Abstract
Rationale
Acute administration of 40 mg paroxetine (a selective serotonin reuptake inhibitor) reportedly increases plasma cortisol in human subjects. This suggests that paroxetine may be a useful tool to probe brain serotonin function.
Objective
To investigate a dose-response relationship for paroxetine administration, and to determine whether a lower dose of paroxetine is sufficient to increase plasma ACTH and cortisol.
Methods
Twenty subjects were tested on three occasions in a double-blind, cross-over design receiving: (a) placebo, (b) paroxetine 20 mg and (c) paroxetine 40 mg administered orally at 8.00 a.m. In addition, five of the 20 subjects received paroxetine 20 mg plus cyproheptadine (a 5-HT2 receptor antagonist) 4 mg and four subjects were given paroxetine 40 mg plus cyproheptadine 4 mg in an open manner. Plasma ACTH and cortisol levels were measured prior to administration and every hour for 6 h thereafter.
Results
Paroxetine, particularly 20 mg rather than 40 mg, significantly increased plasma ACTH and cortisol. Paroxetine 40 mg but not 20 mg caused significantly more nausea than the placebo. Cyproheptadine attenuated ACTH and cortisol responses to 20 mg but not to 40 mg paroxetine.
Conclusions
Low-dose (20 mg) paroxetine has greater potential utility than larger doses as a neuroendocrine challenge test. The endocrine responses to paroxetine are probably mediated at least partially by 5-HT2A/2C receptors.
Similar content being viewed by others
References
Attenburrow M-J, Mitter PR, Whale R, Terao T, Cowen PJ (2001) Low-dose citalopram as a 5-HT neuroendocrine probe. Psychopharmacology 155:323–326
Cowen PJ (1993) Serotonin receptor subtypes in depression: evidence from studies in neuroendocrine regulation. Clin Neuropharmacol 16:S7–S18
Cowen PJ (1998) Neuroendocrine challenge test: what we can learn from them? In: Van der Kar LD (ed) Methods in neuroendocrinology. CRC Press, Boca Raton, pp 205–223
Cowen PJ, Anderson IM, Gartside SE (1990) Endocrinological responses to 5-HT. Ann NY Acad Sci 600:250–259
Heninger GR, Charney DS, Sternberg OE (1984) Serotonergic function in depression: prolactin response to intravenous tryptophan in depressed patients and healthy subjects. Arch Gen Psychiatry 41:398–402
Hoyer D (1988) Functional correlates of serotonin 5-HT1 recognition sites. J Recept Res 8:59
Kahn RS, Wetzler S (1991) m-chlorophenylpiperazine as a probe of serotonin function. Biol Psychiatry 30:1139–1166
Koyama T, Meltzer HY (1986) A biochemical and neuroendocrine study of the serotonergic system in depression. In: Hippius H, Klerman GL, Matussek N (eds) New results in depression. Springer, Berlin, pp 169–188
Laakmann G, Gogath M, Kuss H-J, Zygan K (1984) Comparison of growth hormone and prolactin stimulation induced by clomipramine and desipramine in man in connection with clomipramine metabolism. Psychopharmacology 82:62–67
Lesch KP, Mayer S, Disselkamp-Tietze J, Hoh A, Wiesmann M, Osterheider M, Schulte HM (1990) 5-HT1A receptor responsivity in unipolar depression: evaluation of ipsapirone-induced ACTH and cortisol secretion in patients and controls. Biol Psychiatry 28:620–628
López-Calulla C, Dominquez N (1999) Determination of paroxetine in plasma by high-performance liquid chromatography for bioequivalence studies. J Chromatogr B 724:393–398
López-Ibor JJ, Saiz-Ruiz J, Moral-Igresias L (1989) Neuroendocrine challenges in the diagnosis of depressive disorders. Br J Psychiatry 154:73–76
Meltzer HY, Umberkoman-Witta B, Robertson A, Tricou BJ, Lowy M, Perline R (1984) Effect of 5-hydroxytryptophan on serum cortisol levels in major affective disorders: I. enhanced response in depression and mania. Arch Gen Psychiatry 41:366–374
O'Kean V, Dinan TG (1991) Prolactin and cortisol responses to d-fenfluramine in major depression: evidence for diminished responsivity of central serotonergic function. Am J Psychiatry 148:1009–1115
Power AC, Cowen PJ (1992) Neuroendocrine challenge tests: assessment of 5-HT function in anxiety and depression. Mol Aspects Med 13:205–220
Price LH, Charney DS, Delgado PL, Heninger GR (1991) Serotonin function and depression: neuroendocrine and mood responses to intravenous l-tryptophan in depressed patients and healthy comparison subjects. Am J Psychiatry 148:1518–1525
Raap DK, Van der Kar LD (1999) Minireview: selective serotonin reuptake inhibitors and neuroendocrine function. Life Sci 65:1217–1235
Reist C, Helmeste D, Albers L, Chhay H, Tang SW (1996) Serotonin indices and impulsivity in normal volunteers. Psychiatry Res 60:177–184
Seifritz E, Baumann P, Muller MJ, Annen O, Amey M, Hemmeter U, Hatzinger M, Chardon F, Holsboer-Trachsler E (1996) Neuroendocrine effects of a 20-mg citalopram infusion in healthy males. Neuropsychopharmacology 14:253–263
Terao T, Yoshimura R, Ohmori O, Takano T, Takahashi N, Iwata N, Suzuki T, Abe K (1997) Effect of cholesterol levels on meta-chlorophenylpiperazine-evoked neuroendocrine responses in healthy subjects. Biol Psychiatry 41:974–978
Terao T, Nakamura J, Yoshimura R, Ohmori O, Takahashi N, Shinkai T (2000a) Prediction of lithium response using m-chlorophenylpiperazine challenge test: a preliminary finding. Int Clin Psychopharmacol 15:39–42
Terao T, Nakamura J, Yoshimura R, Ohmori O, Takahashi N, Kojima H, Soeda S, Shinkai T, Nakano H, Okuno T (2000b) Relationship between serum cholesterol levels and meta-chlorophenylpipearazine-induced cortisol responses in healthy men and women. Psychiatry Res 96:167–17
Van der Kar LD (1991) Neuroendocrine pharmacology of serotonergic neurons. Annu Rev Pharmacol Toxicol 31:289–320
Acknowledgements
This research was supported partially by a Grant-in-Aid (C) from the Ministry of Education, Science and Culture of Japan. We thank Dr Iwata (East Asia University) for his contribution to statistical analysis.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Kojima, H., Terao, T., Iwakawa, M. et al. Paroxetine as a 5-HT neuroendocrine probe. Psychopharmacology 167, 97–102 (2003). https://doi.org/10.1007/s00213-003-1406-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00213-003-1406-1