The Anticholinergic Impregnation Scale: Towards The

Home , Alimemazine, Alverine, Anticholinergic, Cyamemazine, Mequitazine, Tropatepine

Therapie (2017) 72, 427—437

Available online at ScienceDirect www.sciencedirect.com

CLINICAL PHARMACOLOGY

The anticholinergic impregnation scale: Towards the

elaboration of a scale adapted to prescriptions in

French psychiatric settings

L’échelle d’imprégnation anticholinergique : vers l’élaboration d’une échelle

adaptée aux prescriptions en milieu psychiatrique franc¸ais

a,b b,c,∗

Jeanne Briet , Hervé Javelot ,

c d

Edwige Heitzmann , Luisa Weiner ,

c e

Catherine Lameira , Philippe D’Athis ,

e a,b

Marie Corneloup , Jean-Louis Vailleau

Pharmacy service, CHS de La Chartreuse, 21000 Dijon, France

PIC network (Psychiatrie Information Communication), EPSM Lille-Métropole, 59487

Armentières, France

Établissement public de santé Alsace Nord, 67170 Brumath, France

Psychiatry II and Inserm unit 1114, university hospital of Strasbourg, 67000 Strasbourg, France

Service of biostatistics and medical informatics, CHU de Dijon, 21000 Dijon, France

Received 6 June 2016; accepted 23 December 2016

Available online 17 February 2017

KEYWORDS Summary

Anticholinergics; Purpose. — Some drugs have anticholinergic activity and can cause peripheral or central side

Anticholinergic drug effects. Several scales exist to evaluate the potential anticholinergic effect of prescribed drugs

scale; but: (i) they are validated in the elderly and mainly assess the cognitive side effect of treat-

Psychiatry ments; (ii) they do not concern some of the drugs frequently used in clinical psychiatry in

France. The aim of our study is to develop a new scale, the anticholinergic impregnation scale

(AIS), with drugs used in France and based on an assessment of the drugs used against peripheral

anticholinergic adverse effects.

∗

Corresponding author. Clinical pharmacy service, Établissement public de santé Alsace Nord (EPS Alsace Nord), 141 avenue de Strasbourg,

67170 Brumath, France.

E-mail address: [email protected] (H. Javelot).

http://dx.doi.org/10.1016/j.therap.2016.12.010

428 J. Briet et al.

Methods. — We assigned a score, ranging from 1 to 3, to a list of 128 drugs with a consensus

approach obtained via literature data and expert opinions. We collected data from 7278 pre-

scriptions in 34 French psychiatric facilities: age, sex, atropinic drugs, laxatives and treatments

of xerophthalmia and xerostomia, in order to evaluate the association between AIS score and

the prescription of drugs aiming to reduce peripheral anticholinergic side effects.

Results. — The most frequently prescribed drugs were cyamemazine (n = 1429; 20%) and

tropatepine (n = 1403; 19%), two drugs marketed almost exclusively in France and with a score

of 3. The frequency of patients with a high AIS score, greater than 5, was signiﬁcantly higher

in patients who received laxatives and treatments of xerostomia. AIS score represents the ﬁrst

validated solution to evaluate anticholinergic load in psychiatry settings in France.

Conclusion. — The anticholinergic problem remains underevaluated in mental health settings.

In order to rule out the confounding factor of mental disease, assessment of peripheral side

effects can be considered more objective than the evaluation of cognitive function in psychiatric

patients. Building scales appropriate for each state also appear essential to obtain an useful

and effective tool in clinical practice.

MOTS CLÉS Résumé Certains médicaments ont une activité anticholinergique et peuvent provoquer des

effets secondaires périphériques ou centraux. Plusieurs échelles existent pour évaluer l’effet

Anticholinergiques ;

anticholinergique potentiel des médicaments prescrits, mais : (i) elles sont validées chez les

Échelle de

médicaments personnes âgées et principalement par le biais des effets cognitifs des traitements ; (ii) elles

n’incluent pas certains médicaments fréquemment utilisés en France et notamment en psychia-

anticholinergiques ;

Psychiatrie trie. Le but de notre étude était de construire une nouvelle échelle, l’« échelle d’imprégnation

anticholinergique » (EIA), intégrant les médicaments utilisés en France et sur la base d’une éval-

uation des médicaments prescrits pour lutter contre les effets indésirables anticholinergiques

périphériques. Notre travail a permis la construction d’une liste de 128 médicaments : (i)

avec une approche de consensus entre les données de la littérature et des avis d’experts et

(ii) en s’appuyant pour sa validation sur 7278 prescriptions recueillies dans 34 établissements

psychiatriques franc¸ais.

