CNS Drugs

, Volume 10, Issue 3, pp 209–222 | Cite as

Hyperprolactinaemia in Antipsychotic-Treated Patients

  • Mark B. Hamner
  • George W. Arana
Adverse Effects


Elevated prolactin (PRL) levels have been considered virtually unavoidable in most patients treated with therapeutic doses of traditional antipsychotics. Clinical effects of such hyperprolactinaemia may include amenorrhoea, galactorrhoea and sexual dysfunction. For clinical symptoms, the management has involved minimising the dosage or the use of a PRL-lowering agent.

A number of criteria have been advanced to define the novel or ‘atypical’ antipsychotic agents. These include a lower propensity to induce extrapyramidal adverse effects, improved efficacy against negative symptoms and treatment-resistant schizophrenia, and no sustained, or a lesser, effect on PRL levels. The new antipsychotics are less likely to produce a sustained elevation of PRL levels and therefore offer potential options in the treatment of patients with antipsychotic-induced hyperprolactinaemia.

This article compares data from preclinical and clinical studies of the effects of these newer agents on plasma PRL levels (PRLP). There is clear evidence that PRL release from the pituitary is regulated by dopamine, with more recent findings suggesting that serotonin (5-hydroxytryptamine; 5-HT), vasoactive intestinal peptide (VIP) and some other neurotransmitters also affect the release of PRL. Hyperprolactinaemia (>20 μg/L) is a well known effect of traditional antipsychotic medications due to dopamine receptor antagonism. Clinical symptoms of hyperprolactinaemia may include amenorrhoea, galactorrhoea, sexual dysfunction, infertility, obesity and hirsutism. Certain of the novel antipsychotics including clozapine, quetiapine and possibly sertindole, have little or no effect on PRL secretion and do not cause hyperprolactinaemia or the associated clinical symptoms. Risperidone and possibly olanzapine and ziprasidone appear to cause some dose-related PRL elevation, especially early in the course of treatment. However, the clinical significance is unclear especially if appropriate therapeutic doses are used. Novel antipsychotics offer a distinct advantage over the traditional compounds with regard to PRL release and should be the treatment of choice for patients in whom hyperprolactinaemia is contraindicated.


