Why does benztropine (anticholinergic medication) worsen Tardive Dyskinesia (TD)?

Why Benztropine Worsens Tardive Dyskinesia

Benztropine and other anticholinergic medications worsen tardive dyskinesia (TD) by aggravating the underlying dopamine hypersensitivity that causes TD, and should be avoided in patients with this condition. 1

Mechanism of Worsening

The pathophysiology explains why anticholinergics are contraindicated in TD:

• TD results from dopamine receptor hypersensitivity in the striatum after chronic dopamine blockade, while drug-induced parkinsonism (DIP) results from decreased dopamine concentrations in the same pathway 2
• Anticholinergics like benztropine block acetylcholine, which normally balances dopamine activity in the basal ganglia 2
• Reducing cholinergic tone further unmasks the dopamine hypersensitivity that drives TD movements, making the involuntary movements worse 1, 2
• This is the opposite of what happens in DIP, where anticholinergics help restore the dopamine-acetylcholine balance 2

Clinical Evidence of Worsening

Multiple sources confirm that anticholinergics aggravate TD:

• The FDA label for benztropine explicitly states: "Antiparkinsonism agents do not alleviate the symptoms of tardive dyskinesia, and in some instances may aggravate them. Benztropine mesylate is not recommended for use in patients with tardive dyskinesia" 1
• Oral benztropine administration led to statistically significant increases in dyskinesia in a controlled study of 36 neuroleptic-treated patients 3
• Benztropine-treated patients had a significant increase in tardive dyskinesia compared to their condition during procyclidine treatment in a 12-week controlled study 4
• The American Academy of Family Physicians guidelines explicitly recommend avoiding benztropine or trihexyphenidyl when extrapyramidal symptoms occur in elderly patients on typical antipsychotics 5

Critical Clinical Pitfall

The major danger is misdiagnosing TD as DIP and treating with anticholinergics, which will worsen the patient's condition:

• DIP presents as bradykinesia, rigidity, and rhythmic tremor appearing within hours to weeks of antipsychotic initiation 2
• TD presents as involuntary abnormal facial movements (lip smacking, puckering, chewing, tongue protrusion) appearing after at least 3 months of treatment 2
• Treatment for DIP (anticholinergics) worsens TD, making accurate diagnosis essential 2

Recommended Management Instead

When TD is present:

• Gradually withdraw the offending antipsychotic if clinically feasible 6, 7
• Switch to atypical antipsychotics with lower D2 affinity if continued antipsychotic treatment is necessary 6, 7
• Consider amantadine (a non-anticholinergic agent) if both DIP and TD coexist, as it may treat DIP without worsening TD 2
• Use FDA-approved VMAT2 inhibitors (valbenazine or deutetrabenazine) for TD treatment 6, 2

Additional Adverse Effects

Beyond worsening TD, anticholinergics cause:

• Cognitive impairment, with significant improvement in cognition observed after anticholinergic discontinuation 8
• Increased anxiety and depression compared to other antiparkinsonian agents 4
• More toxic central and peripheral atropinic effects 4