Structure and toxicity of clozapine and olanzapine on agranulocytosis

Atypical antipsychotics olanzapine and clozapine increase bone loss in female rats with experimental periodontitis

“…A possible mechanism is the direct inhibition of MPO enzymatic activity by covalent modification or even the oxidative system saturation. Olanzapine, despite structural similarity with CLO, is less associated with granulocytopenia, probably due to enhanced stability of its metabolites and the higher pharmacological potency, requiring lower doses for therapeutic effect 14 . Furthermore, the increased bone loss induced by olanzapine in OLA + PD group points to the possibility of mechanisms of bone destruction that are not related to toxicity toward defense cells.…”

“…Clozapine (CLO) and olanzapine (OLA) are two SGAs less prone to cause tardive dyskinesia than first‐generation antipsychotics but are associated with the development of severe metabolic alterations with detectable effects observed in the early weeks of treatment 13 . Clozapine has its use restricted to refractory schizophrenia due to rare but lethal agranulocytosis risk, which requires hematological monitoring 14 . In contrast, OLA is a widely prescribed SGA being indicated as adjuvant or principal therapy for many diseases and off‐label uses 10 .…”

“…13 Clozapine has its use restricted to refractory schizophrenia due to rare but lethal agranulocytosis risk, which requires hematological monitoring. 14 In contrast, OLA is a widely prescribed SGA being indicated as adjuvant or principal therapy for many diseases and off-label uses. 10 The metabolic effects are well described in experimental models that provide mechanistic insights about its affinities for central and peripheral receptors, regulation of anorexigenic/orexigenic signaling, 15 reduction of gut microbiota diversity, 16 hormonal disruption, 17 and modifying the transcription of genes related to lipids and carbohydrates metabolism.…”

Integration analysis of GWAS and expression quantitative trait loci to identify candidate genes and pathways for clozapine‐related neutropaenia

“…Enrichment analysis identified multiple metabolic or catabolic processes that may be related to ANC, such as NADP metabolic processes (GO:0006739) and NADH metabolic processes (GO:0006734). Clozapine contains aryl amines, a piperazine ring, and a readily oxidized N on the side chain, which can be activated by the NADPH/myeloperoxidase (MPO) pathway of granulocytes and bone marrow precursors into free radicals and other reactive groups to stimulate oxidative stress response 41 . In addition, neutrophils themselves can generate hypochlorous acid via the NADPH/myeloperoxidase (MPO) pathway.…”

“…Clozapine contains aryl amines, a piperazine ring, and a readily oxidized N on the side chain, which can be activated by the NADPH/myeloperoxidase (MPO) pathway of granulocytes and bone marrow precursors into free radicals and other reactive groups to stimulate oxidative stress response. 41 In addition, neutrophils themselves can generate hypochlorous acid via the NADPH/ myeloperoxidase (MPO) pathway. Clozapine reacts with hypochlorous acid and is oxidized to produce a reactive metabolite, which can covalently bind to biological macromolecules, directly destroy mature granulocytes and bone marrow precursor cells or bind to cell membranes, stimulate the production of antibodies, and activate T cells to cause cell damage.…”