Adjunctive raloxifene treatment improves attention and memory in men and women with schizophrenia

Abstract

There is increasing clinical and molecular evidence for the role of hormones and specifically estrogen and its receptor in schizophrenia. A selective estrogen receptor modulator, raloxifene, stimulates estrogen-like activity in brain and can improve cognition in older adults. The present study tested the extent to which adjunctive raloxifene treatment improved cognition and reduced symptoms in young to middle-age men and women with schizophrenia. Ninety-eight patients with a diagnosis of schizophrenia or schizoaffective disorder were recruited into a dual-site, thirteen-week, randomized, double-blind, placebo-controlled, crossover trial of adjunctive raloxifene treatment in addition to their usual antipsychotic medications. Symptom severity and cognition in the domains of working memory, attention/processing speed, language and verbal memory were assessed at baseline, 6 and 13 weeks. Analyses of the initial 6-week phase of the study using a parallel groups design (with 39 patients receiving placebo and 40 receiving raloxifene) revealed that participants receiving adjunctive raloxifene treatment showed significant improvement relative to placebo in memory and attention/processing speed. There was no reduction in symptom severity with treatment compared with placebo. There were significant carryover effects, suggesting some cognitive benefits are sustained even after raloxifene withdrawal. Analysis of the 13-week crossover data revealed significant improvement with raloxifene only in attention/processing speed. This is the first study to show that daily, oral adjunctive raloxifene treatment at 120 mg per day has beneficial effects on attention/processing speed and memory for both men and women with schizophrenia. Thus, raloxifene may be useful as an adjunctive treatment for cognitive deficits associated with schizophrenia.

Figure 1

CONSORT flow diagram.

Figure 2

Treatment differences across cognitive measures in the parallel groups analyses. *P≤0.05, **P≤0.001. Figure 2 shows significant improvement from baseline to 6 weeks on measures of immediate verbal memory (Wechsler Memory Scale Revised Logical Memory I, LMI), delayed verbal memory (Wechsler Memory Scale Revised Logical Memory II, LMII), and attention/processing speed (TMT-A Trail Making Test A) in the raloxifene treatment condition. TMT-A results are inversed for comparability. Improvement on memory, attention/processing speed, and verbal fluency (COWAT Controlled Oral Word Association Test) were significantly greater in the raloxifene treatment condition relative to the placebo treatment condition (brackets). There was no significant difference between raloxifene and placebo conditions for Wechsler Adult Intelligence Scale 3rd Edition Letter-Number Sequencing (LNS) test.