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Background: Patients with Parkinson's disease (PD) undergoing long-term levodopa therapy are prone to develop levodopa-induced dyskinesia (LID). Amantadine is the main drug recommended for the treatment of LID by current guidelines, but it is far from meeting clinical needs. Tianqi Pingchan Granule (TPG), a compound Chinese herbal medicine, has been developed to relieve symptom of LID., Objective: This randomized controlled trial evaluated the efficacy and safety of the combination of TPG and amantadine for LID., Design, Setting, Participants and Interventions: This is a randomized double-blind placebo-controlled trial, conducted from January 2020 to August 2021 at 6 sites in Jiangsu, Zhejiang and Shanghai, China. One hundred PD patients with ≥ 0.5 h of LID were randomly assigned to either the TPG plus amantadine group (TPG group) or the placebo plus amantadine group (placebo group), and treated for a period of 12 weeks. To ensure unbiased results, all study participants, investigators and sponsors were unaware of group allocations. Additionally, the data analysts remained blinded until the analysis was finalized., Main Outcome Measures: The primary outcome was assessed using the Unified Dyskinesia Rating Scale (UDysRS) (Range 0-104). The key secondary end point was improvement of motor and non-motor symptoms. Safety analyses included all enrolled patients., Results: One hundred patients were enrolled and randomized into the two treatment groups. The changes in UDysRS at week 12 were -11.02 for the TPG group and -4.19 for the placebo group (treatment difference -6.83 [-10.53 to -3.12]; P = 0.0004). Adverse events were reported for 2 of 50 patients (4.0%) in each of the groups., Conclusion: This study indicated that a 12-week treatment of amantadine plus TPG effectively reduced UDysRS scores and was well tolerated, demonstrating the efficacy and safety of TPG for the treatment of LID in PD., Trial Registration: ClinicalTrials.gov identifier: NCT04173832., Please Cite This Article as: Zhang Y, Zhu XB, Zhao Y, Cui GY, Li WT, Yuan CX, Huang JP, Wan Y, Wu N, Song L, Zhao JH, Liang Y, Xu CY, Liu MJ, Gao C, Chen XX, Liu ZG. Efficacy and safety of Tianqi Pingchan Granule, a compound Chinese herbal medicine, for levodopa-induced dyskinesia in Parkinson's disease: A randomized double-blind placebo-controlled trial. J Integr Med. 2024; 22(5): 545-551., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Shanghai Yueyang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine. Published by Elsevier B.V. All rights reserved.)

Background: Cognitive dysfunction is a non-motor manifestation of Parkinson's disease (PD). We aimed to determine the frequency and patterns of cognitive dysfunction in treated patients with PD and their predictors., Research Design and Methods: This study included 80 patients (male = 48; female = 32) and 30 healthy individuals. They underwent neuropsychiatric evaluations. Measurements included Beck's depression inventory - II (BDI-II), mini-mental state examination (MMSE) and Montreal cognitive assessment (MoCA)., Results: Patients had mean age of 55.56 ± 9.06 yrs, duration of PD of 4.86 ± 2.71 yrs and Hoehn and Yahr Scoring of 2.19 ± 0.89. They were on levodopa/carbidopa therapy and adjuvant therapy with benztropine mesylate, an anticholinergic drug, ( n  = 51) or amantadine sulfate, a dopaminergic drug, ( n  = 29). Sixteen (20%) had moderate depressive symptoms. Mild and moderate cognitive impairments were reported in 38.8% and 28.8% (by MMSE) and 46.3% and 31.3% (by MoCA). Patients had lower global cognitive scoring ( p  = 0.0001) and scorings of different cognitive functions (naming, attention, language, abstraction, memory and orientation) than controls. Patients treated with benztropine had lower cognition than with amantadine. Correlation analyses showed that lower cognition was only associated with chronic PD and its treatment ( p  = 0.0001)., Conclusions: Cognitive dysfunction is common with PD (77.5%) particularly with anticholinergic drugs. De-prescription of anticholinergics is recommended for patients with PD.

