Some Biochemical Correlates of Panic Attacks with Agoraphobia and Their Response to a New Treatment
Thirty-two patients with chronic debilitating agoraphobia and panic attacks participated in a comparative study of the triazolobenzodiazepine alprazolam and the anti-inflammatory agent ibuprofen. After a 2-week placebo washout period, patients were randomly assigned to 8 weeks of treatment with alprazolam (2 to 6 mg/day) or ibuprofen (0.8 to 2.4 g/day). Medication was identically packaged and patients were blind to the treatment condition, but investigators were aware of which medication was dispensed. Alprazolam recipients (mean daily dose: 5.4 mg) improved markedly with respect to physician and patient global rating of disease severity, frequency and severity of panic attacks, and phobic anxiety target symptoms on the 90-Item Hopkins Symptom Check List. Ibuprofen recipients (mean daily dose: 2.13 g) experienced significantly less clinical improvement than patients on alprazolam. After 8 weeks of treatment, ibuprofen patients were crossed over to alprazolam, while the original alprazolam group continued on that drug. The daily dosage ceiling was increased to 10 mg. In the ensuing 4 weeks (mean daily alprazolam dose: 6.3 mg), all patients achieved comparably marked clinical improvement relative to baseline. Pretreatment plasma concentrations of platelet factor 4 and beta-thromboglobulin--two measures of platelet turnover and release--were significantly elevated in patients relative to normal controls. The elevated platelet factor 4 and beta-thromboglobulin normalized during treatment with both drugs. Alprazolam appears to produce rapid and specific clinical improvement in patients with severe agoraphobia and panic attacks and deserves further evaluation under double-blind conditions.
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- "O.G. Cameron et al. Taylor et al. 1986; Shear et al. 1987; Balon e~ al. 1988; Cameron and Nesse 1988; Gorman et al. 1988a; Gorman et al. 1989), plasma (Mathew et al. 1981; Ballenger et al. 1984; Cameron et al. 1984; Nesse et al. 1984, 1985b; Villacres et al. 1987; Cameron and Nesse 1988; Gorman et al. 1988a; Sevy et al. 1989), and urinary (Nesse et al. 1985a; Kosten et al. 1987) catecholamines, and the catecholamine metabolite MHPG (3-methoxy-4- hydroxyphenvlglycol) (Ko et al. 1983; Sheehan et al. 1983; Chamey et al. 1984, 1987; Sevy et al. 1989). However, in several studies sigmficant abnormalities of these variables have not been observed (Charney et al. 1985; Liebowitz et al. 1¢85; Can" et al. 1986; Cameron et al. 1987b; Edlund et al. 1987; Margraf et al. 1987; Pohl et al. 1987; Schneider et ~!. 1987; Cameron and Nesse 1988; Castellani et al. 1988; Crow et al. 1988; Curtis and Gli~ 1988; Uhde et al. 1988; Woods et al. 1987, !988a; Gorman et al. 1989). "
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ABSTRACT: In order to evaluate adrenergic function in anxiety disorders, platelet alpha 2-adrenergic binding parameters and supine and standing blood pressure, pulse, and venous plasma epinephrine and norepinephrine were determined in patients with panic attacks or generalized anxiety disorder and in normal subjects. The maximum number of binding sites (Bmax) for the partial agonist tritiated clonidine was significantly lower for both patient groups than for normal subjects, and the Bmax for the antagonist tritiated yohimbine was significantly lower for panic patients. There were no other substantive differences across groups. Prior exposure to psychotropic drugs might account for the results for clonidine binding, but not for yohimbine. The Bmax for clonidine was correlated with norepinephrine increases upon standing and, for panic patients, with the severity of full unexpected panic attacks. These data provide further evidence of adrenergic receptor abnormalities in people with anxiety disorders.
Available from: Randolph M Nesse
- "Acetylcholinesterase was normal in generalized anxiety patients, while pseudocholinesterase was elevated; no relaxation effect was observed (Mathew et al., 1980b). Finally, 13-thromboglobulin and platelet factor IV were reported to be elevated in panic patients (Sheehan et al., 1983a), although we did not observe this (unpublished data). Thus, monoamine oxidase levels appear to be abnormal; this might be associated with abnormalities in systemic catecholamine levels. "
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ABSTRACT: Among the studies of systemic hormonal and physiological abnormalities associated with anxiety disorders, the most consistent and extensive findings suggest (a) peripheral adrenergic hyperactivity (including increases in norepinephrine but not epinephrine) and functional dysregulation, (b) increased incidence of mitral valve prolapse in panic patients, and (c) normal suppressibility of the hypothalamic-pituitary-adrenal cortical endocrine system with dexamethasone in panic patients. Other less-certain findings include (a) increased circulating concentrations of plasma ACTH and/or cortisol, and prolactin, in panic patients, (b) increased platelet monoamine oxidase activity in generalized anxiety and/or panic patients, (c) decreased gonadal axis activity in some anxious individuals, (d) decreased nighttime melatonin plasma concentrations in panic patients, and (e) peripheral α2 and β-adrenoreceptor down-regulation, with normal serotonin binding parameters. These findings, taken together, provide tentative support for dysfunction in adrenergic and GABAergic central nervous system mechanisms in people with anxiety disorders. Abnormal anxiety and normal stress both show evidence of adrenergic hyperactivity; however, there appear to be differences in hormonal profiles, especially the apparent lack of increase of epinephrine during panic attacks, as well as differences in the reactivity of the system, and in the “trigger” mechanisms which determine when the response occurs.
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ABSTRACT: Alprazolam is a recently marketed triazolobenzodiazepine. The animal pharmacological data reviewed here suggest a potent anxiolytic action. But, in addition, an antidepressant activity was revealed in clinical studies and subsequently studied in animal assays. As an extension of these activities, alprazolam also displays efficacy in panic and phobic disorders. Data relating to a wide range of pharmacological activities and pharmacokinetics of alprazolam are also reviewed.
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