Whether Borna disease virus (BDV-1) is a human pathogen remained controversial until recent encephalitis cases showed BDV-1 infection could even be deadly. This called to mind previous evidence for an infectious contribution of BDV-1 to mental disorders. Pilot open trials suggested that BDV-1 infected depressed patients benefitted from antiviral therapy with a licensed drug (amantadine) which also tested sensitive in vitro. Here, we designed a double-blind placebo-controlled randomized clinical trial (RCT) which cross-linked depression and BDV-1 infection, addressing both the antidepressant and antiviral efficacy of amantadine. The interventional phase II RCT (two 7-weeks-treatment periods and a 12-months follow-up) at the Hannover Medical School (MHH), Germany, assigned currently depressed BDV-1 infected patients with either major depression (MD; N = 23) or bipolar disorder (BD; N = 13) to amantadine sulphate (PK-Merz®; twice 100 mg orally daily) or placebo treatment, and contrariwise, respectively. Clinical changes were assessed every 2–3 weeks by the 21-item Hamilton rating scale for depression (HAMD) (total, single, and combined scores). BDV-1 activity was determined accordingly in blood plasma by enzyme immune assays for antigens (PAG), antibodies (AB) and circulating immune complexes (CIC). Primary outcomes (≥25% HAMD reduction, week 7) were 81.3% amantadine vs. 35.3% placebo responder (p = 0.003), a large clinical effect size (ES; Cohen’s d) of 1.046, and excellent drug tolerance. Amantadine was safe reducing suicidal behaviour in the first 2 weeks. Pre-treatment maximum infection levels were predictive of clinical improvement (AB, p = 0.001; PAG, p = 0.026; HAMD week 7). Respective PAG and CIC levels correlated with AB reduction (p = 0,001 and p = 0.034, respectively). Follow-up benefits (12 months) correlated with dropped cumulative infection measures over time (p < 0.001). In vitro, amantadine concentrations as low as 2.4–10 ng/mL (50% infection-inhibitory dose) prevented infection with human BDV Hu-H1, while closely related memantine failed up to 100,000-fold higher concentration (200 μg/mL). Our findings indicate profound antidepressant efficacy of safe oral amantadine treatment, paralleling antiviral effects at various infection levels. This not only supports the paradigm of a link of BDV-1 infection and depression. It provides a novel possibly practice-changing low cost mental health care perspective for depressed BDV-1-infected patients addressing global needs. The trial was retrospectively registered in the German Clinical Trials Registry on 04th of March 2015. The trial ID is DRKS00007649; https://www.drks.de/drks_web/setLocale_EN.do

中文翻译：

---

在严重抑郁症中针对Borna病病毒1感染的抗病毒治疗观点：双盲安慰剂对照的随机临床试验

在最近的脑炎病例显示BDV-1感染甚至可能致命之前，是否存在Borna病病毒（BDV-1）是否是人类病原体仍存在争议。这使我们想起了先前的证据，证明BDV-1对精神障碍具有感染性。公开试验表明，感染BDV-1的抑郁症患者可从使用许可药物（金刚烷胺）进行抗病毒治疗中受益，该药物也可在体外进行敏感性测试。在这里，我们设计了一项双盲安慰剂对照随机临床试验（RCT），该试验将抑郁症和BDV-1感染联系起来，解决了金刚烷胺的抗抑郁和抗病毒功效。在德国汉诺威医学院（MHH）进行的干预性II期RCT（两个为期7周的治疗期，为期12个月的随访）分配了当前患有抑郁症的BDV-1感染者或重度抑郁症（MD；N = 23）或双相情感障碍（BD； N = 13）分别为硫酸金刚烷胺（PK-Merz®；每天两次，口服100 mg）或安慰剂治疗，相反。每2–3周通过21项汉密尔顿抑郁量表（HAMD）（总分，单项和综合得分）评估临床变化。因此，通过针对抗原（PAG），抗体（AB）和循环免疫复合物（CIC）的酶免疫测定法在血浆中确定了BDV-1活性。主要结局指标（HAMD降低≥25％，第7周）为81.3％金刚烷胺与35.3％的安慰剂应答者（p = 0.003），较大的临床疗效量（ES； Cohen's d）为1.046，且药物耐受性优异。金刚烷胺在头2周内可以安全地减少自杀行为。治疗前最大感染水平可预示临床改善（AB，p = 0.001； PAG，p = 0.026； HAMD第7周）。各自的PAG和CIC水平与AB降低相关（分别为p = 0,001和p = 0.034）。随访收益（12个月）与随着时间的流逝累积感染措施的减少相关（p <0.001）。在体外，金刚烷胺的浓度低至2.4–10 ng / mL（50％的感染抑制剂量）可防止人BDV Hu-H1感染，而密切相关的美金刚胺的浓度却高达100,000倍（200μg/ mL）。我们的发现表明，安全的口服金刚烷胺治疗具有很强的抗抑郁功效，与各种感染水平的抗病毒作用相当。这不仅支持BDV-1感染和抑郁症之间联系的范例。它为抑郁的BDV-1感染患者提供了一种新颖的，可能改变实践的低成本精神卫生保健观点，以满足全球需求。该试验已于2015年3月4日在德国临床试验注册中心进行回顾性注册。试验ID为DRKS00007649；https://www.drks.de/drks_web/setLocale_EN.do