Clozapine Dose Research Articles

Clozapine Dosage in Treatment-Refractory Schizophrenia: A Reply to Dr Grover and Colleagues.

Clozapine Dosage in Treatment-Refractory Schizophrenia: A Reply to Dr Grover and Colleagues.

The effects of clinical and pharmacological factors on the ratio of clozapine to norclozapine in psychiatric patients.

Due to its exceptional effectiveness, clozapine (CLO), whose metabolite is norclozapine (NCLO), is a drug of choice in the management of treatment-resistant schizophrenia. The purpose of this study was to assess the factors modifying the CLO/NCLO ratio (CNR). A total of 446 blood samples (233 of which were drawn from females and 213 from males, aged from 18 to 77 years) were analyzed in this study. The patients were treated at a psychiatric hospital in the period 2016-2021. Serum CLO and NCLO levels were determined with high-performance liquid chromatography coupled with a UV detector. The median CNR was 2.38 (minimum 0.30, maximum 14.36). Our analysis showed that neither sex (p= 0.135) nor smoking (p = 0.774) had any significant effect on the CNR. However, increased doses of CLO resulted in lower CNR values (p = 0.005). Concomitant use of other psychotropic drugs increased the CNR (p = 0.001). The results of our study indicate a need for personalized CLO treatment. Assessing the CNR may be useful in identifying CLO interaction with other psychotropic drugs.

Prevalence and Factors Associated with Hypersalivation in Schizophrenia Inpatients Treated with Clozapine: A Retrospective Study.

Background: Hypersalivation, or excessive production and secretion of saliva, can result from associated disorders or adverse drug reactions. It significantly impacts physical health, psychosocial well-being, and quality of life. Clozapine, a gold standard for treatment-resistant schizophrenia, is known to cause hypersalivation in some patients. Objectives: This study aimed to determine the prevalence of hypersalivation and identify factors associated with its occurrence in patients with schizophrenia treated with clozapine, either as monotherapy or in combination with other antipsychotics. Methods: This retrospective cohort study was conducted using medical records from inpatients diagnosed with schizophrenia at a tertiary psychiatric hospital. Data were collected from patients treated with clozapine between June 1, 2020, and December 31, 2020. Descriptive statistics were used to describe the prevalence of hypersalivation, and multiple logistic regression was performed to assess the association between hypersalivation and patient characteristics. Results: A total of 96 patients were included in the study, with a mean age of 44.03 years (SD = 13.27); 72.9% of the patients were male. The overall prevalence of hypersalivation was 14.6%, with 19.51% of patients on clozapine monotherapy and 10.91% of those on clozapine combined with other antipsychotics experiencing hypersalivation. Male sex appeared to reduce the risk for hypersalivation (adjusted OR: 0.36, 95% CI: 0.10-1.33, P = .13), while the use of electroconvulsive therapy (ECT) significantly increased the risk of hypersalivation (adjusted OR: 5.40, 95% CI: 1.22-24.02, P = .03). Other variables, including age, Body Mass Index (BMI), smoking status, alcohol consumption, clozapine dosage, and use of anticholinergics, were not significantly associated with hypersalivation. Conclusion: The prevalence of hypersalivation in schizophrenia inpatients treated with clozapine was 14.6%. Male sex was associated with a reduced risk of hypersalivation, while ECT use significantly increased the risk. These findings provide valuable insights for clinicians managing patients on clozapine, highlighting the need for careful monitoring, particularly in patients undergoing ECT.

Severe necrotic colitis in an adolescent with polypharmacy and high clozapine doses according to his ancestry.

Severe necrotic colitis in an adolescent with polypharmacy and high clozapine doses according to his ancestry.

Significant haematological alterations in clozapine-treated patients: prevalence and clinical correlation.

