Effects of oral racemic citalopram on neuroendocrine responses Emily R. Hawken a, ⁎ , James A. Owen a,b,c , Dean Van Vugt d , Nicholas J. Delva a,c,d a Providence Continuing Care Centre-Mental Health Services, 752 King St., Kingston, Ontario, Canada K7L 4X3 b Department of Pharmacology and Toxicology, Queen's University, Kingston, Ontario, Canada K7L 3N6 c Department of Psychiatry, Queen's University, Kingston, Ontario, Canada K7L 3N6 d Department of Physiology, Queen's University, Kingston, Ontario, Canada K7L 3N6 Accepted 30 January 2006 Available online 6 March 2006 Abstract Citalopram, a selective serotonin reuptake inhibitor (SSRI), has been used as a neuroendocrine probe to assess serotonin (5-HT) function in human subjects. In an effort to characterize the oral citalopram challenge, we hypothesized that oral racemic citalopram would increase plasma cortisol, prolactin and adrenocorticotropic hormone (ACTH) concentrations; ACTH had not been measured in previous studies on the neuroendocrine effects of citalopram. Nine healthy male subjects initially received 20 mg of citalopram in an open-label study, and subsequently received placebo and 40 mg of citalopram in a single-blind, randomized, cross-over study. The administration of citalopram 20 mg failed to produce a significant neuroendocrine response but 40 mg resulted in reliably increased plasma cortisol concentrations. The 40 mg dose, however, did not reliably influence the levels of plasma prolactin or plasma ACTH. The results of this study indicate that caution should be used in accepting oral racemic citalopram as a potential presynaptic serotonergic challenge agent. Further studies are needed to fully determine the validity of racemic citalopram and the active enantiomer, escitalopram, as 5-HT probes. © 2006 Elsevier Inc. All rights reserved. Keywords: Adrenocorticotrophic hormone; Citalopram; Cortisol; Prolactin; Serotonin 1. Introduction Serotonergic mechanisms have been implicated in a number of psychiatric disorders and their somatic treatments (Maes and Meltzer, 1995; Nicholas et al., 1998; Sobczak et al., 2002). Neuroendocrine challenge paradigms have been used to examine the in vivo activity of serotonergic neurotransmitter systems by measuring hormonal secretion in response to serotonin (5-HT) precursors, releasing agents, reuptake inhibi- tors, agonists and antagonists (Golden et al., 1991; Power and Cowen, 1992; Yatham and Steiner, 1993; Cowen, 1998). These tests are based on the assumptions that the 5-HT system stimulates the release of some pituitary hormones (Yatham and Steiner, 1993; Tuomisto and Mannisto, 1985; Fuller, 1992) and the extent of release of these hormones provides an indirect index of central serotonergic activity (Yatham and Steiner, 1993; Raap and Van de Kar, 1999). Many challenge agents currently employed as pre-synaptic neuroendocrine probes of general 5-HT function are not selective for 5-HT systems (van Praag et al., 1987). For example, the validity of pre-synaptic challenge agents L- tryptophan and 5-hydroxytryptophan (5-HTP; both 5-HT precursors) and fenfluramine (a 5-HT releasing agent) have been questioned because they influence catecholamine metab- olism (L-tryptophan and 5-HTP) or dopaminergic systems (fenfluramine) in addition to 5-HT (Yatham and Steiner, 1993). Furthermore, fenfluramine has been removed from the market because of toxicity, encouraging the search for other reliable pre-synaptic 5-HT probes. Tricyclic antidepressant drugs including clomipramine are also not 5-HT specific, inhibiting both 5-HT and norepinephrine (NE) reuptake, and have other Progress in Neuro-Psychopharmacology & Biological Psychiatry 30 (2006) 694 – 700 www.elsevier.com/locate/pnpbp Abbreviations: ACTH, adrenocorticotrophic hormone; AUC, area under the curve; CIT-20, citalopram 20 mg; CIT-40, citalopram 40 mg; ELISA, enzyme- linked immunosorbent assay; HPLC, high performance liquid chromatography; i.v., intravenous; PLAC, placebo; NE, norepinephrine; p.o., per os; SSRI, selective serotonin reuptake inhibitor; 5-HT, 5-hydoxytryptamine (serotonin); 5- HTP, 5-hydroxytryptophan; Δmax, maximum change. ⁎ Corresponding author. Tel.: +1 613 548 5567x5709; fax: +1 613 548 5563. E-mail address: hawkense@pccchealth.org (E.R. Hawken). 0278-5846/$ - see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.pnpbp.2006.01.017