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Open accessJournal ArticleDOI: 10.1503/JPN.210027

Elevated clozapine levels and toxic effects after SARS-CoV-2 vaccination.

05 Mar 2021-Journal of Psychiatry & Neuroscience (Canadian Medical Association)-Vol. 46, Iss: 2
Abstract: Case studies indicate that coronavirus disease 2019 (COVID-19) can be associated with toxic clozapine levels, requiring monitoring to maintain therapeutic levels and prevent relapses of psychosis.1–4 High clozapine levels are consistent with infection-related inflammation inhibiting cytochrome P450 1A2 (CYP1A2) and slowing clozapine metab olism.5 We report a case of elevated clozapine levels following administration of an mRNA vaccine. A 51-year-old man with schizoaffective disorder treated with clozapine for more than 10 years was living at a mental health residential facility. He was a nonsmoker. Concomitant disorders included diabetes mellitus type 2, gastroesophageal reflux disease, hyperlipidemia, class II obesity and obstructive sleep apnea. Concurrent medications included divalproex, fenofibrate, linagliptin, metformin and pantoprazole. His history was notable for a past motor vehicle accident, with some residual gait impairment and infrequent incontinence. The patient had received yearly influenza vaccinations without complication. During a hospital admission for pneumonia treated with intravenous antibiotics, while taking 500 mg/d clozapine, his clozapine level was elevated (Table 1) and he was over-sedated. Thereafter he was stabilized on 300 mg/d with a plan to monitor his clozapine level monthly. As part of routine care, the patient received the Pfizer-BioNTech vaccine for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19. Adverse events began on the fourth day following vaccination. The patient became delirious, fell repeatedly and was increasingly

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5 results found


Open accessJournal ArticleDOI: 10.3390/NEUROLINT13030044
Abstract: The monoamine hypothesis of depression attributes the symptoms of major depressive disorders to imbalances of serotonin, noradrenaline, and dopamine in the limbic areas of the brain. The preferential targeting of serotonin receptor (SERT) by selective serotonin reuptake inhibitors (SSRIs) has offered an opportunity to reduce the range of these side effects and improve patient adherence to pharmacotherapy. Clozapine remains an effective drug against treatment-resistant schizophrenia, defined as failing treatment with at least two different antipsychotic medications. Patients with schizophrenia who display a constellation of negative symptoms respond poorly to antipsychotic monotherapy. Negative symptoms include the diminution of motivation, interest, or expression. Conversely to the depressive symptomology of interest presently, supplementation of antipsychotics with SSRIs in schizophrenic patients with negative symptoms lead to synergistic improvements in the function of these patients. Fluvoxamine is one of the most potent inhibitors of CYP1A2 and can lead to an increase in clozapine levels. Similar increases in serum clozapine were detected in two patients taking sertraline. However, studies have been contradictory as well, showing no such increases, which are worrying. Clinicians should be aware that clozapine levels should be monitored with any coadministration with SSRIs.

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Topics: Sertraline (59%), Clozapine (59%), Fluvoxamine (58%) ... show more

1 Citations


Open accessJournal ArticleDOI: 10.1055/A-1531-4460
Abstract: Seit Dezember 2020 stehen in der Europaischen Union Impfstoffe gegen SARS-CoV-2 zur Verfugung. Psychisch erkrankte Personen haben ein erhohtes Risiko fur einen schweren oder todlichen Verlauf einer SARS-CoV-2-Infektion. So stellt sich die Frage, inwiefern Interaktionen zwischen den neuen SARS-CoV-2-Impfstoffen und Psychopharmaka zu erwarten sind. Grundsatzlich fehlen bislang noch konkrete Daten uber die Vertraglichkeit und Wirksamkeit einer Impfung gegen SARS-CoV-2 unter Psychopharmakotherapie – aus Untersuchungen zu Impfstoffen gegen andere Krankheitserreger lassen sich jedoch potenzielle Interaktionen ableiten, wie zum Beispiel eine reduzierte Immunantwort mit geringerer klinischer Wirksamkeit oder eine Erhohung von Medikamentenspiegeln aufgrund einer indirekten Hemmung von metabolisierenden Enzymen durch Impfstoffe. Andererseits zeigen depressive Patienten, die mit Antidepressiva medikamentos behandelt werden, eine bessere Immunantwort.