Adis International Limited Haloperidol Clozapine Risperidone Olanzapine 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Daniels GH, Martin JB. Neuroendocrine regulation and diseases of the anterior pituitary and hypothalamus. In: Wilson JD, Braunwald E, Isselbecherk J, et al., editors. Harrison’s principles of internal medicine. New York: McGraw-Hill, 1995Google Scholar
  2. 2.
    Arana GW, Boyd AE, Reichlin S, et al. Prolactin levels in mild depression. Psychosom Med 1977; 39: 193–6PubMedGoogle Scholar
  3. 3.
    Mangurian LP, Walsh RJ, Posner BI. Prolactin enhancement of its own uptake at the choroid plexus. Endocrinology 1992; 131(2): 698–702PubMedCrossRefGoogle Scholar
  4. 4.
    Maes M, Meltzer M. The serotonin hypothesis of major depression. In: Bloom FE, Kupfer DJ, editors. Psychopharmacology: the fourth generation of progress. New York: Raven Press, 1995: 933–4Google Scholar
  5. 5.
    Signs SA, Bing L, Wolford J, et al. Serotonergic involvement in the regulation of prolactin and vasoactive intestinal peptide mRNA expression in the rat anterior pituitary. Mol Cell Endocrinol 1994; 105: 183–91PubMedCrossRefGoogle Scholar
  6. 6.
    Flores CM, Hulihan-Giblin BA, Hornby PJ, et al. Partial characterization of a neurotransmitter pathway regulating the in vivo release of prolactin. Neuroendocrinology 1992; 55: 519–28PubMedCrossRefGoogle Scholar
  7. 7.
    Meltzer HY, Matsubara S, Lee JC. The ratios of serotonin and dopamine2 affinities differentiate atypical and typical anti-psychotic drugs. Psychopharmacol Bull 1989; 25: 390–2PubMedGoogle Scholar
  8. 8.
    Meltzer HY, Nash JF. Effects of antipsychotic drugs on serotonin receptors. Pharmacol Rev 1991; 43: 587–604PubMedGoogle Scholar
  9. 9.
    Meltzer HY, Fang VS. Effect of neuroleptics on serum prolactin in schizophrenic patients. Arch Gen Psychiatry 1976; 33: 279–86PubMedCrossRefGoogle Scholar
  10. 10.
    Marken PA, Haykal RF, Fisher JN. Management of psychotropic-induced hyperprolactinemia. Clin Pharm 1992; 11: 851–6PubMedGoogle Scholar
  11. 11.
    Goebel S, Dietrich M, Jarry H, et al. Indirect evidence to suggest that prolactin mediates the adrenal action of haloperidol to stimulate aldosterone and corticosterone secretion in rats. Endocrinology 1992; 139(2): 914–9CrossRefGoogle Scholar
  12. 12.
    Klibanski A, Need RM, Beitins IZ, et al. Decreased bone density in hyperprolactinemic women. N Engl J Med 1980; Dec 26: 1511-4Google Scholar
  13. 13.
    Halbreich U, Palter S. Accelerated osteoporosis in psychiatric patients: possible pathophysiological processes. Schizophr Bull 1996; 22(3): 447–54PubMedCrossRefGoogle Scholar
  14. 14.
    Schyve P, Smithline F, Meltzer HY. Neuroleptic-induced prolactin elevation and breast cancer: an emerging clinical issue. Arch Gen Psychiatry 1978; 25: 1291–301CrossRefGoogle Scholar
  15. 15.
    Wang DY, Stepniewska KA, Allen DS, et al. Serum prolactin levels and their relationship to survival in women with operable breast cancer. J Clin Epidemiol 1995; 48(7): 959–68PubMedCrossRefGoogle Scholar
  16. 16.
    Adams JB. Human breast cancer: concerted role of diet, prolactin and adrenal C195-steroids in tumorigenesis. Int J Cancer 1992; 50: 854–8PubMedCrossRefGoogle Scholar
  17. 17.
    Halbreich U, Shen J, Panaro V. Are chronic psychiatric patients at increased risk for developing breast cancer? Am J Psychiatry 1996; 153(4): 559–60PubMedGoogle Scholar
  18. 18.
    Windgassen K, Wesselmann U, Schulze-Mönking H. Galactorrhea and hyperprolactinemia in schizophrenia patients on neuroleptics: frequency and etiology. Neuropsychobiology 1996; 33: 142–6PubMedCrossRefGoogle Scholar
