Key words
pharmacovigilance - drug safety - psychotropic drugs - intellectual and developmental
disorders - children
Introduction
Children and adolescents with multiple disabilities have a 3 to 4 times higher
prevalence of mental disorders compared to children without disabilities [1]. Treatment of mental disorders in these
patients is challenging and often involves psychopharmacotherapy. Antipsychotic
drugs are commonly prescribed ‘off-label’ for indications such as
schizophrenia or challenging behaviors, like aggression [2]
[3],
which is associated with an increased risk of adverse drug reactions (ADRs) [3]
[4].
Antipsychotics generally show an unfavorable profile of ADRs with an increased risk
in children and adolescents compared to adults for endocrine, metabolic as well as
neurological complications (such as extrapyramidal motor symptoms, EPS) [5]
[6]
[7]. Children and adolescents
with multiple disabilities and mental disorders (CAMD) are even more vulnerable to
ADRs due to frequent comorbid somatic diseases such as epilepsy or congenital heart
defects [8]. Medications for those somatic
conditions can, in turn, increase the risk of ADRs due to drug interactions.
Moreover, in this group of ADRs, the efficacy and tolerability of medications are
more difficult to assess due to the communicative impairments of the patients, which
can lead to suboptimal dosing or polypharmacy.
Serious ADRs (sADRs) are defined here as fatal or life-threatening adverse reactions
that require hospitalization or the prolongation of existing hospitalization, or
lead to persistent or significant disability [9]. Due to the suspected high prevalence of (s)ADRs under antipsychotic
treatment in CAMD, psychopharmacological therapy surveillance is important.
One potential tool to prevent (s)ADRs is therapeutic drug monitoring (TDM). TDM
determines whether drug levels are within a defined drug-specific therapeutic
reference range, outside of which ADRs are more likely to occur, or whether the drug
is not efficacious. This instrument of pharmacovigilance is well-established in
adult psychiatry [10]
[11]. However, there are still no age-specific
therapeutic reference ranges for minors [10]
despite ongoing research [12]
[13]. Until age- and indication-specific
therapeutic ranges are defined for all psychotropic drugs, TDM is useful in child
and adolescent psychiatric patients to identify ’the therapeutic window of a
patient, to reduce the risk of dose-dependent ADRs, control drug adherence, and in
cases of polypharmacy [10]
[13]
[14].
The detailed, specific indications and practical guidelines for TDM can be found
elsewhere [10]
[13].
Studies with adult patients show that TDM is also useful from a health-economic point
of view, as it can increase therapy efficiency and, in antipsychotic treatment. in
particular, safety [15]
[16]
[17]
[18]
[19] and thus save costs [20]
[21].
This retrospective study aimed to examine the frequency of sADRs in CAMD treated with
antipsychotics and the potential preventability of these sADRs through TDM.
Furthermore, the prolongation of the hospital stay due to sADRs was estimated, as
well as the potential cost savings if TDM had been applied.
Methods
Study design
This monocentric, retrospective clinical cohort study was based on a child and
adolescent psychiatric subsample (health care data of a special clinic for CAMD)
of the KiDSafe project, which was approved by the Ethics Committee of the
University of Wuerzburg (245/18). The data of the overall sample has
been submitted elsewhere. KiDSafe was funded by the Innovation Fund of the Joint
Federal Committee (grant number 01NVF16021). The study was conducted in
accordance with the Declaration of Helsinki (World Medical Association, 2013).
No written informed parental consent was obtained because the routine clinical
data were analyzed retrospectively and anonymized before analysis. Approval was
obtained by the local data protection officer prior to data extraction.
Study population
The study was carried out in the special clinic for CAMD, associated with the
Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy
of a University Hospital. Patients were included in this study if they were
admitted to the special clinic between 2017 and 2018 and were prescribed an
antipsychotic drug during their stay. For this reason, patients’
electronic medical records were screened. The study population included patients
who were already receiving (multiple) antipsychotic medication on admission, as
well as patients who had an antipsychotic (re)started, switched, or had their
dose changed during the inpatient stay. Patient characteristics (age, sex),
(main) psychiatric diagnosis, and all psychotropic drugs administered were
recorded. Cognitive ability was determined with standardized tests or were based
on records or clinical impressions.
