Journal of Neurology

, Volume 260, Issue 2, pp 521–527 | Cite as

Valproate as a treatment for dopamine dysregulation syndrome (DDS) in Parkinson’s disease

  • Ashok Sriram
  • Herbert E. Ward
  • Anhar Hassan
  • Sanjay Iyer
  • Kelly D. Foote
  • Ramon L. Rodriguez
  • Nikolaus R. McFarland
  • Michael S. OkunEmail author
Original Communication


It has been previously well established that the use of dopaminergic agents in Parkinson’s disease may contribute to behavioral disturbances such as dopamine dysregulation syndrome (DDS), impulse control disorders (ICD), and punding. ICD and punding have been most commonly addressed by reducing dose or by discontinuing the use of a dopamine agonist. Treatment of DDS has proven more challenging, and to date there has been no standard approach. In this paper, we review a series of four patients who met criteria for DDS, who were all refractory to medication adjustments. The DDS symptoms responded by the addition of valproic acid in all cases.


Dopamine dysregulation syndrome Parkinson’s disease Impulse control disorder Valproic acid Dominion 



We would like to acknowledge the support of the National Parkinson Foundation Center of Excellence at the University of Florida.

Conflicts of interest

Ashok Sriram: Dr. Sriram has no conflict to report. Herbert E. Ward: Dr. Ward has no conflict to report; Dr. Ward participated as site PI on multiple clinical trials; Dr. Ward did not accept any personal industry honoraria. Anhar Hassan: Dr. Hassan no conflict to report; Dr. Hassan received honoraria from National Parkinson Foundation. Sanjay Iyer: Dr. Iyer has no conflict to report. Kelly D. Foote: Dr. Foote receives no honoraria or personal remuneration from any industry source. His research is funded by NIH and multiple foundation sources; DBS devices for Dr. Foote's research have been provided by Medtronic and Neuropace; Dr. Foote participates as a site in multicenter DBS-related research studies sponsored by St. Jude and Boston Scientific; The University of Florida receives partial funding for Dr. Foote's functional neurosurgery fellowship from Medtronic. Ramon L Rodriguez: Grants/Research Support: Dr. Rodriguez has received research support from Abbott, Biotie Therapeutics, EMD-Serono, Huntington Study Group, Ipsen, Merz Pharmaceuticals, Allergan, National Parkinson Foundation, NIH/NINDS, Teva, but has no owner interest in any pharmaceutical company; Honoraria: Over the last 12 months, Dr. Rodriguez has received honoraria from PeerView Institute for Medical Education, PRIME CME, Corporate Meeting Solutions, Merz Pharmaceuticals; Royalty: None; Speaker Bureaus: None; Contractual Services: The University of Florida Clinic has contracts with Allergan for education services provided by Dr. Rodriguez, but he does not receive any personal compensation for these roles. Nikolaus R. McFarland: Dr. McFarland has no conflicts to report; Dr. McFarland has received research grants from NIH and the Michael J. Fox Foundation, but no receives no industry support. He has also participated in CME activities on movement disorders sponsored by the USF CME office. Michael S. Okun: Dr. Okun serves as a consultant for the National Parkinson Foundation, and has received research grants from NIH, NPF, the Michael J. Fox Foundation, the Parkinson Alliance, Smallwood Foundation, and the UF Foundation; Dr. Okun has previously received honoraria, but in the past >36 months has received no support from industry including travel; Dr. Okun has received royalties for publications with Demos, Manson, and Cambridge (movement disorders books); Dr. Okun has participated in CME activities on movement disorders sponsored by the USF CME office, PeerView, and by Vanderbilt University. The institution and not Dr. Okun receives grants from Medtronic and ANS/St. Jude, and the PI has no financial interest in these grants; Dr. Okun has participated as a site PI and/or co-I for several NIH, foundation, and industry sponsored trials over the years but has not received honoraria.

Ethical standard

All human studies must state that they have been approved by the appropriate ethics committee and have therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki.