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Journal ArticleDOI: 10.1111/ACPS.13379
Abstract: Objective To investigate whether patients with clozapine treatment are at an increased risk of a more severe COVID-19 infection as compared with patients on other antipsychotic drugs. Methods In this register-based cohort study, all residents (age 18 or older) in the Stockholm Region with a psychotic disorder diagnosis and antipsychotic treatment were included (N = 8 233) and followed from March 1, 2020 to January 14, 2021. The exposure was defined as clozapine treatment and the outcome measures (indicating a more severe COVID-19 infection) were: inpatient care, care within intensive care unit or death due to COVID-19 infection. Differences in outcome rates between exposed (n = 966) and unexposed (other antipsychotics; n = 7 267) were examined using Cox proportional hazards models and expressed as hazard ratios (HR) with 95% confidence intervals (CI). Results No statistically significant differences in outcome rates were found between the two groups of patients after adjusting for age, sex, and residence in retirement homes. The adjusted HR for the exposed compared to the unexposed was 0.96 (95% CI: 0.54, 1.70) for inpatient care; 1.69 (0.48, 5.93) for care in intensive care unit (ICU); and 0.86 (0.26, 2.80) for death. Regarding inpatient care, additional adjusting for country of birth, living in socioeconomically vulnerable areas, number of care visits during the previous year, and comorbid medical illnesses did not alter the results. Conclusions Our results may add support to the present guidelines, recommending sustained clozapine treatment during the current COVID-19 pandemic with careful monitoring and readiness to alter drug doses as needed.

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Topics: Intensive care unit (56%), Hazard ratio (54%), Cohort study (51%) ... show more


Journal ArticleDOI: 10.1055/A-1562-2521
01 Sep 2021-Pharmacopsychiatry
Abstract: The Dutch Clozapine Collaboration Group is frequently asked for advice about the management of clozapine-treated patients when infected with or vaccinated against SARS-CoV-2. We provide state of the art information about the risks of SARS-CoV-2 infection for patients on clozapine and we give advice on measures to be taken, especially in regard to the monitoring of clozapine plasma levels, WBC count and differentiation during COVID-19 and after vaccination. We present an overview of relevant editorials, observational studies, and case studies, in which COVID-19 was reported in patients on clozapine. Patients using clozapine may have a higher risk of infection than patients with schizophrenia spectrum disorders (SSD) using other antipsychotics. SARS-CoV-2 infection can result in a dangerous increase of clozapine plasma levels, and granulocytopenia and lymphocytopenia (generally mild and short-term) may also occur, usually not as a result of clozapine treatment. Clozapine intoxication, pneumonia and delirium are the main complications of COVID-19 in patients on clozapine. In order to prevent clozapine intoxication, reduction of the original dose by half is generally recommended in clozapine users who contract COVID-19. When a cytokine storm is suspected in an advanced stage of COVID-19, reduction by three quarters seems more appropriate. If COVID-19 patients on clozapine develop granulocytopenia, SARS-CoV-2, rather than clozapine, should be considered as the cause. Schizophrenia patients in general and clozapine users in particular belong to a high-risk group that warrants early vaccination on a medical indication.

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Topics: Clozapine (55%)
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17 results found


