Skip to main content
Log in

Fenfluramine stimulation of serum cortisol in patients with major affective disorders and healthy controls: further evidence for a central serotonergic action of lithium in man

  • Original Papers
  • Published:
Journal of Neural Transmission Aims and scope Submit manuscript

Summary

In order to investigate the influence of lithium long-term medication on serotonergic neurotransmission, fenfluramine stimulation (FFS) was used for the assessment of hormonal effects under serotonergic control. The cortisol plasma concentration following FFS was examined between 8 a.m. and 1 p.m. in 11 manic-depressive subjects under lithium prophylaxis and in 8 untreated euthymic patients. In addition, 11 healthy subjects with FFS, and 12 other subjects without FFS were investigated. The basal cortisol concentrations show considerable variation. Those of the lithium patients were in general found lower than those of the control groups. In both, the controls and the manic-depressive patients without lithium medication, no gross deviation from the expected physiological decline of morning cortisol values was found. A subtle effect of FFS in healthy subjects could be observed. In the lithium patients, however, a significant inversion of the cortisol secretion pattern with a steep increase between 10 and 12 a.m. could be demonstrated. It is concluded that FFS and lithium long-term medication exert an agonistic influence onto central serotonergic neurotransmission. Pharmacological challenge with fenfluramine may prove to be a useful tool for the investigation of serotonergic mechanisms in biological psychiatry.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  • Abluwalia, P., Singhai, R. L.: Monoamine up-take into synaptosomes from various regions of rat brain following lithium administration and withdrawl. Neuropharmacol.20, 483–487 (1981).

    Google Scholar 

  • Aghajanian, G. K., Wang, R. Y.: Physiology and pharmacology of central serotonergic neurons. In: Psychopharmacology: A Generation in Progress (Lipton, A., Di Mascio, A., Killam, K. F., eds.), pp. 171–183. New York: Raven Press. 1978.

    Google Scholar 

  • Bereits, S. C., Wolff, J.: Lithium Research and Therapy, pp. 443–445. London-New York-San Francisco. 1975.

  • Blundell, J. E., Leshem, M.: Central action of anorexic agents: Effects of amphetamine and fenfluramine in rats with lateral hypothalamic lesions. European J. Pharmacol.28, 81–83 (1974).

    Google Scholar 

  • Born, G. V. R., Grignani, G., Martin, K.: Long-term effect of lithium on the up-take of 5-hydroxytryptamine by human platlets. Br. J. Pharmacol.9, 321–325 (1980).

    Google Scholar 

  • Broderick, P., Lynch, V.: Behavioral and biochemical changes induced by lithium and L-tryptophan in muricidal rats. Neuropsychopharmacol.21, 671–679 (1982).

    Google Scholar 

  • Brown, G. L., Goodwin, F. K., Ballenger, J. C., Goyer, P. F., Major, L. F.: Aggression in human correlates with cerebrospinal fluidamine metabolites. Psychiat. Res.1, 131–139 (1979).

    Google Scholar 

  • Brown, G. L., Ebert, M. H., Goyer, P. F., Jimerson, D. C., Klein, W. J., Bunney, W. E., Goodwin, F. K.: Aggression, suicide, and serotonin: Relationships in CSF amine metabolites. Am. J. Psychiat.139, 741–746 (1982).

    PubMed  Google Scholar 

  • Bunney, W. E., Garland, B. L.: Possible receptor effects of chronic lithium administration. Neuropharmacol.22, 367–372 (1983).

    Google Scholar 

  • Charney, D. S., Heninger, G. R., Reinhard, J. F., Sternberg, D. E., Hafstead, K. M.: The effect of IV L-tryptophan on prolactin, growth hormone, and mood in healthy subjects. Psychopharmacol.78, 38–43 (1982).

    Google Scholar 

  • Charney, D. S., Heninger, G. R., Sternberg, D. E.: Serotonin fonction and mechanism of action of antidepressant treatment. Arch. Gen. Psychiatr.41, 359–365 (1984).

    PubMed  Google Scholar 

  • Clineschmidt, B. V., Zacchei, A. G., Totaro, J. A., Pflueger, A. B., McGuffin, J. C., Wishousky, Th. I.: Fenfluramine and brain serotonin. Ann. N.Y. Acad. Sci.305, 222–241 (1978).

