Abstract
The aim of this study is to meta-analytically assess the efficacy and safety of adjunctive raloxifene for postmenopausal women with schizophrenia. Six studies with 440 patients, including 225 (51.14%) patients on raloxifene and 215 (48.86%) on placebo who completed 13.71 ± 5.09 weeks of treatment, were included in this study. Meta-analysis of Positive and Negative Syndrome Scale total scores and positive, negative, and general symptom scores [standard mean difference (SMD) −0.22 to −0.55, 95% confidence interval (CI) −1.01 to −0.02, p = 0.04–0.01; I 2 = 74–79%] revealed an advantage of adjunctive raloxifene treatment over placebo treatment. There was no significant difference regarding discontinuation rate [risk ratio (RR) = 1.38, p = 0.51] and adverse drug reactions (RR = 1.27, p = 0.57) between the two groups. This meta-analysis showed that adjunctive raloxifene appears to be efficacious and safe for postmenopausal women with schizophrenia. Moreover, raloxifene may be efficacious for patients with less severe symptoms. Future studies with a large sample size are needed to confirm these findings.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Alderson P, Green S, Higgins JPT (2004) Cochrane Reviewers’ Handbook 4.2.2 [updated march 2004]. John Wiley & Sons, Ltd, Chichester
Balshem H, Helfand M, Schünemann HJ, Oxman AD, Kunz R, Brozek J, Vist GE, Falckytter Y, Meerpohl J, Norris S (2011) GRADE guidelines: 3. Rating the quality of evidence. J Clin Epidemiol 64:401–413. https://doi.org/10.1016/j.jclinepi.2010.07.015
Bethea CL, Mirkes SJ, Shively CA, Adams MR (2000) Steroid regulation of tryptophan hydroxylase protein in the dorsal raphe of macaques. Biol Psychiatry 47:562–576. https://doi.org/10.1016/S0006-3223(99)00156-0
Bratek A, Krysta K, Drzyzga K, Barańska J, Kucia K (2016) The role of selective estrogen receptor modulators in the treatment of schizophrenia. Psychiatr Danub 28:45–48
Cariagamartinez A, Saizruiz J, Alelúpaz R (2016) From linkage studies to epigenetics: what we know and what we need to know in the neurobiology of schizophrenia. Front Neurosci 10:202. https://doi.org/10.3389/fnins.2016.00202
Chua WL, de Izquierdo SA, Kulkarni J, Mortimer A (2005) Estrogen for schizophrenia. Cochrane Database Syst Rev 4:CD004719
Corson SL (2009) Breast cancer after use of estrogen plus progestin in postmenopausal women. N Engl J Med 360:573–587. https://doi.org/10.1056/NEJMoa0807684
Davies GC, Huster WJ, Lu Y, Plouffer L, Lakshmanan M (1994) Adverse events reported by postmenopausal women in controlled trials with raloxifene. Obstet Gynecol 93:558–565. https://doi.org/10.1016/S0029-7844(98)00476-1
Di PT (1994) Modulation of brain dopamine transmission by sex steroids. Rev Neurosci 5:27–41. https://doi.org/10.1515/REVNEURO.1994.5.1.27
Fink G, Sumner BE, Rosie R, Grace O, Quinn JP (1996) Estrogen control of central neurotransmission: effect on mood, mental state, and memory. Cell Mol Neurobiol 16:325–344. https://doi.org/10.1007/BF02088099
Gilda Kianimehr FF, Hashempoor S, Khodaei-Ardakani M-R, Rezaei F, Nazari A, Kashani L, Akhondzadeh S (2014) Raloxifene adjunctive therapy for postmenopausal women suffering from chronic schizophrenia: a randomized double-blind and placebo controlled trial. DARU Journal of Pharmaceutical Sciences 22:55–62. https://doi.org/10.1186/2008-2231-22-55
Green S (2008) Cochrane handbook for systematic reviews of interventions: Cochrane book series. Naunyn-Schmiedeberg's Arch Exp Pathol Pharmakol 5:S38. https://doi.org/10.1002/9780470712184
Heringa SM, Begemann MJ, Goverde AJ, Sommer IE (2015) Sex hormones and oxytocin augmentation strategies in schizophrenia: a quantitative review. Schizophr Res 168:603–613. https://doi.org/10.1016/j.schres.2015.04.002
