The euphoric response to equivalent doses of intravenous methylphenidate (MTP) was assessed in a group of 13 Parkinsonian patients affected by major depression, in a group of 11 nondepressed Parkinsonians, in a group of 14 nonparkinsonian subjects suffering from major depression, and finally in a group of 12 controls with no CNS or psychiatric disease. Subjects of all four groups were matched for age, sex and other main characteristics. Depressed and nondepressed Parkinsonians were also matched for duration and severity of illness, and for the type of antiparkinsonian treatment. The response to MTP was evaluated in the context of a double-blind, placebo-controlled study. Parkinsonian patients with major depression exhibited a significant lack of sensitivity to the euphoriant effects of MTP, in comparison with the other three groups. Euphoria produced by central stimulants has been shown to depend on the activity of a dopamine synapse in humans, which is thought to be situated at the limbic terminals of dopamine neurons located in the ventral tegmental area. Degeneration of this system may have predisposed our Parkinsonian patients to major depression.