    PubMed  Google Scholar 

  • Cockson, J., Silverstone, T.: 5-hydroxytryptamine and dopamine pathways in mania. A pilot study of fenfluramine and pimozide. Br. J. Pharmacol.3, 942–947 (1976).

    Google Scholar 

  • Coppen, A., Swade, C., Wood, K.: Lithium restores abnormal platlet 5-HT-transport in patients with affective disorders. Br. J. Psychiat.136, 235–238 (1980).

    Google Scholar 

  • Corona, G. L., Cucchi, M. L., Santagostino, G., Frattini, P., Zerbi, F., Fenoglio, L., Savoldi, F.: Blood noradrenaline and 5-HT levels in depressed women during amitriptyline and lithium treatment. Psychopharmacol.77, 236–241 (1982).

    Google Scholar 

  • Czernik, A., Kleesiek, K.: Neuroendokrinologische Veränderungen unter Langzeitbehandlung mit Lithiumsalzen. Pharmacopsychiat.12, 305–312 (1979).

    Google Scholar 

  • De Montigny, C., Tan, A. T., Caille, G.: Short-term lithium enhances 5-HT neurotransmission in rat administered chronic antidepressant treatments. Presented at Society for Neuroscience, 11th Annual Meeting, Los Angeles, p. 646 (1981).

  • De Montigny, C., Cournoyer, G., Morisette, R., Langlois, R.: Lithium carbonate addition ot tricychc antidepressant-resistant unipolar depression. Arch. Gen. Psychiat.40, 1327–1334 (1983).

    PubMed  Google Scholar 

  • Duhault, J., Beregi, L., Du Boistesselin, R.: General and comparative pharmacology of fenfluramine. Curr. Med. Res. Opin.6, 3–14 (1979).

    Google Scholar 

  • Duhault, J., Malen, Ch., Boulanger, M., Voisin, C., Beregi, L., Schmitt, H.: Fenfluramine and 5-hydroxytryptamine. Arzneim.-Forsch./Drug Res.25, 1755–1762 (1975).

    Google Scholar 

  • Eroglu, L., Atamer-Simsek, S.: Effect of lithium on stress-induced changes in brain levels of monoamines in rats. Arzneim.-Forsch./Drug Res.30, 2115–2117 (1980).

    Google Scholar 

  • Fink, M., Shapiro, D. M., Itil, T. M.: EEG-profiles of fenfluramine, amobarbital, and dextroamphetamine in normal volunteers. Psychopharmacol.22, 369–383 (1971).

    Google Scholar 

  • Friedman, E., Dallob, A., Gershon, L.: The effect of lithium long-term treatment on reserpine-induced supersensitivity in dopaminergic and serotonergic transmission. Life Sci.25, 1263–1266 (1979).

    PubMed  Google Scholar 

  • Garattini, S., Jori, A., Buczko, W., Samanin, R.: The mechanism of action of fenfluramine. Postgrad. Med. J.51, 27–35 (1975).

    Google Scholar 

  • Garattini, S., Samanin, R.: Anorectic drugs and brain neurotransmitter. In: Appetite and food intake (Silverstone, T., ed.), pp. 83–108. (Dahlem Workshop on Appetite and Food-intake.) Berlin: Abakon Verlagsgesellschaft. 1976.

    Google Scholar 

  • Halmi, K. A., Noyes, R., Millard, S. A.: Effect of lithium on plasma cortisol and adrenal response to adrenocorticotropin in man. Clin. Pharmacol. Ther.13, 699–703 (1978).

    Google Scholar 

  • Harrison-Read, P. E.: Evidence from behavioural reactions to fenfluramine, 5-hydrox-tryptophan, and 5-methoxy-N, N-dimethyltryptamine for differentia effects of short-term and long-term lithium on indoleaminergic mechanisms in rats. Br. J. Pharmacol.66, 144–145 (1979).

    Google Scholar 

  • Heninger, G. R., Charney, D. S., Sternberg, D. E.: Lithium carbonate augmentation of antidepressant treatment. Arch. Gen. Psychiat.40, 1335–1342 (1983).

    PubMed  Google Scholar 

  • Heninger, G. R., Charney, D. S., Sternberg, D. E.: Serotonergic function in depression. Prolactin response to intravenous tryptophan in depressed patients and healthy subjects. Arch. Gen. Psychiat.41, 398–402 (1984).

