Department of Medicine, Sunnybrook Health Sciences Centre, Toronto, Canada.
BMJ. 2010 Feb 8;340:c693. doi: 10.1136/bmj.c693.
To characterise whether some selective serotonin reuptake inhibitor (SSRI) antidepressants reduce tamoxifen's effectiveness by inhibiting its bioactivation by cytochrome P450 2D6 (CYP2D6).
Population based cohort study.
Women living in Ontario aged 66 years or older treated with tamoxifen for breast cancer between 1993 and 2005 who had overlapping treatment with a single SSRI.
Risk of death from breast cancer after completion of tamoxifen treatment, as a function of the proportion of time on tamoxifen during which each SSRI had been co-prescribed.
Of 2430 women treated with tamoxifen and a single SSRI, 374 (15.4%) died of breast cancer during follow-up (mean follow-up 2.38 years, SD 2.59). After adjustment for age, duration of tamoxifen treatment, and other potential confounders, absolute increases of 25%, 50%, and 75% in the proportion of time on tamoxifen with overlapping use of paroxetine (an irreversible inhibitor of CYP2D6) were associated with 24%, 54%, and 91% increases in the risk of death from breast cancer, respectively (P<0.05 for each comparison). By contrast, no such risk was seen with other antidepressants. We estimate that use of paroxetine for 41% of tamoxifen treatment (the median overlap in our sample) would result in one additional breast cancer death within five years of cessation of tamoxifen for every 19.7 (95% confidence interval 12.5 to 46.3) patients so treated; the risk with more extensive overlap would be greater.
Paroxetine use during tamoxifen treatment is associated with an increased risk of death from breast cancer, supporting the hypothesis that paroxetine can reduce or abolish the benefit of tamoxifen in women with breast cancer.
通过抑制细胞色素 P450 2D6（CYP2D6）对他莫昔芬的生物活化作用，来确定某些选择性 5-羟色胺再摄取抑制剂（SSRIs）抗抑郁药是否会降低他莫昔芬的疗效。
基于人群的队列研究。
1993 年至 2005 年间在安大略省接受他莫昔芬治疗乳腺癌且在此期间重叠使用单一 SSRI 的年龄在 66 岁及以上的女性。
他莫昔芬治疗完成后死于乳腺癌的风险，作为每个 SSRI 与他莫昔芬同时使用时间比例的函数。
在 2430 名接受他莫昔芬和单一 SSRI 治疗的女性中，有 374 人（15.4%）在随访期间死于乳腺癌（中位随访时间 2.38 年，SD 2.59）。在调整年龄、他莫昔芬治疗持续时间和其他潜在混杂因素后，重叠使用帕罗西汀（一种不可逆的 CYP2D6 抑制剂）的时间比例增加 25%、50%和 75%，分别与乳腺癌死亡风险增加 24%、54%和 91%相关（各比较 P<0.05）。相比之下，其他抗抑郁药则没有这种风险。我们估计，在我们的样本中，帕罗西汀与他莫昔芬重叠使用的中位数为 41%，那么每 19.7 名（95%置信区间 12.5 至 46.3）接受这种治疗的患者中，在停止他莫昔芬治疗后的五年内，将有一名额外的乳腺癌死亡；重叠范围更广的风险更大。
帕罗西汀在他莫昔芬治疗期间的使用与乳腺癌死亡风险增加相关，支持帕罗西汀可降低或消除乳腺癌女性中他莫昔芬疗效的假设。