  1. 1.
    Hoehn M, Yahr M (2011) Parkinsonism: onset, progression, and mortality. Neurology 77(9):874. doi: 10.1212/01.wnl.0000405146.06300.91 CrossRefGoogle Scholar
  2. 2.
    Hughes AJ, Daniel SE, Kilford L, Lees AJ (1992) Accuracy of clinical diagnosis of idiopathic Parkinson’s disease: a clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry 55(3):181–184. doi: 10.1136/jnnp.55.3.181 PubMedCrossRefGoogle Scholar
  3. 3.
    Zhao YJ, Wee HL, Chan Y, Seah SH, Au WL, Lau PN et al (2010) Progression of Parkinson’s disease as evaluated by Hoehn and Yahr stage transition times. Mov Disord 25(6):710–716. doi: 10.1002/mds.22875 PubMedCrossRefGoogle Scholar
  4. 4.
    Hoehn MM (1992) The natural history of Parkinson’s disease in the pre-levodopa and post-levodopa eras. Neurol Clin 10(2):331–339PubMedGoogle Scholar
  5. 5.
    Obeso JA, Rodriguez-Oroz MC, Chana P, Lera G, Rodriguez M, Olanow CW (2000) The evolution and origin of motor complications in Parkinson’s disease. Neurology 55:S13–S20PubMedGoogle Scholar
  6. 6.
    Giovannoni G, O’Sullivan JD, Turner K, Manson AJ, Lees AJL (2000) Hedonistic homeostatic dysregulation in patients with Parkinson’s disease on dopamine replacement therapies. J Neurol Neurosurg Psychiatry 68(4):423–428. doi: 10.1136/jnnp.68.4.423 PubMedCrossRefGoogle Scholar
  7. 7.
    Cantello R (2000) Hedonistic homeostatic dysregulation in patients with Parkinson’s disease on dopamine replacement therapies. J Neurol Neurosurg Psychiatry 69(4):566–567. doi: 10.1136/jnnp.69.4.566a PubMedCrossRefGoogle Scholar
  8. 8.
    Evans AH, Strafella AP, Weintraub D, Stacy M (2009) Impulsive and compulsive behaviors in Parkinson’s disease. Mov Disord 24(11):1561–1570. doi: 10.1002/mds.22505 PubMedCrossRefGoogle Scholar
  9. 9.
    Limotai N, Oyama G, Go C, Bernal O, Ong T, Moum SJ et al (2011) Addiction-like manifestations and Parkinson’s disease: a large single center 9-year experience. Int J Neurosci. doi: 10.3109/00207454.2011.633722 PubMedGoogle Scholar
  10. 10.
    Bondon-Guitton E, Perez-Lloret S, Bagheri H, Brefel C, Rascol O, Montastruc J (2011) Drug-induced parkinsonism: a review of 17 years’ experience in a regional pharmacovigilance center in France. Mov Disord 26(12):2226–2231. doi: 10.1002/mds.23828 PubMedCrossRefGoogle Scholar
  11. 11.
    Easterford K, Clough P, Kellett M et al (2004) Reversible parkinsonism with normal beta-CIT-SPECT in patients exposed to sodium valproate. Neurology 62:1435–1437PubMedCrossRefGoogle Scholar
  12. 12.
    Mahmoud F, Tampi RR (2011) Valproic Acid–Induced parkinsonism in the elderly: a comprehensive review of the literature. Am J Geriatric Pharmacother 9(6):405–412. doi: 10.1016/j.amjopharm.2011.09.002 CrossRefGoogle Scholar
  13. 13.
    Kummer A, Maia DP, Salgado JV, Cardoso FEC, Teixeira AL (2006) Dopamine dysregulation syndrome in Parkinson’s disease: case report. Arquivos De Neuro-Psiquiatria 64(4):1019–1022Google Scholar
  14. 14.
    Gerschlager W, Bloem BR (2009) Managing pathological gambling in Parkinson’s disease with enteral levodopa/carbidopa infusions. Mov Disord 24(12):1858–1860. doi: 10.1002/mds.22652 PubMedCrossRefGoogle Scholar
  15. 15.
    Regina K (2011) Dopaminergic dysregulation syndrome in Parkinson’s disease. J Neurol Sci 310(1–2):271–275. doi: 10.1016/j.jns.2011.07.012 Google Scholar
  16. 16.
    Bandini F, Primavera A, Pizzorno M, Cocito L (2007) Using STN DBS and medication reduction as a strategy to treat pathological gambling in Parkinson’s disease. Parkinsonism Relat Disord 13(6):369–371. doi: 10.1016/j.parkreldis.2006.07.011 PubMedCrossRefGoogle Scholar
