Shinichiro Nakajima1, Hiroyoshi Takeuchi2, Eric Plitman3, Gagan Fervaha4, Philip Gerretsen5, Fernando Caravaggio6, Jun Ku Chung7, Yusuke Iwata8, Gary Remington9, Ariel Graff-Guerrero10. 1. 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. 2. 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. 3. 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. 4. 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. 5. 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. 6. 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. 7. 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. 8. 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. 9. 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. 10. 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.
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. CONCLUSION: 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.
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. CONCLUSION: 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: Nadine Donata Wolf; Georg Grön; Fabio Sambataro; Nenad Vasic; Karel Frasch; Markus Schmid; Philipp Arthur Thomann; Robert Christian Wolf Journal: Schizophr Res Date: 2011-12-16 Impact factor: 4.939
Authors: Fernando Caravaggio; Margaret Hahn; Shinichiro Nakajima; Philip Gerretsen; Gary Remington; Ariel Graff-Guerrero Journal: Med Hypotheses Date: 2015-06-24 Impact factor: 1.538
Authors: Thomas P White; Rebekah Wigton; Dan W Joyce; Tracy Collier; Alex Fornito; Sukhwinder S Shergill Journal: Neuropsychopharmacology Date: 2015-09-09 Impact factor: 7.853