Enhanced tolerability of the 5-hydroxytryptophane challenge test combined with granisetron

Abstract

A recently developed oral serotonergic challenge test consisting of 5-Hydroxytryptophane (5-HTP, 200 mg) combined with carbidopa (CBD, 100 mg + 50 mg) exhibited dose-related neuroendocrine responsiveness and predictable pharmacokinetics. However, its applicability is limited by nausea and vomiting. A randomized, double-blind, placebo-controlled, four-way crossover trial was performed in 12 healthy male volunteers. The 5-HTP/CBD-challenge was combined with two oral anti-emetics (granisetron, 2 mg or domperidone, 10 mg) to investigate its reliability when side-effects are suppressed. The neuroendocrine response (serum cortisol and prolactin), the side-effect profile [Visual Analogue Scale Nausea (VAS)] and vomiting subjects per treatment were the main outcome measures. Compared to 5-HTP/CBD/placebo, 5-HTP/CBD/ granisetron had no impact on cortisol [% change with 95% confidence interval: −7.1% (18.9; 6.5)] or prolactin levels [−9.6% (−25.1; 9.1)]; 5-HTP/CBD/domperidone increased cortisol [+13.0% (−4.2; 33.4)], and increased prolactin extensively [+336.8% (245.7; 451.9)]. Compared to placebo, VAS Nausea increased non-significantly with granisetron [+7.6 mm (−1.3; 16.5)], as opposed to domperidone [+16.2 mm (7.2; 25.2)] and 5-HTP/CBD/placebo [+14.7 mm (5.5; 23.8)]. No subjects vomited with granisetron, compared to two subjects treated with 5-HTP/CBD/placebo and five subjects with domperidone. Compared with 5-HTP/CBD/placebo, granisetron addition decreased C_max of 5-HTP statistically significantly different (from 1483 to 1272 ng/ml) without influencing AUC_{0— ∞}. Addition of granisetron to the combined 5-HTP/CBD challenge suppresses nausea and vomiting without influencing the neuroendocrine response or pharmacokinetics, enhancing its clinical applicability in future psychiatric research and drug development.

Keywords

5-HTP challenge test granisetron HPA-axis pharmacokinetics pharmacodynamics serotonergic function

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References

Arrindell, WA , Ettema, JHM ( 1986) SCL-90. Handleiding bij een multidimensionele psychopathologie-indicator . Swets and Zeitlinger, Lisse .

Bond, A. , Lader, M. ( 1974) The use of analogue scale in rating subjective feelings . Br J Med Psychol 47: 211-218.

Derogatis, LR , Lipman, RS , Covi, L. ( 1973) SCL-90: an outpatient psychiatric rating scale-preliminary report. Psychopharmacol Bull 9: 13-28.

Dumont, GJ , de Visser, SJ , Cohen, AF , Van Gerven, JM ( 2005) Bio-markers for the effects of selective serotonin reuptake inhibitors (SSRIs) in healthy subjects. Br J Clin Pharmacol 59: 495-510.

Endo, T. , Minami, M. , Hirafuji, M. , Ogawa, T. , Akita, K. , Nemoto, M. , et al. (2000) Neurochemistry and neuropharmacology of emesis- the role of serotonin. Toxicology 153: 189-201.

Gartside, SE , Cowen, PJ ( 1990) Mediation of ACTH and prolactin responses to 5-HTP by 5-HT2 receptors. Eur J Pharmacol 179: 103-109.

Gijsman, HJ , Van Gerven, JM , Tieleman, MC , Schoemaker, RC , Pieters, MS , Ferrari, MD , et al. (1998) Pharmacokinetic and pharmacodynamic profile of oral and intravenous metachlorophenylpiperazine in healthy volunteers. J Clin Psychopharmacol 18: 289-295.

Gijsman, HJ , van Gerven, JMA , de Kam, ML , Schoemaker, RC , Pieters, MSM , Weemaes, M. , et al. (2002) Placebo-controlled comparison of three dose-regimens of 5-hydroxytryptophan challenge test in healthy volunteers. J Clin Psychopharmacol 22: 183-189.

Groenestijn, MAC , Akkerhuis, GW , Kupka, RW , Schneider, Nolen, WA ( 1999) Structured clinical interview for DSM-IV axis I disorders . Swets Test, Lisse.

10.

Jorgensen, H. , Knigge, U. , Kjaer, A. , Moller, M. , Warberg, J. ( 2002) Serotonergic stimulation of corticotropin-releasing hormone and pro-opiomelanocortin gene expression. J Neuroendocrinol 14: 788-795.

11.

Lowe, SL , Yeo, KP , Teng, L. , Soon, DK , Pan, A. , Wise, SD , et al. (2006) L-5-Hydroxytryptophan augments the neuroendocrine response to a SSRI. Psychoneuroendocrinology 31: 473-484.

12.

Mitchelson, F. ( 1992) Pharmacological agents affecting emesis. A review (Part I). Drugs 43: 295-315.

13.

Norris, H. ( 1971) The action of sedatives on brain stem oculomotor systems in man. Neuropharmacology 10: 181-191.

14.

Sanger, GJ , Andrews, PL ( 2006) Treatment of nausea and vomiting: gaps in our knowledge . Auton Neurosci 129: 3-16.

15.

Sargent, PA , Williamson, DJ , Cowen, PJ ( 1998) Brain 5-HT neuro-transmission during paroxetine treatment . Br J Psychiatry 172: 49-52.

16.

Smarius, Ljca , Jacobs, GE , Hoeberechts-Lefrandt, DHM , de Kam, ML , van der Post, J. , de Rijk, R. , et al. (2008) Pharmacology of rising oral doses of 5-hydroxytryptophan with carbidopa. J Psychopharmacol OnlineFirst, February 28, 2008.

17.

Tan, M. ( 2003) Granisetron: new insights into its use for the treatment of chemotherapy-induced nausea and vomiting. Expert Opin Pharmacother 4: 1563-1571.

18.

Van de Kar, LD , Rittenhouse, PA , Li, Q. , Levy, AD ( 1996) Serotonergic regulation of renin and prolactin secretion . Behav Brain Res 73: 203-208.