  17. 17.
    Witjas T, Baunez C, Henry JM, Delfini M, Regis J, Cherif AA et al (2005) Addiction in Parkinson’s disease: impact of subthalamic nucleus deep brain stimulation. Mov Disord 20(8):1052–1055. doi: 10.1002/mds.20501 PubMedCrossRefGoogle Scholar
  18. 18.
    De la Casa-Fages B, Grandas F (2012) Dopamine dysregulation syndrome after deep brain stimulation of the subthalamic nucleus in Parkinson’s disease. J Neurol Sci. doi: 10.1016/j.jns.2011.08.014
  19. 19.
    Moum SJ, Price CC, Limotai N, Oyama G, Ward H et al (2012) Effects of STN and GPi deep brain stimulation on impulse control disorders and dopamine dysregulation syndrome. PLoS One 7(1):e29768. doi: 10.1371/journal.pone.0029768 PubMedCrossRefGoogle Scholar
  20. 20.
    Perucca E (2002) Pharmacological and therapeutic properties of valproate. A summary after 35 years of clinical experience. CNS Drugs 16:695–714PubMedCrossRefGoogle Scholar
  21. 21.
    Peterson GM, Maunton M (2005) Valproate: a simple chemical with so much to offer. J Clin Pharm Ther 30:417–421PubMedCrossRefGoogle Scholar
  22. 22.
    Mathew NT, Saper JR, Silberstein SD, Rankin L, Markley HG, Solomon S et al (1995) Migraine prophylaxis with divalproex. Arch Neurol 52(3):281–286. doi: 10.1001/archneur.1995.00540270077022 PubMedCrossRefGoogle Scholar
  23. 23.
    Löscher W (1980) Effect of inhibitors of GABA transaminase on the synthesis, binding, uptake and metabolism of GABA. J Neurochem 34(6):1603–1608. doi: 10.1111/j.1471-4159.1980.tb11250.x PubMedCrossRefGoogle Scholar
  24. 24.
    Macdonald RL, Bergey GK (1979) Valproic acid augments GABA-mediated postsynaptic inhibition in cultured mammalian neurons. Brain Res 170(3):558–562. doi: 10.1016/0006-8993(79)90975-2 PubMedCrossRefGoogle Scholar
  25. 25.
    Tian LM, Alkadhi KA (1994) Valproic acid inhibits the depolarizing rectification in neurons of rat amygdala. Neuropharmacology 33(10):1131–1138PubMedCrossRefGoogle Scholar
  26. 26.
    McLean MJ, Macdonald RL (1986) Sodium valproate, but not ethosuximide, produces use- and voltage-dependent limitation of high frequency repetitive firing of action potentials of mouse central neurons in cell culture. J Pharmacol Exp Ther 237(3):1001–1011PubMedGoogle Scholar
  27. 27.
    De Sarro G, Ascioti C, di Paola ED, Vidal MJ, De Sarro A (1992) Effects of antiepileptic drugs, calcium channel blockers and other compounds on seizures induced by activation of voltage-dependent L calcium channel in DBA/2 mice. Gen Pharmacol 23:1205–1216PubMedCrossRefGoogle Scholar
  28. 28.
    Eikel D, Lampen A, Nau H (2006) Teratogenic effects mediated by inhibition of histone deacetylases: evidence from quantitative structure activity relationships of 20 valproic acid derivatives. Chem Res Toxicol 19:272–278PubMedCrossRefGoogle Scholar
  29. 29.
    Eikel D, Hoffmann K, Zoll K, Lampen A, Nau H (2006) S-2-pentyl-4-pentynoic hydroxamic and its metabolite S-2 metabolite S-2-pentyl-4-pentynoic acid in the NMRI-exencephaly-mouse model: pharmacokinetic profiles, teratogenic effects, and histone deacetylase inhibition abilities of further valproic acid hydroxamates and amides. Drug Metab Dispos 34(4):612–620. doi: 10.1124/dmd.105.008078 PubMedCrossRefGoogle Scholar
  30. 30.
    Töllner K, Wolf S, Löscher W, Gernert M (2011) The anticonvulsant response to valproate in kindled rats is correlated with its effect on neuronal firing in the substantia nigra pars reticulata: a new mechanism of pharmacoresistance. J Neurosci 31(45):16423–16434. doi: 10.1523/JNEUROSCI.2506-11.2011 PubMedCrossRefGoogle Scholar
  31. 31.