Higgins JP, Green S (2008) Cochrane handbook for systematic reviews of interventions: Cochrane book series. Wiley-Blackwell, Hoboken, pp 102–108. https://doi.org/10.1002/9780470712184
Holsen LM, Spaeth SB, Lee JH, Ogden LA, Klibanski A, Whitfield-Gabrieli S, Goldstein JM (2010) Stress response circuitry hypoactivation related to hormonal dysfunction in women with major depression. J Affect Disord 131:379–387. https://doi.org/10.1016/j.jad.2010.11.024
Hu RJ (2003) Diagnostic and statistical manual of mental disorders ( DSM-IV ). Encyclopedia of the Neurological Sciences 35:4–8. https://doi.org/10.1016/B0-12-226870-9/01070-4
Huber TJ, Rollnik J, Wilhelms J, Von ZMA, Emrich HM, Schneider U (2001) Estradiol levels in psychotic disorders. Psychoneuroendocrinology 26:27–35. https://doi.org/10.1016/S0306-4530(00)00034-2
Huertaramos E, Iniesta R, Ochoa S, Cobo J, Miquel E, Roca M, Serranoblanco A, Teba F, Usall J (2014) Effects of raloxifene on cognition in postmenopausal women with schizophrenia: a double-blind, randomized, placebo-controlled trial. European Neuropsychopharmacology the Journal of the European College of Neuropsychopharmacology 24:223–231. https://doi.org/10.1016/j.euroneuro.2013.11.012
Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, Mcquay HJ (1996) Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 17:1–12. https://doi.org/10.1016/0197-2456(95)00134-4
Jarkova NB, Martenyi F, Masanauskaite D, Walls EL, Smetnik VP, Pavo I (2002) Mood effect of raloxifene in postmenopausal women. Maturitas 42:71–75. https://doi.org/10.1016/S0378-5122(01)00303-6
Khan MM (2016) Neurocognitive, neuroprotective, and cardiometabolic effects of raloxifene: potential for improving therapeutic outcomes in schizophrenia. CNS Drugs 30:589–601. https://doi.org/10.1007/s40263-016-0343-6
Khodaie-Ardakani MR, Khosravi M, Zarinfard R, Nejati S, Mohsenian A, Tabrizi M, Akhondzadeh S (2015) A placebo-controlled study of raloxifene added to risperidone in men with chronic schizophrenia. Acta Medica Iranica 53:337–345
Kindler J, Weickert CS, Skilleter AJ, Catts SV, Lenroot R, Weickert TW (2015) Selective estrogen receptor modulation increases hippocampal activity during probabilistic association learning in schizophrenia. Neuropsychopharmacology Official Publication of the American College of Neuropsychopharmacology 40:2388–2397. https://doi.org/10.1038/npp.2015.88
Kindler J, Weickert CS, Schofield PR, Lenroot R, Weickert TW (2016) Raloxifene increases prefrontal activity during emotional inhibition in schizophrenia based on estrogen receptor genotype. Eur Neuropsychopharmacol 26:1930–1940. https://doi.org/10.1016/j.euroneuro.2016.10.009
Kulkarni J, Gurvich C, Lee SJ, Gilbert H, Gavrilidis E, De CA, Berk M, Dodd S, Fitzgerald PB, Davis SR (2010) Piloting the effective therapeutic dose of adjunctive selective estrogen receptor modulator treatment in postmenopausal women with schizophrenia. Psychoneuroendocrinology 35:1142–1147. https://doi.org/10.1016/j.psyneuen.2010.01.014
Kulkarni J, Gavrilidis E, Worsley R, Hayes E (2012) Role of estrogen treatment in the management of schizophrenia. CNS Drugs 26:549–557. https://doi.org/10.2165/11630660-000000000-00000
Kulkarni J, Gavrilidis E, Wang W, Worsley R, Fitzgerald PB, Gurvich C, Van RT, Berk M, Burger H (2014) Estradiol for treatment-resistant schizophrenia: a large-scale randomized-controlled trial in women of child-bearing age. Mol Psychiatry 20:1–8. https://doi.org/10.1038/mp.2014.33
Kulkarni J, Gavrilidis E, Gwini SM, Worsley R, Grigg J, Warren A, Gurvich C, Gilbert H, Berk M, Davis SR (2016) Effect of adjunctive raloxifene therapy on severity of refractory schizophrenia in women: a randomized clinical trial. Jama Psychiatry 73:947–954. https://doi.org/10.1001/jamapsychiatry.2016.1383
