Abstract
This cross-sectional study analyzes spectroscopy data for long-term, never-medicated patients with schizophrenia to examine their levels of γ-aminobutyric acid (GABA) compared with those of healthy controls.
Schizophrenia is a debilitating psychotic disorder in which current pharmacological treatments (based on antagonists or partial agonists of dopamine receptors) have limited effects on negative and cognitive symptoms and a restricted efficacy in around a third of the patients over time, affecting symptom remission, recovery, and quality of life.1 Abnormalities in γ-aminobutyric acid (GABA) have been described in schizophrenia; these alterations have been linked to cognitive deficits observed in the illness.2 Proton magnetic resonance spectroscopy studies have described medial-prefrontal GABA elevations in unmedicated patients at early stages of the disorder,3 while studies in patients with long-term illness are scarce, reporting different results in medicated patients (increases,4 decreases,5 or lack of differences6 in this metabolite). Here, we examined GABA levels in a group of long-term, never-medicated patients with schizophrenia.
Methods
From November 2016 to January 2023, we recruited 21 individuals with chronic schizophrenia, defined by a duration of untreated psychosis longer than 5 years. All included patients were antipsychotic-naive and without comorbid disorders or current substance abuse. We also recruited 22 age- and sex-matched healthy controls. All participants were recruited at the Instituto Nacional de Neurología y Neurocirugía, Mexico City, Mexico. The study was approved by the ethics and scientific committees of this institute, and all participants provided written informed consent.
GABA levels were obtained by proton magnetic resonance spectroscopy at 3 T in a 2.5 × 2.5 × 2.5–cm voxel centered in the medial prefrontal cortex bilaterally (Figure, A), using the Mescher-Garwood point-resolved spectroscopy method (repetition time = 2000 milliseconds, echo time = 68 milliseconds, 2048 points, 256 averages [128 edit-on and 128 edit-off], with water suppression and 16 averages without water suppression). All spectra were quantified using the Matlab-based GABA analysis toolkit Gannet referenced to water signal and corrected to account for the tissue composition of the voxel. GABA values with a model error greater than 10% were rejected from all analyses. Cognition was evaluated with the MATRICS Consensus Cognitive Battery. Independent-sample t tests were used for comparisons of clinical and cognitive variables within groups. Frequency data were analyzed using the χ2 test. Spearman rank correlations were used to examine potential associations between GABA levels, clinical variables, and cognitive domains. Statistical significance was set at P < .05 for all analyses, and P values for correlational analyses were corrected for multiple comparisons through a Bonferroni method. Analyses were performed using SPSS Statistics version 21 (IBM).
Figure. Voxel Placement in the Region of Interest and γ-Aminobutyric Acid (GABA) Levels of the Participants.
A T1-weighted magnetic resonance image (A) showing the location of the medial prefrontal cortex spectroscopy voxel (overlaid in yellow). Levels of GABA (B) in the medial prefrontal cortex of healthy controls and patients with chronic schizophrenia. Horizontal bars indicate the mean value for the groups.
aP = .02.
Results
The demographic and clinical characteristics of all participants are listed in the Table. Spectroscopy data from 7 participants (4 patients with schizophrenia and 3 controls) were rejected from all analyses because of poor quality. Increased GABA levels were found in patients with chronic schizophrenia compared with controls (mean [SD], 4.6 [1.3] vs 3.7 [0.49] institutional units; t = −2.6, P = .02; Cohen d = 0.91) (Figure, B). Also, a negative correlation was found between GABA levels and working memory scores across all study participants (ρ = −0.37, P = .04); however, this correlation did not survive correction for multiple comparisons. No correlation was found between GABA levels and the duration of untreated psychosis (ρ = −0.33, P = .19), nor between GABA levels and other clinical or cognitive measures.
Table. Demographic and Clinical Characteristics of the Study Participants.
| Characteristic | Mean (SD) | Statistic | P value | |
|---|---|---|---|---|
| Healthy controls (n = 19) | Patients with chronic schizophrenia (n = 17) | |||
| Age, y | 36.8 (10.3) | 43.3 (12.5) | t = −1.71 | .10 |
| Sex, No. (%) | χ2 = .03 | .95 | ||
| Male | 11 (58) | 10 (59) | ||
| Female | 8 (42) | 7 (41) | ||
| Educational level, y | 16.6 (4.3) | 9.7 (4.8) | t = 4.30 | <.001 |
| Duration of untreated psychosis, mean (SD) [range], wk | NA | 816 (493) [260-2086] | ||
| PANSS subscale score | ||||
| Positive symptoms | NA | 29.3 (4.1) | ||
| Negative symptoms | NA | 25.2 (7.4) | ||
| General psychopathology | NA | 51.1 (10.4) | ||
| MCCB T scores | ||||
| Speed of processing | 49.8 (12.6) | 22.6 (20.4) | t = 4.5 | <.001 |
| Attention-vigilance | 50.5 (11.2) | 25.3 (14.3) | t = 5.5 | |
| Working memory | 51.6 (11.3) | 29.7 (18.2) | t = 4.1 | |
| Verbal learning | 46.6 (9.9) | 34.1 (9.3) | t = 3.7 | |
| Visual learning | 51.4 (11.1) | 32.5 (14.4) | t = 4.1 | |
| Reasoning-problem solving | 49.6 (10.6) | 36.4 (7.2) | t = 4.1 | |
| Social cognition | 46.6 (9.0) | 28.8 (7.5) | t = 6.1 | |
| Composite score | 49.0 (12.2) | 17.7 (17.7) | t = 5.8 | |
Abbreviations: MCCB, Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery; NA, not applicable; PANSS, Positive and Negative Syndrome Scale.
Discussion
The main limitation of the study was the use of a spectroscopy sequence that does not account for macromolecule contamination of the GABA signal. Future multicenter, longitudinal studies including unmedicated individuals with chronic schizophrenia are needed to confirm these results and determine whether these GABA elevations could help stratify the clinical outcomes of patients and also serve as markers of treatment response and future treatment development targeting the GABAergic system.
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References
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