Patients with affective disorders show an enhanced prevalence of Borna disease virus (BDV)-infection. Furthermore, BDV causes latent infection preferably in limbic central nervous structures and is suggested to be causally related to subtypes of affective disorders, especially with melancholic clinical features or bipolarity. Such a possible link was highlighted by the first report of amantadine showing an antidepressive and an antiviral efficacy against BDV in a patient with a bipolar disorder. This article summarizes clinical studies which followed this first report on the use of amantadine in BDV-infected patients with an affective disorder. A special focus is given on an open clinical study in patients with depression (n = 25), a study in remitted patients with affective disorders (n = 16), and the effect of amantadine on severe hypomanic or moderately manic patients with a bipolar disorder in an on-off-on study. In these studies amantadine reduced clinical symptoms paralleled by a reduction of BDV-infection in depressive patients, it also reduced all three BDV-parameters (BDV-Ab, -AG, and -CICs) in remitted patients, and it even reduced severe hypomania and moderate mania in bipolar patients. These data suggest the existence of an etiopathogenetic link between BDV and subtypes of affective disorders.