Original research
Arch Dis Child: first published as 10.1136/archdischild-2019-317933 on 14 February 2020. Downloaded from http://adc.bmj.com/ on February 18, 2020 at Greenfield Medical Library
1
Netherlands Pharmacovigilance
Centre, ’s-­Hertogenbosch, The
Netherlands
2
Department of Paediatrics,
Medical Center Leeuwarden,
Leeuwarden, The Netherlands
Correspondence to
Dr Corine Ekhart, Netherlands
Pharmacovigilance Centre,
’s-­Hertogenbosch 5237 MH,
Netherlands; ​c.​ekhart@​lareb.​nl
Received 18 July 2019
Revised 30 January 2020
Accepted 30 January 2020
© Author(s) (or their
employer(s)) 2020. No
commercial re-­use. See rights
and permissions. Published
by BMJ.
To cite: Ekhart C, Vries T,
Hunsel F. Arch Dis Child Epub
ahead of print: [please
include Day Month Year].
doi:10.1136/
archdischild-2019-317933
Psychiatric adverse drug reactions in the
paediatric population
Corine Ekhart,1 Tjalling de Vries,2 Florence van Hunsel1
Abstract
Objective  Due to lack of information on drug use in
children, many drugs are used off-­label in paediatrics.
Increased knowledge of adverse drug reactions (ADRs)
would enable a better risk–benefit analysis. Our aim
was to characterise drugs causing psychiatric ADRs in
children by conducting a descriptive study based on
pharmacovigilance reports.
Design  Reports submitted to the Netherlands
Pharmacovigilance Centre Lareb from 2003 to 2016
were used to investigate drugs causing psychiatric ADRs
in the Dutch paediatric population. These data were
corrected for drug utilisation in order to correct the
number of reports for the number of users of a drug.
Main outcome measures  ORs were calculated as a
measure of disproportionality for drug–ADR associations
for three different age groups. Significant drug–ADR
associations were checked if it was labelled in the
product information.
Results  Lareb received 918 reports of psychiatric ADRs,
which constitute 15% of the reports of ADRs in children.
Drugs used for the treatment of ADHD (methylphenidate
and atomoxetine) and drugs used for the treatment of
asthma (montelukast and fluticasone) were the most
frequently reported. However, psychiatric ADRs were also
reported for less often prescribed medications such as
oxybutynin and isotretinoin.
Conclusions  Real-­world data on psychiatric ADRs
in the Dutch paediatric population show a consistent
pattern with what is known from drug labels and the
literature. Reports of psychiatric ADRs should be taken
seriously because of the impact on medication adherence
and the well-­being of the child and its family.
Introduction
Adverse drug reactions (ADRs) are common and
can have many consequences. ADRs can harm the
patient physically, and they can have a profound
effect on adherence and therefore on treatment
success and quality of life.1 During the last years,
there has been an increased interest in occurrence
of ADRs and quality of life in children.2 3 Due to
lack of documentation on efficacy and safety, there
is lack of information in children.3 Many drugs
still have no information in the labelling for use in
paediatrics. Off-­label drug use, therefore, remains
an important public health issue for infants, chil-
dren and adolescents.4 Increased knowledge of
ADRs would enable a better risk–benefit analysis.
Psychiatric ADRs are frequent in the paediatric
population.5 Clavenna and Bonati6 evaluated eight
prospective studies and found that the overall inci-
dence of ADRs was 10.9% in hospitalised children
Ekhart C, et al. Arch Dis Child 2020;0:1–7. doi:10.1136/archdischild-2019-317933
What is already known on this topic?
►► Psychiatric adverse drug reactions are common
in the paediatric population.
►► Insight in the occurrence and nature of
psychiatric adverse drug reactions can help
physicians to anticipate and recognise these
reactions.
What this study adds?
►► 918 reports (15%) of adverse drug reactions in
children concern psychiatric reactions.
►► Drugs used for the treatment of attention deficit
Periodicals. Protected by copyright.
hyperactivity disorder and asthma were the
most frequently reported.
►► Real-­world data on psychiatric adverse drug
reactions match with what is known from drug
labels and the literature.
and 1.0% in outpatient children. A Danish study
characterised ADRs in children reported to the
Danish Medicines Agency in a 10-­ year period.
They found that psychiatric disorders were the
fourth most commonly reported system organ
class (SOC), after general disorders, skin and
subcutaneous disorders and nervous system disor-
ders.7 Wallerstedt et al8 found that 24% of the
reported events in children constitute psychiatric
ADRs, compared with 12% in adults. Chen et al
studied psychiatric and behavioural side effects
of antiepileptic drugs in adolescents and children
with epilepsy. They found that psychiatric and
behavioural side effects occurred in 13.8% of
patients.9 Insight in the occurrence and nature of
psychiatric ADRs in children is important. It can
help physicians caring for children to anticipate
and recognise these reactions.
Postmarketing reporting of ADRs can help to
detect ADRs previously undetected during clinical
trials and in addition gives insight in the real-­world
use of drugs in patients in all age groups, with
different comorbidities than previously included in
trials.10
The aim of the present study was to charac-
terise drugs causing psychiatric ADRs in children
corrected for expenditure data by conducting a
descriptive study during a 14-­year period based on
reports reported to the Netherlands Pharmacovigi-
lance Centre.
   1
 Original research