SAS. Tous droits reserv´ es.´

Abbreviations effects, such as mydriasis, dry skin and mucous membrane,

hyperthermia, urinary retention, constipation, tachycardia,

confusion, attention deﬁcit and memory impairment [1].

AAS anticholinergic activity scale The main classes of anticholinergic drugs are tri-

ADS anticholinergic drug scale cyclic antidepressants, anticholinergic antihistaminics,

ACB anticholinergic cognitive burden scale antiparkinsonian drugs, neuroleptics, urinary antispasmod-

AIS anticholinergic impregnation scale ics, asthma medications and analgesic drugs. Elderly people

ARS anticholinergic risk scale are more vulnerable to anticholinergic effects because of

ATC anatomical therapeutic chemical class polypharmacy, but also because aging results in a greater

CATIE clinical antipsychotic trials of intervention effec- permeability of blood-brain barrier and an alteration of

tiveness study hepatorenal metabolism [2,3]. Thus, an association of drugs

CI conﬁdence intervals with anticholinergic properties in the elderly has to be

CrAS clinician-related anticholinergic score prescribed with caution [4]. Anticholinergic load is also

OR odds ratio relevant to patients with mental illnesses because a great

number of their treatments include anticholinergic prop-

erties [1,5,6]. These properties may cause peripheral or

Introduction central side effects that are hard to distinguish from mental

illness-related symptoms. However, the adverse effects

Drugs with anticholinergic activity are difﬁcult to pre- related to drugs with anticholinergic activity are under-

scribe due to their multiple peripheral and central side evaluated in mental health settings. In order to exclude

Anticholinergic impregnation scale and psychiatric settings 429

the confounding factor of mental disease, assessment of based on a mixed approach, including in vitro data of serum

peripheral side effects could be more useful in detecting anticholinergic activity and clinician-rated scores. Both data

anticholinergic load than neurocognitive assessment in present the respective limits of a theoretical pharmacolog-

patients with mental illnesses. ical approach and a subjective human approach [15].

Several scales have been developed in the past years aim- Similar to a model described in previous studies [15], we

ing to evaluate anticholinergic burden. Among them, seven reported the previously published anticholinergic score for

scales can be considered relevant based on citation analysis each drug, and transformed the observed score into our own

[relevant articles have been selected according to inclu- scale score according to the following criteria:

•

sion/exclusion criteria deﬁned by Salahudeen et al. [7]: the 1 — limited (including anticholinergic potential in vitro)

anticholinergic drug scale (ADS) [8,9], the anticholinergic or moderate effect;

•

risk scale (ARS) [10], the anticholinergic cognitive burden 2 — strong effect (including drugs with anticholinergic

scale (ACB) [11], the anticholinergic burden classiﬁcation effect in high doses);

•

(ABC) [12], the clinician-rated anticholinergic score (CrAS) 3 — very strong (including drugs with proven high anti-

[13], the anticholinergic activity scale (AAS) [14] and the cholinergic potential).

anticholinergic loading scale (ACL)] [15]. The analysis of

these questionnaires shows that: For unrated drugs, classiﬁcation was carried out on the

•

all scales are validated and used in the elderly; same scale (1—3) based on independent ratings by 3 clinical

•

based on citation analysis, ACB, ARS, ADS and CrAS were pharmacists (2 PharmD and 1 PharmD, PhD) and 2 psychia-

the most frequently validated expert-based anticholin- trists (2 MD). In case of discrepancy between published or

ergic scales on adverse outcomes, but they have been clinician-rated scores, the median ranking was applied in

validated in US drugs settings [7]. order to rank the drugs.

Most scales have also established their clinical validity

based on the cognitive effects of speciﬁc drugs (ACB, AAS, Clinical value assessment of the scale

ACL, ABC and CrAS). However, when the burden associated

with anticholinergic drugs improves, it is not associated Aims of the study

with alleviation of cognitive impairment in randomized clin-

As explained above, it is difﬁcult to partial out the anti-

ical trials (mini review including in particular evaluations

cholinergic effects and the effects of the mental illness

with: ARS, ACB and ADS) [16]. Moreover, in a cross-sectional

on cognition, we thus selected the prescription of drugs

analysis from 21 Norwegian nursing homes, high ADS scores

against peripheral anticholinergic side effects as an indirect

were associated with peripheral but not cognitive markers

indicator of anticholinergic burden. From this standpoint,

of cholinergic blockade [17].

we aimed at developing and evaluating whether our scale,

Taken together, these elements indicate that the evalua-

speciﬁcally designed to evaluate drugs in French settings,

tion of anticholinergic side effects in French mental health

is able to discriminate patients with ‘‘high’’ and ‘‘low’’ AIS

settings requires the development of a list of the most rel- scores.

evant prescription drugs in France (complemented by the

assessment of the frequency of prescription of major drugs).

