European Journal of Clinical Pharmacology

, Volume 61, Issue 4, pp 297–302

Drug utilisation by children and adolescents with mental retardation: a population study

Authors

    • Department of Social Pharmacy, Pharmacoepidemiology and PharmacotherapyGroningen University Institute of Drug Exploration (GUIDE)
  • T. Scheers
    • University Center for Child and Adolescent Psychiatry ACCARE
  • K. A. Netjes
    • Department of Social Pharmacy, Pharmacoepidemiology and PharmacotherapyGroningen University Institute of Drug Exploration (GUIDE)
  • E. J. Mulder
    • University Center for Child and Adolescent Psychiatry ACCARE
  • A. de Bildt
    • University Center for Child and Adolescent Psychiatry ACCARE
  • R. B. Minderaa
    • University Center for Child and Adolescent Psychiatry ACCARE
Pharmacoepidemiology and Prescription

DOI: 10.1007/s00228-005-0935-4

Cite this article as:
Tobi, H., Scheers, T., Netjes, K.A. et al. Eur J Clin Pharmacol (2005) 61: 297. doi:10.1007/s00228-005-0935-4

Abstract

Objective

Little is known about the utilisation of drugs by mentally retarded children; population studies are even more sparse. In this study the chronic drug utilisation in children aged 4–18 years with mental retardation in a large population in the Netherlands was investigated.

Methods

Throughout all special schools and (day) care facilities for children with mental retardation in Friesland, parents/representatives were approached requesting participation of their children. Participants were interviewed about a number of aspects including medication use. For 921 of the 1,057 participants, information was available on medication use for those physical and psychiatric illnesses that bothered them or was expected to bother them for at least 3 months per year; 912 of the participants were within the age category under study: 4–18 years.

Results

About 22% of the 912 participants used chronic medication, 47% of whom used two or more drugs. The prevalence of drug use increased with severity of mental retardation from about 17% to 49%. The exception was the 6% of children with borderline intellectual functioning: their medication prevalence was 27%. Overall, 17% of the study population used a nervous system drug, 4% used a respiratory system drug and 3% used an alimentary tract drug. Of the drugs for the nervous system, alimentary tract and respiratory tract, 32% was prescribed off-label. For 3%, we were unable to establish on/off-label use.

Conclusions

Chronic drug utilisation patterns in children and adolescents with mental retardation are different from those in the general paediatric population. These different patterns suggest the need for additional research.

Keywords

Mental retardationMinorsDrug utilisationCentral nervous system agentsPsychopharmacology

Introduction

In recent years, there has been an increasing number of studies on drug use by children, partly due to concerns about the unlicensed and off-label drug use by children [15]. This increasing attention to drug use by children has not yet extended to children with mental retardation. However, a study on psychotropic medication in adults with mental retardation found that 20% of the drugs prescribed were for reasons not in accordance with accepted uses of those drugs [6].

Mental retardation is defined as “a disability characterised by significant limitations both in intellectual functioning and in adaptive behaviour, as expressed in conceptual, social and practical adaptive skills. This disability originates before age 18  years” [7]. The prevalence of mental retardation is estimated at 1% [8]. Only a small amount of empirical data is available on drug use by children with mental retardation.

The few studies on drug utilisation by children with mental retardation focus on psychotropic drugs. Aman and colleagues stated in their review that, for most disorders, there is a lack of empirical data in children and adolescents with mental retardation, and that clinicians need to extrapolate from data on both adults with mental retardation and typically developing children [9]. However, a general review of the literature on psychopharmacology and mental retardation from 1990 to 1999 concluded that a vast majority of the studies published suffered from major methodological flaws [10]. Methodological problems included sample selection (institutional or community based samples), poor study design, incomplete medical information and post-hoc diagnosis of medical problems.

