Long-term Clozapine Research Articles

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.

Long-term persistence of the risk of agranulocytosis with clozapine compared with other antipsychotics: a nationwide cohort and case–control study in Finland

Agranulocytosis is a life-threatening side-effect of clozapine, the only approved drug for treatment-resistant schizophrenia. The long-term profile of this complication has not yet been well established. Here we aim to describe the risk of clozapine-induced agranulocytosis over the long term. We used the entire population of Finland to identify people diagnosed with schizophrenia or schizoaffective disorder between 1972 and 2014 and developed a Kaplan-Meier model of time to diagnosis of agranulocytosis during clozapine versus non-clozapine treatment over a 22-year observation period (1996 to 2017). Next, we developed a nested case-control model for agranulocytosis matching by sex, age, time since diagnosis, and being in the incident cohort on a 1 to 5 ratio. Various durations of use for clozapine and non-clozapine antipsychotic treatment were compared to the modal antipsychotic use duration, deriving adjusted odds ratios (aORs) in a multivariable regression model. Recurrence and lethality rates for clozapine-induced agranulocytosis were described. These data reflect on all individuals with lived experience of schizophrenia in Finland during the study time, although individuals with lived experience were not included in the design of the study. We identified 61 769 people with schizophrenia or schizoaffective disorder (14 037 individuals treated with clozapine and 47 732 individuals treated with non-clozapine antipsychotics), with a mean age of 46·67 years (IQR 34·44-57·61), of whom 30 721 (49·7%) were female and 31 048 (50·3%) were male (data on ethnicity not available). Among those, 398 individuals were diagnosed with agranulocytosis (231 individuals treated with clozapine and 167 individuals treated with non-clozapine antipsychotics), representing a cumulative incidence of agranulocytosis for 1·37% (95% CI 0·58-3·16) on clozapine and 0·13% (0·04-0·23) on non-clozapine antipsychotics. In the case (n=398) versus control (n=1987) model, the risk of clozapine-induced agranulocytosis decreased steeply over time from an aOR of 36·01 (95% CI 16·79-77·22) for less than 6 months on clozapine to 4·38 (1·86-10·34) for clozapine use of 54 months or more. Only one of 3559 individuals starting clozapine died because of clozapine-induced agranulocytosis. The risk of clozapine-induced agranulocytosis decreases steeply over time but might be persistently greater than that of non-clozapine antipsychotics. This long-term risk excess seems small in absolute terms compared with the known magnitude of the advantages of clozapine in relevant outcomes, including life expectancy. Given the widespread underuse of clozapine, relaxing the long-term neutrophil monitoring could favour the advantages of long-term clozapine use, including greater life expectancy, without incurring the intolerable risk of clozapine-induced agranulocytosis. Northwell Health and Sigrid Jusèlius Foundation.

The Involvement of PGRMC1 Signaling in Cognitive Impairment Induced by Long-Term Clozapine Treatment in Rats

Introduction: Progesterone receptor component 1 (PGRMC1) has been identified as a potential target in atypical antipsychotic drug-induced metabolic disturbances as well as neuroprotection in the central nervous system. In our study, we aimed to figure out the essential role of PGRMC1 signaling pathway underlying clozapine-induced cognitive impairment. Methods: In male SD rats, we utilized recombinant adeno-associated viruses (BBB 2.0) and the specific inhibitor of PGRMC1 (AG205) to regulate the expression of PGRMC1 in the brain, with a special focus on the hippocampus. Treatments of clozapine and AG205 were conducted for 28 days, and subsequent behavioral tests including modified elevated plus maze and Morris water maze were conducted to evaluate the cognitive performance. Hippocampal protein expressions were measured by Western blotting. Results: Our study showed that long-term clozapine administration led to cognitive impairment as confirmed by behavioral tests as well as histopathological examination in the hippocampus. Clozapine inhibited neural survival through the PGRMC1/EGFR/GLP1R-PI3K-Akt signaling pathway, leading to a decrease in the downstream survival factor, brain-derived neurotrophic factor (BDNF), and simultaneously promoted neural apoptosis in the rat hippocampus. Intriguingly, by targeting at the hippocampal PGRMC1, we found that inhibiting PGRMC1 mimics, while its upregulation notably mitigates clozapine-induced cognitive impairment through PGRMC1 and its downstream signaling pathways. Conclusion: PGRMC1-overexpression could protect hippocampus-dependent cognitive impairment induced by clozapine. This effect appears to arise, in part, from the upregulated expression of PGRMC1/EGFR/GLP1R and the activation of downstream PI3K-Akt-BDNF and caspase-3 signaling pathways.