In order to do so, we have created a new scale, the anti- Anticholinergic drugs and medications against

cholinergic impregnation scale (AIS). In the present study, anticholinergic peripheral side effects

we conducted a multicenter evaluation of the association

For each prescription, in each facility, an (or some) investi-

between AIS score and the prescription of drugs against

gator(s) (pharmacists or psychiatrists) collected:

peripheral anticholinergic side effects. •

anticholinergic medications pertaining to the pre-

established list of 128 drugs;

•

Methods medications, which were prescribed against anticholiner-

gic peripheral side effects (xerostomia, xerophtalmia and

Population constipation).

We conducted a study in 34 French psychiatric facilities. Three criteria were sought for each item, for laxatives:

Data were collected for each inpatient any given day in each ‘‘no’’ (absence); ‘‘one, with dose < maximum dose’’ or

facility. For each patient, the following data were collected: ‘‘several laxatives, or at least one with dose > maximum rec-

sex, age, illness chronicity and as needed prescriptions. This ommended dose’’ and for treatments against xerostomia or

study was conducted using data collected on 7278 prescrip- xerophtalmia: ‘‘no’’ (absence); ‘‘as needed’’ or ‘‘chronic’’.

tions.

Our study has a pragmatic design, so age and psychiatric

Drugs’ prescribing frequency

diagnosis were not exclusion criteria. We focused on periph-

eral effects because central side effects are more difﬁcult The frequency of treatment prescriptions (prescribed sys-

to interpret in patients with mental health conditions. tematically or ‘‘as needed’’) was assessed:

•

to determine the relevance and the peculiarities of drugs

Scale elaboration prescribed exclusively or almost exclusively in France;

•

to assess the amount of anticholinergic risk that helps

A list of 128 somatic and psychiatric drugs was created. Like the identiﬁcation the anticholinergic burden of these

previous studies with elderly subjects, our scale was built drugs.

430 J. Briet et al.

Statistics Anticholinergic drugs and medications against

® anticholinergic peripheral side effects

All statistical analyses were performed using STATA (Inter-

Thirty-four mental health clinics participated with 7278

cooled Stata 8, Stata Corp LLC, Texas, USA). A stepwise

patients (48—517 per center), women (42%) and men (58%),

logistic regression was conducted with forward selection to

aged between 1 and 102 years (mean = 50). The median

assess association (P < 0.05) between AIS score > 5 (median

AIS score was 6 (mean = 6.8 ± 4.01) for all prescriptions

value) and the variables age, sex, frequency of drugs against

(chronic and as needed) and 5 (mean = 5.03 ± 3.12) for

constipation, xerostomia and xerophtalmia. Odds ratios (OR)

chronic prescriptions only. The median number of anticholin-

are presented with 95% conﬁdence intervals (CI).

ergic medications was 4 (0—14). Only 2.76% of patients had

a AIS score equal to 0. The median score was chosen to

≤

Results separate patients in two groups: low scores ( 5) and high

scores (> 5). Results of logistic regression are presented in

Table 3. Reference modalities are: men, age ≤ 17 years, no

The median AIS score was used as a threshold. AIS score was

prescription of laxatives, no prescription of drugs against

considered high if it was higher than 5. According to our

xerostomia. The frequency of patients with an AIS score

classiﬁcation, this cut-off corresponds to the combination

greater than 5 was signiﬁcantly higher in men, patients

of at least one drug with high anticholinergic activity and

who received laxatives and in patients who received drugs

one drug with very high anticholinergic activity.

against xerostomia (P < 0.0001). Prescription of lubricant eye

drops was not statistically associated with highest scores.

