Concentrations and the Clozapine/Norclozapine Ratio : Effect of Dose, Sex, and Cigarette Smoking.

BACKGROUND: Smoking enhances plasma clozapine clearance, but the magnitude of the effect across the dose and age ranges is unclear. METHODS: We audited clozapine dose and predose plasma clozapine and N -desmethylclozapine (norclozapine) concentrations by sex and smoking habit in samples submitted for clozapine TDM, 1996-2017. RESULTS: There were 105,316/60,792 and 34,288/31,309 samples from male/female smokers/nonsmokers, respectively. There were distinct dose-median plasma concentration trajectories for male/female smokers/nonsmokers across the range <50 to >850 mg d -1 . For both sexes, the percentage difference in median plasma clozapine in nonsmokers versus smokers averaged 50% but was greatest for men (76%) and women (59%) in the 151 to 250 mg d -1 dose band. In men, the percentage difference declined steadily to 34% at doses of ≥850 mg d -1 . In women, the difference after falling initially remained relatively constant at 40% to 54%. The pattern in median plasma clozapine/norclozapine ratio by plasma clozapine concentration and dose groups was independent of sex and smoking habit, but increased with plasma clozapine concentration (higher ratio at higher concentrations) and also changed with dose. Median plasma clozapine concentration and median clozapine dose by sex and smoking habit were similar up to age 60 years. Proportional weight gain was similar over time in smokers and nonsmokers of either sex. IMPLICATIONS: These data explain the variations in the effect size of starting or stopping smoking on plasma clozapine concentration at constant dose reported in different studies. Changes in smoking habit in patients prescribed clozapine require prompt dose adjustment.

Time for a change to clozapine haematological monitoring.

OBJECTIVES: This paper critiques the haematological monitoring guidelines for clozapine. It describes the history of clozapine, as well as the pathophysiology and epidemiology of clozapine-induced neutropenia (CIN) and agranulocytosis (CIA). The paper appraises the extant literature on mandatory clozapine haematological monitoring. CONCLUSION: Contemporary Australian protocols for clozapine haematological monitoring are not consistent with the current evidence base. CIN and CIA are rare occurrences, and the associated risk of death is low. Potential modifications to existing guidelines include changing neutrophil thresholds for patients with benign ethnic neutropenia and reducing the frequency or removing haematological monitoring after two years of clozapine treatment.

Effect of Valproic Acid on the Metabolic Spectrum of Clozapine in Patients With Schizophrenia.

BACKGROUND: Valproic acid (VPA) is frequently used with clozapine (CLZ) as mood stabilizer and/or seizure prophylaxis. Valproic acid is known to reduce N-desmethylclozapine (N-DMC) but not CLZ levels. This leads to the hypothesis that VPA induces the CLZ metabolism via non-N-desmethylation pathways. Therefore, we aimed to investigate the effect of concurrent VPA use on the serum concentrations of a spectrum of CLZ metabolites in patients, adjusting for smoking. METHODS: In total, 288 patients with an overall number of 737 serum concentration measurements of CLZ and metabolites concurrently using VPA (cases, n = 22) or no interacting drugs (controls, n = 266) were included from a routine therapeutic drug monitoring service. Linear mixed model analyses were performed to compare the dose-adjusted concentrations (C/D) of CLZ, N-DMC, CLZ 5N/N+-glucuronides, and metabolite-to-parent ratios in cases versus controls. RESULTS: After adjusting for covariates, the N-DMC (-40%, P < 0.001) and N+-glucuronide C/Ds (-78%, P < 0.001) were reduced in cases versus controls, while the CLZ C/D was unchanged (P > 0.7). In contrast, the 5N-glucuronide C/D (+250%, P < 0.001) and 5N-glucuronide-to-CLZ ratios (+120%, P = 0.01) were increased in cases versus controls. CONCLUSIONS: Our findings show that complex changes in CLZ metabolism underly the pharmacokinetic interaction with VPA. The lower levels of N-DMC seem to be caused by VPA-mediated induction of CLZ 5N-glucuronide formation, subsequently leading to reduced substrate availability for N-desmethylation. Whether the changes in CLZ metabolism caused by VPA affects the clinical outcome warrants further investigation.

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

OBJECTIVE: To investigate the safety of COVID-19 vaccination in patients on clozapine as regards plasma clozapine concentration and haematological parameters. METHODS: We 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. RESULTS: This 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. CONCLUSION: In 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.

