By Andrea Lee, MD
Assistant Professor of Clinical Neurology and Assistant Attending Neurologist, New York-Presbyterian/Weill Cornell Medical College
SYNOPSIS: This retrospective cohort study compared the effect of amantadine on levodopa-induced dyskinesia (LID) onset with use of anticholinergics and monoamine oxidase type B inhibitors in patients with Parkinson’s disease. The authors concluded that early treatment with amantadine may delay LID onset more than treatment with other symptomatic agents.
SOURCE: Wang CC, Wu TL, Lin FJ, et al. Amantadine treatment and delayed onset of levodopa-induced dyskinesia in patients with early Parkinson’s disease. Eur J Neurol 2022;29:1044-1055.
To improve motor symptoms in people with Parkinson’s disease (PD), levodopa is a mainstay of treatment. However, levodopa-induced dyskinesia (LID), which can severely impair the patient’s quality of life, is a risk of long-term exposure to levodopa. Amantadine currently is the only N-methyl-D-aspartate (NMDA) receptor antagonist that provides symptomatic relief for patients with dyskinesia; it often is used in combination with levodopa for patients with LID. Amantadine also may be used as a symptomatic treatment for early PD. Clinical observations suggest that, compared to those who receive other symptomatic treatments, patients who receive amantadine seem to have a delayed onset of LID. Evidence suggests that amantadine likely is effective and useful for the early treatment of PD, but little real-world evidence exists regarding the use of amantadine for lowering the risk of LID.
This hospital-based retrospective cohort study used electronic medical records from Jan. 1, 2009, to Oct. 31, 2016, to compare the time of LID onset in patients treated with amantadine, anticholinergics, or monoamine oxidase type B inhibitors. The analyses included 807, 661, and 518 patients at six-, 12-, and 18-month landmark points, respectively. Among the patients included in the six-month landmark analysis, the two groups were comparable in terms of sex distribution and parkinsonism symptom duration. Overall, the mean duration of symptoms was less than two years, and the mean Hoehn and Yahr stage was approximately 1.6, which was concordant with the definition of early PD. LID was defined as the occurrence of peak-dose dyskinesia, diphasic dyskinesia, and off-dystonia. The clinical manifestations of LID were documented in the medical records by experienced movement disorder specialists and reviewed by two investigators.
Amantadine use was associated with delayed LID onset in the six- and 12-month landmark analyses, with adjusted hazard ratios of 0.65 (95% confidence interval [CI] = 0.49 to 0.86) and 0.64 (95% CI = 0.47 to 0.88), respectively, but not in the 18-month landmark analysis.
COMMENTARY
This study investigated the association between early amantadine treatment and LID onset in patients with PD. The results demonstrated that patients with early PD who received amantadine treatment for at least six months had a significantly lower risk of developing LID than those who received either anticholinergics or MAOBIs for at least six months, but the result was not statistically significant in the 18-month landmark analysis.
The authors postulated that the reasons for the potential beneficial effects of early amantadine treatment on the occurrence of LID may not have resulted from its anti-dyskinetic mechanism only; rather they related amantadine’s protective properties against LID development to those observed in PD models in the laboratory, including anti-glutamate activity, reduction in release of proinflammatory factors from activated microglia, and induction of glial-derived neurotrophic factor expression in astroglia. Since chronic astroglia and microglia activation are associated with neuroinflammation, thereby affecting synaptic activity and neuroplasticity leading to LID, the authors postulated that the anti-inflammatory activity of amantadine could theoretically attenuate this inflammatory process.
Possible explanations for the nonsignificant finding in the 18-month landmark analysis is the exclusion of patients with dyskinesia during the landmark periods; hence the nonsignificant finding could have resulted from the low number of patients analyzed at the 18-month landmark point, leading to a loss of power.
There is a possibility patients who were analyzed at 18 months were more clinically stable or responded better to the treatment than those analyzed at six and 12 months. Therefore, a lower risk of dyskinesia was found in the former group of patients. Overall, this study suggests that amantadine, an NMDA receptor antagonist, not only provides symptomatic relief for patients with LID, but may also delay the onset of LID in early PD patients.
