Skip to main content
SpringerLink
Log in

The atypical antipsychotics olanzapine and quetiapine, but not haloperidol, reduce ACTH and cortisol secretion in healthy subjects

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Rationale

Increased activity of the hypothalamic–pituitary–adrenal (HPA) axis is an important aspect of the pathophysiology of major depression and schizophrenia. Despite the usefulness of atypical antipsychotics in the treatment of depression and their positive influence on cognitive functioning possibly related to their impact on cortisol, little is known about their effect on HPA axis function.

Objective

Therefore, this double-blind, placebo-controlled, randomized cross-over study investigated the influence of the atypical antipsychotics quetiapine and olanzapine in comparison with haloperidol and placebo on plasma adrenocorticotropic hormone (ACTH), cortisol, and prolactin levels. Eleven healthy male volunteers were studied during four sessions one week apart, orally receiving placebo, quetiapine (50 mg), olanzapine (5 mg), or haloperidol (3 mg). Blood samples were taken at hourly intervals from 0900 until 1700 hours. For ACTH, cortisol, and prolactin a significant effect of treatment condition (p≤0.005; p≤0.035; p≤0.0001, respectively) for area under the curve (AUC) was found. In comparison to placebo, quetiapine and olanzapine significantly reduced ACTH (p≤0.002; p≤0.05, respectively) and cortisol (p≤0.005; p≤0.03, respectively). No effect of haloperidol on AUC of ACTH or cortisol levels was observed. In comparison with placebo, haloperidol (p≤0.0001) and olanzapine (p≤0.0001) elevated AUC of prolactin plasma levels, whereas no significant effect was observed for quetiapine as a main effect of treatment condition. The atypical antipsychotics’ strong influence on HPA-function with pronounced ACTH and cortisol lowering is possibly related to the atypicals’ blockade of serotonergic receptors, but blockade of adrenergic or histaminergic receptors may play a role as well. The observed HPA-axis down-regulation may be clinically important for the atypicals’ effects on depressive symptomatology and cognitive functioning.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

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 (Berl) 162:55–62

    Article  CAS  Google Scholar 

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

    PubMed  Google Scholar 

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

    Google Scholar 

  • Alexiadis M, Whitehorn D, Woodley H, Kopala L (2002) Prolactin elevation with quetiapine. Am J Psychiatry 159:1608–1609

    Article  PubMed  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

    CAS  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

    PubMed  CAS  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

    Article  PubMed  CAS  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

    Article  PubMed  CAS  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

    PubMed  CAS  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

    Article  PubMed  CAS  Google Scholar 

  • Belanoff JK, Gross K, Yager A, Schatzberg AF (2001) Corticosteroids and cognition. J Psychiatr Res 35:127–145

    Article  PubMed  CAS  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 

  • Borison RL, Arvanitis LA, Miller BG (1996) ICI 204,636, an atypical antipsychotic: efficacy and safety in a multicenter, placebo-controlled trial in patients with schizophrenia. US SEROQUEL Study Group J Clin Psychopharmacol 16:158–169

    Article  PubMed  CAS  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

    PubMed  CAS  Google Scholar 

  • Brown ES, Varghese FP, McEwen BS (2004) Association of depression with medical illness: does cortisol play a role? Biol Psychiatry 55:1–9

    Article  PubMed  CAS  Google Scholar 

  • Calabrese JR, Macfadden W, McCoy R, Minkwitz M, Wilson E, Mullen J (2004) Double-blind, placebo-controlled study of quetiapine in bipolar depression. In: Association AP (ed) American psychiatric association 157th annual meeting. American Psychiatric Association, New York, USA, p 284, NR756

    Google Scholar 

  • Cohrs S, Pohlmann K, Guan Z, Jordan W, Meier A, Huether G, Rüther E, Rodenbeck A (2004) Quetiapine reduces nocturnal urinary cortisol excretion in healthy subjects. Psychopharmacology (Berl) 174:414–420

    CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Contesse V, Lefebvre H, Lenglet S, Kuhn JM, Delarue C, Vaudry H (2000) Role of 5-HT in the regulation of the brain–pituitary–adrenal axis: effects of 5-HT on adrenocortical cells. Can J Physiol Pharmacol 78:967–983

    Article  PubMed  CAS  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  CAS  Google Scholar 

  • Fuller RW, Snoddy HD (1984) Central dopamine receptors mediating pergolide-induced elevation of serum corticosterone in rats. Characterization by the use of antagonists. Neuropharmacology 23:1389–1394

    Article  PubMed  CAS  Google Scholar 

  • Ghadirian AM, Chouinard G, Annable L (1982) Sexual dysfunction and plasma prolactin levels in neuroleptic-treated schizophrenic outpatients. J Nerv Ment Dis 170:463–467

    Article  PubMed  CAS  Google Scholar 

  • Goodnick PJ, Rodriguez L, Santana O (2002) Antipsychotics: impact on prolactin levels. Expert Opin Pharmacother 3:1381–1391

