First onset of persistent neutropenia in patient undergoing long-term clozapine treatment after vaccination against COVID-19 and SARS-CoV-2 infection in short interval - a case report. / Pierwszorazowa uporczywa neutropenia u pacjenta przewlekle leczonego klozapina po szczepieniu przeciwko COVID-19, krótko poprzedzajacym infekcje wirusem SARS-CoV-2 ­ opis przypadku.

Clozapine is one of the most effective antipsychotic drugs, but its use is limited due to the possibility of severe side effects, such as neutropenia and agranulocytosis. The risk of these complications is the highest at the beginning of the treatment, but they can occur later, particularly when additional risk factors are present. In the described case, either COVID-19 vaccination or the infection itself led to severe neutropenia, which recurred during subsequent independent trials of other antipsychotic drugs. The paper presents the case of a 23-year-old woman diagnosed with early-onset, treatment-resistant schizophrenia who had been undergoing clozapine treatment with satisfying outcome for over 10 years. A week after the first dose of an mRNA vaccine against COVID-19, the patient developed a severe SARS-CoV-2 infection and experienced an extreme neutropenia, followed by a change of treatment. Although the patient fully recovered from the infection, the re-stabilization of her mental state remained unsatisfactory. The introduction of various newly implemented antipsychotic drugs led to partial improvement or another decline in the neutrophil count, despite discontinuing the use of clozapine. The authors discuss a few possible pathomechanisms. Based on our current knowledge, this is the first reported case of persistent neutropenia triggered by various antipsychotic drugs following exposure to SARS-CoV-2 antigens.

Evaluating the impact of COVID-19 on medication adherence and health care utilization among individuals with psychotic disorders who are prescribed long-acting injectables (LAIs) or clozapine: A population-based study in Manitoba, Canada.

BACKGROUND: Ongoing psychiatric follow-up and medication adherence improve outcomes for patients with psychotic disorders. Due to COVID-19, outpatient care may have been disrupted, impacting healthcare utilization. METHODS: A retrospective population-wide study was conducted for adults in Manitoba, Canada. Medication adherence and healthcare utilization were examined from 2019 to 2021. The presence of a diagnosed psychotic disorder was identified in the five years before the index date in each year. The LAI and clozapine cohorts consisted of those who received at least two prescriptions in each year 180 days before the March 20th index date. The change in adherence was measured using the average Medication Possession Ratio. Healthcare utilization rates were compared using Generalized Estimating Equation models. RESULTS: There were no significant differences between LAI and clozapine discontinuation rates before and during the pandemic. In the LAI cohort, general practitioner visits decreased significantly (-3.5 %, p = 0.039) across four quarters of 2021 versus 2019. All-cause hospitalizations decreased by 16.8 % in 2020 versus 2019 (p = 0.0055), while psychiatric hospitalizations decreased by 18.7 % across four quarters in 2020 (p = 0.0052) and 13.7 % in 2021 (p = 0.0425), versus 2019 in the LAI cohort. There was a significant transition to virtual care during the first wave of COVID-19 (71 % in clozapine, 51 % in LAI cohorts). Trends in total outpatient visits and non-psychiatric hospitalizations remained stable. CONCLUSION: COVID-19 had no substantial impact on LAI and clozapine discontinuation rates for patients previously adherent. Outpatient care remained stable, with a significant proportion of visits being done virtually at the outset of the pandemic.

Impacts of exposure to and subsequent discontinuation of clozapine on tripartite synaptic transmission.

BACKGROUND AND PURPOSE: Clozapine is an effective antipsychotic for treatment-resistant schizophrenia, but its discontinuation leads to discontinuation syndrome/catatonia complicated by benzodiazepine-resistance and rhabdomyolysis. EXPERIMENTAL APPROACH: This study determined time-dependent effects of exposure and subsequent discontinuation of clozapine on expression of connexin43, 5-HT receptors, intracellular L-ß-aminoisobutyrate (L-BAIBA) and 2nd-messengers and signalling of AMPK, PP2A and Akt in cultured astrocytes and rat frontal cortex. KEY RESULTS: Intracellular L-BAIBA levels increased during clozapine exposure but immediately recovered after discontinuation. Both exposure to clozapine and L-BAIBA increased connexin43 and signalling of AMPK/Akt time-dependently, but reduced PP2A signalling, 5-HT receptor expression and IP3 level. These changes recovered within 2 weeks after discontinuation, while 5-HT receptors and IP3 transiently increased during the recovery process. L-BAIBA activated AMPK signalling, leading to attenuated PP2A signalling. Astroglial D-serine release was increased by clozapine exposure but continued to increase within 1 week after discontinuation via activation of IP3 receptor function. CONCLUSION AND IMPLICATIONS: Clozapine discontinuation restored PP2A signalling due to decreased L-BAIBA, increased 5-HT receptor expression via probably enhanced 5-HT receptor recycling, but increased astroglial D-serine release persisted by transiently activated IP3 receptors via transiently increased IP3 level. Decreased L-BAIBA caused by clozapine discontinuation is, at least partially, involved in the transiently increased 5-HT receptor and astroglial D-serine release.