Clinical and genetic influencing factors on clozapine pharmacokinetics in Tunisian schizophrenic patients.

Clozapine (Clz) is an atypical antipsychotic, which its pharmacokinetics can be influenced by several factors. The CYP1A2 and CYP2C19, major enzymes implicated in Clz metabolism, present an interethnic variation on their activity caused by single nucleotide polymorphisms (SNPs). The present study investigated the influence of genetic and nongenetic factors on Clz pharmacokinetics in a southern Mediterranean population. We included adult Tunisian schizophrenic patients having received Clz and undergone a therapeutic drug monitoring (TDM) of Clz by morning C0 monitoring. The genomic DNA was extracted using a salting-out procedure. CYP1A2*1F (rs762551;-163C>A), CYP1A2*1C (rs2069514;-3860 G>A) and CYP 2C19*2 (rs4244285; 681G>A) was analyzed using PCR-RFLP. Fifty-one patients were enrolled in the study. The mutant allele (CYP1A2*1F) was the most frequently detected (58.8%). For CYP1A2*1F, Clz dose-normalized (C0/D ratio) was as high as 1.28 ± 0.37 in CC versus 0.67 ± 0.32 ng mL-1 per mg day-1 in AA group (p < 0.001). The influence of genetic (CYP1A2*1F, CYP1A2*1C and CYP2C19*2) and nongenetic parameters (age, weight, gender, tobacco, coffee, and alcohol consumption) on the variation of the Clz C0/D ratio was investigated. Only the CYP1A2*1 F polymorphism correlates significantly with the Clz C0/D variation and could explain 24% of its variability. Our data support a critical role of the CYP1A2 -163C>A on the variation of Clz exposure in Tunisian schizophrenic patients. Considering its narrow therapeutic range, CYP1A2 genotyping combined with TDM of Clz may improve efficacy and safety of this drug. Further studies are needed to investigate this issue.

High-Dose Fluvoxamine Augmentation to Clozapine in Treatment-Resistant Psychosis.

BACKGROUND: Although clozapine is the gold standard for treatment-resistant schizophrenia, more than 30% of patients remain unresponsive to clozapine monotherapy and may benefit from augmentation strategies. Fluvoxamine augmentation of clozapine may be beneficial in treatment resistance because of pharmacokinetic interactions, allowing for lower clozapine dosages with higher clozapine serum levels and an increased clozapine-to-norclozapine ratio, which can modify adverse effects. An augmentation strategy using higher fluvoxamine doses may also improve persistent negative, anxiety, and obsessive-compulsive symptoms through fluvoxamine's serotonergic activity. METHODS: Through chart review, we identified 4 cases of patients with treatment-resistant psychosis who underwent high-dose fluvoxamine augmentation of clozapine to target residual negative symptoms, refractory psychosis, anxiety, and obsessive-compulsive symptoms. FINDINGS: This augmentation strategy continued in 2 patients after discharge who showed clinical improvement without significant adverse effects. Two patients experienced adverse effects that led to the fluvoxamine discontinuation. Despite the fact that fluvoxamine augmentation led to symptom improvement in only 2 patients, all patients achieved high serum clozapine levels. Hematologic parameters were monitored in all patients, and no abnormalities were observed. No severe adverse effects of clozapine were experienced. CONCLUSIONS: Although high variability of responses and adverse effects were observed during fluvoxamine augmentation to clozapine, this strategy was successful in increasing clozapine serum levels. Through fluvoxamine's serotonergic effects, this strategy may confer benefit to residual negative, obsessive, and anxiety symptoms. Limitations of this case series include the retrospective nature, absence of controls, diversity of diagnoses, multiple interventions in each patient, and lack of masked raters.

Development of a simultaneous analytical method for clozapine and its metabolites in human plasma using liquid chromatography/electrospray ionization tandem mass spectrometry with linear range adjusted by in-source collision-induced dissociation.

