Switching treatment-resistant patients with schizophrenia or schizoaffective disorder to olanzapine: a one-year open-label study with five-year follow-up

Karagianis, Jamie; LeDrew, Kellie; Walker, Daniel J.

doi:10.1185/030079903125002108

Cited by 11 publications

(4 citation statements)

References 41 publications

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“…Second, many patients show limited or no therapeutic response despite marked blockade of the D2 receptor [8]. Finally, some patients fail to respond to standard doses of a specific antipsychotic drug, which occurs despite adequate D2 blockade, while interestingly the patient will respond to an equivalent (in terms of D2 blockade) of a second drug [9, 10]. These clinical observations are complemented by imaging studies, which show that antipsychotic D2 blockade can only contribute a small percentage of the variation in antipsychotic effectiveness [11].…”

Section: Introductionmentioning

confidence: 99%

Olanzapine induced DNA methylation changes support the dopamine hypothesis of psychosis

et al. 2013

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BackgroundThe dopamine (DA) hypothesis of schizophrenia proposes the mental illness is caused by excessive transmission of dopamine in selected brain regions. Multiple lines of evidence, including blockage of dopamine receptors by antipsychotic drugs that are used to treat schizophrenia, support the hypothesis. However, the dopamine D2 receptor (DRD2) blockade cannot explain some important aspects of the therapeutic effect of antipsychotic drugs. In this study, we hypothesized that antipsychotic drugs could affect the transcription of genes in the DA pathway by altering their epigenetic profile.MethodsTo test this hypothesis, we examined the effect of olanzapine, a commonly used atypical antipsychotic drug, on the DNA methylation status of genes from DA neurotransmission in the brain and liver of rats. Genomic DNA isolated from hippocampus, cerebellum, and liver of olanzapine treated (n = 2) and control (n = 2) rats were analyzed using rat specific methylation arrays.ResultsOur results show that olanzapine causes methylation changes in genes encoding for DA receptors (dopamine D1 receptor, dopamine D2 receptor and dopamine D5 receptor), a DA transporter (solute carrier family 18 member 2), a DA synthesis (differential display clone 8), and a DA metabolism (catechol-O-methyltransferase). We assessed a total of 40 genes in the DA pathway and found 19 to be differentially methylated between olanzapine treated and control rats. Most (17/19) genes showed an increase in methylation, in their promoter regions with in silico analysis strongly indicating a functional potential to suppress transcription in the brain.ConclusionOur results suggest that chronic olanzapine may reduce DA activity by altering gene methylation. It may also explain the delayed therapeutic effect of antipsychotics, which occurs despite rapid dopamine blockade. Furthermore, given the common nature of epigenetic variation, this lends insight into the differential therapeutic response of psychotic patients who display adequate blockage of dopamine receptors.

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Section: Introductionmentioning

confidence: 99%

Olanzapine induced DNA methylation changes support the dopamine hypothesis of psychosis

et al. 2013

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“…In contrast, the concentration of olanzapine required to activate the same TCC exceeded the plasma concentration of 0.16 mM by 30-50 fold. This suggests that the lower daily dose of olanzapine might be in part responsible for the lack of T cell activation in patients and the significantly lower incidence of blood dyscrasias when compared with clozapine (48,49). To further investigate the nature of the T cell response induced with clozapine and olanzapine, TCC were stimulated with both compounds at therapeutic and T cell stimulatory concentrations, and drug-induced changes in protein expression were analyzed at 8, 24, and 48 h using iTRAQ.…”