  19. 19.
    Wesselmann U, Windgassen J. Galactorrhea: subjective response by schizophrenic patients. Acta Psychiatr Scand 1995; 91: 152–5PubMedCrossRefGoogle Scholar
  20. 20.
    Zito JM, Sofair JB, Jaeger J. Self-reported neuroendocrine effects of antipsychotics in women: a pilot study. Ann Pharmacother 1990; 24: 176–80Google Scholar
  21. 21.
    Meltzer HY. Effect of psychotropic drugs on neuroendocrine function. Psychiatr Clin North Am 1980; 3: 277–98Google Scholar
  22. 22.
    Beaumont PJV, Gelder MG. The effects of phenothiazines on endocrine function: I. Patients with inappropriate lactation and amenorrhoea. Br J Psychiatry 1974; 124: 413–9CrossRefGoogle Scholar
  23. 23.
    Green AI, Brown WA. Prolactin and neuroleptic drugs. Neurol Clin 1988; 6(1): 213–23PubMedGoogle Scholar
  24. 24.
    Van Putten T, Marder SR, Mintz J. Serum prolactin as a correlate of clinical response to haloperidol. J Clin Psychopharmacol 1991; 11(6): 357–61PubMedCrossRefGoogle Scholar
  25. 25.
    Meltzer HY, Daniels S, Fang VS. Clozapine increases rat serum prolactin levels. Life Sci 1975; 17: 339–42PubMedCrossRefGoogle Scholar
  26. 26.
    Meltzer HY, Goode DJ, Schyve PM, et al. Effect of clozapine on human serum prolactin levels. Am J Psychiatry 1979; 136: 1550–5PubMedGoogle Scholar
  27. 27.
    Kane J, Honigfeld G, Singer J, et al. Clozapine for the treatment-resistant schizophrenic: a double-blind comparison with chlorpromazine. Arch Gen Psychiatry 1988; 45: 789–96PubMedCrossRefGoogle Scholar
  28. 28.
    Baldessarini RJ, Frankenburg FR. Clozapine: a novel antipsychotic agent. N Engl J Med 1991; 324(11): 746–54PubMedCrossRefGoogle Scholar
  29. 29.
    Sachar EJ, Gruen PH, Altman N, et al. Use of neuroendocrine techniques in psychopharmacological research. In: Sachar EJ, editor. Hormones, behavior, and psychopathology. New York: Raven Press, 1976: 161–7Google Scholar
  30. 30.
    Nair NPV, Lal S, Cervantes P, et al. Effect of clozapine on apomorphine-induced growth hormone secretion and serum prolactin concentrations in schizophrenia. Neuropsychobiology 1979; 5: 136–42PubMedCrossRefGoogle Scholar
  31. 31.
    Szymanski S, Lieberman J, Pollack S, et al. Clozapine effects on neuroendocrine response to apomorphine challenge testing in chronic neuroleptic nonresponsive schizophrenia: preliminary findings. Biol Psychiatry 1995; 37: 52–5PubMedCrossRefGoogle Scholar
  32. 32.
    Owen RR, Gutierrez-Esteinou R, Hsiao J, et al. Effects of clozapine and fluphenazine treatment on responses to m-chlorophenylpiperazine infusions in schizophrenia. Arch Gen Psychiatry 1993; 50: 636–44PubMedCrossRefGoogle Scholar
  33. 33.
    American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 3rd ed, rev. Washington, DC: American Psychiatric Association, 1987Google Scholar
  34. 34.
    Lee HS, Kim CH, Song DH, et al. Clozapine does not elevate serum prolactin levels in healthy men. Biol Psychiatry 1995; 38: 762–4PubMedCrossRefGoogle Scholar
  35. 35.
    Gudelsky GA, Meltzer HY. Activation of tuberoinfundibular neurons following the acute administration of atypical anti-psychotics. Neuropsychopharmacology 1989; 2: 45–51PubMedCrossRefGoogle Scholar
  36. 36.
    Meltzer HY, Maes M, Lee MA. The cimetidine-induced increase in prolactin secretion in schizophrenia: effect of clozapine. Psychopharmacology 1993; 112: S95–104PubMedCrossRefGoogle Scholar
  37. 37.
    Bowden CR, Voina SJ, Woestenborghs R, et al. Stimulation by risperidone of rat prolactin secretion in vivo and in cultured pituitary cells in vivo. J Pharmacol Exp Ther 1992; 262: 699–706PubMedGoogle Scholar
