Plasma prolactin levels are associated with the severity of illness in drug-naive first-episode psychosis female patients

  • Manuel Delgado-AlvaradoEmail author
  • Diana Tordesillas-Gutierrez
  • Rosa Ayesa-Arriola
  • Manuel Canal
  • Victor Ortiz-García de la Foz
  • Javier Labad
  • Benedicto Crespo-Facorro
Original Article


Patients with schizophrenia frequently present hyperprolactinemia as a consequence of antipsychotic treatment. However, an increase in circulating prolactin levels has also been shown in patients without previous treatment. Our objective was to compare prolactin levels between antipsychotic-naive first-episode psychosis (AN-FEP) patients and healthy controls (HC). As part of an FEP program (Programa Asistencial Fases Iniciales de Psicosis [PAFIP]), 270 AN-FEP patients and 153 HC were eligible for this study. Serum prolactin levels were measured by an automated immunochemiluminescent assay. Subjects’ sex and having an AN-FEP diagnosis both had an effect on prolactin levels, with higher levels in women than in men, and in AN-FEP patients than in HC. Moreover, plasma prolactin levels showed a negative correlation with the SAPS scores in AN-FEP female patients. AN-FEP patients have increased levels of prolactin, which might be stress-induced. This, together with the association of higher prolactin with a lower severity of the disease, suggests that prolactin might play a neuroprotective role, especially in women.


First-episode psychosis Prolactin Schizophrenia Women 



The authors wish to thank all PAFIP research team and all patients and family members who participated in the study.


This work was supported by Fundación Instituto de Investigación Marqués de Valdecilla (NCT0235832 and NCT02534363).

Compliance with ethical standards

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent was obtained from all individual participants included in the study.

Conflict of interest

M.D-A. held a Rio Hortega Research Grant from Instituto de Salud Carlos III. J.L. has received honoraria for lectures or advisory boards from Janssen, Otsuka, and Lundbeck. B. C.-F. received in the last 3 years research funding from Lundbeck that was deposited into research accounts at the CIBERSAM. B. C.-F. has received in the last 3 years honoraria for his participation as a speaker at educational events from Otsuka, Lundbeck, and Johnson & Johnson and has been a consultant and/or advisor to or has received honoraria from Alkermes, Lundbeck, Otsuka, Casen Recordati, and Teva. D. T.-G. declares that she has no conflict of interest. R. A.-A. declares that she has no conflict of interest. V. O.-G. declares that he has no conflict of interest.