Clozapine (CLZ) is a key drug in treatment-resistant schizophrenia. Therapeutic drug monitoring (TDM) of CLZ and its metabolites, N-desmethylclozapine and clozapine N-oxide, is required to monitor and manage the risks of side effects. Although quantification methods for TDM have been developed for CLZ and its metabolites, they were not sufficiently accurate for the quantification of CLZ owing to the upper limits of the calibration curves. An analytical method using high-performance liquid chromatography/electrospray ionization tandem mass spectrometry was developed and validated for the simultaneous measurement of CLZ and its metabolites in human plasma. To expand the concentration range of the calibration curves, we used a linear range shift technique using in-source collision-induced dissociation (CID). Using our approach, the linearity and quantitative range were improved compared to those reported by previous studies, and were sufficient for TDM in clinical practice. The intra- and inter-assay accuracy was 84.6%-114.8%, and the intra- and inter-assay precisions were ≤9.1% and ≤9.9%, respectively. Moreover, all samples from patients with treatment-resistant schizophrenia were successfully quantified. Therefore, our novel analytical method using in-source CID had the appropriate performance to measure the plasma concentrations of CLZ and its metabolites for TDM in clinical practice.

Association Between N-Desmethylclozapine and Clozapine-Induced Sialorrhea: Involvement of Increased Nocturnal Salivary Secretion via Muscarinic Receptors by N-Desmethylclozapine.

Clozapine-induced sialorrhea (CIS) is a common side effect of clozapine. There is no established standard treatment of CIS since the underlying mechanism remains unknown. This study aimed to elucidate the mechanisms involved in CIS. In our clinical study, a prospective observational study evaluated the association between serum and saliva concentrations of clozapine or its metabolites and Drooling Severity and Frequency Scale (DSFS) score. In our in vivo study, we first developed a new CIS animal model; subsequently, we measured salivary secretion and concentrations of clozapine or its metabolites in the animal model. In our in vitro study, we measured the calcium ion (Ca2+) response to evaluate the effect of clozapine or its metabolites on human salivary gland cell line (HSY cells) and then examined whether their effect was inhibited by atropine. In our clinical study, serum and saliva N-desmethylclozapine concentrations were significantly correlated with nocturnal DSFS score. In our in vivo study, daily single oral administration of 100 mg/kg clozapine for 7 days significantly increased salivary secretion in rats. Furthermore, N-desmethylclozapine concentrations in serum and submandibular glands of the rats were higher than clozapine concentrations. In our in vitro study, N-desmethylclozapine only elicited an increase in the intracellular Ca2+ in HSY cells. N-desmethylclozapine-induced Ca2+ responses were inhibited by atropine. These results suggest that N-desmethylclozapine is implicated in CIS by increasing nocturnal salivation via the muscarinic receptors. Moreover, our developed animal model that reflects CIS in clinical condition plays a key role as a bridge between basic and clinical research. SIGNIFICANCE STATEMENT: Clozapine-induced sialorrhea (CIS) is a severe and frequent adverse reaction, but the mechanism underlying CIS is less well understood. This paper reports that N-desmethylclozapine, a metabolite of clozapine, is implicated in CIS by increasing nocturnal salivation via the muscarinic receptors and that oral administration of clozapine at 100 mg/kg once daily for 7 days to rat is the optimum method for establishing the new animal model reflecting the clinical scenario of CIS.

Impact of CYP1A2, CYP2C19, and CYP2D6 genotype- and phenoconversion-predicted enzyme activity on clozapine exposure and symptom severity.

Clozapine is an atypical antipsychotic metabolized by CYP1A2, CYP2D6, and CYP2C19 enzymes. Among 66 adult schizophrenia patients treated with clozapine-based combination therapies, we explored the impact of genotype-predicted CYP1A2, CYP2D6, and CYP2C19 activity on dose-adjusted clozapine concentrations and symptom severity, with and without correction for inhibitors and inducers of these enzymes. Uncorrected activity scores were not associated with dose-adjusted clozapine concentrations or symptom severity. CYP1A2 and CYP2D6 activity scores corrected for known inducers (i.e., smoking) and inhibitors (e.g., concomitant medications) were associated with dose-adjusted clozapine levels and in the case of CYP1A2, symptom severity. However, smoking status and certain inhibitors of clozapine metabolism (i.e., esomeprazole) explained significantly more variance in dose-adjusted clozapine levels relative to corrected activity scores. These findings highlight the clinical importance of nongenetic factors (smoking, concomitant medications) and suggest that the added utility of CYP1A2, CYP2D6, and CYP2C19 activity scores to guide clozapine dosing is currently limited.

Impact of smoking behavior on clozapine blood levels - a systematic review and meta-analysis.

