Rechallenging With Clozapine Following Neutropenia: Treatment Options for Refractory Schizophrenia

Department of Psychiatry, Yale University, 34 Park St., New Haven, CT 06519, USA.
American Journal of Psychiatry (Impact Factor: 12.3). 08/2008; 165(7):813-8. DOI: 10.1176/appi.ajp.2008.07111823
Source: PubMed
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Available from: Judson A Brewer, Dec 10, 2015
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    • "Although add-on G-CSF or lithium are favourable therapeutic options when clozapine is rechallenged, physicians should be aware of the potential dangers of recurrent blood dyscrasias[Hazewinkel et al. 2013]. In case of neutropenia, coprescribing of lithium is supported by published reports[Ghaznavi et al. 2008;Kanaan and Kerwin, 2006]. A retrospective case analysis that presented all patients who had a clozapine rechallenge with lithium coprescribed reported the utility and safety of lithium in clozapine rechallenge. "
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    ABSTRACT: Objective: Clozapine is a second-generation antipsychotic used for treatment-resistant schizophrenia. Despite its effectiveness, clozapine is largely underused due to serious side effects such as leukopenia or neutropenia. We aimed to review whether to continue, discontinue or rechallenge clozapine treatment after such haematological side effects.
    Full-text · Article · Dec 2015 · Therapeutic Advances in Psychopharmacology
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    • "The authors proposed that polypharmacy may have contributed to the initial episode of neutropenia as well as the failed rechallenge. There are other similar case reports in which the patients were taking additional psychotropic medications that carry a risk for blood dyscrasia, namely valproic acid, haloperidol, or risperidone.16,17 "
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    ABSTRACT: We describe a case of a patient whose clozapine was discontinued after a "red result" following R-CHOP (rituximab with cyclophosphamide, hydroxydaunorubicin, Oncovin, and prednisolone) chemotherapy for large B-cell lymphoma. In some cases, manufacturers grant permission, on compassionate grounds, for clozapine to be continued or reinitiated following assessment by their consultant hematologist. Other than a recent case report, there is not much literature surrounding this medical issue. However, since the two leading causes of mortality in schizophrenia are cancer and cardiac disease, this is not an uncommon occurrence. Clinicians are reluctant to prescribe clozapine in view of its side-effect profile, despite its proven efficacy for managing treatment-resistant schizophrenia. The alternative is to prescribe two antipsychotics to manage symptoms. This approach may be associated with increased side effects, and evidence for actual benefits is scant. The consequences were disastrous in this case, as the individual not only relapsed following clozapine discontinuation, but the therapy for this treatable form of lymphoma had to be delayed. He was eventually admitted to an inpatient unit after having been stable for 15 years. We managed to stabilize him with olanzapine and aripiprazole which enabled the heme-oncology group to resume R-CHOP therapy with filgrastim (granulocyte colony-stimulating factor). Even so, he continued to exhibit severe psychotic symptoms, with religious delusions and auditory hallucinations. We therefore applied for permission to rechallenge him on clozapine. Permission was granted when protocol conditions were met, and reinitiation went without any adverse events. The patient's symptoms showed improvement within a few weeks, and the other antipsychotics were discontinued once clozapine was titrated up to 300 mg. The decision to reinitiate clozapine following a red result is not to be taken lightly, but needs to be considered in terms of the risks versus benefits. More literature surrounding this issue would be of great benefit to clinicians, patients, and their families.
    Full-text · Article · Aug 2013 · Neuropsychiatric Disease and Treatment
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    • "We suggest that complete blood counts be performed twice each week for at least 3 months after the rechallenge since the rechallenge-associated neutropenia or agranulocytosis occurs faster, and is more severe, than during the initial treatment with clozapine (Dunk et al., 2006). The co-prescribing of lithium is supported by a careful review of published reports (Ghaznavi et al., 2008) and neurological adverse reactions (e.g., tremors, involuntary movements, seizures, cognitive abnormalities) may be prevented by keeping the plasma lithium levels at around 0.4 mmol/L (Kanaan and Kerwin, 2006). Time to rechallenge, speed of titration and total dose have not been shown to influence the hematological outcome, but they have been only rarely documented and need further study. "
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    ABSTRACT: Clozapine is widely prescribed for treatment refractory patients with schizophrenia, but its use is limited by potentially life threatening adverse effects. Rechallenge after these complications has been occasionally attempted in patients with severe psychotic symptoms. To review the outcome of clozapine rechallenge after potentially life threatening adverse effects. Electronic, all-language, literature search (1972-2011) followed by demographic and clinical data extraction. The outcome of rechallenge was considered favorable when the lower bound of the 95% confidence interval (CI) of the proportion of patients who could continue clozapine was >50%. Altogether, 138 patients (mean age: 36.3years, 65.7% male, 57.6% Caucasian, virtually all with schizophrenia spectrum diagnosis) underwent clozapine rechallenge after developing neutropenia (n=112), agranulocytosis (n=15), neuroleptic malignant syndrome (NMS) (n=5), myocarditis (n=4), pericarditis (n=1) and lupus erythematosus (n=1). Rechallenge strategies were heterogeneous and not systematically evaluated. Clozapine rechallenge was successful in 78/112 patients (69.6%, CI: 60.6-77.4) after neutropenia, 3/15 (20%, CI: 7.1-45.2) after agranulocytosis, 5/5 (100%, CI: 56-100) after NMS, 3/4 (75%, CI: 30-95) after myocarditis, 1/1 after pericarditis, and 0/1 after clozapine-induced lupus. Successfully rechallenged patients were followed for 16-96weeks. None of the rechallenged patients died. Although controlled studies are clearly needed, using a priori, confidence interval-based criteria, case reports/series suggest that in refractory patients who benefited from clozapine, careful rechallenge can be considered after neutropenia and NMS, but not after agranulocytosis and myocarditis.
    Full-text · Article · Nov 2011 · Schizophrenia Research
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