A review on psychopharmacoepidemiology of mental retardation covering the years 1966–1995 struggled with the fact that most studies did not report psychotropic drug use for children and adults with mental retardation separately [11]. The prevalence of psychotropic drug use in institutionalised people with mental retardation was shown to range from 12% to 49%, and in communities from 11% to 29%. More recently, data were reported on children aged 11–19 years old at the time of admission to a dual diagnosis treatment unit in a state-funded psychiatric hospital in the USA [12]. At some point in time prior to admission, about 85% of these selected children had received neuroleptics, 78% antidepressants and 46% psychostimulants.

The general aim of the present study was to provide insight into the medication used by a general population of children with mental retardation for both physical and psychiatric conditions that bothered them for 3 months or longer and to identify patient characteristics associated with this medication use. Also, off-label use will be investigated for the most frequently used drug groups.

Methods

Through all schools and facilities for children and adolescents with mental retardation in the Dutch province of Friesland, subjects were recruited for an epidemiological study into behavioural problems, health problems, medication use and other concerns. Historically in the Netherlands, the vast majority of children suspected of mental retardation will be known by a facility for the mentally retarded or a school for special education by the age of 4 years. The caretakers of all 1,436 children and adolescents with mental retardation known to be visiting a school for special education or known by facilities for children and adolescents with mental retardation in the province of Friesland were approached. No participants were excluded based on aetiology or level of mental retardation [13]. The study was approved by the medical ethics committee of the University of Groningen.

The severity of mental retardation was classified according to the DSM-IV-TR in the categories of borderline intellectual functioning (IQ over 70), mild retardation (IQ range 50–55 to 70), moderate (35–40 to 50–55), severe (20–25 to 35–40) and profound (IQ below 20–25) [8]. Participants were classified into a category based on their performance on standardised tests, as previously described [14]. A maximum time difference of 2 years was allowed between inclusion in the study and IQ testing. Subjects were regarded as institutionalised when they lived less than 4 days a week at home with their parents.

As part of a comprehensive structured parent interview, information concerning the use of medication and diagnosis was obtained. Additional information from medical records was not available. Knowledge of medication was sought for those physical and psychiatric illnesses that bothered the child or were expected to bother the child for at least 3 months per year.

The brand or generic drug names mentioned by the parents were classified according to the World Health Organisation anatomical therapeutic classification (ATC) system [14]. Only for drugs that could possibly be classified in several categories was the purpose of the pharmacotherapy according to the parents used to decide on the ATC category.

Off-label use of the drugs mentioned by the parents was assessed by referring to the Farmacotherapeutisch Kompas 1999, the annually published Dutch reference for governmental approved drugs [15], because most of the data were collected in 1999. We used a scoring list identical to that used previously in a study of off-label drug use in the general paediatric population [4]. This scoring list made a distinction between several levels of product information. Drug use was classified as off-label based on the age criterion when the child was younger than the age mentioned in the Farmacotherapeutisch Kompas, or when the Farmacotherapeutisch Kompas did not mention use in children at all, or advised against use in children. Use was regarded as off-label based on the indication criterion when the indication as mentioned by the parents did not fit in the range of indications mentioned in the Farmacotherapeutisch Kompas.

The association between chronic medication use and the categorical variables severity of mental retardation, sex and place of living were analysed using chi-squared tests. Difference in average age was tested using a two-sided t-test. When variables were significantly associated with chronic medication use in univariate analyses, they were included in a logistic regression model to check whether they contributed significantly in the presence of other variables according to the Wald test. Tests were regarded as statistically significant when P<0.01. All analyses were done using SPSS 12.0.

Results

Of the 1,436 children known to facilities and schools for children with mental retardation, the parents of 1,057 were willing to let their child participate. For 921 of the 1,057 participants, information on medication use was available. Since 9 children were not within the age range 4–18 years, 912 children were included in this study.

