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Introduction: Clozapine may affect the outcome of severe COVID-19 infection due to its anti-inflammatory and immunosuppressant effects. This study aimed to investigate whether the risk of COVID-19 changed in schizophrenic patients using clozapine and to compare patients using clozapine with other antipsychotics in terms of COVID-19 severity. Methods: A total of 732 patients who were registered and followed up with a diagnosis of schizophrenia were included in the study. These patients' sociodemographic data, smoking status, medications, comorbidities, COVID-19 PCR results, and COVID-19 outcomes (inpatient care admission, intensive care unit admission, death) were retrospectively analyzed. Results: Of the 732 patients included in our study, 177 were using clozapine. Ninety-six of 732 patients were diagnosed with COVID-19, and 34 of these were being treated with clozapine. We found that clozapine use was an independent risk factor for COVID-19 positivity (OR=1.81 95% CI=1.13-2.90), inpatient care admission (OR=3.01, 95% CI=1.12-8.06). Conclusion: In our study, clozapine use was associated with an increased risk of COVID-19 positivity and inpatient care admission; however, it was not associated with ICU admission or death. Due to the frequent follow-up of patients using clozapine and the effects of clozapine on immunity, the frequency and/or identification of COVID-19 may be increased in these patients. Clozapine toxicity, granulocytopenia or agranulocytosis during the COVID-19 infection may have increased these patients' hospitalisation frequency.
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Though not common, drug-induced pericarditis is a serious condition, since pericardial tamponade, should it develop, may be life-threatening. As the number of drugs is constantly expanding, so does the proportion of those capable of causing pericarditis. The authors reviewed the relevant literature in the PubMed database and complemented it with information from the VigiBase database. In their article, the authors present current knowledge about the mechanisms of origin and level of risk of drug-induced pericarditis and discuss relevant information on individual drugs divided into 7 classes. Some medicines are associated with a high risk of developing pericarditis, a fact to be taken into account when treating patients with these agents. © 2022 Czech Society of Cardiology Z.S. All rights reserved.
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Serotonin syndrome associated with clozapine withdrawal and concurrent selective serotonin reuptake inhibitor (SSRI) use has previously been reported. A 56-year-old female with schizophrenia was admitted for pyrexia, rigidity, and altered mental state after her second dose of clozapine restart. She had discontinued her long-term clozapine 2 weeks prior. She developed ventilatory failure, reduced consciousness, eye deviation, and worsening rigidity, requiring ICU support. Examination showed a right upper motor neurone syndrome with absent ankle reflexes. She had raised inflammatory markers and creatine kinase. Serum neuropathy, encephalitis screen, and COVID PCR were negative. Respiratory investigations were unfruitful. MRI head and spine did not show brain or cord signal change to correlate to signs. Lumbar puncture showed a quiet CSF, negative culture, viral PCR, and encephalitis antibodies. EEG showed bihemispheric background slowing. Despite clinical improvement, repeat examination showed persistent signs. She was diagnosed with serotonin syndrome after developing a bilateral tremor. Treatment with cyproheptadine correlated with an improvement in her signs, cognitive state, and EEG. Serotonin syndrome can present with reversible neuromuscular signs. With clozapine withdrawal, it can require a prolonged time course of recovery in contrast with classical serotonin syndrome. Cyprohepta- dine can cause agranulocytosis and this delays clozapine restart.
