The role of glutamate

UNDERSTANDING THE ROLE OF GLUTAMATE IN PARKINSON’S DISEASE1

Dopamine is only part of the story when it comes to controlling motor complications.

MOD/MOA Slide Show Legend
Role of Glutamate in Parkinson's disease: GOOD movement with dopamine and glutamate regulated
How Amantadine is Believed to Work: OFF time inconsistently remedied by levodopa
How Amantadine is Believed to Work: Dyskinesia with excessive dopaminergic tone during peak levodopa levels
How Amantadine is Believed to Work: OFF time in Parkinson's disease from overactive glutamatergic signaling
How Amantadine is Believed to Work: Dyskinesia from overactive glutamatergic signaling
How Amantadine is Believed to Work: NMDA antagonism reduces unbalanced signaling
How Amantadine is Believed to Work: NMDA antagonism reduces unbalanced signaling

Reducing glutamate hyperactivity THROUGH THE NMDA RECEPTOR COULD BE CRITICAL TO REDUCING dyskinesia and OFF time1

NMDA, N-methyl-D-aspartate. A synthetic amino acid C5H9ND4 that binds selectively to a subset of glutamate receptors on neurons.1

How amantadine is believed to work

Amantadine is an NMDA antagonist used in PD treatment7*

How Amantadine Is Believed to Work in Parkinson's disease Treatment

WHY AMANTADINE FOR RESTORING GOOD MOVEMENT?

  • Amantadine is used for symptomatic treatment for PD and can reduce levodopa-induced dyskinesia9-11
  • The mechanism by which amantadine exerts efficacy in the treatment of dyskinesia in patient with PD is unknown9
    • May work by reducing excessive glutamatergic activity, which contributes to dyskinesia and OFF3,7
    • Amantadine may have direct and indirect effects on dopamine neurons; it exerts dopaminergic-like side effects such as hallucinations and dizziness in humans9
  • Common daily dosing of amantadine HCl IR in PD is 100 mg BID9
* Amantadine is a low-affinity, noncompetitive NMDA antagonist, which means inhibition of the NMDA channel occurs at a different binding site than the active site where the substrate binds.1

INDICATION and important safety information

GOCOVRI® (amantadine) extended release capsules is indicated:

  • For the treatment of dyskinesia in patients with Parkinson’s disease receiving levodopa-based therapy, with or without concomitant dopaminergic medications
  • As adjunctive treatment to levodopa/carbidopa in patients with Parkinson’s disease experiencing “off” episodes

It is not known if GOCOVRI is safe and effective in children.

IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS
GOCOVRI is contraindicated in patients with creatinine clearance below 15 mL/min/1.73 m2.

WARNINGS AND PRECAUTIONS

Falling Asleep During Activities of Daily Living and Somnolence: Patients treated with Parkinson’s disease medications have reported falling asleep during activities of daily living. If a patient develops daytime sleepiness during activities that require full attention (e.g., driving a motor vehicle, conversations, eating), GOCOVRI should ordinarily be discontinued or the patient should be advised to avoid potentially dangerous activities.

Suicidality and Depression: Monitor patients for depression, including suicidal ideation or behavior. Prescribers should consider whether the benefits outweigh the risks of treatment with GOCOVRI in patients with a history of suicidality or depression.

Hallucinations/Psychotic Behavior: Patients with a major psychotic disorder should ordinarily not be treated with GOCOVRI because of the risk of exacerbating psychosis. Observe patients for the occurrence of hallucinations throughout treatment, especially at initiation and after dose increases.

Dizziness and Orthostatic Hypotension: Monitor patients for dizziness and orthostatic hypotension, especially after starting GOCOVRI or increasing the dose.

Withdrawal-Emergent Hyperpyrexia and Confusion: Rapid dose reduction or abrupt discontinuation of GOCOVRI, may cause an increase in the symptoms of Parkinson’s disease or cause delirium, agitation, delusions, hallucinations, paranoid reaction, stupor, anxiety, depression, or slurred speech. Avoid sudden discontinuation of GOCOVRI.

Impulse Control/Compulsive Behaviors: Patients may experience urges (e.g. gambling, sexual, money spending, binge eating) and the inability to control them. It is important for prescribers to ask patients or their caregivers about the development of new or increased urges. Consider dose reduction or stopping medications.

ADVERSE REACTIONS
The most common adverse reactions (>10%) were hallucination, dizziness, dry mouth, peripheral edema, constipation, fall, and orthostatic hypotension.

View the full Prescribing Information.

References:
  1. Encarnacion EV, Hauser RA. Levodopa-induced dyskinesias in Parkinson's disease: etiology, impact on quality of life, and treatments. Eur Neurol. 2008;60(2):57-66.
  2. Rajan R, Popa T, Quartarone A, Ghilardi MF, Kishore A. Cortical plasticity and levodopa-induced dyskinesias in Parkinson’s disease: connecting the dots in a multicomponent network. Clin Neurophysiol. 2017;128(6):992-999.
  3. Duty S. Targeting glutamate receptors to tackle the pathogenesis, clinical symptoms and levodopa-induced dyskinesia associated with Parkinson’s disease. CNS Drugs. 2012;26(12):1017-1032.
  4. Gerfen CR, Surmeier DJ. Modulation of striatal projection systems by dopamine. Annu Rev Neurosci. 2011;34:441–466.
  5. Surmeier DJ, Ding J, Day M, Wang Z, Shen W. D1 and D2 dopamine-receptor modulation of striatal glutamatergic signaling in striatal medium spiny neurons. Trends Neurosci. 2007;30(5):228-235.
  6. Manson A, Stirpe P, Schrag A. Levodopa-induced-dyskinesias clinical features, incidence, risk factors, management and impact on quality of life. J Parkinsons Dis. 2012;2(3):189-198.
  7. Parsons CG, Quack G, Bresink I, et al. Comparison of the potency, kinetics and voltage-dependency of a series of uncompetitive NMDA receptor antagonists in vitro with anticonvulsive and motor impairment activity in vivo. Neuropharmacology. 1995;34(10):1239-1258.
  8. Ahmed I, Bose SK, Pavese N, et al. Glutamate NMDA receptor dysregulation in Parkinson’s disease with dyskinesias. Brain. 2011;134(4):979-986.
  9. Symmetrel [Prescribing Information]. Chadds Ford, PA. Endo Pharmaceuticals Inc; 2009.
  10. Crosby N, Deane KH, Clarke CE. Amantadine in Parkinson’s disease. Cochrane Database Syst Rev. 2003;(1):CD003468.
  11. Elmer LW, Juncos JL, Singer C, et al. Pooled analyses of phase III studies of ADS-5102 (amantadine) extended-release capsules for dyskinesia in Parkinson’s disease. CNS Drugs. 2018;32(4):387-398.