Scale elaboration

We created a list of 128 drugs with anticholinergic prop-

erties (AIS = 1: 70 drugs, AIS = 2: 23 drugs, AIS = 3: 35 Discussion

drugs) (Table 1). Each drug has a score, which repre-

sents its anticholinergic potential. The drugs included: In a recent review, 7 scales were shown to be relevant

19 antidepressants, 21 antipsychotics, mood stabilizers in order to evaluate anticholinergic burden [7]: ADS, ARS,

and antiepileptics, 9 anxiolytics or hypnotics, 14 H1- ACB, ABC, CrAS, AAS and ACL. Theses scales are well suited

antihistamines, 10 antiparkinsonian drugs, 10 drugs for to elderly populations and generally assess cognitive side

gastrointestinal disorders, 12 drugs related to cardiovascular effects. However, neurocognitive assessment is less reliable

illnesses, 6 analgesics, 6 antibiotics, 5 urinary antispasmod- in patients with psychiatric illnesses and recent data sug-

ics, 5 corticoids, 3 muscle relaxants, 2 parasympatholytics gest that the use of validated anticholinergic rating scales

or sympathomimetics, 2 immunosuppressants, 2 antiasth- based on the peripheral effects might be particularly impor-

matic drugs and 2 others drugs (Table 1 with anatomical tant [17]. Moreover, most scales have been validated in US

therapeutic chemical [ATC] codes). drugs settings [7]. Thus, the assessment of the anticholiner-

gic burden of French prescriptions is not satisfying based on

the current available tools.

Clinical value assessment of the scale

Published data on anticholinergic load in psychiatric sett-

ings is fairly limited. Most of the available data concern the

Drugs’ prescribing frequency

anticholinergic effects of psychotropic drugs presented by

The treatments (Table 2) that are more frequently pre-

class; they focus mainly on antipsychotics and [1,18—20],

scribed with a very strong anticholinergic effect (score 3)

less often on antidepressants [21]. To our knowledge, the

are:

• largest study to date that focused on the anticholinergic bur-

for drugs prescribed ‘‘systematically’’ (% of prescrip-

den in psychiatry was made by Minzenberg et al. [5]. Their

tions): cyamemazine (20), tropatepine (19);

• study involved 106 patients with schizophrenia who had had

for drugs prescribed ‘‘as needed’’ (% of prescriptions):

a neuropsychological assessment and clinician-rated scores

cyamemazine (15), tropatepine (7), hydroxyzine (4).

of the effects of their prescribed treatments. Therefore, it is

crucial to take into account two variables that might affect

The treatments that are more frequently prescribed with

prescriptions: whether they were prescribed in psychiatric

a strong anticholinergic effect (score 2) are:

• settings, and in which country the prescriptions were made.

for drugs prescribed ‘‘systematically’’ (% of prescrip-

To our knowledge, there were no available scales aiming

tions): loxapine (18), olanzapine (10);

• at assessing anticholinergic burden in psychiatric settings in

for drugs prescribed ‘‘as needed’’ (% of prescriptions):

France.

levomepromazine (methotrimeprazine — 3).

Thus, in order to elaborate a scale that was well suited

The treatments that are more frequently prescribed with

to the French psychiatric context, we created an extensive

a limited or moderate anticholinergic effect (score 2) are:

list of 128 drugs with anticholinergic properties (with scores

•

for drugs prescribed ‘‘systematically’’ (% of prescrip-

ranging from 1 to 3 points) (Table 1). The drugs included

tions): risperidone (17), diazepam (17), oxazepam (16),

comprised 19 antidepressants, 17 antipsychotics and mood

alimemazine (14), haloperidol (14) and valproic acid or

stabilizers, 15 antihistaminics, 10 antiparkinsonian drugs

sodium divalproex or valpromide (14);

and 8 anxiolytics or hypnotics to ensure an optimal eval-

•

for drugs prescribed ‘‘as needed’’ (% of prescriptions):

uation of psychiatric prescriptions.

diazepam (10), alimemazine (9), oxazepam (7), alprazo-

Anticholinergic scores obtained in our study are higher

lam (4) and clorazepate (4).

than those reported in previous studies. Moreover, the

Anticholinergic impregnation scale and psychiatric settings 431

Table 1 Anticholinergic Impregnation Scale scoring for 128 drugs.

