In an open study the cholinolytic biperiden was administered to 10 severely depressed inpatients in an average dose of 12 mg per day for 30 days. Patients were classified according to the International Classification of Diseases, the research Diagnostic Criteria and the Newcastle Scale. A significant improvement was demonstrated in the global score of the Hamilton Depression Scale (p less than 0.001). Especially the factors retardation (p less than 0.001) and agitation (p less than 0.001) and the items depressed mood (p less than 0.001), initial insomnia (p less than 0.05), work and interest (p less than 0.001) and gastrointestinal symptoms (p less than 0.001) could favorably be influenced. Nevertheless, biperiden treatment had to be discontinued after three weeks in two patients because of a paranoid syndrome in one case and symptoms of inner restlessness and disturbances of vital feelings in the other case. There was a positive correlation between the clinical response and the cortisol non-suppressability to dexamethasone prior to the study (p less than 0.03). These results taken together with other findings from the literature suggest that cholinergic mechanisms may have an important impact on the pathogenesis of certain forms of depression.