Background/aim: A few case reports of central nervous system (CNS) symptoms caused by amantadine intoxication have been published, detailing various types of symptoms and differing times to onset. We encountered a patient who developed CNS symptoms with amantadine. This prompted us to investigate the types, time to onset, and outcome of CNS adverse reactions to amantadine by analyzing data from a pharmacovigilance database., Patients and Methods: The patient was evaluated at Chutoen General Hospital, Shizuoka, Japan. Analysis was performed using the Japanese Adverse Drug Event Report (JADER) database., Results: In our case, the amantadine blood concentration was 4,042 ng/ml, i.e., in the toxic range. The time to onset was 26 days for dyskinesia and 90 days for depressed level of consciousness. Symptoms resolved when amantadine was discontinued. The JADER database contained 974 cases of adverse reactions to amantadine. The most frequently reported CNS adverse reaction was hallucination, with a reporting odds ratio of 64.28 (95% confidence interval=52.67-78.46). Positive signals were detected for all CNS adverse reactions. For all CNS reactions, clinical outcomes were poor in a comparatively low percentage of cases. Most CNS reactions occurred soon after administration of amantadine, usually within approximately one month., Conclusion: Because most CNS adverse reactions to amantadine usually occur within approximately one month of initiating treatment, healthcare providers should exercise heightened vigilance in monitoring patients for such reactions during this period., (Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Objective: To assess amantadine use and associated factors in the patients with Parkinson's disease (PD)., Background: Immediate-release amantadine is approved for the treatment of PD and is largely used in clinical practice to treat "levodopa-induced dyskinesia (LIDs). Its use varies according to countries and PD stages. The prospective NS-Park cohort collects features of PD patients followed by 26 French PD Expert Centres., Methods: Variables used for the analyses included demographics, motor and non-motor PD symptoms and motor complications [motor fluctuations (MFs), LIDs)], antiparkinsonian pharmacological classes and levodopa equivalent daily dose (LEDD). We evaluated: (i) prevalence of amantadine use and compared clinical features of amantadine users vs. non-users (cross-sectional analysis); (ii) factors associated with amantadine initiation (longitudinal analysis); (iii) amantadine effect on LIDs, MFs, apathy, impulse control disorders and freezing of gait (Fog) (longitudinal analysis)., Results: Amantadine use prevalence was 12.6% (1,585/12,542, median dose = 200 mg). Amantadine users were significantly younger, with longer and more severe PD symptoms, greater LEDD and more frequent use of device-aided/surgical treatment. Factors independently associated with amantadine initiation were younger age, longer PD duration, more frequent LIDs, MFs and FoG, higher LEDD and better cognitive function. 9 of the 658 patients on amantadine had stopped it at the following visit, after 12-18 months (1.3%). New users of amantadine presented a higher improvement in LIDs and MF compared to amantadine never users., Conclusions: About 12% of PD patients within the French NS-Park cohort used amantadine, mostly those with younger age and more severe PD. Amantadine initiation was associated with a subsequent reduction in LIDs and MFs., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Objective: To quantify the benefits versus harms of amantadine in the treatment of irritability and aggression following traumatic brain injury., Methods: Secondary outcome data from a randomized controlled multisite trial of amantadine 100 mg twice daily were used to calculate number-needed-to-treat (NNT). Given prior findings of positive clinician-perceived effects and low incidence of adverse events, we hypothesized low number-needed-to-treat for benefit (NNTB; high benefit) and high number-needed-to-treat for harm (NNTH; low risk) based on the clinician ratings, supporting the use of amantadine in clinical practice. Specifically, NNTB values were calculated using number of individuals with improvement on the Clinician Global Impressions-Global Improvement scale (GI). NNTH values were computed using number of individuals with worsening on the GI and experiencing serious and any adverse events., Results: Based on clinician ratings, on average for every six patients treated with amantadine rather than placebo, one extra patient would be expected to improve (NNTB = 6.4; 95% confidence interval [CI]: [3.3-76.8]). More participants in the placebo group worsened than in the amantadine group, but the result was not statistically significant (NNTH = -92.4; 95% CI: [NNTB -32.9 to infinity to NNTH -19.2]). The amantadine and placebo groups did not differ on the numbers of adverse events experienced during the trial., Conclusion: Clinician ratings suggest modest benefit of amantadine 100 mg twice daily with low risk to appropriately selected patients with adequate renal clearance. Thus, amantadine should be considered a treatment option for the experienced brain injury clinician. These data may support treatment decisions when a pharmaceutical agent is being considered to control irritability/aggression., (© 2023 The Authors. PM&R published by Wiley Periodicals LLC on behalf of American Academy of Physical Medicine and Rehabilitation.)

Background: Opsoclonus is a rare disorder characterized by conjugate multidirectional, horizontal, vertical, and torsional saccadic oscillations, without intersaccadic interval, resulting from dysfunction within complex neuronal pathways in the brainstem and cerebellum. While most cases of opsoclonus are associated with autoimmune or paraneoplastic disorders, infectious agents, trauma, or remain idiopathic, opsoclonus can also be caused by medications affecting neurotransmission. This review was prompted by a case of opsoclonus occurring in a patient with Multiple System Atrophy, where amantadine, an NMDA-receptor antagonist, appeared to induce opsoclonus., Methods: Case report of a single patient and systematized review of toxic/drug-induced opsoclonus, selecting articles based on predefined criteria and assessing the quality of included studies., Results: The review included 30 articles encompassing 158 cases of toxic/drug-induced opsoclonus. 74% of cases were attributed to bark scorpion poisoning, followed by 9% of cases associated with chlordecone intoxication. The remaining cases were due to various toxics/drugs, highlighting the involvement of various neurotransmitters, including acetylcholine, glutamate, GABA, dopamine, glycine, and sodium channels, in the development of opsoclonus., Conclusion: Toxic/drug-induced opsoclonus is very rare. The diversity of toxics/drugs impacting different neurotransmitter systems makes it challenging to define a unifying mechanism, given the intricate neuronal pathways underlying eye movement physiology and opsoclonus pathophysiology., Competing Interests: The authors have no competing interests to declare., (Copyright: © 2024 The Author(s).)

Wilson disease is a rare genetic disorder of copper metabolism causing hepatic dysfunction and neuro-psychiatric manifestations. While psychosis in Wilson disease is uncommon, it can occur, especially with certain medications. We describe a 40-year-old woman diagnosed with Wilson disease who developed psychotic symptoms following the initiation and dose escalation of amantadine, a drug commonly used to treat parkinsonism associated with the disorder. Her symptoms included delusions of persecution, irritability and anomalous self-experiences such as 'made' phenomena, which are typically seen in schizophrenia. The psychosis resolved after discontinuing amantadine, without worsening her neurological symptoms. This underscores the importance of monitoring for psychiatric side-effects, particularly Schneiderian first-rank symptoms, in patients with Wilson disease being treated with amantadine. The findings suggest a probable adverse drug reaction, highlighting the need for careful evaluation and dose adjustments in such complex clinical cases.

Competing Interests: Competing interests: None declared.

