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Quetiapine reduces nocturnal urinary cortisol excretion in healthy subjects

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Abstract

Rationale

Hypothalamic-pituitary-adrenal (HPA) axis dysfunction is a frequent finding in psychiatric disorders, including psychotic depression and schizophrenia. Conflicting results exist concerning the influence of antipsychotics on the HPA-axis.

Objective

Therefore, this double-blind, placebo-controlled, randomized cross-over study investigated the effect of quetiapine on nocturnal urinary cortisol and melatonin excretion in 13 healthy male subjects under conditions of undisturbed and experimentally disturbed sleep.

Methods

Volunteers were studied 3 times for 3 consecutive nights (N0, adaptation; N1, standard sleep conditions; N2, acoustic stress) 4 days apart. Placebo, quetiapine 25 mg or quetiapine 100 mg was administered orally 1 h before bedtime on nights 1 and 2. Urine produced during the 8-h bedtime period was collected for later determination of cortisol and melatonin concentrations by standard radioimmunoassays.

Results

MANOVA showed a significant effect for N1 vs. N2 with elevated total amount of cortisol (p<0.005) and melatonin (p<0.05) excretion after acoustic stress. Both quetiapine 25 mg and 100 mg significantly (p<0.0005) reduced the total amount of cortisol excretion in comparison to placebo. No interaction effect of stress condition was observed. There was no effect of quetiapine on melatonin levels.

Conclusion

The significant reduction of nocturnal cortisol excretion following quetiapine reflects a decreased activity of the HPA-axis in healthy subjects. This finding may be an important aspect in quetiapine’s mode of action in different patient populations.

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References

  • Abi Saab W, Seibyl JP, D’Souza DC, Karper LP, Gueorgueva R, Abi Dargham A, Wong ML, Rajhans S, Erdos JP, Heninger GR, Charney DS, Krystal JH (2002) Ritanserin antagonism of m-chlorophenylpiperazine effects in neuroleptic-free schizophrenics patients: support for serotonin-2 receptor modulation of schizophrenia symptoms. Psychopharmacology 162:55–62

    Article  PubMed  Google Scholar 

  • Adityanjee, Schulz SC (2002) Clinical use of quetiapine in disease states other than schizophrenia. J Clin Pschiatry 63:32–38

    CAS  Google Scholar 

  • al Damluji S (1993) Adrenergic control of the secretion of anterior pituitary hormones. Bailliere’s Clin Endocrinol Metab 7:355–392

    Google Scholar 

  • Allolio B, Deuss U, Kaulen D, Winkelmann W (1983) Effect of meclastine, a selective H1 receptor antagonist, upon ACTH release. Clin Endocrinol (Oxf) 19:239–245

    Google Scholar 

  • Allolio B, Schulte HM, Deuss U, Winkelmann W (1987) Cyproheptadine inhibits the corticotropin releasing hormone (CRH)-induced hormone release in normal subjects. Horm Metab Res Suppl 16:36–38

    CAS  PubMed  Google Scholar 

  • Altamura AC, Boin F, Maes M (1999) HPA axis and cytokines dysregulation in schizophrenia: potential implications for the antipsychotic treatment. Eur Neuropsychopharmacol 10:1–4

    Google Scholar 

  • Baptista T, Alastre T, Contreras Q, Martinez JL, Araujo de Baptista E, Paez X, Hernandez L (1997a) Effects of the antipsychotic drug sulpiride on reproductive hormones in healthy men: relationship with body weight regulation. Pharmacopsychiatry 30:250–255

    CAS  PubMed  Google Scholar 

  • Baptista T, Molina MG, Martinez JL, de Quijada M, Calanche de Cuesta I, Acosta A, Paez X, Martinez JM, Hernandez L (1997b) Effects of the antipsychotic drug sulpiride on reproductive hormones in healthy premenopausal women: relationship with body weight regulation. Pharmacopsychiatry 30:256–262

