Animal, postmortem, and genetic studies indicate that schizophrenia is associated with abnormalities in glutamatergic neurotransmission (1), but it is unclear whether antipsychotic treatment may impact on glutamate dysfunction in patients. Our recent meta-analysis suggests that schizophrenia is associated with a general elevation in glutamate metabolites, with some variation observed across brain regions and patient subgroups (2). Elevations in frontal cortical or hippocampal glutamate may lead to secondary elevations in striatal dopamine release, characteristic of schizophrenia (3–6). Observations of glutamate dysfunction prior to illness onset (7–9), and in patients who are antipsychotic naïve or who have received minimal antipsychotic treatment (10, 11), suggest that glutamatergic dysregulation is a pathological feature of schizophrenia, rather than an effect of antipsychotic exposure. However, it is unknown whether antipsychotic treatment can reduce, or indeed worsen, glutamatergic abnormalities. Potentially, modulation of glutamatergic transmission with antipsychotic treatment could occur via downstream effects of D2 antagonism and/or via interactions at other receptor subtypes. Alternatively, if current antipsychotics do not adequately address glutamatergic dysfunction, this would support the suggestion that adjunctive treatment with glutamatergic agents may have additional therapeutic benefit.

The idea that antipsychotics may modulate glutamatergic neurotransmission is supported by experimental animal studies showing a reduction in frontal cortical glutamate following administration of some, but not all antipsychotics (12–19). In rodents, decreases in frontal glutamate have been observed using ex vivo proton nuclear magnetic resonance (¹H-NMR) following administration of clozapine and olanzapine, but not haloperidol, risperidone, or aripiprazole (12). In vivo microdialysis studies in rodents have demonstrated reductions in pharmacologically induced elevations in frontal glutamate by risperidone, paliperidone, clozapine, aripipirazole, olanzapine, and haloperidol (13–19). However, a lack of significant effects of haloperidol on resting or stimulated glutamate metabolites in the rat brain have also been reported (19–22), and when antipsychotics are administered in the absence of pharmacologically stimulated glutamate release, antipsychotic-induced glutamate elevations may also be observed (23, 24). Together, these studies may suggest that antipsychotic glutamate-modulatory effects may be dependent on the animal model or glutamatergic assay, as well as the level of basal glutamatergic tone. Differential effects of antipsychotics may also be mediated by differing receptor binding profiles, and it has been suggested that downregulation of 5HT_2A receptors by antipsychotics with high 5HT_2A affinity may be important in reducing glutamatergic signaling (15, 16).

In man, brain glutamate levels can be measured in vivo using proton magnetic resonance spectroscopy (¹H-MRS), usually within a specific a priori brain region of interest. Depending on the achieved resolution, ¹H-MRS can provide concentration estimates for glutamate and glutamine or, at lower field strengths, the combined glutamate plus glutamine signal, which is termed Glx. The idea that antipsychotics may reduce glutamate elevation in schizophrenia is supported by a cross-sectional study that detected an elevation in Glx in non-medicated, but not in medicated schizophrenia (25). In our recent meta-analysis, meta-regression showed no significant relationship between regional glutamate, glutamine, or Glx and mean chlorpromazine equivalent antipsychotic dose (2). Nonetheless, longitudinal studies examining glutamate metabolites before and after antipsychotic treatment are required to address this question directly. Several such studies have now been published and the purpose of this article is to provide systematic review of their findings.

As a second objective, we also review the relationships between glutamate and symptomatic response in longitudinal studies of antipsychotic treatment. Cross-sectional ¹H-MRS studies show that glutamate metabolite levels differ between patients who have or have not responded well to antipsychotic treatment (26–29). This may suggest that glutamate level may predict the degree to which symptoms are likely to respond to antipsychotic administration, or that symptom reduction occurs in parallel with antipsychotic glutamatergic modulation. We, therefore, appraised the evidence from longitudinal studies for the value of glutamate levels in predicting or monitoring antipsychotic response.

The initial search identified 51 articles, of which 40 were excluded at the title and abstract screening stage. At the full-text screening, one study was excluded as it was not available in English (33). Analysis of the sample reported in Ref. (34) was subsequently extended (35). One article (36) was excluded as it reported a subsample of participants included in a larger cohort and longer term follow-up (31). This resulted in final inclusion of eight original articles (10, 31, 32, 34, 37–40).

The main finding of this review is that the majority of studies reported a numerical reduction in glutamate metabolites following antipsychotic treatment in schizophrenia, with half of the reviewed studies finding significant reductions in at least one brain region. In contrast, no significant increases in glutamate metabolites were reported. Schizophrenia is associated with a general increase in glutamate metabolites, which varies with region and with illness stage (2). This review provides some suggestion that antipsychotics may reduce glutamatergic elevations in schizophrenia but indicates that this effect may be relatively small or limited to subgroups of patients.