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 12.5 mg oral dose of CLZ. Twenty-nine volunteers, including 20 males and 9 females, were recruited, and 2 mL 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 130 h, 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 ± 9.63 ng/mL, 4.53 ± 3.61 h, 57.65 ± 23.77 L/h and 53.58 ± 52.28 h, respectively. The maximum concentration, the time of maximum concentration, and the elimination half-life of the metabolite N-desmethylclozapine were 3.08 ± 1.19 ng/mL, 9.38 ± 9.33 h and 62.67 ± 82.57 h, respectively; of clozapine-N-oxide were 1.15 ± 0.36 ng/mL, 4.53 ± 2.19 h and 19.15 ± 23.11 h, 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.

Association of new-onset diabetes mellitus in adults with schizophrenia treated with clozapine versus patients treated with olanzapine, risperidone, or quetiapine: A systematic review and meta-analysis.

INTRODUCTION: Many articles suggest that clozapine was strongly associated with a higher incidence of new-onset diabetes mellitus, and the issue has remained unsettled. Many articles have compared clozapine with FGAs, but few have compared clozapine with SGAs. We aimed to compare the risk of new-onset diabetes mellitus in adults with schizophrenia treated with clozapine and other SGAs. METHODS: We conducted a comprehensive search of databases from their inception up until August 26, 2023. The specific databases include PubMed, Embase and others. We included non-randomized controlled trials involving the use of SGAs such as clozapine, olanzapine, risperidone, quetiapine, amisulpride, and zotepine, with a focus on new-onset diabetes mellitus as an outcome. We utilized odds ratio with 95 % credible intervals (95 % CI) as our effect size measures. The study protocol is registered with PROSPERO, number CRD42024511280. RESULTS: We included 7 studies with sufficient data to include in the meta-analysis. A total of eight studies with 641,48 participants met the eligibility criteria. The OR of the incidence rates of new-onset diabetes between clozapine and olanzapine was 0.95 (95 % CI:[0.82-1.09]), between clozapine and risperidone was 1.25 (95 % CI: [1.09-1.44]), between clozapine and quetiapine was 1.44 (95 % CI: [0.92-2.25]). CONCLUSION: In patients with schizophrenia, clozapine has been found to have a higher rate of new-onset diabetes mellitus compared to risperidone. However, there was no significant difference in incidence rate between clozapine versus olanzapine and quetiapine. These findings can assist clinicians in balancing the risks and benefits of those drugs.

Polypharmacy to Clozapine Monotherapy in Treatment-Resistant Schizophrenia: A Case Report and Review of the Literature.

This case report discusses a 25-year-old Middle Eastern female with a 14-year history of schizophrenia, managed as an inpatient for nearly eight years. Initially referred to a psychiatrist at age 12, with one-year-long concerns about preoccupation with the idea of having a serious illness, depressed mood, decreased appetite, social withdrawal, and aggression, she underwent multiple admissions, various medication combinations, and electroconvulsive therapy but remained resistant to treatment until clozapine monotherapy was initiated in 2023. After starting clozapine, improvements were noted in speech, communication, and eye contact, though negative symptoms and bouts of aggression persisted. This case highlights the efficacy of clozapine monotherapy in managing treatment-resistant schizophrenia after years of ineffective polypharmacy treatment. The importance of clozapine in treating treatment-resistant schizophrenia cannot be understated. Despite its efficacy, clozapine is often underutilised globally due to concerns about adverse effects and the need for blood monitoring, leading to the overuse of antipsychotic polypharmacy. This polypharmacy is associated with higher adverse event rates, increased costs, and uncertain long-term safety. This case report demonstrates the successful management of treatment-resistant schizophrenia with clozapine monotherapy. The patient's significant improvement supports the need to prioritise clozapine, highlighting its benefits over polypharmacy and advocating for its broader use to enhance patient outcomes.

