Abstract：
Disruptions of the hypothalamic-pituitary axis can cause an arginine vasopressin deficiency, also known as central diabetes insipidus. Patients with this condition are at high risk of additional oxytocin deficiency owing to the close anatomical proximity of oxytocin-producing neurons; however, no conclusive evidence for such a deficiency has been reported. We aimed to use 3,4-methylenedioxymethamphetamine (MDMA, also known as ecstasy), a strong activator of the central oxytocinergic system, as a biochemical and psychoactive provocation test to investigate oxytocin deficiency in patients with arginine vasopressin deficiency (central diabetes insipidus).
This single-centre, case-control study with nested, randomised, double-blind, placebo-controlled crossover trial included patients with arginine vasopressin deficiency (central diabetes insipidus) and healthy controls (matched 1:1 by age, sex, and BMI) and was conducted at the University Hospital Basel, Basel, Switzerland. We used block randomisation to assign participants to receive either a single oral dose of MDMA (100 mg) or placebo in the first experimental session; patients received the opposite treatment at the next session, with a wash-out period of at least 2 weeks between the two sessions. Participants and investigators assessing the outcomes were masked to assignment. Oxytocin concentrations were measured at 0, 90, 120, 150, 180, and 300 min after MDMA or placebo. The primary outcome was the area under the plasma oxytocin concentration curve (AUC) after drug intake. The AUC was compared between groups and conditions using a linear mixed-effects model. Subjective drug effects were assessed throughout the study using ten-point visual analogue scales. Acute adverse effects were assessed before and 360 min after drug intake using a 66-item list of complaints. This trial is registered with ClinicalTrials.gov, NCT04648137.
Between Feb 1, 2021, and May 1, 2022, we recruited 15 patients with arginine vasopressin deficiency (central diabetes insipidus) and 15 healthy controls. All participants completed the study and were included in the analyses. In healthy controls, median plasma oxytocin concentration was 77 pg/mL (IQR 59-94) at baseline and increased by 659 pg/mL (355-914) in response to MDMA, resulting in an AUC of 102 095 pg/mL (41 782-129 565); in patients, baseline oxytocin concentration was 60 pg/mL (51-74) and only slightly increased by 66 pg/mL (16-94) in response to MDMA, resulting in an AUC of 6446 pg/mL (1291-11 577). The effect of MDMA on oxytocin was significantly different between groups: the AUC for oxytocin was 82% (95% CI 70-186) higher in healthy controls than in patients (difference 85 678 pg/mL [95% CI 63 356-108 000], p<0·0001). The increase in oxytocin in healthy controls was associated with typical strong subjective prosocial, empathic, and anxiolytic effects, whereas only minimal subjective effects were observed in patients, in agreement with the lack of increase in oxytocin concentrations. The most frequently reported adverse effects were fatigue (eight [53%] healthy controls and eight [53%] patients), lack of appetite (ten [67%] healthy controls and eight [53%] patients), lack of concentration (eight [53%] healthy controls and seven [47%] patients), and dry mouth (eight [53%] healthy controls and eight [53%] patients). In addition, two (13%) healthy controls and four (27%) patients developed transient mild hypokalaemia.
These findings are highly suggestive of clinically meaningful oxytocin deficiency in patients with arginine vasopressin deficiency (central diabetes insipidus), laying the groundwork for a new hypothalamic-pituitary disease entity.
Swiss National Science Foundation, Swiss Academy of Medical Sciences, and the G&J Bangerter-Rhyner Foundation.
This single-centre, case-control study with nested, randomised, double-blind, placebo-controlled crossover trial included patients with arginine vasopressin deficiency (central diabetes insipidus) and healthy controls (matched 1:1 by age, sex, and BMI) and was conducted at the University Hospital Basel, Basel, Switzerland. We used block randomisation to assign participants to receive either a single oral dose of MDMA (100 mg) or placebo in the first experimental session; patients received the opposite treatment at the next session, with a wash-out period of at least 2 weeks between the two sessions. Participants and investigators assessing the outcomes were masked to assignment. Oxytocin concentrations were measured at 0, 90, 120, 150, 180, and 300 min after MDMA or placebo. The primary outcome was the area under the plasma oxytocin concentration curve (AUC) after drug intake. The AUC was compared between groups and conditions using a linear mixed-effects model. Subjective drug effects were assessed throughout the study using ten-point visual analogue scales. Acute adverse effects were assessed before and 360 min after drug intake using a 66-item list of complaints. This trial is registered with ClinicalTrials.gov, NCT04648137.
