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Beata Galińska-Skok,1 Agata Szulc,2 Aleksandra Małus,1 Beata Konarzewska,1 Urszula Cwalina,3 Eugeniusz Tarasów,4 Napoleon Waszkiewicz1 1Department of Psychiatry, Medical University of Białystok, Choroszcz, Poland; 2Department of Psychiatry, Faculty of Health Sciences, Medical University of Warsaw, Pruszków, Poland; 3Department of Statistics and Medical Informatics, Medical University of Białystok, Białystok, Poland; 4Department of Radiology, Medical University of Białystok, Białystok, Poland Purpose: Investigation of the longitudinal effect of schizophrenia on changes in various brain-metabolite levels and their relationships with cognitive deficits that have not been fully explained yet.Methods: Five years subsequent to their first examination for their first episode of schizophrenia, eleven patients from an original group of 30 were reexamined. Their cognitive functions were assessed with the Wisconsin Card Sorting Test. Magnetic resonance imaging and proton magnetic resonance spectroscopy were performed on a 1.5 T scanner. Voxels of 8 cm3 were positioned in the left frontal lobe, left temporal lobe, and the left thalamus. The study had a naturalistic design, and patients were treated with various antipsychotics.Results: No significant statistical differences between the baseline and follow-up in N-acetylaspartate (NAA:creatine plus phosphocreatine [Cr] and NAA/H2O) levels were observed in any region of interest. We found a significant statistical correlation between 5-year difference in frontal NAA/Cr levels and duration of the last antipsychotic treatment in this period (R=0.908, P=0.012). We found a trend (P=0.068) toward lower choline-containing compounds (Cho/Cr ratio) in the temporal lobe over 5 years and a trend (P=0.079) in higher glutamate–glutamine–GABA (Glx/H2O) levels in the left thalamus. The patients showed social and clinical improvement at follow-up examination, and there were no changes in Wisconsin Card Sorting Test results.Conclusion: The observed tendency toward decline in choline ratio might have been due to decreased temporal cell density or impaired neuron-membrane or myelin functions. A tendency for higher Glx levels suggest the involvement of thalamus dysfunction in the chronic schizophrenia process. The lack of NAA decrease might have been due to effective antipsychotic treatment. Further longitudinal studies on large patient groups are required to confirm these metabolic changes in schizophrenia. Keywords: first-episode schizophrenia, proton magnetic resonance spectroscopy, longitudinal study, cognitive functioning, N-acetylaspartate, choline

Importance: Proton magnetic resonance spectroscopy (1H-MRS) studies indicate that altered brain glutamatergic function may be associated with the pathophysiology of schizophrenia and the response to antipsychotic treatment. However, the association of altered glutamatergic function with clinical and demographic factors is unclear., Objective: To assess the associations of age, symptom severity, level of functioning, and antipsychotic treatment with brain glutamatergic metabolites., Data Sources: The MEDLINE database was searched to identify journal articles published between January 1, 1980, and June 3, 2020, using the following search terms: MRS or magnetic resonance spectroscopy and (1) schizophrenia or (2) psychosis or (3) UHR or (4) ARMS or (5) ultra-high risk or (6) clinical high risk or (7) genetic high risk or (8) prodrome* or (9) schizoaffective. Authors of 114 1H-MRS studies measuring glutamate (Glu) levels in patients with schizophrenia were contacted between January 2014 and June 2020 and asked to provide individual participant data., Study Selection: In total, 45 1H-MRS studies contributed data., Data Extraction and Synthesis: Associations of Glu, Glu plus glutamine (Glx), or total creatine plus phosphocreatine levels with age, antipsychotic medication dose, symptom severity, and functioning were assessed using linear mixed models, with study as a random factor., Main Outcomes and Measures: Glu, Glx, and Cr values in the medial frontal cortex (MFC) and medial temporal lobe (MTL)., Results: In total, 42 studies were included, with data for 1251 patients with schizophrenia (mean [SD] age, 30.3 [10.4] years) and 1197 healthy volunteers (mean [SD] age, 27.5 [8.8] years). The MFC Glu (F1,1211.9 = 4.311, P = .04) and Glx (F1,1079.2 = 5.287, P = .02) levels were lower in