Pharmacologic groups ATC Code International AIS score Data from [6] Data from [7]

non-proprietary name

a,b,c,d

Antidepressants (19) N06A Amitriptyline 3 H H

Amoxapine 3 H? H

c,d

Bupropion 1 L? L

Citalopram 1 L L

b,c

Clomipramine 3 H H

Dosulepine 2 L M

c,d

Doxepine 3 H H

Duloxetine 1 L? —

b,d

Fluoxetine 1 L L

b,c

Fluvoxamine 1 L L

a,b,c,d

Imipramine 3 H H

Maprotiline 3 H? H

Mirtazapine 1 L L

b,c,d

Nortriptyline 3 H H/M

Paroxetine 2 L H/M/L

Phenelzine 1 L L

b,d

Sertraline 1 0 L

a,c,d

Trazodone 1 L L

b,c

Trimipramine 3 H H

b,c

Antipsychotics, N05A Clozapine 3 H H/M

normothymics and

antiepileptics (21)

a,b,d

Chlorpromazine 3 H H

Cyamemazine 3 — —

Fluphenazine 3 H H/L

a,c

Haloperidol 1 L M/L

Levomepromazine 2 H H

(methotrimeprazine)

Lithium 1 L L

b,c

Loxapine 2 L M

Olanzapine 2 L H/M/L

a,c

Perphenazine 3 H? H/M/L

b,c

Pimozide 2 L M

Pipotiazine 1 — —

a,d

Prochlorperazine 2 L M/L

Propericiazine 1 — —

c,d

Quetiapine 2 L H/M/L

b,c,d

Risperidone 1 L L

N03 Sodium 1 L? L divalproexb/valpromide

Valproic acid 1 L? L

b,c

Carbamazepine 2 0 M/L

Clonazepam 1 L L

b,c

Oxcarbazepine 2 L M

b,c,d

Anxiolytics or hypnotics (9) N05B Alprazolam 1 H? H/L

b,d

Chlordiazepoxide 1 L L

b,c

Clorazepate 1 H? H/L

b,c,d

Diazepam 1 L L

Lorazepam 1 L? L

Oxazepam 1 L? L

a,b,c,d

Hydroxyzine 3 H H

N05C Midazolam 1 L? L

Temazepam 1 L L

432 J. Briet et al.

Table 1 (Continued)

Pharmacologic groups ATC Code International AIS score Data from [6] Data from [7]

non-proprietary name

H1-antihistamines (14) R06A Alimemazine 1 L M/L

Brompheniramine 3 H H

a,d

Cetirizine 2 L M/L

a,b,c,d

Chlorphenamine 3 — H

Cyproheptadine 3 H H/M

Desloratadine 3 — L

Dexchlorpheniramine 3 H H

a,b,c,d

Diphenhydramine 3 H H

Doxylamine 2 — H

Fexofenadine 2 L M

Loratadine 2 L M/L

Mequitazine 3 — —

a,b,c

Promethazine 3 H H

Triprolidine 2 — —

a,c

Antiparkinsonian (10) N04 Amantadine 2 L M/L

Biperiden 3 — —

Bromocriptine 1 L L

a,d

Carbidopa 1 L? L

Entacapone 1 L L

Levodopa 1 0 —

Pramipexol 1 L? L

Selegiline 1 L? L

b,c,d

Trihexyphenidyle 3 H H

Tropatepine 3 H H

a,b

Drugs for gastrointestinal A02 Cimetidine 2 L M/L

disorders (10)

Famotidine 1 L? L

Nizatidine 1 — —

Ranitidine 1 L M/L

A03 Alverine 1 L? M/L

a,c,d

Atropine 3 H H

Domperidone 1 L L

Metoclopramide 1 H? L

b,c

A06 Dimenhydrinate 3 H H

A07 Loperamide 2 L M/L

a,b,c

Drugs related to B01 Warfarin 1 0 L

cardiovascular system (12)

b,c

C01 Digoxin 1 H? H/L

Disopyramide 2 L M/L

b,c

Isosorbide 1 L? L

Quinidine 1 — L

b,c

C03 Chlortalidone 1 L? L

b,c

Triamterene 1 L? L

C07 Atenolol 1 0 L

c,d

Metoprolol 1 0 L

C08 Diltiazem 1 L? L

b,c

Nifedipine 1 0 L

b,c

C09 Captopril 1 L? L

b,c,d

Analgesics (6) N02 Codeine 1 L M/L

b,c

Fentanyl 1 L L

b,c,d

Morphine 1 L L

b,d

Oxycodone 1 L L

Pethidine 2 — —

Tramadol 1 L M/L

Anticholinergic impregnation scale and psychiatric settings 433

Table 1 (Continued)