Clozapine is an atypical antipsychotic crucial for treatment-resistant schizophrenia, characterised by its multi-receptor targeting, including serotonin (5-HT2A, 5-HT2C) and dopamine (D1, D2, D3, D4) receptors, among others. This broad mechanism is effective against positive symptoms of schizophrenia with a lower incidence of extrapyramidal side effects. However, clozapine poses significant haematological risks, notably agranulocytosis, necessitating stringent blood monitoring protocols. This study examined haematological parameters in 157 patients on clozapine therapy, analysing the prevalence and clinical correlations of haematological abnormalities such as leucocytosis, thrombocytosis, and alterations in red blood cell distribution width (RDW) and mean platelet volume (MPV). The findings revealed leucocytosis in 36.9% of patients, thrombocytosis in 8.9%, and elevated RDW in 23.6%. Notably, higher clozapine doses were associated with leucocytosis, though no significant correlations were found between clozapine dose, duration of use, and changes in RDW, mean corpuscular haemoglobin concentration, or MPV. The study's results underscore the necessity of regular haematological monitoring to mitigate the risks of clozapine therapy while leveraging its therapeutic benefits. Additionally, the study suggests personalised dosing strategies to balance efficacy and safety, particularly in managing clozapine-induced haematological changes.

Challenges in Validating Population Pharmacokinetic Models for Clozapine Dosage Prediction and Therapeutic Drug Monitoring

Challenges in Validating Population Pharmacokinetic Models for Clozapine Dosage Prediction and Therapeutic Drug Monitoring

Nifedipine May Be an Inhibitor of Clozapine Metabolism, as Seen in 5 Patients: 2 from a US Double-Blind Study and 3 from a German TDM Study

Background: Clozapine is the only licensed antipsychotic for treatment-refractory schizophrenia. Therapeutic drug monitoring (TDM) refers to the measurement of clozapine concentration. Clozapine TDM can be used to optimize treatment, particularly by identifying pharmacokinetic interactions between clozapine and comedications. Methods: We identified 5 cases of patients with available clozapine concentrations who were concomitantly receiving nifedipine and clozapine. These cases were drawn from 2 independent datasets: 2 from a double-blind, randomized clinical trial in the United States and 3 from a German TDM naturalistic database. As an index of clozapine clearance, we used the trough-level concentration-to-dose (C/D) ratios to estimate the minimum therapeutic doses. To estimate dose-correction factors for nifedipine treatment, we included only clozapine concentrations at steady state. We divided the clozapine minimum therapeutic doses (MTD) from the on-condition by the off-nifedipine condition. Results: In 4 patients, the ratio of on/off nifedipine for MTD ranged between 0.58 and 0.82. Another patient had no data and had to be compared with published control data (female smoker of African ancestry), providing a correction factor of 0.52 after eliminating 5 concentrations contaminated by the development of obesity. Conclusions: In the absence of access to TDM, when prescribing nifedipine to clozapine-treated patients, we recommend reducing the daily dose of clozapine by one-third because of the weak inhibition of clozapine metabolism. With access to TDM, TDM should guide dosing as unusual patients may need larger dose reductions, as it is possible that in some patients, nifedipine may be a moderate inhibitor requiring halving clozapine dose. Further prospective studies are warranted.

Abstract 4120830: A Curious Case of Clozapine Carditis with Cardiac Convalescence

