title: Pharmacogenetics of clozapine treatment response and side-effects in schizophrenia: an update.
abstract: BACKGROUND
  Clozapine (CLZ) is the most effective treatment for treatment-resistant schizophrenia (SCZ) patients, with potential added benefits of reduction in suicide risk and aggression. However, CLZ is also mainly underused due to its high risk for the potentially lethal side-effect of agranulocytosis as well as weight gain and related metabolic dysregulation. Pharmacogenetics promises to enable the prediction of patient treatment response and risk of adverse effects based on patients' genetics, paving the way toward individualized treatment.
  
  
  METHODS
  This article reviews pharmacogenetics studies of CLZ response and side-effects with a focus on articles from January 2012 to February 2015, as an update to the previous reviews. Pharmacokinetic genes explored primarily include CYP1A2, while pharmacodynamic genes consisted of traditional pharmacogenetic targets such as brain-derived neurotrophic factor as well novel mitochondrial genes, NDUFS-1 and translocator protein.
  
  
  CONCLUSIONS
  Pharmacogenetics is a promising avenue for individualized medication of CLZ in SCZ, with several consistently replicated gene variants predicting CLZ response and side-effects. However, a large proportion of studies have yielded mixed results. Large-scale Genome-wide association studies (e.g., CRESTAR) and targeted gene studies with standardized designs (response measurements, treatment durations, plasma level monitoring) are required for further progress toward clinical translation. Additionally, in order to improve study quality, we recommend accounting for important confounders, including polypharmacy, baseline measurements, treatment duration, gender, and age at onset.
authors.affiliation: a 1 Campbell Family Research Institute, Pharmacogenetics Research Clinic, Centre for Addiction and Mental Health , Toronto, Ontario, Canada +1 416 535 8501 ; +1 416 979 4666 ; daniel.mueller@camh.ca.|b 2 University of Toronto, Department of Laboratory Medicine and Pathobiology , Ontario, Canada.
authors.forename: Venuja
authors.initials: V
authors.lastname: Sriretnakumar
authors.affiliation: a 1 Campbell Family Research Institute, Pharmacogenetics Research Clinic, Centre for Addiction and Mental Health , Toronto, Ontario, Canada +1 416 535 8501 ; +1 416 979 4666 ; daniel.mueller@camh.ca.|c 3 University of Toronto, Institute of Medical Sciences , Ontario, Canada.
authors.forename: Eric
authors.initials: E
authors.lastname: Huang
authors.affiliation: a 1 Campbell Family Research Institute, Pharmacogenetics Research Clinic, Centre for Addiction and Mental Health , Toronto, Ontario, Canada +1 416 535 8501 ; +1 416 979 4666 ; daniel.mueller@camh.ca.|c 3 University of Toronto, Institute of Medical Sciences , Ontario, Canada.|d 4 University of Toronto, Department of Psychiatry , Ontario, Canada.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Müller
mesh_terms: D014150:Antipsychotic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D003024:Clozapine / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D055106:Genome-Wide Association Study; D006801:Humans; D010597:Pharmacogenetics; D057285:Precision Medicine; D012559:Schizophrenia / Q000188:drug therapy* / Q000235:genetics
chemical_list: D014150:Antipsychotic Agents; D003024:Clozapine
keywords: antipsychotics; clinical response; clozapine; genetics; pharmacogenetics; schizophrenia; side effects