We report a case of a man with spinocerebellar ataxia (SCA) on high-dose amantadine who was admitted for acute on chronic dysphagia secondary to progression of SCA. Four days after oral medications were held due to patient's dysphagia, he developed fever, tachycardia and mild rigidity in extremities and became obtunded. Despite antibiotics treatment, the vitals and mental status changes persisted for 8 days. When amantadine was resumed, the patient's vital signs and encephalopathy improved within 2 days. This is among the first reports of amantadine withdrawal syndrome (AWS) in a patient without Parkinson's disease. Our case reinforces the importance of careful medication review at admission and consideration of pharmacologic side effects with not only medication initiation but also discontinuation., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Considering the known derangements in the dopaminergic neurotransmitter systems following traumatic brain injury (TBI), dopamine agonists are used as a pharmacologic option. In this study, we evaluate the effects of amantadine hydrochloride on the functional improvement of severe TBI patients., Methods: Within a triple-blinded (patients, intervention administrators, and outcome assessors) placebo-controlled randomized clinical trial, we evaluated the effects of amantadine (100 mg BD (twice a day) for 14 days, then 150 mg BD for another 7 days, and 200 mg BD for another 21 days) on outcome measurements of weekly mean Glasgow Outcome Scale (GOS) and Disability Rating Scale (DRS), through six weeks of trial for 57 patients (29 amantadine, 28 placeboes) with severe TBI admitted in our hospital., Results: Although both groups had improvement in their DRS, the change from baseline was significantly better in the amantadine group (10.88±5.24 for amantadine vs. 8.04±4.07 for placebo, P=0.015). No significant difference was observed between groups for GOS (1.04±0.55 for amantadine vs. 1.12±1.05 for placebo, P=0.966)., Conclusions: Based on our findings, amantadine hydrochloride might improve the speed of functional ability improvement in severe TBI patients, evaluated by DRS, and is also well tolerated by patients. Although, there were some limitations in this study, including small sample size, short time interval, not providing a wash-off period and invalidity of GOS for measuring recovery rates in short-term periods.

Amantadine is an N-methyl-d-aspartate receptor agonist with secondary dopaminergic activity that is used to treat Parkinson's disease-related dyskinesia and to treat fatigue in multiple sclerosis. It is primarily renally excreted and so impaired kidney function prolongs its half-life and may lead to toxicity. We describe a woman with multiple sclerosis taking amantadine who developed acute renal impairment, which triggered florid visual hallucinations that resolved on stopping the medication., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Amantadine hydrochloride is a risky drug for triggering delirium in dialysis patients; however, it is often administered casually. Furthermore, little is known regarding the recovery and prognosis of dialysis patients with amantadine-associated delirium. Data of this retrospective cohort study were collected from a local hospital database for hospitalizations between January 2011 and December 2020. Patients were divided into 2 cohorts: early recovery (recovery within 14 days) and delayed recovery (recovery more than 14 days). The cases were analyzed together with the intermonth temperature using descriptive statistics. A Kaplan-Meier survival curve and binary logistic regression were applied for the analyses of prognoses and factors. A total of 57 patients were included in this study. The most common symptoms were hallucinations (45.61%) and muscle tremors (43.86%). Early recovery was observed in 63.16% of the patients. Only 3.51% of the cases occurred in local summer (June, July, and August). Better prognoses for survival (hazard ratio [HR] = 0.066, 95% confidence interval [95% CI] = 0.021-0.212) and hospitalization costs (7968.42 ± 3438.43 CNY vs 12852.38 ± 9361.13 CNY, P = .031) were observed in patients with early recovery than in those with delayed recovery. In the multivariate logistic regression adjusted by 1:1 propensity score matching, delayed recovery was independently caused by insomnia (P = .022, = 10.119, 95% CI = 1.403-72.990) and avoided in patients with urine volume over 300 mL (P = .029, = 0.018, 95% CI = 0.006-0.621). The increment (per 100 mg) of cumulative dose (P = .190, = 1.588, 95% CI = 0.395-3.172) tended to be a risk of delayed recovery. The area under curve of the receiver operating characteristic curve was 0.867, with a sensitivity of 90.5% and a specificity of 82.4% at the cutoff point (cutoff = 0.432). For amantadine-associated delirium in dialysis patients with uneven seasonal distribution, early recovery with better prognosis should be the aim of treatment by giving priority to the remedy of insomnia., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

The trajectory of the use of dopamine replacement therapy (DRT) in Parkinson's disease (PD) is variable and doses may need to be increased, but also tapered. The plan for dose adjustment is usually done as per drug information recommendations from the licensing bodies, but there are no clear guidelines with regards to the best practice regarding the tapering off schedule given sudden dose reductions of drugs such as dopamine agonists may have serious adverse consequences. A systematic literature search was, therefore, performed to derive recommendations and the data show that there are no controlled studies or evidence-based recommendations how to taper or discontinue PD medication in a systematic manner. Most of the data were available on the dopamine agonist withdrawal syndrome (DAWS) and we found only two instructions on how to reduce pramipexole and rotigotine published by the EMA. We suggest that based on the available data, levodopa, dopamine agonists (DA), and amantadine should not be discontinued abruptly. Abrupt or sudden reduction of DA or amantadine in particular can lead to severe life-threatening withdrawal symptoms. Tapering off levodopa, COMT inhibitors, and MAO-B inhibitors may worsen motor and non-motor symptoms. Based on our clinical experience, we have proposed how to reduce PD medication and this work will form the basis of a future Delphi panel to define the recommendations in a consensus., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Studies on the efficacy of amantadine as a treatment for apathy after brain injury are scarce and of low quality. We examined the efficacy and safety of amantadine for treatment of apathy in two individuals with brain injury.Two double-blind, randomized, single-case experimental (baseline-amantadine-placebo-withdrawal) design (SCED) studies. Apathy measures included a Visual Analogue Scale (VAS), the Neuropsychiatric Inventory (NPI) apathy subscale and the Behavior Rating Inventory of Executive Function for Adults "Initiate" subscale. Safety measures included a rating scale of possible side effects of amantadine and physical examinations.No difference in apathy symptoms (VAS) between baseline and amantadine phase was found in case 1 (NAP = 0.55). Surprisingly, in case 2, apathy symptoms deteriorated from baseline to amantadine phase (NAP = 0.28, 90% CI = -0.69 to -0.20) and improved from amantadine to placebo phase (NAP = 0.92, 90% CI = 0.60-1.00). This improvement was also found on the NPI apathy subscale. Side effects of amantadine were observed in case 2.In this SCED study, amantadine did not improve apathy symptoms in two individuals with brain injury. However, this study shows that side effects of amantadine can occur which lead to a significant decrease in well-being. More high quality studies are required.

Amantadine was originally developed as an antiviral agent for influenza A. However, it also has off-label uses for Parkinson disease, multiple sclerosis, and in the management of extrapyramidal symptoms. The mechanism of action in these conditions has yet to be elucidated. Ocular side effects from systemic amantadine are rare but have been described in three previous reports of amantadine-associated corneal edema in the pediatric population. We present an additional case of amantadine-associated transient visual impairment in a patient, which was associated with significant regression and worsening of his underlying neurodevelopmental status., (Published by Elsevier Inc.)

