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

Abstract

Cholecystokinin-tetrapeptide (CCK-4) induces panic attacks both in patients with panic disorder (PD) and healthy volunteers. It has been shown that panic elicited by CCK-4 is improved after treatment with antidepressants. Moreover, a reduction of CCK-4-induced panic has also been demonstrated after treatment with lorazepam in single subjects and after selective GABAergic treatment with vigabatrin. Although benzodiazepines are widely used as anxiolytics, no controlled study on the effects of benzodiazepines on CCK-4-induced panic symptoms is available so far. Therefore, we investigated the effects of alprazolam and placebo on CCK-4-induced panic symptoms in a double-blind, placebo-controlled study. A total of 30 healthy subjects were challenged with 50 mg CCK-4. Out of these 30 subjects, 26 showed a marked panic response to CCK-4. Subjects were rechallenged after a 7-day interval and treated with 1 mg alprazolam or placebo 1 h prior to the second CCK-4 challenge. Panic was assessed using the acute panic inventory (API) and a DSM-IV-derived panic symptom scale (PSS). Moreover, the number of reported symptoms and self-rated anxiety and arousal were recorded. We found a significant reduction of the API and PSS scores and of the number of reported symptoms compared to placebo. Moreover, compared to placebo the CCK-4-induced ACTH and cortisol release were significantly attenuated during the CCK-4 challenge after alprazolam treatment. However, also placebo treatment reduced CCK-4-induced anxiety and HPA-axis activation to a certain extent. In conclusion, our data show that alprazolam reduces CCK-4-induced panic, which supports the hypothesis of a possible interaction between the GABA and the CCK system.

Acute Shift in Glutamate Concentrations Following Experimentally Induced Panic with Cholecystokinin Tetrapeptide—A 3T-MRS Study in Healthy Subjects

“…In our study, CCK-4-induced panic attacks were furthermore accompanied by a marked and significant HPA axis stimulation, which is in line with several previous reports (Kellner et al, 2000;Koszycki et al, 1998;Zwanzger et al, 2003). Although data on the relationship of glutamate and HPA axis activity in humans are scarce, some reports show that glutamate is increased in stress-related situations.…”

“…The main finding was that CCK-4-induced panic was accompanied by a rapid and significant increase of Glx concentrations in the ACC. Moreover, panic was associated with a marked increase in the HPA axis stimulation as described previously (Kellner et al, 2000;Koszycki et al, 1998;Zwanzger et al, 2003).…”

“…Moreover, panic symptoms elicited by CCK-4 are attenuated after pharmacological treatment: Several studies have shown that treatment with antidepressants, which currently represent first-line treatment for PD, lead to a reduction of panic experimentally induced by CCK-4 (Bradwejn and Koszycki, 1994;Shlik et al, 1997). Similarly, anxiolytics such as the benzodiazepine alprazolam ameliorate CCK-4-induced panic attacks in healthy volunteers (Zwanzger et al, 2003). Such effects have also been observed in larger samples using XBD173, a ligand of the translocator (TPSO) protein (Rupprecht et al, 2009), which recently has been identified as a possible new treatment target for anxiety (Rupprecht et al, 2010;Nothdurfter et al, 2012).…”

Functional neuroanatomy of CCK‐4‐induced panic attacks in healthy volunteers

“…Keeping in line with previous investigations using the PSS [Flint et al, 1998;Koszycki et al, 1998;Zwanzger et al, 2003] subjects were classified as panickers if they fulfilled all of the following criteria after CCK-4 administration: a sudden onset of panic symptoms, an endorsement of at least four PSS symptoms and a subjective experience of anxiety/fear/apprehension of at least moderate intensity (a score of 2 or higher in the respective PSS item), the remaining subjects were considered as nonpanickers.…”

Panic Induction with Cholecystokinin-Tetrapeptide (CCK-4) Increases Plasma Concentrations of the Neuroactive Steroid 3α, 5α Tetrahydrodeoxycorticosterone (3α, 5α-THDOC) in Healthy Volunteers

“…This peripherally secreted neuroactive steroid (Reddy and Rogawski, 2002;Reddy, 2003;Purdy et al, 1991) and its precursor deoxycorticosterone (DOC) (Barbaccia et al, 1996) increase following acute stress and may counteract the anxiety and neuroendocrine consequences of maternal separation (Patchev et al, 1997). While various studies show an increase in ACTH and cortisol secretion following challenge with CCK-4 (Koszycki et al, 1998;Zwanzger et al, 2003), no data are available on 3a, 5a-THDOC levels during experimentally induced panic in humans. Therefore, we quantified plasma 3a, 5a-THDOC concentrations before and after challenge with 50 mg CCK-4 in healthy volunteers, using a highly sensitive and specific gas chromatography/ mass spectrometry (GC/MS) analysis.…”