Kumari V (2011) Sex differences and hormonal influences in human sensorimotor gating: implications for schizophrenia. Curr Top Behav Neurosci 8:141–154. https://doi.org/10.1007/7854_2010_117
Labad J, Martorell L, Huerta-Ramos E, Cobo J, Vilella E, Rubio-Abadal E, Garcia-Pares G, Creus M, Núñez C, Ortega L (2016) Pharmacogenetic study of the effects of raloxifene on negative symptoms of postmenopausal women with schizophrenia: a double-blind, randomized, placebo-controlled trial. European Neuropsychopharmacology the Journal of the European College of Neuropsychopharmacology 26:1683–1689. https://doi.org/10.1016/j.euroneuro.2016.08.006
Lafuente A, Esquifino AI (2002) Effects of long-lasting raloxifene treatment on serum prolactin and gonadotropin levels in postmenopausal women. july 1 - july 15 -OT 12hrs (7/1,3,4) july 16 - july 31 - OT 4hrs (7/31) paid aug 1 - aug 15 -OT 1511hrs (8/1,2,3,4) paid 147:461–465. https://doi.org/10.1530/eje.0.1470461
Littleton-Kearney MT, Ostrowski NL, Cox DA, Rossberg MI, Hurn PD (2002) Selective estrogen receptor modulators: tissue actions and potential for CNS protection. Cns Drug Reviews 8:309–330. https://doi.org/10.1111/j.1527-3458.2002.tb00230.x
Meitzen J, Mermelstein PG (2011) Estrogen receptors stimulate brain region specific metabotropic glutamate receptors to rapidly initiate signal transduction pathways. J Chem Neuroanat 42:236–241. https://doi.org/10.1016/j.jchemneu.2011.02.002
Millan MJ, Fone K, Steckler T, Horan WP (2014) Negative symptoms of schizophrenia: clinical characteristics, pathophysiological substrates, experimental models and prospects for improved treatment. Eur Neuropsychopharmacol 24:645–692. https://doi.org/10.1016/j.euroneuro.2014.03.008
Moen MD, Keating GM (2008) Raloxifene: a review of its use in the prevention of invasive breast cancer. Drugs 68:2059–2083. https://doi.org/10.2165/00003495-200868140-00008
Moher D, Liberati A, Tetzlaff J, Altman DG (2014) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Revista Española De Nutrición Humana Y Dietética 18:889–896. https://doi.org/10.1136/bmj.b2535
Mortimer AM (2007) Relationship between estrogen and schizophrenia. Expert Rev Neurother 7:45–55. https://doi.org/10.1586/14737175.7.1.45
Mowatt G, Grimshaw JM, Davis DA, Mazmanian PE (2001) Getting evidence into practice: the work of the Cochrane effective practice and organization of care group (EPOC). J Contin Educ Health Prof 21:55–60. https://doi.org/10.1002/chp.1340210109
Naylor KE, Jacques RM, Peel NFA (2016) Response of bone turnover markers to raloxifene treatment in postmenopausal women with osteopenia. Osteoporos Int 27:2585–2592. https://doi.org/10.1007/s00198-016-3573-z
Peuskens J, Pani L, Detraux J, De HM (2014) The effects of novel and newly approved antipsychotics on serum prolactin levels: a comprehensive review. CNS Drugs 28:421–453. https://doi.org/10.1007/s40263-014-0157-3
Riecher-Rössler A, Häfner H (1993) Schizophrenia and oestrogens—is there an association? Eur Arch Psychiatry Clin Neurosci 242:323–328. https://doi.org/10.1007/BF02190244
Riecher-Rössler A, Kulkarni J (2010) Estrogens and gonadal function in schizophrenia and related psychoses, vol 8. Springer, Berlin, pp 155–171. https://doi.org/10.1007/7854_2010_100
Rodante D, Usall J (2014) Raloxifene as adjuvant in the treatment of schizophrenia: a review of efficacy and safety issues. J of Symptoms and Signs 3:229–237
Sánchez MG, Morissette M, Di PT (2013) Oestradiol modulation of serotonin reuptake transporter and serotonin metabolism in the brain of monkeys. J Neuroendocrinol 25:560–569. https://doi.org/10.1111/jne.12034