Background: ADS-5102, a delayed-release, extended-release (DR/ER) amantadine, improved walking speed in MS in a Phase 2 trial., Objective: The aim of this study was to present primary results of a Phase 3, double-blind, ADS-5102 trial (INROADS) for walking speed., Methods: Adult participants with MS and walking impairment, not currently using amantadine or dalfampridine, underwent 4-week placebo run-in before randomization 1:1:1 to placebo, 137 or 274 mg/day ADS-5102 for 12 weeks. Primary outcome was the proportion of responders (20% increase in Timed 25-Foot Walk (T25FW) speed) for 274 mg ADS-5102 versus placebo at end of double-blind (Study Week 16). Additional measures included Timed Up and Go (TUG), 2-Minute Walk Test (2MWT), and 12-item Multiple Sclerosis Walking Scale (MSWS-12)., Results: In total, 558 participants were randomized and received double-blind treatment. Significantly more participants responded with 274 mg ADS-5102 (21.1%) versus placebo (11.3%). Mean T25FW speed also significantly improved (0.19 ft/s) versus placebo (0.07 ft/s). Other measures were not significant using prespecified hierarchical testing procedure. Adverse events led to discontinuation for 3.8% (placebo), 6.4% (137 mg ADS-5102), and 20.5% (274 mg ADS-5102)., Conclusion: INROADS met its primary endpoint, showing a significantly greater proportion of participants with meaningful improvement in walking speed for 274 mg ADS-5102 versus placebo. Numeric dose response was seen for some secondary efficacy outcomes and adverse events.

Background and Purpose: Levodopa-induced dyskinesia (LID) is a common motor complication in patients with Parkinson's disease (PD). Although amantadine is indicated for LID treatment, it is uncertain whether early treatment with amantadine reduces the risk of LID in patients with PD. We aimed to evaluate the association between amantadine treatment and LID onset in patients with early-stage PD., Methods: This was a hospital-based retrospective cohort study that used electronic medical records from January 1, 2009 to October 31, 2016. The effect of amantadine on LID onset was compared with those of anticholinergics and monoamine oxidase type B inhibitors in patients with PD. Propensity-score weighting and landmark analysis were used to reduce potential confounding. The time to LID onset was analyzed using Cox models. Sensitivity analyses were performed to determine the robustness of the results., Results: The analyses included 807, 661, and 518 patients at 6-, 12-, and 18-month landmark points, respectively. Amantadine use was associated with delayed LID onset in the 6- and 12-month landmark analyses, with adjusted hazard ratios of 0.65 (95% confidence interval [CI] = 0.49-0.86) and 0.64 (95% CI = 0.47-0.88), respectively. Sensitivity analysis findings were comparable to those of the main analysis., Conclusions: Early treatment with amantadine may delay LID onset more than treatment with other symptomatic agents. Further studies are needed to elucidate the mechanism of amantadine in LID onset delay and to validate our findings., (© 2021 European Academy of Neurology.)

Background: Amantadine is sometimes used to treat fatigue in multiple sclerosis., Objectives: To report a patient with secondary progressive multiple sclerosis (SPMS) who developed late-onset side effects of amantadine which were initially felt to represent a progression of her SPMS., Methods: A single retrospective case report., Results: Symptoms of cognitive deterioration, ataxia and hallucinations resolved completely on cessation of the amantadine she had been prescribed several years beforehand., Conclusion: Clinicians involved in the management of the symptoms of SPMS should be aware of the potential for cumulative side effects of drugs used to treat symptoms and consider their potential role in precipitating neurological deterioration.

The best practice for the initiation of symptomatic motor treatment for Parkinson's disease is an ongoing topic of debate. Fueled by interpretation of the results of the LEAP and MED Parkinson's disease studies, many practitioners opt for early initiation of levodopa formulations, avoiding dopamine agonists to circumvent potential deleterious side effects, namely impulse control disorder. Compared with levodopa, monoamine oxidase inhibitors may lack necessary potency. Ignored in this academic debate is another therapeutic option for patients with Parkinson's disease requiring treatment initiation: amantadine. Amantadine was first reported effective in the treatment of Parkinson's disease in 1969 and several studies were published in the 1970s supporting its efficacy. Currently, amantadine is mainly utilized as an add-on therapy to mitigate levodopa-related dyskinesia and, more recently, new long-acting amantadine formulations have been developed, with new indications to treat motor fluctuations. Amantadine has not been reported to cause dyskinesia and is rarely implicated in impulse control disorder., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Purpose: Amantadine is commonly used to treat Parkinson's disease. A case of myoclonus and asterixis was associated with amantadine is reported., Case Summary: An 80-year-old man with Parkinson's disease diagnosed in 2015 was started on amantadine for treatment of progressive tremor and orofacial dyskinesias induced by levodopa. He took amantadine 100mg orally daily for 7 days, then increased to 100mg twice a day thereafter. The patient complained of "worsening tremor" after 9 days and amantadine was decreased to 100mg daily. After 1 month on this dose, the patient reported that his "tremor" persisted and experienced visual hallucinations. His examination demonstrated diffuse myoclonus throughout his extremities and trunk, as well as asterixis when attempting to stand or holding his arms antigravity. Laboratory testing for renal and hepatic failure was unrevealing. Amantadine was reduced to 50mg daily for 4 days and then discontinued. Myoclonus resolved 3 days after discontinuation of amantadine., Conclusion: While amantadine-induced myoclonus is rare, health care providers should be vigilant in monitoring for signs and symptoms of myoclonus following amantadine initiation.

