How effective is benztropine at preventing extrapyramidal symptoms (EPS)?

Comment by InpharmD Researcher

Overall, there is a paucity of data comparing benztropine's efficacy for the prevention of drug-induced extrapyramidal symptoms (EPS). Two dated studies with major limitations revealed that when compared with amantadine, benztropine is found to be comparable in terms of efficacy; however, benztropine presented with more adverse events. Another outdated publication that compared chlorpromazine with benztropine indicated that the prophylactic use of benztropine had no effect in reducing the rate of EPS.

Background

A 2018 Cochrane review evaluated whether the use or the withdrawal of anticholinergic drugs is clinically effective for the treatment of people with both antipsychotic-induced tardive dyskinesia and schizophrenia or other chronic mental illnesses. This review was an update to its 2017 version and included two trials that were not previously identified. However, the efficacy of benztropine was not evaluated in any of the included studies, which highlights the lack of available literature on determining benztropine's effectiveness in managing tardive dyskinesia. [1]

Literature Review

A search of the published medical literature revealed 3 studies investigating the researchable question:

How effective is benztropine at preventing drug-induced extrapyramidal symptoms (EPS)?

Level of evidence

C - Multiple studies with limitations or conflicting results Read more→

Please see Tables 1-3 for your response.

Comparison of Benztropine Mesylate and Amantadine HCL in Neuroleptic-induced Extrapyramidal Symptoms
Design	Prospective, double-blinded, randomized study N= 41
Objective	To discuss the method and the results of a maximal 7-day study comparing amantadine HCL with a control agent, benztropine mesylate in management of neuroleptic-induced extrapyramidal symptoms (EPS)
Study Groups	Amantadine (n= 22) Benztropine (n= 19)
Inclusion Criteria	Age 18 years or older, clinically-significant EPS, on the afflicting agent within 48 hours of hospitalization
Exclusion Criteria	Pregnancy; Parkinson's disease; significant cardiovascular, renal, or hepatic disease
Methods	Patients were randomized to receive either benztropine mesylate 2 mg or amantadine HCL 100 mg, both given BID (morning and afternoon). If improvements were not observed within 48 hours, the dose was increased to TID (third dose given midday). If symptoms persisted despite a maximum dose of capsules, the treatment was considered a failure.
Duration	7 days
Outcome Measures	Comparison of the efficacy of two drugs made by measuring the improvement of the severity scores
Baseline Characteristics		Study patients (N= 41)
	Age, years	33
	Female	17
	Diagnosis Schizophrenia Manic depressive illness Psychotic depression Chronic organic brain syndrome Acute psychosis Acute catatonic state	30 2 2 2 4 1
	Final dose on last day of study Benztropine 2 mg Benztropine 4 mg Benztropine 6 mg Amantadine 100 mg Amantadine 200 mg Amantadine 400 mg	1 15 3 3 15 4
Results	Endpoint	Amantadine (n= 22)	Benztropine (n= 19)
	Improvement in Parkinsonism Syndrome, Dystonic, and Akathisia scores	22/22	19/19
	Improvement in Parkinsonism Syndrome scores	20/21	18/18
	Improvement in Dystonic scores	21/21	17/17
	Improvement in Akathisia scores	5/5	4/6
	There was no incidence of tardive dyskinesia and it could not be evaluated.
Adverse Events	Amantadine versus benztropine: dry mouth (2 vs 6), visual disturbance (2 vs 6), urinary hesitancy (0 vs 1), constipation (0 vs 2)
Study Author Conclusions	In this study, both benztropine mesylate and amantadine HCL were found to be highly effective as contraactive agents for neuroleptic-induced EPS. Amantadine HCL produced a significantly lower occurrence of anticholinergic side effects. Thus, from our data, a merit of amantadine HCL over benztropine mesylate is its reduced association with atropine-like side effects, yet without compromising efficacy.
InpharmD Researcher Critique	This is an older study that may not reflect current clinical practice. Baseline data and procedures for follow-up is limited.

