l-5-Hydroxytryptophan augments the neuroendocrine response to a SSRI

https://doi.org/10.1016/j.psyneuen.2005.11.005Get rights and content

Summary

The objective of the study was to assess l-5-hydroxytryptophan's (l-5HTP) augmentation effect on the neuroendocrine response to a SSRI (citalopram). A neuroendocrine challenge study was conducted in healthy Asian male subjects. The neuroendocrine response to oral citalopram and l-5HTP was measured primarily as the prolactin and cortisol area under the response curve (or AUC). The study comprised 2 studies: Study 1. A double blind, randomised dose ranging study was conducted with l-5HTP (50–200 mg) to explore the prolactin and/or cortisol dose response and select a dose that provided a threshold neuroendocrine response. Study 2. A randomized comparison of citalopram 20 vs 40 mg was used to assess the effect of these doses on prolactin and cortisol. Based on the results of the dose response assessments with l-5HTP and cortisol, 200 mg l-5HTP was subsequently used in Study 2 to explore the augmentation of the neuroendocrine response to 20 mg citalopram. Citalopram, but not l-5HTP, increased prolactin AUC(0–3 h) while 5HTP and citalopram increased cortisol AUC(0–3 h). A 200 mg dose of l-5HTP significantly augmented the prolactin and cortisol response AUC(0–3 h) to 20 mg oral citalopram. The results of the study suggest that an augmented neuroendocrine challenge may be a suitable marker to demonstrate increased 5-HT-mediated responses when exploring novel agents as improved SSRIs.

Introduction

The serotonin (5HT) system has been implicated in the pathogenesis of depression. First, 5HT deficits have been reported in patients with depression: the number of 5HT receptor and uptake sites are reduced, although not consistently (Leake et al., 1991, Cryan and Leonard, 2000, Sargent et al., 2000) and levels of 5HT metabolites are reduced in the brain and cerebrospinal fluid (CSF) of depressed subjects compared to age-matched controls (Traskman et al., 1981, Asberg, 1997, Deakin, 2003). Secondly, certain drugs, which act on the serotonergic system like 5HT2a antagonists and selective serotonin reuptake inhibitors (SSRIs), have been used successfully to treat depression (Goodnick and Goldstein, 1998, Ban, 2001). SSRIs act by increasing synaptic 5HT concentrations by inhibiting its reuptake via transporters. However, one limitation of SSRI therapy is its relative slow onset of action, often requiring several weeks of treatment before significant clinical improvement is seen. This delay in clinical response may be due, in part, to the action of presynaptic somatodentritic 5HT1a autoreceptors, which dampen increases in 5HT activity induced by blockade of the serotonin transporter. The subsequent desensitization of the 5HT1a receptors over time with continued SSRI treatment may be needed for recovery in 5HT neuronal firing and an increase in serotonergic neurotransmission through postsynaptic 5HT1a receptors (Hjorth et al., 2000, Blier, 2003). Thus, presynaptic autoreceptors may limit SSRI action by inhibiting serotonergic activity and one approach to enhance the efficacy of SSRIs would be to find pharmacological mechanisms, which produce an early and sustained enhancement in 5HT activity.

There is evidence that drugs like pindolol and buspirone that act at the 5HT1a receptor may improve the clinical efficacy of SSRIs (DeBattista et al., 1998, Pérez et al., 2001). The aim of the present study was to explore a biochemical model of SSRI augmentation, which would assess whether a biochemical response to serotonergic stimulation by an SSRI in healthy volunteers could be augmented by a synergistic enhancement of serotonergic function. While it is not known if biochemical augmentation will be predictive of clinical augmentation in depression, any potential novel antidepressant demonstrating an augmented biochemical response could be considered for further clinical development.

Since direct measurement of synaptic serotonergic activity is not possible in humans, alternative markers of 5HT function need to be utilized in the clinical setting. As the anterior pituitary hormones prolactin and cortisol are known to respond to 5HT stimulation, a reasonable indirect approach to assess central serotinergic transmission is to study the effects of serotonergic probes on these hormones (Dinan, 1998). In human studies of serotonergic function, the effects on plasma hormone levels have been extensively investigated in healthy volunteers and patient populations (Price et al., 1990, Power and Cowen, 1992, Cowen, 2000, Sobczak et al., 2002). Serotonergic challenges used have included SSRIs such as paroxetine, citalopram, fluvoxamine and clomipramine. Single doses of these compounds have been shown to increase levels of prolactin and/or cortisol in healthy volunteers (Golden et al., 1989, Cowen, 1993, Spigset and Mjörndal., 1997, Kapitany et al., 1999, Porter et al., 1999, Attenburrow et al., 2001, Bhagwagar et al., 2002, Kojima et al., 2003). As these hormones may be useful markers of serotonergic activity, the neuroendocrine response to serotonergic challenges may index synaptic 5HT.