Introduction: Parkinsonism-hyperpyrexia syndrome (PHS) is a rare and potentially fatal complication of Parkinson disease (PD) characterized by a neuroleptic malignant-like syndrome due to abrupt discontinuation of antiparkinsonian medications., Case Report: A 79-year-old woman with late-stage PD presented at the hospital with neuropsychiatric and uncontrolled parkinsonian motor symptoms. Soon after the abrupt discontinuation of amantadine, the patient suddenly presented with global rigidity, global unresponsiveness, diaphoresis, tachycardia, recurrent hyperpyrexia, and a mildly elevated creatine kinase, which lead to the diagnosis of PHS. Amantadine was then reinitiated and her symptoms resolved within 10 days., Conclusions: Amantadine is an antiparkinsonian medication scarcely associated with PHS. The few reported cases are further summarized and discussed in this article. This case highlights the importance of early recognition of PHS, which may be caused by changes in other antiparkinson agents such as amantadine, and the need to slowly titrate such agents., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Abstract: Drug-induced parkinsonism is the most common type of drug-induced movement disorder, whose symptoms can decrease patient quality of life and reduce medication compliance. Tacrolimus is a routinely used immunosuppressant agent after liver transplantation, with a well-known neurotoxic profile. There have been rare reports of tacrolimus-induced parkinsonism, but its pharmacologic management and functional impact remain poorly characterized in the literature. We present a case of tacrolimus-induced parkinsonism in a 62-year-old man after a liver transplant, resulting in significant neurologic impairments and multiple barriers to hospital discharge. His tremor, rigidity, bradykinesia, gait dysfunction, dysphonia, and dysphagia significantly improved after starting low-dose amantadine, with increased functional independence that allowed for a safe discharge. This is the first case in the literature detailing tacrolimus-induced parkinsonism's functional impairments improving with amantadine monotherapy., Competing Interests: Conflicts of Interest and Source of Funding: The authors have no conflicts of interest declare., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Methylphenidate, modafinil, and amantadine are commonly prescribed medications for alleviating fatigue in multiple sclerosis; however, the evidence supporting their efficacy is sparse and conflicting. Our goal was to compare the efficacy of these three medications with each other and placebo in patients with multiple sclerosis fatigue., Methods: In this randomised, placebo-controlled, four-sequence, four-period, crossover, double-blind trial, patients with multiple sclerosis who reported fatigue and had a Modified Fatigue Impact Scale (MFIS) score of more than 33 were recruited at two academic multiple sclerosis centres in the USA. Participants received oral amantadine (up to 100 mg twice daily), modafinil (up to 100 mg twice daily), methylphenidate (up to 10 mg twice daily), or placebo, each given for up to 6 weeks. All patients were intended to receive all four study medications, in turn, in one of four different sequences with 2-week washout periods between medications. A biostatistician prepared a concealed allocation schedule, stratified by site, randomly assigning a sequence of medications in approximately a 1:1:1:1 ratio, in blocks of eight, to a consecutive series of numbers. The statistician and pharmacists had no role in assessing the participants or collecting data, and the participants, caregivers, and assessors were masked to allocation. The primary outcome measure was the MFIS measured while taking the highest tolerated dose at week 5 of each medication period, analysed by use of a linear mixed-effect regression model. This trial is registered with ClinicalTrials.gov, NCT03185065 and is closed., Findings: Between Oct 4, 2017, and Feb 27, 2019, of 169 patients screened, 141 patients were enrolled and randomly assigned to one of four medication administration sequences: 35 (25%) patients to the amantadine, placebo, modafinil, and methylphenidate sequence; 34 (24%) patients to the placebo, methylphenidate, amantadine, and modafinil sequence; 35 (25%) patients to the modafinil, amantadine, methylphenidate, and placebo sequence; and 37 (26%) patients to the methylphenidate, modafinil, placebo, and amantadine sequence. Data from 136 participants were available for the intention-to-treat analysis of the primary outcome. The estimated mean values of MFIS total scores at baseline and the maximal tolerated dose were as follows: 51·3 (95% CI 49·0-53·6) at baseline, 40·6 (38·2-43·1) with placebo, 41·3 (38·8-43·7) with amantadine, 39·0 (36·6-41·4) with modafinil, and 38·6 (36·2-41·0) with methylphenidate (p=0·20 for the overall medication effect in the linear mixed-effect regression model). As compared with placebo (38 [31%] of 124 patients), higher proportions of participants reported adverse events while taking amantadine (49 [39%] of 127 patients), modafinil (50 [40%] of 125 patients), and methylphenidate (51 [40%] of 129 patients). Three serious adverse events occurred during the study (pulmonary embolism and myocarditis while taking amantadine, and a multiple sclerosis exacerbation requiring hospital admission while taking modafinil)., Interpretation: Amantadine, modafinil, and methylphenidate were not superior to placebo in improving multiple sclerosis fatigue and caused more frequent adverse events. The results of this study do not support an indiscriminate use of amantadine, modafinil, or methylphenidate for the treatment of fatigue in multiple sclerosis., Funding: Patient-Centered Outcomes Research Institute., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Gocovri® (amantadine) extended release capsules are approved for the treatment of dyskinesia in patients with Parkinson's disease (PD) receiving levodopa-based therapy., Objective: To evaluate the long-term safety, tolerability, and efficacy of Gocovri in patients with PD experiencing levodopa-induced dyskinesia., Methods: In this 2-year open-label trial, patients completing double-blind Gocovri clinical trials or excluded from prior trials because of deep-brain stimulation (DBS) received Gocovri 274 mg once daily at bedtime. The primary objective was to evaluate long-term safety and tolerability. In addition, dyskinesia and OFF time were assessed using Part IV (Motor Complications) scores on the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS)., Results: Among 223 enrolled patients (mean PD duration, 11.7 years; mean levodopa use, 9.3 years), 75.8% completed 1 year of treatment and 57.8% completed the trial, with a median treatment duration of 1.9 years. Common adverse events were fall (32.7%), hallucination (24.2%), peripheral edema (16.1%), constipation (13.5%), and urinary tract infection (10.3%); 31 patients (13.9%) discontinued because of adverse events considered related to study drug. At baseline, MDS-UPDRS Part IV scores were lower for patients continuing Gocovri (mean, 6.5 points) than for previous placebo (9.4) or DBS groups (10.5) but were similar for all groups by week 8 (6.3, 6.2, 6.4, respectively), and remained low for the duration of the trial (at week 100: 6.9, 7.3, 7.0, respectively)., Conclusions: In patients with PD, Gocovri showed long-term safety and tolerability consistent with double-blind trial findings, and durable reduction in motor complications (dyskinesia and OFF time).