  38. 38.
    Huang M-L, Van Peer A, Woestenborghs R, et al. Pharmacokinetics of the novel antipsychotic agent risperidone and the prolactin response in healthy subjects. Clin Pharmacol Ther 1993; 54(3): 257–68PubMedCrossRefGoogle Scholar
  39. 39.
    Otton SV, Schadel M, Cheung SW, et al. CYP2D6 phenotype determines the metabolic conversion of hydrocodone to hydromorphone. Clin Pharmacol Ther 1993; 54: 463–72PubMedCrossRefGoogle Scholar
  40. 40.
    Dickson RA, Dalby JT, Williams R, et al. Risperidone-induced prolactin elevations in premenopausal women with schizophrenia. Am J Psychiatry 1995 Jul; 152: 1102–3PubMedGoogle Scholar
  41. 41.
    Peuskens J. Risperidone in the treatment of patients with chronic schizophrenia: a multinational, multicentre, double-blind, parallel-group study versus haloperidol. Br J Psychiatry 1995; 166: 712–26PubMedCrossRefGoogle Scholar
  42. 42.
    Chouinard G, Jones B, Remington G, et al. A Canadian multi-center placebo-controlled study of fixed doses of risperidone and haloperidol in the treatment of chronic schizophrenic patients. J Clin Psychopharmacol 1993; 13(1): 25–40PubMedCrossRefGoogle Scholar
  43. 43.
    Marder SR, Meibach RC. Risperidone in the treatment of schizophrenia. Am J Psychiatry 1994; 151: 825–35PubMedGoogle Scholar
  44. 44.
    Kleinberg DL, Brecher M, Davis JM. Prolactin levels and adverse events in patients treated with risperidone. 6th World Congress of Biological Psychiatry; 1997 Jun 22–27; NiceGoogle Scholar
  45. 45.
    Bymaster FP, Calligaro DO, Falcone JF, et al. Radioreceptor binding profile of the atypical antipsychotic olanzapine. Neuropsychopharmacology 1996; 120: 67–74Google Scholar
  46. 46.
    Nyberg S, Farde L, Halldin C. A PET study of 5-HT2 and D2 dopamine receptor occupancy induced by olanzapine in healthy subjects. Neuropsychopharmacology 1997; 16: 1–7PubMedCrossRefGoogle Scholar
  47. 47.
    Beasley C, Tollefson G, Tran P, et al. Olanzapine versus placebo and haloperidol: acute phase results of the North American double-blind olanzapine trial. Neuropsychopharmacology 1996; 14: 111–23PubMedCrossRefGoogle Scholar
  48. 48.
    Crawford AMK, Beasley Jr CM, Tollefson GD. The acute and long-term effect of olanzapine compared with placebo and haloperidol on serum prolactin concentrations. Schizophr Res 1997; 26: 41–54PubMedCrossRefGoogle Scholar
  49. 49.
    Tollefson GD, Beasley CM, Tran PV, et al. Olanzapine versus haloperidol in the treatment of schizophrenia and schizoaffective and schizophreniform disorders: results of an international collaborative trial. Am J Psychiatry 1997; 154(4): 457–65PubMedGoogle Scholar
  50. 50.
    Sailer CR, Salama AI. Seroquel: biochemical profile of a potential atypical antipsychotic. Psychopharmacology 1993: 112: 285–92CrossRefGoogle Scholar
  51. 51.
    Goldstein JM. Preclinical profile of Seroquel (quetiapine): an atypical antipsychotic with clozapine-like pharmacology. In: Holliday SG, Ancill RJ, MacEwan GW, editors. Schizophrenia: breaking down the barrier. New York: John Wiley & Sons, 1996: 209–36Google Scholar
  52. 52.
    Wetzel H, Szegedi A, Hain Ch, et al. 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 1995; 119: 231–8PubMedCrossRefGoogle Scholar
  53. 53.
    Hamner MB, Arvanitis L, Miller B, et al. Plasma prolactin in schizophrenic subjects treated with Seroquel™ (ICI 204,636). Psychopharmacol Bull 1996; 32: 107–10PubMedGoogle Scholar
  54. 54.
    Hamner MB, Arvanitis LA, Miller BG, et al. Plasma prolactin in schizophrenic patients treated with Seroquel. Biol Psychiatry 1995; 37: 683CrossRefGoogle Scholar