Between Feb 1, 2021, and May 1, 2022, we recruited 15 patients with arginine vasopressin deficiency (central diabetes insipidus) and 15 healthy controls. All participants completed the study and were included in the analyses. In healthy controls, median plasma oxytocin concentration was 77 pg/mL (IQR 59-94) at baseline and increased by 659 pg/mL (355-914) in response to MDMA, resulting in an AUC of 102 095 pg/mL (41 782-129 565); in patients, baseline oxytocin concentration was 60 pg/mL (51-74) and only slightly increased by 66 pg/mL (16-94) in response to MDMA, resulting in an AUC of 6446 pg/mL (1291-11 577). The effect of MDMA on oxytocin was significantly different between groups: the AUC for oxytocin was 82% (95% CI 70-186) higher in healthy controls than in patients (difference 85 678 pg/mL [95% CI 63 356-108 000], p<0·0001). The increase in oxytocin in healthy controls was associated with typical strong subjective prosocial, empathic, and anxiolytic effects, whereas only minimal subjective effects were observed in patients, in agreement with the lack of increase in oxytocin concentrations. The most frequently reported adverse effects were fatigue (eight [53%] healthy controls and eight [53%] patients), lack of appetite (ten [67%] healthy controls and eight [53%] patients), lack of concentration (eight [53%] healthy controls and seven [47%] patients), and dry mouth (eight [53%] healthy controls and eight [53%] patients). In addition, two (13%) healthy controls and four (27%) patients developed transient mild hypokalaemia.
These findings are highly suggestive of clinically meaningful oxytocin deficiency in patients with arginine vasopressin deficiency (central diabetes insipidus), laying the groundwork for a new hypothalamic-pituitary disease entity.
Swiss National Science Foundation, Swiss Academy of Medical Sciences, and the G&J Bangerter-Rhyner Foundation.
摘要：
背景：下丘脑-垂体轴的破坏可导致精氨酸加压素缺乏，也被称为中央尿崩症。由于产生催产素的神经元在解剖学上非常接近，因此患有这种疾病的患者存在其他催产素缺乏症的高风险;然而，没有关于这种缺陷的确凿证据的报道。我们的目标是使用3,4-亚甲二氧基甲基苯丙胺（MDMA，也称为摇头丸)，中枢氧化系统的强激活剂，作为生化和精神激发试验，以调查精氨酸加压素缺乏（中枢尿崩症）患者的催产素缺乏。
方法：这种单中心，巢式病例对照研究，随机化，双盲,安慰剂对照交叉试验包括精氨酸加压素缺乏症（中枢性尿崩症）患者和健康对照（按年龄1：1匹配，性别,和BMI），并在巴塞尔大学医院进行，巴塞尔,瑞士。我们使用区组随机分配参与者在第一个实验阶段接受单次口服MDMA（100mg）或安慰剂；患者在下一个阶段接受相反的治疗，两次会议之间至少有2周的时间。评估结果的参与者和研究人员被掩盖为分配。在MDMA或安慰剂后0、90、120、150、180和300分钟测量催产素浓度。主要结果是药物摄入后血浆催产素浓度曲线下的面积（AUC）。使用线性混合效应模型在组和条件之间比较AUC。在整个研究中使用十点视觉模拟量表评估主观药物效果。使用66项投诉清单评估药物摄入之前和之后360分钟的急性不良反应。该试验已在ClinicalTrials.gov注册，NCT04648137。
结果：在2021年2月1日至2022年5月1日之间，我们招募了15名精氨酸加压素缺乏症（中枢性尿崩症）患者和15名健康对照。所有参与者完成研究并纳入分析。在健康的控制中，基线时血浆中值催产素浓度为77pg/mL(IQR59-94),MDMA后升高659pg/mL(355-914),导致AUC为102095pg/mL（41782-129565）；在患者中，基线催产素浓度为60pg/mL（51-74），对MDMA的反应仅略微增加了66pg/mL（16-94），导致6446pg/mL的AUC(1291-11577)。MDMA对催产素的影响在组间有显著差异：健康对照组的催产素AUC比患者高82%（95%CI70-186）（差异85678pg/mL[95%CI63356-108000]，p<0·0001)。健康对照组中催产素的增加与典型的强烈主观亲社会相关，同情，和抗焦虑作用，而在患者中只观察到最小的主观影响，与催产素浓度缺乏增加一致。最常报告的不良反应是疲劳（8[53％]健康对照和8[53％]患者）。食欲不振（10名[67%]健康对照和8名[53%]患者），注意力不集中（8个[53%]健康对照和7个[47%]患者），和口干（8名[53%]健康对照和8名[53%]患者）。此外,2例(13%)健康对照和4例(27%)患者出现短暂性轻度低钾血症.