    Article  PubMed  CAS  Google Scholar 

  • Gruen PH, Sachar EJ, Langer G, Altman N, Leifer M, Frantz A, Halpern FS (1978) Prolactin responses to neuroleptics in normal and schizophrenic subjects. Arch Gen Psychiatry 35:108–116

    PubMed  CAS  Google Scholar 

  • Hamner MB, Arvanitis LA, Miller BG, Link CG, Hong WW (1996) Plasma prolactin in schizophrenia subjects treated with Seroquel (ICI 204,636). Psychopharmacol Bull 32:107–110

    PubMed  CAS  Google Scholar 

  • Harrow M, Yonan CA, Sands JR, Marengo J (1994) Depression in schizophrenia: are neuroleptics, akinesia, or anhedonia involved? Schizophr Bull 20:327–338

    PubMed  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Hornig M, Amsterdam JD (2003) Prolactin, growth hormone, insulin, glucagon, and parathyroid hormone. In: Wolkowitz OM, Rothschild AJ (eds) Psychoneuroendocrinology. The Scientific basis of clinical practice. American Psychiatrist Publishing, Arlington, pp 107–136

    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  CAS  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 (Berl) 112:S90–S94

    Article  CAS  Google Scholar 

  • Kapur S, Zipursky R, Jones C, Shammi CS, Remington G, Seeman P (2000) A positron emission tomography study of quetiapine in schizophrenia: a preliminary finding of an antipsychotic effect with only transiently high dopamine D2 receptor occupancy. Arch Gen Psychiatry 57:553–559

    Article  PubMed  CAS  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 (Berl) 84:66–70

    Article  CAS  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

    Article  PubMed  CAS  Google Scholar 

  • Laakmann G, Schule C, Baghai T, Waldvogel E (1999) Effects of mirtazapine on growth hormone, prolactin, and cortisol secretion in healthy male subjects. Psychoneuroendocrinology 24:769–784

    Article  PubMed  CAS  Google Scholar 

  • Langer G, Sachar EJ, Gruen PH, Halpern FS (1977) Human prolactin responses to neuroleptic drugs correlate with antischizophrenic potency. Nature 266:639–640

    Article  PubMed  CAS  Google Scholar 

  • Marco EJ, Wolkowitz OM, Vinogradov S, Poole JH, Lichtmacher J, Reus VI (2002) Double-blind antiglucocorticoid treatment in schizophrenia and schizoaffective disorder: a pilot study. World J Biol Psychiatry 3:156–161

    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

    Article  PubMed  CAS  Google Scholar 

  • Mauri M, Sinforiani E, Bono G, Vignati F, Berselli ME, Attanasio R, Nappi G (1993) Memory impairment in Cushing’s disease. Acta Neurol Scand 87:52–55

    Article  PubMed  CAS  Google Scholar 

  • Meltzer HY (1989) Clinical studies on the mechanism of action of clozapine: the dopamine–serotonin hypothesis of schizophrenia. Psychopharmacology (Berl) 99(Suppl):S18–S27

    Article  Google Scholar 

  • Meltzer HY, Fang VS (1976) The effect of neuroleptics on serum prolactin in schizophrenic patients. Arch Gen Psychiatry 33:279–286

    PubMed  CAS  Google Scholar 

  • Möller HJ (2003) Management of the negative symptoms of schizophrenia: new treatment options. CNS Drugs 17:793–823

    Article  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  PubMed  CAS  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

    Article  PubMed  CAS  Google Scholar 

  • Nemeroff CB (1997) Dosing the antipsychotic medication olanzapine. J Clin Psychiatry 58(Suppl 10):45–49

    PubMed  CAS  Google Scholar 

  • Nurnberger JI 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 (Berl) 84:200–204

    Article  CAS  Google Scholar 

  • Purdon SE, Jones BD, Stip E, Labelle A, Addington D, David SR, Breier A, Tollefson GD (2000) Neuropsychological change in early phase schizophrenia during 12 months of treatment with olanzapine, risperidone, or haloperidol. The Canadian Collaborative Group for research in schizophrenia. Arch Gen Psychiatry 57:249–258

    Article  PubMed  CAS  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

    Article  PubMed  CAS  Google Scholar 

  • Rubin RT, Poland RE, O’Connor D, Gouin PR, Tower BB (1976) Selective neuroendocrine effects of low-dose haloperidol in normal adult men. Psychopharmacologia 47:135–140

    Article  PubMed  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  PubMed  CAS  Google Scholar 

  • Schule C, Baghai T, Zwanzger P, Ella R, Eser D, Padberg F, Moller HJ, Rupprecht R (2003) Attenuation of hypothalamic–pituitary–adrenocortical hyperactivity in depressed patients by mirtazapine. Psychopharmacology (Berl) 166:271–275

    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

    Article  PubMed  CAS  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

    Article  PubMed  CAS  Google Scholar 

  • Shelton RC, Tollefson GD, Tohen M, Stahl S, Gannon KS, Jacobs TG, Buras WR, Bymaster FP, Zhang W, Spencer KA, Feldman PD, Meltzer HY (2001) A novel augmentation strategy for treating resistant major depression. Am J Psychiatry 158:131–134