Disseminated herpes zoster in an Immunocompetent patient on long-term Clozapine: case report

Disseminated herpes zoster is characterized by more than 20 herpetic lesions distributed across other body parts outside the affected dermatome. Disseminated herpes zoster occurs more frequently in immunocompromised patients and only a handful of case reports highlighted itsoccurrence in immunocompetent individuals. Clozapine use has been linked to decreased immune functioning, but no conclusive evidence to categorize clozapine as an immunosuppressive drug has been published. Here we report a case of a 65-year-old immunocompetent man on long-term clozapine who presented with vesicular lesions in a non-dermatomal distribution and was diagnosed to have disseminated zoster. Bangladesh J Medicine 2023; 34(3): 241-244

The case of a geriatric female experiencing frequent falls and epileptic seizures during long-term low-dose clozapine and extended-release bupropion treatment

There are few reports describing the incidence of seizures in patients prescribed a combination of clozapine and bupropion for the treatment of psychiatric disorders, despite the known drug-drug interaction associated with concomitant use. We report the case of a 67-year-old geriatric woman who experienced multiple falls and seizures while receiving a low daily dose of clozapine 200 mg and bupropion extended-release (XL) 150 mg. There was no recurrence of seizure activity after discontinuation of bupropion and initiation of an antiepileptic drug, divalproex. This case report suggests that bupropion in combination with low-dose clozapine may increase the risk of seizures in elderly patients.

As-Required Filgrastim for Late-Onset Neutropenia Complicating Long-Term Clozapine Treatment: a Case Report.

Clozapine is considered the most effective antipsychotic for schizophrenia, but it can cause neutropenia and even agranulocytosis. We describe the first case in Hong Kong involving the use of filgrastim, a recombinant form of human granulocyte colony-stimulating factor, to enable clozapine continuation therapy for a severely ill patient with treatment-resistant schizoaffective disorder who developed recurrent neutropenia after almost 20 years of continuous clozapine therapy. Therefore, clinical vigilance is important, regardless of clozapine treatment duration. Filgrastim can facilitate long-term clozapine therapy in patients with clozapine-induced neutropenia.

Vortex keratopathy after photorefractive keratectomy in a patient on long-term clozapine treatment

Background: Vortex keratopathy is a corneal entity characterized by corneal deposits at the level of the basal epithelium in the form of a whorl-like pattern in the interpalpebral portions of the cornea. Medications such as amiodarone, chloroquine, hydroxychloroquine, indomethacin, phenothiazines, ibuprofen, and naproxen bind to the cellular lipids of the basal epithelial layer of the cornea, producing a characteristic whorl pattern. Here, we report a case of bilateral central vortex keratopathy with slight vision impairment 3 weeks after uneventful photorefractive keratectomy (PRK) in a woman on long-term clozapine treatment.
 Case Presentation: A 42-year-old woman presented to the outpatient clinic for refractive surgery for the correction of bilateral moderate myopia. Her best-corrected distance visual acuity was 20 / 20 in both eyes. She had been on antipsychotic clozapine tablets 400 mg / day for the past 6 years to manage a psychiatric disorder. On detailed preoperative slit-lamp examination, her corneas were clear, with perilimbal conjunctival pigmentations. Other ocular examination results were unremarkable. At the 3-week follow-up after an uneventful PRK, her uncorrected distance visual acuity was 20 / 25 in the right eye and 20 / 20 in the left eye, with complaints of slightly unclear vision in both eyes. Slit-lamp examination revealed bilateral corneal subepithelial deposits in a whorl-like pattern reminiscent of vortex keratopathy. The deposits were restricted to the epithelial and subepithelial regions and did not extend to the stroma without evident stromal haze. Dilated fundus examination results were normal bilaterally. Despite excellent refractive outcomes and visual acuity in both eyes, she was dissatisfied and complained of unclear vision. She was administered with lubricating eye drops and placed on regular follow-ups. At the 4-month follow-up, the vortex lines were cleared centrally, and she reported improvement in vision. Anterior-segment optical coherence tomography of the cornea revealed no epithelial deposits in the central part of the cornea and residual deposits in the temporal peripheral cornea, indicating clearing of the deposits from the central cornea and explaining the subjective improvement in vision. Her final best-corrected distance visual acuity was 20/20 in both eyes with an unremarkable ocular examination.
 Conclusions: Our case indicates a potential causal relationship between long-term clozapine treatment and development of temporary, visually significant vortex keratopathy after uneventful PRK. Further large-scale studies are required to verify the causal relationship between the long-term clozapine administration and the development of vortex keratopathy following surface ablation photorefractive procedures.