  1. Addington D, Addington J, Maticka-Tyndale E (1993) Assessing depression in schizophrenia: the Calgary Depression Scale. Br J Psychiatry Suppl (22):39–44Google Scholar
  2. Akhondzadeh S, Rezaei F, Larijani B, Nejatisafa AA, Kashani L, Abbasi SH (2006) Correlation between testosterone, gonadotropins and prolactin and severity of negative symptoms in male patients with chronic schizophrenia. Schizophr Res 84(2–3):405–410CrossRefPubMedGoogle Scholar
  3. Albayrak Y, Beyazyuz M, Beyazyuz E, Kuloglu M (2014) Increased serum prolactin levels in drug-naive first-episode male patients with schizophrenia. Nord J Psychiatry 68(5):341–346CrossRefPubMedGoogle Scholar
  4. Andreasen N (1984) The Scale for the Assessment of Positive Symptoms (SAPS). The University of Iowa, Iowa City, pp 1–2Google Scholar
  5. Andreasen NC (1989) Scale for the Assessment of Negative Symptoms (SANS). Br J Psychiatry 155(Suppl 7):53–58Google Scholar
  6. Aston J, Rechsteiner E, Bull N, Borgwardt S, Gschwandtner U, Riecher-Rossler A (2010) Hyperprolactinaemia in early psychosis-not only due to antipsychotics. Prog Neuro-Psychopharmacol Biol Psychiatry 34(7):1342–1344CrossRefGoogle Scholar
  7. Baggaley M (2008) Sexual dysfunction in schizophrenia: focus on recent evidence. Hum Psychopharmacol 23(3):201–209CrossRefPubMedGoogle Scholar
  8. Cabrera-Reyes EA, Limon-Morales O, Rivero-Segura NA, Camacho-Arroyo I, Cerbon M (2017) Prolactin function and putative expression in the brain. Endocrine 57(2):199–213CrossRefPubMedGoogle Scholar
  9. Chatterjee SB (1988) Dopamine related hormone levels in acute schizophrenia: (a study of 84 patients). Indian J Psychiatry 30(1):7–11PubMedPubMedCentralGoogle Scholar
  10. Cookson JC, Silverstone T, Rees L (1982) Plasma prolactin and growth hormone levels in manic patients treated with pimozide. Br J Psychiatry 140:274–279CrossRefPubMedGoogle Scholar
  11. Crespo-Facorro B, Pelayo-Teran JM, Perez-Iglesias R, Ramirez-Bonilla M, Martinez-Garcia O, Pardo-Garcia G, Vazquez-Barquero JL (2007) Predictors of acute treatment response in patients with a first episode of non-affective psychosis: sociodemographics, premorbid and clinical variables. J Psychiatr Res 41(8):659–666CrossRefPubMedGoogle Scholar
  12. De Hert M, Detraux J, Stubbs B (2016) Relationship between antipsychotic medication, serum prolactin levels and osteoporosis/osteoporotic fractures in patients with schizophrenia: a critical literature review. Expert Opin Drug Saf 15(6):809–823CrossRefPubMedGoogle Scholar
  13. Duval F, Mokrani MC, Monreal J, Bailey P, Valdebenito M, Crocq MA, Macher JP (2003) Dopamine and serotonin function in untreated schizophrenia: clinical correlates of the apomorphine and d-fenfluramine tests. Psychoneuroendocrinology 28(5):627–642CrossRefPubMedGoogle Scholar
  14. Faron-Gorecka A, Kusmider M, Solich J, Kolasa M, Szafran K, Zurawek D, Pabian P, Dziedzicka-Wasylewska M (2013) Involvement of prolactin and somatostatin in depression and the mechanism of action of antidepressant drugs. Pharmacol Rep 65(6):1640–1646CrossRefPubMedGoogle Scholar
  15. Garcia-Rizo C, Fernandez-Egea E, Oliveira C, Justicia A, Parellada E, Bernardo M, Kirkpatrick B (2012) Prolactin concentrations in newly diagnosed, antipsychotic-naive patients with nonaffective psychosis. Schizophr Res 134(1):16–19CrossRefPubMedGoogle Scholar
  16. Grattan DR (2015) 60 years of neuroendocrinology: the hypothalamo-prolactin axis. J Endocrinol 226(2):T101–T122CrossRefPubMedPubMedCentralGoogle Scholar
  17. Grigg J, Worsley R, Thew C, Gurvich C, Thomas N, Kulkarni J (2017) Antipsychotic-induced hyperprolactinemia: synthesis of world-wide guidelines and integrated recommendations for assessment, management and future research. Psychopharmacology 234:3279–3297CrossRefPubMedGoogle Scholar
  18. Grube BS, Bilder RM, Goldman RS (1998) Meta-analysis of symptom factors in schizophrenia. Schizophr Res 31(2–3):113–120CrossRefPubMedGoogle Scholar
  19. Gudelsky GA, Nansel DD, Porter JC (1981) Role of estrogen in the dopaminergic control of prolactin secretion. Endocrinology 108(2):440–444CrossRefPubMedGoogle Scholar
