Dopaminomimetic psychosis in Parkinson's disease patients: diagnosis and treatment.
Dopaminomimetic agents, which were rationally designed to reverse dopamine deficits in the substantia nigra and ventral tegmental area of the parkinsonian midbrain, effectively attenuate deficits in motor and non-motor behavior thought to be elicited by dopamine deficiencies in the striatal and frontal limbic regions, respectively. On the other hand, dopaminomimetic medications may also induce perturbations in postsynaptic peptides, causing dopaminergic hypersensitivity. Drug-induced chronic dopaminomimetic psychosis afflicts about one-fifth of PD patients on dopaminergic regimens. Although the long-held mechanism for psychosis in PD is excessive stimulation of mesocorticolimbic dopamine receptors, interactions between dopamine and serotonin, as well as participation of serotonin-modulated GABAergic neurons may also contribute to the pathophysiology. Reduction or withdrawal of anticholinergic agents, amantadine, and dopamine precursors or agonists constitutes a first approach to the problem but is often insufficient. Unfortunately, typical antipsychotic agents such as haloperidol, which selectively antagonizes dopamine D-2 receptors, can induce extrapyramidal syndromes such as tardive parkinsonism. On the other hand, emerging atypical neuroleptics such as clozapine, quetiapine, and olanzapine, which antagonize 5HT-2A receptors (among others), inhibit D-2 receptors to a lesser degree and exhibit selective binding to mesolimbic (vs. striatal) dopamine receptors. The limbic selectivity of these agents appears to be of greater magnitude than that typical of risperidone. In addition, the selective antiserotonergic agent ondansetron is a prospective therapeutic option. The pharmacologic properties of these agents are explored.
Wolters
E C
EC
Graduate School Neurosciences Amsterdam, Research Institute Neurosciences VU, Department of Neurology AZVU, The Netherlands.
D000978:Antiparkinson Agents / Q000009:adverse effects* / Q000627:therapeutic use; D018491:Dopamine Agonists / Q000009:adverse effects* / Q000627:therapeutic use; D006801:Humans; D010300:Parkinson Disease / Q000175:diagnosis* / Q000188:drug therapy; D011605:Psychoses, Substance-Induced / Q000209:etiology*
D000978:Antiparkinson Agents; D018491:Dopamine Agonists