Case Presentation: Clozapine is an antipsychotic used in treatment-resistant schizophrenia. Its use has been limited by adverse events, rarely including myocarditis. Here, we describe a rare case of clozapine-induced myocarditis and the improvement of cardiac function with avoidance of clozapine for one week and initiation of guideline-directed medical therapy (GDMT). A 29-year-old man with schizophrenia on risperidone and paroxetine was admitted with schizophrenia decompensation and suicidal ideations. He was transitioned to clozapine with improvement in his psychiatric symptoms. Thirteen days after starting clozapine, he developed nausea, vomiting, tachycardia, and low-grade fever. He had leukocytosis but it was thought to be, in part, secondary to methylprednisolone before rituximab infusions for his multiple sclerosis. An electrocardiogram revealed sinus tachycardia, and troponin, which was taken in the setting of clozapine therapy, was 6. Four days later, his fever and tachycardia with chills and dyspnea persisted; troponin was in the forties and increased to 235 within a few hours. Over the next 36 hours, troponin peaked at 3,600. C-reactive protein and erythrocyte sedimentation rates were elevated at 20.5 and 51, compared to 1.8 and 3 respectively upon initiation of symptoms a few days earlier. A respiratory viral panel, blood and urine cultures, human immunodeficiency virus, and an autoimmune workup were unrevealing. Clozapine was held. A transthoracic echocardiogram revealed a reduced systolic function with a left ventricular ejection fraction (LVEF) of 40%. A cardiac magnetic resonance imaging revealed acute myocarditis with LVEF 24%. He was started on GDMT and a repeat echocardiogram six days later revealed normalization of systolic function with LVEF 56% with clinical improvement. His last dose of clozapine was seven days earlier. He was discharged on GDMT and clozapine was added to his allergy list. Discussion: Myocarditis is a serious and rare adverse event to clozapine therapy. Symptoms are non-specific and delays in diagnosis may lead to myocardial damage and fatal arrhythmias. In light of the patient’s presentation, unrevealing workup, and improvement with avoidance of clozapine, we believe that the individual had clozapine-induced myocarditis. It is important to highlight the occurrence of this rare outcome to consider this toxicity and initiate treatment in time.

Clozapine Toxicity Predictor: Deep neural network model predicting clozapine toxicity and its therapeutic dose range

Clozapine is the gold standard for treatment-resistant schizophrenia; however, its superior efficacy is accompanied by potentially serious adverse events (neutropenia, seizures, constipations, pneumonia), many of which are also concentration-dependent. As such, clozapine dose titration should be guided by therapeutic drug monitoring (TDM). However, access to TDM is often limited. The present study describes a new deep neural network that can predict the concentrations, toxicity and therapeutic dose range for clozapine and norclozapine. The model was trained on basic clinical data (biological sex, age, clozapine daily dose, BMI, CRP and number of CYP 1A2 and 3A4 substrates, inhibitors and inducers) from 69 patients treated with different clozapine doses. Our findings provide the training efficacy data for the model, as well as an analysis of clozapine and norclozapine blood concentrations in a test group of three additional patients, to demonstrate its practical capabilities. The model is licensed on a free and permissive 2-Clause BSD license and is available to all clinicians; it can be accessed as a web application, available at https://csk.umed.pl/clotop.

Effect of Valproate Coprescription on Clozapine Pharmacokinetics in Clinical Practice.

Sodium valproate has been coprescribed with clozapine for seizure prophylaxis and for augmentation in treatment-refractory schizophrenia. However, the effect of valproate on clozapine metabolism and on the incidence of clozapine-related side effects is unclear. We compared clozapine dose and plasma clozapine and N-desmethylclozapine (norclozapine) concentrations in smokers and nonsmokers of both sexes in samples submitted for clozapine therapeutic drug monitoring, 1996-2017 in relation to valproate coprescription. There were 1217 (665 patients) and 3823 (1600 patients) samples from nonsmokers and from smokers, respectively, who were coprescribed valproate and clozapine. Data from 9774 (5065 patients) and 15,465 (7298 patients) samples from nonsmokers and from smokers, respectively, for whom drugs other than valproate were coprescribed were used as controls. Valproate coprescription in nonsmokers was associated with an increase in average plasma clozapine of 22.5%, suggesting moderate inhibition of clozapine metabolism, but there was no marked effect of valproate coprescription on plasma clozapine in smokers. In all the valproate-treated groups (male and female smokers and nonsmokers), the median plasma norclozapine concentration and the median plasma clozapine-to-norclozapine ratio were significantly lower and higher, respectively, as compared with the controls. Mixed-effects models showed a significant dose-response effect of valproate on lowering the plasma norclozapine concentration and on increasing the plasma clozapine-to-norclozapine ratio. Given the complexity of the effect of valproate coadministration on clozapine pharmacokinetics and the possibility that the toxicity of clozapine may be enhanced in the presence of valproate, the use of these drugs in combination must now be questioned in all patients and not only in women of childbearing age.