Impact of clozapine once-daily versus multiple-daily dosing regimen on relapse in patients with treatment-resistant schizophrenia: A 1-year retrospective cohort study.

RATIONALE: 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. OBJECTIVE: To investigate the effect of once-daily versus multiple-daily dosing regimens of clozapine on relapse in patients with TRS. METHODS: 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). RESULTS: 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 (> 300 mg/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). CONCLUSIONS: Once-daily clozapine dosing may not be associated with an increased relapse 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.

Novel mimetic tissue standards for precise quantitative mass spectrometry imaging of drug and neurotransmitter concentrations in rat brain tissues.

Understanding the relationship between the concentration of a drug and its therapeutic efficacy or side effects is crucial in drug development, especially to understand therapeutic efficacy in central nervous system drug, quantifying drug-induced site-specific changes in the levels of endogenous metabolites, such as neurotransmitters. In recent times, evaluation of quantitative distribution of drugs and endogenous metabolites using matrix-assisted laser desorption/ionization (MALDI)-mass spectrometry imaging (MSI) has attracted much attention in drug discovery research. However, MALDI-MSI quantification (quantitative mass spectrometry imaging, QMSI) is an emerging technique, and needs to be further developed for practicable and convenient use in drug discovery research. In this study, we developed a reliable QMSI method for quantification of clozapine (antipsychotic drug) and dopamine and its metabolites in the rat brain using MALDI-MSI. An improved mimetic tissue model using powdered frozen tissue for QMSI was established as an alternative method, enabling the accurate quantification of clozapine levels in the rat brain. Furthermore, we used the improved method to evaluate drug-induced fluctuations in the concentrations of dopamine and its metabolites. This method can quantitatively evaluate drug localization in the brain and drug-induced changes in the concentration of endogenous metabolites, demonstrating the usefulness of QMSI.

Effect of Common Cold on Serum Clozapine Concentrations in Hospitalized Patients with Schizophrenia.

Objective: The present study aims to investigate the effect of common cold on the serum clozapine concentrations in hospitalized patients with schizophrenia. Methods: A total of 65 schizophrenic patients with common cold receiving clozapine treatment were retrospectively enrolled. The demographic data, medication situation, clozapine concentration, and parameters of routine haematological and biochemical laboratory tests were obtained from the medical record system. The serum clozapine concentration and clozapine concentration/dose (C/D) ratios between the baseline period and cold period were compared by paired-sample t tests. Association between the changes in serum concentration and C/D ratios of clozapine and changes in white blood cell (WBC) and neutrophil (NE) counts was evaluated using Pearson correlation analysis. Results: The serum clozapine concentration (t = -9.856, P < 0.001) and clozapine C/D ratios (t = -10.071, P < 0.001) were found to be significantly elevated in the cold period compared to the baseline period. Moreover, the changes in the serum clozapine concentration were found to be significantly elevated in female patients compared to male patients (t = -2.483, P = 0.017). Furthermore, changes in the serum clozapine concentration were positively correlated to the changes in WBC (r = 0.303, P = 0.014) and NE (r = 0.315, P = 0.011) counts. Similarly, changes in clozapine C/D ratios were positively correlated to the changes in WBC (r = 0.275, P = 0.027) and NE (r = 0.328, P = 0.008) counts. Conclusion: The serum clozapine concentrations in patients with schizophrenia during the common cold period were increased, which might by related to the elevated WBC and NE counts.

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.

Exploration of Clozapine-Induced Cardiomyopathy and Its Mechanism.