Of these 912 participants, 577 (63.3%) were male and 335 (36.7%) female. The median age was 11.6 years (interquartile range 8.8–14.6 years). With respect to level of mental retardation, 58 of the 912 (6.4%) were classified as borderline intellectual functioning and 462 (50.7%) as mildly, 217 (23.8%) as moderately, 104 (11.4%) as severely and 67 (7.3%) as profoundly mentally retarded. For 4 subjects (0.4%), the IQ level was not measured. Most subjects (787 of 912 or 86.3%) lived the major part of the week at home with their family. Of the 114 subjects who were institutionalised the major part of the week, 47 (41.2%) had a severe or profound mental retardation. For 11 of the 912 youths (1.2%), living arrangements were unknown.

For 21.8% of the participants (199 of 912), the parents or caretakers reported a total of 355 drugs being used. Table 1 depicts the listed drugs. The most frequently mentioned drugs were for the nervous system, used by 151 of the 912 children (16.6%); for the respiratory system, used by 40 children (4.4%); and the alimentary tract, used by 27 children (3.0%). Psychotropic medication, defined as all nervous system drugs except for the antiepileptics, was used by 9.6% of the children (88 of 912). Nearly 47% of the subjects who used medication (93 of 199) or 10.2% of the total population (93 of 912) used two or more drugs.
Table 1

Drugs mentioned by parents for both physical and psychiatric conditions. ADHD attention deficit hyperactivity disorder, GORD gastro-oesophageal reflux disease

ATC

Description

n times cited

n children

A

Alimentary tract and metabolism

33

27

 A02B

Peptic ulcer and GORD

 2

 2

 A03F

Propulsives

 3

 3

 A06A

Laxatives

 19

 17

 A10A

Insulins and analogues

 2

 2

 A11

Vitamins

 7

 7

B

Blood and blood forming organs

4

2

C

Cardiovascular system

6

5

D

Dermatologicals

5

5

G

Genito-urinary system and sex hormones

3

3

H

Systemic hormonal preparations excluding sex hormones and insulins

4

4

J

Anti-infectives for systemic use

9

8

L

Antineoplastic and immunomodulating agents

2

1

M

Musculo-skeletal system

2

2

N

Nervous system

211

151

 N02CX02

Clonidine

 29

 27

 N03A

Antiepileptics

 105

 74

 N04

Anti-Parkinson drugs

 2

 2

 N05A

Antipsychotics

 42

 38

 N05B

Anxiolytics

 7

 6

 N05C

Hypnotics and sedatives

 4

 4

 N06A

Antidepressants

 2

 2

 N06B

Psychostimulants, agents used for ADHD and nootropics

 20

 20

R

Respiratory system

64

40

 R01A

Decongestants and other nasal preparations for topical use

 4

 4

 R03

Drugs for obstructive airway disease

 48

 29

 R05

Cough and cold medications

 3

 3

 R06A

Antihistamines for systemic use

 9

 9

S

Sensory organs

3

2

V

Various

2

2

Unknown

Unidentifiable

7

5

Total

 

355

199

In both girls and boys the prevalence of chronic drug use was 21.8%. There was no evidence of a difference in average age between the subjects who used medication and those who did not (11.5 years and 11.7 years respectively; P=0.63). The use of medication increased with severity of mental retardation from 17% (79 of 462) in children with mild mental retardation to 49% (33 of 67) in children with profound mental retardation (P<0.001). The exception was subjects with a borderline IQ level: 16 of the 58 (27.6%) used medication, partly due to higher levels of nervous system drug use other than antiepileptics, i.e. antipsychotics, clonidine and psychostimulants (Table 2). For 3.6% (14 of 388) of the children and adolescents with mental retardation who rated at least as moderate, regular use of laxatives was reported. Of the institutionalised subjects, 38.6% (44 of 114) used chronic medication, nearly twice the 19.7% (155 of 787) in subjects who were not institutionalised (P<0.001).
Table 2

Number of children using certain drug groups per level of mental retardation

 

Severity of mental retardation

 