Unidentified CYP2D6 genotype does not affect pharmacological treatment for patients with first episode psychosis.

Research on the pharmacogenetic influence of hepatic CYP450 enzyme 2D6 (CYP2D6) on metabolism of drugs for psychosis and associated outcome has been inconclusive. Some results suggest increased risk of adverse reactions in poor and intermediate metabolizers, while others find no relationship. However, retrospective designs may fail to account for the long-term pharmacological treatment of patients. Previous studies found that clinicians adapted risperidone dose successfully without knowledge of patient CYP2D6 phenotype. Here, we aimed to replicate the results of those studies in a Dutch cohort of patients with psychosis (N = 418) on pharmacological treatment. We compared chlorpromazine-equivalent dose between CYP2D6 metabolizer phenotypes and investigated which factors were associated with dosage. This was repeated in two smaller subsets; patients prescribed pharmacogenetics-actionable drugs according to published guidelines, and risperidone-only as done previously. We found no relationship between chlorpromazine-equivalent dose and phenotype in any sample (complete sample: p = 0.3, actionable-subset: p = 0.82, risperidone-only: p = 0.34). Only clozapine dose was weakly associated with CYP2D6 phenotype (p = 0.03). Clinicians were thus not intuitively adapting dose to CYP2D6 activity in this sample, nor was CYP2D6 activity associated with prescribed dose. Although the previous studies could not be replicated, this study may provide support for existing and future pharmacogenetic research.

Polycythemia under Clozapine: A Case Study

Clozapine is widely recognized as a last-resort treatment for resistant schizophrenia, due to its efficacy in reducing persistent symptoms and lowering the risk of suicidal behavior. However, its use is limited by severe side effects, including hematological complications such as agranulocytosis. A less documented but significant complication is clozapine-induced polycythemia. This case study explores the development of polycythemia in a patient undergoing clozapine treatment for refractory schizophrenia. Despite the reduction of clozapine doses, polycythemia persisted, necessitating continued treatment due to the lack of alternative therapeutic options. The patient’s hematological abnormalities were managed through regular phlebotomies, and close collaboration between psychiatric and hematological services. This case emphasizes the importance of rigorous hematological monitoring in patients on clozapine and calls for further research into its effects on the hematopoietic system, particularly concerning polycythemia. The mechanisms underlying this association are not well understood but may involve immune-mediated responses, bone marrow alterations, and metabolic changes, necessitating multidisciplinary management for optimal patient care.

P11: Clozapine-Induced Thrombocytopenia: Whether or Not to Continue Clozapine Treatment when Platelet Count Falls

Objectives: To determine if and when to continue clozapine in patients with clozapine-induced thrombocytopenia.Methods: A case report and literature review of a geriatric patient with Parkinson’s disease (PD) psychosis, on longstanding treatment with clozapine with recent development of thrombocytopenia, is presented.Results: 85-year-old male with a history of PD complicated with sialorrhea, constipation, levodopa-induced dyskinesia, rapid eye movement sleep behavior disorder, neurocognitive impairment, and PD psychosis who follows up with the Emory Brain Health Center. Medications include carbidopa-levodopa, clozapine, donepezil, and rasagiline. He reports distressing delusional jealousy and egodystonic visual hallucinations. He has tried multiple antipsychotics with insufficient response. He has been on clozapine for nearly 10 years with moderate efficacy. His current dose is 62.5mg daily. Absolute neutrophil counts have been normal, but he developed thrombocytopenia. Though he had normal platelets at baseline, his platelets fell to 134,000/μL and have gradually decreased within a year, most recently to 82,000/μL. He has been asymptomatic without easy bleeding or bruising. His clozapine dose has remained the same with ongoing laboratory monitoring. He follows with his primary care doctor and was referred to hematology.Conclusions: The literature on clozapine-induced thrombocytopenia is limited. Incidence is variable and ranges from 0.083%-8.2% in larger samples. Most cases occur within the first 18 weeks of clozapine initiation. It is generally transient and self-resolving, usually lasting under 13 weeks, though a case report noted it to last up to 40 months. It is imperative to have hematologic baselines. The manufacturer recommends discontinuing the drug when platelet counts fall below 100,000/μL, resuming therapy when they return to normal, and permanently discontinuing if this reoccurs. UK guidelines recommend that if platelet counts fall below 50,000/μL, clozapine should be discontinued, with monitoring frequency increased. Therapy can be resumed once platelet counts normalize and if asymptomatic. Special caution must be taken in geriatric patients who are prone to fall and balance-related injuries.

