Selective GABAergic treatment for panic? Investigations in experimental panic induction and panic disorder

Abstract

gamma-Aminobutyric acid (GABA) is the most important inhibitory neurotransmitter in the central nervous system (CNS). It exerts its rapid inhibitory action mostly through GABA(A) receptors, which are targets for benzodiazepines, barbiturates, neuroactive steroids and distinct anticonvulsive agents. There is considerable evidence that dysfunction of GABA(A) receptors or dysregulation of GABA concentrations in the CNS (or both) plays an important role in the pathophysiology of panic disorder. Currently, benzodiazepines are the only drugs directly targeting the GABA(A) receptors that are approved for the treatment of anxiety disorders. Because of their well-known anxiolytic effects, they are widely used in this setting, but side effects limit their use in long-term treatment. The question of whether drugs that selectively increase GABA concentrations in the CNS could improve symptoms of anxiety has been discussed. Recent investigations by our group have demonstrated that enhancement of endogenous GABA (through blockade of GABA transaminase by vigabatrin or through inhibition of GABA transporters by tiagabine) exerts anxiolytic effects on experimentally induced panic. Our studies in healthy volunteers have shown that both compounds lead to a significant reduction in panic symptoms elicited by cholecystokinin-tetrapeptide. Moreover, benzodiazepine-like effects on the activity of the hypothalamic-pituitary-adrenal axis have been observed in association with vigabatrin treatment. Small open studies in patients with panic disorder also showed an improvement in panic and anxiety with both compounds. This review summarizes our recent research on the effects of selective GABAergic treatment in experimentally induced panic and outlines the possible role of compounds targeting the GABA binding site of the GABA(A)-benzodiazepine receptor for the treatment of panic and anxiety.

Fig. 1: Illustration of the metabolism of γ-aminobutyric acid (GABA). GABA is synthesized from glutamate by glutamic acid decarboxylase (GAD). After synaptic release, GABA is removed by reuptake through the GABA-transporter I (GAT) and degraded by GABA-transaminase (GABA-T). Vigabatrin (VGB) is an irreversible inhibitor of GABA-T. Tiagabine (TGB) inhibits GABA-reuptake by blockade of GAT I.

Fig. 2: Effects of vigabatrin in patients with severe panic disorder. During the 4-week trial, all 3 patients reported almost full remission of their symptoms as reflected by the rating scores. Ratings were based on the Hamilton Anxiety Rating Scale (HAM-A), the Bandelow Agoraphobia Scale (BAS) and a panic attack diary reporting weekly number of panic attacks (PAs).

Fig. 3: Effects of tiagabine in patients with panic disorder. During the 4-week trial, 3 patients reported a marked reduction of their panic and anxiety. One patient dropped out because of side effects (data not shown). Ratings were based on the Hamilton Anxiety Rating Scale (HAM-A), the Bandelow Agoraphobia Scale (BAS) and a panic attack diary reporting weekly number of panic attacks (PAs).