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BACKGROUND: To minimise infection during COVID-19, the clozapine haematological monitoring interval was extended from 4-weekly to 12-weekly intervals in South London and Maudsley NHS Foundation Trust. AIMS: To investigate the impact of this temporary policy change on clinical and safety outcomes. METHOD: All patients who received clozapine treatment with extended (12-weekly) monitoring in a large London National Health Service trust were included in a 1-year mirror-image study. A comparison group was selected with standard monitoring. The proportion of participants with mild to severe neutropenia and the proportion of participants attending the emergency department for clozapine-induced severe neutropenia treatment during the follow-up period were compared. Psychiatric hospital admission rates, clozapine dose and concomitant psychotropic medication in the 1 year before and the 1 year after extended monitoring were compared. All-cause clozapine discontinuation at 1-year follow-up was examined. RESULTS: Of 569 participants, 459 received clozapine with extended monitoring and 110 controls continued as normal. The total person-years were 458 in the intervention group and 109 in the control group, with a median follow-up time of 1 year in both groups. During follow-up, two participants (0.4%) recorded mild to moderate neutropenia in the intervention group and one (0.9%) in the control group. There was no difference in the incidence of haematological events between the two groups (IRR = 0.48, 95% CI 0.02-28.15, P = 0.29). All neutropenia cases in the intervention group were mild, co-occurring during COVID-19 infection. The median number of admissions per patient during the pre-mirror period remained unchanged (0, IQR = 0) during the post-mirror period. There was one death in the control group, secondary to COVID-19 infection. CONCLUSIONS: There was no evidence that the incidence of severe neutropenia was increased in those receiving extended monitoring.
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The antipsychotic clozapine is known to have immune-modulating effects. Clozapine treatment has been reported to be associated with increased risk of COVID-19 infection. However, it remains unclear whether this is because of increased testing of this patient group, who are closely monitored. We linked anonymised health records from mental health services in Cambridgeshire (UK), for patients taking antipsychotic medication, with data from the local COVID-19 testing hub. Patients receiving clozapine were more likely to be tested for COVID-19, but not to test positive. Increased testing in patients receiving clozapine suggests prudent judgement by clinicians, considering the overall health vulnerabilities of this group.
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BACKGROUND/OBJECTIVES: There have been concerns that clozapine treatment may undermine the capacity of the body to fight infection and increase the vulnerability to contracting COVID-19. This review of recent cohort studies investigated (1) whether people with a severe psychiatric disorder are at increased risk of COVID-19 and complications, (2) the immunological response of clozapine-users who contract COVID-19, and (3) patients' perspectives on COVID-19 and the pandemic response. METHODS: A systematic search of EMBASE, Medline, Pubmed, and PsycINFO databases using PRISMA guidelines using "COVID-19", "clozapine", and "vaccination" terms. RESULTS: 18 studies (out of 330 identified) met all criteria (N = 119 054 including 8045 on clozapine). There was no strong evidence that clozapine users may be at increased risk of contracting COVID-19 or developing complications after adjusting for medical comorbidities. Hematological studies showed temporary reductions in neutrophils in COVID-19-positive patients and vaccination suggesting a clozapine effect in defence against infection. Vaccination studies did not report major adverse effects. Increased plasma levels of clozapine and neutropenia however point to COVID-19-related interference of clozapine metabolism. Patient surveys reported limited impact on mental health and positive attitudes regarding pandemic response. CONCLUSION: This review did not find compelling evidence that the immune system of clozapine users put them at risk of COVID-19 and further complications. Evidence of drug-infection interactions however points to the importance of adhering to consensus guidelines about clozapine therapy during the pandemic. More evidence using longitudinal designs is required to examine the longer-term effects of COVID-19 and vaccination in this vulnerable population.
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Background: Schizophrenia is considered one of the major risk factors for mortality from SARS-CoV-2 infection. Early antiviral treatment is important to decrease the risk of mortality. Currently, Paxlovid (nirmatrelvir-ritonavir) has been widely used in SARS-CoV-2 patients with risk factors. However, drug-drug interactions with anti-psychotics are prominent and complicated. Case presentation: We report a clozapine-treated patient with SARS-CoV-2 infection who developed neutropenia after coadministration with Paxlovid. In this case, clozapine was used for over 15 years, without neutropenia development. However, severe neutropenia (absolute neutrophil count = 523/µl) developed 3 days after the coadministration of Paxlovid 2 doses per day, valproic acid 1,000 mg per day and clozapine 100 mg per day. The development of neutropenia may be attributed to the complicated interaction among Paxlovid, SARS-CoV-2 infection, valproic acid, fluvoxamine and clozapine. Conclusions: Neutropenia is a rare but life-threatening event if a concomitant infection occurs. The risk may increase during SARS-CoV-2 infection and the coadministration of clozapine and Paxlovid. Although the exact causes of neutropenia in this patient are not fully clear, the white blood cell count and absolute neutrophil count should be closely monitored during the administration of Paxlovid in clozapine-treated patients with SARS-CoV-2 infection.
