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Pharmacological Strategies for the Management of Levodopa-Induced Dyskinesia in Patients with Parkinson’s Disease

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Abstract

l-Dopa-induced dyskinesias (LID) are the most common adverse effects of long-term dopaminergic therapy in Parkinson’s disease (PD). However, the exact mechanisms underlying dyskinesia are still unclear. For a long time, nigrostriatal degeneration and pulsatile stimulation of striatal postsynaptic receptors have been highlighted as the key factors for the development of LID. In recent years, PD models have revealed a wide range of non-dopaminergic neurotransmitter systems involved in pre- and postsynaptic changes and thereby contributing to the pathophysiology of LID. In the current review, we focus on therapeutic LID targets, mainly based on agents acting on dopaminergic, glutamatergic, serotoninergic, adrenergic, and cholinergic systems. Despite a large number of clinical trials, currently only amantadine and, to a lesser extent, clozapine are being used as effective strategies in the treatment of LID in clinical settings. Thus, in the second part of the article, we review the placebo-controlled trials on LID treatment in order to disentangle the changing scenario of drug development. Promising results include the extension of l-dopa action without inducing LID of the novel monoamine oxidase B- and glutamate-release inhibitor safinamide; however, this had no obvious effect on existing LID. Others, like the metabotropic glutamate-receptor antagonist AFQ056, showed promising results in some of the studies; however, confirmation is still lacking. Thus, to date, strategies of continuous dopaminergic stimulation seem the most promising to prevent or ameliorate LID. The success of future therapeutic strategies once moderate to severe LID occur will depend on the translation from preclinical experimental models into clinical practice in a bidirectional process.

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The authors Eva Schaeffer, Andrea Pilotto, and Daniela Berg report no conflicts of interest and no funding.

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  1. Department of Neurodegeneration, Hertie Institute for Clinical Brain Research, University of Tuebingen, Hoppe Seyler-Strasse 3, 72076, Tübingen, Germany

    Eva Schaeffer, Andrea Pilotto & Daniela Berg

  2. German Center of Neurodegenerative Diseases (DZNE), Tübingen, Germany

    Eva Schaeffer & Daniela Berg

  3. Neurology Unit, Centre for Ageing Brain and Neurodegenerative Disorders, University of Brescia, Brescia, Italy

    Andrea Pilotto

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Schaeffer, E., Pilotto, A. & Berg, D. Pharmacological Strategies for the Management of Levodopa-Induced Dyskinesia in Patients with Parkinson’s Disease. CNS Drugs 28, 1155–1184 (2014). https://doi.org/10.1007/s40263-014-0205-z

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