    CAS  PubMed  Google Scholar 

  • Barbieri C, Parodi M, Bruno S, Bertassi F, Benaglia D, Moser P, Meroni R, Dubini A (1984) Effects of acute administration of zetidoline, a new antidopaminergic drug, on plasma prolactin and aldosterone levels in man. Eur J Clin Pharmacol 26:29–32

    CAS  PubMed  Google Scholar 

  • Beckmann H, Wetterberg L, Gattaz WF (1984) Melatonin immunoreactivity in cerebrospinal fluid of schizophrenic patients and healthy controls. Psychiatry Res 11:107–110

    Article  CAS  PubMed  Google Scholar 

  • Bilder RM, Goldman RS, Volavka J, Czobor P, Hoptman M, Sheitman B, Lindenmayer JP, Citrome L, McEvoy J, Kunz M, Chakos M, Cooper TB, Horowitz TL, Lieberman JA (2002) Neurocognitive effects of clozapine, olanzapine, risperidone, and haloperidol in patients with chronic schizophrenia or schizoaffective disorder. Am J Psychiatry 159:1018–1028

    Article  PubMed  Google Scholar 

  • Breier A, Buchanan RW, Waltrip RW, 2nd, Listwak S, Holmes C, Goldstein DS (1994) The effect of clozapine on plasma norepinephrine: relationship to clinical efficacy. Neuropsychopharmacology 10:1–7

    CAS  PubMed  Google Scholar 

  • Cohrs S, Rodenbeck A, Guan Z, Pohlmann K, Jordan W, Meier A, Ruether E (2004) Sleep promoting properties in healthy subjects. Psychopharmacology (in press)

  • Collu R, Jequier JC, Leboeuf G, Letarte J, Ducharme JR (1975) Endocrine effects of pimozide, a specific dopaminergic blocker. J Clin Endocrinol Metab 41:981–984

    CAS  PubMed  Google Scholar 

  • Cross EM, Chaffin WW (1982) Use of the binomial theorem in interpreting results of multiple tests of significance. Educ Psychol Manage 42:25–34

    Google Scholar 

  • de Koning P, de Vries MH (1995) A comparison of the neuro-endocrinological and temperature effects of DU 29894, flesinoxan, sulpiride and haloperidol in normal volunteers. Br J Clin Pharmacol 39:7–14

    PubMed  Google Scholar 

  • Doering S, Wedekind D, Pilz J, Bandelow B, Adler L, Huether G (2001) Cortisolbestimmung im Nachturin—Vorstellung einer Methode für die psychoneuroendokrinologische Forschung. Z Psychosom Med Psychother 47:42–57

    CAS  PubMed  Google Scholar 

  • Fanget F, Claustrat B, Dalery J, Brun J, Terra JL, Marie Cardine M, Guyotat J (1989) Melatonine et schizophrenie. Encephale 15:505–510

    CAS  PubMed  Google Scholar 

  • Ferrier IN, Arendt J, Johnstone EC, Crow TJ (1982) Reduced nocturnal melatonin secretion in chronic schizophrenia: relationship to body weight. Clin Endocrinol (Oxf) 17:181–187

    Google Scholar 

  • Fleiss JL (1999) The design and analysis of clinical experiments. Wiley, New York

  • Hamner MB, Deitsch SE, Brodrick PS, Ulmer HG, Lorberbaum JP (2003) Quetiapine treatment in patients with posttraumatic stress disorder: an open trial of adjunctive therapy. J Clin Psychopharmacol 23:15–20

    Article  CAS  PubMed  Google Scholar 

  • Hatzimanolis J, Lykouras L, Markianos M, Oulis P (1998) Neurochemical variables in schizophrenic patients during switching from neuroleptics to clozapine. Prog Neuropsychopharmacol Biol Psychiatry 22:1077–1085

    Article  CAS  PubMed  Google Scholar 

  • Hennig J, Rzepka U, Mai B, Netter P (1995) Suppression of HPA-axis activity by haloperidol after experimentally induced heat stress. Prog Neuropsychopharmacol Biol Psychiatry 19:603–614

    Article  CAS  PubMed  Google Scholar 

  • Holsboer F (2000) The corticosteroid receptor hypothesis of depression. Neuropsychopharmacology 23:477–501

