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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

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Abstract

Rationale

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.

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.

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Acknowledgements

This work is supported by a grant from Bayer Vital GmbH, Germany, the Swedish Medical Research Council, grant 10414, and the Karolinska Institute, Stockholm, Sweden. The authors would like to thank Petra Bastanier, Dr. Irmingard Gebert, and Dr. Renate Forster-Bölz for their help with this project. We gratefully acknowledge the laboratory work of Anna Ulmer and Jürgen Diegmann and their colleagues. Pure compounds (R/S-CIT and metabolites) were kindly provided by Lundbeck, Switzerland. None of the authors has conflicting interests, which interfere with the integrity of the contents of the article.

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Authors and Affiliations

  1. Department of Psychiatry and Psychotherapy, Klinikum Fulda, P.O. Box 2364, 36013, Fulda, Germany

    Georg Nikisch & Adelheid Czernik

  2. Clinical Neuroscience, Division of Psychiatry, Karolinska University Hospital Huddinge, Stockholm, Sweden

    Aleksander A. Mathé & Hans Ågren

  3. Department of Medical Laboratory, Klinikum Fulda, Fulda, Germany

    Jutta Thiele & Jürgen Bohner

  4. Unité de Biochimie et Psychopharmacologie Clinique, University Department of Adult Psychiatry, Centre of Psychiatric Neurosciences, Prilly-Lausanne, Switzerland

    Chin B. Eap & Pierre Baumann

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  1. Georg Nikisch
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Correspondence to Georg Nikisch.

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Nikisch, G., Mathé, A.A., Czernik, A. et al. 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. Psychopharmacology 181, 751–760 (2005). https://doi.org/10.1007/s00213-005-0034-3

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