Long-Term Benzodiazepine Use and Salivary Cortisol The Netherlands Study of Depression and Anxiety (NESDA)

Background: As benzodiazepines (BZDs) have anxiolytic effects, it is expected that they influence the stress system. During short-term treatment, BZD use was found to suppress cortisol levels. However, little research has been done on the effects of long-term BZD administration on the hypothalamic-pituitary-adrenal (HPA) axis.

Methods: The association between long-term BZD use and cortisol levels was investigated in subjects of the Netherlands Study of Depression and Anxiety with a lifetime diagnosis of anxiety or depression (n = 1531). The subjects were categorized as "daily BZD users[(n = 96), "infrequent BZD users[(n = 172), and "nonusers[(n = 1263). Possible associations between characteristics of BZD use (dose, duration, and dependence) and salivary cortisol levels were analyzed.

Main Outcome Measure: Subjects provided 7 saliva samples, from which 4 cortisol indicators were calculated: the cortisol awakening response, diurnal slope, evening cortisol, and cortisol suppression after ingestion of 0.5 mg of dexamethasone.

Results: Daily users used BZDs for a median duration of 26.5 months and had a median daily dosage of 6.0 mg as measured in diazepam equivalents. Evening cortisol levels were significantly lower in daily users (P = 0.004; effect size: d = 0.24) and infrequent users (P = 0.04; effect size: d = 0.12) compared to nonusers. We did not. find significant differences in the cortisol awakening response, diurnal slope, or in the dexamethasone suppression test.

Conclusions: Despite the. finding of slightly lower evening cortisol levels in daily and infrequent BZD users compared to nonusers, results indicate that long-term BZD use is not convincingly associated with HPA axis alterations.