    Article  CAS  PubMed  Google Scholar 

  • Huether G (1996) The central adaptation syndrome: psychosocial stress as a trigger for adaptive modifications of brain structure and brain function. Prog Neurobiol 48:569–612

    Article  CAS  PubMed  Google Scholar 

  • Jakovljevic M, Muck Seler D, Pivac N, Crncevic Z (1998) Platelet 5-HT and plasma cortisol concentrations after dexamethasone suppression test in patients with different time course of schizophrenia. Neuropsychobiology 37:142–145

    Article  CAS  PubMed  Google Scholar 

  • Jezova Repcekova D, Klimes I, Jurcovicova J, Vigas M (1979) Effect of adrenergic receptor blockade on cortisol and GH response to insulin-induced hypoglycemia in man. Int J Clin Pharmacol Biopharm 17:64–67

    PubMed  Google Scholar 

  • Jiang HK, Wang JY (1998) Diurnal melatonin and cortisol secretion profiles in medicated schizophrenic patients. J Formos Med Assoc 97:830–837

    CAS  PubMed  Google Scholar 

  • Kahn RS, Siever L, Davidson M, Greenwald C, Moore C (1993) Haloperidol and clozapine treatment and their effect on m-chlorophenylpiperazine-mediated responses in schizophrenia: implications for the mechanism of action of clozapine. Psychopharmacology 112: S90–S94

    CAS  PubMed  Google Scholar 

  • Laakmann G, Wittmann M, Gugath M, Mueller OA, Treusch J, Wahlster U, Stalla GK (1984) Effects of psychotropic drugs (desimipramine, chlorimipramine, sulpiride and diazepam) on the human HPA axis. Psychopharmacology 84:66–70

    CAS  PubMed  Google Scholar 

  • Laakmann G, Wittmann M, Schoen HW, Zygan K, Weiss A, Meissner R, Mueller OA, Stalla GK (1986) Effects of receptor blockers (methysergide, propranolol, phentolamine, yohimbine and prazosin) on desimipramine-induced pituitary hormone stimulation in humans—III. Hypothalamo-pituitary-adrenocortical axis. Psychoneuroendocrinology 11:475–489

    CAS  PubMed  Google Scholar 

  • Lammers CH, Garcia Borreguero D, Schmider J, Gotthardt U, Dettling M, Holsboer F, Heuser IJ (1995) Combined dexamethasone/corticotropin-releasing hormone test in patients with schizophrenia and in normal controls: II. Biol Psychiatry 38:803–807

    Article  CAS  PubMed  Google Scholar 

  • Lerer B, Ran A, Blacker M, Silver H, Weller MP, Drummer D, Ebstein B, Calev A (1988) Neuroendocrine responses in chronic schizophrenia. Evidence for serotonergic dysfunction. Schizophr Res 1:405–410

    Article  CAS  PubMed  Google Scholar 

  • Markianos M, Hatzimanolis J, Lykouras L (1999) Switch from neuroleptics to clozapine does not influence pituitary-gonadal axis hormone levels in male schizophrenic patients. Eur Neuropsychopharmacol 9:533–536

    Google Scholar 

  • Meltzer HY (1989) Clinical studies on the mechanism of action of clozapine: the dopamine-serotonin hypothesis of schizophrenia. Psychopharmacology 99:S18–27

    PubMed  Google Scholar 

  • Meltzer HY, Lee MA, Jayathilake K (2001) The blunted plasma cortisol response to apomorphine and its relationship to treatment response in patients with schizophrenia. Neuropsychopharmacology 24:278–290

    Article  CAS  PubMed  Google Scholar 

  • Monteleone P, Maj M, Fusco M, Kemali D, Reiter RJ (1992) Depressed nocturnal plasma melatonin levels in drug-free paranoid schizophrenics. Schizophr Res 7:77–84

    Article  CAS  PubMed  Google Scholar 

  • Monteleone P, Maj M, Franza F, Fusco R, Kemali D (1993) The human pineal gland responds to stress-induced sympathetic activation in the second half of the dark phase: preliminary evidence. J Neural Transm Gen Sect 92:25–32