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

Smoking enhances plasma clozapine clearance, but the magnitude of the effect across the dose and age ranges is unclear. 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. 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. 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.

Clozapine-associated adverse drug reactions in 38,349 psychiatric inpatients: drug surveillance data from the AMSP project between 1993 and 2016

Clozapine is a second-generation antipsychotic drug that offers superior treatment results in patients with schizophrenia but is also associated with significant risks. This study analyzes data on pharmacotherapy with clozapine and the associated adverse drug reactions (ADRs) in an inpatient setting including 38,349 patients. Data about the use of clozapine and reports of severe ADRs within the period 1993–2016 were obtained from the multicentered observational pharmacovigilance program “Arzneimittelsicherheit in der Psychiatrie” (AMSP). In total, 586 severe clozapine-associated ADRs were documented (1.53% of all patients exposed). Patients aged ≥65 years had a higher risk of ADRs than patients aged <65 years (1.96 vs. 1.48%; p = 0.021). Significantly more ADRs were attributed to clozapine alone (396; 67.6% of all 586 ADRs) than to a combination with other drugs. The most frequent ADRs were grand mal seizures (0.183% of all 38,349 patients exposed), delirium (0.180%), increased liver enzymes (0.120%), and agranulocytosis (0.107%). We detected 24 cases (0.063%) of clozapine-induced extrapyramidal symptoms, of which 8 (0.021%) were attributed to clozapine alone. Five ADRs resulted in death (0.013%): 2 due to agranulocytosis (41 cases total) (mortality = 4.88%) and 3 due to paralytic (sub)ileus (16 cases) (mortality = 18.75%). The median dose of clozapine in all patients treated was 300 mg/day, in patients who developed ADRs 250 mg/day. The main risk factor for an ADR was pre-existing damage of the affected organ system. Overall, the results of this study highlight the importance of alertness—especially of frequently overlooked symptoms—and appropriate monitoring during treatment with clozapine, even at low doses.

A study of the pharmacokinetics of clozapine and its metabolites by the dynamics of its distribution in the oral fluid of healthy volunteers.

Clozapine (CLZ) -related accidents or crimes are common in the world. Oral fluid drug detection is a convenient measure of dealing with things like that. There has not been any literature reported detailedly the representation rule of clozapine and its metabolites in oral fluid so far. The study aimed to describe the pharmacokinetics of CLZ and its metabolites N-desmethylclozapine and clozapine-N-oxide in human oral fluid after a single 12.5mg oral dose of CLZ. Twenty-nine volunteers, including 20 males and 9 females, were recruited, and 2mL oral fluid was collected from each participant at post-consumption time-points of prior (zero), 0.5, 1.5, 3, 5, 8, 12, 24, 36, 51, 82, and 130h, respectively. Analytes of interest were extracted with solid-phase extraction and analyzed with liquid chromatography tandem mass spectrometry method. Pharmacokinetic parameters were calculated using the pharmacokinetic software DAS according to the non-compartment model. The maximum concentration, the time of maximum concentration, oral clearance, and the elimination half-life of clozapine were 16.57 ± 9.63ng/mL, 4.53 ± 3.61h, 57.65 ± 23.77 L/h and 53.58 ± 52.28h, respectively. The maximum concentration, the time of maximum concentration, and the elimination half-life of the metabolite N-desmethylclozapine were 3.08 ± 1.19ng/mL, 9.38 ± 9.33h and 62.67 ± 82.57h, respectively; of clozapine-N-oxide were 1.15 ± 0.36ng/mL, 4.53 ± 2.19h and 19.15 ± 23.11h, respectively. It was the first study on the pharmacokinetics of CLZ and its metabolites in the oral fluid of Chinese healthy volunteers, and it provided a basis for the therapeutic drug monitoring and toxicological interpretation in clozapine-related cases.