Treatment resistance in schizophrenia: a meta-analysis of prevalence and correlates.

To determine the prevalence and correlates of treatment-resistant schizophrenia (TRS) through a systematic review and meta-analysis. Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria, an electronic search was performed in PubMed and Embase through May 17, 2022. All study designs that assessed a minimum of 20 schizophrenia-spectrum patients and provided data on TRS prevalence or allowed its calculation were included. Estimates were produced using a random-effects model meta-analysis. The TRS prevalence across 50 studies (n = 29,390) was 36.7% (95%CI 33.1-40.5, p < 0.0001). The prevalence ranged from 22% (95%CI 18.4-25.8) in first-episode to 39.5% (95%CI 32.2-47.0) in multiple-episode samples (Q = 18.27, p < 0.0001). Primary treatment resistance, defined as no response from the first episode, was 23.6% (95%CI 20.5-26.8) vs. 9.3% (95%CI 6.8-12.2) for later-onset/secondary (≥ 6 months after initial treatment response). Longer illness duration and recruitment from long-term hospitals or clozapine clinics were associated with higher prevalence estimates. In meta-regression analyses, older age and poor functioning predicted greater TRS. When including only studies with lower bias risk, the TRS prevalence was 28.4%. Different study designs and recruitment strategies accounted for most of the observed heterogeneity in TRS prevalence rates. The results point to early-onset and later-onset TRS as two separate disease pathways requiring clinical attention.

Pharmacogenomic-guided clozapine administration based on HLA-DQB1, HLA-B and SLCO1B3-SLCO1B7 variants: an effectiveness and cost-effectiveness analysis.

The identification of pharmacogenetic factors that increase the susceptibility to clozapine-induced agranulocytosis or granulocytopenia (CIAG) has received increasing interest. The SLCO1B3-SCLO1B7 variant (rs149104283) and single amino acid changes in human leukocyte antigen (HLA) HLA-DQB1 (126Q) and HLA-B (158T) were associated with an increased risk of CIAG. In this study, we evaluated the effectiveness and cost-effectiveness of adding the SLCO1B3-SCLO1B7 to HLA variants as a new pharmacogenomic (PGx) approach and explored the evolution of a cohort of schizophrenic patients taking long-term clozapine as a third-line antipsychotic medication. The decision model included probabilistic and deterministic sensitivity analyses to assess the expected costs and quality-adjusted life-years (QALYs). The current monitoring scheme was compared with the PGx-guided strategy, where all patients underwent pre-emptively a genetic test before taking clozapine, over 10 years. By adding the SLCO1B3-SCLO1B7 variant into HLA variants, CIAG sensitivity increased from 36.0% to 43.0%, the specificity decreased from 89.0% to 86.9%, and the probability of cost-effectiveness improved from 74.1% to 87.8%. The incremental cost-effectiveness ratio was £16,215 per QALY and remained below the conventional decision threshold (£30,000 or US$50,000 per QALY). Therefore, the SLCO1B3-SCLO1B7 variant, as an additional risk allele to HLA variants, increases preemptive test sensitivity and improves the effectiveness and cost-effectiveness of PGx-guided clozapine administration.

Correlation of Orexin-A and brain-derived neurotrophic factor levels in metabolic syndrome and cognitive impairment in schizophrenia treated with clozapine