    CAS  PubMed  Google Scholar 

  • Monteleone P, Natale M, La Rocca A, Maj M (1997) Decreased nocturnal secretion of melatonin in drug-free schizophrenics: no change after subchronic treatment with antipsychotics. Neuropsychobiology 36:159–163

    CAS  PubMed  Google Scholar 

  • Monteleone P, Tortorella A, Borriello R, Cassandro P, Maj M (1999) Prolactin hyperresponsiveness to d-fenfluramine in drug-free schizophrenic patients: a placebo-controlled study. Biol Psychiatry 45:1606–1611

    Article  CAS  PubMed  Google Scholar 

  • Murburg MM, Paly D, Wilkinson CW, Veith RC, Malas KL, Dorsa DM (1986) Haloperidol increases plasma beta endorphin-like immunoreactivity and cortisol in normal human males. Life Sci 39:373–381

    Article  CAS  PubMed  Google Scholar 

  • Murburg MM, Wilkinson CW, Raskind MA, Veith RC, Dorsa DM (1993) Evidence for two differentially regulated populations of peripheral beta-endorphin-releasing cells in humans. J Clin Endocrinol Metab 77:1033–1040

    CAS  PubMed  Google Scholar 

  • Nurnberger JL Jr, Simmons Alling S, Kessler L, Jimerson S, Schreiber J, Hollander E, Tamminga CA, Nadi NS, Goldstein DS, Gershon ES (1984) Separate mechanisms for behavioral, cardiovascular, and hormonal responses to dextroamphetamine in man. Psychopharmacology 84:200–204

    CAS  PubMed  Google Scholar 

  • Rao ML, Gross G, Strebel B, Braunig P, Huber G, Klosterkotter J (1990) Serum amino acids, central monoamines, and hormones in drug-naive, drug-free, and neuroleptic-treated schizophrenic patients and healthy subjects. Psychiatry Res 34:243–257

    Article  CAS  PubMed  Google Scholar 

  • Rao ML, Gross G, Strebel B, Halaris A, Huber G, Braunig P, Marler M (1994) Circadian rhythm of tryptophan, serotonin, melatonin, and pituitary hormones in schizophrenia. Biol Psychiatry 35:151–163

    Article  CAS  PubMed  Google Scholar 

  • Richelson E, Souder T (2000) Binding of antipsychotic drugs to human brain receptors focus on newer generation compounds. Life Sci 68:29–39

    CAS  PubMed  Google Scholar 

  • Robinson S, Rosca P, Durst R, Shai U, Ghinea C, Schmidt U, Nir I (1991) Serum melatonin levels in schizophrenic and schizoaffective hospitalized patients. Acta Psychiatr Scand 84:221–224

    CAS  PubMed  Google Scholar 

  • Rodenbeck A, Cohrs S, Jordan W, Huether G, Rüther E, Hajak G (2003). The sleep-improving effects of doxepin are paralleled by a normalized plasma cortisol secretion in primary insomnia. Psychopharmacology 170:423–428

    CAS  PubMed  Google Scholar 

  • Ryan MC, Collins P, Thakore JH (2003) Impaired fasting glucose tolerance in first-episode, drug-naive patients with schizophrenia. Am J Psychiatry 160:284–289

    Article  PubMed  Google Scholar 

  • Sandyk R, Kay SR, Awerbuch GI, Iacono RP (1991) Risk factors for neuroleptic-induced movement disorders. Int J Neurosci 61:149–188

    CAS  Google Scholar 

  • Scheepers FE, Gespen de Wied CC, Kahn RS (2001) The effect of olanzapine treatment on m-chlorophenylpiperazine-induced hormone release in schizophrenia. J Clin Psychopharmacol 21:575–582

    Article  CAS  PubMed  Google Scholar 

  • Seeman TE, McEwen BS, Singer BH, Albert MS, Rowe JW (1997) Increase in urinary cortisol excretion and memory declines: MacArthur studies of successful aging. J Clin Endocrinol Metab 82:2458–2465

