Effects of raloxifene on cognition in postmenopausal women with schizophrenia: a 24-week double-blind, randomized, parallel, placebo-controlled trial

  • Elena Huerta-RamosEmail author
  • Javier Labad
  • Jesus Cobo
  • Christian Núñez
  • Marta Creus
  • Gemma García-Parés
  • Daniel Cuadras
  • José Franco
  • Eva Miquel
  • Julio-César Reyes
  • Silvia Marcó-García
  • Judith Usall
Original Paper


We assessed the utility of raloxifene (60 mg/day) as an adjuvant treatment for cognitive symptoms in postmenopausal women with schizophrenia in a 24-week, double-blind, randomized, placebo-controlled study. Patients were recruited from the inpatient and outpatient services of Parc Sanitari Sant Joan de Déu, Hospital Universitari Institut Pere Mata, and Corporació Sanitària Parc Taulí. Seventy eight postmenopausal women with schizophrenia were randomized to either adjunctive raloxifene or placebo. Sixty-eight began the clinical trial (37 women on raloxifene adjunct) and 31 on placebo adjunct. The outcome measures were: memory, attention and executive function. Assessment was conducted at baseline and at week 24. Between groups homogeneity was tested with the Student's t test for continuous variables and/or the Mann–Whitney U test for ordinal variables and the χ2 test or Fisher's exact test for categorical variables. The differences between the two groups in neuropsychological test scores were compared using the Student's t test. The sample was homogenous with respect to age, formal education, illness duration and previous pharmacological treatment. The addition of raloxifene to antipsychotic treatment as usual showed no differences in cognitive function. The daily use of 60 mg raloxifene as an adjuvant treatment in postmenopausal women with schizophrenia has no appreciable effect. Identifier: NCT01573637.


Raloxifene Schizophrenia Cognition Clinical trial 



The Stanley Medical Research Institute (#10T-1392). The members of RALOPSYCAT Group are Carolina Rodríguez (nurse), Isabel Beneitez (psychiatrist), Joan Costa (clinician), Lourdes Castro (nurse), Silvia Teba (nurse), Laura Milian (nurse), Alexandrina Foix (nurse), Sonia Rivero (psychiatrist), Marian Cavero (psychiatrist), María Argemí (psychiatrist), Fernando Teba (psychiatrist), Belén Arranz (psychiatrist), Elena Rubio (psychiatrist), Marta Coromina (psychiatrist), Ángeles Santos (nurse), Jose Luis Bogas (nurse), Ana Barber (nurse), Carlota Romans (psychiatrist), Manel Márquez (psychiatrist), Anna Sabata (nurse), Lourdes Nieto (psychologist), Eva Willikens (psychologist), Enrich Blanch (nurse), Siddharta Acebillo (psychiatrist), Ramón Coronas (psychiatrist), Laura Ortega (nurse), Ignasi Coll (psychiatrist), Joaquín Valero (psychiatrist), Jesús Rodríguez (psychiatrist), Modesto Pérez (psychiatrist), Inés Niubó (psychiatrist), Montse Tost (psychologist), Mari Pau Monfort (pharmacist), Lourdes Martorell (biologist), Elisabet Vilella (biologist), Judith Usall (psychiatrist), Elena Huerta-Ramos (psychologist), Javier Labad (psychiatrist), Jesús Cobo (psychiatrist), Christian Núñez (psychologist), Marta Creus (psychologist), Gemma García-Parés (psychiatrist), Daniel Cuadras (statistical), José Franco (psychiatrist), Eva Miquel (pharmacist), Julio-César Reyes (psychiatrist), Mercedes Roca (psychiatrist).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.


  1. 1.
    Fioravanti M, Bianchi V, Cinti ME (2012) Cognitive deficits in schizophrenia: an updated metanalysis of the scientific evidence. BMC Psychiatry 12:64. CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Tandon R, Nasrallah HA, Keshavan MS (2010) Schizophrenia, “just the facts” 5. Treatment and prevention. Past, present, and future. Schizophr Res 122:1–23. CrossRefPubMedGoogle Scholar
  3. 3.
