Physostigmine, a cholinesterase inhibitor which increases central acetylcholine levels, has been found in man to decrease manic symptoms, antagonize methylphenidate-induced behavioral activation, and induce severe depression and psychomotor retardation in marijuana intoxicated normals. In the current study, physostigmine was found to increase depressed mood in patients with an affective component to their symptoms (manics, depressives, and schizoaffectives). Schizophrenics without an affective component did not become depressed. After physostigmine administration, all subject groups showed a significant increase in symptoms including lethargy, slowed thoughts, withdrawal, apathy, decreased energy, decreased thoughts, motor retardation, and feeling drained, indicating a state of psychomotor retardation; and all became less cheerful, friendly, and talkative. The above information is compatible with the hypothesis that acetylcholine may be involved in the etiology of affective disorders.