title: Neuroimaging findings in treatment-resistant schizophrenia: A systematic review: Lack of neuroimaging correlates of treatment-resistant schizophrenia.
abstract: BACKGROUND
  Recent developments in neuroimaging have advanced the understanding of biological mechanisms underlying schizophrenia. However, neuroimaging correlates of treatment-resistant schizophrenia (TRS) and superior effects of clozapine on TRS remain unclear.
  
  
  METHODS
  Systematic search was performed to identify neuroimaging characteristics unique to TRS and ultra-resistant schizophrenia (i.e. clozapine-resistant [URS]), and clozapine's efficacy in TRS using Embase, Medline, and PsychInfo. Search terms included (schizophreni*) and (resistan* OR refractory OR clozapine) and (ASL OR CT OR DTI OR FMRI OR MRI OR MRS OR NIRS OR PET OR SPECT).
  
  
  RESULTS
  25 neuroimaging studies have investigated TRS and effects of clozapine. Only 5 studies have compared TRS and non-TRS, collectively providing no replicated neuroimaging finding specific to TRS. Studies comparing TRS and healthy controls suggest that hypometabolism in the prefrontal cortex, hypermetabolism in the basal ganglia, and structural anomalies in the corpus callosum contribute to TRS. Clozapine may increase prefrontal hypoactivation in TRS although this was not related to clinical improvement; in contrast, evidence has suggested a link between clozapine efficacy and decreased metabolism in the basal ganglia and thalamus.
  
  
  CONCLUSIONS
  Existing literature does not elucidate neuroimaging correlates specific to TRS or URS, which, if present, might also shed light on clozapine's efficacy in TRS. This said, leads from other lines of investigation, including the glutamatergic system can prove useful in guiding future neuroimaging studies focused on, in particular, the frontocortical-basal ganglia-thalamic circuits. Critical to the success of this work will be precise subtyping of study subjects based on treatment response/nonresponse and the use of multimodal neuroimaging.
authors: Multimodal Imaging Group - Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, Canada; Geriatric Mental Health Division, Centre for Addiction and Mental Health, Toronto, Canada; Department of Psychiatry, University of Toronto, Toronto, Canada; Department of Neuropsychiatry, School of Medicine, Keio University, Tokyo, Japan. Electronic address: shinichiro_nakajima@hotmail.com.
authors: Shinichiro
authors: S
authors: Nakajima
authors: Department of Psychiatry, University of Toronto, Toronto, Canada; Department of Neuropsychiatry, School of Medicine, Keio University, Tokyo, Japan; Schizophrenia Division, Complex Mental Illness Program, Centre for Addiction and Mental Health, Toronto, Canada. Electronic address: hirotak@dk9.so-net.ne.jp.
authors: Hiroyoshi
authors: H
authors: Takeuchi
authors: Multimodal Imaging Group - Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, Canada; Institute of Medical Science, University of Toronto, Toronto, Canada. Electronic address: plitmaneric@gmail.com.
authors: Eric
authors: E
authors: Plitman
authors: Schizophrenia Division, Complex Mental Illness Program, Centre for Addiction and Mental Health, Toronto, Canada; Institute of Medical Science, University of Toronto, Toronto, Canada. Electronic address: gagan.fervaha@camh.ca.
authors: Gagan
authors: G
authors: Fervaha
authors: Multimodal Imaging Group - Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, Canada; Geriatric Mental Health Division, Centre for Addiction and Mental Health, Toronto, Canada; Department of Psychiatry, University of Toronto, Toronto, Canada; Institute of Medical Science, University of Toronto, Toronto, Canada. Electronic address: philgerretsen@yahoo.com.
authors: Philip
authors: P
authors: Gerretsen
authors: Multimodal Imaging Group - Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, Canada; Institute of Medical Science, University of Toronto, Toronto, Canada. Electronic address: fernando.caravaggio@gmail.com.
authors: Fernando
authors: F
authors: Caravaggio
authors: Multimodal Imaging Group - Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, Canada; Institute of Medical Science, University of Toronto, Toronto, Canada. Electronic address: junku.chung@mail.utoronto.ca.
authors: Jun Ku
authors: JK
authors: Chung
authors: Multimodal Imaging Group - Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, Canada; Department of Psychiatry, University of Toronto, Toronto, Canada; Department of Neuropsychiatry, School of Medicine, Keio University, Tokyo, Japan. Electronic address: yusuke.iwata2010@gmail.com.
authors: Yusuke
authors: Y
authors: Iwata
authors: Department of Psychiatry, University of Toronto, Toronto, Canada; Schizophrenia Division, Complex Mental Illness Program, Centre for Addiction and Mental Health, Toronto, Canada; Campbell Research Institute, Centre for Addiction and Mental Health, Toronto, Canada. Electronic address: gary.remington@camh.ca.
authors: Gary
authors: G
authors: Remington
authors: Multimodal Imaging Group - Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, Canada; Geriatric Mental Health Division, Centre for Addiction and Mental Health, Toronto, Canada; Department of Psychiatry, University of Toronto, Toronto, Canada; Campbell Research Institute, Centre for Addiction and Mental Health, Toronto, Canada. Electronic address: ariel_graff@yahoo.com.mx.
authors: Ariel
authors: A
authors: Graff-Guerrero
mesh_terms: D014150:Antipsychotic Agents / Q000009:adverse effects / Q000627:therapeutic use; D004351:Drug Resistance; D006801:Humans; D059906:Neuroimaging; D012559:Schizophrenia / Q000175:diagnosis* / Q000188:drug therapy*
chemical_list: D014150:Antipsychotic Agents
keywords: Clozapine; Glutamate; Neuroimaging; Schizophrenia; Treatment-resistance