OBJECTIVE: Tobacco smoking significantly impacts clozapine blood levels and has substantial implications on individual efficacy and safety outcomes. By investigating differences in clozapine blood levels in smoking and non-smoking patients on clozapine, we aim to provide guidance for clinicians how to adjust clozapine levels for patients on clozapine who change their smoking habits. METHODS: We conducted a meta-analysis on clozapine blood levels, norclozapine levels, norclozapine/clozapine ratios, and concentration to dose (C/D) ratios in smokers and non-smokers on clozapine. Data were meta-analyzed using a random-effects model with sensitivity analyses on dose, ethnic origin, and study quality. RESULTS: Data from 23 studies were included in this meta-analysis with 21 investigating differences between clozapine blood levels of smokers and non-smokers. In total, data from 7125 samples were included for the primary outcome (clozapine blood levels in ng/ml) in this meta-analysis. A meta-analysis of all between-subject studies (N = 16) found that clozapine blood levels were significantly lower in smokers compared with non-smokers (Standard Mean Difference (SMD) -0.39, 95% confidence interval (CI) -0.55 to -0.22, P < 0.001, I2  = 80%). With regard to the secondary outcome, C/D ratios (N = 16 studies) were significantly lower in the smoker group (n = 645) compared with the non-smoker group (n = 813; SMD -0.70, 95%CI -0.84 to -0.56, P < 0.00001, I2  = 17%). CONCLUSION: Smoking behavior and any change in smoking behavior is associated with a substantial effect on clozapine blood levels. Reductions of clozapine dose of 30% are recommended when a patient on clozapine stops smoking. Reductions should be informed by clozapine steady-state trough levels and a close clinical risk-benefit evaluation.

Comparison of Novel Immunoassay With Liquid Chromatography/Tandem Mass Spectrometry (LC-MS/MS) for Therapeutic Drug Monitoring of Clozapine.

BACKGROUND: Clozapine is the most effective antipsychotic for treatment-resistant schizophrenia. Although serum clozapine levels can help guide treatment, they are underutilized owing to requirements for frequent venous blood draws and lack of immediate results. METHODS: Clozapine levels measured with a novel immunoassay technology (which enables point-of-care development) were compared with those measured by standard liquid chromatography/tandem mass spectrometry (LC-MS/MS). Frozen serum aliquots of 117 samples (N = 48 patients with schizophrenia on clozapine; N = 24 patients with schizophrenia not on clozapine; N = 45 healthy controls) were sent to a national reference laboratory (NRL) for clozapine level determination by LC-MS/MS, and matching samples were subjected to novel immunoassay (3 runs). At a later date, another frozen aliquot from the same date was sent to the NRL for repeat testing. RESULTS: The NRL obtained 18 false-positive clozapine results (mean 42.39 ± 32.06, range 21-159 ng/mL) in participants not on clozapine (N = 3) and healthy controls (N = 15). The immunoassay showed no false-positive clozapine results. The clozapine levels were correlated between both assays (r = 0.84, P < 0.0001), despite 16% higher clozapine levels with immunoassay (482.08 ± 270.88 ng/mL immunoassay, 414.98 ± 186.29 ng/mL LC-MS/MS [P = 0.03]). Agreement analysis using concordance correlation coefficient (CCC) for LC-MS/MS of the 2 aliquots yielded CCC = 0.869; 95% confidence interval = 0.690-0.970, whereas higher agreement results were observed for the 3 runs of immunoassay (CCC = 0.99; 95% confidence interval = 0.979-0.997). CONCLUSIONS: The lack of false positives observed with immunoassay, higher repeat performance agreement, and good correlation with LC-MS/MS may indicate the more robust performance of immunoassay than that of LC-MS/MS clozapine-level determination.

Clozapine and Norclozapine Plasma Levels in Patients Switched Between Different Liquid Formulations.