Likewise, the administration of l-tryptophan and l-5HTP to increase 5HT synthesis, and presumably also its release into the synapse, has been reported to elevate prolactin and/or cortisol, in healthy volunteers (Charney et al., 1982, Lee et al., 1991, van Vliet et al., 1996, Gijsman et al., 2002). Similar hormonal effects have been observed with d-fenfluramine, which releases 5HT into the synapse, and m-chlorophenylpiperazine (or mCPP) which is an agonist at postsynaptic 5HT receptors, including 5HT1B and 5HT2A/C (Kalus et al., 1992, Sommers et al., 1994, Broocks et al., 1997, Sher et al., 2003). Taken together, these neuroendocrine challenge tests support the hypothesis that prolactin and cortisol release from the anterior pituitary is under serotonergic control.

Based on the previous body of work described above, a biochemical augmentation of an SSRI was investigated using citalopram as the SSRI and l-5HTP to augment the prolactin and cortisol response to citalopram in healthy volunteers. Several subchronic clinical studies in patients have investigated the effect of treatments for depression like SSRIs on neuroendocrine responsivity to serotonergic agents. A 200 mg dose of l-5HTP significantly enhanced cortisol and prolactin levels in patients with major depression being treated with fluoxetine compared to untreated patients (Meltzer et al., 1997). Similarly, the cortisol response to the TCA clomipramine was enhanced by 100 mg l-5HTP (Sargent et al., 1998). Other studies in depressed patients demonstrated cortisol and prolactin release induced by l-tryptophan or d,l-fenfluramine could similarly be enhanced by SSRIs or TCAs (Price et al., 1989, Shapira et al., 1989, Cowen et al., 1990, O'Keane et al., 1992).

Citalopram was selected as the SSRI because of its high selectivity for the 5HT reuptake transporter and no known intrinsic activity at any 5-HT receptor subtype or at any other neurotransmitter system (Hyttel, 1982). Previous studies had demonstrated that administration of single doses of IV and oral citalopram up to 20 and 40 mg, respectively, resulted in increases in prolactin and cortisol release in healthy volunteers (Seifritz et al., 1996, Kapitany et al., 1999, Attenburrow et al., 2001, Flory et al., 2004, Hennig and Netter, 2002, Gotjen et al., 2002, Nadeem et al., 2004). l-5HTP was selected as the augmenting agent as it is also well tolerated in subjects (Lee et al., 1991), easily absorbed, crosses the blood brain barrier and is highly effective at raising serotonin levels because it is the immediate precursor of serotonin. The oral administration of 200 mg l-5HTP has been shown to stimulate prolactin and cortisol responses in healthy subjects (Meltzer and Maes, 1994), but not consistently (Gijsman et al., 2002).

Before an augmentation strategy could be investigated, the dose response curve of the serotonergic challenges was explored in order to define a minimal endocrine response. This was warranted given the conflicting data from previous studies investigating l-5HTP as a neuroendocrine challenge, and the fact that no study had yet explored the prolactin or cortisol response to more than one dose of oral citalopram. Doses of both oral citalopram and l-5HTP that elicited a threshold neuroendocrine response were then used in combination to explore the augmentation of synaptic 5HT.

Section snippets

Methods

This study was conducted as two studies. In the first study, a randomized, double blind, three period design was used to explore the neuroendocrine dose response to l-5HTP. In the second part, a three period, open label design was used to explore the neuroendocrine dose response to citalopram and subsequently to assess the augmentation of the neuroendocrine response to citalopram by l-5HTP.

The study was conducted at the Clinical Research Unit (CRU), Lilly-NUS Centre for Clinical Pharmacology,

Subjects

A total of 52 healthy Asian male subjects took part in the two studies. Twenty-four subjects with an average age of 26 years (21–49 years) and BMI 23 kg/m2 (20–27 kg/m2), participated in Study 1. In Study 2, 28 subjects with an average age of 27 years (21–50 years) and BMI 24 kg/m2 (19–30 kg/m2), participated in the citalopram dose response (period 1) and subsequently 13 and 12 subjects from the selected citalopram dose group participated in the l-5HTP dosing and augmentation, respectively (periods

Results

All 24 subjects completed Study 1. All 28 subjects completed period 1 of Study 2. Of the 14 subjects in the selected citalopram dose group in Study 2, 13 participated in and completed period 2 (200 mg l-5HTP). Of these, 12 participated and completed period 3 (200 mg l-5HTP and selected dose of citalopram). The two subjects who did not participate in the respective period withdrew from the study voluntarily. In all, data from all 52 subjects were included into the analysis.

Neuroendocrine dose response

Administration of acute doses of oral citalopram resulted in increased release of prolactin and cortisol. The cortisol response is consistent with other single oral dose studies with 20 mg (Hennig and Netter, 2002, Nadeem et al., 2004) or 40 mg (Gotjen et al., 2002) citalopram in healthy volunteers. However, there was less agreement with respect to the prolactin response. While the prolactin response to a single oral dose of 40 mg citalopram is similar to the results reported by Gotjen and

Acknowledgements

This study was supported by Eli Lilly & Company, Indianapolis, IN, USA.

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