Background: The effect of repeated intravenous amantadine (IVAM) in advanced Parkinsonism has not been studied in depth., Objectives: To report the experience of our medical center with repeated IVAM infusions in patients with advanced Parkinsonism., Methods: Thirty patients with advanced Parkinsonism of various etiologies were enrolled in an open-label retrospective study. All patients were treated with IVAM infusions in a neurological daycare center. Treatment was initiated with a loading dose of 200/400 mg per day for 5 days followed by a once-daily maintenance dose of 200/400 mg every 1 to 3 weeks. Patients and their caregivers participated in a structured interview and independently completed a clinical global impression of changes scale questionnaire on various motor and non-motor symptoms., Results: Patient mean age was 73.3 ± 9.7 years, average disease duration was 6.2 ± 5.7 years, and mean Hoehn and Yahr score was 3.2 ± 0.84. Mean duration of the IVAM treatment was 15.1 ± 11.6 months. An improvement in general function was reported by 91% of the patients and 89% of the caregivers. Most of the patients reported improvement in tremor and rigidity, as well as in gait stability, freezing of gait, and reduced falls. The treatment was safe with few side effects., Conclusions: Our data suggest that repeated IVAM infusions could be an effective treatment against various motor symptoms and for improvement of mobility in patients with advanced Parkinsonism. Further randomized clinical trials with a larger sample size using objective measures are warranted to validate our results.

Purpose: To evaluate the progression of corneal endothelial changes in patients with Parkinson disease (PD) on long-term oral amantadine therapy., Methods: A prospective comparative longitudinal observational study of 90 patients (180 eyes) with PD on more than 6 months of oral amantadine therapy, 30 amantadine naive patients with PD, and 30 healthy controls (age and gender matched). Corneal endothelial cell parameters (endothelial cell density, percentage hexagonality of the cells, and coefficient of variation) and corneal subbasal nerve fiber layer changes were studied over a follow-up period of 1 year., Results: The amantadine patients with PD group had a statistically significant decrease in endothelial cell density (1.51% vs. 0.94% vs. 0.55%) (P = 0.04), decrease of percentage hexagonality of the cells (4.98% vs. 3.56% vs. 2.31%) (P = 0.01), and increase of coefficient of variation (6.12% vs. 4.80% vs. 3.30%) (P = 0.03) compared with amantadine naive patients with PD and controls, respectively. Analysis of changes in the patients with PD based on the daily dosage of amantadine showed greater change in endothelial parameters in patients who were on 400 mg amantadine., Conclusions: Long-term amantadine therapy seems to effect changes on corneal endothelium.

Aim: To determine the effectiveness and safety of extended-release amantadine (ADS-5102) for levodopa-induced dyskinesias (LID) in patients with Parkinson disease (PD) by conducting a meta-analysis of relevant trials. Methods: The electronic databases were searched on or before March 1, 2019 for relevant trials. Only randomized, double-blind, parallel-group, placebo-controlled trials using ADS-5102 for LID in PD were included. Results: The ADS-5102 showed a reduction in the dyskinesia scores (mean difference: -9.56: CI: -10.05 to -9.07; p < 0.00001) and in the on time without troublesome dyskinesia (mean difference 2.50: CI 2.38 to 2.63; p < 0.00001). The adverse events identified in ADS-5102 were visual hallucinations, constipation, dry mouth and fall. Conclusion: ADS-5102 can be used as an adjunct therapy for LID.

Introduction: Levodopa-induced dyskinesia (LID) is a significant impediment to the long-term use of levodopa for Parkinson's disease (PD). Relatively few studies exist that have described safe and effective therapy for LID. There is thus a significant need for therapy that can control LID to allow for greater sustainability of levodopa therapy. Amantadine extended release (ER) is currently the only FDA-approved medication for the treatment of LID. While other medications have demonstrated efficacy in treating the motor symptoms of PD, amantadine ER is the only one that has been shown, in several clinical trials, to reduce LID and reduce OFF time. Areas Covered: In this review, the authors present the findings of amantadine ER including its efficacy and safety. The authors also provide their expert perspectives on its use and its future prospects. Expert opinion: Several therapies are currently being used and studied for controlling LID, an unmet need in therapy for PD. Amantadine ER has potential to supplement levodopa therapy in PD and improve patient therapeutic outcomes.

Background: Walking impairment causes disability and reduced quality of life in patients with multiple sclerosis (MS)., Objective: Characterize the safety and efficacy of ADS-5102 (amantadine) extended release capsules, 274 mg administered once daily at bedtime in patients with MS with walking impairment., Methods: This randomized, double-blind, placebo-controlled, 4-week study was conducted at 14 trial sites in the United States. Study objectives included safety and tolerability of ADS-5102, and efficacy assessments (Timed 25-Foot Walk (T25FW), Timed Up and Go (TUG), 2-Minute Walk Test, and Multiple Sclerosis Walking Scale-12). Fatigue, depression, and cognition also were assessed., Results: A total of 60 patients were randomized (30 to ADS-5102 and 30 to placebo); 59 of whom were treated. The most frequent adverse events (AEs) were dry mouth, constipation, and insomnia. Five ADS-5102 patients and no placebo patients discontinued treatment due to AEs. One patient in the ADS-5102 group experienced a serious AE-suspected serotonin syndrome. A 16.6% placebo-adjusted improvement was seen in the T25FW test ( p < 0.05). A 10% placebo-adjusted improvement in TUG was also observed. No changes in fatigue, depression, or cognition were observed., Conclusion: ADS-5102 was generally well tolerated. These data demonstrate an effect of ADS-5102 on walking speed. Further studies are warranted to confirm these observations.

