Mechanisms of flumazenil-induced panic.

摘要

Reduction of GABA neurotransmission in animals causes anxiety, cardio-respiratory and neuroendocrine activation (reactions resembling human panic attacks). In patients with panic disorder (PD), flumazenil (normally an antagonist at the benzodiazepine binding site of the common GABAA receptor subtypes) may cause panic directly by acting as a partial inverse agonist, thus reducing GABA effect. Alternatively, flumazenil-induced panic may reflect a negative (cognitive) reaction to somatic symptoms experienced during the challenge. Both possibilities were tested. Thyrotropin-releasing hormone (which is not panicogenic in PD patients) induced equal or greater somatic panic-related symptoms than flumazenil in healthy volunteers (HV), suggesting that catastrophic misinterpretation of somatic symptoms may not be the primary mechanism of flumazenil-induced panic in PD. Consequently, behavioral, cardio-respiratory and cortisol responses to flumazenil were compared between patients with (1) pure PD (P), (2) comorbid PD and depression (P + D) and (3) depression, and HV in a double blind, placebo-controlled crossover design. The reproducibility of flumazenil effects was assessed in the P and HV groups. Flumazenil induced panic attacks specifically in patients with PD (P and P + D), although this effect was not highly reproducible in each P subject. The sum intensity of panic symptoms showed better reproducibility. The lack of marked physiological activation during flumazenil-induced panic suggests that flumazenil does not act globally as an inverse agonist in PD. Responses to flumazenil may be consistent with a more restricted regional expression of GABA A receptor subtypes at which flumazenil exhibits inverse agonist activity. Panic attacks following flumazenil were frequently associated with catastrophic cognitions, but it is unclear whether these were the causes or concomitants of panic. None of the assessed cognitive variables significantly predicted increases in panic symptomatology in PD patients. Plasma flumazenil concentrations did not differ between PD panickers and non-panickers, ruling out a pharmacokinetic mechanism as the major determinant of responses to flumazenil. The results provide indirect evidence that flumazenil induces panic by a more direct route rather than via cognitive mechanisms, although cognitive factors may modulate the intensity of responses. Possible mechanisms of flumazenil-induced panic and their relation to spontaneous panic are discussed.