结论：这些发现高度提示精氨酸加压素缺乏症（中心性尿崩症）患者存在有临床意义的催产素缺乏症，为下丘脑-垂体疾病的新实体奠定基础。
背景：瑞士国家科学基金会，瑞士医学科学院,以及G&JBangerter-Rhyner基金会.
方法：这种单中心，巢式病例对照研究，随机化，双盲,安慰剂对照交叉试验包括精氨酸加压素缺乏症（中枢性尿崩症）患者和健康对照（按年龄1：1匹配，性别,和BMI），并在巴塞尔大学医院进行，巴塞尔,瑞士。我们使用区组随机分配参与者在第一个实验阶段接受单次口服MDMA（100mg）或安慰剂；患者在下一个阶段接受相反的治疗，两次会议之间至少有2周的时间。评估结果的参与者和研究人员被掩盖为分配。在MDMA或安慰剂后0、90、120、150、180和300分钟测量催产素浓度。主要结果是药物摄入后血浆催产素浓度曲线下的面积（AUC）。使用线性混合效应模型在组和条件之间比较AUC。在整个研究中使用十点视觉模拟量表评估主观药物效果。使用66项投诉清单评估药物摄入之前和之后360分钟的急性不良反应。该试验已在ClinicalTrials.gov注册，NCT04648137。
结果：在2021年2月1日至2022年5月1日之间，我们招募了15名精氨酸加压素缺乏症（中枢性尿崩症）患者和15名健康对照。所有参与者完成研究并纳入分析。在健康的控制中，基线时血浆中值催产素浓度为77pg/mL(IQR59-94),MDMA后升高659pg/mL(355-914),导致AUC为102095pg/mL（41782-129565）；在患者中，基线催产素浓度为60pg/mL（51-74），对MDMA的反应仅略微增加了66pg/mL（16-94），导致6446pg/mL的AUC(1291-11577)。MDMA对催产素的影响在组间有显著差异：健康对照组的催产素AUC比患者高82%（95%CI70-186）（差异85678pg/mL[95%CI63356-108000]，p<0·0001)。健康对照组中催产素的增加与典型的强烈主观亲社会相关，同情，和抗焦虑作用，而在患者中只观察到最小的主观影响，与催产素浓度缺乏增加一致。最常报告的不良反应是疲劳（8[53％]健康对照和8[53％]患者）。食欲不振（10名[67%]健康对照和8名[53%]患者），注意力不集中（8个[53%]健康对照和7个[47%]患者），和口干（8名[53%]健康对照和8名[53%]患者）。此外,2例(13%)健康对照和4例(27%)患者出现短暂性轻度低钾血症.
结论：这些发现高度提示精氨酸加压素缺乏症（中心性尿崩症）患者存在有临床意义的催产素缺乏症，为下丘脑-垂体疾病的新实体奠定基础。
背景：瑞士国家科学基金会，瑞士医学科学院,以及G&JBangerter-Rhyner基金会.