Aim: The role of the glutamatergic system in the pathogenesis of obsessive-compulsive disorder (OCD) has been shown by numerous studies. The aim of the present randomized, double-blind, placebo-controlled, 12-week trial was to assess the efficacy and tolerability of amantadine as an adjuvant to fluvoxamine in the treatment of patients with moderate to severe OCD., Methods: One hundred patients diagnosed with moderate to severe OCD were randomized into two parallel groups to receive fluvoxamine (100 mg twice a day) plus placebo or fluvoxamine (100 mg twice a day) plus amantadine (100 mg daily) for 12 weeks. All patients received 100 mg/day fluvoxamine for 28 days followed by 200 mg/day for the rest of the trial, regardless of their treatment groups. Patients were evaluated for response to treatment using the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) at baseline and at Weeks 4, 10, and 12. The main outcome measure was to assess the efficacy of amantadine in improving the OCD symptoms., Results: Repeated-measure analysis of variance showed a significant effect for Time × Treatment interaction (Greenhouse-Geisser corrected: F = 3.84, d.f. = 1.50, P = 0.03) in the Y-BOCS total score and a significant effect for Time × Treatment interaction (Greenhouse-Geisser corrected: F = 5.67, d.f. = 1.48, P < 0.01) in the Y-BOCS Obsession subscale score between the two groups., Conclusion: The results of this study suggest that amantadine may be effective as an augmentative agent in the treatment of moderate-to-severe OCD., (© 2018 The Authors. Psychiatry and Clinical Neurosciences © 2018 Japanese Society of Psychiatry and Neurology.)

Purpose: An adverse effect of amantadine, a drug used for Parkinson's disease, is corneal edema. While corneal endothelial cell loss is noted with amantadine toxicity, the reversibility of corneal edema suggests that amantadine affects active mechanisms regulating corneal hydration. Although mainly known as a NMDA receptor antagonist, amantadine is also a K + -channel blocker. The purpose of this study was to investigate potential mechanisms of amantadine's toxic effects on corneal endothelium., Methods: Bovine corneas were used for short-circuit current measurements of corneal endothelial active ion transport to compare the effects of amantadine with an NMDA receptor agonist (NMDA) and antagonist (D-APV), and the K + -channel blockers BaCl 2 and clotrimazole. Cell death and changes in cell morphology were observed using annexin V stain, alizarin red S staining of the intercellular junctions, ZO-1 immunolocalization, and phalloidin stain of the actin cytoskeleton., Results: Amantadine caused a transient decrease in the short-circuit current that mimicked the effect of clotrimazole. BaCl 2 , and the NMDA receptor agonist and antagonist had no effect on the short-circuit current. Tissue incubation with amantadine caused an increase in cell area (measured by ZO-1 localization) and cell height (measured by phalloidin stain) but did not increase apoptotic cell death (annexin V stain)., Conclusions: The similarity of amantadine and clotrimazole effects on the short-circuit current and the effects on cell volume suggest that amantadine's actions on corneal endothelium are mediated via K + channels. The observed absence of cell death and transient effect on short-circuit current support the reported reversibility of amantadine-induced corneal edema., (Published by Elsevier Ltd.)

Background: Parkinson's disease (PD) patients using levodopa commonly develop dyskinesia and OFF episodes that reduce quality of life., Objective: Evaluate prevalence of troublesome dyskinesia and OFF through the day, assessed by 30-minute intervals, as well as the mean number and duration of troublesome dyskinesia and OFF episodes, transitions between PD states, and effects of Gocovri® (amantadine) extended release capsules on these episodes., Methods: Evaluate diary data from pooled Gocovri phase 3, placebo-controlled trials-analyzed for 17 hours following wake-up-at baseline and week 12., Results: Diaries were evaluable for 162 patients. At baseline, 67% of patients woke up OFF, with prevalence decreasing to 13% at 2 hours and then remaining relatively steady at ∼12% (range, 6-17%) across half-hour intervals thereafter. Troublesome dyskinesia prevalence rose steadily from 5% to 24% over the first 2 hours, then fluctuated between 20% and 44% through the rest of the waking day. At baseline, patients experienced a mean of 3.0 daily episodes of troublesome dyskinesia (average duration 2.0 hours each), and 2.2 daily episodes of OFF (average duration 1.1 hour each). At week 12, Gocovri-treated patients showed greater reductions than placebo in troublesome dyskinesia and OFF episodes per day (treatment difference: -1.0 episodes and -0.4 episodes, respectively) and average episode duration (treatment difference: -0.6 hours and -0.3 hours, respectively). Mean duration of individual episodes of ON without troublesome dyskinesia (Good ON) increased by 5.0 hours for Gocovri, compared with 2.0 hours for placebo. Patients taking Gocovri experienced 2.2 fewer transitions between states than patients taking placebo., Conclusions: Troublesome dyskinesia and OFF occurred in the morning and throughout the waking day. Gocovri-treated patients experienced fewer, shorter episodes of both troublesome dyskinesia and OFF, thereby increasing the duration of continuous Good ON episodes and reducing the frequency of transitions between motor states.

Amantadine is commonly prescribed as a neurostimulant in patients with brain injuries. This is a case of a 14-year-old male with a history of brain tumor that developed corneal edema after initiation of amantadine, a rare but documented side effect of this medication. After discontinuation of amantadine, the corneal edema resolved within two months, but endothelial cells density remained low. LEVEL OF EVIDENCE: V., (Copyright © 2018 American Academy of Physical Medicine and Rehabilitation. Published by Elsevier Inc. All rights reserved.)