    Article  PubMed  CAS  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 

  • 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  PubMed  CAS  Google Scholar 

  • Tohen M, Vieta E, Calabrese J, Ketter TA, Sachs G, Bowden C, Mitchell PB, Centorrino F, Risser R, Baker RW, Evans AR, Beymer K, Dube S, Tollefson GD, Breier A (2003) Efficacy of olanzapine and olanzapine–fluoxetine combination in the treatment of bipolar I depression. Arch Gen Psychiatry 60:1079–1088

    Article  PubMed  CAS  Google Scholar 

  • Tuomisto J, Mannisto P (1985) Neurotransmitter regulation of anterior pituitary hormones. Pharmacol Rev 37:249–332

    PubMed  CAS  Google Scholar 

  • Turrone P, Kapur S, Seeman MV, Flint AJ (2002) Elevation of prolactin levels by atypical antipsychotics. Am J Psychiatry 159:133–135

    Article  PubMed  Google Scholar 

  • Velligan DI, Newcomer J, Pultz J, Csernansky J, Hoff AL, Mahurin R, Miller AL (2002) Does cognitive function improve with quetiapine in comparison to haloperidol? Schizophr Res 53:239–248

    Article  PubMed  Google Scholar 

  • Volavka J, Czobor P, Cooper TB, Sheitman B, Lindenmayer JP, Citrome L, McEvoy JP, Lieberman JA (2004) Prolactin levels in schizophrenia and schizoaffective disorder patients treated with clozapine, olanzapine, risperidone, or haloperidol. J Clin Psychiatry 65:57–61

    Article  PubMed  CAS  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 (Berl) 103:443–448

    Article  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  PubMed  CAS  Google Scholar 

  • Weizman A, Maoz B, Treves I, Asher I, Ben David M (1985) Sulpiride-induced hyperprolactinemia and impotence in male psychiatric outpatients. Prog Neuropsychopharmacol Biol Psychiatry 9:193–198

    Article  PubMed  CAS  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  PubMed  CAS  Google Scholar 

  • Wetzel H, Szegedi A, Hain C, Wiesner J, Schlegel S, Benkert O (1995) Seroquel (ICI 204 636), a putative “atypical” antipsychotic, in schizophrenia with positive symptomatology: results of an open clinical trial and changes of neuroendocrinological and EEG parameters. Psychopharmacology (Berl) 119:231–238

    Article  CAS  Google Scholar 

  • Wieck A, Haddad PM (2003) Antipsychotic-induced hyperprolactinaemia in women: pathophysiology, severity and consequences. Selective literature review. Br J Psychiatry 182:199–204

    Article  PubMed  CAS  Google Scholar 

  • Wilcox CS, Aminoff MJ, Millar JG, Keenan J, Kremer M (1975) Circulating levels of corticotrophin and cortisol after infusions of l-DOPA, dopamine and noradrenaline, in man. Clin Endocrinol (Oxf) 4:191–198

    CAS  Google Scholar 

  • Wolkowitz OM, Reus VI (1999) Treatment of depression with antiglucocorticoid drugs. Psychosom Med 61:698–711

    PubMed  CAS  Google Scholar 

  • Zerssen von D, Koeller DM (1976) Die Beschwerden-Liste (Manual). Klinische Selbstbeurteilungsskalen aus dem Muenchner Psychiatrischen Informationssystem (PSYCHIS). Beltz-Verlag, Beltz-Verlag

Download references

Acknowledgements

We are grateful to the dedicated staff of the Sleep Medicine Center of the Department of Psychiatry and Psychotherapy, University of Göttingen, Germany, including Roswitha Bianco, Iris Bossmann, Brigitte Marxen, and Andreas Müller-Struck.

Author information

Authors and Affiliations

  1. Department of Psychiatry and Psychotherapy, Georg-August University of Göttingen, von-Siebold Stra, β, e 5, 37075, Göttingen, Germany

    Stefan Cohrs, Cornelia Röher, Wolfgang Jordan, Andreas Meier, Gerald Huether, Eckart Rüther & Andrea Rodenbeck

  2. Department of Clinical and Experimental Endocrinology, University of Goettingen, Göettingen, Germany

    Wolfgang Wuttke

Authors
  1. Stefan Cohrs
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Cornelia Röher
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wolfgang Jordan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Andreas Meier
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Gerald Huether
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Wolfgang Wuttke
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Eckart Rüther
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Andrea Rodenbeck
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Stefan Cohrs.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cohrs, S., Röher, C., Jordan, W. et al. The atypical antipsychotics olanzapine and quetiapine, but not haloperidol, reduce ACTH and cortisol secretion in healthy subjects. Psychopharmacology 185, 11–18 (2006). https://doi.org/10.1007/s00213-005-0279-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-005-0279-x

Keywords

Search

Navigation