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Introduction: Clozapine is a drug that can cause several side effects. Among the less commonly described is a drug-induced lung disease. Due to its non-specific clinical presentation, it represents a diagnostic challenge. The diagnosis is made based on: 1. Association of exposure to the agent and development of symptoms, 2. Pulmonary infiltration, 3. Exclusion of other causes, 4. Withdrawal of symptoms when the agent is excluded from therapy. To date, there have been only a few descriptions of this condition. Objective(s): Case report of rare side effect of clozapine. Method(s): Case report Results: Case report: male patient (37) with schizophrenia, was hospitalized after a brutal suicide attempt. The PCR test for COVID-19 that was routinely performed on admission was negative. After the introduction of clozapine into therapy, the patient became febrile. There was a drop in oxygen saturation, a Lung CT scan showed inflammatory changes (ground-glass opacities ), and COVID-19 pneumonia was suspected. Due to the worsening of the mental state, the dose of clozapine was increased. The physical condition further deteriorated: febrile, sO2 declining. After repeated PCR tests for COVID-19 (all negative), interstitial pneumonia caused by clozapine was suspected, and clozapine was excluded from therapy. The physical condition started to improve. Quetiapine was introduced, and occasional episodes of agitation were relieved with intramuscular diazepam. In the following days, the patient's mental state improved and he was discharged. Conclusion(s): Despite its superiority over other antipsychotics, clozapine was with good rationale ranked third in treatment guidelines for schizophrenia.
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Introduction: Together with agranulocytosis, fever and immflamatory manifestations are clozapine side effects to be monitorized during initial treatment. In the context of COVID-19 pandemic, implied mechanisms, and symptomatology should be carefully controlled. Objective(s): To analyze the clinical analytic and inflammatory chracterisctics the resembles and differenciates clozapine immune response and SARS-CoV-2 infection. To describe a case of clozapine induced fever and pneumonitis during COVID-19 pandemic. Method(s): A case of clozapine-induced pneumonitis during COVID-19 pandemic is described.- A mini-review of clozapine inflamamtory effects, induced-pneumonitis and SARS-CoV-2 was performed. Result(s): A 33 year old afrolatin male started treatment with clozapine up to 250 mg daily. He developed fever and respiratory symptoms in the 11th day of treatment. The exploration revealed pulmonary sounds decreased and 91% basal saturation, making the probable causes viral infection (local incidence of SARS-CoV-2 >800/100000hab), nosocomial bacterial infection or pulmonary thromboembolism. The patient was isolated due to probable COVID-19. Blood tests showed leucocytosis (13400/mcL), Lymphocytopenia (11.8%), high PCR (14.4mg/dL), Ferritine (506.9ng/ mL), Fibrinigen (663.83 mg/dL), D-Dimer (1.61mg/dL), and Interleukin-9 /25.8pg/mL). The angioTC revealed a pleural efusion and ground glass infiltrates (figure1). Only after 2 weeks eosinophilia was discovered (88/mcL) After 2 negative consecutieve PCRs for SARS-CoV-2, no imrovement with ampirical antibiotics and all infectious pannels negative, we started decreasing clozapine with improvement of the symptoms and resolution after suspending clozapine completely. Conclusion(s): Clozapine may induce a generalize inflammatory response mediated by interleukin-6. Patients treated with clozapine may exhibit fever and rarely, insterstitial lung inflammation. The expression of induced pneumonitis resembles viral infections, particularly SARS-CoV-2.
