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      G-CSF mediated neutrophil augmentation in a unique case of comorbid idiopathic Parkinson’s disease and treatment-resistant schizophrenia on clozapine

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          Abstract

          Treatment of psychosis in Parkinson’s disease (PD) is challenging; pharmacological options are limited, with clozapine considered most effective. The risk of agranulocytosis restricts the use of clozapine, but, where this occurs, cautious re-challenge with granulocyte stimulating factor can be successful. We present a unique case of a patient who developed early-onset PD on a background of antecedent treatment-resistant schizophrenia, who had been treated effectively with clozapine for over 15 years with no adverse events. However, during a hospital admission intended to optimise her Parkinsonian medications, she developed persistent neutropenia necessitating clozapine discontinuation. Numerous attempts to re-challenge with clozapine failed until augmentation with lithium and G-CSF was trialled. Two doses of G-CSF led to a sustained increase in the neutrophil count, allowing the continuation of clozapine therapy in the 1 year of follow up. This illustrates the potential for G-CSF to be used to facilitate clozapine use in a patient population not described previously. Neutrophil augmentation allowed the sustained continuation of this effective therapy, treating her psychotic symptoms without detriment to her movement disorder. We suggest that G-CSF might be considered as a treatment option in other cases where clozapine-associated neutropenia obstructs its use.

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          Most cited references26

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          Pathophysiology of parkinsonism.

          The motor signs of Parkinson's disease are thought to result in large part from a reduction of the level of dopamine in the basal ganglia. Over the last few years, many of the functional and anatomical consequences of dopamine loss in these structures have been identified, both in the basal ganglia and in related areas in thalamus and cortex. This knowledge has contributed significantly to our understanding of the link between the degeneration of dopamine neurons in the midbrain and the development of parkinsonism. This review discusses the evidence that implicates electrophysiologic changes (including altered discharge rates, increased incidence of burst firing, interneuronal synchrony, oscillatory activity, and altered sensorimotor processing) in basal ganglia, thalamus, and cortex, in parkinsonism. From these studies, parkinsonism emerges as a complex network disorder, in which abnormal activity in groups of neurons in the basal ganglia strongly affects the excitability, oscillatory activity, synchrony and sensory responses of areas of the cerebral cortex that are involved in the planning and execution of movement, as well as in executive, limbic or sensory functions. Detailed knowledge of these changes will help us to develop more effective and specific symptomatic treatments for patients with Parkinson's disease.
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            Clozapine-induced agranulocytosis/granulocytopenia: mechanisms and monitoring.

            Clozapine-induced agranulocytosis/granulocytopenia (CIAG) is an uncommon condition, but potentially fatal in consequences. The pathogenesis, despite multiple experiments, is not fully elucidated. The current theory suggests reactive oxygen species - nitrenium ion as the most important factor of CIAG. In this review, mechanism and monitoring of CIAG will be discussed.
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              Olanzapine in the treatment of dopamimetic-induced psychosis in patients with Parkinson's disease.

              Studies in elderly patients demonstrate antipsychotic efficacy and favorable safety profiles for olanzapine. We report results from two placebo-controlled, double-blind studies of olanzapine for treatment of dopamimetic drug-induced psychosis in patients with Parkinson's disease (PD). Patients were treated with olanzapine or placebo for 4 weeks while dopamimetic therapy was held constant. Olanzapine was initiated at 2.5 mg/day, with 2.5-mg/day increases allowed every 3 to 4 days up to the maximum dose of 15 mg/day. Olanzapine patients showed significant improvements from baseline on positive symptoms and most efficacy measures, but no significant treatment-group differences were observed. Olanzapine performed significantly worse than placebo in both studies on the Unified Parkinson's Disease Rating Scale (UPDRS) total, Motor, and Activities of Daily Living scales, but not the UPDRS Tremor item or Complications scores. Corrected QT interval, vital signs, and body weight were not significantly different from placebo. These findings did not demonstrate superior efficacy of olanzapine for treatment of dopamimetic-induced psychosis in PD. The initial dose-titration schedule and mild baseline levels of psychosis may account for these findings. Future studies involving gradual dose titration are needed to explore further olanzapine's optimum use for patients with PD with treatment-related psychosis.
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                Author and article information

                Contributors
                Journal
                Ther Adv Psychopharmacol
                Ther Adv Psychopharmacol
                TPP
                sptpp
                Therapeutic Advances in Psychopharmacology
                SAGE Publications (Sage UK: London, England )
                2045-1253
                2045-1261
                16 September 2020
                2020
                : 10
                : 2045125320956414
                Affiliations
                [1-2045125320956414]King’s College Hospital NHS Foundation Trust, London, UK
                [2-2045125320956414]South London and Maudsley NHS Foundation Trust, London, UK
                [3-2045125320956414]Institute of Psychiatry, Psychology and Neuroscience, London, UK
                [4-2045125320956414]South London and Maudsley NHS Foundation Trust, London, UK
                [5-2045125320956414]Institute of Psychiatry, Psychology and Neuroscience, London, UK
                [6-2045125320956414]UCL Institute of Mental Health, London, UK
                [7-2045125320956414]South London and Maudsley NHS Foundation Trust, 1st Floor, Cheyne Wing, King’s College Hospital, London, SE5 9RS, UK
                [8-2045125320956414]Institute of Psychiatry, Psychology and Neuroscience
                [9-2045125320956414]King’s College Hospital NHS Foundation Trust, London, UK
                Author notes
                Author information
                https://orcid.org/0000-0001-8779-1068
                Article
                10.1177_2045125320956414
                7498832
                32973999
                0ec6c544-678d-4edd-96d9-df76309479b5
                © The Author(s), 2020

                This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License ( https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages ( https://us.sagepub.com/en-us/nam/open-access-at-sage).

                History
                : 9 June 2020
                : 10 August 2020
                Categories
                Case Report
                Custom metadata
                January-December 2020
                ts1

                agranulocytosis,clozapine,g-csf,parkinson’s,schizophrenia
                agranulocytosis, clozapine, g-csf, parkinson’s, schizophrenia

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