  20. Haddad PM, Wieck A (2004) Antipsychotic-induced hyperprolactinaemia: mechanisms, clinical features and management. Drugs 64(20):2291–2314CrossRefPubMedGoogle Scholar
  21. Ittig S, Studerus E, Heitz U, Menghini-Muller S, Beck K, Egloff L, Leanza L, Andreou C, Riecher-Rossler A (2017) Sex differences in prolactin levels in emerging psychosis: indication for enhanced stress reactivity in women. Schizophr Res 189:111–116CrossRefPubMedGoogle Scholar
  22. Jaroenporn S, Nagaoka K, Kasahara C, Ohta R, Watanabe G, Taya K (2007) Physiological roles of prolactin in the adrenocortical response to acute restraint stress. Endocr J 54(5):703–711CrossRefPubMedGoogle Scholar
  23. Jimena P, Aguirre MA, Lopez-Curbelo A, de Andres M, Garcia-Courtay C, Cuadrado MJ (1998) Prolactin levels in patients with systemic lupus erythematosus: a case controlled study. Lupus 7(6):383–386CrossRefPubMedGoogle Scholar
  24. Jose J, Nandeesha H, Kattimani S, Meiyappan K, Sarkar S, Sivasankar D (2015) Association between prolactin and thyroid hormones with severity of psychopathology and suicide risk in drug free male schizophrenia. Clinica Chimica Acta 444:78–80CrossRefGoogle Scholar
  25. Keks NA, McKenzie DP, Low LH, McGorry PD, Hill C, Kulkarni J, Singh BS, Copolov DL (1992) Multidiagnostic evaluation of prolactin response to haloperidol challenge in schizophrenia: maximal blunting in Kraepelinian patients. Biol Psychiatry 32(5):426–437CrossRefPubMedGoogle Scholar
  26. Kirkpatrick B, Carpenter WT, Maeda K, Buchanan RW, Breier A, Tamminga CA (1992) Plasma prolactin as a predictor of relapse in drug-free schizophrenic outpatients. Biol Psychiatry 32(11):1049–1054CrossRefPubMedGoogle Scholar
  27. Kirschbaum C, Pirke KM, Hellhammer DH (1993) The ‘Trier Social Stress Test’--a tool for investigating psychobiological stress responses in a laboratory setting. Neuropsychobiology 28(1–2):76–81CrossRefPubMedGoogle Scholar
  28. Kleinman JE, Weinberger DR, Rogol AD, Bigelow LB, Klein ST, Gillin JC, Wyatt RJ (1982) Plasma prolactin concentrations and psychopathology in chronic schizophrenia. Arch Gen Psychiatry 39(6):655–657CrossRefPubMedGoogle Scholar
  29. Kuruvilla K, Kuruvilla A, Kanagasabapathy AS (1986) Serum prolactin levels in schizophrenia: effects of neuroleptic medication - a preliminary study. Indian J Psychiatry 28(3):237–241PubMedPubMedCentralGoogle Scholar
  30. Kuruvilla A, Srikrishna G, Peedicayil J, Kuruvilla K, Kanagasabapathy AS (1993) A study on serum prolactin levels in schizophrenia: correlation with positive and negative symptoms. Int Clin Psychopharmacol 8(3):177–179CrossRefPubMedGoogle Scholar
  31. Labad J, Stojanovic-Perez A, Montalvo I, Sole M, Cabezas A, Ortega L, Moreno I, Vilella E, Martorell L, Reynolds RM, Gutierrez-Zotes A (2015) Stress biomarkers as predictors of transition to psychosis in at-risk mental states: roles for cortisol, prolactin and albumin. J Psychiatr Res 60:163–169CrossRefPubMedGoogle Scholar
  32. Lally J, Ajnakina O, Stubbs B, Williams HR, Colizzi M, Carra E, Fraietta S, Gardner-Sood P, Greenwood KE, Atakan Z, Mondelli V, Ismail K, Howes O, Taylor DM, Smith S, Hopkins D, Murray RM, Gaughran F (2017) Hyperprolactinaemia in first episode psychosis - a longitudinal assessment. Schizophr Res 189:117–125CrossRefPubMedGoogle Scholar
  33. Lennartsson AK, Jonsdottir IH (2011) Prolactin in response to acute psychosocial stress in healthy men and women. Psychoneuroendocrinology 36(10):1530–1539CrossRefPubMedGoogle Scholar
  34. Lindheim SR, Legro RS, Bernstein L, Stanczyk FZ, Vijod MA, Presser SC, Lobo RA (1992) Behavioral stress responses in premenopausal and postmenopausal women and the effects of estrogen. Am J Obstet Gynecol 167(6):1831–1836CrossRefPubMedGoogle Scholar
  35. Maeda K, Kato Y, Ohgo S, Chihara K, Yoshimoto Y, Yamaguchi N, Kuromaru S, Imura H (1975) Growth hormone and prolactin release after injection of thyrotropin-releasing hormone in patients with depression. J Clin Endocrinol Metab 40(3):501–505CrossRefPubMedGoogle Scholar
  36. Marano RJ, Ben-Jonathan N (2014) Minireview: extrapituitary prolactin: an update on the distribution, regulation, and functions. Mol Endocrinol 28(5):622–633CrossRefPubMedPubMedCentralGoogle Scholar