    PubMed  Google Scholar 

  • Knapp, S., Mandell, A. J.: Coincidence of blockade of synaptosomal 5-hydroxytryptamine uptake and decrease in tryptophan hydroxylase activity: Effects of fenfluramine. J. Pharmacol. Exp. Ther.198, 123–132 (1976).

    PubMed  Google Scholar 

  • Knapp, S., Mandell, A. J.: Lithium and chlorimipramine differentially alter bilateral asymmetry in mesocortical serotonin metabolites and kinetic conformation of midbrain tryptophan hydroxylase with respect to tetrahydrobiopterin cofactor. Neuropharmacol.19, 1–7 (1979).

    Google Scholar 

  • Lerer, B., Ebstein, R. B., Felix, A., Belmaker, R. H.: Lithium amelioration of reserpine-induced hypoactivity in rats. Int. Pharmacopsychiat.15, 338–343 (1980).

    Google Scholar 

  • Mandell, A. J., Knapp, S.: A neurobiological model for the symmetrical prophylactic action of lithium in bipolar affective disorder. Pharmacopsychiat.9, 116–126 (1976).

    Google Scholar 

  • Mandell, A. J., Knapp, S.: Asymmetry and mood, emergent properties of serotonin regulation. Arch. Gen. Psychiat.36, 909–916 (1979).

    PubMed  Google Scholar 

  • Maggi, A., Enna, S. J.: Regional alteration in rat brain neurotransmitter systems following chronic lithium treatment. J. Neurochem.34, 888–892 (1980).

    PubMed  Google Scholar 

  • Meltzer, H. Y., Witta, B., Tricou, B. J., Simonovic, M., Fang, V., Manov, G.: Effects of serotonin precursors and serotonin agonists on plasma hormone levels. In: Serotonin in Biological Psychiatry (Ho, B. T., Schoolar, J. C., Usdin, E., eds.), pp. 117–139. Raven Press. 1982.

  • Meltzer, H. Y., Arora, R. C., Baber, R., Tricou, B. J.: Serotonin uptake in blood platelets of psychiatric patients. Arch. Gen. Psychiat.38, 1322–1326 (1981).

    PubMed  Google Scholar 

  • Meltzer, H. Y., Arora, R. C., Goodnick, P.: Effect of lithium carbonate on serotonin uptake in blood platelets of patients with affective disorders. J. Affect. Disorders5, 215–221 (1983).

    PubMed  Google Scholar 

  • Meltzer, H. Y., Lowy, M., Robertson, A., Goodnick, P., Perline, R.: Effect of 5-hydroxytryptophan on serum cortisol levels in major affective disorders. Arch. Gen. Psychiat.41, 391–397 (1984).

    PubMed  Google Scholar 

  • Mühlbauer, H. D.: Human aggression and the role of central serotonin. Pharmacopsychiat. (in press).

  • Mühlbauer, H. D., Hardt, W.: The influence of lithium salts and antidepressive medication on the serum prolactin level. Pharmacopsychiat.13, 213–217 (1980).

    Google Scholar 

  • Mühlbauer, H. D., Graef, K. J., Müller-Oerlinghausen, B.: Neuroendokrine Aspekte der Lithium-Prophylaxe. In: Biologische Psychiatrie (Beckmann, H., ed.), p. 211–217. Stuttgart: G. Thieme. 1981.

    Google Scholar 

  • Mühlbauer, H. D., Müller-Oerlinghausen, B.: The fenfluramine test: A simple tool for investigations on lithium-induced changes of serotonergic neurotransmission in manic-depressive patients. Arzneim.-Forsch./Drug Res.32, 897 (1982).

    Google Scholar 

  • Mühlbauer, H. D., Müller-Oerlinghausen, B.: Veränderungen der serotonergen Neurotransmission bei manisch-depressiven Patienten unter Lithium-Prophylaxe. In: Forschungen zur Biologischen Psychiatrie (Hopf, A., Beckmann, H., eds.), pp. 192–197. Berlin-Heidelberg-New York-Tokyo: Springer. 1984.

    Google Scholar 

  • Müller, E. E., Nisticó, G., Scapagnini, U.: Neurotransmitters and Anterior Pituitary Function. New York-San Francisco-London: Academic Press. 1977.

