Effects of vigabatrin on the GABAergic system as determined by [123I]iomazenil SPECT and GABA MRS.
OBJECTIVE
To evaluate effects of vigabatrin (VGB) by using [123I]iomazenil single-photon emission computed tomography (SPECT) to estimate central gamma-aminobutyric acid (GABA(A))/benzodiazepine receptors (BZRs), and magnetic resonance spectroscopy (MRS) to assess tissue GABA levels.


METHODS
Six patients with partial seizures had both SPECT and MRS before and 25-84 days after starting VGB (3 g p.o., q.d.). SPECT was acquired by using the constant-infusion method and, after nonuniform attenuation correction, coregistered with T1-weighted MR Imaging (MRI) A volume of interest (VOI) of 3 x 2 x 2 cc over the occipital cortex, used for MRS acquisition, was positioned on both MRI and coregistered SPECT. Occipital activity was divided by either total plasma activity or plasma [123I]iomazenil concentration to estimate BZR distribution volume (V(T)-p and V'(T), respectively). Wilcoxon's test was used for VOI differences in GABA levels, BZR V(T)-p or V'(T). SPM96 (either no global normalization or proportional scaling) was used to compare BZR V(T)-p changes in the patients with and without VGB with test-retest data in eight healthy age-matched controls.


RESULTS
Occipital GABA levels were increased threefold (without VGB, 1.1+/-0.1 micromol/g; with VGB, 2.9+/-0.5 micromol/g; p = 0.027). BZR distribution volumes showed no change, when estimated by either V(T)-p (without VGB, 6.00+/-0.91 ml/g; with VGB, 5.86+/-0.44 ml/g; p = 0.92) or V(T) (without VGB, 41.1+/-11.2 ml/g; with VGB, 41.2+/-9.9 ml/g; p = 0.75). No significant changes were detected by SPM96.


CONCLUSIONS
A clinically effective dose of VGB caused a threefold increase in tissue GABA levels but was not associated with a substantial BZR downregulation.
Verhoeff
N P
NP
Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut 06516, USA. verhoeff@orpheus.med.yale.edu
Petroff
O A
OA
Hyder
F
F
Zoghbi
S S
SS
Fujita
M
M
Rajeevan
N
N
Rothman
D L
DL
Seibyl
J P
JP
Mattson
R H
RH
Innis
R B
RB
D000328:Adult; D000927:Anticonvulsants / Q000494:pharmacology*; D005260:Female; D005442:Flumazenil / Q000031:analogs & derivatives*; D006801:Humans; D007457:Iodine Radioisotopes; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008875:Middle Aged; D009778:Occipital Lobe / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism; D018079:Receptors, GABA / Q000032:analysis* / Q000187:drug effects*; D015899:Tomography, Emission-Computed, Single-Photon / Q000706:statistics & numerical data*; D020888:Vigabatrin / Q000494:pharmacology*
D000927:Anticonvulsants; D007457:Iodine Radioisotopes; D018079:Receptors, GABA; D005442:Flumazenil; C063038:iomazenil; D020888:Vigabatrin