What is the mechanism of action of amantadine in patients with traumatic brain injury (TBI)?

Mechanism of Action of Amantadine in Traumatic Brain Injury

Amantadine acts primarily as a dopamine receptor agonist and NMDA receptor antagonist to promote neurological recovery after traumatic brain injury by enhancing dopaminergic neurotransmission and reducing excitotoxicity in injured brain tissue. 1, 2

Primary Mechanisms

Dopaminergic Enhancement

• Amantadine functions as a dopamine receptor agonist, stimulating dopaminergic pathways that are disrupted following TBI 3, 1
• The drug addresses the known derangements in dopaminergic neurotransmitter systems that occur after brain injury 4
• This dopaminergic stimulation helps facilitate recovery of the nervous system and promotes neurological function 3

NMDA Receptor Antagonism

• Amantadine blocks NMDA (N-methyl-D-aspartate) receptors, which reduces excitotoxic damage in injured neural tissue 1, 2
• This mechanism helps protect neurons from secondary injury cascades that follow the initial traumatic insult 2

Clinical Effects on Brain Function

Cognitive and Arousal Improvements

• The drug enhances focused and sustained attention, concentration, orientation, alertness, arousal, and psychomotor processing speed 5
• Amantadine increases responsiveness in low-arousal patients, with 8 of 9 such patients showing increased level of responsiveness in one case series 5
• Improvements in cognition appear most consistently in the intermediate-term (4-6 weeks after treatment completion) rather than immediate short-term effects 2

Functional Recovery Timeline

• One high-quality RCT demonstrated significant improvement in the Disability Rating Scale (DRS) with amantadine versus placebo (10.88±5.24 vs 8.04±4.07, P=0.015) over a 6-week treatment period 4
• Another RCT showed important rise in Glasgow Coma Scale between day 1 and day 7 of treatment (p=0.044), though longer-term effects were not significant 3
• The rate of functional ability improvement appears accelerated with amantadine, though long-term cognitive outcomes remain unclear 4, 2

Important Clinical Caveats

Evidence Quality Limitations

• The evidence base consists primarily of small RCTs with heterogeneous methodologies, making definitive conclusions difficult 2
• Most studies evaluate only severe TBI in adults, limiting generalizability to other TBI severities 2
• Long-term effects (6 months post-injury) have not shown superiority over placebo in available trials 2

Safety Profile

• Amantadine is generally well-tolerated in TBI patients, with consistently low rates of severe adverse events across studies 2
• Reported adverse effects include pedal edema, hypomania, seizures (0.7% incidence), elevated liver enzymes (1.9%), visual hallucinations, and rare cardiac death (0.3%) 2, 5
• Five of 12 patients in one case series experienced possible side effects, though most were manageable 5

Areas of Inconsistent Response

• Memory improvement, assaultiveness, and confusion show inconsistent responses to amantadine 5
• Depression and sexual inappropriateness do not appear to respond to the medication 5
• Agitation may improve dramatically in some patients (2 of 3 with severe agitation showed resolution), but this is not universal 5

Contextual Note on Neurostimulants in Brain Injury

While the question specifically asks about amantadine, it's worth noting that the American Heart Association/American Stroke Association found it reasonable to use neurostimulants (including amantadine) to promote consciousness recovery in severe acute brain injuries, though this was based on extrapolation from limited data with only 11% of patients having subarachnoid hemorrhage rather than TBI 6. The median time to initiation was approximately 19 days post-injury 6.