Progress in Neuro-Psychopharmacology and Biological Psychiatry
Neurometabolite levels in antipsychotic-naïve/free patients with schizophrenia: A systematic review and meta-analysis of 1H-MRS studies
Introduction
Proton magnetic resonance spectroscopy (1H-MRS) permits the in vivo quantification of neurometabolites such as glutamate (Glu), glutamine (Gln), N-acetylaspartate (NAA), choline (Cho), creatine (Cr), myo-inositol (mI), and γ-Aminobutyric acid (GABA) (Abbott and Bustillo, 2006). Accumulating evidence suggests these neurometabolites are altered in patients with schizophrenia (Schwerk et al., 2014).
Glutamatergic and GABAergic neurometabolites are of particular interest, given that hypofunctioning N-methyl d-aspartate (NMDA) receptors on GABAergic neurons as well as abnormal glutamatergic and GABAergic neurotransmission are implicated in the pathophysiology of schizophrenia (Coyle, 2006). Previous studies have reported increases in Glu, Gln, and Glu + Gln (Glx) levels in the early stages of schizophrenia (prodromal phase and first-episode of psychosis [FEP]) (Bartha et al., 1997; de la Fuente-Sandoval et al., 2011, de la et al., 2013; Kegeles et al., 2012; Kraguljac et al., 2013; Theberge et al., 2002). A recent meta-analysis observed elevated Glu within the thalamus (Thal), and elevated Glx within the medial temporal lobe (mTem) and basal ganglia (BG), in patients compared to healthy controls (HCs) (Merritt et al., 2016). Conversely, a recent 7T 1H-MRS study found lower Glu levels in the occipital lobe (Occ) of medicated, chronic patients with schizophrenia (Thakkar et al., 2017). Similarly, including both medicated and unmedicated patients, another meta-analysis reported greater age-related reductions in frontal Glu and Gln in patients compared to HCs (Marsman et al., 2013); these results could be confounded by the mixed effects of both age and medication as older subjects tend to have a longer history of treatment. Collectively, these results suggest that glutamatergic neurometabolites may be increased in the early stages of schizophrenia and lowered or normalized during later stage of illness. However, no meta-analysis has examined glutamatergic neurometabolite levels exclusively in unmedicated patients with schizophrenia. Moreover, there are a limited number of studies measuring GABA levels (Taylor and Tso, 2015). A recent meta-analysis reported trend-level lower GABA levels with combining all brain regions in patients with schizophrenia (Schur et al., 2016). Notably, this meta-analysis also included both medicated and unmedicated subjects.
Abnormalities in other neurometabolites, including NAA, Cho, Cr, and mI, have also been reported (Brugger et al., 2011; Kraguljac et al., 2012). Lower NAA levels, indicative of reduced neuronal integrity (Brugger et al., 2011; Maddock and Buonocore, 2012), have typically been observed in patients versus HCs (Brugger et al., 2011; Kraguljac et al., 2012; Marsman et al., 2013; Ohrmann et al., 2005). Differences in Cho, which is implicated in cell membrane metabolism (Bertolino and Weinberger, 1999), have not been found in a previous meta-analysis (Kraguljac et al., 2012). However, studies have reported higher Cho levels in patients with FEP (Bustillo et al., 2002; Plitman et al., 2016). Cr, involved in storage and transport of cellular energy, is often used as an internal reference for other metabolites. However, studies have noted both increased and decreased levels of Cr in patients with schizophrenia (Bustillo et al., 2002; Ongur et al., 2009). mI is often interpreted as a marker of glial activity or content (Kim et al., 2005). Both elevated and decreased mI levels have been reported in patients with schizophrenia (Chang et al., 2007; Plitman et al., 2016). Thus, current 1H-MRS findings in schizophrenia is still inconclusive.
Several factors may confound neurometabolite assessment by 1H-MRS in schizophrenia including age/illness-progression or medication status (Brandt et al., 2016; Szulc et al., 2013). One cross-sectional study reported lower Glx, NAA, and Cr levels in medicated patients compared to age-matched unmedicated patients (Ohrmann et al., 2005). However, other studies did not find any differences between age-matched medicated and unmedicated patients (Kegeles et al., 2012; Wood et al., 2008). The effects of medication on neurometabolite levels have also been examined with longitudinal studies. Some studies have reported Glu and Gln reductions, and NAA elevations after AP administration in AP-naïve patients (de la Fuente-Sandoval et al., 2013; Gan et al., 2014; Stanley et al., 1996; Theberge et al., 2007), while other studies did not observe any changes (Choe et al., 1996; Szulc et al., 2011). Due to the limited evidences, it remains unclear whether AP use or age/illness-progression alter neurometabolite levels. Thus, the aim of the present study was to perform a meta-analysis of neurometabolite levels in unmedicated (i.e. AP-naïve/free) patients with schizophrenia.
Section snippets
Search strategy and selection criteria
Meta-analyses were conducted according to the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) (Moher et al., 2009). Published articles from 1950 to May 2017 were searched without language restrictions, using Embase, Medline, and PsycINFO. The search terms were: (schizophreni* OR psychosis) AND (“never-treated” OR “first-episode” OR untreated OR unmedicated OR naive OR free OR discontinu* OR withdraw*) AND (MRS OR “magnetic resonance spectroscopy”). Three authors (YI,
Study characteristics
A total of 27 studies were identified (Aoyama et al., 2011; Bartha et al., 1999; Bartha et al., 1997; Bustillo et al., 2002; Cecil et al., 1999; Choe et al., 1994; Choe et al., 1996; Crocker et al., 2014; de la Fuente-Sandoval et al., 2011, de la et al., 2013; Fannon et al., 2003; Gan et al., 2014; He et al., 2012; Kegeles et al., 2012; Kelemen et al., 2013; Kraguljac et al., 2013; Marenco et al., 2016; Ohrmann et al., 2005, Ohrmann et al., 2007; Plitman et al., 2016; Stanley et al., 1996,
Main findings
To our knowledge, this is the first comprehensive meta-analysis to examine neurometabolite levels measured by 1H-MRS in exclusively AP-naïve/free patients with schizophrenia. Of the subjects included in the present work, the majority (76.3%) were AP-naïve. In addition, the subjects were young (26.0 ± 4.0 years old) and had a short DUP (1.8 ± 1.7 years). Thus, our results are less likely to be severely influenced by AP use, illness progression, or aging. Importantly, our meta-analysis includes
Conclusion
In conclusion, the present meta-analysis revealed lower NAA levels in the Thal of AP-naïve/free patients with schizophrenia. However, we failed to perform analyses in several regions due to the lack of data. Going forward, it is important to map neurometabolite level differences between various brain regions to determine suitable ROIs. In an effort to overcome limitations, it would be beneficial to have two or more ROIs within a single study or to utilize multi-voxel MRS acquisition methods.
Contributors
YI, SN, EP did the literature search. YI and MY extracted the data. YI did the statistical analysis and prepared the figures. All authors interpreted the data, wrote the report, and approved the final version of the manuscript.
Funding
None.
Declaration of interests
YI has received fellowship grants from Canadian Institute of Health Research (CIHR), Keio University Medical Science Foundation, Mitsukoshi Foundation, Japan Foundation for Aging and Health, and manuscript fees from Dainippon Sumitomo Pharma. SN has received fellowship grants from CIHR and manuscript fees from Dainippon Sumitomo Pharma and Kyowa Hakko Kirin. EP has received research support from an Ontario Graduate Scholarship and a CIHR Canada Graduate Scholarship – Master's, and currently
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