Pharmacologic groups ATC Code International AIS score Data from [6] Data from [7]

non-proprietary name

Antibiotics (6) J01 Ampicilline 1 L? L

Cefoxitin 1 L? L

Clindamycine 1 L? L

Gentamicine 1 L? L

Piperacilline 1 L? L

Vancomycine 1 L? L

b,c

Urinary antispasmodics (5) G04 Flavoxate 3 H H

a,b,c

Oxybutynine 3 H H/M

Solifenacine 3 — H

b,c

Tolterodine 3 H H/M

Trospium 3 — H

Corticoids (5) H02 Dexamethasone 1 L? L

b,c

Hydrocortisone 1 L? M

Methylprednisolone 1 L? L

b,c

Prednisone/prednisolone 1 −/L L/L

Triamcinolone 1 L? L

a,d

Muscle relaxants (3) M03 Baclofen 2 L M

a,d

Methocarbamol 1 L L

Tizanidine 3 H H

b,c,d

Parasympatholytics or A04 Scopolamine 3 H H

sympathomimetics (2)

R01 Pseudoephedrine 2 L? M

Immunosuppressants (2) L04 Azathioprine 1 L? L

Cyclosporin 1 L? L

Antiasthmatic drugs (2) R03 Ipratropium 3 H H

b,c

Theophylline 1 L M/L

Others (2) N02 Methadone 2 L M

M04 Colchicine 1 H? H/L

Comparisons with the latest reviewed data in the literature: Duran et al. (2013) [6] (H for ‘‘high potency anticholinergics’’, H? for ‘‘strong

discrepancies in highly-scored drugs, not conﬁrmed in Martindale ’’), L for ‘‘low potency anticholinergics’’, L? for ‘‘discrepancies in

drugs that received low grades, not conﬁrmed in Martindale ’’ and 0 for drugs with ‘‘improbable anticholinergic action’’ and Salahudeen

et al. (2015) [7] (H: high anticholinergic activity medicines, M: moderate anticholinergic activity medicines, L: low anticholinergic

activity medicines and H/M, H/M/L, H/L and M/L — corresponding to the previous abbreviations — refer to drugs with ‘‘inconsistent

validation’’); ‘‘—’’ means unavailable data in the two articles. ATC code: anatomical therapeutic chemical code. A02 — Drugs for

acid related disorders, A03 — Drugs for functional gastrointestinal disorders, A04 — Antiemetics and antinauseants, A06 — Drugs for

constipation, A07 — Antidiarrheals, intestinal anti-inﬂammatory/anti-infective agents, B01 — Antithrombotic agents, C01 — Cardiac

therapy, C03 — Diuretics, C07 — Beta blocking agents, C08 — Calcium channel blockers, C09 — Agents acting on the renin-angiotensin

system, G04 — Urologicals, H02 — Corticosteroids for systemic use, J01 — Antibacterials for systemic use, L04 — Immunosuppress-

ants, M03 — Muscle relaxants, M04 — Antigout preparations, N02 — Analgesics, N03 — Antiepileptics, N04 — Antiparkinson drugs,

N05 — Psycholeptics, N05B — Anxiolytics and N05C — Hypnotics and sedatives, N06 — psychoanaleptics, N06A — Antidepressants,

N05 — Psycholeptics, N05A — Antipsychotics, R01 — Nasal preparations, R03 — Drugs for obstructive airway, R06A — Antihistamine for

systemic use.

ARS (Anticholinergic Risk Scale; Rudolph et al., [10]).

ADS (Anticholinergic Drug Scale; Carnahan et al., [8,9]).

ACB (Anticholinergic Cognitive Burden Scale; Boustani et al., [11]).

CrAS (Clinician-rated Anticholinergic Score; Han et al., [13]).

434 J. Briet et al.

Table 2 Twelve anticholinergic drugs most prescribed (systematically or as needed).

Drugs prescribed ‘‘systematically’’ Drugs prescribed ‘‘as needed’’

Drugs AIS score n (%) Drugs AIS score n (%)

b,c

Cyamemazine 3 1429 (20) Loxapine 2 1516 (21)

Tropatepine 3 1403 (19) Cyamemazine 3 1089 (15)

b,c b,c,d,f

Loxapine 2 1295 (18) Diazepam 1 737 (10)

a,c,d,g c,e

Risperidone 1 1272 (17) Alimemazine 1 651 (9)

b,c,d,f e

Diazepam 1 1206 (17) Tropatepine 3 508 (7)

b,g b,g

Oxazepam 1 1139 (16) Oxazepam 1 504 (7)

c,e a,b,c,e

Alimemazine 1 1038 (14) Hydroxyzine 3 324 (4)

a,c,g b,c,d,e,g

Haloperidol 1 1022 (14) Alprazolam 1 270 (4)

b,c,e

Valproic acid or sodium 1 986 (14) Clorazepate 1 266 (4)

divalproex or valpromide

a,b,c,d,f

Olanzapine 2 761 (10) Levomepromazine 2 220 (3)

(methotrimeprazine)b,c,e

Letters underlined if the scale gives the same score that AIS.