    Üçok A, Çakır S, Duman ZÇ et al (2006) Cognitive predictors of skill acquisition on social problem solving in patients with schizophrenia. Eur Arch Psychiatry Clin Neurosci 256:388–394. CrossRefPubMedGoogle Scholar
  4. 4.
    Soria V, González-Rodríguez A, Huerta-Ramos E et al (2018) Targeting hypothalamic-pituitary-adrenal axis hormones and sex steroids for improving cognition in major mood disorders and schizophrenia: a systematic review and narrative synthesis. Psychoneuroendocrinology. CrossRefPubMedGoogle Scholar
  5. 5.
    Audesirk T, Cabell L, Kern M, Audesirk G (2003) Beta-estradiol influences differentiation of hippocampal neurons in vitro through an estrogen receptor-mediated process. Neuroscience 121:927–934CrossRefPubMedGoogle Scholar
  6. 6.
    Ciriza I, Carrero P, Azcoitia I et al (2004) Selective estrogen receptor modulators protect hippocampal neurons from kainic acid excitotoxicity: differences with the effect of estradiol. J Neurobiol 61:209–221. CrossRefPubMedGoogle Scholar
  7. 7.
    Steinberg KK, Thacker SB, Smith SJ et al (1991) A meta-analysis of the effect of estrogen replacement therapy on the risk of breast cancer. JAMA 265:1985–1990CrossRefPubMedGoogle Scholar
  8. 8.
    Velázquez-Zamora DA, Garcia-Segura LM, González-Burgos I (2012) Effects of selective estrogen receptor modulators on allocentric working memory performance and on dendritic spines in medial prefrontal cortex pyramidal neurons of ovariectomized rats. Horm Behav 61:512–517. CrossRefPubMedGoogle Scholar
  9. 9.
    Goekoop R, Barkhof F, Duschek EJJ et al (2006) Raloxifene treatment enhances brain activation during recognition of familiar items: a pharmacological fMRI study in healthy elderly males. Neuropsychopharmacology. CrossRefPubMedGoogle Scholar
  10. 10.
    Wong J, Seeman MV, Shapiro H (2003) Case report: raloxifene in postmenopausal women with psychosis: preliminary findings. Am J Geriatr Psychiatry Off J Am Assoc Geriatr Psychiatry 11(697):698Google Scholar
  11. 11.
    Kulkarni J, Gurvich C, Gilbert H et al (2008) Hormone modulation: a novel therapeutic approach for women with severe mental illness. Aust N Z J Psychiatry 42:83–88. CrossRefPubMedGoogle Scholar
  12. 12.
    Huerta-Ramos E, Iniesta R, Ochoa S et al (2014) Effects of raloxifene on cognition in postmenopausal women with schizophrenia: a double-blind, randomized, placebo-controlled trial. Eur Neuropsychopharmacol 24:223–231CrossRefPubMedGoogle Scholar
  13. 13.
    Huerta-Ramos E, Ochoa S, Roca M et al (2015) The effect of raloxifene on symptoms and cognitive functioning in a postmenopausal schizophrenia patient: a case report. Arch Womens Ment Health 18:259–261. CrossRefPubMedGoogle Scholar
  14. 14.
    Weickert TW, Weinberg D, Lenroot R et al (2015) Adjunctive raloxifene treatment improves attention and memory in men and women with schizophrenia. Mol Psychiatry 20:685–694. CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Ji E, Weickert CS, Lenroot R et al (2016) Adjunctive selective estrogen receptor modulator increases neural activity in the hippocampus and inferior frontal gyrus during emotional face recognition in schizophrenia. Transl Psychiatry 6:e795. CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Kulkarni J, Gavrilidis E, Gwini SM et al (2016) Effect of adjunctive raloxifene therapy on severity of refractory schizophrenia in women: a randomized clinical trial. JAMA Psychiatry 73:947–954. CrossRefPubMedGoogle Scholar
  17. 17.