    Löscher W (2002) Basic pharmacology of valproate: a review after 35 years of clinical use for the treatment of epilepsy. CNS Drugs 16:669–694PubMedCrossRefGoogle Scholar
  32. 32.
    Rapoport SI, Basselin M, Kim H, Rao JS (2009) Bipolar disorder and mechanisms of action of mood stabilizers. Brain Res Rev 61(2):185–209. doi: 10.1016/j.brainresrev.2009.06.003 PubMedCrossRefGoogle Scholar
  33. 33.
    Ramadan E, Basselin M, Taha AY, Cheon Y, Chang L, Chen M et al (2011) Chronic valproate treatment blocks D2-like receptor-mediated brain signaling via arachidonic acid in rats. Neuropharmacology 61(8):1256–1264. doi: 10.1016/j.neuropharm.2011.07.025 PubMedCrossRefGoogle Scholar
  34. 34.
    Guidotti A, Auta J, Chen Y, Davis JM, Dong E, Gavin DP et al (2011) Epigenetic GABAergic targets in schizophrenia and bipolar disorder. Neuropharmacology 60(7–8):1007–1016. doi: 10.1016/j.neuropharm.2010.10.021 PubMedCrossRefGoogle Scholar
  35. 35.
    Jornada LK, Valvassori SS, Steckert AV, Moretti M, Mina F, Ferreira CL et al (2011) Lithium and valproate modulate antioxidant enzymes and prevent ouabain-induced oxidative damage in an animal model of mania. J Psychiatr Res 45(2):162–168. doi: 10.1016/j.jpsychires.2010.05.011 PubMedCrossRefGoogle Scholar
  36. 36.
    Evans AH, Pavese N, Lawrence AD, Tai YF, Appel S, Doder M et al (2006) Compulsive drug use linked to sensitized ventral striatal dopamine transmission. Ann Neurol 59(5):852–858. doi: 10.1002/ana.20822 PubMedCrossRefGoogle Scholar
  37. 37.
    Evans AH, Lawrence AD, Cresswell SA, Katzenschlager R, Lees AJ (2010) Compulsive use of dopaminergic drug therapy in Parkinson’s disease: reward and anti-reward. Mov Disord 25(7):867–876. doi: 10.1002/mds.22898 PubMedCrossRefGoogle Scholar
  38. 38.
    Lawrence AD, Evans AH, Lees AJ (2003) Compulsive use of dopamine replacement therapy in Parkinson’s disease: reward systems gone awry? Lancet Neurol 2(10):595–604. doi: 10.1016/S1474-4422(03)00529-5 PubMedCrossRefGoogle Scholar
  39. 39.
    Voon V, Sohr M, Lang AE, Potenza MN, Siderowf AD, Whetteckey J et al (2011) Impulse control disorders in Parkinson disease: a multicenter case control study. Ann Neurol 69(6):986–996. doi: 10.1002/ana.22356 PubMedCrossRefGoogle Scholar
  40. 40.
    Hicks CW, Pandya MM, Itin I, Fernandez HH (2011) Valproate for the treatment of medication-induced impulse-control disorders in three patients with Parkinson’s disease. Parkinsonism Relat Disord 17(5):379–381. doi: 10.1016/j.parkreldis.2011.03.003 PubMedCrossRefGoogle Scholar
  41. 41.
    Voon V, Gao J, Brezing C, Symmonds M, Ekanayake V, Fernandez H et al (2011) Dopamine agonists and risk: impulse control disorders in Parkinson’s disease. Brain 134(5):1438–1446. doi: 10.1093/brain/awr080 PubMedCrossRefGoogle Scholar
  42. 42.
    Kelley BJ, Duker AP, Chiu P (2012) Dopamine agonists and pathologic behaviors. Parkinson’s Dis 2012:603631. doi: 10.1155/2012/603631 Google Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Ashok Sriram
    • 1
  • Herbert E. Ward
    • 2
  • Anhar Hassan
    • 1
  • Sanjay Iyer
    • 3
  • Kelly D. Foote
    • 4
  • Ramon L. Rodriguez
    • 1
  • Nikolaus R. McFarland
    • 1
  • Michael S. Okun
    • 1
    • 4
    Email author
  1. 1.Department of NeurologyCenter for Movement Disorders and NeurorestorationGainesvilleUSA
  2. 2.Department of PsychiatryCenter for Movement Disorders and NeurorestorationGainesvilleUSA
  3. 3.CMC Neurology, EdgehillCharlotteUSA
  4. 4.Department of NeurosurgeryCenter for Movement Disorders and NeurorestorationGainesvilleUSA

Personalised recommendations