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

Abstract

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.

Cortisol response to diazepam: its relationship to age, dose, duration of treatment, and presence of generalized anxiety disorder

“…These results are opposite from the results of a recently completed study (Pomara et al 2004), in which we found that chronic 21-day treatment with therapeutic doses of alprazolam (0.5 mg PO bid) in healthy elderly resulted in an increase in pre-drug morning plasma cortisol, which was related to increases in anxiety and depressive symptoms. The differential effects of chronic diazepam and alprazolam treatment on interdose cortisol levels suggest that intrinsic differences among BZPs in potency, elimination half-life, and other pharmacodynamic factors can impact on HPA axis activity and highlight the need for more prospective studies with multiple sampling times encompassing a 24-h period to confirm these findings.…”

Long-Term Benzodiazepine Use and Salivary Cortisol

“…Most studies on the effects of short-term BZD treatment (maximum of 3 months) on the hypothalamic-pituitary-adrenal (HPA) axis in human subjects reported a decrease in cortisol levels, 1Y11 although some studies reported mixed results. 12,13 These inconsistencies may be explained by differences in dosages and half-lives of the BZDs used 13 and by disparities in the time points used in the assessments (only predrug and postdrug measurements, 13 at certain time intervals, 6,8,10Y12,14 or for a full circadian cycle 1,2,5 ). Differences in patient groups, 12,13 and measurements of basal versus stress-provoked cortisol levels may also influence the results.…”

“…12,13 These inconsistencies may be explained by differences in dosages and half-lives of the BZDs used 13 and by disparities in the time points used in the assessments (only predrug and postdrug measurements, 13 at certain time intervals, 6,8,10Y12,14 or for a full circadian cycle 1,2,5 ). Differences in patient groups, 12,13 and measurements of basal versus stress-provoked cortisol levels may also influence the results. 3,13 In general, the studies measured plasma cortisol levels 1Y3,5,6,9,11,13 or urinary free cortisol as measures of HPA axis activity.…”

Sex-related elevation in cortisol during chronic treatment with alprazolam associated with enhanced cognitive performance

“…We previously reported an elevation in interdose blood cortisol levels after 3 weeks of chronic alprazolam treatment in the absence of any other evidence of drug withdrawal (Pomara et al 2004). In contrast, neither treatment with a low dose of alprazolam nor lorazepam resulted in a significant cortisol response.…”

“…The effects of these medications on plasma cortisol levels were also determined and described in a previous publication (Pomara et al 2004), which showed an interdose elevation in cortisol after 3 weeks of treatment with alprazolam 0.5 mg bid but not during treatment with lorazepam. In this report, we focused on possible sex-related differences in cortisol response in the subjects who were randomly assigned to receive 0.5 mg alprazolam or placebo who had cortisol levels available for the 3-week study (13 women and 12 men).…”