Open accessJournal ArticleDOI: 10.3389/FIMMU.2018.00754
Abstract: C-reactive protein (CRP) is an acute inflammatory protein that increases up to 1000-fold at sites of infection or inflammation. CRP is produced as a homo-pentameric protein, termed native CRP (nCRP), which can irreversibly dissociate at sites of inflammation and infection into five separate monomers, termed monomeric CRP (mCRP). CRP is synthesised primarily in liver hepatocytes but also by smooth muscle cells, macrophages, endothelial cells, lymphocytes and adipocytes. Evidence suggests estrogen in the form of hormone replacement therapy influences CRP levels in the elderly. Having been traditionally utilised as a marker of infection and cardiovascular events, there is now growing evidence that CRP plays important roles in inflammatory processes and host responses to infection including the complement pathway, apoptosis, phagocytosis, nitric oxide (NO) release and the production of cytokines, particularly interleukin-6 and tumour necrosis factor-alpha. Unlike more recent publications, the findings of early work on CRP can seem somewhat unclear and at times conflicting since it was often not specified which particular CRP isoform was measured or utilised in experiments and whether responses attributed to nCRP were in fact possibly due to dissociation into mCRP or lipopolysaccharide contamination. In addition, since antibodies for mCRP are not commercially available, few laboratories are able to conduct studies investigating the mCRP isoform. Despite these issues and the fact most CRP research to date has focussed on vascular disorders, there is mounting evidence that CRP isoforms have distinct biological properties, with nCRP often exhibiting more anti-inflammatory activities compared to mCRP. The nCRP isoform activates the classical complement pathway, induces phagocytosis and promotes apoptosis. On the other hand, mCRP promotes the chemotaxis and recruitment of circulating leukocytes to areas of inflammation and can delay apoptosis. The nCRP and mCRP isoforms work in opposing directions to inhibit and induce NO production respectively. In terms of pro-inflammatory cytokine production, mCRP increases interleukin-8 and monocyte chemoattractant protein-1 production whereas nCRP has no detectable effect on their levels. Further studies are needed to expand on these emerging findings and fully characterise the differential roles each CRP isoform at sites of local inflammation and infection.

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Topics: Inflammation (51%), Classical complement pathway (51%), Cytokine (50%)

645 Citations


Open accessJournal ArticleDOI: 10.1038/S41586-020-2814-7
22 Oct 2020-Nature
Abstract: An effective vaccine is needed to halt the spread of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic. Recently, we reported safety, tolerability and antibody response data from an ongoing placebo-controlled, observer-blinded phase I/II coronavirus disease 2019 (COVID-19) vaccine trial with BNT162b1, a lipid nanoparticle-formulated nucleoside-modified mRNA that encodes the receptor binding domain (RBD) of the SARS-CoV-2 spike protein1. Here we present antibody and T cell responses after vaccination with BNT162b1 from a second, non-randomized open-label phase I/II trial in healthy adults, 18–55 years of age. Two doses of 1–50 μg of BNT162b1 elicited robust CD4+ and CD8+ T cell responses and strong antibody responses, with RBD-binding IgG concentrations clearly above those seen in serum from a cohort of individuals who had recovered from COVID-19. Geometric mean titres of SARS-CoV-2 serum-neutralizing antibodies on day 43 were 0.7-fold (1-μg dose) to 3.5-fold (50-μg dose) those of the recovered individuals. Immune sera broadly neutralized pseudoviruses with diverse SARS-CoV-2 spike variants. Most participants had T helper type 1 (TH1)-skewed T cell immune responses with RBD-specific CD8+ and CD4+ T cell expansion. Interferon-γ was produced by a large fraction of RBD-specific CD8+ and CD4+ T cells. The robust RBD-specific antibody, T cell and favourable cytokine responses induced by the BNT162b1 mRNA vaccine suggest that it has the potential to protect against COVID-19 through multiple beneficial mechanisms. In a phase I/II dose-escalation clinical trial, the mRNA COVID-19 vaccine BNT162b1 elicits specific T cell and antibody responses that suggest it has protective potential.

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Topics: T cell (63%), CD8 (59%), Vaccine trial (57%) ... show more