Shang Y, Brown M (2002) Molecular determinants for the tissue specificity of SERMs. Science 295:2465–2468. https://doi.org/10.1126/science.1068537
Sharma E, Raveendranathan D, Shivakumar V, Jayaram N, Rao NP, Venkatasubramanian G (2012) Beneficial effects of add-on raloxifene in schizophrenia. Archives of Women's Mental Health 15:147–148. https://doi.org/10.1007/s00737-012-0259-1
Sribnick EA, Wingrave JM, Matzelle DD, Wilford GG, Ray SK, Banik NL (2005) Estrogen attenuated markers of inflammation and decreased lesion volume in acute spinal cord injury in rats. J Neurosci Res 82:283–293. https://doi.org/10.1002/jnr.20622
Sterne JAC, Higgins JPT (2011) Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials. BMJ 343:d4002. https://doi.org/10.1136/bmj.d4002
Talonen S, Väänänen J, Kaltiala-Heino R (2017) Gender differences in first onset schizophrenia spectrum psychoses. Nordic Journal of Psychiatry 2:1–8. https://doi.org/10.1080/08039488.2016.1245783
Taylor R, Langdon R (2006) Understanding gender differences in schizophrenia: a review of the literature. Curr Psychiatr Rev 2:255–265. https://doi.org/10.2174/157340006776875987
Torrey EF, Davis JM (2012) Adjunct treatments for schizophrenia and bipolar disorder: what to try when you are out of ideas. Clinical Schizophrenia & Related Psychoses 5:208–216. https://doi.org/10.3371/CSRP.5.4.5
Usall J, Huertaramos E, Labad J, Cobo J, Núñez C, Creus M, Parés GG, Cuadras D, Franco J, Miquel E (2011) Raloxifene as an adjunctive treatment for postmenopausal women with schizophrenia: a 24-week double-blind, randomized, parallel, placebo-controlled trial. The Journal of clinical psychiatry 72:1552–1557. https://doi.org/10.4088/JCP.10m06610
Usall J, Huerta-Ramos E, Labad J, Cobo J, Nunez C, Creus M, Pares GG, Cuadras D, Franco J, Miquel E, Reyes JC, Roca M, Group R (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. https://doi.org/10.1093/schbul/sbv149
Weickert TW, Weinberg D, Lenroot R, Catts SV, Wells R, Vercammen A, O'Donnell M, Galletly C, Liu D, Balzan R (2015) Adjunctive raloxifene treatment improves attention and memory in men and women with schizophrenia. Mol Psychiatry 20:S339–S340. https://doi.org/10.1038/mp.2015.11
Weiser M, Levi L, Burshtein S, Hagin M, Matei VP, Podea D, Micluția I, Tiugan A, Păcală B, Grecu IG, Noy A, Zamora D, Davis JM (2017) Raloxifene plus antipsychotics versus placebo plus antipsychotics in severely ill decompensated postmenopausal women with schizophrenia or schizoaffective disorder: a randomized controlled trial.[J]. J Clin Psychiatry 23:1–14. https://doi.org/10.4088/JCP.15m10498
Wong J, Seeman MV, Shapiro H (2003) Case report: raloxifene in postmenopausal women with psychosis: preliminary findings. Am J Geriatr Psychiatr 11:697–698. https://doi.org/10.1176/appi.ajgp.11.6.697
Yaffe K, Krueger K, Cummings SR, Blackwell T, Henderson VW, Sarkar S, Ensrud K, Grady D (2005) Effect of raloxifene on prevention of dementia and cognitive impairment in older women: the multiple outcomes of raloxifene evaluation (MORE) randomized trial. Am J Psychiatr 162:683–690. https://doi.org/10.1176/appi.ajp.162.4.683
Funding
This study was funded by the Natural Science Foundation of Liaoning Province (Project No. 2015020481).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Ethical approval
This article does not contain any studies with human participants or animals performed by any of the authors.
Rights and permissions
About this article
Cite this article
Wang, Q., Dong, X., Wang, Y. et al. Raloxifene as an adjunctive treatment for postmenopausal women with schizophrenia: a meta-analysis of randomized controlled trials. Arch Womens Ment Health 21, 31–41 (2018). https://doi.org/10.1007/s00737-017-0773-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00737-017-0773-2