Amantadine

Indications

• FDA-approved for drug-induced extrapyramidal reactions in adults, which is the indication that matters most in psychiatric practice.
• FDA-approved for parkinsonism, including idiopathic, post-encephalitic and arteriosclerotic forms, usually as an adjunct rather than monotherapy.
• The extended-release capsule is approved for levodopa-induced dyskinesia and for OFF episodes in Parkinson disease on levodopa.
• Retains an approved influenza A indication, but CDC no longer recommends it because circulating strains are almost universally resistant.
• Used off-label for antipsychotic-induced parkinsonism and akathisia when adding anticholinergic burden is undesirable.
• Off-label for fatigue in multiple sclerosis and for apathy, irritability and aggression after traumatic brain injury, with modest evidence.

Mechanism of action

• Weak non-competitive NMDA receptor antagonist, the property that underlies its anti-dyskinetic effect and its benefit for fatigue.
• Increases presynaptic dopamine release and blocks dopamine reuptake, raising striatal dopamine without direct receptor agonism.
• Mild anticholinergic activity contributes to relief of drug-induced parkinsonism and also to confusion in vulnerable patients.
• Its antiviral action comes from blockade of the influenza A M2 proton channel, now largely irrelevant because of resistance.
• Unlike benztropine it does not worsen tardive dyskinesia and produces much less cognitive impairment, which drives its psychiatric use.

Pharmacokinetics

• Oral bioavailability is high at 86-94% with peak concentrations 2-4 h after immediate-release dosing and no meaningful food effect.
• Elimination half-life is 10-25 h with normal renal function but can extend to a week or more in end-stage renal disease.
• Amantadine is not appreciably metabolized: roughly 90% is excreted unchanged in urine by filtration and active tubular secretion.
• Because clearance is renal, accumulation in kidney disease produces delirium, myoclonus, hallucinations and livedo reticularis.
• Hemodialysis removes only small amounts, so dialysis neither substitutes for dose reduction nor rescues toxicity quickly.

Dosing

• Drug-induced extrapyramidal reactions: 100 mg twice daily, increasing to 300 mg/day in divided doses if response is inadequate.
• Parkinsonism: 100 mg once or twice daily, with doses up to 400 mg/day in divided doses only under close supervision.
• Extended-release capsules for levodopa-induced dyskinesia: 137 mg at bedtime for one week, then 274 mg at bedtime.
• Reduce for renal impairment: 100 mg daily at creatinine clearance 30-50, 100 mg every other day at 15-29, and 200 mg every 7 days below 15.
• Start patients over 65 at 100 mg once daily, since age-related decline in creatinine clearance is the usual cause of toxicity.
• Do not stop abruptly in Parkinson disease, where withdrawal can precipitate a parkinsonian crisis or a syndrome resembling NMS.

Adverse effects

• Nausea, dizziness, insomnia, dry mouth and anorexia occur in roughly 5-10% and are usually mild at standard doses.
• Livedo reticularis of the lower limbs and ankle edema are characteristic, dose-related, benign and reversible on stopping.
• Confusion, visual hallucinations and frank delirium occur most often in older patients, in renal impairment or with other anticholinergics.
• Anticholinergic effects including urinary retention, constipation and blurred vision matter in men with prostatic hypertrophy.
• Impulse control disorders such as gambling and hypersexuality, and worsening of psychosis, follow from its dopaminergic action.
• Rare but serious effects include corneal edema, leukopenia, suicidal ideation and a neuroleptic malignant-like syndrome on abrupt withdrawal.

Monitoring

• Creatinine clearance at baseline and periodically, because renal function alone determines the correct dose.
• Mental status, hallucinations and sleep at each visit, particularly in patients over 65 or with cognitive impairment.
• Inspect the legs for livedo reticularis and check for peripheral edema, which are easily mistaken for vasculitis or heart failure.
• Track extrapyramidal response with a Simpson-Angus or Barnes akathisia rating when treating antipsychotic-induced symptoms.
• Ask directly about gambling, spending, sexual behavior and suicidal ideation, none of which patients report spontaneously.

Interactions

• Additive anticholinergic burden with benztropine, tricyclics, diphenhydramine and oxybutynin, which markedly raises delirium risk.
• Other dopaminergic drugs increase both benefit and the risk of psychosis, especially in patients with schizophrenia.
• Triamterene-hydrochlorothiazide, quinine and quinidine compete for renal tubular secretion and raise amantadine concentrations.
• Alcohol and other central nervous system depressants add to dizziness, confusion and orthostatic symptoms, particularly in older adults.
• Live attenuated influenza vaccine should be separated from amantadine by about 2 weeks because of residual antiviral activity.

Special populations

• Pregnancy: avoid where possible, since first-trimester case reports describe cardiovascular and limb malformations.
• Lactation: amantadine enters human milk and may suppress lactation through its dopaminergic action, so it is not recommended.
• Pediatric use is established only for the influenza indication from age 1 year; there is no established pediatric dose for extrapyramidal symptoms.
• Geriatric patients need lower doses and closer surveillance for delirium, hallucinations, urinary retention and falls.
• Renal impairment drives every dose adjustment, down to 200 mg every 7 days in end-stage disease including patients on hemodialysis.

Clinical pearls

• Dose it by creatinine clearance; accumulation shows up first as confusion and hallucinations.
• Livedo reticularis on the legs is benign and dose-related, not vasculitis; do not panic.
• Good choice for antipsychotic EPS when anticholinergic burden must be kept down.