    CAS  PubMed  Google Scholar 

  • Seggie J, Campbell L, Brown GM, Grota LJ (1985) Melatonin and N-acetylserotonin stress responses: effects of type of stimulation and housing conditions. J Pineal Res 2:39–49

    CAS  PubMed  Google Scholar 

  • Seibyl JP, Krystal JH, Price LH, Woods SW, D’Amico C, Heninger GR, Charney DS (1991) Effects of ritanserin on the behavioral, neuroendocrine, and cardiovascular responses to meta-chlorophenylpiperazine in healthy human subjects. Psychiatry Res 38:227–236

    CAS  PubMed  Google Scholar 

  • Shamir E, Laudon M, Barak Y, Anis Y, Rotenberg V, Elizur A, Zisapel N (2000) Melatonin improves sleep quality of patients with chronic schizophrenia. J Clin Psychiatry 61:373–377

    CAS  PubMed  Google Scholar 

  • Shamir E, Barak Y, Shalman I, Laudon M, Zisapel N, Tarrasch R, Elizur A, Weizman R (2001) Melatonin treatment for tardive dyskinesia: a double-blind, placebo-controlled, crossover study. Arch Gen Psychiatry 58:1049–1052

    Article  CAS  PubMed  Google Scholar 

  • Shirayama Y, Hashimoto K, Suzuki Y, Higuchi T (2002) Correlation of plasma neurosteroid levels to the severity of negative symptoms in male patients with schizophrenia. Schizophr Res 58:69–74

    Article  PubMed  Google Scholar 

  • Smith JA, Mee TJ, Barnes JL (1977) Elevated melatonin serum concentrations in psychiatric patients treated with chlorpromazine [proceedings]. J Pharm Pharmacol 29:30 pp

    Google Scholar 

  • Smith JA, Barnes JL, Mee TJ (1979) The effect of neuroleptic drugs on serum and cerebrospinal fluid melatonin concentrations in psychiatric subjects. J Pharm Pharmacol 31:246–248

    CAS  PubMed  Google Scholar 

  • Sonino N, Fava GA, Fallo F, Franceschetto A, Belluardo P, Boscaro M (2000) Effect of the serotonin antagonists ritanserin and ketanserin in Cushing’s disease. Pituitary 3:55–59

    Article  CAS  PubMed  Google Scholar 

  • von Bahr C, Wiesel FA, Movin G, Eneroth P, Jansson P, Nilsson L, Ogenstad S (1991) Neuroendocrine responses to single oral doses of remoxipride and sulpiride in healthy female and male volunteers. Psychopharmacology 103:443–448

    PubMed  Google Scholar 

  • Walder DJ, Walker EF, Lewine RJ (2000) Cognitive functioning, cortisol release, and symptom severity in patients with schizophrenia. Biol Psychiatry 48:1121–1132

    Article  CAS  PubMed  Google Scholar 

  • Welker HA, Vollrath L (1984) The effects of a number of short-term exogenous stimuli on pineal serotonin-N-acetyltransferase activity in rats. J Neural Transm 59:69–80

    CAS  PubMed  Google Scholar 

  • Wetzel H, Wiesner J, Hiemke C, Benkert O (1994) Acute antagonism of dopamine D2-like receptors by amisulpride: effects on hormone secretion in healthy volunteers. J Psychiatr Res 28:461–473

    Article  CAS  PubMed  Google Scholar 

  • Wik G (1995) Effects of neuroleptic treatment on cortisol and 3-methoxy-4-hydroxyphenylethyl glycol levels in blood. J Endocrinol 144:425–429

    CAS  PubMed  Google Scholar 

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Acknowledgement

We thank AstraZeneca for funding of the study and supply of quetiapine and placebo.

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Correspondence to Stefan Cohrs.

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Cohrs, S., Pohlmann, K., Guan, Z. et al. Quetiapine reduces nocturnal urinary cortisol excretion in healthy subjects. Psychopharmacology 174, 414–420 (2004). https://doi.org/10.1007/s00213-003-1766-6

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  • DOI: https://doi.org/10.1007/s00213-003-1766-6

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