Impact of clozapine once-daily versus multiple-daily dosing regimen on relapse in patients with treatment-resistant schizophrenia:A1-year retrospective cohort study.

Clozapine, the standard treatment for treatment-resistant schizophrenia (TRS), is generally recommended in a multiple-daily dosing regimen. However, it is commonly administered once daily in clinical practice. Few studies have compared the longitudinal clinical outcomes of these two dosing regimens. To investigate the effect of once-daily versus multiple-daily dosing regimens of clozapine on relapse in patients with TRS. This retrospective cohort study included patients with TRS who commenced treatment with clozapine during hospitalization and were discharged between April 2012 and January 2022 from a tertiary psychiatric hospital in Japan. Relapse, defined as a psychiatric exacerbation requiring re-hospitalization within the first-year post-discharge, was analyzed. Multivariable Cox proportional hazards regression analysis compared the relapse risk between once-daily and multiple-daily dosing regimens. A subgroup analysis was conducted to examine the potential interactions between dosing regimen and dose category (low versus high dose). Among 179 patients, 107 (59.8%) received clozapine once daily. No significant difference in the relapse risk was observed between once-daily and multiple-daily dosing regimens (adjusted hazard ratio [aHR]: 1.16; 95% confidence interval [CI]: 0.68-1.99; p = 0.58). However, in patients receiving high doses of clozapine (> 300mg/day), multiple-daily dosing increased the relapse risk compared to once-daily dosing (aHR: 2.23; 95% CI: 1.00-4.97; p = 0.049). Once-daily clozapine dosing may not be associated with an increasedrelapse risk. The increased relapse risk in high-dose multiple-daily dosing may be confounded by unmeasured non-adherence. Further randomized controlled trials are required to validate these findings.

Evaluating Reduced Blood Monitoring Frequency and the Detection of Hematological Abnormalities in Clozapine-Treated Patients With Schizophrenia: A Chart Review Study From the COVID-19 Pandemic.

In response to Health Canada's March 2020 directive, patients on clozapine for over 12 months were allowed to extend hematological testing intervals from 4 to 8 weeks during the COVID-19 pandemic. We hypothesized that this change would not affect the timely detection of hematological abnormalities in patients with severe mental illness. A chart review was conducted of patients at the Royal Ottawa who were prescribed clozapine from March 2019 to March 2021. We analyzed clinical and hematological data from electronic health records and Clozaril Support and Assistance Network database to compare occurrences of hematological abnormalities [leukopenia (white blood cell count <3.5 × 109/L) and agranulocytosis (absolute neutrophil count <0.5 × 109/L)] from March 17, 2020 to March 16, 2021, between standard and extended monitoring protocols using binomial logistic and zero-inflated negative binomial regressions. Of 621 patients, 196 were on extended blood monitoring, and 425 followed standard blood monitoring. Clozapine dose did not differ between groups (standard: 370 ± 201mg; extended: 352 ± 172mg; P = .14, ds = 0.10). Clozapine treatment duration up to March 2021 was 12.6 ± 8.3 years, with the extended group (10 ± 7.9 years) having a significantly (P < .01, ds = 0.50) shorter duration than the standard (14 ± 8.2 years). Extended monitoring did not significantly impact likelihood of detecting hematological abnormalities (OR = 0.83, 95% CI [0.58,1.41], P = .55) after controlling for age, sex, total bloodwork, and other psychotropics associated with neutrophil counts (ie, valproate, olanzapine). No patient on the extended regimen developed agranulocytosis. Reducing blood monitoring frequency in patients on clozapine for more than 12 months did not compromise detection of hematological abnormalities.