    Kindler J, Weickert CS, Schofield PR et al (2016) Raloxifene increases prefrontal activity during emotional inhibition in schizophrenia based on estrogen receptor genotype. Eur Neuropsychopharmacol J Eur Coll Neuropsychopharmacol 26:1930–1940. CrossRefGoogle Scholar
  18. 18.
    Weiser M, Levi L, Burshtein S et al (2017) Raloxifene plus antipsychotics versus placebo plus antipsychotics in severely ill decompensated postmenopausal women with schizophrenia or schizoaffective disorder. J Clin Psychiatry. CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    de Boer J, Prikken M, Lei WU et al (2018) The effect of raloxifene augmentation in men and women with a schizophrenia spectrum disorder: a systematic review and meta-analysis. NPJ Schizophrenia 4:1. CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Usall J, Huerta-Ramos E, Labad J et al (2016) Raloxifene as an adjunctive treatment for postmenopausal women with schizophrenia: a 24-week double-blind, randomized, parallel, placebo-controlled trial. Schizophr Bull 42:309–317. CrossRefPubMedGoogle Scholar
  21. 21.
    Labad J, Martorell L, Huerta-Ramos E et al (2016) Pharmacogenetic study of the effects of raloxifene on negative symptoms of postmenopausal women with schizophrenia: a double-blind, randomized, placebo-controlled trial. Eur Neuropsychopharmacol 26:1683–1689. CrossRefPubMedGoogle Scholar
  22. 22.
    Bieber E, Sanfilippo JS, Horowitz IR, MIS (2006) Clinical gynecology. Cambridge University Press, PhiladelphiaGoogle Scholar
  23. 23.
    JAVA (2013) Declaration of Helsinki World Medical Association Declaration of Helsinki. Bull World Health Organ 79:373–374Google Scholar
  24. 24.
    Usall J, Huerta-Ramos E, Labad J et al (2016) Raloxifene as an adjunctive treatment for postmenopausal women with schizophrenia: a 24-week double-blind, randomized, parallel, placebo-controlled trial. Schizophr Bull. CrossRefPubMedGoogle Scholar
  25. 25.
    Gardner DM, Murphy AL, O’Donnell H et al (2010) International consensus study of antipsychotic dosing. Am J Psychiatry 167:686–693. CrossRefPubMedGoogle Scholar
  26. 26.
    Kay SR, Fiszbein A, Opler LA (1987) The Positive and Negative Syndrome Scale (PANSS) for schizophrenia. Schizophr Bull 13:261–276CrossRefPubMedGoogle Scholar
  27. 27.
    Benedet MJ, Alexandre MA (1998) Test de Aprendizaje Verbal España-Complutense (TAVEC). TEA Ediciones, MadridGoogle Scholar
  28. 28.
    Moscovitch M, Umiltà C (1990) Modularity and neuropsychology: implications for the organization of attention and memory in normal and brain-damaged people. In: Schwartz MF (ed) Modular deficits in Alzheimer type dementia. MIT Press, CambridgeGoogle Scholar
  29. 29.
    Conners CK (2002) Conners’ Continuous Performance Test CPT-II. Technical Guide and Software Manual. Multi Health Systems, North Tonawanda, NYGoogle Scholar
  30. 30.
    Reitan R, Wolfson D (1995) Category test and Trail Making Test as measures of frontal lobe functions. Clin Neuropsychol 9:50–56CrossRefGoogle Scholar
  31. 31.
    Stroop JR (1935) Studies of interference in serial verbal reactions. J Exp Psychol 18:643–662CrossRefGoogle Scholar
  32. 32.
