Elsevier

Biological Psychiatry

Volume 45, Issue 3, 1 February 1999, Pages 321-326
Biological Psychiatry

Original Articles
Behavioral, neuroendocrine, and cardiovascular response to flumazenil: no evidence for an altered benzodiazepine receptor sensitivity in panic disorder

https://doi.org/10.1016/S0006-3223(98)00295-9Get rights and content

Abstract

Background: Flumazenil is a benzodiazepine receptor antagonist thought to be panicogenic in patients with panic disorder but not in control subjects. The present study was undertaken to compare the effects of flumazenil in patients with panic disorder and those in healthy control subjects, and also to determine whether panic disorder is characterized by a hypothesized shift in the benzodiazepine receptor “set-point” and a differential response to flumazenil.

Methods: Eight patients with panic disorder and 8 matched control subjects were given infusions of saline and flumazenil in randomized order. Psychopathological changes, cardiovascular parameters, together with adrenocorticotropic hormone (ACTH) and cortisol secretion were recorded.

Results: Patient and control subjects responded to flumazenil uniformly; there was no evidence for an anxiogenic activity of flumazenil in control subjects or panic disorder patients. ACTH and cortisol levels were also not differentially influenced by flumazenil or panic disorder diagnosis. Heart rate and systolic blood pressure in both groups were slightly but significantly reduced by flumazenil compared to saline.

Conclusions: These findings do not support the view that panic disorder patients and control subjects respond differentially to flumazenil or that the suggested shift in the benzodiazepine receptor “set-point,” which leads to an inverse agonistic activity of flumazenil, characterizes panic disorder.

Introduction

Preclinical and clinical studies have implicated the benzodiazepine–γ-aminobutyric acid-A (GABAA) receptor complex in the pathophysiology of anxiety; benzodiazepines are used to reduce anxiety (Ströhle in press), whereas inverse agonists at the benzodiazepine receptor, such as β-carbolines, have been reported to provoke anxiety (Dorow and Duka 1986). Flumazenil is a specific benzodiazepine receptor ligand that has been shown to antagonize most of the pharmacologic effects of benzodiazepines Hunkeler et al 1981, Darragh et al 1982; however, agonistic and inverse agonistic effects of flumazenil on the sleep electroencephalogram and electrophysiological parameters have also been reported Schopf et al 1984, Polc 1988, Steiger et al 1994. Because flumazenil also produces panic attacks in panic disorder patients but not in control subjects Nutt et al 1990, Woods et al 1991, Nutt et al (1990) have suggested a shift in the benzodiazepine receptor “set-point” toward an inverse agonistic action of flumazenil in patients with panic disorder. Inverse agonists at the GABAA receptor increase anxiety, pulse rate, and blood pressure Mohler and Okada 1977, Dorow et al 1983; however, whether the hypothezised shift in the benzodiazepine receptor “set-point” occurs in all patients with panic disorder was recently questioned, as lactate-sensitive patients with panic disorder do not experience anxiogenic or panic-provoking effects after flumazenil administration (Ströhle et al 1998). Comparing the psychopathological, cardiovascular, and endocrine effects of flumazenil in panic disorder patients and control subjects will further help to clarify whether there is an altered benzodiazepine receptor sensitivity in panic disorder.

The hypothalamic–pituitary–adrenocortical (HPA) system is influenced by the GABAA receptor function in a highly complex manner, with benzodiazepines reducing HPA activity (Christensen et al 1992). In contrast, inverse agonists have been shown to increase the secretion of corticosteroids De Boer et al 1991, Dorow et al 1983. Flumazenil has been reported as attenuating the activating effects of corticotropin-releasing hormone (CRH) Britton et al 1988, Strohle and Wiedemann 1996, indicating a partial agonistic activity of flumazenil on the stimulated HPA system activity.

Because cardiovascular and HPA system activity may furthermore reflect flumazenil activity, we compared behavioral, neuroendocrine, and cardiovascular effects in patients with panic disorder and also in healthy matched control subjects to further study whether flumazenil acts as an inverse agonist, thereby indicating a shift of the GABAA receptor in patients with panic disorder. If this is so, then it can be assumed that flumazenil activates the HPA and the cardiovascular system of patients with panic disorder.

Section snippets

Methods and materials

Eight patients (4 women and 4 men) with a diagnosis of panic disorder (mean duration of illness = 31.8 ± 13.3 months) but without a comorbid Axis I disorder as assessed with the Structured Clinical Interview for DSM-III-R (Spitzer et al 1987) were studied. Without a significant reduction of panic attack frequency 2 patients have received antidepressants (trimipramine 75 mg/day and opipramol 25 mg/day until 2 and 3 weeks before the study) and 3 patients benzodiazepines on demand (0–3 times per

Results

None of the subjects experienced a panic attack in the flumazenil or saline (placebo) condition. Analysis of variance did not indicate a significant treatment or time effect on the API or the arousal scores. Furthermore, no differential effects of flumazenil on API or arousal scores were found when patients with panic disorder were compared with control subjects (Table 1).

With regard to hormones, neither of the factors treatment and group had a significant main effect on plasma cortisol and

Discussion

The major finding of our study is that compared to healthy control subjects, patients with panic disorder do not experience increased anxiogenic or panic-provoking effects after administration of the benzodiazepine receptor antagonist flumazenil. In addition, neither hormonal alterations nor changes in cardiovascular parameters indicate that flumazenil exerts an inverse agonistic activity in such patients. Further evidence for a slight partial agonistic activity of flumazenil in panic disorder

Acknowledgements

The authors wish to thank Dr. A. Yassouridis for statistical advice and G. Gajewsky for technical assistance.

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