Dogma disputed: is tardive dyskinesia due to postsynaptic dopamine receptor supersensitivity?

The most popular theory of the pathophysiology of neuroleptic-induced tardive dyskinesia (TD) attributes the movement disorder to central postsynaptic dopamine receptor supersensitivity. This hypothesis is based on circumstantial evidence. A consideration of the available clinical and animal data suggests the following: (1) Central catecholaminergic overactivity is present in TD and it could result from presynaptic and/or postsynaptic disturbances. (2) Postsynaptic dopamine receptor supersensitivity is a normal consequence of neuroleptic administration and is not sufficient to explain why TD develops only in a proportion of patients receiving long-term neuroleptic treatment. Postsynaptic dopaminergic supersensitivity may be responsible for withdrawal dyskinesias, but clinical studies do not support the supersensitivity hypothesis in most patients with persistent TD. (3) Noradrenergic hyperactivity and presynaptic dopaminergic overactivity may be necessary for the induction of at least certain subtypes of TD.