patients than in healthy volunteers, and although creatine levels appeared lower in patients, the difference was not significant (F1,1395.9 = 3.622, P = .06). In both patients and volunteers, the MFC Glu level was negatively associated with age (Glu to Cr ratio, F1,1522.4 = 47.533, P < .001; cerebrospinal fluid-corrected Glu, F1,1216.7 = 5.610, P = .02), showing a 0.2-unit reduction per decade. In patients, antipsychotic dose (in chlorpromazine equivalents) was negatively associated with MFC Glu (estimate, 0.10 reduction per 100 mg; SE, 0.03) and MFC Glx (estimate, -0.11; SE, 0.04) levels. The MFC Glu to Cr ratio was positively associated with total symptom severity (estimate, 0.01 per 10 points; SE, 0.005) and positive symptom severity (estimate, 0.04; SE, 0.02) and was negatively associated with level of global functioning (estimate, 0.04; SE, 0.01). In the MTL, the Glx to Cr ratio was positively associated with total symptom severity (estimate, 0.06; SE, 0.03), negative symptoms (estimate, 0.2; SE, 0.07), and worse Clinical Global Impression score (estimate, 0.2 per point; SE, 0.06). The MFC creatine level increased with age (estimate, 0.2; SE, 0.05) but was not associated with either symptom severity or antipsychotic medication dose., Conclusions and Relevance: Findings from this mega-analysis suggest that lower brain Glu levels in patients with schizophrenia may be associated with antipsychotic medication exposure rather than with greater age-related decline. Higher brain Glu levels may act as a biomarker of illness severity in schizophrenia.

Introduction: Proton magnetic resonance spectroscopy (¹H MRS) enables the evaluation of in vivo brain function. The purpose of the study was to compare ¹H MRS measurements in schizophrenic patients, who were clinical responders after short-term antipsychotic treatment, with non-responders and healthy controls., Methods: We investigated a group of 47 patients diagnosed with schizophrenia. Patients were examined twice--once after a period of at least 7 days without neuroleptics and the second time at least 4 weeks after therapy with stable doses of medication. The follow-up was available in 42 patients. Baseline MRS measurements of clinical responders were compared with non-responders and the group of healthy controls (N=26). We assessed the following metabolite ratios: NAA (N-acetylaspartate), Glx (complex of GABA, glutamine and glutamate), Cho (choline) and mI (myo-inositol) to creatinine (Cr) in the left frontal and temporal lobes and the thalamus., Results: Responders showed a significantly lower baseline frontal Glx/Cr level than non-responders. Both groups had a significantly lower NAA/Cr ratio in the frontal lobe than the controls, but only non-responders had a significantly lower NAA/Cr ratio in the thalamus., Conclusions: Our results confirm the relationship between the glutamatergic system and pathophysiology of schizophrenia and suggest a significant value of ¹H MRS examination in the assessment of the future treatment effect., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Proton magnetic resonance spectroscopy ((1)H MRS) enables the observation of brain function in vivo. Several brain metabolites can be measured by the means of (1)H MRS: N-acetylaspartate (NAA), choline containing compounds (Cho), myo-inositol (mI) and glutamate (Glu), glutamine (Gln) and GABA (together as Glx complex or separately). (1)H MRS measures have been found to be abnormal in psychotic disorders such as schizophrenia. Here we specifically review the influence exerted by antipsychotic drugs on brain metabolism, as detected by (1)H MRS. We systematically reviewed the available literature and uncovered 27 studies, 16 before-after treatment and 11 cross-sectional. Most of them addressed the effects of antipsychotics in schizophrenia and mainly focusing on NAA alterations. Follow up studies indicated antipsychotic drugs may act by increasing NAA levels in selected brain areas (the frontal lobe and thalamus), especially during the short-time observation. This phenomenon seems to vanish after longer observation. Other studies indicated that glutamate measures are decreasing along with the duration of the disease, suggesting both a neurodegenerative process present in schizophrenic brain as well as an influence of antipsychotics. The above results were reviewed according to the most recent theories in the field accounting for the impact of antipsychotics (1)HMRS measures.