Illustration of GABA-A receptor. Eight types of receptor subunits have been cloned, with multiple subtypes within some classes: alpha 1-6, beta 1-4, gamma 1-4, delta, epsilon, pi, rho 1-3, and theta, but the majority of GABA-A receptors consist of alpha, beta and gamma subunits, with a stoichiometry of 2:2:1 (
Möhler ). In some cases, the epsilon or delta subunit may replace the gamma subunit. The combination of different subunit isoforms characterises GABA-A receptors expressed in specific areas of the brain and modulates different functions. The BZD binding site is located at the interface of adjacent alpha and gamma subunits, therefore, the presence of the gamma isoform is instrumental in determining BZD sensitivity, while the specific alpha isoform contributes to different selectivity and sensitivity. et al., 2001; Rudolph et al., 2001
BZD structure and examples. Upper left: the three rings are required for BZD receptor binding activity. Substituents in position 1,2, and partially in position 7, influence pharmacokinetics and half-life but not the affinity and activity of the individual drug at the BZD receptor site. BZDs can also be classified according to the relative position of the nitrogen atom in the heterocyclic ring, as 1,2; 1,3; 1,4; 1,5 or 2,4. Upper right: position R2’ can be unsubstituted or contain a halogen atom (F or Cl), a process called halogenation. Halogenation generally increases BZD activity, for example, as is the case for triazolam and lorazepam which represent the Cl-substituted form of alprazolam and oxazepam, respectively. Lower left: the amide group in position 2 in the diazepine ring can be replaced by a heterocycle ring, such as imidazole or triazole, generating two distinct subgroups of heterocyclic BZDs, referred to as “imidazo- and triazolo-BZDs”. Midazolam is an example of imidazo-BZDs, while alprazolam and triazolam (upper right) are examples of triazolo-BZDs. Lower right: clobazam and diazepam, as examples of 1,4 and 1,5 BZDs, with similar structure.
Atkinson Morley Regional Neuroscience Centre, St George's University Hospitals NHS Foundation Trust, London
Department of Neuropsychiatry, South West London & St George's Mental Health Trust, London
Institute of Medical and Biomedical Sciences, St George's University of London, London, United Kingdom
Correspondence: Marco Mula
Atkinson Morley Regional Neuroscience Centre,
St George's University Hospitals NHS Foundation Trust,
London SW17 0QT,
Anxiety disorders represent a common psychiatric comorbidity in patients with epilepsy, affecting prognosis and quality of life. However, they are still underdiagnosed and undertreated. In clinical practice, a number of compounds are currently used as anxiolytics, with benzodiazepines being the most popular. Other drug classes, especially antiepileptic drugs, are increasingly prescribed for the treatment of anxiety. This article discusses the neurobiological targets and basic neuropharmacological aspects of anxiolytics in order to give the reader clear insight into their activity and mechanism of action. Clinical data regarding the treatment of anxiety in both adults and children with epilepsy are also summarised, emphasising the need for further studies.