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Introduction: Common side effects are agranulocytosis and myocardiopathy. There are reports of myocardite related to m-rna vaccine for covid-19 (Pfizer-Bionteck), while the interactions with clozapine has not been yet studied. Objective(s): The object of the study is to explore the safety of COVID-19 vaccination at patients treated with clozapine. Method(s): We report a group of 27 patients from the psychiatric rehabilitation unit of the General Hospital of Corfu who were treated with clozapine and another group of 27 patients on different antipsychotic. Levels of clozapine were measured before the 1st vaccination and one month after the individuals were fully vaccinated, as well their COVID antibodies. For myocarditis detection we used CRP >1mg/dl and quadruplication of the troponin of reference. Result(s): No significant difference has been observed among the 2 groups in relation to antibody production, No difference has been detected between clozapine and nor-clozapine serum levels before and after vaccination. While there was no case of myocarditis or vein embolism noticed. Conclusion(s): It seems that patients treated with clozapine develop immune response to COVID-19 as individuals in any other antipsychotic. No major side effects were reported at the two groups leading as to the conclusion that treatment with clozapine sould not be an obstacle for COVID-19 vaccination. Thus to the small number of patients in this study further research is needed.
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As managing COVID-19 complications has become more prevalent in psychiatry, its effects can range from provoking new illnesses in previously healthy individuals to inducing relapses in patients in remission. However, an aspect of COVID-19's influence that is not well documented is its effect on medication responsiveness. In this case, we present a 28-year-old male diagnosed with treatment-resistant schizophrenia for eight years. While in remission on a maintenance dose of clozapine, he was admitted to the hospital with signs of severe psychosis after testing positive for COVID-19. On admission, he did not have any other major stressors and no prior comorbidities that could have induced the relapse. Despite being on a higher dose of clozapine for four weeks while hospitalized, the patient's psychosis did not improve. This raises the question if his infection had altered his response to medication that previously brought on remission.
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Mechanisms of cortical psychoses are approached by complementing big data-driven genetics and imaging with a putatively subverted neurovascular "reverse plumbing" by arteries. The "cortical spread" of grey matter loss in schizophrenia and the mid-pericallosal "congestion" in fMRI of periodic catatonia - treatable electromagnetically along arteries - are interpreted in terms of the fastest interstitial outflow through the Cerebral IntraMural Reverse Arterial Flow-engine (CIMURAF, Treviranus 2018-19) draining "waste" via arterio-adventitial lymphatics to the neck. Such repetitively sliding segments of CIMURAF are wrung downstream by muscles likely steered by the neurovascular pterygopalatine ganglion. At the pericallosal artery, along its ideal long straight segment, this likely happens diverging from the mid-callosum towards the front and the back. In the case of a convergent inversion a mid-callosal clash will result, which is observable in psychoses as a mid-callosal high-flow-spot simultaneously with hyper-perfusions of branches and "backwatering" of pial vessels with reactive waste - till date interpreted psycho-mathematically. CIMURAF might also accelerate the perivascular intrusion of MCs by flushing autocrine signals (of which electro-magnetism moves the dipoles) through a putative periadventitial counter-current. Psychoses plausible occur through tryptase-mediated attacks operated by mast cells against oligodendrocytes` cytoskeleton (Medic 2009) and probably via complement-4 (Schizophrenia WG, 2014) against neurons. Usually MCs are essential long-lived "orchestrators" of homeostases and immune or barrier defences interacting with nerves, immunocytes, organs, and routes. MCs after somatic programming as to "destination & destiny" (Treviranus 2017a, 6.2., 2018) rapidly intrude also into the brain`s parenchyma, first within the lymphatics and then putatively by crossing-over to extraluminal arterial routes. MCs transverse the BBBs, while macrophages only trespass in "disease"(Faraco et al. 2017). Both can be "subverted" by a list of microbes (and putatively blown up by COVID-19 within walls). Enuresis and MCs' reactions to clozapine add to the interactive support from (epi-)genetics and imaging. Copyright © Medicinska naklada - Zagreb, Croatia