The mean change in Glx over antipsychotic treatment was estimated from the available data as a decrease in the range of 6.5% across regions, which would require a within-subjects’ sample size of 24 patients to achieve 80% power. Only three of the eight available studies had sample sizes of 24 or more patients (32, 34, 37) and the three studies with the smallest sample sizes (10, 38, 40) were the studies that did not find significant effects of antipsychotics on glutamatergic measures, suggesting that they may have been underpowered. Two of these smaller studies (38, 40) also differed in that they recruited patients with long antipsychotic medication histories, which may have also limited the ability to observe further glutamatergic reduction.

Our estimates of percentage reduction in glutamatergic metabolites following antipsychotic treatment in schizophrenia and the associated sample size calculations are limited by the availability of relatively few published studies. These studies have also investigated different brain regions, and glutamate dysfunction in schizophrenia may vary by region as well as by illness stage (2). In some cases, it was also necessary to extract values from published figures, which is less accurate than using reported values, and measures included both creatine-scaled or voxel CSF corrected data. As further studies become available, estimates of the percentage reduction can be updated and formal meta-analyses of effect sizes can be performed including inspection of potential influences such as regional specificity, patient subgroups, and duration of antipsychotic treatment. General limitations of ¹H-MRS include the estimation of the total concentrations of glutamate metabolites in the voxel, rather than imaging of glutamate involved in neurotransmission specifically, and inability to resolve glutamate from glutamine at lower field strengths and thereby interpretation of the combined Glx signal. Advanced methodological approaches, such as ¹H-MRS at high field strengths or ¹³C-MRS to inspect glutamate cycling may address some of these issues in future studies.

Reductions in glutamate metabolites following antipsychotic treatment would be consistent with the cross-sectional report of elevated prefrontal cortical Glx in non-antipsychotic medicated but not antipsychotic-medicated schizophrenia (25). While the mechanism by which antipsychotics might reduce glutamate is not yet clear, rodent studies also find reductions in basal or stimulated glutamate following administration of some antipsychotics (12–19), which may relate to the 5HT_2A antagonist activity of atypical agents (16, 41, 42). Atypical antipsychotics may also indirectly modulate glutamate release by modifying glutamatergic receptor activity or density (43–45). The majority of patients included in the reviewed studies were prescribed atypical antipsychotics, which may, therefore, have increased the potential to observe glutamatergic reductions. Future studies could specifically compare the ability of D2-selective antipsychotics to antipsychotics with marked 5HT_2A affinity to modulate glutamate in schizophrenia.

The timescales over which antipsychotic effects on glutamatergic measures have been evaluated range from 4 weeks (37) to 7 years (31). It might be predicted that longer durations of antipsychotic treatment may be associated with progressive glutamate reductions. Across the included studies, there was not suggestion of this, for example significant decreases in frontal Glx were observed after administration of antipsychotics for 1–6 months (32, 39), but not 12 or 80 months (10, 31). Individual studies that included repeated glutamatergic measurement also do not evidence progressive glutamatergic reduction (10, 31). This may suggest that antipsychotic effects on glutamatergic systems are most apparent within the initial stages of treatment, which could be explored in future studies. A further consideration for longitudinal assessment of glutamatergic measures in schizophrenia is the potential interacting effects of other confounds, such as disease progression, aging effects, or volumetric changes. The study of longest duration detected correlations between the reductions in thalamic glutamine and gray matter loss in the superior temporal gyrus over 30 months (36), and gray matter loss in frontal, parietal, temporal, and limbic regions over 7 years (31), possibly reflecting excitotoxic processes.

The second aim of this article was to review the potential relationships between glutamate and the degree of antipsychotic response in longitudinal studies. Our review only identified one study prospectively examining the relationship between baseline glutamate and subsequent response, which reported higher baseline Glx/Cr across voxels in the frontal and temporal lobes and thalamus in subsequent antipsychotic non-responders than responders (35). Two studies also reported correlations between the extent of glutamatergic reduction and the extent of symptomatic improvement over the antipsychotic treatment period (32, 37). These findings are consistent with observations of higher frontal glutamate levels in some (26, 27, 46), but not all (29), cross-sectional studies comparing treatment-responsive and non-responsive schizophrenia, and of higher striatal Glx/Cr in treatment resistant compared to treatment-responsive patients (29). The observation that glutamate levels may predict antipsychotic response (35) is also supported by recent pharmacogenomic findings that single nucleotide polymorphisms in genes encoding glutamatergic proteins associate with response to risperidone in first episode psychosis (47). In contrast, the conflicting result of an increase in frontal Glx/Cr in olanzapine responders compared to non-responders was reported in one study (38), and several studies reported no correlations between glutamatergic change and symptomatic improvement (34, 38–40). The idea that antipsychotic administration is less effective in reducing glutamate and improving symptoms in patients with the highest levels of glutamate before treatment could be further explored through re-analysis of existing longitudinal ¹H-MRS studies, and investigated in future longitudinal studies potentially combining glutamate ¹H-MRS with glutamate genetic approaches.

AE and AB performed the literature searches and data extraction. KM and GM checked data for accuracy. All authors contributed to interpretation of the data and the final draft of the manuscript.

The views expressed are those of the authors and do not necessarily represent those of the NHS, NIHR, or Department of Health.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.