BACKGROUND AND OBJECTIVE: Clozapine is the drug of choice for treatment-resistant schizophrenia. The primary objective of this study was to compare plasma clozapine and N-desmethylclozapine levels in patients switched between 2 liquid formulations [Denzapine suspension and clozapine oral solution (St George's ZTAS)]. Secondary objectives included comparison of safety, tolerability, and patient acceptability. METHODS: This was a noninterventional, observational, prospective follow-up of patients consecutively switched between formulations of clozapine liquid in a large inner-city NHS mental health trust. The authors also performed retrospective analysis of outcomes from patient case notes. RESULTS: The authors identified 43 patients receiving Denzapine suspension in the trust. Data were available for 43 patients switched from Denzapine to clozapine oral solution (St George's ZTAS), among whom, 15 (32%) were excluded from the analysis. Of the 28 patients for whom data were available, the 90% confidence interval for the ratio of mean values for corrected Cmin 91.5 (85.2%-98.4%) and uncorrected Cmin 91.2 (84.4%-98.6%) were within the guideline range of bioequivalence (80%-125%). Safety and tolerability profiles were comparable between the 2 formulations (P = 0.10). Patient acceptability was also similar between the brands in most domains. However, there was a taste preference for Denzapine suspension. CONCLUSIONS: No significant difference in clozapine plasma levels was observed after switching from Denzapine suspension to a recently introduced clozapine solution. This study also highlights the significance of medicinal characteristics such as taste for patient acceptability and compliance.

The effects of augmenting clozapine with oxytocin in schizophrenia: An initial case series.

BACKGROUND: Debilitating symptoms of schizophrenia often persist after sustained treatment with atypical antipsychotics. To date, clozapine has been the most effective of the atypical antipsychotics; however, negative symptoms may persist, indicating a critical need to develop augmenting treatment approaches. METHODS: A retrospective chart review evaluated outcomes for 5 young adult inpatients with treatment-resistant schizophrenia who were prescribed off-label oxytocin (OT; 10 IU/sublingual, 1 time per day, to 20 IU/sublingual, 3 times per day) after their therapeutic response to clozapine plateaued (dose range: 200 to 600 mg). The augmented treatment was well tolerated and continued for at least 1 year after discharge from the hospital, with continued outpatient follow-up by the treating psychiatrist. Evaluation included the Positive and Negative Syndrome Scale and clinical review based on both self and parent/guardian reports. RESULTS: The augmentation of clozapine with sublingual OT in young adults with treatment-resistant schizophrenia appeared to reduce negative symptoms, maintain lowered positive symptoms, and increase occupational and social functioning (eg, return to work or school), as noted by family members. CONCLUSIONS: Future controlled, prospective studies should investigate the possibility that OT can significantly reduce negative symptoms of chronic psychotic illnesses that are inadequately responsive to clozapine or other antipsychotic medications alone.

The Effects of Co-prescription of Pantoprazole on the Clozapine Metabolism.

BACKGROUND: Polypharmacy including somatic medications such as proton pump inhibitors is a common phenomenon in psychiatric care. The aim of this study was to evaluate the pantoprazole effects on clozapine metabolism. METHODS: A large therapeutic drug-monitoring database containing plasma concentrations of CLZ was analyzed. The results were stratified into four groups: a non-smoking (n=250) and a smoking group (n=326), and two groups co-medicated with pantoprazole: non-smokers (n=26) and smokers (n=29). The analysis was based on the non-parametrical Mann-Whitney U test (M-W-U) with a significance level of 0.05. RESULTS: Differences reached statistical significance for pharmacokinetic parameters between CLZ monotherapy and co-medication with pantoprazole neither in smokers nor in non-smokers (p>0.05 for M-W-U in pairwise comparisons). In patients with clozapine monotherapy, smokers had a higher daily dosage of CLZ compared to non-smokers (mean dosage 363±181 vs. 291±145 mg/day, p<0.001 for M-W-U). CONCLUSIONS: Adding pantoprazole to an ongoing treatment with clozapine does not alter the metabolism of clozapine to a significant extent.

Professional perception of clozapine use in patients with dual psychosis.

INTRODUCTION: Patients with psychotic disorders often have substance use disorders and other addictions. The objective of this study was to know the current treatment situation of these patients focusing on clozapine, which was proposed in most consensus as antipsychotic of first choice in this indication. MATERIAL AND METHODS: A survey with 14 questions on aspects related to the treatment and management of the dual disorders was developed, emphasizing the role of clozapine in this disease. RESULTS: The survey was answered by 199 experts in mental illnesses (90.5% physicians and 9.5% psychologists). A total of 88.4% of experts were able to prescribe clozapine, but the majority (89.4%) administered the drug to patients with resistant schizophrenia without considering a dual disorder. Only 30.8% considered the use of clozapine in patients with dual psychosis. The underutilization of clozapine in these patients was mainly attributed to controls of the pharmacovigilance plan, including frequent leukocyte count (57.1%), and lack of drug education (35.6%). The main measures proposed to increase its use are fewer blood tests (29.3%), more training (27.8%), and fewer administrative problems (25.1%). CONCLUSIONS: In order to improve the treatment of patients with dual psychosis, it is necessary to simplify the therapy and increase the training of professionals in the use of atypical antipsychotics, especially clozapine, designed to be the drug of choice in the main expert consensus.