  55. 55.
    Arvanitis LA. Clinical profile of Seroquel™ (quetiapine): an overview of recent clinical studies. In: Holliday SG, Ancill RJ, MacEwan GW, editors. Schizophrenia: breaking down the barrier. New York: John Wiley & Sons, 1996: 209–36Google Scholar
  56. 56.
    Small JG, Hirsch SR, Arvanitis LA, et al. Quetiapine in patients with schizophrenia: a high- and low-dose double-blind comparison with placebo. Arch Gen Psychiatry 1997; 54: 549–57PubMedCrossRefGoogle Scholar
  57. 57.
    Arvanitis LA, Miller BG, Seroquel 13 Study Group. Multiple fixed doses of ‘Seroquel’ (quetiapine) in patients with acute exacerbation of schizophrenia: a comparison with haloperidol and placebo. Biol Psychiatry 1997; 42: 233–46PubMedCrossRefGoogle Scholar
  58. 58.
    Goldstein JM, Arvanitis LA, Cantillon M. Low incidence of reproductive/hormonal side effects with ‘Seroquel’ (quetiapine fumarate) is supported by its lack of elevation of plasma prolactin concentrations. 36th Annual Meeting of the American College of Neuropsychopharmacology: 1997 Dec: HonoluluGoogle Scholar
  59. 59.
    Skarsfeldt T. Electrophysiological profile of the new atypical neuroleptic, sertindole, on midbrain dopamine neurones in rats: acute and repeated treatment. Synapse 1992; 10: 25–33PubMedCrossRefGoogle Scholar
  60. 60.
    van Kammen DP, McEvoy JP, Targum SD, et al. A randomized, controlled, dose-ranging trial of sertindole in patients with schizophrenia. Psychopharmacology 1996; 124: 168–75PubMedCrossRefGoogle Scholar
  61. 61.
    Seeger TF, Seymor PA, Schmidt AW, et al. Ziprasidone (CP-88,059): a new antipsychotic with combined dopamine and serotonin receptor antagonist activity. J Pharmacol Exp Ther 1995; 275: 101–13PubMedGoogle Scholar
  62. 62.
    Bench CJ, Lammerstma AA, Grasby PM, et al. The time course of binding to striatal dopamine D2 receptors by the neuroleptic ziprasidone (CP-88, 059-01) determined by positron emission tomography. Psychopharmacology 1996; 124: 141–7PubMedCrossRefGoogle Scholar
  63. 63.
    Beaumont P, Bruwer J, Pimstone P, et al. Bromo-ergocryptine in the treatment of phenothiazine-induced galactorrhea. Br J Psychiatry 1975; 126: 285–8CrossRefGoogle Scholar
  64. 64.
    Dorevitch A, Aronzon R, Stark M. Psychotic exacerbation attributed to low-dose bromocriptine treatment of galactorrhea and hyperprolactinemia. Acta Obstet Gynaecol Scand 1991; 70(4–5): 375–6CrossRefGoogle Scholar
  65. 65.
    Webster J, Piscitelli G, Polli A, et al. A comparison of cabergo-line and bromocriptine in the treatment of hyperprolactinemic amenorrhea. N Engl J Med 1994 Oct 6; 331(14): 904–9PubMedCrossRefGoogle Scholar
  66. 66.
    Correa N, Opler LA, Kay SR. Amantadine in the treatment of neuroendocrine side effects of neuroleptics. J Clin Psychopharmacol 1987; 7: 91–5PubMedCrossRefGoogle Scholar
  67. 67.
    Siever LJ. The effect of amantadine on prolactin levels and galactorrhea in neuroleptic-treated patients. J Clin Psychopharmacol 1981; 1: 2–7PubMedCrossRefGoogle Scholar
  68. 68.
    Physician’s desk reference. Montvale (NJ): Medical Economics Company, 1998Google Scholar
  69. 69.
    Yamada K, Kanba S, Murata T, et al. Effectiveness of shakuyaku-kanzo-to in neuroleptic-induced hyperprolactinemia: a preliminary report. Psychiatry Clin Neurosci 1996; 50: 341–2PubMedCrossRefGoogle Scholar

Copyright information

© Adis International Limited 1998

Authors and Affiliations

  1. 1.Department of Psychiatry and Behavioral SciencesMedical University of South Carolina, and the Ralph H. Johnson Department of Veterans Affairs Medical CenterCharlestonUSA

Personalised recommendations