    Google Scholar 

  • Müller-Oerlinghausen, B.: Lithium long-term medication-does it act via serotonin? Pharmacopsychiat. (in press).

  • Müller-Oerlinghausen, B., Bauer, H., Girke, W., Kanowski, S., Goncalves, N.: Impairment of vigilance and performance under lithium treatment. Studies in patient and normal volunteers. Pharmakopsychiat.10, 67–78 (1977).

    Google Scholar 

  • Murphy, D. L., Colburn, R. W., Davis, J. M., Bunney, W. E.: Stimulation by lithium of monoamine uptake in human platelets. Life Sci.8, 1187–1193 (1969).

    PubMed  Google Scholar 

  • Murphy, D. I., Slater, S., De la Vega, C. E., Lipper, S.: The serotonergic neurotransmitter system in the affective disorders-a preliminary evaluation of the antidepressant and antimanic effects of fenfluramine. In: Neuropsychopharmacology (Demker, P., Thomas-Radouko, C., Villeneuve, A., eds.), pp. 675–682. Oxford: Pergamon Press. 1978.

    Google Scholar 

  • Orosco, M., Bremond, J., Jacquot, C., Cohen, Y.: Fenfluramine and brain transmitter in the obese zucker rat. Neuropharmacol.23, 183–188 (1984).

    Google Scholar 

  • Pearce, J. B.: Fenfluramine in mania. Lancet1, 800, 427 (1973).

    Google Scholar 

  • Platman, St. R., Fieve, R. F.: Lithium carbonate and plasma cortisol response in the affective disorders. Arch. Gen. Psychiat.18, 591–594 (1968).

    PubMed  Google Scholar 

  • Platman, S. R., Hilton, J. G., Koss, M. C.: Production of cortisol in patients with manic-depressive psychosis treated with lithium carbonate. Dis. Nerv. Syst.32, 542–544 (1971).

    PubMed  Google Scholar 

  • Poitou, P., Guerinot, F., Bohoun, C.: Effect of lithium on central metabolism of 5-hydroxytryptamine. Psychopharmacol.38, 75 (1974).

    Google Scholar 

  • Rommelspacher, H., Strauss, S.: Effect of lesions of raphe nuclei on the activity of catecholaminergic and serotonergic neurones in various brain regions of the ratin vivo. J. Neural Transm.49, 51–62 (1980).

    PubMed  Google Scholar 

  • Sangdee, C., Franz, D. N.: Lithium enhancement of central 5-HT transmission induced by 5-HT precursors. Biol. Psychiat.15, 59–75 (1980).

    PubMed  Google Scholar 

  • Schubert, J.: Effects of chronic lithium treatment on monoamine metabolism in rat brain. Psychopharmacol.32, 301–311 (1973).

    Google Scholar 

  • Steranka, L. R., Sanders-Bush, E.: Species differences in the rate of disappearance of fenfluramine and its effects on brain serotonin neurons. Biochem. Pharmacol.28, 3103–3107 (1979).

    PubMed  Google Scholar 

  • Swann, A. C., Heninger, G. R., Roth, R. H., Maas, J. W.: Differential effects of short- and long-term lithium on tryptophan uptake and serotonergic function in cat brain. Life Sci.28, 347–354 (1981).

    PubMed  Google Scholar 

  • Sotelo, C., Zamora, A.: Lack of morphological changes in the neurons of the B 9 group in rats treated with fenfluramine. Curr. Med. Res. Opin.6, 55–62 (1978).

    Google Scholar 

  • Treiser, S., Kellar, K. J.: Lithium: Effects on serotonin receptors in rat brain. Eur. J. Pharmacol.64, 183–185 (1980).

    PubMed  Google Scholar 

  • Yuwiler, A., Benett, B. L., Brammer, G. L., Geller, E.: Lithium treatment and tryptophan transport through the blood-brain barrier. Biochem. Pharmacol.28, 2709–2712 (1979).

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mühlbauer, H.D., Müller-Oerlinghausen, B. Fenfluramine stimulation of serum cortisol in patients with major affective disorders and healthy controls: further evidence for a central serotonergic action of lithium in man. J. Neural Transmission 61, 81–94 (1985). https://doi.org/10.1007/BF01253053

Download citation

  • Received:

  • Revised:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01253053

Keywords

Navigation