  37. 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(3):278–290CrossRefPubMedGoogle Scholar
  38. Morales T (2011) Recent findings on neuroprotection against excitotoxicity in the hippocampus of female rats. J Neuroendocrinol 23(11):994–1001CrossRefPubMedGoogle Scholar
  39. Nicholas L, Dawkins K, Golden RN (1998) Psychoneuroendocrinology of depression. Prolactin Psychiatr Clin North Am 21(2):341–358CrossRefPubMedGoogle Scholar
  40. Nordstrom AL, Farde L (1998) Plasma prolactin and central D2 receptor occupancy in antipsychotic drug-treated patients. J Clin Psychopharmacol 18(4):305–310CrossRefPubMedGoogle Scholar
  41. Otani K, Kondo T, Ishida M, Tanaka O, Yasui N, Suzuki A, Kaneko S (1996) Plasma prolactin concentration and psychopathology of schizophrenia. Prog Neuro-Psychopharmacol Biol Psychiatry 20(8):1369–1374CrossRefGoogle Scholar
  42. Patil MJ, Henry MA, Akopian AN (2014) Prolactin receptor in regulation of neuronal excitability and channels. Channels (Austin) 8(3):193–202CrossRefGoogle Scholar
  43. Petrikis P, Tigas S, Tzallas AT, Archimandriti DT, Skapinakis P, Mavreas V (2016) Prolactin levels in drug-naive patients with schizophrenia and other psychotic disorders. Int J Psychiatry Clin Pract 20(3):165–169CrossRefPubMedGoogle Scholar
  44. Riecher-Rossler A, Rybakowski JK, Pflueger MO, Beyrau R, Kahn RS, Malik P, Fleischhacker WW, Group, E.S (2013) Hyperprolactinemia in antipsychotic-naive patients with first-episode psychosis. Psychol Med 43(12):2571–2582CrossRefPubMedGoogle Scholar
  45. Rodrigues R, Anderson KK (2017) The traumatic experience of first-episode psychosis: a systematic review and meta-analysis. Schizophr Res 189:27–36CrossRefPubMedGoogle Scholar
  46. Shrivastava A, Johnston M, Bureau Y, Shah N (2012) Baseline serum prolactin in drug-naive, first-episode schizophrenia and outcome at five years: is it a predictive factor? Innov Clin Neurosci 9(4):17–21PubMedPubMedCentralGoogle Scholar
  47. Spoov J, Bredbacka PE, Stenman UH (2010) An abnormal relation between basal prolactin levels and prolactin response to 12.5 microg TRH i.v. in drug-naive patients with first-episode schizophrenia. Schizophr Res 119(1–3):41–46CrossRefPubMedGoogle Scholar
  48. Torner L (2016) Actions of prolactin in the brain: from physiological adaptations to stress and neurogenesis to psychopathology. Front Endocrinol (Lausanne) 7:25Google Scholar
  49. Torner L, Karg S, Blume A, Kandasamy M, Kuhn HG, Winkler J, Aigner L, Neumann ID (2009) Prolactin prevents chronic stress-induced decrease of adult hippocampal neurogenesis and promotes neuronal fate. J Neurosci 29(6):1826–1833CrossRefPubMedGoogle Scholar
  50. Traustadottir T, Bosch PR, Matt KS (2005) The HPA axis response to stress in women: effects of aging and fitness. Psychoneuroendocrinology 30(4):392–402CrossRefPubMedGoogle Scholar
  51. Villada C, Espin L, Hidalgo V, Rubagotti S, Sgoifo A, Salvador A (2017) The influence of coping strategies and behavior on the physiological response to social stress in women: the role of age and menstrual cycle phase. Physiol Behav 170:37–46CrossRefPubMedGoogle Scholar
  52. Winning S (2002) Hyperprolactinaemia caused by antipsychotic drugs. Physical complications of mental illness must be remembered. BMJ 324(7348):1278CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Austria, part of Springer Nature 2018

Authors and Affiliations

  • Manuel Delgado-Alvarado
    • 1
    • 2
    • 3
    Email author
  • Diana Tordesillas-Gutierrez
    • 1
    • 2
    • 4
  • Rosa Ayesa-Arriola
    • 1
    • 4
  • Manuel Canal
    • 1
    • 2
  • Victor Ortiz-García de la Foz
    • 1
  • Javier Labad
    • 2
    • 5
  • Benedicto Crespo-Facorro
    • 1
    • 2
    • 4
  1. 1.Psychiatry AreaIDIVAL Research InstituteSantanderSpain
  2. 2.Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM)MadridSpain
  3. 3.Department of NeurologySierrallana HospitalTorrelavegaSpain
  4. 4.Department of Psychiatry, University Hospital Marqués de Valdecilla, School of MedicineUniversity of CantabriaSantanderSpain
  5. 5.Department of Mental HealthParc Taulí Hospital UniversitariSabadellSpain

Personalised recommendations