Glutamate-dopamine matters in psychosis
Authors: Dennis Hernaus, Thérèse van Amelsvoort
Journal: The Lancet Psychiatry (2018)

In The Lancet Psychiatry, Sameer Jauhar and colleagues1Jauhar S McCutcheon R Borgan F et al.The relationship between cortical glutamate and striatal dopamine in first-episode psychosis: a cross-sectional multimodal PET and magnetic resonance spectroscopy imaging study.Lancet Psychiatry. 2018; (published online Sept 17.)http://dx.doi.org/10.1016/S2215-0366(18)30268-2Summary Full Text Full Text PDF PubMed Scopus (62) Google Scholar present a formal investigation into the association between cortical glutamate and striatal presynaptic dopamine function in first-episode psychosis. This study was motivated by the notion that increased striatal dopamine function, as well as perturbed cortical glutamate function, possibly mediated via N-methyl-D-aspartate (NMDA) receptor hypofunction, have long been thought to be two principal neurochemical abnormalities associated with psychotic symptoms. Using a commendable multimodal approach in a cohort (first-episode psychosis n=28, controls n=20), Jauhar and colleagues1Jauhar S McCutcheon R Borgan F et al.The relationship between cortical glutamate and striatal dopamine in first-episode psychosis: a cross-sectional multimodal PET and magnetic resonance spectroscopy imaging study.Lancet Psychiatry. 2018; (published online Sept 17.)http://dx.doi.org/10.1016/S2215-0366(18)30268-2Summary Full Text Full Text PDF PubMed Scopus (62) Google Scholar compared assessments of striatal dopamine synthesis capacity and anterior cingulate cortex glutamate in patients with first-episode psychosis for the first time. Crucially, they observed that increased striatal dopamine synthesis capacity correlated with lower anterior cingulate cortex glutamate concentrations in patients with first-episode psychosis (β −1·71 × 10−4, SE 7·63 × 10−5, r=−0·40, p=0·03). This correlation was absent in controls (r=0·20, p=0·39; group difference in correlation strength Z=−2·01, p=0·04). The authors hypothesise, while acknowledging methodological limitations, that the negative association between striatal dopamine synthesis capacity and anterior cingulate cortex glutamate concentration might suggest a deficit in an indirect pathway, by which hypofunction of NMDA receptors preferentially expressed on inhibitory γ-aminobutyric acid (GABA) interneurons could drive increased striatal dopamine synthesis capacity. This interpretation is consistent with the observations that cortical GABAergic interneurons control striatal dopamine release2Karreman M Moghaddam B The prefrontal cortex regulates the basal release of dopamine in the limbic striatum: an effect mediated by ventral tegmental area.J Neurochem. 1996; 66: 589-598Crossref PubMed Scopus (298) Google Scholar and that hypofunction of NMDA receptors on GABAergic interneurons leads to increased amphetamine-induced striatal dopamine release.3Nakao K Jeevakumar V Jiang SZ et al.Schizophrenia-like dopamine release abnormalities in a mouse model of NMDA receptor hypofunction.Schizophr Bull. 2018; (published online Jan 31.)DOI:10.1093/schbul/sby003Crossref PubMed Scopus (21) Google Scholar Thus, in this respect, the work of Jauhar and colleagues1Jauhar S McCutcheon R Borgan F et al.The relationship between cortical glutamate and striatal dopamine in first-episode psychosis: a cross-sectional multimodal PET and magnetic resonance spectroscopy imaging study.Lancet Psychiatry. 2018; (published online Sept 17.)http://dx.doi.org/10.1016/S2215-0366(18)30268-2Summary Full Text Full Text PDF PubMed Scopus (62) Google Scholar might have provided new mechanistic insights into the origin of psychotic symptoms. One intriguing observation was the absence of a group difference in the striatal influx constant (Kicer, a well-established measure of dopamine synthesis capacity) between patients with first-episode psychosis (Kicerapproximately 0·0128) and controls, which had numerically even greater dopamine synthesis capacity (Kicerapproximately 0·013). Although this is in contrast to previous work, striatal dopamine synthesis capacity did correlate with positive symptom severity in first-episode psychosis. The authors suggested that the absence of a group difference in striatal dopamine synthesis capacity might be explained by the presence of treatment non-responders, who might have normative striatal dopamine synthesis capacity.4Demjaha A Egerton A Murray RM et al.Antipsychotic treatment resistance in schizophrenia associated with elevated glutamate levels but normal dopamine function.Biol Psychiatry. 2014; 75: e11-e13Summary Full Text Full Text PDF PubMed Scopus (230) Google Scholar In our view, this scenario would have crucial implications for the interpretation of the negative association between striatal dopamine synthesis capacity and glutamate concentration in the anterior cingulate cortex. The presence of treatment non-responders—suggested by lower striatal dopamine synthesis capacity in first-episode psychosis—introduces the possibility that the observed association might not bespeak a neurochemical mechanism. Rather, the association might be interpreted as a recapitulation of previous findings in two discrete patient subgroups: people who respond to treatment with antipsychotics, characterised by increased striatal dopamine synthesis capacity and unchanged anterior cingulate cortex glutamate concentration, and people who did not respond to antipsychotic treatment, who might have unaffected striatal dopamine synthesis capacity and increased anterior cingulate cortex glutamate concentration.4Demjaha A Egerton A Murray RM et al.Antipsychotic treatment resistance in schizophrenia associated with elevated glutamate levels but normal dopamine function.Biol Psychiatry. 