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.


METHODS
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.
Department of Psychiatry, Leiden University Medical Centre, Leiden, The Netherlands. L.manthey@lumc.nl
Leonie
L
Manthey
Erik J
EJ
Giltay
Tineke
T
van Veen
Arie Knuistingh
AK
Neven
Sophie A
SA
Vreeburg
Brenda W J H
BW
Penninx
Frans G
FG
Zitman
D000328:Adult; D001008:Anxiety Disorders / Q000188:drug therapy / Q000378:metabolism* / Q000523:psychology; D001569:Benzodiazepines / Q000008:administration & dosage*; D002940:Circadian Rhythm / Q000187:drug effects / Q000502:physiology; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D003866:Depressive Disorder / Q000188:drug therapy / Q000378:metabolism* / Q000523:psychology; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000737:chemistry / Q000378:metabolism*; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D009426:Netherlands; D012463:Saliva / Q000187:drug effects* / Q000378:metabolism*; D013997:Time Factors
D001569:Benzodiazepines; D006854:Hydrocortisone