SU84. Neurometabolite Levels in Antipsychotic Naive/Free Patients With Schizophrenia: A Meta-Analysis of 1H-MRS Studies

Abstract

Background: Studies using proton magnetic resonance spectroscopy (1H-MRS) have reported altered neurometabolite levels in patients with schizophrenia. It has been repeatedly noted that levels of glutamatergic neurometabolite are elevated in patients within the early stages of schizophrenia. On the other hand, N-acetylaspartate (NAA) levels are typically found to be lower in patients with schizophrenia. Regarding other neurometabolites, results seem to be less consistent. Importantly, previous studies have suggested that the influence of antipsychotic (AP) administration is a possible confounding factor that may affect neurometabolite level assessment. Thus, the aim of the present study was to examine neurometabolite levels in APnaive/free patients with schizophrenia through a metaanalysis. Method(s): A literature search was conducted using Embase, Medline, and PsycINFO to identify studies that compared neurometabolite levels in AP-naive/free patients with schizophrenia to healthy controls (last search: June 2016). Eight neurometabolites, glutamate, glutamine, glutamate +glutamine (Glx), NAA, choline, creatine, myo-inositol, and gamma-Aminobutyric acid (GABA), and 7 brain regions, medial prefrontal cortex, dorsolateral prefrontal cortex, frontal white matter [FWM], occipital lobe, basal ganglia, hippocampus/medial temporal cortex, and thalamus [Thal], were examined. Standardized mean differences (SMDs) were calculated to assess neurometabolite level differences between groups. Analyses were performed when 2 or more studies were available. Moderator analyses were also performed to examine the influences of study characteristics on the differences in neurometabolite levels between groups. Subgroup analyses were performed for the following categorical characteristics: (a) studies only with AP-naive subjects and (b) MRI magnetic field strength (o 3 T or = 3 T). Metaregression analyses were conducted for the following continuous characteristics: (a) age, (b) gender proportion, and (c) duration of untreated psychosis (DUP). Metaregression was performed if at least 5 datasets including neurometabolite levels and characteristics data were available in order to minimize the effect by chance. Owing to the number of comparisons, the significance level was set at a pvalue ofo 0.05/the number of performed primary analyses. Result(s): Twenty-two studies were included in the analysis. Sixteen studies (72.7 %) included only AP-naive patients with schizophrenia, whereas 5 studies (22.7 %) included both AP-naive and AP-free patients with schizophrenia. One study (4.5 %) included only AP-free patients with schizophrenia. The total number of subjects was 1142 (AP-naive schizophrenia = 461 [40.4 %], AP-free schizophrenia = 108 [9.5 %], and HC = 573 [50.2 %]). The age of the subjects was 26.3 +/- 4.1 years old, the proportion of males was 66.7 +/- 13.0 %, and the DUP was 1.5 +/- 1.2 years. PANSS total scores were 77.7 +/- 26.1, indicating moderate illness severity. Out of 56 potential comparisons (7 brain regions and 8 neurometabolites), a total of 29 analyses were performed (6 brain regions for Cho, Glx, and NAA, 3 for Cr and mI, 2 for GABA and Glu, and 1 for Gln). Thus, we considered a P value less than 0.0017 (0.05/29) to be significant. The results of the primary analysis showed lower thalamic NAA levels in the patient group (3 studies, n = 174, SMD =-0.56, P = 0.0005). No differences were identified for other neurometabolites. In the subgroup analysis only examining AP-naive studies, there were no differences between groups. In the subgroup analysis examining magnetic field strength (o 3 T or = 3 T), lower NAA levels were observed in theo 3 T subgroup within the FWM (2 studies, n = 134, SMD =-0.65, P = 0.0004). In the meta-regression analysis, no relationships were found between SMD of neurometabolite levels and subjects characteristics (i.e., age, gender, and DUP). Conclusion(s): This study extends previously reported metaanalysis findings demonstrating a decrease of NAA levels in patients with schizophrenia. Given the previous reported decrease in NAA of chronic schizophrenia, the present finding may suggest that NAA is decreased in schizophrenia throughout their illness course. On the other hand, previously reported alterations of glutamatergic neurometabolite levels were not observed in the present study. The limitation of this study is the small number of included subjects and studies. Overall, future studies should continue to study neurometabolite levels in AP-naive patients with schizophrenia to further elucidate the underlying pathophysiology of the illness and to facilitate the development of potential treatments.