ARS (Anticholinergic Risk Scale; Rudolph et al. [10]).

ADS (Anticholinergic Drug Scale; Carnahan et al. [8,9]).

ACB (Anticholinergic Cognitive Burden Scale; Boustani et al. [11]).

CrAS Clinician-rated Anticholinergic Score; Han et al. [13]).

ABC (Anticholinergic Burden Classiﬁcation; Ancelin et al. [12]).

AAS (anticholinergic activity scale; Ehrt et al. [14]).

ACL (anticholinergic loading scale; Sittironnarit et al. [15]).

amount of anticholinergic drugs per prescription is higher 75.2 ± 6.8), and showed a mean on the ACB score of 1.8 ± 1.1

than those found in other studies [22—25]. However, the (6.08 ± 4.01, for AIS in our study) and 52% of patient had an

available data showed results of studies with elderly peo- ACB score equal to 0 (only 2.76% had AIS score equal to 0 in

ple in geriatric settings with very different prescription our study). These data, similar to others available in the lit-

characteristics. For example, Fox et al. [22] conducted a erature, highlight the need of speciﬁc studies in psychiatric

large study, which included 13,004 participants (mean age: settings with patients younger than 65 years.

Table 3 Estimated odds ratio (OR) of high scores anticholinergic impregnation scale (AIS) [> 5] for variables retained by

logistic regression.

AIS score > 5 AIS score ≤ 5 OR [CI (95%)] P-value Sex

Men 1912 (45.40%) 2299 (54.60%) 0.71 [0.64—0.79] < 0.0001

Women 1123 (36.62%) 1944 (63,38%) Age

≤ 17 years 26 (27.96%) 67 (72,04%) 1.68 [1.04—2.70] < 0.0001

18—64 years 2640 (46.71%) 3012 (53,29%)

≥ 65 years 369 (24.07%) 1164 (75,93%) 0.53 [0.32—0.86] < 0.0001 Laxatives

No use 1284 (33.98%) 2495 (66,02%) 2.03 [1.81—2.28] < 0.0001

Prescription of one laxative, with dose < maximum 1015 (47.10%) 1140 (52.90%)

recommended dose

Prescription of several laxatives, or at least 1 with 736 (54.76%) 608 (45,24%) 2.74 [2.39—3.14] < 0.0001

dose > maximum recommended dose

Treatments against xerostomia

No use 2517 (38.49%) 4023 (61,51%) 3.38 [2.84—4.01] < 0.0001

Use 518 (70.19%) 220 (29,81%)

CI (95%): 95% conﬁdence interval. a

Reference: men.

Reference: ≤ 17 years.

Reference: no use.

Anticholinergic impregnation scale and psychiatric settings 435

In our study, a high anticholinergic burden (AIS score > 5) anticholinergic load; it is incorporated into the present in

was associated with a higher rate of prescription of two any rating scale anticholinergic load. Tropatepine marketed

anticholinergic side effects correctors: laxatives and drugs only in France is the second most frequently systematically

against xerostomia. Hugues et al. [26] found in 182 senior prescribed treatment and has a very strong anticholinergic

care home residents in Australia that greater anticholinergic load; it is only integrated in the ABC scale [12]. These

load was associated with numerous side effects, including data show the importance of a validated scale with these

hypertension, dry mouth, dry eyes, constipation and uri- molecules in order to achieve a reliable evaluation of the

nary hesitancy. Many psychotropic treatments may induce anticholinergic burden in psychiatric services in France,

constipation (as antidepressants or certain antipsychotics due to the existence of very local and strong anticholin-

and mood stabilizers). Among antidepressants, tricyclic ergics agents, frequently prescribed in France (and often

antidepressants induce more frequently constipation and considered obsolete by other drug agencies in the world).

are associated with very high anticholinergic scores, while The use of a system to alert the prescriber of anti-

among the mood stabilizers, carbamazepine and oxcar- cholinergic load may lead to a decrease of anticholinergic

bazepine, associated with elevated anticholinergic scores, prescriptions [25]. Therefore, this new list could help pre-

exhibit higher risks of constipation compared to valproic scribers to reduce anticholinergic load in patients although

acid and lamotrigine. Talley et al. [27] studied risk fac- it does not allow the prediction of the occurrence of side

tors for chronic constipation based on three large samples effects.

