Abstract
BackgroundWhether 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.MethodsThe 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).ResultsPrimary 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).ConclusionsOur 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.Trial registrationThe 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
Highlights
Whether Borna disease virus (BDV-1) is a human pathogen remained controversial until recent encephalitis cases showed Borna disease virus 1 (BDV-1) infection could even be deadly
Statistical analyses on the strength of association within and between clinical and infection variables were done through calculating Pearson’s correlation coefficient (r) and Spearman’s coefficient of rank correlation (2-tailed) by aid of up-to-date SPSS software, completed using version 19.0 (IBM SPSS Statistics for Windows, released 2010). This is the first report on the clinical and antiviral efficacy of amantadine in BDV-1 infected depressive patients evaluated in a company-independent randomized clinical trial (RCT) and conducted in a placebo-controlled cross-over and double-blind design
We applied the design of a double-blind placebocontrolled phase II RCT which cross-linked depression and BDV-1 infection to evaluate the antidepressant and antiviral effect of amantadine
Summary
Whether Borna disease virus (BDV-1) is a human pathogen remained controversial until recent encephalitis cases showed BDV-1 infection could even be deadly. Depressive disorders contributed to the largest proportion (40.5%) of disability-adjusted life years (DALYs) within mental diseases They accounted for almost one third of the global suicide burden (10.4 of 36.2 million DALYs), over 80% attributable to low and middle income countries [2]. A completely novel capacity of amantadine as antiviral compound against human Borna disease virus (BDV-1) strains coincided with antidepressant effects in a BDV-infected patient with therapy-resistant bipolar depression [6]. This serendipitous discovery and further supportive open trials [7, 8] led us to conduct a “proof of concept” randomized double-blind placebo-controlled cross-over trial reported here. The novel rationale included a paradigm shift which cross-linked both depression with BDV-1 infection, and anti-BDV capacity of amantadine with antidepressant efficacy in infected patients
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