Chronic administration of benzodiazepines—V. Rapid onset of behavioral and neurochemical alterations after discontinuation of alprazolam

Lopez, Fred; Miller, Lawrence G.; Greenblatt, David J.; Chesley, Shelley; Schatzki, Andrew; Shader, Richard I.

doi:10.1016/0028-3908(90)90007-e

Cited by 29 publications

(12 citation statements)

References 23 publications

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“…In particular, hyperactivity and a reduced seizure threshold are associated with upregulation at the gamma-aminobutyric acid-A (GABAA) receptor complex. Generally similar results have been obtained with the benzodiazepines lorazepam, alprazolam, and clonazepam (Lopez et al 1990;Galpern et al 1990Galpern et al , 1991a.…”

supporting

confidence: 68%

Chronic Benzodiazepine Administration XI Concurrent Administration of PK11195 Attenuates Lorazepam Discontinuation Effects

Byrnes

Miller

Perkins

et al. 1993

Neuropsychopharmacol

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supporting

confidence: 68%

Chronic Benzodiazepine Administration XI Concurrent Administration of PK11195 Attenuates Lorazepam Discontinuation Effects

Byrnes

Miller

Perkins

et al. 1993

Neuropsychopharmacol

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“…The elevation in morning cortisol might reflect early stages of alprazolam withdrawal. Indeed, BZP discontinuation has been associated with drug withdrawal and activation of the HPA axis (Lopez et al, 1990b;Mellman and Uhde, 1986;Owens et al, 1991). In our study, cortisol elevations were not associated with significant increases in other symptoms of withdrawal, but this could be due to the fact that this investigation was not specifically designed to address this question.…”

Section: Discussionmentioning

confidence: 99%

“…Abrupt withdrawal and gradual tapering of alprazolam and other shortelimination half-life BZPs have been shown to result in increased cortisol secretion and activation of other indices of HPA axis activity (Lopez et al, 1990b;Mellman and Uhde, 1986;Owens et al, 1991). Thus, given the relatively short elimination half-life of alprazolam and a prolonged interdose interval, it is possible that a marked drop in plasma drug concentration could trigger increased HPA axis activity in the period prior to morning dose.…”

Section: Introductionmentioning

confidence: 99%

Interdose Elevation in Plasma Cortisol During Chronic Treatment with Alprazolam but not Lorazepam in the Elderly

Pomara

Willoughby

Ritchie

et al. 2003

Neuropsychopharmacol

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Benzodiazepines (BZPs) have been shown to reduce hypothalamic-pituitary-adrenal (HPA) axis activity acutely in normal humans. In contrast, the effects of chronic BZP treatment on the HPA axis have not been well studied, especially in the geriatric population. This study examined the acute and chronic effects (3 weeks) of alprazolam and lorazepam on plasma cortisol in 68 subjects (60-83 years) who received 0.25 or 0.50 mg b.i.d. alprazolam, or 0.50 or 1.0 mg b.i.d. lorazepam, or placebo orally according to a randomized, doubleblind, placebo-controlled parallel design. Memory assessment and blood samples for plasma cortisol were obtained prior to the morning dose on days 0, 7, 14, and 21, and at 1, 2.5, and 5 h postdrug on days 0 and 21. Assessments of anxiety and depression were carried out at days 0, 7, 14, and 21 before drug administration. Plasma cortisol was affected compared to placebo only by the 0.5 mg alprazolam dose. During the first and the last day of treatment, there was a significant drop in cortisol at 2.5 h after alprazolam compared to placebo. The predose cortisol levels increased significantly during chronic alprazolam treatment, and correlations were found between these cortisol changes and changes in depression, anxiety, and memory scores. These findings suggest that even a short period of chronic treatment with alprazolam, but not lorazepam, may result in interdose HPA axis activation in the elderly, consistent with drug withdrawal. If confirmed, this effect may contribute to an increased risk for drug escalation and dependence during chronic alprazolam treatment.

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“…Although the 1,4 benezodiazepine anxiolytics are eective and safe drugs with a rapid onset of action, there is a practical need for drugs which have fewer sedative eects, a lower dependence potential and lack an interaction with alcohol. Similarly, the benzodiazepine hypnotics are liable to tolerance following prolonged use, cause amnesia and have an abuse potential (Lopez et al, 1990). It is possible that partial agonists may oer therapeutic advantages over the conventional full agonists; the partial agonist bretazil is a good example of this Delini-Stula, 1992), although it is not entirely devoid of undesirable side eects.…”

Section: Diversity Of Drugs Acting On the Benzodiazepine Receptormentioning

confidence: 98%

Therapeutic applications of benzodiazepine receptor ligands in anxiety

Leonard

1999

Hum. Psychopharmacol. Clin. Exp.

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In this short review, evidence is presented to show that the benzodiazepines produce their variety of pharmacological eects by activating speci®c receptors that form part of the main inhibitory neurotransmitter receptor system, the g-amino-butyric acid (GABA) system, in the mammalian brain. Dierent classes of benzodiazepine receptor ligands have been developed which can alleviate anxiety or produce anxiety according to the ®ne structural changes that occur when the ligands interact with the benzodiazepine receptor. There is some evidence that endogenous substances in the brain can cause either an increase or a reduction in the anxiety state by acting on the benzodiazepine receptor. The unique nature of the benzodiazepine receptor, and the disparate properties of the drugs that act on this receptor, should allow plenty of scope for the development of novel compounds with selective anxiolytic and other properties in the future. Lastly, despite the evidence from animal studies that benzodiazepine receptor function changes in response to drug treatment, there is little evidence from human brain studies that such changes are relevant to the phenomena of tolerance, dependence and withdrawal eects that have been the recent cause for public concern.

show abstract

Chronic administration of benzodiazepines—V. Rapid onset of behavioral and neurochemical alterations after discontinuation of alprazolam

Cited by 29 publications

References 23 publications

Chronic Benzodiazepine Administration XI Concurrent Administration of PK11195 Attenuates Lorazepam Discontinuation Effects

Chronic Benzodiazepine Administration XI Concurrent Administration of PK11195 Attenuates Lorazepam Discontinuation Effects

Interdose Elevation in Plasma Cortisol During Chronic Treatment with Alprazolam but not Lorazepam in the Elderly

Therapeutic applications of benzodiazepine receptor ligands in anxiety

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