Antagonists anxiety disorders

Figure 19.8 A schematic representation of the GABAa receptor shift hypothesis. This proposes that patients with panic disorder have dysfunctional GABAa receptors such that the actions of drugs that behave as antagonists in normal subjects are expressed as inverse agonism in panic patients. It is unlikely that this theory extends to generalised anxiety disorder (GAD), for which benzodiazepine agonists are highly effective treatments, but it could explain why these drugs are relatively ineffective at treating panic disorder. (Based on Nutt et al. 1990)...

This remarkable lability of a memory trace, which permits a reorganization of an existing memory in a retrieval environment, provides a theoretical basis for both psychotherapeutic and pharmacotherapeutic intervention for traumatic stress exposure as well as other anxiety disorders. Administration of P-receptor and NMDA receptor antagonists shortly after trauma exposure or spontaneous panic attacks as well as after reactivation of memory associated with the anxiety-inducing event may reduce the strength of the original memory. 

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Although promising in preclinical models of anxiety, the 5-HT3 receptor antagonist ondansetron has limited efficacy in panic disorder (Schneier et al. 1996) however, at higher doses (1 mg), ondansetron was superior to placebo in a study of patients with generalized anxiety disorder (Freeman et al. 1997). 

Ondansetron. The S-HTj antagonist ondansetron has been reported to be effective in the treatment of generalized anxiety disorder, with efficacy comparable to that of diazepam [Lader 1991). Sedation and rebound anxiety during withdrawal from ondansetron were not observed [Lader 1991). Ondansetron has been considered for phase 111 clinical trials for the treatment of social phobia and panic disorder. 

Tropisetron. The 5-FIT3 antagonist tropisetron has also been reported to be effective in the treatment of patients with generalized anxiety disorder [Lecrubier et al. 1993). The anxiolytic effect of tropisetron develops quickly, is dose dependent, and is accompanied by satisfactory tolerability and safety. The incidence of adverse events, including headache, nausea, constipation, and nervousness, is low and the severity is generally mild. The most typical adverse effects of benzodiazepine anxiolytics, such as fatigue, muscle relax-... 

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