Border (n=58)

Mild (n=462)

Moderate (n=217)

Severe (n=104)

Profound (n=67)

Any drug

16

79

45

25

33

Nervous system (N)

 Antiepileptics (N03A)

1

21

18

5

28

 Antipsychotics (N05A)

4

18

8

6

2

 Clonidine (N02CX02)

3

15

4

4

1

 Psychostimulants (N06B)

2

11

4

3

0

 Other N

2

2

3

3

4

Respiratory system (R)

 For obstructive airway disease (R03)

3

15

6

2

3

 Other R

1

5

3

2

3

Alimentary tract and metabolism (A)

 Laxatives (A06A)

0

2

3

4

7

 Other A

0

3

3

2

3

Although institutionalisation and level of mental retardation were associated (P<0.001), they each had an independent significant effect on the odds of using chronic medication adjusted for the other in a logistic regression model (severity of mental retardation, P<0.001; institutionalised, P<0.004).

Table 3 shows that 200 of the 308 prescribed drugs for the nervous system, the respiratory system and the alimentary tract were prescribed on-label (64.9%), and 98 (31.8%) were prescribed off-label. In 10 cases (3.2%), there was insufficient information on the exact product used to ascertain with certainty whether the product was used off-label. Of the 211 drugs for the nervous system, 72 (34.1%) were used off-label. Both the indication and age criterion contributed significantly to this off-label use, with 60 solely based on the indication criterion (28.4%) and 51 solely based on the age criterion (24.2%). The major contributor clonidine, is registered in the Netherlands for the treatment of migraine and hypertension in adults only. In these subjects, clonidine was mainly used for attention deficit hyperactivity disorder (ADHD)-related symptoms. Antipsychotics were also responsible for a large portion of off-label use based on the indication criterion because they were often prescribed for symptoms related to ADHD (8 of 19) and disorders in the autism spectrum (10 of 19). Of the 42 antipsychotics, 8 (19%) were prescribed to children younger than the license mentioned. Of the other 11 nervous system drugs prescribed off-label, 7 were anxiolytics—6 of which were prescribed because of the age criterion. Of the 72 subjects with epilepsy who received antiepileptics, 9 (12.5%) had also received laxatives on a regular basis.
Table 3

On-label and off-label use of frequently reported medication

 

On-label

Off-label

Unknowna

Criterion

 

Indication

Age (years)

Any

 

Nervous system (N)

  Antiepileptics (N03A)

94

5

3

8

3

 Antipsychotics (N05A)

20

19

8

22

0

 

 Clonidine (N02CX02)

0

29

29

29

0

 Psychostimulants (N06B)

18

2

1

2

0

 Other N

3

5

10

11

1

 Total N

135

60

51

72

4

Respiratory system (R)

 For obstructive airway disease (R03)

33

0

12

12

3

 Other R

11

4

2

5

0

 Total R

44

4

14

17

3

Alimentary tract & and metabolism (A)

 Laxatives (A06A)

16

0

1

1

2

  Other A

5

1

8

8

1

  Total A

21

1

9

9

3

Total

200

65

74

98

10

a Insufficient information on the exact product used to ascertain with certainty whether the used product meets the indication criterion or the age criterion

Of the 33 alimentary drugs, 9 (27.2%) were used off-label; 4 of these were vitamins and 3 propulsives. In the respiratory drug group, 17 of the 64 (26.6%) were off-label. Off-label use in these two drug groups was mainly due to the age of the child.

Discussion

In this first population-based study on children and adolescents with mental retardation, about 22% received medication for those physical and psychiatric illnesses that bothered them or were expected to bother them for at least 3 months per year. The most commonly used drug groups were for the nervous system, the respiratory system, and the alimentary tract and metabolism. In our study, institutionalised children and adolescents used more chronic medication than children and adolescents who lived with their parents. Institutionalisation and level of mental retardation each remained a significant factor in the odds of chronic medication use after taking the other into account. The off-label drug use ranged from about 27% (the respiratory system and alimentary tract and metabolism) to 34% in the drugs for the nervous system. The main contributors to off-label use were clonidine and antipsychotics.