Orexin-A and brain-derived neurotrophic factor (BDNF) are implicated in regulating metabolic syndrome (MetS) and cognitive impairment of schizophrenia. However, the associations among them remains unclear. Here, we aimed to investigate the relationship between Orexin-A levels, BDNF, MetS, clinical symptom profile, and cognitive function in schizophrenia patients following long-term clozapine treatment. We measured Orexin-A and BDNF levels in 140 schizophrenia patients with and without MetS. We assessed clinical symptoms on the Positive and Negative Syndrome Scale and cognitive function by the assessment of Neuropsychological Status (RBANS), and examined their associations with Orexin-A. Patients with MetS had significantly lower Orexin-A levels and higher coding test, attention span and delayed retention in RBANS (P < 0.05). Correlation analysis showed that Orexin-A was associated with BDNF, TG, HDLC, PANSS active social avoidance and emotional withdrawal significantly. Besides, Orexin-A significantly interacted with BDNF for metabolic and cognitive profiles including waist circumference, delayed retention and list recognition. Logistic regression analysis showed that Orexin-A level (odds ratio [OR] = 0.380, 95% confidence interval [CI]: 0.151–0.952, P = 0.039) and total illness duration (OR = 0.932, 95% CI: 0.875–0.991, P = 0.025) were predictive variables of MetS. However, there was no significant relationship between Orexin-A and cognitive function after adjustment for age, sex and educational levels. Totally, a lower plasma Orexin-A level seems to be related to metabolic parameters more than cognitive profiles. The interaction of Orexin-A with BDNF may be partly responsible for worse MetS and better cognition of elderly schizophrenia, but the causal relationship needs further clarification.

SELECTED NEUROLOGIC AND PSYCHIATRIC OUTCOMES IN PATIENTS TREATED WITH CLOZAPIN (Review Article)

Clozapine is a second-generation antipsychotic mostly used for treatment-resistant schizophrenia and acute suicidality. Although clozapine’s efficacy is well-documented, it has various side effects which need to be promptly addressed. In this article, we focus on neurological and psychiatric side effects. Among these side effects, seizure is a well-known complication of clozapine therapy. The articles that we reviewed concerning seizures and EEG changes in association with clozapine plasma levels and doses, found significant relations in some but not all cases. In addition to seizures, extrapyramidal side effects are common adverse effects of clozapine which can be an acute or chronic condition. Clozapine is also associated with ocular disturbances such as retinal pigmentation. It has also been shown to cause cataplexy. Moreover, clozapine can cause significant sedation. Effects of clozapine on sleep is still a controversial subject. The studies demonstrate inconsistent results. Cholinergic rebound syndrome is a rare complication of longterm clozapine use, which itself can be the inducer of insomnia. Apart from this, hypersalivation is one of the most frequent side effects with a paradoxical pathophysiology. Finally, clozapine is associated with severe psychiatric side effects, some of which need prompt intervention.

Long-term treatment with clozapine and other antipsychotic drugs and the risk of haematological malignancies in people with schizophrenia: a nationwide case-control and cohort study in Finland

Clozapine is the most efficacious treatment for schizophrenia and is associated with lower overall mortality than are other antipsychotic drugs, despite the risk of agranulocytosis. Preliminary reports over the past 10 years suggest a possible risk of haematological malignancies, but the issue has remained unsettled. We aimed to study the risk of haematological malignancies associated with use of clozapine and other antipsychotics. We did a nationwide case-control (and cohort) study of people with schizophrenia, using prospectively gathered data from Finnish national registers. A nested case-control study was constructed by individually matching cases of lymphoid and haematopoietic tissue malignancy with up to ten controls without cancer by age, sex, and time since first schizophrenia diagnosis. For the case-control study, we restricted inclusion criteria to malignancies diagnosed on a histological basis, and excluded individuals outside of the age range 18-85 years, and any patients that had a previous malignancy. Analyses were done using conditional logistic regression adjusting for comorbid conditions. For the case-control study 516 patients with a first-time diagnosis of lymphoid and haematopoietic tissue malignancy during years 2000-17 and diagnosed after their first diagnosis of schizophrenia were identified. 102 patients were excluded due to diagnosis that was without a histological basis, five patients were excluded because of their age, and 34 were excluded for a previous malignancy, resulting in 375 patients being matched to controls. We selected up to ten controls without cancer (3734 in total) for each case from the base cohort of people with schizophrenia. For the cohort study, data for 55 949 people were included for analysis. Cumulative incidence of haematological malignancies during the mean follow-up of 12·3 years (SD 6·5) was 102 (0·7%) cases among 13 712 patients who had used clozapine (corresponding to event rate of 61 cases per 100 000 person-years), and during mean follow-up of 12·9 years (SD 7·2) was 235 (0·5%) malignancies among 44 171 patients having used other antipsychotic medication than clozapine (corresponding to 41 cases per 100 000 person-years). Of the 375 individuals with haematological malignancies (305 lymphomas, 42 leukaemia, 22 myelomas, 6 unspecified) observed from 2000-17, 208 (55%) were males and 167 (45%) were female. Ethnicity data were not available. Compared with non-use of clozapine (most had used other antipsychotics and a few had used no antipsychotics), clozapine use was associated with increased odds of haematological malignancies in a dose-response manner (adjusted odds ratio 3·35, [95% CI 2·22-5·05] for ≥5000 defined daily dose cumulative exposure, p<0·0001). Exposure to other antipsychotic drugs was not associated with increased odds. A complementary analysis showed that the clozapine-related risk increase was specific for haematological malignancies, because no such finding was observed for other malignancies. Over 17 years of follow-up of the base cohort, 37 deaths occurred due to haematological malignancy among patients exposed to clozapine (26 with ongoing use at time of haematological malignancy diagnosis, and 11 in patients who did not use clozapine at the exact time of their cancer diagnosis), whereas only three deaths occurred due to agranulocytosis. Unlike other antipsychotics, long-term clozapine use is associated with increased odds of haematological malignancies. Long-term clozapine use has a higher effect on mortality due to lymphoma and leukaemia than due to agranulocytosis. However, acknowledging that the absolute risk is small compared with the previously observed absolute risk reduction in all-cause mortality is important. Our results suggest that patients and caregivers should be informed about warning signs of haematological malignancies, and mental health clinicians should be vigilant for signs and symptoms of haematological malignancy in patients treated with clozapine. The Finnish Ministry of Social Affairs and Health and Academy of Finland.