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Service or Program: The number of COVID-19 infections have increased dramatically since March 2020 in Qatar. Measures have been taken to minimize the risk of exposure to COVID-19 including medication home delivery by postal service and by using telemedicine at The Mental Health Service (MHS), a tertiary care hospital in Qatar. In order to continue patients' access to care during the pandemic, the Medication Therapy Management (MTM) clinic at MHS would like to utilize clinical pharmacists to offer patient counseling, medication reviews, and develop medication action plans with the patients via telepharmacy. Justification/Documentation: Patients for whom counseling is essential to ensure positive outcomes of therapy were identified;patients on lithium or clozapine (phase 1), patient on newly prescribed psychotropics or on antipsychotic polypharmacy (phase 2), females on valproate in childbearing age (phase 3). The aim of this quality improvement (QI) project was to improve the number of patients currently receiving MTM service from baseline (90) by 20% by September 2020, 50% by December 2020 and 80% by March 2021. Outcome measure included percentage increase in patients from baseline who are receiving telepharmacy service, process measures included the percentage compliance of filling the Moresky Medication Adherence Scale-4 by the pharmacist, the percentage of referrals to other MHS services, balance measures were patient/caregivers and staff satisfaction. The improvement in outcome measure was successfully achieved in each phase;phase 1 - 28%, phase 2 - 82%, phase 3 - 127%. QI tools were used as appropriate. Adaptability: This service was intended to be provided by clinical pharmacists to adult patients registered under MHS. Similar service can easily be adapted to another setting by clinical pharmacists using comparable strategies and measures. Significance: The lessons learnt from this QI project will help in increasing patients' access to care, promote better utilization of resources, and allow better communication and management of patients.
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Introduction Safety studies have shown that COVID-19 vaccinations can provoke inflammatory processes in patients. The subsequent release of cytokines is accompanied by an increased inflammatory marker, C-reactive protein (CRP) [1]. For some antipsychotic drugs, inflammatory processes have been associated with increased drug levels, even above therapeutically approved ranges [2] [3]. It is not clear, whether this holds also true for COVID-19 vaccinations. Methods We present a case series comprising of 10 inpatients at the CIMH treated with an antipsychotic drug. Patients received a first, second or third dose of the COVID-vaccination Comirnaty in the morning. Blood samples were taken directly before the injection and were followed on day 1 and 4 while constant dosing. Blood testing included drug levels, safety laboratory, and CRP. Results CRP levels were elevated in nine patients;four of those also presented an increase in antipsychotic drug levels within a few days after COVID-19 vaccination. Blood level changes were i)+0%,+24%,+125%,+116% in quetiapine-, ii)+0%,+0%,+100% in olanzapine-, iii)+0,+42% in clozapine-treated patients, and iv)+205% in one risperidone-treated patient. As a result, three patients had drug levels above the therapeutically recommended range. Conclusion We present a series of patients with increased antipsychotic drug levels after COVID-19 vaccinations mediated via inflammatory processes. The intensity of inflammatory reactions strongly varies across patients. Hence, COVID-19 vaccinations may constitute an unpredictable risk factor for increased drug levels. Therapeutic drug monitoring can help to prevent safety risks in those patients with supra-therapeutic drug levels.