Arch Dis Child: first published as 10.1136/archdischild-2019-317933 on 14 February 2020. Downloaded from http://adc.bmj.com/ on February 18, 2020 at Greenfield Medical Library
and reports in which the suspect drug could not be classified
Age group 1–3 Number of ICSRs of a specific ADR Number of users according to an ATC code (eg, herbals). Furthermore, reports
drug of interest a b of children <1 year old were excluded since it is hard to reli-
other suspect drugs c d ably identify psychiatric ADRs in this age group. Reports were
taken into account if there was at least one ADR reported in the
MedDRA SOC psychiatric disorders.
Methods An Odds Ratio (OR) was calculated as a measure of dispro-
The Netherlands Pharmacovigilance Centre Lareb is responsible
portionality for ADRs in the (SOC) psychiatric disorders on
for the spontaneous reporting system in the Netherlands and
MedDRA preferred term level (PT). An OR was calculated as
collects and analyses reports of suspected ADRs since 1991. Up
a division in which the numerator was the number of cases in
to May 2019, the Lareb database has accumulated over 226 000
which the drug of interest was used and a specific ADR was
reports. The reports are primarily received from healthcare
reported, divided by the number of users of that drug; the
professionals and patients, either directly or via pharmaceutical
denominator was the number of cases using other suspect drugs
manufacturers. Reported ADRs are coded using the Medical
reporting that specific ADR divided by the number of users of
Dictionary for Regulatory Activities (MedDRA) terminology,
these other suspect drugs. This OR takes the expenditure data
version 20.1.11 Drugs are coded according to the Anatomical
into account. An example of an OR calculation(table 0):
Therapeutic Chemical (ATC) classification system.12 Trained
OR=(a × d) / (b × c)
assessors assess all directly received individual reports on a case-­
If the OR is statistically significant, then the ADR is signifi-
by-­case basis. For the assessment of the strength of the causal
cantly associated with the drug of interest in reference to other
relationship between the drug and reported ADR, the Naranjo
reports in the database. It is expressed as a point estimate with
algorithm was used.13 The causality score is calculated as a mean
corresponding 95% CIs. At least three reports have to be present
score of all the individual causality scores of the individual case
in the database to compute a reliable OR. We calculated ORs for
safety reports (ICSRs) of an association. There are four cate-
ADRs based on a subset of the Lareb database (data restricted
gories: definite (score of ≥9), probable (score of 5–8), possible
to children aged 1–18 years). ORs were calculated for three
(score of 1–4) and doubtful (score of 0). All ADR reports are
different age groups separately: 1–3 years, 4–12 years and 13–18
included in the database regardless of causality or seriousness.
years. The OR offers insight into disproportionality of an associ-

Periodicals. Protected by copyright.

