Elsevier

Psychiatry Research

Volume 88, Issue 2, 8 November 1999, Pages 75-88
Psychiatry Research

The citalopram challenge test in patients with major depression and in healthy controls

https://doi.org/10.1016/S0165-1781(99)00082-7Get rights and content

Abstract

Neuroendocrine challenge tests in depressed patients have revealed a blunted hormonal reaction to serotonergic stimuli. In the present study, citalopram was chosen as the serotonergic agent for neuroendocrine stimulation. Compared to earlier challenge agents, citalopram has the advantage of serotonergic selectivity, its application is well tolerated and the possibility of intravenous application reduces pharmacokinetic interference. Sixteen patients suffering from an acute episode of major depression and 16 healthy controls underwent the stimulation procedure with 20 mg of citalopram and placebo. Whereas significant differences in the secretion of prolactin and cortisol between citalopram and placebo challenge were observed in the control group, no differences were found in the group of depressed patients. Comparison of depressed patients and controls showed a significantly blunted prolactin secretion in patients. Differences in cortisol secretion following serotonergic stimulation with citalopram did not become significant. The stimulation procedure was well tolerated in all subjects, although a higher number of side effects was observed in the control group. The amount of side effects did not correlate with the hormone responses. These results are in line with the hypothesis of serotonergic hypofunction in depressed patients. In conclusion, the 20-mg citalopram challenge test is thought to be a promising tool for further investigation of serotonergic function in psychiatric illness.

Introduction

Altered activity of the central serotonin [5-hydroxytryptamine (5-HT)] system has been linked to a variety of psychiatric diseases such as major depression (Charney et al., 1982, Heninger et al., 1984, Deakin et al., 1990, Kahn et al., 1990, Price et al., 1990), panic disorders (Den Boer et al., 1987, Van Vliet et al., 1996) and schizophrenia (Meltzer, 1995). In major depressive disorder earlier clinical studies found diminished 5-HT function and lower plasma concentrations of serotonin metabolites in patients suffering from an acute depressive episode (Coccaro et al., 1989).

One effective clinical approach to reveal possible abnormalities of the central 5-HT system is the use of serotonin agonists to stimulate hormonal secretion (Lewis and Sherman, 1985, Van Praag et al., 1987). Certain anterior pituitary hormones (cortisol, ACTH, growth hormone, and prolactin) are known to respond to serotonergic stimulation. The rise in prolactin secretion followed by the elevation of its peripheral plasma level has been the most consistent parameter in past serotonergic challenge studies.

In psychiatric diseases with a known altered function of the 5-HT system, changes in the neuroendocrine response to serotonergic stimulation have been shown. For instance in major depression, a blunted hormonal response has repeatedly been reported (e.g. Heninger et al., 1984, O’Keane and Dinan, 1991).

Many substances with different sites of action have been tested as serotonergic probes of neuroendocrine function, but none of them fulfilled all the required criteria for a valid test (Van Praag et al., 1987). For instance, the serotonin precursor l-tryptophan produced a dose-dependent rise in prolactin level (Charney et al., 1982), but studies on effects on other transmitter systems and studies including 5-HT receptor blockage could not show that this response was only mediated via the 5-HT system (Van Praag et al., 1987, Smith et al., 1991). A widely used serotonergic agent in challenge studies is fenfluramine, a 5-HT releasing agent (Siever et al., 1984, Asnis et al., 1988). Attempts have been made to reduce the possible dopaminergic effects of this compound by using the d-isomer of the racemic dl-fenfluramine (Kasper, 1991, Maes et al., 1991, O’Keane and Dinan, 1991, Lichtenberg et al., 1992). Another problem with this substance is that it is, normally, available for oral administration only.

Problems with the selectivity for the 5-HT system have also occurred when using buspirone (Meltzer et al., 1983), a 5-HT1A receptor agonist. The dopaminergic activity of buspirone (Meltzer et al., 1992) reduces its usefulness as a serotonergic probe. Better results could be gained by using meta-chlorophenylpiperazine (m-CPP) (Charney et al., 1987), but some uncertainty still remains about the possible dopaminergic mechanisms of this probe. In addition, significant psychopathological side effects were reported after i.v. administration of m-CPP (Murphy et al., 1989).

