Prescribing anticholinergics in specific patient populations
In addition to the adverse effects described above, benztropine can affect cognition, as we observed in Ms. P. The cholinergic system plays a role in human cognition, and blockade of muscarinic receptors has been associated with impairments in working memory and prefrontal tasks.12 These adverse cognitive effects are more pronounced in certain populations, including patients with schizophrenia and older adults.
Schizophrenia is associated with declining cognitive function, and the cognitive faculties of patients with schizophrenia may be worsened by anticholinergics. In patients with schizophrenia, social interactions and social integration are often impacted by profound negative symptoms such as social withdrawal and poverty of thought and speech.13 In a double-blind study by Baker et al,14 benztropine was found to have an impact on attention and concentration in patients with chronic schizophrenia. Baker et al14 found that patients with schizophrenia who were switched from benztropine to placebo increased their overall Wechsler Memory Scale scores compared to those maintained on benztropine. One crosssectional analysis found that a higher anticholinergic burden was associated with impairments across all cognitive domains, including memory, attention/control, executive and visuospatial functioning, and motor speed domains.15 Importantly, a higher anticholinergic medication burden was associated with worse cognitive performance.15 In addition to impairments in cognitive processing, anticholinergics have been associated with a decreased ability to benefit from psychosocial programs and impaired abilities to manage activities of daily living.4 In another study exploring the effects of discontinuing anticholinergics and the impact on movement disorders, Desmarais et al16 found patients experienced a significant improvement in scores on the Brief Assessment of Cognition in Schizophrenia after discontinuing anticholinergics. Vinogradov et al17 noted that “serum anticholinergic activity in schizophrenia patients shows a significant association with impaired performance in measures of verbal working memory and verbal learning memory and was significantly associated with a lowered response to an intensive course of computerized cognitive training.” They felt their findings underscored the cognitive cost of medications with high anticholinergic burden.
Geriatric patients. Careful consideration should be given before starting benztropine in patients age ≥65. The 2019 American Geriatric Society’s Beers Criteria18 recommend avoiding benztropine in geriatric patients; the level of recommendation is strong. Furthermore, the American Geriatric Society designates benztropine as a medication that should be avoided, and a nondrug approach or alternative medication be prescribed independent of the patient’s condition or diagnosis. In a recently published case report, Esang et al19 highlighted several salient findings from previous studies on the risks associated with anticholinergic use:
- any medications a patient takes with anticholinergic properties contribute to the overall anticholinergic load of a patient’s medication regimen
- the higher the anticholinergic burden, the greater the cognitive deficits
- switching from an FGA to an SGA may decrease the risk of EPS and may limit the need for anticholinergic medications such as benztropine for a particular patient.
One must also consider that the effects of multiple medications with anticholinergic properties is probably cumulative.
Alternatives for treating drug-induced parkinsonism
Antipsychotics exert their effects through antagonism of the D2 receptor, and this is the same mechanism that leads to parkinsonism. Specifically, the mechanism is believed to be D2 receptor antagonism in the striatum leading to disinhibition of striatal neurons containing GABA.11 This disinhibition of medium spiny neurons is propagated when acetylcholine is released from cholinergic interneurons. Anticholinergics such as benztropine can remedy symptoms by blocking the signal of acetylcholine on the M1 receptors on medium spiny neurons. However, benztropine also has the propensity to decrease cholinergic transmission, thereby impairing storage of new information into long-term memory as well as impair perception of time—similar to effects seen with (for instance) diphenhydramine.20
The first step in managing drug-induced parkinsonism is to monitor symptoms. The APA Guideline recommends monitoring for acute-onset EPS at weekly intervals when beginning treatment and until stable for 2 weeks, and then monitoring at every follow-up visit thereafter.4 The next recommendation for long-term management of drug-induced parkinsonism is reducing the antipsychotic dose, or replacing the patient’s antipsychotic with an antipsychotic that is less likely to precipitate parkinsonism,4 such as quetiapine, iloperidone, or clozapine.11 If dose reduction is not possible, and the patient’s symptoms are severe, pharmacologic management is indicated. The APA Guideline recommends amantadine as a first-line agent because it is associated with fewer peripheral adverse effects and less impairment in cognition compared with benztropine.4 In a small (N = 60) doubleblind crossover trial, Gelenberg et al20 found benztropine 4 mg/d—but not amantadine 200 mg/d—impaired free recall and perception of time, and participants’ perception of their own memory impairment was significantly greater with benztropine. Amantadine has also been compared to biperiden, a relatively selective M1 muscarinic receptor muscarinic agent. In a separate double-blind crossover study of 26 patients with chronic schizophrenia, Silver and Geraisy21 found that compared to amantadine, biperiden was associated with worse memory performance. The recommended starting dose of amantadine for parkinsonism is 100 mg in the morning, increased to 100 mg twice a day and titrated to a maximum daily dose of 300 mg/d in divided doses.4
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