TY - JOUR
T1 - Glutamatergic neurometabolites and cortical thickness in treatment-resistant schizophrenia
T2 - Implications for glutamate-mediated excitotoxicity
AU - Shah, Parita
AU - Plitman, Eric
AU - Iwata, Yusuke
AU - Kim, Julia
AU - Nakajima, Shinichiro
AU - Chan, Nathan
AU - Brown, Eric E.
AU - Caravaggio, Fernando
AU - Torres, Edgardo
AU - Hahn, Margaret
AU - Chakravarty, M. Mallar
AU - Remington, Gary
AU - Gerretsen, Philip
AU - Graff-Guerrero, Ariel
N1 - Funding Information:
This work was supported by the Ontario Mental Health Foundation (Type A grant) and the Canadian Institutes of Health Research (MOP-142493 and MOP-141968). These organizations had no role in study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit this paper for publication.Dr. Plitman reports receiving funding from Canadian Institute of Health Research (CIHR) and the Healthy Brains for Healthy Lives Postdoctoral Fellowship. Dr. Iwata reports receiving fellowship grants from Keio University Medical Science Foundation, Mitsukoshi Foundation, Japan Foundation for Aging and Health, and manuscript fees from Dainippon Sumitomo Pharma. Dr. Nakajima has received fellowship grants from CIHR, research support from Japan Society for the Promotion of Science, Japan Agency for Medical Research and Development, Japan Research Foundation for Clinical Pharmacology, Naito Foundation, Takeda Science Foundation, Uehara Memorial Foundation, Daiichi Sankyo, and manuscript fees or speaker's honoraria from Dainippon Sumitomo Pharma and Yoshitomi Yakuhin within the past three years. Dr. Hahn reports being on an advisory board for Alkermes in the past. Dr. Remington reports external funding from CIHR, travel support from Neurocrine Biosciences, and research support from HLS. Dr. Gerretsen reports receiving research support from CIHR, Ontario Ministry of Health and Long-Term Care, Ontario Mental Health Foundation (OMHF), and the Centre for Addiction and Mental Health (CAMH). Dr. Graff-Guerrero has received research support from the following external funding agencies: the CIHR, US NIH, OMHF, NARSAD, Mexico Instituto de Ciencia y Tecnolog?a del Distrito Federal, Consejo Nacional De Ciencia Y Tecnolog?a, Ministry of Economic Development and Innovation of Ontario, Ontario AHSC AFP Innovation Fund and W. Garfield Weston Foundation. All other authors report no conflict of interest.
Funding Information:
This work was supported by the Ontario Mental Health Foundation (Type A grant) and the Canadian Institutes of Health Research ( MOP-142493 and MOP-141968 ). These organizations had no role in study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit this paper for publication.
Publisher Copyright:
© 2020 Elsevier Ltd
PY - 2020/5
Y1 - 2020/5
N2 - Treatment-resistant schizophrenia may be related to structural brain alterations. However, the mechanisms underlying these changes remain unclear. The present study had two main aims: (1) to explore differences in cortical thickness between patients with treatment-resistant schizophrenia non-responsive to clozapine (ultra-treatment-resistant schizophrenia, UTRS), patients with treatment-resistant schizophrenia responsive to clozapine (Cloz-Resp), patients responsive to first-line non-clozapine antipsychotics (FL-Resp), and healthy controls (HCs); and (2) to test our hypothesis of structural compromise as a manifestation of neurotoxic effects from elevated glutamate (Glu) (i.e. glutamate-mediated excitotoxicity) by examining the relationships between glutamatergic neurometabolite levels (Glu and glutamate + glutamine (Glx)) in the dorsal anterior cingulate cortex (dACC) and cortical thickness. T1-weighted images and 1H-MRS data were obtained from UTRS (n = 24), Cloz-Resp (n = 25), FL-Resp (n = 19), and HCs (n = 26). Vertex-wise analyses showed that patients with UTRS had widespread cortical thinning in the bilateral frontal, temporal, parietal, and occipital gyri compared to HCs and FL-Resp patients. In the patient group, negative associations were found between dACC Glx levels and cortical thickness in the right dorsolateral prefrontal cortex after correcting for multiple comparisons and controlling for age, sex, antipsychotic dose, and illness severity. In conclusion, glutamate-mediated excitotoxicity may be one of the mechanisms underlying structural compromise seen in treatment-resistant schizophrenia. Future studies should longitudinally examine the associations between glutamatergic neurometabolite levels and cortical thickness in the context of treatment and illness progression.
AB - Treatment-resistant schizophrenia may be related to structural brain alterations. However, the mechanisms underlying these changes remain unclear. The present study had two main aims: (1) to explore differences in cortical thickness between patients with treatment-resistant schizophrenia non-responsive to clozapine (ultra-treatment-resistant schizophrenia, UTRS), patients with treatment-resistant schizophrenia responsive to clozapine (Cloz-Resp), patients responsive to first-line non-clozapine antipsychotics (FL-Resp), and healthy controls (HCs); and (2) to test our hypothesis of structural compromise as a manifestation of neurotoxic effects from elevated glutamate (Glu) (i.e. glutamate-mediated excitotoxicity) by examining the relationships between glutamatergic neurometabolite levels (Glu and glutamate + glutamine (Glx)) in the dorsal anterior cingulate cortex (dACC) and cortical thickness. T1-weighted images and 1H-MRS data were obtained from UTRS (n = 24), Cloz-Resp (n = 25), FL-Resp (n = 19), and HCs (n = 26). Vertex-wise analyses showed that patients with UTRS had widespread cortical thinning in the bilateral frontal, temporal, parietal, and occipital gyri compared to HCs and FL-Resp patients. In the patient group, negative associations were found between dACC Glx levels and cortical thickness in the right dorsolateral prefrontal cortex after correcting for multiple comparisons and controlling for age, sex, antipsychotic dose, and illness severity. In conclusion, glutamate-mediated excitotoxicity may be one of the mechanisms underlying structural compromise seen in treatment-resistant schizophrenia. Future studies should longitudinally examine the associations between glutamatergic neurometabolite levels and cortical thickness in the context of treatment and illness progression.
KW - Clozapine
KW - Excitotoxicity
KW - Glutamate
KW - Schizophrenia
KW - Thickness
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U2 - 10.1016/j.jpsychires.2020.02.032
DO - 10.1016/j.jpsychires.2020.02.032
M3 - Article
C2 - 32169688
AN - SCOPUS:85081004876
VL - 124
SP - 151
EP - 158
JO - Journal of Psychiatric Research
JF - Journal of Psychiatric Research
SN - 0022-3956
ER -