Seriousness corresponds to any untoward medical occurrence
that results in death, is life threatening, requires inpatient
(prolongation of) hospitalisation, results in disability or is a
congenital anomaly/birth defect.14
All reports of children aged 1–18 years, entered into the
Lareb database from 1 January 2003 to 31 December 2016,
were included in this study. This time period was chosen since
expenditure data of drugs are available of the corresponding
period. Expenditure data were extracted from the GIP database
(the drug information system of the Dutch healthcare insurance
board).15 This database contains information on the use of medi-
cines and medical devices in the Netherlands. We extracted the
data on the use of medicines of all Dutch children aged 1–18
years old. We excluded reports of vaccinations (ATC code J07)
ation, not into causality.
For each drug–ADR association per age category with three or
more reports, we checked if the ADR was labelled in the Dutch
Summary of Product Characteristics (SmPC), available through
the Dutch Medicines Evaluation Board.16
Results
From 1 January 2003 to 31 December 2016, Lareb received
5991 reports concerning children aged 1–18 years. Of these
reports, 918 reports (15%) contained ADRs in the SOC psychi-
atric disorders. A total of 1478 psychiatric ADRs were reported
in these 918 reports (figure 1). The majority of the reports were
non-­serious (n=762, 83%) and 156 reports (17%) were serious.

Figure 1  Flow chart of the selected reports. ADRs, adverse drug reactions; ICSR, individual case safety report.
2 Ekhart C, et al. Arch Dis Child 2020;0:1–7. doi:10.1136/archdischild-2019-317933

Figure 2  Number of individual case safety reports (ICSRs) for each age.
Seriousness is determined on a report level and not on individual
PT level. Therefore, serious reports could be serious due to core-
ported PTs and not necessarily psychiatric PTs. The outcome of
the ADR was reported for 1094 ADRs (74%): drug withdrawn/
dose reduced – ADR recovered (n=842, 57%), drug withdrawn/
dose reduced – ADR not recovered (n=89, 6%), dose not
changed – ADR recovered (n=89, 6%) and dose not changed –
ADR not recovered (n=74, 5%).
The number of reports reported for each age are shown in
figure 2. Five hundred and forty (59%) reports concerned boys
and 371 (40%) reports concerned girls. In seven (1%) reports,
sex was unknown. The percentage boys and girls differed
between the age groups (table 1).
Associations who were reported three or more times and
who had a disproportional OR are presented in tables 2–4 on
MedDRA PT level for ADRs. For these associations, labelling in
the SmPC is also shown. The causality of the associations based
on the average Naranjo score of individual reports is shown in
tables 2–4 as the causality score.
A total of 674 different drugs (counted for chemical subgroup
level ATC7) were suspected to have caused the psychiatric
adverse reactions. The top 10 of reported suspect drugs for each
age group is presented in table 5.
Medication associated with psychiatric symptoms
Age group 1–3 years
In the age group 1–3 years, associations concern palivizumab,
montelukast, fluticasone, valproic acid and azithromycin
(table 2).
Age group 4–12 years
In the age group 4–12 years most reported drugs are used for
the indication asthma, such as montelukast and fluticasone, or
Table 1  Number of boys and girls per age group
Age group Male, n (%) Female, n (%) Unknown, n (%)
1–3 years 69 (59) 44 (38) 3 (3)
4–12 years 331 (72) 125 (27) 2 (0)
13–18 years 140 (41) 202 (59) 2 (0)
Ekhart C, et al. Arch Dis Child 2020;0:1–7. doi:10.1136/archdischild-2019-317933
Original research
Arch Dis Child: first published as 10.1136/archdischild-2019-317933 on 14 February 2020. Downloaded from http://adc.bmj.com/ on February 18, 2020 at Greenfield Medical Library
attention deficit hyperactivity disorder (ADHD), such as methyl-
phenidate and atomoxetine (table 3).
The reports of phenytoin and drug dependence concern three
Periodicals. Protected by copyright.
different cases. These have been described elsewhere.17
There are six reports of abnormal behaviour associated with
montelukast. Abnormal behaviour is not mentioned in the
product information16; however, side effects such as aggression,
agitation, anxiety, irritability and restlessness, which are associ-
ated with abnormal behaviour, are known side effects.
The reports of oxybutynin and abnormal behaviour concern
patients who develop different behaviour (then who they usually
are). The parents describe this as a completely different child was
seen, with behaviour that was out of character of the child. On
withdrawal, the behaviour returned to normal.
Risperidone is used as first-­line treatment of tics.18 However,
we received three reports of tics associated with the use of risper-
idone. In the literature it was reported that a worsening of pre-­
existing tics was seen on risperidone monotherapy.19
Age group 13–18 years
Drugs used in the age group 13–18 years are more diverse and
consider indications such as ADHD (methylphenidate and atom-
oxetine), psychiatric disorders (antidepressants such as sertraline
and paroxetine and antipsychotic drugs such as risperidone),
isotretinoin for acne and oral contraceptives (table 4).
Five reports of levothyroxine and depressed mood concern
changing of the packaging from a bottle to a blister by the manu-
facturer. This resulted in patients being dysregulated and there-
fore presenting with various symptoms.20
There are a lot of similarities for the associations between
the various age groups. ADRs reported for a specific drug in
a specific age group are similar for the ADRs reported for that
drug in another age group. For instance, valproic acid in age
group 1–3 is associated with abnormal behaviour. This is also
the case in age group 4–12 years. Furthermore, atomoxetine in
age group 13–18 years is associated with anger, aggression and
depression. This is also the case in age group 4–12 years.
Most frequently reported medications with psychiatric ADRs
are shown in table 5. In total, methylphenidate and atomoxe-
tine account for 23% (208/918) of the reports of psychiatric
ADRs. Also, drugs used in asthma are seen in the top 10. Inhaled
3
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Arch Dis Child: first published as 10.1136/archdischild-2019-317933 on 14 February 2020. Downloaded from http://adc.bmj.com/ on February 18, 2020 at Greenfield Medical Library
Table 2  Associations age group 1–3 years
Drug Adverse reaction Number of reports OR Lower limit OR Upper limit OR SmPC Causality score
Palivizumab Listless 3 6127.8 1011.2 37132.8 No Possible
Montelukast Aggression 4 212.7 69.8 648.7 Yes Probable
Valproic acid Abnormal behaviour 3 123.0 36.6 414.1 Yes Possible
Fluticasone Agitation 4 5.9 2.0 17.3 Yes Possible
Azithromycin Aggression 3 6.6 1.9 22.8 Yes Possible
SmPC, Summary of Product Characteristics.