Section: Discussionmentioning

confidence: 99%

Characterization of Clozapine-Responsive Human T Cells

Ogese

Lister

Jenkins

et al. 2020

The Journal of Immunology

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Use of the atypical antipsychotic clozapine is associated with life-threatening agranulocytosis. The delayed onset and the association with HLA variants are characteristic of an immunological mechanism. The objective of this study was to generate clozapine-specific T cell clones (TCC) and characterize pathways of T cell activation and cross-reactivity with clozapine metabolites and olanzapine. TCC were established and characterized by culturing PBMCs from healthy donors and patients with a history of clozapine-induced agranulocytosis. Modeling was used to explore the drug–HLA binding interaction. Global TCC protein changes were profiled by mass spectrometry. Six well-growing clozapine-responsive CD4+ and CD8+ TCC were used for experiments; activation of TCC required APC, with clozapine interacting directly at therapeutic concentrations with several HLA-DR molecules. TCC were also activated with N-desmethylclozapine and olanzapine at supratherapeutic concentrations. Marked changes in TCC protein expression profiles were observed when clozapine treatment was compared with olanzapine and the medium control. Docking of the compounds into the HLA-DRB1*15:01 and HLA-DRB1*04:01 binding clefts revealed that clozapine and olanzapine bind in a similar conformation to the P4–P6 peptide binding pockets, whereas clozapine N-oxide, which did not activate the TCC, bound in a different conformation. TCC secreted Th1, Th2, and Th22 cytokines and effector molecules and expressed TCR Vβ 5.1, 16, 20, and 22 as well as chemokine receptors CXCR3, CCR6, CCR4, and CCR9. Collectively, these data show that clozapine interacts at therapeutic concentrations with HLA-DR molecules and activates human CD4+ T cells. Olanzapine only activates TCC at supratherapeutic concentrations.

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“…A troca de clozapina para olanzapina (5 a 25 mg/dia) elevou a resposta em mais de 40% dos pacientes nos estudos prospectivos (Henderson et al, 1998;Dossenbach et al, 2000), embora, em outro estudo, a maior redução nos sintomas psicóticos tenha sido observada nas semanas 3 e 6 (Dossenbach et al, 2000). Estudos posteriores de transferência sob condições naturalistas, principalmente da risperidona, revelaram resultados similares (Lindenmayer et al, 2001(Lindenmayer et al, e 2002Rodriguez-Perez et al, 2002;Chiu et al, 2003;Karagianis et al, 2003). Em resumo, há evidências da superioridade da olanzapina em relação ao haloperidol ou à clorpromazina, mas evidências limitadas de eficá-cia similar à clozapina no tratamento da esquizofrenia refratária ao tratamento (Nível B).…”

Section: Eficácia Dos Antipsicóticos De Segunda Geraçãounclassified

Diretrizes da Federação Mundial das Sociedades de Psiquiatria Biológica para o tratamento biológico da esquizofrenia. Parte 1: tratamento agudo

Falkai¹,

Wobrock²,

Lieberman³

et al. 2006

Rev. psiquiatr. clín.

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ResumoEstas diretrizes para o tratamento biológico da esquizofrenia foram desenvolvidas pela Força-Tarefa da Federação Mundial das Sociedades de Psiquiatria Biológica (World Federation of Societies of Biological Psychiatry, WFSBP). A meta fixada durante o desenvolvimento destas diretrizes foi rever sistematicamente todas as evidências disponíveis referentes ao tratamento da esquizofrenia, tanto no âmbito clínico como científico, e chegar a um consenso sobre as principais recomendações para a prática psiquiátrica. Estas diretrizes são destinadas a todos os médicos que atendem e tratam de pacientes portadores de esquizofrenia. Os dados usados para desenvolver estas diretrizes foram extraídos primariamente de vários painéis e diretrizes nacionais de tratamento para esquizofrenia, assim como de metanálises, revisões e estudos clínicos randomizados sobre a eficácia do tratamento farmacológico e de outras intervenções terapêuticas biológicas, identificadas por uma busca nas bases de dados MedLine e Biblioteca Cochrane. A literatura identificada foi avaliada no que diz respeito à solidez das evidências a favor da eficácia de uma dada intervenção e,

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Switching treatment-resistant patients with schizophrenia or schizoaffective disorder to olanzapine: a one-year open-label study with five-year follow-up

Abstract: Olanzapine may be a treatment option for patients who fail to respond to treatment with other antipsychotics. Importantly, this is one of the first reports showing that patients with schizophrenia can be maintained on atypical antipsychotic monotherapy for at least 5 years.

Cited by 11 publications

References 41 publications

Olanzapine induced DNA methylation changes support the dopamine hypothesis of psychosis

Olanzapine induced DNA methylation changes support the dopamine hypothesis of psychosis

Characterization of Clozapine-Responsive Human T Cells

Diretrizes da Federação Mundial das Sociedades de Psiquiatria Biológica para o tratamento biológico da esquizofrenia. Parte 1: tratamento agudo

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