Physostigmine reversal of delirium from second generation antipsychotic exposure: a retrospective cohort study from a regional poison center

Introduction Physostigmine is an effective antidote for antimuscarinic delirium. There is little evidence for its use to reverse delirium following second generation antipsychotic exposure. The purpose of this study is to describe the safety and effectiveness of physostigmine in reversing delirium from second generation antipsychotic exposure. Methods This is a retrospective cohort study of all patients reported to a single regional poison center treated with physostigmine following a second generation antipsychotic exposure from January 1, 2000 to April 15, 2021. The poison center electronic medical record was queried to identify cases and for data abstraction. The primary outcome was the positive response rate to physostigmine, as determined by two trained abstractors. Secondary outcomes included physostigmine dosing, and adverse events. Results Of 147 charts reviewed, 138 individual patients were included, and the response to physostigmine was reported in 128 patients. The most common second-generation antipsychotic exposure was quetiapine (97; 70.3 percent). A positive response to physostigmine was noted in 106/128 (82.8 percent) patients [95 percent confidence interval 68.9–83.6 percent]. Median number of physostigmine doses was 1 (interquartile range 1–3; range 1–9). The median total physostigmine dose received was 2 mg (interquartile range 2–6 mg; range 0.15–30 mg). The positive physostigmine response rate for patients with an antimuscarinic co-ingestion was not significantly different compared to patients with a different co-ingestion or no co-ingestion (25/34 versus 81/94; P = 0.09). Adverse events were reported in four (2.9 percent) patients, including one death. Discussion A positive response to physostigmine to treat antimuscarinic delirium from second generation antipsychotic exposure was reported in 82.8 percent of patients, which is similar to previous physostigmine studies. Adverse events were infrequent, and included diaphoresis (one 0.7 percent), seizure (one; 0.7 percent), and bradycardia (one; 0.7 percent). One (0.7%) patient suffered a cardiac arrest 60 minutes after receiving physostigmine to treat antimuscarinic delirium following having received increasing clozapine doses over the previous month. Conclusions In this study, physostigmine appears to be a safe and effective treatment for antimuscarinic delirium from second generation antipsychotic exposure. Further studies are needed to validate the safety and effectiveness of physostigmine for this indication.

Use of Clozapine in persons with a history of seizures: A retrospective study

BackgroundSeizures are considered to be one of the dreaded side effects of clozapine, and due to this, the use of clozapine is avoided in patients with treatment-resistant schizophrenia. Resultantly, there is little information about the use of clozapine among patients with seizure disorder. AimTo assess the safety of clozapine in patients with history of seizures in their lifetime before starting clozapine and receiving clozapine for the management of psychotic disorders. ResultsOut of the 958 patients, 35 (3.65 %) had a history of at least one seizure episode before starting clozapine, with a mean of 5.06 (SD: 7.23; Median: 3.00) seizures before starting clozapine. The mean duration between the last seizure and the starting of clozapine was 123.75 (SD: 124.99; Median: 84) months, with nine patients having an episode of seizure in the previous 12 months and 15 patients being seizure-free for more than ten years. About one-fourth (25.7 %; nine out of 35) of the patients had recurrence of seizure while receiving clozapine for a mean duration of about five years. When the recurrence of seizure after starting clozapine was evaluated in patients receiving antiepileptics along with clozapine, the incidence of at least one seizure was 26.67 % (4 out of 15), and among those not receiving antiepileptics, the incidence of at least one seizure was 25 % (5 out of 20). The dose of clozapine at which seizure was noted ranged from 12.5 mg to 600 mg/day with a mean of 236.25 (SD: 169.04; Median: 162.5) mg/day. In none of the patients, clozapine had to be stopped due to the continuation of seizures. ConclusionAbout one-fourth of the patients with history of an episode of seizure have recurrence of seizure while receiving clozapine. The demographic and clinical variables do not differ between those who develop and who do not develop seizures after starting clozapine, including concomitant use of antiepileptics.