corticosteroids alone or combined with salmeterol account for
7% (65/918) and montelukast accounts for 4% (40/918) of the
reports of psychiatric ADRs. However, psychiatric ADRs were
also reported for less often prescribed medications such as
oxybutynin and isotretinoin.
Discussion
In this study, we found that 918 reports of ADRs in children
(15%) concern psychiatric signs and symptoms. Drugs used for
the treatment of ADHD and asthma were the most frequently
reported. Psychiatric ADRs associated with these drugs are agita-
tion, aggression, abnormal behaviour and tics.
From previous studies, it is known that children experience
a wide range of ADRs.21 The reporting pattern seen in studies
based on spontaneously reported ADRs differs between paedi-
atric age subgroups. This could partially be due to susceptibilities
to specific drug-­related problems in certain age groups. However,
common drug usage in these age groups and childhood diseases

Table 3  Associations age group 4–12 years

Drug Adverse reaction Number of reports OR Lower limit OR Upper limit OR SmPC Causality score
Phenytoin Drug dependence 3 154870.4 7602.2 3154998.0 No Possible
Atomoxetine Tic 7 227.3 98.4 524.9 Yes Possible

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Atomoxetine Aggression 7 109.4 49.7 241.1 Yes Possible
Atomoxetine Depression 6 316.6 123.6 810.8 Yes Possible
Atomoxetine Suicidal ideation 5 383.7 133.1 1106.5 Yes Possible
Atomoxetine Anger 4 198.6 66.7 591.4 Yes Possible
Atomoxetine Insomnia 4 112.6 39.6 320.1 Yes Possible
Atomoxetine Depressed mood 3 110.1 33.0 367.4 Yes Possible
Montelukast Abnormal behaviour 6 28.2 12.2 65.4 No Possible
Montelukast Nightmare 4 63.0 21.2 187.4 Yes Possible
Montelukast Insomnia 4 35.7 12.6 101.4 Yes Possible
Montelukast Aggression 4 18.8 6.8 51.8 Yes Possible
Montelukast Restlessness 3 42.3 12.5 143.0 Yes Possible
Montelukast Depressed mood 3 34.9 10.5 116.4 Yes Possible
Paracetamol Hallucination 3 52.8 16.3 171.7 Yes Possible
Methylphenidate Aggression 16 11.6 6.6 20.6 Yes Probable
Methylphenidate Tic 15 27.3 13.7 54.1 Yes Possible
Methylphenidate Insomnia 8 10.1 4.6 22.3 Yes Possible
Methylphenidate Hallucination 8 8.2 3.8 17.8 Yes Possible
Methylphenidate Agitation 7 11.5 4.8 27.1 Yes Possible
Methylphenidate Abnormal behaviour 7 4.1 1.9 9.0 Yes Possible
Methylphenidate Anger 6 13.1 5.1 33.8 Yes Possible
Methylphenidate Depressed mood 6 9.8 3.9 24.5 Yes Possible
Methylphenidate Hallucination, visual 5 23.4 7.4 73.7 Yes Probable
Methylphenidate Sleep disorder 5 10.9 4.0 30.0 Yes Possible