636 Citations


Journal ArticleDOI: 10.1016/J.VACCINE.2012.06.086
24 Aug 2012-Vaccine
Abstract: Background We evaluated the safety and immunogenicity profiles of 3 novel influenza vaccine constructs consisting of the globular head of the HA1 domain of the Novel H1N1 genetically fused to the TLR5 ligand, flagellin. HA1 was fused to the C-terminus of flagellin in VAX128A, replaced the D3 domain of flagellin in VAX128B and was fused in both positions in VAX128C. Methods In a dose escalation trial, 112 healthy subjects 18–49 and 100 adults ≥65 years old were enrolled in a double blind, placebo controlled clinical trial at two centers. Vaccines were administered IM at doses ranging from 0.5 to 20 μg. VAX128C was selected for second study performed in 100 subjects 18–64 years old comparing 1.25 and 2.5 μg doses. All subjects were followed for safety and sera collected pre- and post-vaccination were tested by hemagglutination-inhibition (HAI). Serum C-reactive protein and cytokine levels were also measured. Conclusions In the first study high HAI titers and high seroconversion and seroprotection rates were observed at doses ≥2.5 μg in adults 18–49. In adults ≥65 years, the vaccines doses of ≥4 μg were required to induce a ≥4-fold rise in HAI titer, 50% seroconversion and 70% seroprotection. Based on safety, VAX128A was tested up to 8 μg, VAX128B to 16 μg and VAX128C to 20 μg. Dose escalation for VAX128A was stopped at 8 μg because one subject had temperature 101.6 °F associated with a high CRP response, VAX128B was stopped at 16 μg because of a severe AE associated with a high CRP and IL-6 response. VAX128C was not stopped before reaching the 20 μg dose. In the second study VAX128C was well tolerated among 100 subjects who received 1.25 or 2.5 μg. The peak GMT was 385 (95%CI 272–546), 79% (71–87%) seroconversion and 92% (84–96%) seroprotection. Discussion Flagellin adjuvanted vaccines can be designed to minimize reactogenicity and retain immunogenicity, thereby representing a promising next generation vaccine technology.

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Topics: Seroconversion (54%), Influenza vaccine (53%), Reactogenicity (52%) ... show more

111 Citations


Journal ArticleDOI: 10.1016/J.SCHRES.2012.06.020
Abstract: Clozapine remains the drug of choice for treatment resistant schizophrenia, but is associated with potentially life threatening side effects, including agranulocytosis and myocarditis. Immunological mechanisms may be involved in the development of these side effects or in the unique antipsychotic efficacy in subgroups of schizophrenia patients. This systematic review presents the immunomodulatory effects of clozapine from human in vitro and in vivo studies and relates these findings to the developments of adverse and therapeutic effects of clozapine. Several studies confirm the immunomodulatory actions of clozapine, but only few studies investigated their relationship to the unique adverse and therapeutic effects of clozapine. During the first month of clozapine treatment, up to 50% of patients develop fever and flu like symptoms, which is seemingly driven by increased cytokines. Within the same time period, the risk of side-effects with a suspected immunological mechanism peaks. Patients developing fever during the first weeks of treatment should have a thorough physical examination, and measurements of white blood cell count, absolute neutrophil count, ECG, C-reactive protein, creatinine kinase, and troponin to exclude infection, agranulocytosis, myocarditis and neuroleptic malignant syndrome. To what degree the unique antipsychotic efficacy of clozapine in subgroups of schizophrenia patients is related to its immunomodulatory effects has not been studied. Research relating the immunomodulatory actions of clozapine and its early markers to clinically relevant adverse and therapeutic outcomes is hoped to provide new leads for the understanding of the pathophysiology of schizophrenia and aid the development of novel treatment targets.

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Topics: Clozapine (59%), Neuroleptic malignant syndrome (54%), Antipsychotic (53%) ... show more

105 Citations


Journal ArticleDOI: 10.1016/J.LAB.2005.03.009
Abstract: Despite wide use of the influenza vaccine, relatively little is known about its effect on the measurement of inflammatory markers. Because inflammatory markers such as C-reactive protein (CRP) are increasingly being used in conjunction with lipids for the clinical assessment of cardiovascular disease and in epidemiologic studies, we evaluated the effect of influenza vaccination on markers of inflammation and plasma lipid concentrations. We drew blood from 22 healthy individuals 1 to 6 hours before they were given an influenza vaccination and 1, 3, and 7 days after the vaccination. Plasma CRP, interleukin (IL)-6, monocyte chemotactic protein 1, tumor necrosis factor α, IL-2 soluble receptor α, and serum amyloid A were measured, and differences in mean concentrations of absolute and normalized values on days 1, 3, and 7 were compared with mean baseline values. There was a significant increase in mean IL-6 ( P P P P = .05), whereas the mean increase in normalized serum amyloid A was significant only on day 1 ( P P P P

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Topics: Influenza vaccine (56%), Serum amyloid A (54%), C-reactive protein (53%) ... show more

81 Citations


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