A Comparative Study of the Pharmacokinetics of Clozapine N-Oxide and Clozapine N-Oxide Hydrochloride Salt in Rhesus Macaques.

Translating chemogenetic techniques from nonhuman primates to potential clinical applications has been complicated in part due to in vivo conversion of the chemogenetic actuator, clozapine N-oxide (CNO), to its pharmacologically active parent compound, clozapine, a ligand with known side effects, including five boxed warnings from the Food and Drug Administration. Additionally, the limited solubility of CNO requires high concentrations of potentially toxic detergents such as dimethylsulfoxide (DMSO). To address these concerns, pharmacokinetic profiling of commercially available CNO in DMSO (CNO-DMSO, 10% v/v DMSO in saline) and a water-soluble salt preparation (CNO-HCl, saline) was conducted in rhesus macaques. A time course of blood plasma and cerebrospinal fluid (CSF) concentrations of CNO and clozapine was conducted (30-240 minutes post-administration) following a range of doses (3-10 mg/kg, i.m. and/or i.v.) of CNO-DMSO or CNO-HCl. CNO-HCl resulted in 6- to 7-fold higher plasma concentrations of CNO compared to CNO-DMSO, and relatively less clozapine (3%-5% clozapine/CNO in the CNO-DMSO group and 0.5%-1.5% clozapine/CNO in the CNO-HCl group). Both groups had large between-subjects variability, pointing to the necessity of performing individual CNO pharmacokinetic studies prior to further experimentation. The ratio of CNO measured in the CSF was between 2% and 6% of that measured in the plasma and did not differ across drug preparation, indicating that CSF concentrations may be approximated from plasma samples. In conclusion, CNO-HCl demonstrated improved bioavailability compared with CNO-DMSO with less conversion to clozapine. Further investigation is needed to determine if brain concentrations of clozapine following CNO-HCl administration are pharmacologically active at off-target monoaminergic receptor systems in the primate brain.

Impact of CYP1A2 genetic polymorphisms on pharmacokinetics of antipsychotic drugs: a systematic review and meta-analysis.

OBJECTIVE: To determine the impact of CYP1A2 genetic polymorphisms on the pharmacokinetics of CYP1A2-metabolized antipsychotic drugs in humans by means of systematic review and meta-analysis. METHOD: A systematic search was conducted in PubMed and Scopus databases as of June 26, 2018. Studies reporting the pharmacokinetic parameters of CYP1A2-metabolized antipsychotic drugs in individuals who were genotyped for CYP1A2 genetic polymorphisms were retrieved. Pharmacokinetic parameters of individuals who have mutant alleles of a CYP1A2 genetic polymorphism were compared with the wild-type individuals. Pooled-effect estimates, presented as standardized mean difference, were calculated by means of the fixed-effect or random-effects model, as appropriate. RESULTS: Ten studies involving 872 clozapine users, seven studies involving 712 olanzapine users, and two studies involving 141 haloperidol users were included. All but one study reported no associations between any CYP1A2 genetic polymorphisms and the pharmacokinetics of CYP1A2-metabolized antipsychotic drugs. The pooled-effect estimates through meta-analyses of seven studies demonstrated no significant associations between the -163C>A or -2467delT polymorphism and clozapine or olanzapine concentrations in the blood. CONCLUSIONS: This study suggests that CYP1A2 genetic polymorphisms have no significant impact on the pharmacokinetics of CYP1A2-metabolized antipsychotic drugs. CYP1A2 genotyping may have no clinical implications for personalized dosing of CYP1A2-metabolized antipsychotic drugs.

Reduction in N-Desmethylclozapine Level Is Determined by Daily Dose But Not Serum Concentration of Valproic Acid-Indications of a Presystemic Interaction Mechanism.