References:

Stenson RL, Donion PT, Meyer JE. Comparison of benztropine mesylate and amantadine HCl in neuroleptic-induced extrapyramidal symptoms. Compr Psychiatry. 1976;17(6):763-768. doi:10.1016/0010-440x(76)90024-9

Extrapyramidal Side Effects in Chlorpromazine Recipients
Design	Prospective cohort study N= 654
Objective	To analyze the emergence of extrapyramidal symptoms (EPS) in chlorpromazine recipients according to the presence of benztropine prophylaxis
Study Groups	Benztropine prophylaxis (n= 86) No benztropine prophylaxis (n= 586)
Inclusion Criteria	Consecutively monitored psychiatric inpatients, chlorpromazine recipients
Exclusion Criteria	Not specified
Methods	Selected patients from four hospitals in the United States and one in Finland were divided based on their status of benztropine administration. A patient was considered as having received benztropine prophylaxis if both benztropine and chlorpromazine were administered for at least 24 hours prior to the appearance of EPS.
Duration	From 1968 to 1974
Outcome Measures	Emergence of EPS
Baseline Characteristics		All chlorpromazine recipients (N= 654)
	Age, years	35
	Female	50%
	Primary diagnosis Schizophrenia Affective psychosis Personality disorder Others	55% 10% 7% 28%
Results	Endpoint	Benztropine prophylaxis (n= 86)	No benztropine prophylaxis (n= 586)
	No. with EPS Aged < 30 Aged ≥ 30 Male Female	8 (9.3%) 5/42 (11.9%) 3/44 (6.8%) 5/45 (11.1%) 3/41 (7.3%)	60 (10.6%) 33/255 (12.9%) 27/313 (8.6%) 34/282 (12.1%) 26/286 (9.1%)
	Types of EPS Dystonia Akinesia Other symptoms	4 (4.7%) 3 (3.5%) 1 (1.2%)	19 (3.4%) 18 (3.2%) 23 (4.1%)
	Mean daily dose of chlorpromazine, mg	309 ± 191	273 ± 43
	The rates of EPS among 29 patients who received doses of 3 mg or more of benztropine (6.9%) and among 57 patients who received a lower dose (10.5%) were consistent with random variation.
Study Author Conclusions	The frequency of EPS attributed to chlorpromazine among 86 patients who received benztropine for the prevention of EPS was similar to that of the 568 patients who received chlorpromazine alone. The data in this small sample indicated that the prophylactic use of benztropine had no effect in reducing the rate of EPS.
InpharmD Researcher Critique	The study is limited to its small sample size, outdated publication, and lack of standardized benztropine regimens for EPS prophylaxis across study centers. Without a formal statistical analysis, the findings are merely descriptive.

References:

Swett C Jr, Cole JO, Shapiro S, Slone D. Extrapyramidal side effects in chlorpromazine recipients: emergence according to benztropine prophylaxis. Arch Gen Psychiatry. 1977;34(8):942-943. doi:10.1001/archpsyc.1977.01770200080009