Methylphenidate Hallucination, auditory 4 21.8 6.2 77.3 Yes Possible
Methylphenidate Depression 4 7.3 2.5 21.5 Yes Possible
Methylphenidate Anxiety 4 3.6 1.3 10.2 Yes Possible
Methylphenidate Psychotic disorder 3 14.0 3.6 54.3 Yes Possible
Methylphenidate Suicidal ideation 3 7.6 2.2 26.5 Yes Possible
Methylphenidate Restlessness 3 5.2 1.5 17.5 Yes Possible
Valproic acid Abnormal behaviour 4 32.7 11.9 90.2 Yes Possible
Oxybutynin Abnormal behaviour 4 30.0 10.9 82.7 No Possible
Oxybutynin Aggression 3 22.9 7.2 73.1 Yes Probable
Risperidone Tic 3 26.1 8.0 85.6 No Possible
Fluticasone Abnormal behaviour 11 6.2 3.2 11.9 Yes Possible
Fluticasone Aggression 7 3.8 1.7 8.4 Yes Possible
Salmeterol/fluticasone Abnormal behaviour 4 7.7 2.8 21.2 Yes Possible
SmPC, Summary of Product Characteristics.

4 Ekhart C, et al. Arch Dis Child 2020;0:1–7. doi:10.1136/archdischild-2019-317933

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Arch Dis Child: first published as 10.1136/archdischild-2019-317933 on 14 February 2020. Downloaded from http://adc.bmj.com/ on February 18, 2020 at Greenfield Medical Library
Table 4  Associations age group 13–18 years
Drug Adverse reaction Number of reports OR Lower limit OR Upper limit OR SmPC Causality score
Sertraline Hallucination and auditory 4 (10* including duplicates) 1692.6 642.5 4459.0 Yes Possible
Sertraline Nightmare 3 (5† including duplicates) 538.6 186.7 1554.0 Yes Possible
Sertraline Psychotic disorder 3 209.1 61.1 715.0 Yes Possible
Paroxetine Anorgasmia 3 8807.3 440.7 176026.2 Yes Possible
Paroxetine Libido decreased 3 338.7 96.3 1191.9 Yes Possible
Atomoxetine Anger 4 1524.9 340.7 6825.2 Yes Possible
Atomoxetine Depression 3 171.6 50.9 578.5 Yes Possible
Atomoxetine Aggression 3 127.1 38.5 419.8 Yes Probable
Venlafaxine Suicidal ideation 3 355.6 106.2 1190.5 Yes Possible
Risperidone Abnormal behaviour 4 275.4 73.9 1026.0 No Possible
Fluoxetine Suicidal ideation 5 182.6 68.7 485.2 Yes Possible
Fluoxetine Insomnia 3 115.0 34.1 387.7 Yes Possible
Quetiapine Aggression 3 172.7 52.3 571.1 No Possible
Montelukast Nightmare 3 111.4 31.7 391.2 Yes Possible
Levothyroxine Depressed mood 5 64.9 25.5 165.1 No Possible
Isotretinoin Depression 4 61.6 21.0 181.3 Yes Possible
Isotretinoin Depressed mood 4 30.0 10.7 84.1 Yes Possible
Isotretinoin Mood swings 3 46.2 13.7 156.3 Yes Possible
Isotretinoin Suicidal ideation 3 38.2 11.5 127.3 Yes Possible
Methylphenidate Insomnia 6 17.9 7.1 45.4 Yes Possible
Methylphenidate Aggression 6 12.7 5.2 31.0 Yes Possible
Methylphenidate Depressed mood 6 8.2 3.5 19.5 Yes Possible

Periodicals. Protected by copyright.

