Panic disorder agonists

Beginning in the 1960s, ben2odia2epiae anxiolytics and hypnotics rapidly became the standard prescription dmg treatment. In the 1980s, buspkone [36505-84-7] (3), which acts as a partial agonist at the serotonin [50-67-9] (5-hydroxytryptamine, 5-HT) type lA receptor, was approved as treatment for generali2ed anxiety. More recently, selective serotonin reuptake inhibitors (SSRIs) have been approved for therapy of panic disorder and obsessive—compulsive behavior. 

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)...

CCK8 concentrations were found to be lower in panic patients than in normal control subjects (Brambilla et al. 1993) and the CCK-B receptors were hyper-sensitive in panic disorders (Akiyoshi et al. 1996). Accordingly, CCK-B receptor agonists such as pentagastrin or CCK-4 have panic-like anxiogenic effects in humans (Radu et al. 2002). Clinical trials, however, have provided inconclusive data about the anxiolytic potential of CCK-B antagonists (Shlik et al. 1997). 

The panicogenic effects of CCK-B agonists and the ability of CCK-B antagonists to block this effect raise the question of therapeutic efficacy of CCK-B antagonists on spontaneous panic attacks. Thus far, the only clinical trial carried out is inconclusive. Kramer and colleagues [1995] used a multicenter, placebo-controlled, double-blind trial to investigate the efficacy of L-365,260 [30 mg four times a day] in patients with panic disorder with or... 

The enhanced sensitivity of patients with panic disorder to the effects of CCK-B agonists might be the consequence of an aberration of the CCK system. This aberration could exist at any level of production of CCK, spanning from gene encoding to synthesis, release, and metabolism, or at the receptor level. Molecular biology and biochemistry approaches are needed for further investigations. 

Ballenger JG, McDonald S, Noyes R, et al The first double bhnd, placebo controlled trial of a partial benzodiazepine agonist abecarnil (ZK 112-119) in generalized anxiety disorder. Psychopharmacol Bull 27 171-179, 1991 Ballenger JG, Wheadon DE, Steiner M, et al Double-blind, fixed-dose, placebo-con-trolled study of paroxetin in the treatment of panic disorder. Am J Psychiatry 155 36-42, 1998... 

Kellner CH, Beale MD, Pritchett JT, et al Electroconvulsive therapy and Parkinson s disease the case for further study. Psychopharmacol Bull 30 495-500, 1994 Kellner M, Wiedemann K, Kiieg J-C, et al Effects of the dopamine autoreceptor agonist roxindole in patients with depression and panic disorder (abstract). Neuropsychopharmacology 10 1018, 1994... 

Van Vliet IM, Westenberg HGM, den Boer JA Effects of the 5-HTj, receptor agonist flesinoxan in panic disorder. Psychopharmacology 127 174-180, 1996b Vanderhaeghen J, Crawley J Neuronal cholecystokinin. Ann N Y Acad Sci 448 1-697, 1985... 

Beta-adrenoceptor antagonists, particularly propranolol, have been shown to be effective for anxiety symptoms particularly in situational anxiety and GAD. Buspirone, an azaspirodecanedione, is an agonist at 5-HTlA receptors and seems to have anxiolytic effects, though it is less potent than the BDZs and the effects take up to three weeks to become evident. There is high first pass metabolism and a considerable proportion of the effect is due to a metabolite (1-PP). The principal adverse effects of buspirone are nausea, gastrointestinal upset and headache. Antidepressant drugs, both the older tricyclic antidepressants and the newer drugs, have been demonstrated to have anxiolytic effects in mixed anxiety-depressive patients, GAD and panic disorder. 

Norepinephrine One theory about the biological basis of panic disorder is that there is an initial excess of norepinephrine (Fig. 9—3). This theory is supported by evidence that panic disorder patients are hypersensitive to alpha-2 antagonists and hyposensitive to alpha-2 agonists. Thus, yohimbine, an alpha-2 antagonist, acts as a promoter of norepinephrine release by cutting the brake cable of the presyn-aptic norepinephrine autoreceptor, as shown earlier in Figure 7—6. The consequence... 

FIGURE 9—4. Another theory about the biological basis of panic disorder is an abnormality in the set point for benzodiazepine receptors. Perhaps the sensitivity of these receptors is switched to the left in this spectrum, rendering the receptors less sensitive to full agonists and experiencing antagonists as inverse agonists. 

Nonbenzodiazepine ligands at benzodiazepine sites This is a variation on the theme of partial benzodiazepine agonists, as these agents act at the same or similar site as benzodiazepines but are not structurally related to them. Thus, the pharmacology of nonbenzodiazepines is that of a partial agonist, but their chemistry is different from that of a benzodiazepine. This is similar to the approach that novel sedative-hypnotics such as zaleplon and zolpidem have taken, and perhaps a less sedating nonbenzodiazepine partial agonist could hold promise for the treatment of panic disorder. 

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