Recent articles on Raloxifene as an adjuvant treatment for Schizophrenia.

Recent articles underlying the utility of Selective Estrogen Receptor Modulator (SERM) Raloxifene as an adjuvant treatment for patients suffering with schizophrenia (1-8).

Two new clinical trials (1,2) added new evidence for the efficacy of Raloxifene as an adjuvant treatment for women suffering with schizophrenia. Kulkarni et al. (1) analyzed a new randomized trial with 56 participants, 26 were randomized to raloxifene 120 mg/d and 30 were randomized to placebo. Raloxifene produced a greater reduction in the PANSS total score. In addition, the clinical trial of Usall et al. (2) with 70 postmenopausal women with schizophrenia (DSM-IV) randomized to either adjunctive raloxifene (38 women) or adjunctive placebo (32 women), showed that addition to raloxifene improved negative and general psychopathological symptoms, compared with antipsychotic medication alone, in postmenopausal women with schizophrenia. These data replicate previous results with larger samples and longer follow-ups.

Current  reviews (3,4) suggesting that Raloxifene, a selective estrogen receptor modulator, was identified as useful to improve negative, positive, and general psychopathological symptoms, and also cognitive functions (5) with and adequate short-term secondary effect pattern. SERMs could be an effective augmentation strategy in the treatment of both men women with schizophrenia, but the reviewer suggested too further research to study potential long-term side effects (1). On the other hand, in animal models, Raloxifene increases forebrain neurogenesis and enhances working memory and synaptic plasticity, altered  in schizophrenia. Raloxifene also reduces oxidative stress and neuroinflammation, which are potent etiological factors in the neuropathology of schizophrenia (2). Different studies in postmenopausal women, also showed that raloxifene reduces the risks for atherosclerosis, diabetes mellitus, and weight gain (2). The reviewer added some new insights into the neurocognitive, neuroprotective, and cardiometabolic effects of raloxifene in relation to therapeutic outcomes in schizophrenia (2).

On the other hand, adjunctive raloxifene significantly increased activation in the right hippocampus and left inferior frontal gyrus in 20 people suffering for schizophrenia, compared with the placebo condition (family-wise error, P<0.05). This study (6) provides the first evidence suggesting that adjunctive raloxifene treatment changes neural activity in brain regions associated with facial emotion recognition in schizophrenia. In fact, Weickert et al. (5) suggesting that oestrogen-based therapies may be useful in reversing the cognitive deficits associated with schizophrenia. A possible mechanism of action may include anti-inflammatory effects of oestrogen-based treatments.

Labad et al. (7) studied four single nucleotide polymorphisms (SNPs) in 65 postmenopausal women with schizophrenia randomized to either 60 mg/day adjunctive raloxifene (36 women) or adjunctive placebo (29 women). The study suggests that genetic variants in UGT1A8 and ESR1 genes modulate the treatment response to adding raloxifene to antipsychotic treatment in postmenopausal women with schizophrenia.

Finally, clinical cases (8) added new interesting data for the utility of Selective Estrogen Receptor Modulators (SERM), as Raloxifene, for the adjuntive treatment of schizophrenia.



1. Kulkarni J, Gavrilidis E, Gwini SM, Worsley R, Grigg J, Warren A, Gurvich C, Gilbert H, Berk M, Davis SR. Effect of Adjunctive Raloxifene Therapy on Severity of Refractory Schizophrenia in Women: A Randomized Clinical Trial. JAMA Psychiatry. 2016 Sep 1;73(9):947-54. doi: 10.1001/jamapsychiatry.2016.1383.

2. Usall J, Huerta-Ramos E, Labad J, Cobo J, Núñez C, Creus M, Parés GG, Cuadras D, Franco J, Miquel E, Reyes JC, Roca M; RALOPSYCAT Group. Raloxifene as an Adjunctive Treatment for Postmenopausal Women With Schizophrenia: A 24-Week Double-Blind, Randomized, Parallel, Placebo-Controlled Trial. Schizophr Bull. 2016 Mar;42(2):309-17. doi: 10.1093/schbul/sbv149. Epub 2015 Nov 20.

3. Bratek A, Krysta K, Drzyzga K, BaraƄska J, Kucia K. The role of selective estrogen receptor modulators in the treatment of schizophrenia. Psychiatr Danub. 2016 Sep;28(Suppl-1):45-48

4.  Khan MM. Neurocognitive, Neuroprotective, and Cardiometabolic Effects of Raloxifene: Potential for Improving Therapeutic Outcomes in Schizophrenia. CNS Drugs. 2016 Jul;30(7):589-601. doi: 10.1007/s40263-016-0343-6.

5. Weickert TW, Allen KM, Weickert CS.Potential Role of Oestrogen Modulation in the Treatment of Neurocognitive Deficits in Schizophrenia. CNS Drugs. 2016 Feb;30(2):125-33. doi: 10.1007/s40263-016-0312-0.

6. Ji E, Weickert CS, Lenroot R, Kindler J, Skilleter AJ, Vercammen A, White C, Gur RE, Weickert TW. Adjunctive selective estrogen receptor modulator increases neural activity in the hippocampus and inferior frontal gyrus during emotional face recognition in schizophrenia. Transl Psychiatry. 2016 May 3;6:e795. doi: 10.1038/tp.2016.59.

7. Labad J, Martorell L, Huerta-Ramos E, Cobo J, Vilella E, Rubio-Abadal E, Garcia-Pares G, Creus M, Núñez C, Ortega L, Miquel E; RALOPSYCAT Group, Usall J. Pharmacogenetic study of the effects of raloxifene on negative symptoms of postmenopausal women with schizophrenia: A double-blind, randomized, placebo-controlled trial. Eur Neuropsychopharmacol. 2016 Oct;26(10):1683-9. doi: 10.1016/j.euroneuro.2016.08.006. Epub 2016 Aug 18.

8. Grigg J, Worsley R, Kulkarni J. Raloxifene for schizophrenia and symptoms of hyperprolactinaemia? Aust N Z J Psychiatry. 2016 Sep 28.