Cholinergic hyperactivity and negative symptoms: behavioral effects of physostigmine in normal controls

Intravenous infusion of physostigmine (a centrally active anticholinesterase agent) in normal subjects leads to a syndrome of psychomotor inhibition; this has been proposed as a model for selected symptoms of depression. In view of its similarity to the negative schizophrenic syndrome, we compared the 'physostigmine syndrome' to the negative symptom profile by evaluating the behavioral effects of intravenous physostigmine infusion in seven normal volunteers. Observer ratings and self description revealed significant withdrawal, apathy, alogia, lethargy, decreased energy, slowed thoughts, diminished affective responsivity, and reduced hedonic capacity. Subjects did not report sadness, ideas of hopelessness, worthlessness, or guilt. These findings support the implication of cholinergic hyperactivity as one mechanism in the pathophysiology of negative schizophrenic symptoms.