The potential of (1)H-MRS in CNS drug development

RATIONALE: Proton magnetic resonance spectroscopy ((1)H-MRS) is a cross-species neuroimaging technique that can measure concentrations of several brain metabolites, including glutamate and GABA. This non-invasive method has promise in developing centrally acting drugs, as it can be performed repeatedly within-subjects and be used to translate findings from the preclinical to clinical laboratory using the same imaging biomarker. OBJECTIVES: This review focuses on the utility of single-voxel (1)H-MRS in developing novel glutamatergic or GABAergic drugs for the treatment of psychiatric disorders and includes research performed in rodent models, healthy volunteers and patient cohorts. RESULTS: Overall, these studies indicate that (1)H-MRS is able to detect the predicted pharmacological effects of glutamatergic or GABAergic drugs on voxel glutamate or GABA concentrations, although there is a shortage of studies examining dose-related effects. Clinical studies have applied (1)H-MRS to better understand drug therapeutic mechanisms, including the glutamatergic effects of ketamine in depression and of acamprosate in alcohol dependence. There is an emerging interest in identifying patient subgroups with ‘high’ or ‘low’ brain regional (1)H-MRS glutamate levels for more targeted drug development, which may require ancillary biomarkers to improve the accuracy of subgroup discrimination. CONCLUSIONS: Considerations for future research include the sensitivity of single-voxel (1)H-MRS in detecting drug effects, inter-site measurement reliability and the interpretation of drug-induced changes in (1)H-MRS metabolites relative to the known pharmacological molecular mechanisms. On-going technological development, in single-voxel (1)H-MRS and in related complementary techniques, will further support applications within CNS drug discovery.