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Background: Catatonia, a motor dysregulation syndrome with behavioral components, has undergone many conceptual changes since its inception as a syndrome by Kahlbaum in 1874. Prevalence of catatonia in consultation-liaison services is approximately 5.5 percent in patients aged 65 and older.1 Stuporous catatonia is most common, but catatonia may present in excited or malignant subtypes. Together, the subtypes have over 40 documented signs and symptoms, making catatonia difficult to diagnose and appropriately treat.2 Catatonia involves hyperactivation of the orbitofrontal cortex (OFC) and ventromedial prefrontal cortex. GABA, NMDA, and dopamine have been implicated. GABA-A agonism by benzodiazepines improve catatonia by normalizing OFC activity.3 Case: A 66-year-old male with schizophrenia was admitted to a medical unit for failure to thrive after not eating for three days. He had not taken his medications for 2 weeks including chlorpromazine, quetiapine, oxcarbazepine, and clonazepam. Upon psychiatric consult, the patient exhibited staring, grimacing, echopraxia, and negativism. He was diagnosed with stuporous catatonia. 30 minutes after lorazepam challenge (2 milligram intravenous lorazepam), the patient was moving, conversing, and eating. After second dose of lorazepam, the patient became difficult to redirect, displaying stereotypy, verbigeration, and hitting. Additional doses of lorazepam were unsuccessful in breaking excited catatonia. History revealed previous catatonic episodes, including nine months prior when the patient was admitted to a gero-psychiatric unit. He initially presented in stuporous state, normalized with lorazepam, then transitioned to excited state. He received 16 milligrams of lorazepam in 24 hours without successful termination of excited catatonia. Lorazepam in combination with carbamazepine, clozapine, or valproic acid was unsuccessful. Catatonia was successfully treated with 10 sessions of electroconvulsive therapy (ECT) with lorazepam, clozapine, and valproic acid. Maintenance ECT was not continued because of the COVID pandemic, and the patient was admitted to a state facility after regression. Discussion: Catatonia is often encountered on consultation-liaison services in general hospital settings. We observed conversion of stuporous catatonia to excited catatonia after administration of lorazepam. This treatment-resistant catatonia ultimately required ECT. No reported cases of stuporous catatonia transitioning to excited catatonia were found on thorough literature review. Recognition of this conversion may be difficult and may require development of a catatonia scale that clearly identifies the presenting subtype. This is a challenge;clinical signs are not mutually exclusive among subtypes. This patient’s clinical course may provide insight into the identification of treatment-resistant catatonia, and accurate identification is necessary to allow for timely escalation of treatment. References: 1. Solmi M, et al. Prevalence of catatonia and its moderators in clinical samples: Results from a meta-analysis and meta-regression analysis. Schizophrenia Bulletin. 2017;44(5):1133–50. 2. Fink M, Taylor MA. The catatonia syndrome. Archives of General Psychiatry. 009;66(11):1173. 3. Ellul P, Choucha W. Neurobiological approach of Catatonia and Treatment Perspectives. Frontiers in Psychiatry. 2015;6.
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Background: Clozapine (CLZ) is used for treatment-resistant schizophrenia (TRS). Adverse reactions to clozapine include neutropenia. In March 2020, WHO declared the COVID-19 pandemic and after, psychiatrists raised concerns regarding continuation of clozapine, due to multiple restrictions. We aimed to provide a study on the association between neutropenia and clozapine in patients with schizophrenia and COVID-19. Aim: To assess the neutrophil count in patients with schizophrenia treated with clozapine and infected with COVID-19. Methods: The study patients with schizophrenia, according to DSM-5, admitted to the Clinical Hospital of Psychiatry and Neurology Brasov, Romania, between April 2020 and October 2021. The inclusion criteria included positive RT-PCR (real-time PCR) test for COVID-19 and treatment with clozapine. We assessed three values of ANC (absolute neutrophil count): before COVID-19 infection (last ANC obtained at mandatory check), during infection and 1 month after resolution (first negative PCR test). Results: Of the 105 cases, 95 did not have neutropenia. Fifty-nine patients were males (62.1%), mean age was 43.5 years (SD = 12.1) with an average of clozapine treatment of 52.4 months (SD = 11.9). At baseline, they had a small reduction in the ANC mean value (4.41 × 109/l; SD = 2.22) which did not constitute a statistically significant decline from the prior to COVID-19 mean value of 4.66 × 109/l (SD = 2.34; p = 0.45). Values were also normal in the first month after negative PCR testing (4.45 × 109/l; SD = 2.35; p = 0.91). A total of 10 patients (9.5%) had neutropenia. The age, dose of clozapine and duration of treatment were not statistically different compared to the group without neutropenia. Conclusion: Psychiatrists and other health professionals should keep in mind that neutrophil count may decrease during COVID-19 infection in patients taking clozapine and in some cases, neutropenia may even occur. We assumed that neutropenia could be caused by COVID-19 and clozapine interaction.