Dutasteride treatment for reducing heavy drinking in AUD: Predictors of efficacy

摘要 酒精使用障碍的药物治疗选择仍然有限，只有三种FDA批准的化合物 (双硫兰、纳曲酮和氨基己酸酯)。最近的研究强调了用于治疗癌症的药物的潜力 其他适应症的治疗对帮助患者减少饮酒是有用的。对其他药物的研究， 尤其是那些通过新机制发挥作用的药物，需要扩大药物治疗的范围 解决酒精使用问题的选择。此外，确定个体受试者水平的疗效预测因子是 需要更好地个性化药物治疗治疗建议。 广泛的临床前研究表明，神经活性类固醇调节酒精和支持的重要作用 神经活性类固醇调节剂作为酒精使用障碍(AUD)治疗选择的检查。 度他雄胺是一种治疗良性前列腺肥大和雄激素性脱发的广泛处方药物，可阻断a。 是生产神经活性类固醇的关键步骤，是治疗AUD的有前途的候选药物。 对男性酗酒者进行为期12周的非酒精性尿崩症随机对照试验的中期分析 表明度他雄胺在酗酒者中耐受性很好，在帮助受试者减少饮酒方面有疗效。 结果表明，度他雄胺可能对有基线负面情绪或 伴侣蛋白FKBP5的应激反应等位基因携带者参与糖皮质激素的调节， 雄激素和孕激素受体的功能。这项为期24周的治疗研究将采用一种创新的步骤 治疗随机安慰剂对照设计考察度他雄胺降低 在190名寻求治疗的男性和女性中，有危险酒精使用水平的样本都在饮酒。在… 12周的安慰剂无反应者将过渡到度他雄胺，度他雄胺无反应者将过渡到度他雄胺 对于纳曲酮，FDA批准了具有减少大量饮酒效果的药物。基线 焦虑和感受到的生活压力的测量将与压力一起单独进行检查。 FKBP5的弹性和反应性基因型别作为度他雄胺治疗疗效的预测因子。

Abstract Pharmacotherapy options for alcohol use disorders remain limited, with only three FDA approved compounds (disulfiram, naltrexone and acamprosate). Recent studies highlight the potential for medications used for the treatment of other indications to be useful in helping patients reduce drinking. Study of additional agents, particularly those that act through novel mechanisms, is needed to expand the range of pharmacotherapy options for alcohol use problems. Additionally, identification of individual subject level predictors of efficacy are needed to better personalize pharmacotherapy treatment recommendations. Extensive preclinical studies indicate that neuroactive steroids mediate important effects of alcohol and support the examination of neuroactive steroid modulators as treatment options for alcohol use disorders (AUD). Dutasteride, a widely prescribed medication for benign prostatic hypertrophy and androgenic hair loss, blocks a key step in the production of neuroactive steroids and represents a promising candidate for treatment of AUD. Interim analysis from the first 12-week RCT of dutasteride for AUD in a sample of male heavy drinkers indicates that dutasteride is well tolerated in alcoholics and has efficacy in helping subjects reduce drinking. Results suggest that dutasteride may be particularly helpful for patients with baseline negative mood or are carriers of a stress-reactive allele of a chaperone protein, FKBP5, involved in regulation of glucocorticoid, androgen and progesterone receptor function. This 24-week treatment study will use an innovative step therapy randomized placebo controlled design to examine the safety and efficacy of dutasteride to reduce drinking among a sample of 190 treatment seeking men and women with hazardous levels of alcohol use. At 12-weeks placebo non-responders will transition to dutasteride and dutasteride non-responders will transition to naltrexone, an FDA approved medication with demonstrated efficacy for reducing heavy drinking. Baseline measures of anxiety and perceived life stress will be examined separately and in conjunction with stress resilient vs. reactive genotypes of FKBP5 as predictors of dutasteride treatment efficacy.