Oral glycine administration increases brain glycine/creatine ratios in men: a proton magnetic resonance spectroscopy study

Abstract

Oral high-dose glycine administration has been used as an adjuvant treatment for schizophrenia to enhance glutamate neurotransmission and mitigate glutamate system hypofunction thought to contribute to the disorder. Prior studies in schizophrenia subjects documented clinical improvements after 2 weeks of oral glycine administration, suggesting that brain glycine levels are sufficiently elevated to evoke a clinical response within that time frame. However, no human study has reported on brain glycine changes induced by its administration. We utilized a noninvasive proton magnetic resonance spectroscopy ((1)H-MRS) technique termed echo time-averaged (TEAV) (1)H-MRS, which permits noninvasive quantification of brain glycine in vivo, to determine whether 2 weeks of oral glycine administration (peak dose of 0.8 g/kg/day) increased brain glycine/creatine (Gly/Cr) ratios in 11 healthy adult men. In scans obtained 17 h after the last glycine dose, brain (Gly/Cr) ratios were significantly increased. The data indicate that it is possible to measure brain glycine changes with proton spectroscopy. Developing a more comprehensive understanding of human brain glycine dynamics may lead to optimized use of glycine site agonists and glycine transporter inhibitors to treat schizophrenia, and possibly to treat other disorders associated with glutamate system dysfunction.

Figures

Figure 1

Top Panels: D0 TEAV 1H-MRS voxel placement and resultant spectra from one study subject (Panels A–B). Bottom Panels: D14 TEAV 1H-MRS voxel placement and resultant spectrum (Panels C–D). Panel D inset: LC-Model Gly* fit spectrum extractions for D0 and D14. Resonance peak assignments are as follows: 1) N-acetylasparate, 2) glutamate, 3) total creatine, 4) choline, 5) Gly*, 6) myo-inositol, 7) glutamate/glutamine, 8) total creatine, 9) myo-inositol. Unsuppressed water line widths, which reflect metabolite line widths, for D0 and D14 averaged 7.84 ± 0.66 and 7.84 ± 0.44 Hz, respectively, indicating comparable water and metabolite line widths on the different scan days. Panels A and C demonstrate good voxel overlap in repeat scans. Panels B and D document the Gly* resonance and its change after glycine administration.

Figure 2

Brain Gly*/Cr ratios at D0 and D14 for all study subjects. The Gly*/Cr ratio increased in 10 of 11 subjects who completed the glycine dosing protocol (ANOVA F1,10=18.8, P < 0.002).