Drug treatment of Parkinson's disease in the 1990s. Achievements and future possibilities.

Advances in the medical treatment of Parkinson's disease have improved the disability related to complications of long term levodopa therapy, including motor fluctuations, dyskinesias and neuropsychiatric toxicity. A range of new dopamine agonists are in various stages of preclinical and clinical development. Cabergoline appears to be effective in improving moderate motor fluctuations, and a number of dopamine partial agonists that can act as either agonists or antagonists depending on the degree of denervation and receptor sensitivity are being investigated. Apomorphine represents a significant advance in the treatment of well developed motor fluctuations in selected patients who are able to master the technique of subcutaneous administration. The catecholamine-O-methyl transferase inhibitors are proving useful in phase III studies in the management of patients with moderate motor fluctuations. A role for glutamate antagonists is supported by animal and early clinical data, although the poor therapeutic index associated with the currently available nonselective, noncompetitive glutamate antagonists has prompted a search for more selective antagonists with less toxicity. The management of levodopa-induced dyskinesias remains a major therapeutic challenge. Some reports of dopamine partial agonists, selective D2 receptor antagonists and atypical antipsychotics being useful await confirmation. Neuropsychiatric toxicity probably remains the major dose-limiting adverse effect of levodopa and is a major reason for parkinsonian patients being admitted to nursing homes. The development of new atypical antipsychotics with improved therapeutic indices, along with the possible use of serotonergic antagonists, may improve management of this difficult problem. The challenge will be to fit these new forms of treatment into our present range of available drugs and to assess their relative role within the emerging framework of functional neurosurgery for parkinsonian disability.