Monash Alfred Psychiatry Research Centre, Alfred Hospital and Monash University Central Clinical School, Monash University, Melbourne, Australia.
Department of Epidemiology and Preventative Medicine, Monash University, Melbourne, Australia.
JAMA Psychiatry. 2016 Sep 1;73(9):947-54. doi: 10.1001/jamapsychiatry.2016.1383.
A substantial proportion of women with schizophrenia experience debilitating treatment-refractory symptoms. The efficacy of estrogen in modulating brain function in schizophrenia has to be balanced against excess exposure of peripheral tissue. Raloxifene hydrochloride is a selective estrogen receptor modulator (mixed estrogen agonist/antagonist) with potential psychoprotective effects and fewer estrogenic adverse effects.
To determine whether adjunctive raloxifene therapy reduces illness severity in women with refractory schizophrenia.
DESIGN, SETTING, AND PARTICIPANTS: This 12-week, double-blind, placebo-controlled, randomized clinical trial with fortnightly assessments was performed at an urban tertiary referral center and a regional center from January 1, 2006, to December 31, 2014. Participants included 56 women with schizophrenia or schizoaffective disorder and marked symptom severity despite substantial and stable antipsychotic doses. Data were analyzed using intention to treat as the basis.
Adjunctive raloxifene hydrochloride, 120 mg/d, or placebo for 12 weeks.
The primary outcome was the change in the Positive and Negative Syndrome Scale (PANSS) total score. Clinical response (defined as a ≥20% decrease in PANSS total score from baseline) and change in PANSS subscale scores, mood, cognition, reproductive hormone levels, and adverse events were also assessed.
Of the 56 participants (mean [SD] age, 53 [7.7] years; age range, 40-70 years; mean [SD] duration of psychotic illness, 24 [11] years), 26 were randomized to raloxifene and 30 were randomized to placebo. Raloxifene produced a greater reduction in the PANSS total score relative to placebo (β = -6.37; 95% CI, -11.64 to -1.10; P = .02) and resulted in an increased probability of a clinical response (hazard ratio, 5.79; 95% CI, 1.46 to 22.97; P = .01). A significant reduction was found in the PANSS general symptom scores for the raloxifene compared with the placebo (β = -3.72; 95% CI, -6.83 to -0.61; P = .02) groups. For patients who completed the full 12-week trial, there was not a statistically significant treatment effect on PANSS positive symptom scores (β for change in raloxifene vs placebo, -1.92; 95% CI, -3.83 to 0.00; P = .05). Change in mood, cognition, and reproductive hormone levels and the rate of adverse events did not differ between groups.
Raloxifene hydrochloride, 120 mg/d, reduces illness severity and increases the probability of a clinical response in women with refractory schizophrenia. This large trial of raloxifene in this patient population offers a promising, well-tolerated agent that has potential application in clinical practice.
clinicaltrials.gov Identifier: NCT00361543.
重要性：相当一部分患有精神分裂症的女性经历着使人虚弱的治疗抵抗症状。雌激素调节精神分裂症患者大脑功能的功效必须与外周组织过度暴露的风险相平衡。盐酸雷洛昔芬是一种选择性雌激素受体调节剂（混合雌激素激动剂/拮抗剂），具有潜在的精神保护作用和较少的雌激素不良作用。
目的：确定辅助盐酸雷洛昔芬治疗是否能降低难治性精神分裂症女性的疾病严重程度。
设计、地点和参与者：这是一项为期 12 周的双盲、安慰剂对照、随机临床试验，每两周进行一次评估，于 2006 年 1 月 1 日至 2014 年 12 月 31 日在城市三级转诊中心和区域中心进行。参与者包括 56 名患有精神分裂症或分裂情感障碍的女性，尽管有大量和稳定的抗精神病药物剂量，但症状仍明显严重。数据分析采用意向治疗作为基础。
干预措施：辅助盐酸雷洛昔芬，每天 120 毫克，或安慰剂，治疗 12 周。
主要结果和测量：主要结果是阳性和阴性症状量表（PANSS）总分的变化。还评估了临床反应（定义为 PANSS 总分从基线下降≥20%）和 PANSS 子量表评分、情绪、认知、生殖激素水平以及不良反应的变化。
结果：在 56 名参与者（平均[标准差]年龄，53[7.7]岁；年龄范围，40-70 岁；平均[标准差]精神病病程，24[11]年）中，26 名被随机分配到雷洛昔芬组，30 名被随机分配到安慰剂组。雷洛昔芬组相对于安慰剂组 PANSS 总分降低更大（β=-6.37；95%置信区间，-11.64 至-1.10；P=0.02），且临床反应的可能性增加（危险比，5.79；95%置信区间，1.46 至 22.97；P=0.01）。与安慰剂组相比，雷洛昔芬组的 PANSS 一般症状评分显著降低（β=-3.72；95%置信区间，-6.83 至-0.61；P=0.02）。对于完成整个 12 周试验的患者，PANSS 阳性症状评分的治疗效果没有统计学意义（雷洛昔芬与安慰剂相比，改变的β值为-1.92；95%置信区间，-3.83 至 0.00；P=0.05）。情绪、认知和生殖激素水平的变化以及不良反应的发生率在两组之间没有差异。
结论和相关性：盐酸雷洛昔芬，每天 120 毫克，可降低难治性精神分裂症女性的疾病严重程度，并增加临床反应的可能性。这项针对雷洛昔芬在这一患者群体中的大型试验提供了一种有希望的、耐受性良好的药物，在临床实践中具有潜在的应用。
试验注册：clinicaltrials.gov 标识符：NCT00361543。