Methylphenidate Suicidal ideation 4 9.2 3.2 26.7 Yes Possible
Methylphenidate Drug dependence 3 304.1 15.2 6071.4 Yes Possible
Methylphenidate Irritability 3 50.7 10.2 251.1 Yes Possible
Methylphenidate Agitation 3 30.4 7.3 127.3 Yes Probable
Methylphenidate Hallucination and visual 3 30.4 7.3 127.3 Yes Possible
Methylphenidate Psychotic disorder 3 8.9 2.6 30.5 Yes Possible
Methylphenidate Anxiety 3 8.4 2.5 28.7 Yes Possible
Methylphenidate Hallucination 3 8.0 2.4 27.1 Yes Possible
Cyproterone/oestrogen Libido decreased 3 14.0 4.0 49.3 Yes Possible
Cyproterone/oestrogen Mood swings 3 9.6 2.8 32.5 Yes Possible
Cyproterone/oestrogen Depressed mood 3 4.6 1.4 14.8 Yes Possible
Ethinylestradiol/levonorgestrel Mood swings 6 2.9 1.1 7.4 Yes Possible
*Seven of the reports of sertraline and auditory hallucination are duplicates of the same patient described in a literature report. So there are four unique reports of sertraline and auditory
hallucination.38
†Three of the reports of sertraline and nightmare are duplicates of the same patient described in a literature report. So there are three unique reports of sertraline and nightmare.38
SmPC, Summary of Product Characteristics.

related to age could also be an explanation.22 In a study of US
children and adolescents, the most commonly used medication
classes were asthma medications, antibiotics, ADHD medica-
tions, topical agents and antihistamines. Drugs for the indication
asthma and ADHD medications and contraceptives showed an
increasing linear trend with age, whereas drugs like antibiotics,
antihistamines and upper respiratory combination medications
showed a decreasing linear trend with age.23
In our study, from the age group 1–3 years and onwards, corti-
costeroids and montelukast become more important as possible

Table 5  Top 10 suspect drugs for the various age groups

1–3 years (Ntot=116) 4–12 years (Ntot=458) 13–18 years (Ntot=344)
Suspect drug N Suspect drug N Suspect drug N
Montelukast 10 Methylphenidate 99 Methylphenidate 50
Amoxicillin 10 Atomoxetine 44 Ethinylestradiol/levonorgestrel 21
Palivizumab 9 Montelukast 30 Sertraline 16
Beclomethasone 8 Fluticasone 25 Isotretinoin 16
Fluticasone 8 Valproic acid 17 Atomoxetine 15
Salbutamol 6 Oxybutynin 14 paroxetine 14
Amoxicillin/clavulanic acid 4 Risperidone 14 Fluoxetine 13
Valproic acid 4 Beclomethasone 12 Levothyroxine 11
Azithromycin 3 Salmeterol/fluticasone 12 Risperidone 10
Domperidone 2 Paracetamol 11 Cyproterone/oestrogen 9
Ntot is total number of reports.

Ekhart C, et al. Arch Dis Child 2020;0:1–7. doi:10.1136/archdischild-2019-317933 5