BACKGROUND: Valproic acid (VPA) is frequently used together with clozapine (CLZ) as mood-stabilizer or for the prevention of seizures in patients with psychotic disorders. VPA is known to reduce levels of the pharmacologically active CLZ-metabolite N-desmethylclozapine (N-DMC), but factors determining the degree of this interaction are unknown. Here, we investigated the relationship between VPA dose and serum concentration on N-DMC levels in a large patient population adjusting for sex, age, and smoking habits as covariates. METHODS: A total of 763 patients with steady-state serum concentrations of CLZ and N-DMC concurrently using VPA (cases, n = 76) or no interacting drugs (controls, n = 687) were retrospectively included from a therapeutic drug monitoring service at Diakonhjemmet Hospital, Oslo, between March 2005 and December 2016. In addition to information about prescribed doses, age, sex, smoking habits, and use of other interacting drugs were obtained. The effects of VPA dose and serum concentration on dose-adjusted N-DMC levels were evaluated by univariate correlation and multivariate linear mixed-model analyses adjusting for covariates. RESULTS: The dose-adjusted N-DMC levels were approximately 38% lower in VPA users (cases) versus nonusers (controls) (P < 0.001). Within the VPA cases, a negatively correlation between VPA dose and dose-adjusted N-DMC levels was observed with an estimated reduction of 1.42% per 100-mg VPA dose (P = 0.033) after adjusting for sex, age, and smoking. By contrast, there was no correlation between VPA serum concentration and dose-adjusted N-DMC levels (P = 0.873). CONCLUSIONS: The study shows that VPA dose, not concentration, is of relevance for the degree of reduction in N-DMC level in clozapine-treated patients. Presystemic induction of UGT enzymes or efflux transporters might underlie the reduction in N-DMC level during concurrent use of VPA. Our findings indicate that a VPA daily dose of 1500 mg or higher provides a further 21% reduction in N-DMC concentration. This is likely a relevant change in the exposure of this active metabolite where low levels are associated with implications of CLZ therapy.

Clozapine and desmethylclozapine: correlation with neutrophils and leucocytes counting in Mexican patients with schizophrenia.

PURPOSE: The aim of present study is to measure plasma clozapine (CLZ) and N-desmethyl clozapine (DMC) as biomarkers to correlate drug concentrations with the appearance of preclinical adverse hematic effects. METHODS: A high-performance liquid chromatographic method, using a diode-array (ultraviolet) detector, was validated to obtain reliable concentrations of CLZ and DMC, its main metabolite, in plasma of 41 schizophrenic patients taking CLZ. Blood neutrophils and leucocytes counting were concurrently assessed as a proxy to subclinical adverse reactions. RESULTS: The analytical method employed was linear, reproducible, and stable to measure concentrations of CLZ between 30 and 1000 ng/mL, while 12.5-560 ng/mL of the metabolite. The method allowed us to correlate CLZ plasma concentrations, the time taking CLZ and CLZ dose as determinants of neutrophils' counting with a R2 = 0.447, using a multiple regression analysis model. Likewise, the correlation of leucocyte counting vs CLZ plasma levels and CLZ time, showed a R2 = 0.461. DMC correlated significantly with both neutrophils and leucocytes counting, but was excluded from the regression when CLZ concentration was included in the model. Finally, no other hematological adverse reactions were recorded. One patient presented a cardiovascular complication. The negative correlation between clozapine and neutrophil count observed in patients, suggest that CLZ itself, but not DMC, could be related to hematologic side-effects. CONCLUSION: The findings of this study, demonstrate for the first time, that plasma levels of CLZ and time taking the drug are independent determinants of blood neutrophils and leucocytes, so the monitoring of plasma CLZ may be useful in the clinic practice to determine safe dosing of the drug.

Electrochemical determination of the antipsychotic medication clozapine by a carbon paste electrode modified with a nanostructure prepared from titania nanoparticles and copper oxide.

A nanostructure was prepared from titania nanoparticles and copper oxide (TiO2NP@CuO) and used to modify a carbon paste electrode (CPE). The modified CPE is shown to enable sensitive voltammetric determination of the drug clozapine (CLZ). The sensor was characterized by various techniques and some key parameters were optimized. Under the optimum conditions and at a working potential of 0.6 V (vs. Ag/AgCl), the modified CPE has two linear response ranges, one from 30 pmol L-1 to 4 nmol L-1 of CLZ, the other from 4 nmol L-1 to 10 µmol L-1. The detection limit is as low as 9 pM. The transfer coefficient (α) and catalytic rate constant (kcat) were calculated and the reliability of the sensor was estimated for CLZ sensing in real samples where it gave satisfactory results. Graphical abstract Applicability of the TiO2NP@CuO nanostructures in fabrication of an efficient clozapine (CLZ) sensor based on the use of a carbon paste electrode.