title: Is treatment-resistant schizophrenia categorically distinct from treatment-responsive schizophrenia? a systematic review.
abstract: Schizophrenia is a highly heterogeneous disorder, and around a third of patients are treatment-resistant. The only evidence-based treatment for these patients is clozapine, an atypical antipsychotic with relatively weak dopamine antagonism. It is plausible that varying degrees of response to antipsychotics reflect categorically distinct illness subtypes, which would have significant implications for research and clinical practice. If these subtypes could be distinguished at illness onset, this could represent a first step towards personalised medicine in psychiatry. This systematic review investigates whether current evidence supports conceptualising treatment-resistant and treatment-responsive schizophrenoa as categorically distinct subtypes.
  
  
  
  A systematic literature search was conducted, using PubMed, EMBASE, PsycInfo, CINAHL and OpenGrey databases, to identify all studies which compared treatment-resistant schizophrenia (defined as either a lack of response to two antipsychotic trials or clozapine prescription) to treatment-responsive schizophrenia (defined as known response to non-clozapine antipsychotics).
  
  
  
  Nineteen studies of moderate quality met inclusion criteria. The most robust findings indicate that treatment-resistant patients show glutamatergic abnormalities, a lack of dopaminergic abnormalities, and significant decreases in grey matter compared to treatment-responsive patients. Treatment-resistant patients were also reported to have higher familial loading; however, no individual gene-association study reported their findings surviving correction for multiple comparisons.
  
  
  
  Tentative evidence supports conceptualising treatment-resistant schizophrenia as a categorically different illness subtype to treatment-responsive schizophrenia. However, research is limited and confirmation will require replication and rigorously controlled studies with large sample sizes and prospective study designs.
authors.affiliation: Psychosis Studies Department, Institute of Psychiatry, Psychology and Neuroscience, King's College London, 16 De Crespigny Park, Denmark Hill, London, SE5 8AF, UK. amy.gillespie@kcl.ac.uk.
authors.forename: Amy L
authors.initials: AL
authors.lastname: Gillespie
authors.affiliation: Psychosis Studies Department, Institute of Psychiatry, Psychology and Neuroscience, King's College London, 16 De Crespigny Park, Denmark Hill, London, SE5 8AF, UK.
authors.forename: Ruta
authors.initials: R
authors.lastname: Samanaite
authors.affiliation: Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.|University of Exeter Medical School, Exeter University, St Luke's Campus, Exeter, UK.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Mill
authors.affiliation: Psychosis Studies Department, Institute of Psychiatry, Psychology and Neuroscience, King's College London, 16 De Crespigny Park, Denmark Hill, London, SE5 8AF, UK.
authors.forename: Alice
authors.initials: A
authors.lastname: Egerton
authors.affiliation: Psychosis Studies Department, Institute of Psychiatry, Psychology and Neuroscience, King's College London, 16 De Crespigny Park, Denmark Hill, London, SE5 8AF, UK.
authors.forename: James H
authors.initials: JH
authors.lastname: MacCabe
mesh_terms: D014150:Antipsychotic Agents / Q000627:therapeutic use*; D002986:Clinical Trials as Topic / Q000379:methods; D003024:Clozapine / Q000627:therapeutic use; D006801:Humans; D011446:Prospective Studies; D012559:Schizophrenia / Q000175:diagnosis* / Q000188:drug therapy* / Q000235:genetics; D016896:Treatment Outcome
chemical_list: D014150:Antipsychotic Agents; D003024:Clozapine
keywords: Classification; Clozapine; Schizophrenia; Treatment refractory; Treatment resistance; Treatment response