Vigabatrin Decreases Cholecystokinin-Tetrapeptide (CCK-4) Induced Panic in Healthy Volunteers

Abstract

Vigabatrin increases gamma aminobutyric acid (GABA) levels by irreversible inhibition of the GABA-catabolizing enzyme GABA-transaminase (GABA-T). Preclinical studies suggest anxiolytic effects in vigabatrin treated rats. Anxiolytic effects in patients with panic disorder (PD) could therefore be expected. To evaluate putative anxiolytic properties of vigabatrin in humans, CCK-4-induced panic symptoms were studied in healthy volunteers before and after vigabatrin treatment. After placebo-controlled administration of 50 g CCK-4, ten healthy volunteers received vigabatrin for seven days with a daily dosage of 2 g. The treatment period was followed by a second CCK-4 challenge. Panic and anxiety were assessed using the Acute Panic Inventory (API) score and a DSM-IV derived panicsymptom-scale (PSS). ACTH and cortisol plasma levels were determined during the CCK-4 challenge. All subjects reported a marked reduction of CCK-4-induced panic symptoms and anxiety after seven days of vigabatrin treatment both in the API-and PSS-scores. MoreoverThe new antiepileptic drug vigabatrin is a selective irreversible inhibitor of GABA-transaminase (GABA-T), the main degradative enzyme of GABA (Harden 1994). Vigabatrin increases CSF GABA levels by 2 to 3-fold when administered in anticonvulsant doses (Ben-Menachem 1989). Preclinical studies suggest that vigabatrin has anxiolytic properties in addition to its anticonvulsant effects. Sayin et al. (1992) compared the anxiolytic effects of diazepam and vigabatrin in rats and found a significant decrease of anxiety with both substances using the elevated plus maze test. Sherif and colleagues investigated the effects of GABA-transaminase inhibition on exploratory behaviour in socially isolated rats using both the elevated plus maze and the open field NO . 5 test (Sherif et al. 1994;Sherif and Oreland 1995). Despite these promising results in animal models it is still unclear whether vigabatrin exerts anxiolytic properties also in humans.CCK-4 has potent anxiogenic properties both in patients with panic disorder and in healthy volunteers (Bradwejn et al. 1990;Bradwejn et al. 1991a;Bradwejn et al. 1991b). Recent data suggest that CCK-4-induced panic is attenuated by antipanic treatment. A decrease of the anxiogenic effects of CCK-4 has been shown after treatment with benzodiazepines in healthy volunteers (de Montigny 1989). Moreover, antidepressants that are commonly used as antipanic treatment, e.g. imipramine (Bradwejn and Koszycki 1994a), fluvoxamine (van Megen etal. 1997) and citalopram (Shlik et al. 1997) reduced CCK-4-induced panic in patients with panic disorder.CCK-4-induced panic appears to be a suitable model to assess anxiolytic properties of psychopharmacological drugs in humans. To evaluate the putative anxiolytic properties of the selective GABA transaminase inhibitor vigabatrin, we therefore studied the effects of treatment with vigabatrin for seven days on CCK-4-induced panic symptoms in healthy male volunteers. METHODSTen male healthy volunteers (mean age ϭ 30.7 years, S...

Effects of Alprazolam on Cholecystokinin-Tetrapeptide-Induced Panic and Hypothalamic–Pituitary–Adrenal-Axis Activity: A Placebo-Controlled Study

“…Similarly, in a prior study we observed a blunted HPA system response after selective GABAergic treatment with vigabatrin in healthy volunteers (-'-)) and the placebo group (PLC 1 (-J-) and PLC 2 (-K-)). (Zwanzger et al, 2001). Both findings are congruent with several preclinical and clinical data showing an inhibition of the HPA-axis activity after treatment with benzodiazepines.…”

“…Administration of vigabatrin, an inhibitor of the GABA-transaminase, in 10 healthy volunteers significantly attenuated symptoms provoked by CCK-4. Reductions of the API score by 45% and of the PSS score by 54% were observed after vigabatrin treatment (Zwanzger et al, 2001). This effect size is similar to the results after alprazolam treatment in the current study.…”

“…However, no change in heart rate has been found after treatment with imipramine or vigabatrin (Zwanzger et al, 2001). …”

“…Panic symptoms were assessed using the acute panic inventory (API) (Dillon et al, 1987) and a DSM-IV-derived panic symptom scale (PSS) (Bradwejn et al, 1990) as described previously (Zwanzger et al, 2001). Moreover, 100 mm visual analogue scales (VAS) for self-rated anxiety and arousal were used.…”

“…They found no difference in CCK-4-induced panic symptoms and cardiovascular effects in either group and concluded that CCK-4-induced anxiety is not mediated by benzodiazepine receptors . In a recent investigation our group showed a marked and significant reduction of CCK-4-induced panic in 10 healthy volunteers after selective GABAergic treatment with vigabatrin, a selective inhibitor of the main GABA catabolizing enzyme GABA transaminase (Zwanzger et al, 2001).…”