Objective: The aim of this study was to assess clinical response to a high-dose intravenous (IV) amantadine given for 5 consecutive days in patients with multiple system atrophy parkinsonism (MSA-P)., Methods: Subjects with a diagnosis of MSA-P treated with IV amantadine were included. Patients' disease severity before and after therapy was evaluated using the Unified Multiple System Atrophy Rating Scale (UMSARS)., Results: Fourteen subjects (8 females) were included. In 10 subjects (71.4%), clinical improvement was noted. The UMSARS score after treatment decreased by 2 points (median [interquartile range, 0-3]) when compared with UMSARS score at baseline (P = 0.0020). Upon examining the walking parameter, a trend of improvement was shown (P = 0.0625) (range, 0-1 points). Neither specific demographic parameters nor occurrence of adverse effects was found to be a predictive factor for improvement. Adverse events were mild and transient except for one patient who experienced acute psychosis prompting treatment cessation, upon which psychosis resolved., Conclusions: Our preliminary data show that IV amantadine may be a safe and effective therapy in MSA-P. A double-blind placebo-controlled trial is needed to establish the true benefit of amantadine therapy.

The anti-influenza virus drug oseltamivir has been reported to have several pharmacological actions including blocking of nicotinic acetylcholine receptor channels and activation of the dopaminergic system. These pharmacological actions highly overlap those of amantadine, another anti-influenza virus drug authorized in Japan, and ester-type local anesthetics. Moreover, oseltamivir and amantadine can clinically induce similar adverse neuropsychiatric reactions. In the present study, from the database of the Pharmaceuticals and Medical Devices Agency (PMDA), we surveyed 2576 drugs for which neuropsychiatric side effects similar to those of oseltamivir, amantadine and local anesthetics (abnormal behavior, confusion, consciousness disturbance, convulsion, delirium, delusion, hallucination, myoclonus, tremor) are listed as "clinically significant adverse reactions", and found 327 that had at least one of these adverse reactions. Other neuraminidase inhibitors (laninamivir, peramivir and zanamivir) did not elicit such adverse reactions. By discussing the pharmacological effects of drugs that elicit these adverse reactions, we propose that the similarity of adverse neuropsychiatric reactions between oseltamivir and amantadine is possibly attributable to their common pharmacological effects.

An 86-year-old woman presented with generalized chorea in the face and extremities, which gradually progressed for two weeks. Cranial CT revealed a chronic subdural hematoma (CSDH) that covered the left parietal lobe. Discontinuation of amantadine did not improve the chorea. The hematoma was evacuated and the chorea completely subsided in a week. The pathogenesis leading to chorea in CSDH remains unclear. A unilateral hematoma presenting with generalized chorea similar to the present patient and two others with unilateral CSDH causing ipsilateral hemichorea have been reported. The rarity of these movement disorders due to CSDH indicates that these patients had a preclinical dysfunction within neuronal networks interconnecting basal ganglia the cerebral cortex. Our findings confirmed that CSDH could cause chorea, and further neuroimaging to evaluate cerebrovascular disease, taking a detailed family history and obtaining information about current medications might reveal factors likely to precipitate the development of chorea.

Background: Although levodopa is considered the most effective pharmacotherapy for motor symptoms of Parkinson's disease (PD), chronic use is associated with motor complications, including fluctuating response and unpredictable, involuntary movements called dyskinesia. ADS-5102 (amantadine) extended-release (ER) capsules (GOCOVRI TM ) is a recent US FDA-approved treatment for dyskinesia in PD patients. ADS-5102 is a high-dose, ER formulation of amantadine, administered orally once daily at bedtime, that achieves high plasma drug concentrations throughout the day., Objective: In this study, we present pooled results from two randomized, double-blind, placebo-controlled, phase III ADS-5102 trials., Patients and Methods: The two studies in PD patients with dyskinesia shared design and eligibility criteria, differing only in treatment duration. Results from common assessment time points were pooled., Results: At 12 weeks, the least squares (LS) mean change in total score on the Unified Dyskinesia Rating Scale among 100 patients randomized to ADS-5102 and 96 patients randomized to placebo was - 17.7 (standard error [SE] 1.3) vs. - 7.6 (1.3) points, respectively (- 10.1 points, 95% confidence interval [CI] - 13.8, - 6.5; p < 0.0001). The relative treatment difference between groups was 27.3% (p < 0.0001). At 12 weeks, the LS mean change in OFF time was - 0.59 (0.21) vs. +0.41 (0.20) h/day, a difference of - 1.00 h/day (95% CI - 1.57, - 0.44; p = 0.0006). For both efficacy measures, a significant difference from placebo was attained by two weeks, the first post-baseline assessment, and was maintained throughout 12 weeks. In the pooled ADS-5102 group, the most common adverse events were hallucination, dizziness, dry mouth, peripheral edema, constipation, falls, and orthostatic hypotension., Conclusions: These analyses provide further evidence supporting ADS-5102 as an adjunct to levodopa for treating both dyskinesia and OFF time in PD patients with dyskinesia. Clinicaltrials.gov identifier: NCT02136914 and NCT02274766.

Objective: To assess the effects of amantadine on anger and aggression among individuals with a chronic traumatic brain injury (TBI)., Methods: A cohort of 118 persons with chronic TBI (>6 months postinjury) and moderate-severe aggression selected from a larger cohort of 168 participants enrolled in a parallel-group, randomized, double-blind, placebo-controlled trial of amantadine 100 mg twice daily (n = 82) versus placebo (n = 86) for treatment of irritability were studied. Anger and aggression were measured at treatment days 0, 28, and 60 using observer-rated and participant-rated State-Trait Anger Expression Inventory-2 (STAXI-2) and Neuropsychiatric Inventory-Agitation/Aggression domain (NPI-A) Most Problematic and Distress scores., Results: Participant-rated day 60 NPI-A Most Problematic (adjusted P = .0118) and NPI-A Distress (adjusted P = .0118) were statistically significant between the 2 groups, but STAXI-2 differences were not significant after adjustment for multiple comparisons. Substantial improvements were noted in both amantadine and placebo groups (70% vs 56% improving at least 3 points on day 60 Observer NPI-A; P = .11)., Conclusion: Amantadine 100 mg twice daily in this population with chronic TBI appears to be beneficial in decreasing aggression from the perspective of the individual with TBI. No beneficial impact on anger was found., Trial Registration: clinicaltrials.gov Identifier: NCT00779324; http://www.clinicaltrials.gov/ct2/show/NCT00779324?term=irritability&rank=6.