Case Report: The Challenges of Assessing and Managing Dysphagia in Two Patients on Long-term Clozapine

<h3>Introduction</h3> Introduction: The risk of clozapine associated dysphagia is between 1/1000 and 1/10000 (1). The associated complications of aspiration, pneumonia and mortality are also observed to be elevated with clozapine use(2). There is also limited evidence suggesting that risk is dose and age dependent (2), We present two cases illustrating the potential complex presentations of dysphagia in patients on clozapine. <h3>Methods</h3> Methods: The first case is a 61-year-old male veteran with history of chronic schizophrenia admitted for worsening psychosis. He has been on clozapine up to 550mg since 2001, with clozapine/norclozapine levels at 452/232. Exam was remarkable for an AIMS score of 25. During admission patient reported odynophagia, dysphagia and a 40-pound weight loss. Initial workup revealed candida esophagitis. 21-day course of fluconazole yielded no improvement. Inpatient team did not increase dose due to concern for esophageal dysmotility. Manometry is pending at the writing of this case report, hydroxyzine was reduced and benztropine discontinued to reduce anticholinergic burden. The second patient was a 51-year-old female with history of schizoaffective disorder, chronic PTSD, alcohol use disorder, bulimia nervosa, temporal lobe epilepsy, iron deficiency anemia, and GERD. Patient was on clozapine from 2009 until 2016. In 2015, she reported dysphagia worsening for one year with solid food dysphagia, choking, and sialorrhea. Subsequent manometry revealed type II achalasia and clozapine was discontinued within one year and switched to aripiprazole and eventually olanzapine. Over subsequent years, patient's dysphagia worsened and led to severe malnutrition. In 2020, she underwent Heller's myotomy with Dor fundoplication, with the expectation that dysphagia may remain given multifactorial etiology including polypharmacy. Patient also received a PEG tube. In 2020-2021, patient had more than 20 admissions for recurrent aspiration pneumonitis. In July 2021, she was admitted for replacement of a PEG tube and patient went into pulseless electrical arrest. Aspiration was cited as a factor in her death. <h3>Results</h3> Discussion: Dysphagia with antipsychotics can be mediated by multiple mechanisms including parkinsonism, acute dystonic reactions, tardive dyskinesia, sialorrhea, xerostomia, and sedation. Management approaches include reduction of clozapine and switching to another antipsychotic although these interventions may not reduce dysphagia. Aspiration on clozapine leads to a release of cytokines which can increase serum concentration of clozapine and in turn, side-effects (3). <h3>Conclusions</h3> Conclusion: These two cases illustrate the challenges in assessing and managing dysphagia in patients on clozapine. In both cases, dysphagia became an issue years after initiation of clozapine. In the first case, the veteran's dysphagia was likely mediated by tardive dyskinesia and oversedation. In the second case, dysphagia was likely mediated by sialorrhea, oversedation and other multiple comorbidities. More systematic studies are needed to better characterize risk of clozapine associated dysphagia and treatment approaches. <h3>This research was funded by</h3> none

The disquietude of clozapine continuation during the COVID-19 pandemic.

