Any reasonable, informed clinician will accept the overwhelming epidemiologic evidence implicating neuroleptic drugs in the causation of tardive dyskinesia, with the caveat that not every case that looks like tardive dyskinesia is neuroleptic-related. Spontaneous dyskinesia (Marsden, 1985; Casey, 1987) and dyskinesias induced by drugs other than neuroleptics, such as antihistamines, antidepressants, and metoclopramide, often are indistinguishable from tardive dyskinesia. As Marsden (1985) pointed out, the causative relationship implies either that neuroleptics induce tardive dyskinesia in individuals who otherwise would not develop it or that neuroleptics precipitate tardive dyskinesia in patients who already carry the substrate for development of tardive dyskinesia.

Patients exposed to neuroleptics differ regarding variables such as age at first neuroleptic exposure, time since the start of neuroleptic treatment, duration of neuroleptic treatment (i.e., actual time on neuroleptics), number and duration of neuroleptic-free intervals, number of neuroleptics used, amount of neuroleptic (i.e., total quantity delivered), average neuroleptic dosage, and maximum neuroleptic dosage. Other areas of interest include comparisons of exposures to high- and low-potency neuroleptics, the number of neuroleptics simultaneously prescribed, the route of administration (depot vs. oral), and different schedules, such as a dose once daily versus twice daily (BID), or doses as needed (PRN) (oral and/or intramuscular). Only adequate knowledge of the pathogenesis of tardive dyskinesia will enable us to decide which of these drug variables are of particular relevance to tardive dyskinesia.