Subtyping schizophrenia by treatment response: Antipsychotic development and the central role of positive symptoms

Jimmy Lee, Hiroyoshi Takeuchi, Gagan Fervaha, Gwen Li Sin, George Foussias, Ofer Agid, Saeed Farooq, Gary Remington

Research output: Contribution to journalReview articlepeer-review

37 Citations (Scopus)


We have recently proposed a model for subtyping schizophrenia based on antipsychotic (AP) treatment response. Evidence suggests that APs, both old and new, are comparable in terms of efficacy; however, one AP, clozapine, is uniquely effective in one subgroup of patients (that is, those with treatment-resistant schizophrenia [TRS]). This permits us to subdivide schizophrenia into 3 specific groups: AP responsive, clozapine responsive, and clozapine resistant. Here, we integrate this model with current criteria related to TRS and ultraresistant schizophrenia, the latter referred to in our model as clozapine resistant. We suggest several modifications to existing criteria, in line with current evidence and practice patterns, particularly emphasizing the need to focus on positive symptoms. While APs can favourably impact numerous dimensions related to schizophrenia, it is their effect on positive symptoms that distinguishes them from other psychotropics. Further, it is positive symptoms that are central to AP and clozapine resistance, and it is these people that place the greatest demands on acute and long-term inpatient resources. In moving AP development forward, we advocate specifically focusing on positive symptoms and capitalizing on the evidence we have of 3 subtypes of psychosis (that is, positive symptoms) based on treatment response, implicating 3 distinguishable forms of underlying pathophysiology. Conversely, pooling these groups risks obfuscating potentially identifiable differences. Such a position does not challenge the importance of dopamine D2 receptor blockade, but rather highlights the need to better isolate those other subgroups that require something more or entirely different.

Original languageEnglish
Pages (from-to)515-522
Number of pages8
JournalCanadian Journal of Psychiatry
Issue number11
Publication statusPublished - 2015 Nov


  • Antipsychotic
  • Clozapine
  • Psychosis
  • Treatment-resistant
  • Ultraresistant

ASJC Scopus subject areas

  • Psychiatry and Mental health


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