Effects of tiagabine on cholecystokinin-tetrapeptide (CCK-4)-induced anxiety in healthy volunteers

Abstract

There is increasing evidence that a dysregulation of the gamma-aminobutyric acid (GABA) system plays a role in the pathophysiology of panic disorder. Selective enhancement of GABAergic neurotransmission has been shown to improve anxiety in experimental animals and in patients with panic disorder. Tiagabine is an antiepileptic drug, which increases GABA via selective blockade of GABA reuptake. Apart from its anticonvulsant activity anxiolytic properties could therefore be suggested. To investigate the putative anxiolytic properties of the GABA reuptake blocker tiagabine, we studied the impact of tiagabine treatment on cholecystokinin tetrapeptide (CCK-4)-induced panic. Fifteen healthy volunteers received 15 mg tiagabine daily for 1 week. A CCK-4 challenge was performed before and after treatment. Panic was assessed using the API- and PSS-score. There was a marked improvement of CCK-4-induced panic after 1 week of treatment. Both API- and PSS-scores showed a significant reduction. Our results suggest anxiolytic properties of tiagabine in humans, which provide sufficient rationale to assess its putative anxiolytic effects in patients with panic disorder under controlled conditions.

Evaluation of the CCK-4 model as a challenge paradigm in a population of healthy volunteers within a proof-of-concept study

“…Therefore, the CCK-4 challenge does not only constitute a model to study the pathophysiology of panic disorder but can serve as a useful tool to evaluate the antipanic potential of novel anxiolytic compounds . First evidence for putative anxiolytic effects of GABA-ergic antiepileptic drugs such as vigabatrine and tiagabine (Zwanzger et al 2001(Zwanzger et al , 2003b and of a metatropic glutamate (2/3) receptor agonist (Kellner et al 2005) came from their ability to decrease CCK-4-induced panic symptoms. A major advantage of this approach is that such studies can be performed in healthy controls Kellner et al 2005;Lines et al 1995;Zwanzger et al 2001Zwanzger et al , 2003b.…”

Targeting the Modulation of Neural Circuitry for the Treatment of Anxiety Disorders

“…A Connectome Hypothesis. Anxiety is a complex emotional response that involves multiple neurotransmitters acting at various receptors within the limbic system (i.e., hippocampus, parahippocampal gyrus, cingulate gyrus, hypothalamus, and amygdala) and within the paralimbic regions of the cerebral cortex such as the orbital and medial prefrontal cortex (Rauch et al, 1997;Simpson et al, 2000;Pape and Stork, 2003;Phillips et al, 2003;Sah et al, 2003;Yilmazer-Hanke et al, 2003;Zwanzger et al, 2003;Kang-Park et al, 2004;Phan et al, 2004). From a neural systems perspective, fear and anxiety seem to be controlled by two major circuits: those involved in our most primitive innate responses to simple and overt threatening stimuli, and those involved in moderating responses to more complex situations.…”

Effect of time of preparation on pentagastrin-induced symptom, endocrine and cardiovascular responses

“…Animal and human studies show that CCK-B agonists (pentagastrin and the closely related peptide CCK-4) produce anxiogenic effects, stimulate cardiovascular activity and activate the hypothalamic-pituitary-adrenal (HPA) axis (Abelson and Liberzon, 1999;Zwanzger et al, 2003;Rotzinger and Vaccarino, 2003;Khan et al, 2004a). In panic disorder patients, CCK-B agonists also produce most of the classic symptoms of a panic attack (Bradwejn, et al 1990;Abelson and Nesse, 1994;Koszycki et al, 1998;Abelson et al, 1999).…”