Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada.
Can J Psychiatry. 2024 Mar;69(3):183-195. doi: 10.1177/07067437231203433. Epub 2023 Oct 5.
Treatment-emergent sexual dysfunction is frequently reported by individuals with major depressive disorder (MDD) on antidepressants, which negatively impacts treatment adherence and efficacy. We investigated the association of polymorphisms in pharmacokinetic genes encoding cytochrome-P450 drug-metabolizing enzymes, and , and the transmembrane efflux pump, P-glycoprotein (i.e., ), on treatment-emergent changes in sexual function (SF) and sexual satisfaction (SS) in the Canadian Biomarker Integration Network in Depression 1 (CAN-BIND-1) sample.
A total of 178 adults with MDD received treatment with escitalopram (ESC) from weeks 0-8 (Phase I). At week 8, nonresponders were augmented with aripiprazole (ARI) (i.e., ESC + ARI, = 91), while responders continued ESC (i.e., ESC-Only, = 80) from weeks 8-16 (Phase II). SF and SS were evaluated using the sex effects (SexFX) scale at weeks 0, 8, and 16. We assessed the primary outcomes, SF and SS change for weeks 0-8 and 8-16, using repeated measures mixed-effects models.
In ESC-Only, intermediate metabolizer (IM) + poor metabolizers (PMs) showed treatment-related improvements in sexual arousal, a subdomain of SF, from weeks 8-16, relative to normal metabolizers (NMs) who showed a decline, (2,54) = 8.00, < 0.001, = 0.048. Specifically, IM + PMs reported less difficulty with having and sustaining vaginal lubrication in females and erection in males, compared to NMs. Furthermore, ESC-Only females with higher concentrations of ESC metabolite, S-desmethylcitalopram (S-DCT), and S-DCT/ESC ratio in serum demonstrated more decline in SF ( = -0.42, = 0.004, = 0.034) and SS ( = -0.43, = 0.003, = 0.034), respectively, which was not observed in males. ESC-Only females also demonstrated a trend for a correlation between S-DCT and sexual arousal change in the same direction ( = -0.39, = 0.009, = 0.052).
metabolizer phenotypes may be influencing changes in sexual arousal related to ESC monotherapy. Thus, preemptive genotyping of may help to guide selection of treatment that circumvents selective serotonin reuptake inhibitor-related sexual dysfunction thereby improving outcomes for patients. Additionally, further research is warranted to clarify the role of S-DCT in the mechanisms underlying ESC-related changes in SF and SS. This CAN-BIND-1 study was registered on clinicaltrials.gov (Identifier: NCT01655706) on 27 July 2012.
抗抑郁药治疗引发的性功能障碍在患有重度抑郁症（MDD）的个体中经常被报告，这对治疗依从性和疗效产生负面影响。我们研究了在加拿大抑郁生物标志物整合网络 1（CAN-BIND-1）样本中，编码细胞色素 P450 药物代谢酶的药代动力学基因和跨膜外排泵 P-糖蛋白（即）中的多态性与性功能（SF）和性满意度（SS）治疗中出现的变化之间的关联。
共有 178 名 MDD 成年人接受了 0-8 周（第 I 阶段）的依地普仑（ESC）治疗。在第 8 周，无应答者加用阿立哌唑（ARI）（即 ESC+ARI，=91），而应答者继续接受 ESC（即 ESC-Only，=80）治疗，从第 8 周至第 16 周（第 II 阶段）。SF 和 SS 使用性影响（SexFX）量表在第 0、8 和 16 周进行评估。我们使用重复测量混合效应模型评估第 0-8 周和 8-16 周的 SF 和 SS 变化的主要结局。
在 ESC-Only 中，中间代谢物（IM）+不良代谢物（PM）组与正常代谢物（NM）组相比，在第 8-16 周时，性唤起（SF 的一个亚域）的治疗相关性改善，（2，54）=8.00，<0.001，=0.048。具体而言，与 NM 相比，IM+PM 组报告女性阴道润滑和男性勃起更容易出现问题。此外，ESC-Only 女性的 ESC 代谢物 S-去甲基西酞普兰（S-DCT）血清浓度和 S-DCT/ESC 比值较高，其 SF（=−0.42，=0.004，=0.034）和 SS（=−0.43，=0.003，=0.034）下降更明显，但在男性中没有观察到这种情况。ESC-Only 女性的 S-DCT 与性唤起变化之间也呈现出相同方向的相关性趋势（=−0.39，=0.009，=0.052）。
代谢物表型可能会影响与 ESC 单药治疗相关的性唤起变化。因此，预先对进行基因分型可能有助于指导选择避免选择性 5-羟色胺再摄取抑制剂相关性功能障碍的治疗方法，从而改善患者的治疗效果。此外，还需要进一步研究来阐明 S-DCT 在 ESC 相关 SF 和 SS 变化机制中的作用。这项 CAN-BIND-1 研究于 2012 年 7 月 27 日在 clinicaltrials.gov（标识符：NCT01655706）上注册。
