Topiramate increases cerebral GABA in healthy humans

Kuzniecky, Ruben; Hetherington, Hoby P.; Ho, Schild; Pan, Jullie W.; Martin, Roy C.; Gilliam, Frank; Hugg, James W.; Faught, Edward

doi:10.1212/wnl.51.2.627

Cited by 99 publications

(72 citation statements)

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“…In humans, TPM increases cerebral GABA, homocarnosine, and pyrrolidinone concentrations (18,19). These potential antiepileptic mechanisms were not expected from in vitro and rodent model studies (13).…”

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confidence: 89%

“…Patients with epilepsy treated daily with TPM have higher brain GABA levels than do patients treated with carbamazepine (CBZ), gabapentin (GBP), lamotrigine (LTG), phenobarbital (PB), phenytoin (PHT), primidone (PRM), or valproate (VPA) (19). In healthy human subjects, TPM raises brain GABA within 3 h of the first, oral, 200-mg dose (18). The acute pharmacodynamic effects of TPM on GABA metabolism have not been reported in patients with epilepsy.…”

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confidence: 99%

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Topiramate Rapidly Raises Brain GABA in Epilepsy Patients

Petroff¹,

Hyder

Rothman

et al. 2001

Epilepsia

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Summary: Purpose:The short-and long-term pharmacodynamic effects of topiramate (TPM) on brain ␥-aminobutyric acid (GABA) metabolism were studied in patients with complex partial seizures.Methods: In vivo measurements of GABA, homocarnosine, and pyrrolidinone were made of a 14-cc volume in the occipital cortex using 1 H spectroscopy with a 2.1-Tesla magnetic resonance spectrometer and an 8-cm surface coil. Fifteen patients (four men) were studied serially after the first, oral dose (100 mg) of TPM.Results: The first dose of TPM increased brain GABA within 1 h. Within 4 h, GABA was increased by 0.9 mM (95% CI, 0.7-1.1). Brain GABA remained elevated for Ն24 h. Pyrrolidinone and homocarnosine increased slowly during the first day. Daily TPM therapy (median, 300 mg; range, 200-500) increased GABA (0.3 mM; 95% CI, 0.1-0.5), homocarnosine (0.4 mM; 95% CI, 0.3-0.5), and pyrrolidinone (0.15 mM; 95% CI, 0.10-0.19), compared with levels before TPM. There was no dose response evident with daily TPM doses of 200-500 mg.Conclusions: TPM promptly elevates brain GABA and presumably offers partial protection against further seizures within hours of the first oral dose. Patients may expect to experience the effects of increased homocarnosine and pyrrolidinone within 24 h.

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confidence: 89%

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confidence: 99%

Topiramate Rapidly Raises Brain GABA in Epilepsy Patients

Petroff¹,

Hyder

Rothman

et al. 2001

Epilepsia

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“…Several groups have actively pursued the measurement of GABA, both at rest and under the modulation of a variety of agents. 70,[73][74][75][76][77][78][79][80][81][82] Note that all of these studies have been performed either at fields higher than 1.5 T or with special spectral editing sequences, or a combination of both.…”

Section: Amino Acidsmentioning

confidence: 99%

Recent Advances in Magnetic Resonance Neurospectroscopy

Rosen

Lenkinski

2007

Neurotherapeutics

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Summary:Over the past two decades, proton magnetic resonance spectroscopy (proton MRS) of the brain has made the transition from research tool to a clinically useful modality. In this review, we first describe the localization methods currently used in MRS studies of the brain and discuss the technical and practical factors that determine the applicability of the methods to particular clinical studies. We also describe each of the resonances detected by localized solvent-suppressed proton MRS of the brain and discuss the metabolic and biochemical information that can be derived from an analysis of their concentrations. We discuss spectral quantitation and summarize the reproducibility of both single-voxel and multivoxel methods at 1.5 and 3-4 T. We have selected three clinical neurologic applications in which there has been a consensus as to the diagnostic value of MRS and summarize the information relevant to clinical applications. Finally, we speculate about some of the potential technical developments, either in progress or in the future, that may lead to improvements in the performance of proton MRS.

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“…212 We are not aware of any neuroimaging study that examined GABA receptors after treatment with mood stabilizers in mood disorder patients. In vivo MRS studies found an increase in human GABA levels after gabapentin, 213 topiramate, 214 and vigabatrin administration, 215 which are new anticonvulsants suggested to be effective in particular cases of mood disorders.…”

Section: Gabaergic Modulation In the Treatment Of Mood Disordersmentioning

confidence: 99%

“…Hyperforin, a major component of hypericum extract, which has been reported to be effective as antidepressant, 245 may inhibit GABA synaptosomal uptake in rat forebrain, elevating GABA levels. 246 It is stimulating to note that Griffin 98,102 No association between GABA A subunit genes and lithium-responsive bipolar patients 185,218 Valproate m in rat brain 199À203 and cultured neurons 203 m GABA turnover 190,191 and GAD activity 204 174,175 NEW AC m in rat brain 192,193 m GABA A receptor b3 m in human brain 213,214 subunit in rat hippocampus 172 165,253 IMAO m in rat brain 224,237,239,240 kGAD and GABA-T in rat brain 224 2 in rat brain 224,225 2 in rat frontal cortex 230 Other and Mellon 247 have reported that certain SSRIs directly alter the activity of neurosteroidogenic enzymes in the CNS. As the authors suggested, this effect may lead to increased production of neurosteroids in the brain, potentially modulating GABA-associated behaviors.…”

Section: 218mentioning

confidence: 99%