title: Optimizing outcomes in clozapine rechallenge following neutropenia: a cohort analysis.
abstract: OBJECTIVE
  Certain patients with treatment-refractory schizophrenia may be rechallenged with clozapine following previous neutropenia. Evidence guiding patient selection and the effectiveness of lithium and granulocyte-colony stimulating factor (G-CSF) in rechallenge is limited, and factors associated with successful outcomes are unclear.
  
  
  METHODS
  Outcomes were studied in patients rechallenged with clozapine at a tertiary referral center between January 2007 and December 2013, following 1 or more previous trials terminated due to neutropenia, defined as an absolute neutrophil count (ANC) < 1.5 × 10(9)/L. Demographic characteristics, details of each clozapine trial including ANC, and coprescribed medication were extracted, and factors associated with rechallenge outcomes were examined.
  
  
  RESULTS
  Nineteen patients underwent clozapine rechallenge following previous neutropenia; 4 (21%) experienced further neutropenia, 2 of which developed agranulocytosis. Compared to successfully rechallenged patients, unsuccessfully rechallenged patients were significantly older (t = 2.10, P = .05), experienced onset of neutropenia sooner (W = 10.0, P = .03), and were more commonly coprescribed valproate. In addition to 5 patients with benign ethnic neutropenia (BEN), 8 patients not of an ethnicity associated with BEN also had idiopathic low neutrophil counts at baseline; lithium and G-CSF coprescription facilitated successful rechallenge in these patients.
  
  
  CONCLUSIONS
  In this selected population, the initial neutropenia was unlikely to be related to clozapine in a substantial proportion of cases. This group was successfully rechallenged following careful consideration of the risks and benefits, and lithium and G-CSF contributed to allowing continued clozapine therapy. In addition to black patients, other ethnic groups can have persistently low ANC unrelated to clozapine.
authors.affiliation: Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, 16 De Crespigny Park, London SE5 8AF, UK nicholas.meyer@kcl.ac.uk.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Meyer
authors.forename: Siobhan
authors.initials: S
authors.lastname: Gee
authors.forename: Eromona
authors.initials: E
authors.lastname: Whiskey
authors.forename: David
authors.initials: D
authors.lastname: Taylor
authors.forename: Aleksandar
authors.initials: A
authors.lastname: Mijovic
authors.forename: Fiona
authors.initials: F
authors.lastname: Gaughran
authors.forename: Sukhi
authors.initials: S
authors.lastname: Shergill
authors.forename: James H
authors.initials: JH
authors.lastname: MacCabe
mesh_terms: D000328:Adult; D018692:Antimanic Agents / Q000627:therapeutic use; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D003024:Clozapine / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D015331:Cohort Studies; D004359:Drug Therapy, Combination; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000627:therapeutic use; D006801:Humans; D007958:Leukocyte Count; D018020:Lithium Compounds / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009503:Neutropenia / Q000097:blood / Q000139:chemically induced / Q000208:ethnology; D009504:Neutrophils; D017063:Outcome Assessment, Health Care; D012559:Schizophrenia / Q000097:blood / Q000188:drug therapy*; D014635:Valproic Acid / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D018692:Antimanic Agents; D014150:Antipsychotic Agents; D018020:Lithium Compounds; D016179:Granulocyte Colony-Stimulating Factor; D014635:Valproic Acid; D003024:Clozapine