2014; 75: e11-e13Summary Full Text Full Text PDF PubMed Scopus (230) Google Scholar One observation that would argue in favour of a mechanistic explanation (eg, low anterior cingulate cortex glutamate concentration driving increased striatal dopamine synthesis capacity) is the negative association between anterior cingulate cortex glutamate concentration and positive symptom severity. However, more research is warranted here in light of the positive correlation between anterior cingulate cortex glutamate concentration and symptom severity in a highly powered study of individuals with first-episode psychosis5Egerton A Broberg BV Van Haren N et al.Response to initial antipsychotic treatment in first episode psychosis is related to anterior cingulate glutamate levels: a multicentre (1)H-MRS study (OPTiMiSE).Mol Psychiatry. 2018; (published online June 7.)DOI:10.1038/s41380-018-0082-9Crossref Scopus (74) Google Scholar and following a ketamine challenge,6Poels EM Kegeles LS Kantrowitz JT et al.Imaging glutamate in schizophrenia: review of findings and implications for drug discovery.Mol Psychiatry. 2014; 19: 20-29Crossref PubMed Scopus (159) Google Scholar, 7Stone JM Dietrich C Edden R et al.Ketamine effects on brain GABA and glutamate levels with 1H-MRS: relationship to ketamine-induced psychopathology.Mol Psychiatry. 2012; 17: 664-665Crossref PubMed Scopus (220) Google Scholar the systematic evidence for raised MR spectroscopy indices of glutamatergic activity in psychosis,6Poels EM Kegeles LS Kantrowitz JT et al.Imaging glutamate in schizophrenia: review of findings and implications for drug discovery.Mol Psychiatry. 2014; 19: 20-29Crossref PubMed Scopus (159) Google Scholar and the preliminary observations suggesting that altered cortical glutamate function might be especially related to negative and cognitive symptom severity.8Gruber O Chadha Santuccione A Aach H Magnetic resonance imaging in studying schizophrenia, negative symptoms, and the glutamate system.Front Psychiatry. 2014; 5: 32Crossref PubMed Scopus (33) Google Scholar We believe that the interesting association between subcortical dopamine synthesis capacity, cortical glutamate, and psychotic symptoms reported by Jauhar and colleagues1Jauhar S McCutcheon R Borgan F et al.The relationship between cortical glutamate and striatal dopamine in first-episode psychosis: a cross-sectional multimodal PET and magnetic resonance spectroscopy imaging study.Lancet Psychiatry. 2018; (published online Sept 17.)http://dx.doi.org/10.1016/S2215-0366(18)30268-2Summary Full Text Full Text PDF PubMed Scopus (62) Google Scholar warrants new research into the association between in vivo measures of neurotransmitter function and molecular mechanisms. In preclinical models, this could be achieved by a systematic investigation into how candidate mechanisms for psychotic disorders (ie, NMDA receptor hypofunction, GABAergic interneuron dysfunction, or increased striatal dopamine function), together and in isolation, affect assessments of dopamine synthesis capacity measured with 18F-L-dihydroxyphenylalanine (18F-DOPA) and glutamate indexed with MR spectroscopy. In light of the various outcome measures typically used in MR spectroscopy studies (eg, glutamate, glutamine, or both combined), improving molecular understanding of the glutamate signal should receive priority. In human patients, this could be achieved by a comparison of MR spectroscopy glutamate measures (preferably acquired with high-field MR spectroscopy, which has greater signal-to-noise ratio9Pradhan S Bonekamp S Gillen JS et al.Comparison of single voxel brain MRS AT 3T and 7T using 32-channel head coils.Magn Reson Imaging. 2015; 33: 1013-1018Summary Full Text Full Text PDF PubMed Scopus (40) Google Scholar) with NMDA receptor function, for example by use of 11C N-(2-chloro-5-thiomethylphenyl)-N'-(3-[11C]methoxy-phenyl)-N-methylguanidine (GMOM) PET.10van der Doef TF Golla SS Klein PJ et al.Quantification of the novel N-methyl-d-aspartate receptor ligand [11C]GMOM in man.J Cereb Blood Flow Metab. 2016; 36: 1111-1121Crossref PubMed Scopus (16) Google Scholar These approaches might ultimately allow for a more mechanistic interpretation of our neurochemical assays. Additionally, large-scale longitudinal studies will be essential to translate neurochemical assays into predictors of treatment response and psychosis risk at the individual level. One initial approach could be to track the treatment response of Jauhar and colleagues'1Jauhar S McCutcheon R Borgan F et al.The relationship between cortical glutamate and striatal dopamine in first-episode psychosis: a cross-sectional multimodal PET and magnetic resonance spectroscopy imaging study.Lancet Psychiatry. 2018; (published online Sept 17.)http://dx.doi.org/10.1016/S2215-0366(18)30268-2Summary Full Text Full Text PDF PubMed Scopus (62) Google Scholar diagnostically heterogeneous first-episode psychosis sample, which could yield preliminary insights into which predictors (ie, striatal dopamine synthesis capacity, anterior cingulate cortex glutamate, or some combination of both) are most informative, and, whether the striatal dopamine synthesis capacity-anterior cingulate cortex glutamate association might be understood best as a symptom mechanism or a marker of treatment response. We declare no competing interests. The relationship between cortical glutamate and striatal dopamine in first-episode psychosis: a cross-sectional multimodal PET and magnetic resonance spectroscopy imaging studyThese observations are consistent with the hypothesis that cortical glutamate dysfunction is related to subcortical dopamine synthesis capacity and psychosis. Although the precise mechanistic relationship between cortical glutamate and dopamine in vivo remains unclear, our findings support further studies to test the effect of modulating cortical glutamate in the treatment of psychosis. Full-Text PDF Open Access