In this study, by pooling the clinical data of patients who died with a history of long-term clozapine use and by examining their hearts, it was found that long-term clozapine use can lead to cardiomyopathy and that its presentation resembles arrhythmogenic cardiomyopathy (ACM), i.e., it exhibits a predominantly right ventricular fatty infiltration with mild left ventricular damage. The transcriptomic data of rat cardiomyocytes after clozapine intervention were analyzed by transcriptomic approach to explore the causes of clozapine cardiomyopathy. The cause of clozapine cardiomyopathy was then explored by a transcriptomic approach, which revealed that its clozapine action on cardiomyocytes enriched cardiomyocyte-related differential genes in biological processes such as muscle development and response to hypoxia, as well as pathways such as fatty acid metabolism and cellular autophagy. Transcriptomic analysis showed that Egr1, Egr2, ler2, Jun, Mapk9, Nr1d2, Atf3, Bhlhe40, Crem, Cry1, Cry2, Dbp were hub genes for clozapine injury to the myocardium, and that these genes may play an important role in the myocardial ACM-like changes caused by clozapine. Combined with the results of pathological examination and transcriptomic analysis, it can be concluded that the long-term action of clozapine on cardiomyocytes leads to cellular autophagy and subsequent structural remodeling of the heart, and in the remodeling affects fatty acid metabolism, which eventually leads to ACM-like changes.

Characteristics and causes of reported clozapine-related medication errors: analysis of the Ministry of Health database in Saudi Arabia.

BACKGROUND: Clozapine has shown great efficacy in treating treatment-resistant schizophrenia, but it is associated with a variety of medication- related safety problems. Despite this, there remains a lack of research on medication errors (MEs) associated with its use. AIM: To characterize the nature and contributory factors of clozapine-related MEs reported from government hospitals and primary care centres in Saudi Arabia (SA). METHOD: A cross-sectional analysis was carried out on MEs related to clozapine use reported to the General Administration of Pharmaceutical Care at the Ministry of Health (MOH) in Saudi Arabia between 2018 and 2022. The data were analysed descriptively to examine the nature and contributory factors of MEs. RESULTS: A total of 1,165 MEs were reported. The majority of reported errors involved patients aged > 18 years old, with 72.2% (n = 841) being male. The central region was found to report errors more frequently (32.3%, n = 376). Pharmacists were reported to detect errors most frequently (59.6%, n = 695). MEs most often occurred in the prescribing stage (77.8%, n = 906), with "missing prescription information" (30.1%, n = 351) being the most frequent finding. The most frequent contributing factor was the lack of policy (33.1%, n = 351). The majority of errors did not reach the patients (92.3%, n = 1,075), and those that did reach patients rarely resulted in harm (0.3%, n = 2). CONCLUSION: This study identified areas for improvement which could expedite the development of remedial interventions to reduce the risk of errors.

Severe neutropenia unrelated to clozapine in patients receiving clozapine.

BACKGROUND: Clozapine is known to cause agranulocytosis. Mandatory monitoring schemes are aimed at reducing the risk of agranulocytosis and of the consequences of agranulocytosis. All cases of agranulocytosis occurring in people prescribed clozapine are assumed to be caused by clozapine. METHODS: In a previous study, we examined a cohort of patients listed on our hospital database as having had clozapine-induced agranulocytosis and applied specific criteria to identify those with confirmed clozapine-related, life-threatening agranulocytosis. In this study, we examine the cases not meeting these specific criteria. RESULTS: In the original study, 9 of 23 cases met the criteria for clozapine-induced, life-threatening agranulocytosis. Of the 13 remaining cases for whom data were available, 5 were probably caused by clozapine but were not life-threatening. Three cases were the result of concomitant cancer chemotherapy. Three were anomalous results probably related to measurement error. For the remaining two cases, the cause was not identified. CONCLUSION: Not all cases of agranulocytosis occurring in people taking clozapine are caused by clozapine. The widely used threshold criterion-based diagnosis overestimates the risk of agranulocytosis. True clozapine-related agranulocytosis is best identified by pattern-based criteria: rapid fall in neutrophil counts over around 2 weeks to below 0.5 × 109/L for two consecutive days (unless clozapine is stopped very early or granulocyte colony stimulating factor is given) where other possible causes (benign ethnic neutropenia, cancer chemotherapy) can be ruled out.

Increased antipsychotic drug concentration in hospitalized patients with mental disorders following COVID-19 infection: a call for attention.