The disquietude of clozapine continuation during the COVID-19 pandemic.

Sex-dependent effects of long-term clozapine or haloperidol medication on red blood cells and liver iron metabolism in Sprague Dawley rats as a model of metabolic syndrome

BackgroundPatients with liver diseases often have some form of anemia. Hematological dyscrasias are known side effects of antipsychotic drug medication and the occurrence of agranulocytosis under clozapine is well described. However, the sex-dependent impact of clozapine and haloperidol on erythrocytes and symptoms like anemia, and its association with hepatic iron metabolism has not yet been completely clarified. Therefore, in the present study, we investigated the effect of both antipsychotic drugs on blood parameters and iron metabolism in the liver of male and female Sprague Dawley rats.MethodsAfter puberty, rats were treated orally with haloperidol or clozapine for 12 weeks. Blood count parameters, serum ferritin, and liver transferrin bound iron were determined by automated counter. Hemosiderin (Fe3+) was detected in liver sections by Perl’s Prussian blue staining. Liver hemoxygenase (HO-1), 5’aminolevulinate synthase (ALAS1), hepcidin, heme-regulated inhibitor (HRI), cytochrome P4501A1 (CYP1A1) and 1A2 (CYP1A2) were determined by Western blotting.ResultsWe found anemia with decreased erythrocyte counts, associated with lower hemoglobin and hematocrit, in females with haloperidol treatment. Males with clozapine medication showed reduced hemoglobin and increased red cell distribution width (RDW) without changes in erythrocyte numbers. High levels of hepatic hemosiderin were found in the female clozapine and haloperidol medicated groups. Liver HRI was significantly elevated in male clozapine medicated rats. CYP1A2 was significantly reduced in clozapine medicated females.ConclusionsThe characteristics of anemia under haloperidol and clozapine medication depend on the administered antipsychotic drug and on sex. We suggest that anemia in rats under antipsychotic drug medication is a sign of an underlying liver injury induced by the drugs. Changing hepatic iron metabolism under clozapine and haloperidol may help to reduce these effects of liver diseases.

Leukopenija kao jedini simptom kovid-19 kod pacijenata obolelih od shizofrenije na terapiji klozapinom

Patients suffering from Covid-19 often have leukopenia, most often lymphopenia, as an accompanying laboratory manifestation of the clinical syndrome, but there are indications that at the beginning of the disease they also have mild neutropenia. Clozapine can have hematological side effects in terms of leukopenia - most often neutropenia. The paper presents a patient with schizophrenia who is on long-term Clozapine therapy. At the time when leukopenia was detected in the blood count, he was mentally stable and physically asymptomatic. He had a reduced number of leukocytes as the only symptom of infection with the new coronavirus SARS CoV 2, which we confirmed by PCR. In this paper, we present the clinical picture of COVID-19 in connection with the possible overlapping etiology of leukopenia, which can also appear as a separate symptom of infection with the SARS CoV 2 coronavirus and be a hematological side effect of Clozapine treatment.

Predictors of laxative use in inpatients with schizophrenia on clozapine.

Constipation, a clinical manifestation of gastrointestinal hypomotility, is a common and potentially serious complication of clozapine therapy, requiring laxatives for its prevention and treatment. We explored the predictive factors of the increased laxative use in inpatients receiving a long-term clozapine therapy. In the cross-sectional study of 93 patients in a psychiatric rehabilitation hospital, we examined a four-week prevalence of laxative use and a range of demographic and clinical factors associated with the number of prescribed laxatives. Seventy-four percent of inpatients with schizophrenia were prescribed laxatives, and they were statistically significant older and taking higher daily doses of clozapine. In generalized Poisson regression analysis, the clozapine dose, age, and comorbid diabetes mellitus and hypothyroidism were independently associated with the number of concurrently used laxatives. No association was found between the laxatives and gender, duration of clozapine treatment, and the number of other medications with a potential to cause constipation. The clozapine dose, age, diabetes mellitus, and hypothyroidism were shown to be the independent predictors of the increased laxative use among inpatients on clozapine and might be associated with the increased risk of clozapine-induced constipation and gastrointestinal hypomotility.