Singh et al. reported that many but not all studies in the general mentally retarded population show an increase of severity of mental retardation correlated with an increase of psychotropic drug use [11]. Although we found a relationship between severity of mental retardation and the use of medication, this was complicated by the children and adolescents with borderline intellectual functioning who used relatively more psychotropic drugs. The children and adolescents with a borderline IQ level in the present study cannot be regarded as representative of children and adolescents with a borderline IQ level in general, since the population under study did attend schools and used facilities aimed at children and adolescents with mental retardation.

The reported use of psychotropic drugs of 9.6% is slightly lower than the minimum of 11% found in the literature for a school-based study on children and adolescents with mental retardation [11]. In our population of children and adolescents with mental retardation, the prevalence of psychostimulant use was 2.2% (20 of 912), about twice that in the general paediatric population of that age that same year in the Netherlands [16]. Neither drugs for the nervous system nor drugs for the alimentary tract and metabolism were among the ten most widely used drug groups in the general population aged 0–16 years old [17]. The percentage of children and adolescents with mental retardation using drugs for the respiratory system (4.4%) is lower than the 7% using anti-asthma drugs in the general Dutch paediatric population. Please note that in drug utilisation studies in the general population, everyone who received at least one prescription that year was counted as a user [16, 17], and that the reported prevalence of asthma and/or recurrent wheezing varies between 13% and 17% in large population studies [18].

In the literature it has been reported that 23.8% of the institutionalised children and adults with an IQ of less than 50 used laxatives regularly [19]. This is higher than the 3.6% we found among children and adolescents with mental retardation that rated at least as moderate. This difference could partly result from the fact that our study reports on a paediatric population with mental retardation and not on institutionalised children and adolescents only. However, undertreatment should not be ruled out.

The 28% off-label prescribing of nervous system drugs based on the indication criterion in our study was higher than the 20% unaccepted uses reported in adults with mental retardation [6]. We also showed that off-label prescribing is not limited to psychotropic drugs. Similar to children and adolescents in the general paediatric population [20], psychotropic drugs are more often prescribed off-label to children and adolescents with mental retardation than drugs for the alimentary tract or the respiratory system. However, larger numbers than those in this current study are needed to warrant a valid comparison between off-label prescribing in children and adolescents with mental retardation and in the general paediatric population. It is important to realise that off-label prescribing does not necessarily mean prescribing without any safety and efficacy information. For example, for the use of clonidine in the treatment of ADHD-related symptoms, there is some information on the limited safety and efficacy [21].

This study has several limitations. A first limitation of the study is subject recruitment. It is possible that some relatively higher functioning mentally retarded children, who were able to visit “normal” schools without additional services from other institutions, were not included in the study. However during the period in which this study was conducted, the vast majority of children with developmental problems were visiting schools for special education. Second, there is no absolute guarantee that the 912 subjects with information on medication use are representative of the total population, although they are representative of the study participants. Third, and more seriously a limitation, is the way medication use was enquired after. Parents were only asked to report medication used for those physical and psychiatric illnesses that bothered the child or were expected to bother the child for at least 3 months per year. To answer this question, parents needed to estimate the (anticipated) duration of illnesses, which may have resulted in some misclassification. By limiting the question like this, the comparison of results between this study and the literature was complicated. It would be worthwhile to try and obtain pharmacy data on these children and adolescents with mental retardation in future research.

This study suggests that drug utilisation patterns in children and adolescents with mental retardation are quite different from those in the general paediatric population. These different patterns suggest the need for additional research, especially since a significant portion of the most frequently chronically used drugs are prescribed off-label in this vulnerable population.

Copyright information

© Springer-Verlag 2005