Purpose: Examine the alterations in antipsychotic concentrations following coronavirus disease-2019 (COVID-19) infection among hospitalized patients with mental disorders and conduct an analysis of the factors influencing these changes. Methods: Data were collected from inpatients at Beijing Huilongguan Hospital between December 12, 2022, and January 11, 2023, pre- and post-COVID-19. Based on the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, 329 inpatients with mental disorders were included (3 with incomplete data excluded). Primary outcomes assessed changes in antipsychotic concentrations pre- and post-COVID-19, while secondary outcomes examined factors linked to concentration increases and antipsychotic dose adjustments. Results: Clozapine (P < 0.001), aripiprazole (P < 0.001), quetiapine (P = 0.005), olanzapine (P < 0.001), risperidone (P < 0.001), and paliperidone (P < 0.001) concentrations increased post-COVID-19 in patients with mental disorders. Notably, clozapine concentration surpassing pre-infection levels was highest. Clozapine users were more likely to adjust their dose (50.4%) compared to olanzapine (17.5%) and other antipsychotics. Moreover, traditional Chinese patent medicines and antibiotics during COVID-19 infection were associated with antipsychotic reduction or withdrawal (OR = 2.06, P = 0.0247; OR = 7.53, P = 0.0024, respectively). Conclusion: Antipsychotic concentrations in hospitalized patients with mental disorders increased after COVID-19 infection, that may be related not only to COVID-19, but also to the use of Chinese patent medicines during infection. The pre-infection concentration and types of antipsychotics, patient's gender, and combination of traditional Chinese medicine or antibiotics, were factors found to correlate with increased drug concentrations and necessitate dose adjustments.

A Pharmacovigilance Study on Clozapine in the Food and Drug Administration Adverse Event Reporting System: A Regional Comparative Analysis.

Objective: This pharmacovigilance study evaluated the profile of clozapine-related adverse events by region using the Food and Drug Administration Adverse Event Reporting System (FAERS). Methods: We categorized each case into five regions (America, Europe/West Asia, Oceania, Asia, and Africa) based on the reporting country information in the FAERS database. The number of clozapine-related adverse events reported in each region was aggregated according to the preferred term (PT) and the Standardized Medical Dictionary for Regulatory Activities (MedDRA) Query (SMQ). Results: A total of 101,872 clozapine-related adverse events were registered in the FAERS database. In America and Europe, leukocyte or neutrophil count abnormalities accounted for half of the top 10 PTs by relative reporting rate. However, Asia had higher relative reporting rates of pyrexia and salivary hypersecretion (13.91% and 10.85%, respectively). Regarding the SMQ, the relative reporting rates of infective pneumonia, convulsions, extrapyramidal syndrome, gastrointestinal obstruction, and hyperglycaemia/new onset diabetes mellitus were higher in Asia than in other regions (5.26%, 9.72%, 12.65%, 5.13%, and 8.26%, respectively), with significant differences even after adjusting for confounding factors using multivariate logistic regression analysis. Conclusion: Spontaneous reports of adverse events associated with clozapine show regional disparities, particularly in Asia, where concentration-dependent adverse events are more frequently reported. However, the spontaneous reporting system has several limitations, requiring further research for validation.

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

BACKGROUND: Seizures 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. AIM: To 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. RESULTS: Out 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. CONCLUSION: About 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.

An experience of using Clozapine in elderly patients with mental disorders.

BACKGROUND: There is little information on using clozapine in elderly patients with mental disorders from India. AIM: To evaluate the sociodemographic and clinical profile of elderly (age ≥ 60 years) patients started on clozapine. METHODOLOGY: The clozapine registry in the department was screened to identify elderly patients who were started on clozapine. Treatment records of these patients were reviewed to extract sociodemographic and clinical details. RESULTS: Out of the available information of 1058 patients in the registry, 42 (3.96 %) were elderly (≥ 60 years) patients. About two-thirds of the patients had treatment resistance, i.e., their psychotic illness had not responded to two adequate trials of antipsychotics, and the second most common indication for starting clozapine was tardive dystonia or tardive dyskinesia (23.8 %). The mean dose of clozapine was 135.89 (SD: 109.6; Range: 37.5-500; median: 87.5) mg/day. The mean duration of clozapine use at the time of data extraction for the study sample was 3.55 (SD: 2.15; Range 0.3-9; median: 3) years. At the last follow-up, about three-fourths of patients were experiencing at least one side effect, with constipation being the most common side effect, followed by sedation, weight gain, and hypersalivation. In only four patients, clozapine was stopped during the follow-up. In terms of effectiveness, majority of the patients were rated as much improved or very much improved on Clinical Global Impression-Improvement subscale. CONCLUSION: Clozapine can be safely used in elderly patients with mental disorders. Hence, clozapine should not be withheld in elderly patients with mental disorders whenever indicated.

