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

Abstract

Rationale: A dysregulation of the hypothalamicpituitary-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-D 21 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. Conclusion: 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.

Different responses to dexamethasone and prednisolone in the same depressed patients

“…However, treatment of animals with antidepressants upregulates both the MR and the GR (reviewed in Pariante 2004;Pariante et al 2004b), an effect that is present also with serotonergic drugs (Bjartmar et al 2000) and antagonists of the corticotropin-releasing hormone (CRH) receptor (Post et al 2005). Moreover, antidepressants do not affect corticosteroid receptor function in depressed patients who are still unwell, like in our sample (Cotter et al 2002;Bauer et al 2002Bauer et al , 2003Kunzel et al 2003), and indeed early normalization of HPA axis activity during antidepressant treatment predicts the clinical response (Heuser et al 1996;Zobel et al 2001;Inder et al 2001;Nikisch et al 2005). Finally, the above-mentioned study by Young et al (Young et al 2003) finds normal MR function in depressed patients who were antidepressant-free.…”

Alterations in Stress Reactivity After Long‐Term Treatment with Paroxetine in Women with Posttraumatic Stress Disorder

“…40 Nikisch et al looked at long-term (16 weeks) citalopram administration in patients with major depression and found reduced responsiveness of HPA axis. 41 Their results showed a time-dependent reduction of ACTH and cortisol response during the combined dexamethasone/CRH test both in treatment responders and nonresponders. Rinne et al found that 12 weeks of fluvoxamine treatment 42 in women with Borderline Personality Disorder (BPD) resulted in a reduction of the hyperresponsiveness of the HPA axis on the dexamethasone/CRH test.…”

Approaching the shared biology of obesity and depression: the stress axis as the locus of gene–environment interactions

“…85 Traditional antidepressants such as fluoxetine, citalopram and imipramine all decrease CRH, ACTH and cortisol levels. [86][87][88][89] A slight rise in CRH may be detected immediately after starting treatment with citalopram, which turns into a decrease after continuous administration. 90 We have demonstrated that leptin replacement therapy in leptin-deficient adults with established pathological obesity results not only in profound weight loss and behavioral effects, but also in changes on the endocrine stress axis.…”