What is the preferred treatment between Artane (trihexyphenidyl) and amantadine for managing extrapyramidal symptoms (EPS) in geriatric patients?

Amantadine is Preferred Over Artane (Trihexyphenidyl) for EPS in Geriatric Patients

For geriatric patients with extrapyramidal symptoms, amantadine should be the first-line agent rather than trihexyphenidyl (Artane), primarily because anticholinergic medications cause significant cognitive impairment, delirium, and paradoxical agitation in elderly patients, while amantadine lacks these anticholinergic effects. 1, 2

Primary Rationale: Anticholinergic Burden in Elderly

• The American Family Physician explicitly recommends avoiding benztropine or trihexyphenidyl when treating EPS in elderly patients with Alzheimer's disease due to heightened sensitivity to anticholinergic effects 1
• Anticholinergic medications like trihexyphenidyl can cause delirium, drowsiness, and paradoxical agitation in geriatric populations 2
• The American Geriatrics Society advises avoiding medications that induce delirium in older adults, specifically including anticholinergics 3
• Elderly patients experience more severe cognitive impairment from anticholinergics compared to younger adults, with particular deficits in memory acquisition and mood 4

Evidence Supporting Amantadine's Superior Safety Profile

• In a controlled study of older persons, amantadine demonstrated fewer CNS side effects compared to anticholinergics (including rimantadine comparison showing 13% CNS symptoms with amantadine vs higher rates with anticholinergics) 5
• Amantadine administered at standard clinical doses did not impair new memory acquisition in elderly subjects, whereas anticholinergics significantly impaired free recall, recognition memory, and self-rated memory function 4
• A double-blind study found amantadine comparable in efficacy to benztropine for treating drug-induced EPS, but with fewer side effects 6
• Amantadine was significantly better tolerated than anticholinergics on self-report measures, particularly in elderly subjects 4

Equivalent Efficacy Between Agents

• Multiple double-blind studies demonstrate that amantadine and anticholinergics (biperiden, benztropine) have similar efficacy in relieving neuroleptic-induced parkinsonian EPS 7, 8, 6
• Both amantadine 100 mg twice daily and biperiden 2 mg three times daily showed equal effectiveness in treating haloperidol-induced EPS, with no significant differences between treatment groups 7
• A crossover study of 26 schizophrenic patients found amantadine and biperiden equally effective in relieving EPS, with both showing significant improvement over placebo 8

Practical Dosing Recommendations

Amantadine Dosing in Geriatrics:

• The daily dose for persons ≥65 years should not exceed 100 mg for treatment, as renal function declines with age 5
• For elderly women (who have smaller average body size), doses may need further reduction below 100 mg daily 5
• Patients should be observed carefully for adverse reactions, with dose reduction or discontinuation if CNS side effects develop 5
• Dose reduction to 100 mg/day is mandatory for creatinine clearance <10 mL/min 5

Trihexyphenidyl Dosing (if unavoidable):

• Initial dose should be low (1 mg) and increased gradually, especially in patients over 60 years 9
• Total daily dosage for drug-induced parkinsonism ranges 5-15 mg, though some achieve control with as little as 1 mg daily 9
• The FDA label emphasizes individualized dosing with particular caution in elderly patients 9

Clinical Algorithm for EPS Management in Geriatrics

1. First-line: Amantadine 100 mg daily (or less if renal impairment or frailty present) 5, 4
2. Monitor for CNS effects (nervousness, anxiety, insomnia, lightheadedness) which occur in ~13% of patients 5
3. If inadequate response after 1-2 weeks, consider dose reduction of the offending antipsychotic rather than adding anticholinergics 1, 2
4. Alternative strategy: Switch to lower EPS-risk antipsychotic (quetiapine > aripiprazole > olanzapine) rather than adding anticholinergics 3, 1
5. Reserve trihexyphenidyl only for patients who fail amantadine AND cannot switch antipsychotics, using lowest effective dose (start 1 mg daily) 9

Important Caveats and Contraindications

• Amantadine has anticholinergic effects itself and should not be used in patients with untreated angle closure glaucoma 5
• Serious CNS side effects with amantadine (marked behavioral changes, delirium, hallucinations, agitation, seizures) have been observed most often in elderly persons with renal insufficiency, seizure disorders, or psychiatric disorders 5
• Hemodialysis contributes minimally to amantadine clearance, so dose adjustment is critical in renal failure 5
• Anticholinergics should never be used prophylactically—only treat EPS after symptoms develop 1, 2
• Abrupt withdrawal of either agent may result in acute exacerbation of parkinsonian symptoms or neuroleptic malignant syndrome 9

Special Consideration: Tardive Dyskinesia Risk

• Anticholinergic treatment of EPS has been associated with induction or exacerbation of tardive dyskinesia 7
• Both amantadine and anticholinergics did not exacerbate TD-type movements in controlled studies, and may actually ameliorate mild TD 8
• This provides additional rationale for preferring amantadine, given its lack of anticholinergic cognitive burden while maintaining similar TD safety profile 8