Novel variants in GABAA receptor subunits: A possible association with benzodiazepine resistance in patients with drug-resistant epilepsy

Chakraborty, Aphrodite; Dey, Soumil; Kumar, Krishan; Dixit, Aparna Banerjee; Tripathi, Manjari; Sharma, Mehar Chand; Chandra, P. Sarat; Banerjee, Jyotirmoy

doi:10.1016/j.eplepsyres.2022.107056

Cited by 3 publications

(3 citation statements)

References 53 publications

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“…Moreover, Bowser et al [178] discovered that individuals with epilepsy who carried the R43Q mutation in the GABRG2 gene had reduced sensitivity to BZDs. Similarly, a recent study reported a possible association between two polymorphisms in GABRA2 and GABRA5 genes and drug-resistant epilepsy [179]. Overall, research assessing the pharmacodynamic variability of anxiolytic drugs remains a relatively new field.…”

Section: Pharmacodynamic Variabilitymentioning

confidence: 97%

The Role of Pharmacogenetics in Personalizing the Antidepressant and Anxiolytic Therapy

Radosavljević

Štrac

Jančić

et al. 2023

Genes

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Pharmacotherapy for neuropsychiatric disorders, such as anxiety and depression, has been characterized by significant inter-individual variability in drug response and the development of side effects. Pharmacogenetics, as a key part of personalized medicine, aims to optimize therapy according to a patient’s individual genetic signature by targeting genetic variations involved in pharmacokinetic or pharmacodynamic processes. Pharmacokinetic variability refers to variations in a drug’s absorption, distribution, metabolism, and elimination, whereas pharmacodynamic variability results from variable interactions of an active drug with its target molecules. Pharmacogenetic research on depression and anxiety has focused on genetic polymorphisms affecting metabolizing cytochrome P450 (CYP) and uridine 5’-diphospho-glucuronosyltransferase (UGT) enzymes, P-glycoprotein ATP-binding cassette (ABC) transporters, and monoamine and γ-aminobutyric acid (GABA) metabolic enzymes, transporters, and receptors. Recent pharmacogenetic studies have revealed that more efficient and safer treatments with antidepressants and anxiolytics could be achieved through genotype-guided decisions. However, because pharmacogenetics cannot explain all observed heritable variations in drug response, an emerging field of pharmacoepigenetics investigates how epigenetic mechanisms, which modify gene expression without altering the genetic code, might influence individual responses to drugs. By understanding the epi(genetic) variability of a patient’s response to pharmacotherapy, clinicians could select more effective drugs while minimizing the likelihood of adverse reactions and therefore improve the quality of treatment.

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Section: Pharmacodynamic Variabilitymentioning

confidence: 97%

The Role of Pharmacogenetics in Personalizing the Antidepressant and Anxiolytic Therapy

Radosavljević

Štrac

Jančić

et al. 2023

Genes

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“…77,78 Preclinical epilepsy models confirmed this alteration in the responsiveness of voltage-gated sodium channels. 79 DRE in patients has also been associated with changes in γaminobutyric acid (GABA)ergic neurotransmission, including subunit configuration, 80 binding dynamics, 24 and signaling of the GABA A receptors. 81 It has been stated that the target hypothesis does not explain why patients are resistant to multiple ASMs with different mechanisms.…”

Section: Target Hypothesismentioning

confidence: 99%

“…DRE in patients has also been associated with changes in γ‐aminobutyric acid (GABA)ergic neurotransmission, including subunit configuration, 80 binding dynamics, 24 and signaling of the GABA A receptors 81 …”

Section: Potential Mechanisms Of Drementioning

confidence: 99%

Revisiting the concept of drug‐resistant epilepsy: A TASK1 report of the ILAE/AES Joint Translational Task Force

Auvin,

Galanopoulou,

Moshé

et al. 2023

Epilepsia

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Despite progress in the development of anti‐seizure medications (ASMs), one third of people with epilepsy have drug‐resistant epilepsy (DRE). The working definition of DRE, proposed by the International League Against Epilepsy (ILAE) in 2010, helped identify individuals who might benefit from presurgical evaluation early on. As the incidence of DRE remains high, the TASK1 workgroup on DRE of the ILAE/American Epilepsy Society (AES) Joint Translational Task Force discussed the heterogeneity and complexity of its presentation and mechanisms, the confounders in drawing mechanistic insights when testing treatment responses, and barriers in modeling DRE across the lifespan and translating across species. We propose that it is necessary to revisit the current definition of DRE, in order to transform the preclinical and clinical research of mechanisms and biomarkers, to identify novel, effective, precise, pharmacologic treatments, allowing for earlier recognition of drug resistance and individualized therapies.

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Drug-resistant epilepsy and its selected complications in children

Knopek,

Iwanicka,

Boryczka

2024

Ann. Acad. Med. Siles.

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Padaczka lekooporna (<i>drug-resistant epilepsy</i> – DRE) u dzieci jest jedną z najczęściej diagnozowanych chorób układu nerwowego. Pomimo dostępności farmakoterapii o różnych mechanizmach działania lekooporność determinuje brak możliwości osiągnięcia zamierzonego efektu terapeutycznego. Mając na uwadze złożoną etiologię omawianej jednostki chorobowej, istnieje pilna potrzeba zgłębiania wiedzy w zakresie determinantów DRE, jak i możliwości poprawy jakości życia pacjentów oraz ich rodzin. Praca stanowi opis z podsumowaniem najnowszych osiągnięć i aktualnego stanu wiedzy odnoszącego się do charakterystyki klinicznej, epidemiologii, możliwych powikłań, a szczególnie podłoża genetycznego DRE w polskiej populacji dzieci.

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Novel variants in GABAA receptor subunits: A possible association with benzodiazepine resistance in patients with drug-resistant epilepsy

Cited by 3 publications

References 53 publications

The Role of Pharmacogenetics in Personalizing the Antidepressant and Anxiolytic Therapy

The Role of Pharmacogenetics in Personalizing the Antidepressant and Anxiolytic Therapy

Revisiting the concept of drug‐resistant epilepsy: A TASK1 report of the ILAE/AES Joint Translational Task Force

Drug-resistant epilepsy and its selected complications in children

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