Original research
causes of psychiatric ADRs. Behavioural changes after inhaled
corticosteroids have been reported before, although these seemed
rare in some studies.24 25 Other studies in groups of children who
studied the relationship between behaviour and inhaled corti-
costeroids did not show an association,26 even in young chil-
dren with high adherence.27 This does not rule out that on an
individual level children can exhibit different behaviour after
inhaled corticosteroids due to individual vulnerability.
We received 46 reports of psychiatric ADRs associated with
montelukast in children. Behavioural problems as an ADR have
been described.28 In a recent review of both Dutch and interna-
tional pharmacovigilance databases, strong statistical associations
were found between montelukast and depression, aggression,
suicidal ideation and abnormal behaviour.29 A systematic review
of ADRs of drugs used in the treatment of asthma found that
about one in three of the reported adverse reactions is associated
with montelukast.25
In total, most reports were received on methylphenidate
(n=149) and atomoxetine (n=59). These medications are used
in the treatment of ADHD. Reported ADRs were mood disor-
ders, hallucination, aggression and tics, among others. These
findings are in line with a recent study from the US Food and
Drug Administration, who found that drugs used for the indi-
cation ADHD, such as methylphenidate and atomoxetine,
increased the reporting rate of ADRs connected with mood
and emotional disturbances, producing significant Reporting
Odds Ratios30 Many children with ADHD have psychological
or psychiatric comorbidities, making it difficult to recognise
behavioural changes as ADRs.30 In a recent systematic review
on the adverse drug events during ADHD treatment, it was
found that in clinical trials symptoms as irritability, anxiety and
sadness were found less in children on methylphenidate than
placebo.31
Remarkable were the reports on abnormal behaviour and
aggression after oxybutynin. Oxybutynin has anticholinergic
activity and is used for micturition problems. In the product
information, it is mentioned that oxybutynin should be used
with caution in children aged 5 years and older, since they are
more susceptible to psychiatric side effects.15
We received three reports of aggression associated with the
use of quetiapine in age group 13–18 years. The effects of queti-
apine on aggression are not straightforward. Controlled studies
have shown that quetiapine resulted in an improvement in
aggression.32 However, it has also been reported that quetiapine
causes irritability and aggression. Adolescents less than 25 years
of age have a higher risk of these effects.33
Quite a number of disproportionate associations were found
for selective serotonin reuptake inhibitors (SSRIs) in age group
13–18 years. For the paediatric population, a special warning is
listed in the SmPC about suicide-­related behaviours and hostility.
In addition, only limited evidence is available concerning long-­
term safety data in children and adolescents. SSRIs should there-
fore be used with caution in the paediatric population.15
Strengths and limitations of this study
The strength of our study is that our data were corrected for
drug utilisation. In this way, the number of reports is corrected
for the number of users. Previous studies who also used data
from spontaneous reporting systems were not able to correct for
the number of users of a drug and therefore relied on the number
of other reported ADRs as a proxy for the number or users.7 34
However, since reporting of ADRs is known to be biased, the
true number of users is to be preferred.
6 Ekhart C, et al. Arch Dis Child 2020;0:1–7. doi:10.1136/archdischild-2019-317933
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In tables 2–4, ORs can have extremely high values. This is a
result of mathematical handling of low numbers. This phenom-
enon has been reported before by Wallerstedt et al.8
Information received by pharmacovigilance centres is neither
always complete nor homogenous and is prone to bias.35 For
instance, under-­reporting is very common.36 The number of
ICSRs concerning psychiatric ADRs is low (918 ICSRs during
14 years). Therefore, true risks of ADRs cannot be estimated
from our data. Several studies have suggested that less than 10%
of detected ADRs are effectively reported to medicine regulatory
authorities.37 Furthermore, the causality of the reported ADRs
and suspect drugs is not always certain. Nevertheless, a volun-
tary reporting system is useful in identifying early warnings of
drug-­related harm, which is important in a vulnerable popula-
tion such as the paediatric population.
Associations are shown on drug level based on ATC7 and
MedDRA PTs. This, for instance, means that related terms such
as depression and depressed mood are shown separately and not
grouped together.
Conclusion
In conclusion, real-­world data on psychiatric ADRs in the Dutch
paediatric population show a consistent pattern with what is
known from drug labels and the literature. Although we did not
find any new safety signals in the current study, spontaneous
Periodicals. Protected by copyright.
reports have an important place in paediatric ADR signal detec-
tion. Psychiatric ADRs were reported most often for medications
used for the treatment of ADHD and asthma but can also occur
after other medications. Reports of psychiatric ADRs should be
taken seriously, because they can have a major impact on medica-
tion adherence and on the well-­being of the child and its family.
Acknowledgements  We would like to thank Joep Scholl for support with the
queries and Vincent de Valk for providing the GIP data.
Funding  The authors have not declared a specific grant for this research from any
funding agency in the public, commercial or not-­for-­profit sectors.
Competing interests  None declared.
Patient consent for publication  Not required.
Provenance and peer review  Not commissioned; externally peer reviewed.
Data availability statement  All data relevant to the study are included in the
article or uploaded as supplementary information.
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