    Reeve WV, Schandler SL (2001) Frontal lobe functioning in adolescents with attention deficit hyperactivity disorder. Adolescence 36:749–765PubMedGoogle Scholar
  33. 33.
    Fisher LM, Freed DM, Corkin S (1990) Stroop Color-Word Test performance in patients with Alzheimer’s disease. J Clin Exp Neuropsychol 12:745–758. CrossRefPubMedGoogle Scholar
  34. 34.
    Seisdedos N, Corral S, Cordero A, de la Cruz MVH, Pereña JMV (1999) WAIS III. Manual Técnico. TEA Ediciones, MadridGoogle Scholar
  35. 35.
    Strauss E, Sherman EMS, Spreen O (2006) A compendium of neuropsychological tests: administration, norms, and commentary, 3rd edn. Oxford University Press, New YorkGoogle Scholar
  36. 36.
    Bender R, Lange S (2001) Adjusting for multiple testing–when and how? J Clin Epidemiol 54:343–349CrossRefPubMedGoogle Scholar
  37. 37.
    Lingjaerde O, Ahlfors UG, Bech P et al (1987) The UKU side effect rating scale. A new comprehensive rating scale for psychotropic drugs and a cross-sectional study of side effects in neuroleptic-treated patients. Acta Psychiatr Scand Suppl 334:1–100CrossRefPubMedGoogle Scholar
  38. 38.
    Iikuni N, Hamaya E, Nihojima S et al (2012) Safety and effectiveness profile of raloxifene in long-term, prospective, postmarketing surveillance. J Bone Miner Metab 30:674–682. CrossRefPubMedGoogle Scholar
  39. 39.
    Yang ZD, Yu J, Zhang Q (2013) Effects of raloxifene on cognition, mental health, sleep and sexual function in menopausal women: a systematic review of randomized controlled trials. Maturitas 75:341–348. CrossRefPubMedGoogle Scholar
  40. 40.
    Gurvich C, Hudaib A, Gavrilidis E et al (2019) Raloxifene as a treatment for cognition in women with schizophrenia: the influence of menopause status. Psychoneuroendocrinology 100:113–119. CrossRefPubMedGoogle Scholar
  41. 41.
    Yin W, Maguire SM, Pham B et al (2015) Testing the critical window hypothesis of timing and duration of estradiol treatment on hypothalamic gene networks in reproductively mature and aging female rats. Endocrinology. CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Vila È, Huerta-Ramos E, Núñez C et al (2018) Specificity proteins 1 and 4 in peripheral blood mononuclear cells in postmenopausal women with schizophrenia: a 24-week double-blind, randomized, parallel, placebo-controlled trial. Eur Arch Psychiatry Clin Neurosci. CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Elena Huerta-Ramos
    • 1
    • 2
    • 3
    • 4
    Email author
  • Javier Labad
    • 5
  • Jesus Cobo
    • 5
  • Christian Núñez
    • 1
    • 2
    • 4
  • Marta Creus
    • 6
  • Gemma García-Parés
    • 7
  • Daniel Cuadras
    • 1
    • 2
    • 4
  • José Franco
    • 6
  • Eva Miquel
    • 1
  • Julio-César Reyes
    • 6
  • Silvia Marcó-García
    • 1
    • 2
    • 4
  • Judith Usall
    • 1
    • 2
    • 3
    • 4
  1. 1.Parc Sanitari Sant Joan de DéuBarcelonaSpain
  2. 2.Fundació Sant Joan de DéuBarcelonaSpain
  3. 3.Instituto de Salud Carlos III, Centro de Investigación en Red de Salud Mental (CIBERSAM)MadridSpain
  4. 4.Institut de Recerca Sant Joan de DéuBarcelonaSpain
  5. 5.Corporació Sanitària Parc TaulíBarcelonaSpain
  6. 6.Institut Pere MataTarragonaSpain
  7. 7.Hospital Nostra Senyora de MeritxellEscaldes-EngordanyAndorra

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