A Controlled Trial of Amantadine in Drug-Induced Extrapyramidal Disorders
Design	Double-blind, parallel-group study N= 44
Objective	To assess the efficacy and adverse effects of amantadine hydrochloride for the treatment of drug-induced extrapyramidal symptoms (EPS)
Study Groups	Amantadine Benztropine
Inclusion Criteria	Physically healthy adult schizophrenics (men and women) from inpatient services, being treated with antipsychotic drugs, and in whom extrapyramidal side effects developed during the course of therapy
Exclusion Criteria	Severe organic diseases, women known to be pregnant, patients who had been given anti-parkinsonism drugs prior to the development of extrapyramidal side effects, and intensity of EPS exhibited to be a sufficient degree in the opinion of the rating psychiatrist
Methods	When any of the extrapyramidal target symptoms were first noted in a patient, the project psychiatrist examined the patient and rated the severity of each symptom on a scale of 0 (not present) to 3 (severe). Patients were randomly assigned to either 100 mg amantadine or 2 mg benztropine treatment groups. The medications were initiated at a starting dose of one capsule BID and raised to a maximum dosage of four capsules daily if the side effects seemed resistant to treatment.
Duration	28 days
Outcome Measures	EPS and global EPS improvement ratings 28 days following initiation of the anti-parkinsonism medications
Baseline Characteristics	Pretreatment extrapyramidal symptoms	Number of patients exhibiting symptoms		Average severity rating
	Dystonic reactions	32		1.91
	Dyskinetic reactions	25		1.77
	Akathisia	24		1.71
	Muscle weakness and limpness	35		1.83
	Rigidity	41		2.19
	Facial masking	15		1.54
	Tremors of extremities	43		1.89
	The majority of patients in each treatment group continued to receive two capsules per day throughout the study (16 in the benztropine group, 15 in the amantadine group). Five additional patients in each treatment group were raised to four capsules per day during the second week, and one patient in the benztropine group was raised to six capsules per day in the second study week
Results	Comparison of symptom control with those patients originally exhibiting symptom pretreatment*
		Amantadine		Benztropine
		Pretreatment	Day 28	Pretreatment	Day 28
	Dystonic reactions	1.76 (N= 17)	0.00 (N= 10)	2.07 (N= 15)	0.00 (N= 13)
	Dyskinetic reactions	1.78 (N= 18)	0.08 (N= 13)	1.76 (N= 17)	0.00 (N= 15)
	Akathisia	1.69 (N= 13)	0.00 (N= 9)	1.73 (N= 11)	0.10 (N= 9)
	Muscle weakness and limpness	1.88 (N= 18)	0.30 (N= 10)	1.76 (N= 17)	0.07 (N= 14)
	Rigidity	2.00 (N= 21)	0.14 (N= 14)	2.24 (N= 21)	0.00 (N= 17)
	Tremors, facial	1.50 (N= 10)	0.00 (N= 8)	1.60 (N= 5)	0.00 (N= 4)
	Tremors, extremities	1.73 (N= 22)	0.29 (N= 14)	2.14 (N= 21)	0.11 (N= 21)
	Global extrapyramidal symptoms improvement ratings**
	Day	Amantadine (No.)		Benztropine (No.)
	1	1.95 (22)		2.23 (22)
	28	3.57 (14)		3.83 (18)
	Symptom code: 0=none; 1=mild; 2=moderate; and 3=severe * Rating code: 1 = no improvement or worse; 2 = slight improvement; 3 = notable improvement; 4 = complete remission of symptom
Adverse Events	Amantadine vs. benztropine: loss of appetite (1 vs. 7), dry mouth (3 vs. 5), constipation (2 vs. 6), listlessness (3 vs. 5), urinary retention (2 vs. 4), blurred vision (2 vs. 4), muscle weakness (2 vs. 4), excitement (4 vs. 2), deficiency of sweat (0 vs. 3), difficulty in speech (3 vs. 0), mental confusion (1 vs. 2), skin rash (0 vs. 2), nausea (0 vs. 2), vomiting (0 vs. 2), nervousness (0 vs. 2), swallowing difficulty (1 vs. 1)
Study Author Conclusions	Amantadine was found to be comparable in effect to benztropine mesylate but with fewer side effects. The potential role of amantadine may be in the treatment of patients with drug-induced EPS for whom medication with anticholinergic properties is contraindicated.
InpharmD Researcher Critique	This study provided limited data on baseline characteristics as well as the number of patients allocated to each treatment group. No data were disclosed in terms of the long-term efficacy of these drugs. The findings of this study are further limited by its small sample size and an outdated publication that may not reflect the current clinical practice guidelines.

References:

DiMascio A, Bernardo DL, Greenblatt DJ, Marder JE. A controlled trial of amantadine in drug-induced extrapyramidal disorders. Arch Gen Psychiatry. 1976;33(5):599-602. doi:10.1001/archpsyc.1976.01770050055008