Clozapine Metabolism is Associated With Absolute Neutrophil Count in Individuals With Treatment-Resistant Schizophrenia.

Up to one-third of those with schizophrenia fail to respond to standard antipsychotics and are considered to have treatment-resistant schizophrenia, a condition for which clozapine is the only evidence-based medication. While up to 60% of treated individuals obtain therapeutic benefits from clozapine, it is currently underprescribed worldwide, partly because of concerns related to its broad adverse effect profile. In particular, the potential effects of clozapine on the immune system have gained relevance after a recent study showed that drug plasma concentrations were inversely correlated with neutrophil counts in individuals routinely undergoing treatment. Seeking to investigate this relationship in more detail, we extracted metabolic, immune, and genetic data from a UK cohort of long-term clozapine users linked to a clozapine monitoring service, CLOZUK2 (N = 208). Whilst a correlation analysis was compatible with the original results, a multiple linear regression accounting for dose and other confounding factors additionally allowed us to estimate the decrease in absolute neutrophil counts to approximately 141 cells/mm3 for every 0.1 mg/L increase in clozapine concentration. However, this association was attenuated after controlling for the metabolic ratio between clozapine and its main metabolite, norclozapine, which was itself negatively associated with neutrophil concentrations. Further analyses revealed that these relationships are likely moderated by genetic factors, as three pharmacogenomic SNPs previously associated to norclozapine plasma concentrations and the metabolic ratio (rs61750900, rs2011425 and rs1126545) were shown to be independently associated with a variation in neutrophil counts of about 400 cells/mm3 per effect allele. Such results are compatible with an effect of norclozapine, but not necessarily clozapine, on immune cell counts, and highlight the need for further investigations into the potential role of genetic determinants of clozapine pharmacokinetics in the occurrence of adverse effects during treatment.

Neutropenia in patients treated with clozapine during COVID-19 infection

IntroductionClozapine is the most effective antipsychotic for treatment resistant schizophrenia but adverse reactions to clozapine include neutropenia. Patients with COVID-19 infection frequently experience lymphopenia, but not neutropenia.The impact of clozapine treatment in the presence of COVID-19 is unknownObjectivesShow 2 cases of neutropenia in patients treated with long-term clozapine during COVID-19 infection.MethodsSubjects: 48 admitted patients to a long-stay psychiatric unit. COVID-19 infection confirmed by positive nasopharyngeal swab for viral ribonucleic acid of SARS-CoV-2. Hematological controls between March and April 2020.Results16 patients (33%) treated with clozapine.18 patients (37’5%) had COVID-19 infection, of which 5 (10’4%) were treated with clozapine; 2 presented neutropenia. 1- 56-year-old woman diagnosed with schizophrenia on clozapine since 2009. Begins to have a dry cough and fever with positive COVID-19 swab (day 0). Slight leukopenia without neutropenia was observed on day 1. On day 7, neutropenia was observed with an absolute neutrophil count (ANC) of 1100. We decided to suspend clozapine and to initiate daily hematological controls. The ANC on day 8 was 970. Over the next few days the ANC will progressively improve until neutropenia resolved (day 22). 2- 55-year-old woman who required a transfer to a general hospital because of respiratory complications from COVID-19. She presented significant leukopenia (1’01x 10^3/uL) and neutropenia (ANC 100). Clozapine was not withdrawn. She was treated with granulocyte colony-stimulating factor.ConclusionsAn urgent full blood count will be required to exclude neutropenia with appropriate action. Further research will be needed to clarify the possible relationship between COVID-19, clozapine and neutropenia.DisclosureNo significant relationships.

A Case of Heart Failure with Preserved Ejection Fraction Secondary to Long-Term Clozapine Use

We present the case of a 55-year-old female, on very low dose Clozapine treatment for Schizophrenia, who presented with shortness of breath and in atrial fibrillation and with no previous history of cardiac failure. Chest X Ray showed evidence of bilateral pulmonary oedema and bilateral pleural effusion, and a diagnosis of acute heart failure with preserved ejection fraction was made based on echocardiographic findings and raised brain naturetic peptide (BNP) levels. This was the patient’s first presentation to hospital with heart failure related symptoms. Initial medical management included diuretics which did not improve her symptoms. With no other aetiology obvious her clozapine was stopped.