Methylphenidate for gait impairment in Parkinson disease

Espay, Alberto J.; Dwivedi, Alok; Payne, Martha E.; Gaines, Laura; Vaughan, Jennifer E.; Maddux, Brian N.; Slevin, John T.; Gartner, Maureen; Sahay, Alok; Revilla, Fredy J.; Duker, Andrew P.; Shukla, Rakesh

doi:10.1212/wnl.0b013e3182143537

Cited by 87 publications

(50 citation statements)

References 31 publications

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“…ppERK/ERK1 values with their corresponding global AIMs over all treatments showing a significant correlation between ppERK1 and dyskinesia severity. Correlation analysis, n = 7, R = .86, P = .003. study), methylphenidate [which also affects NET function (Pan et al, 1994)] tended to increase LID (Devos et al, 2007;Espay et al, 2011). Exacerbation of dyskinesia in a clinical setting may go unnoticed given the absence of baseline readings before DMI administration.…”

Section: Norepinephrine Transporter and L-dopa Dyskinesiamentioning

confidence: 92%

Norepinephrine Transporter Inhibition with Desipramine Exacerbates L-DOPA–Induced Dyskinesia: Role for Synaptic Dopamine Regulation in Denervated Nigrostriatal Terminals

2014

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Pharmacological dopamine (DA) replacement with Levodopa [L-dihydroxyphenylalanine (L-DOPA)] is the gold standard treatment of Parkinson's disease (PD). However, long-term L-DOPA treatment is complicated by eventual debilitating abnormal involuntary movements termed L-DOPA-induced dyskinesia (LID), a clinically significant obstacle for the majority of patients who rely on L-DOPA to alleviate PD-related motor symptoms. The manifestation of LID may in part be driven by excessive extracellular DA derived from L-DOPA, but potential involvement of DA reuptake in LID severity or expression is unknown. We recently reported that in 6-hydroxydopamine (6-OHDA)-lesioned striatum, norepinephrine transporter (NET) expression increases and may play a significant role in DA transport. Furthermore, L-DOPA preferentially inhibits DA uptake in lesioned striatum. Therefore, we hypothesized that desipramine (DMI), a NET antagonist, could affect the severity of LID in an established LID model. Whereas DMI alone elicited no dyskinetic effects in lesioned rats, DMI 1 L-DOPA-treated rats gradually expressed more severe dyskinesia compared with L-DOPA alone over time. At the conclusion of the study, we observed reduced NET expression and norepinephrine-mediated inhibition of DA uptake in the DMI 1 L-DOPA group compared with L-DOPA-alone group in lesioned striatum. LID severity positively correlated with striatal extracellular signal-regulated protein kinase phosphorylation among the three treatment groups, with increased ppERK1/2 in DMI 1 L-DOPA group compared with the L-DOPA-and DMI-alone groups. Taken together, these results indicate that the combination of chronic L-DOPA and NET-mediated DA reuptake in lesioned nigrostriatal terminals may have a role in LID severity in experimental Parkinsonism.

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Section: Norepinephrine Transporter and L-dopa Dyskinesiamentioning

confidence: 92%

Norepinephrine Transporter Inhibition with Desipramine Exacerbates L-DOPA–Induced Dyskinesia: Role for Synaptic Dopamine Regulation in Denervated Nigrostriatal Terminals

2014

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“…In small open-label studies, the epinephrine precursor L-threo-DOPS was found to have beneficial effects on freezing and gait disturbances in PD patients (Tohgi et al, 1993;Giladi, 2008;Devos et al, 2010). Furthermore, methylphenidate, a mixed dopamine and noradrenaline reuptake inhibitor, was found to show benefit on gait and freezing scores in a randomized controlled trial of 17 advanced PD patients , but results of a more recent trial in 27 PD patients revealed that methylphenidate did not improve gait and tended to worsen measures of motor functions, sleepiness, and quality of life (Espay et al, 2011). Other trials using lower doses of this compound in PD patients with gait impairment are currently underway.…”

Section: Non-dopaminergic Therapiesmentioning

confidence: 99%

Parkinson's Disease Therapeutics: New Developments and Challenges Since the Introduction of Levodopa

Smith

Wichmann

Factor

et al. 2011

Neuropsychopharmacol

194

137

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The demonstration that dopamine loss is the key pathological feature of Parkinson's disease (PD), and the subsequent introduction of levodopa have revolutionalized the field of PD therapeutics. This review will discuss the significant progress that has been made in the development of new pharmacological and surgical tools to treat PD motor symptoms since this major breakthrough in the 1960s. However, we will also highlight some of the challenges the field of PD therapeutics has been struggling with during the past decades. The lack of neuroprotective therapies and the limited treatment strategies for the nonmotor symptoms of the disease (ie, cognitive impairments, autonomic dysfunctions, psychiatric disorders, etc.) are among the most pressing issues to be addressed in the years to come. It appears that the combination of early PD nonmotor symptoms with imaging of the nigrostriatal dopaminergic system offers a promising path toward the identification of PD biomarkers, which, once characterized, will set the stage for efficient use of neuroprotective agents that could slow down and alter the course of the disease.

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“…One pilot study reported significantly improved attention after administration of a single dose of the dopamine reuptake inhibitor methylphenidate, but with no change to memory or visuospatial performance [19]. However, tolerability of methylphenidate is in question as sleepiness and worsened motor function and quality of life were reported with use of this medication in one study [20], and increased heart rate and weight loss in another [21].…”

Section: Mild Cognitive Impairment and Dementia In Pdmentioning

confidence: 99%

Treatment of Cognitive, Psychiatric, and Affective Disorders Associated with Parkinson's Disease

Connolly

Fox

2014

Neurotherapeutics

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Neuropsychiatric symptoms are common in Parkinson's disease (PD) and add significantly to the burden of disease. These symptoms are most commonly part of the disease spectrum owing to pathological changes within relevant brain regions. Neuropsychiatric problems include disorders of cognition, ranging from mild cognitive impairment to dementia, psychotic symptoms, including, most commonly, well-formed visual hallucinations and paranoid delusions, and mood disorders, such as depression and anxiety. The other common cause of neuropsychiatric problem is secondary to use of dopaminergic drugs. Some PD patients may develop behavioral disorders, including impulse control disorders (ICDs) and addictive symptoms. Psychosis can be due to a mixture of underlying pathology, with triggering or worsening of symptoms with changes to PD medications. Currently, management of these disorders primarily uses therapies developed for general psychiatry and cognitive neurology, rather than specifically for PD. However, significant adverse effects, such as worsening of the motor symptoms of PD, can limit use of some drug therapies. Identification of drug-induced symptoms, such as ICDs, enables withdrawal of the offending drug as the principal management strategy. Research is ongoing in an effort to develop more specific therapies for PD-related neuropsychiatric symptoms.

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Methylphenidate for gait impairment in Parkinson disease

Abstract: NCT00526630.

Cited by 87 publications

References 31 publications

Norepinephrine Transporter Inhibition with Desipramine Exacerbates L-DOPA–Induced Dyskinesia: Role for Synaptic Dopamine Regulation in Denervated Nigrostriatal Terminals

Norepinephrine Transporter Inhibition with Desipramine Exacerbates L-DOPA–Induced Dyskinesia: Role for Synaptic Dopamine Regulation in Denervated Nigrostriatal Terminals

Parkinson's Disease Therapeutics: New Developments and Challenges Since the Introduction of Levodopa

Treatment of Cognitive, Psychiatric, and Affective Disorders Associated with Parkinson's Disease

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