Long-term citalopram administration reduces responsiveness of HPA axis in patients with major depression: relationship with S-citalopram concentrations in plasma and cerebrospinal fluid (CSF) and clinical response.
BACKGROUND
A dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is a well-documented neurobiological finding in major depression. Moreover, clinically effective therapy with antidepressant drugs may normalize the HPA axis activity.


OBJECTIVE
The aim of this study was to test whether citalopram (R/S-CIT) affects the function of the HPA axis in patients with major depression (DSM IV).


METHODS
Twenty depressed patients (11 women and 9 men) were challenged with a combined dexamethasone (DEX) suppression and corticotropin-releasing hormone (CRH) stimulation test (DEX/CRH test) following a placebo week and after 2, 4, and 16 weeks of 40 mg/day R/S-CIT treatment.


RESULTS
The results show a time-dependent reduction of adrenocorticotrophic hormone (ACTH) and cortisol response during the DEX/CRH test both in treatment responders and nonresponders within 16 weeks. There was a significant relationship between post-DEX baseline cortisol levels (measured before administration of CRH) and severity of depression at pretreatment baseline. Multiple linear regression analyses were performed to identify the impact of psychopathology and hormonal stress responsiveness and R/S-CIT concentrations in plasma and cerebrospinal fluid (CSF). The magnitude of decrease in cortisol responsivity from pretreatment baseline to week 4 on drug [delta-area under the curve (AUC) cortisol] was a significant predictor (p<0.0001) of the degree of symptom improvement following 16 weeks on drug (i.e., decrease in HAM-D21 total score). The model demonstrated that the interaction of CSF S-CIT concentrations and clinical improvement was the most powerful predictor of AUC cortisol responsiveness.


CONCLUSIONS
The present study shows that decreased AUC cortisol was highly associated with S-CIT concentrations in plasma and CSF. Therefore, our data suggest that the CSF or plasma S-CIT concentrations rather than the R/S-CIT dose should be considered as an indicator of the selective serotonergic reuptake inhibitors (SSRIs) effect on HPA axis responsiveness as measured by AUC cortisol response.
Nikisch
Georg
G
Department of Psychiatry and Psychotherapy, Klinikum Fulda, P.O. Box 2364, 36013, Fulda, Germany. Georg.Nikisch@klinikum-fulda.de
Mathé
Aleksander A
AA
Czernik
Adelheid
A
Thiele
Jutta
J
Bohner
Jürgen
J
Eap
Chin B
CB
Agren
Hans
H
Baumann
Pierre
P
D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D000328:Adult; D001812:Blood-Brain Barrier / Q000187:drug effects; D015283:Citalopram / Q000008:administration & dosage* / Q000493:pharmacokinetics; D003346:Corticotropin-Releasing Hormone / Q000494:pharmacology*; D003865:Major Depressive Disorder / Q000134:cerebrospinal fluid / Q000188:drug therapy* / Q000523:psychology; D003907:Dexamethasone / Q000494:pharmacology; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism*; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects*; D008134:Long-Term Care; D008297:Male; D008875:Middle Aged; D010913:Pituitary-Adrenal System / Q000187:drug effects*; D011379:Prognosis; D019233:Retreatment; D017211:Treatment Failure
D015283:Citalopram; D003907:Dexamethasone; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone; D006854:Hydrocortisone