Cerebral glutamate levels over two years in initially antipsychotic-naïve first-episode patients with psychosis are related to clinical symptoms and cognition

Abstract Although emerging evidence supports glutamatergic dysfunction in schizophrenia, clinical trials with glutamatergic compounds have overall been negative. This may be due to changes in glutamate levels during the course of illness. To address this, we measured glutamate levels in dorsal anterior cingulate cortex (dACC) and left thalamus in 57 initially antipsychotic-naïve patients with first-episode psychosis (FEP) aged 22.6 ± 5.0 years (58% females) and 55 healthy controls (HC) on a 3T MR scanner at baseline, after six weeks (48 FEP and 53 HC), six months (37 FEP and 49 HC), and two years (35 FEP and 45 HC). Positive and negative symptoms and cognitive function in tests of attention and spatial working memory were assessed at all visits. Linear mixed models were used in statistical analyses. We found lower glutamate levels in dACC in FEP (p=0.03) that was associated with deficits in attention at all visits (p<0.05). Thalamic glutamate levels did not differ between groups, but higher levels were related to more pronounced positive symptoms at all visits (p=0.02). The relation between thalamic glutamate levels and negative symptoms was altered over time (negative symptoms*time: p=0.003) due to a significant positive association after two years (p=0.04) but not at other visits. For other metabolites, thalamic NAA were lower in FEP (p=0.04) and total creatine was increased after 6 weeks treatment (p=0.01), whereas dACC glx levels were lower after two years (p=0.02). The results suggest that greater positive symptom severity is related to higher thalamic glutamate levels and cognitive deficits to lower dACC glutamate levels during the first two years of illness. Furthermore, higher thalamic glutamate levels after two years are associated with more severe negative symptomatology. Findings imply that glutamatergic compounds decreasing thalamic and increasing dACC glutamate levels may be beneficial in FEP over the first two years of illness. Competing Interest Statement Dr. Bojesen received lecture fees from Lundbeck Pharma A/S. Dr. Glenthoej was the head of the Lundbeck Foundation Centre of Excellence for Clinical Interven-tion and Neuropsychiatric Schizophrenia Research (CINS) from January 2009 to December 2021, which was partially financed by an independent grant from the Lundbeck Foundation based on international review and partially financed by the Mental Health Services in the Capital Region of Denmark, the University of Copenhagen, and other foundations. All grants are the property of the Mental Health Services in the Capital Region of Denmark and administrated by them. She has no other conflicts to disclose. Dr. Ebdrup is part of the Advisory Board of Eli Lilly Denmark A/S, Janssen-Cilag, Lundbeck Pharma A/S, and Takeda Pharmaceutical Company Ltd; and has received lecture fees from Bristol-Myers Squibb, Boehringer Ingelheim, Otsuka Pharma Scandinavia AB, Eli Lilly Company, and Lundbeck Pharma A/S. The rest of the authors have no conflicts of interest to disclose. Clinical Trial NCT02339844 Funding Statement This study was funded by an independent grant from the Lundbeck Foundation (R155-2013-16337) for the Lundbeck Foundation Centre of Excellence for Clinical Intervention and Neuropsychiatric Schizophrenia Research (CINS) (B Glenthoej); and a Ph.D. grants from the Faculty of Health and Medical Sciences, University of Copenhagen (KB Bojesen) as well as a post doc grant from the re-search Fund 2022 in the Capital Region of Denmark (KB Bojesen); grants from the Woerzner (B Glenthoej) and Gerhard Linds Foundations (KB Bojesen); and support from the Mental Health Ser-vices, Capital Region of Denmark (B Glenthoej). Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Ethical Committee on Biomedical Research Ethics in the Capital Region of Denmark gave ethical approval for this work (H-3-2013-149) I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data Availability All data produced in the present study may be available upon reasonable request to the authors through a formal collaboration agreement