Integrating Physiotherapy in Neuroleptic Malignant Syndrome Management: A Case Report.

Neuroleptic malignant syndrome (NMS) is a rare but potentially fatal condition characterized by hyperthermia, autonomic dysregulation, altered mental status, and muscular rigidity. It typically results from the blockade of dopamine receptors by antipsychotic medications. We present the case of a 70-year-old female who developed NMS after non-compliant use of clozapine. She presented with symptoms including irrelevant talk, breathlessness, and generalized muscle weakness. On examination, she was drowsy with a Glasgow Coma Scale score of 11, tachycardia, tachypnea, and hypertonicity in all limbs. Diagnostic evaluations revealed increased urea and creatinine levels, raised creatine phosphokinase, and metabolic acidosis, which are consistent with NMS. Medical management included the discontinuation of clozapine and the initiation of bromocriptine. The report emphasizes how important physical therapy is to the NMS recovery process. The goals of physical therapy were to improve functional mobility, lessen muscle rigidity, and avoid problems from extended immobility. Kinesthetic stimulation, active cycle breathing methods, soft rocking motions, neural warmth, weight-bearing exercises, and mobility training were all incorporated into the protocol. Significant progress was observed in the patient's degree of consciousness, movement, and oxygen reliance over a two-week period. With the patient eventually managing room air without additional oxygen, the Glasgow Coma Scale score improved, and the ICU Mobility Scale score increased from 1 to 5. This instance emphasizes the need for prompt diagnosis and all-encompassing NMS care, with physiotherapy playing a critical role. Physiotherapy can significantly enhance overall healing, improve respiratory function, and facilitate neuromuscular re-education through tailored therapies. The results indicate that physiotherapy has to be regarded as a crucial component of the multidisciplinary strategy for managing NMS, with the goal of enhancing patient outcomes and quality of life. More studies are required to optimize physiotherapy interventions for NMS patients.

Aggressive behaviour and diabetes: A clinical case of atypical metabolic improvement during clozapine treatment.

Aggressive and violent behaviour is a challenging psychiatric emergency to manage, especially among vulnerable categories such as patients with Intellectual Developmental Disorder. Although there is some evidence that clozapine may be useful as an anti-violence compound, its use is limited by common metabolic complications. An adult patient presented with obesity, type II diabetes mellitus, compulsive food intake, severe Intellectual Developmental Disorder, and a treatment-resistant aggressive behaviour. Clozapine was administered resulting in reduced aggressive behaviour. Unexpectedly, a reduction in the food craving as well as a sustained improvement in both anthropometric parameters and glycemic control were observed during the clozapine treatment. Our case report, describes these findings for the first time, highlighting the need for more clinical research to investigate both the efficacy of clozapine in the Intellectual Developmental Disorder populations and its long-term effects with special regard to the metabolic outcomes in this type of patients.

Comparative Effectiveness of Amisulpride and Clozapine in the Treatment of Schizophrenia: A Systematic Review and Meta-Analysis.

In approximately one-third of individuals with schizophrenia, the illness demonstrates a poor response to standard antipsychotic treatments. Although a relatively small proportion fails to achieve remission after the initial exposure to either first- or second-generation antipsychotic drugs, the condition often becomes progressively more resistant to medication following subsequent relapses. We conducted comprehensive searches in databases such as PubMed and PubMed Central, extracting and assessing data quality using the Cochrane risk-of-bias tool for randomized clinical trials (RCTs). A random effects model was employed to calculate the pooled prevalence and explore heterogeneity, utilizing the I2 statistic. Subgroup analyses differentiated between experimental and placebo groups, while sensitivity analyses assessed the robustness of our findings, and publication bias was examined. Our meta-analysis included a sample size of 323 patients from seven studies out of the 10 selected articles. The pooled sample evaluated the effectiveness of amisulpride and clozapine in treating schizophrenia, with Positive and Negative Syndrome Scale (PANSS)-positive and PANSS-negative scores used in the subgroup analysis. The analysis revealed a heterogeneity of 78% and a statistically significant p-value of <0.05, favoring amisulpride and clozapine for treating schizophrenia either as monotherapy or in combination. These findings indicate that the effectiveness of these drugs is statistically significant. Our study underscores the necessity of conducting larger RCTs to further elucidate the optimal dosage and guideline criteria for prescribing amisulpride, clozapine, or their combination for patients resistant to first- and second-generation antipsychotics.