of patients [patients diagnosed with chronic constipa- The score was used in French hospitals, through this

tion (n = 7251), patients diagnosed with constipation of study, to evaluate prescriptions practice, to educate pre-

unspeciﬁed chronicity (n = 6441), and controls (n = 7103)]; scribers regarding anticholinergic load. It was important also

antidepressants and anticonvulsants were associated with to educate nurses who, on the one hand, may have an impact

the highest risk among drugs, but not antipsychotics. on the overall anticholinergic load via as needed prescrip-

Although constipation has globally received little attention tion, and, on the other hand, are often the ﬁrst to hear about

in studies conducted in psychiatry, it has been frequently complaints concerning constipation, dry mouth or dry eyes.

reported with atypical antipsychotics in their association There are two major limitations in our study. First, we did

with anticholinergic agents [28]. However, atypical antipsy- not take dosage ranges into consideration in the calculation

chotics are also well-known to induce constipation linked exposure. Second, we assume that the treatments against

to their anticholinergics activities. Among them, clozap- side effects were prescribed due to anticholinergic burden.

ine, olanzapine, loxapine and quetiapine show a higher risk

compared to haloperidol, risperidone and aripiprazole [28].

In phase 3 of the clinical antipsychotic trials of interven- Conclusion

tion effectiveness (CATIE) study, anticholinergic side effects

(urinary hesitancy, dry mouth and constipation) occurred in Prescribers in psychiatric settings must keep in mind anti-

a similar prevalence between typical and atypical antipsy- cholinergic burden, since numerous psychotropic drugs

chotics, 15% versus 18%, respectively [29]. Moreover, plasma present with anticholinergic properties and, high anticholin-

concentrations of olanzapine are higher in patients who ergic load is, in turn, associated with the increase of

have reported anticholinergic side effects in the past, espe- peripheral or central anticholinergic side effects.

cially constipation [30]. Although xerostomia may occur by This AIS score of anticholinergic drugs represents the ﬁrst

various ways (modulations activities of muscarinic, alpha- validated solution to assess anticholinergic load in French

adrenergic, serotoninergic or benzodiazepines receptors), psychiatry because of ‘‘typically French’’ drugs, such as

anticholinergic side effects with blockage of the muscarinic cyamemazine and tropatepine were integrated in it. These

M3 receptors remains a strong pharmacological explanation drugs exhibited a high anticholinergic score, and were used

[31]. Kersten et al. [17] reported that patients with ADS on this original validation integrating evaluation of the

≥

scores 6 expressed a 0.7-fold lower saliva production com- prescription of drugs against peripheral anticholinergic side

pared to patients with an ADS score of 3. effects.

Among the 12 anticholinergic drugs most prescribed in

France (Table 3):

•

for drugs prescribed systematically, cyamemazine and Acknowledgements

tropatepine are the two most commonly prescribed (20%

and 19% of prescriptions, respectively) and they have a Réseau PIC (Psychiatrie Information Communication) with:

very high AIS score; Bengeloun F. , EPSMDA Prémontré, 02320 Prémontré, France;

•

for medication prescribed ‘‘as needed’’, cyamemazine Tramier V. , CHS Ainay Le Château, 03360 Ainay Le Château,

and tropatepine are the second and ﬁfth most frequently France; Honoré S., CH Edouard Toulouse, 13917 Marseille,

prescribed drugs, respectively (15% and 7% of prescrip- France; Roberge C., Colombe M., Auclair V. , Gabriel-

tions, respectively). Bordenave C., EPSM Caen, 14012 Caen, France; Chollet

A., CH Jonzac, 17500 Jonzac, France; Vailleau JL., CHS La

Furthermore, loxapine, which presents a strong AIS Chartreuse, 21033 Dijon, France; Berthe S., Fondation Bon

score, is the third treatment most prescribed systematically Sauveur, 22140 Bégard, France; Heil M., CH Perigueux, 24000

and the most frequently prescribed treatment ‘‘as needed’’ Périgueux, France; Duntze E., Fondation John Bost, 24130

(18% and 21% of prescriptions, respectively). Cyamemazine La Force, France; Goarin C., EPS Etienne Gourmelen, 29107

marketed in France and Portugal is the most systemat- Quimper, France; Lelievre J., CHRU de Brest, 29609 Brest,

ically prescribed treatment and presents a very strong France; Segond M., Friedl J., Molinier A., Bonnet L., CH

436 J. Briet et al.

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