Among the serotonin reuptake inhibitors, clomipramine has been reported to produce a stable dose-dependent prolactin release (Laakmann et al., 1984, Golden et al., 1992). Because of its various other neurotransmitter effects—especially, for example, the noradrenergic effect — it was questioned, whether clomipramine meets the requirements for a valid serotonergic probe. However, Anderson et al. (1992) reported that the noradrenergic metabolite desmethyl-clomipramine is not present during the crucial time frame of the challenge, when the agent is administered intravenously.

In light of the lack of selectivity for the serotonergic system that characterizies nearly all the reported agents, the selective serotonin reuptake inhibitors (SSRIs) are of special interest for the development of further neuroendocrinological stimulation procedures. The first experiences in challenge studies in human subjects with SSRIs have involved a design using, for instance, fluvoxamine, fluoxetine (Fuller et al., 1976) for challenge pretreatment. A neuroendocrine response after acute citalopram administration was for the first time observed in animals by Meltzer et al. (1981). Seifritz et al. (1996) were the first to report neuroendocrine effects of citalopram in healthy human subjects. After acute intravenous infusion of 20 mg of citalopram, the most pronounced response they observed was a consistent transient increase of prolactin and cortisol (Seifritz et al., 1996). Sleep deprivation led to the blunting of the citalopram induced prolactin response in healthy male subjects, whereas the cortisol response was not significantly altered (Seifritz et al., 1997). With paroxetine as a challenge agent in healthy male subjects, Reist et al. (1996) reported a significant hormone response of cortisol but no effect on the prolactin blood levels. Paroxetine was administered orally in this study.

The widely used antidepressant citalopram provides many advantages as a serotonergic probe in view of its known pharmacological profile. It is the SSRI with the highest selectivity for the serotonin reuptake transporter, with no known intrinsic activity at any 5-HT receptor subtype or at any other neurotransmitter system (Hyttel, 1982). Possible side effects are rather mild, and the drug is usually well tolerated by patients and healthy volunteers. Another major advantage of using citalopram for challenge studies is that it is available for intravenous application. In this way pharmacokinetic differences are reduced and the duration of the stimulation procedure is shortened compared to a challenge design with oral application.

In this study for the first time an SSRI is tested as a serotonergic challenge agent in a group of depressed patients. It is the aim of this ongoing project to study the usefulness of citalopram in detecting potential differences in stimulated prolactin and cortisol secretion between depressed patients and healthy controls.

Section snippets

Patients

Sixteen patients were included, consisting of 10 females and six males. Age ranged from 20 to 58 years (mean 40.7, S.D. 13.2). All of the subjects were inpatients at the psychiatric unit at the Department of General Psychiatry of the University of Vienna. The patients gave their written informed consent. The study design was approved by the Ethics Committee of the University of Vienna. Psychiatric diagnosis was established independently by at least two experienced psychiatrists following an

Results

Baseline values (t0) of prolactin and cortisol did not differ within the same individual between the two challenge conditions (placebo and citalopram). For comparison of patients and controls, average baseline values (calculated between the values of placebo challenge and the values of citalopram challenge) were used. There was a difference between patients and healthy subjects in the baseline values (mean±S.D.) of plasma prolactin (controls: 16.4±5.2 ng/ml; patients: 11.3±4.7 ng/ml; t=−2.928;

Discussion

Intravenous challenge with the SSRI citalopram produced a significant difference in neuroendocrine response between depressed patients and healthy controls. Following the selective serotonergic stimulation, a blunted response of prolactin secretion was found in patients compared to controls, whereas differences in cortisol secretion did not become significant.

In healthy controls after intravenous application of 20 mg citalopram, a consistent and pronounced increase of prolactin and a slight,

Acknowledgements

We gratefully acknowledge the laboratory work of Eva Maria Muzik, Christine Roijka, Susanne Keim and Beatrix Silnusek. Karin Jelinek RN, Rosemarie Reiss RN, Anna Staudinger RN, and Renate Wolf RN and their colleagues at the inpatient wards and Mag. Sylvia Trinkl provided very helpful medical and organisational assistance with the stimulation procedures. We are very thankful to Paul Wyckoff, MA for his help with the manuscript. The study was suported in part by the ‘Jubiläumsfonds der

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