To the Editor: With regard to Raquel E. Gur, M.D., Ph.D., et al.’s (1) demonstration that higher doses of typical neuroleptics are associated with increased subcortical volumes, Nancy C. Andreasen, M.D., Ph.D., (2) wrote that 10 years ago, "no one thought that treatment could produce structural changes in the brain!" (p. 1658).

This is not the case. In 1977, Jellinger (3) reviewed the extensive literature on neuropathological changes induced by chronic neuroleptic therapy and noted that under some circumstances, neuroleptics could lead to changes that later might result in irreversible damage, especially in the caudate. As concerns over tardive dyskinesia mounted, more investigators began to pursue the association between structural brain changes, neuroleptics, and dyskinetic movements. By 1987, Waddington et al. (4) noted that eight of 11 systematic studies had found evidence of structural brain changes associated with neuroleptic-induced involuntary movements. In 1992, Dean and Borchardt (5), in a lengthy examination of the risks and the benefits of neuroleptic therapy, reviewed multiple studies performed over the previous two decades that documented ventricular enlargement, striatal atrophy, cellular degeneration, and cognitive impairment in some patients treated with neuroleptics, often in association with tardive dyskinesia.

It seems clear, then, that concerns over structural brain changes induced by neuroleptics have been present for almost three decades. There seems little doubt that such changes are in part responsible for the development of neuroleptic-induced movement disorders and cognitive impairment, although research in this area has been complicated by studies—too numerous to list here—that clearly show the presence of parkinsonism and dyskinetic movements in neuroleptic-naive patients.

Given these issues, perhaps Dr. Andreasen’s editorial comments should have included a question: Why did Dr. Gur et al. fail to include data on the prevalence and severity of abnormal movements in their cohort? Correlative data on the location, severity, and laterality of abnormal movements and anatomical changes surely would have been of great interest.