Frequency of serious adverse drug reactions
A checklist based on the Pediatric Adverse Event Rating Scale (PAERS) [22] was created. For all patients receiving
antipsychotics, discharge letters, consultation reports, inpatient
documentation, and clinical test reports (vital signs, laboratory parameters,
ECG, and EEG) were reviewed to identify instances of possible serious adverse
events with a possible causal relationship to the drug (considered as sADR) as
defined according to EMA [9] and WHO [23]. A ‘possible causal
relationship’ describes a temporal relationship between the drug and the
adverse event without ruling out that an underlying disease or other medication
may be responsible for the event.
Potential preventability of serious adverse drug reactions
The Schumock score [24] was used to assess
the potential preventability of a sADR ([Table
1]). The sequence of events from prescription to administration to
medication intake was assessed for errors according to seven criteria. If any of
these criteria was fulfilled, the sADR was considered preventable. One
medication could fulfill more than one criterion of preventability. Criterion 3
was considered fulfilled if no TDM was performed for the antipsychotic suspected
to be the cause of the sADR. In this case, the sADR was classified as
‘potentially preventable through TDM.’
Table 1 Schumock score for assessing the preventability of
adverse drug reactions [24].]
Criterion number
|
Question
|
Answer
|
1
|
Was the drug involved in the ADR not considered
appropriate for the patient’s clinical
condition?
|
yes/no
|
2
|
Was the dose, route, and frequency of administration not
appropriate for the patient’s age, weight, and
disease state?
|
yes/no
|
3
|
Was required therapeutic drug monitoring or other
necessary laboratory tests not performed?
|
yes/no
|
4
|
Was there a history of allergy or previous reactions to the
drug?
|
yes/no
|
5
|
Was a drug interaction involved in the reaction?
|
yes/no
|
6
|
Was a toxic serum drug level documented?
|
yes/no
|
7
|
Was poor compliance involved in the reaction?
|
yes/no
|
Estimation of treatment prolongation due to sADRs and potential cost savings from
their prevention
The ‘prolongation of the hospital stay’ due to the sADR was
measured as the duration (in days) until the symptoms of the sADRs subsided
after stopping the medication or reducing the dose. This was determined from the
case documentation.
To estimate the cost-saving potential by preventing sADRs through TDM, we
calculated the ‘prolongation of the hospital stay’ of the
patients in whom sADRs occurred and no TDM was performed (Schumock Criterion 3).
Saved costs were calculated by multiplying those prolonged days by the average
base daily rate of the special clinic per patient based on the current German
flat-rate remuneration system for psychiatry and psychosomatics (at least 400
€/day).
Data analysis
Statistical analysis was performed using SPSS version 26. Descriptive results are
reported with mean,+/− standard deviation (SD), and
range.
Results
Patient characteristics
During the survey period, 124 CAMD (65% male, 69%≥12
years) were treated within the framework of a multimodal treatment concept. One
hundred two (82%) were administered at least one antipsychotic drug in
monotherapy or polypharmacy during inpatient treatment. The characteristics of
those patients are mentioned in [Table
2]. The most frequent diagnoses were developmental disorders (ICD-10 F8).
The vast majority of patients (91%) had mild to moderate intellectual
disabilities. The total number of antipsychotic prescriptions in the 102
children and adolescents was 273. Substances used most often were pipamperone
(n=56), risperidone (n=48) and aripiprazole (n=44).
Table 2 Characteristics of patients with multiple
disabilities and mental disorders treated with antipsychotics
(n=102).
|
m±SD
|
Age (years)
|
13.4±3.5
|
<12 years, n=33 (32%)
|
≥12 years, n=69 (68%)
|
IQ (n=56)
|
54.1±12.7
|
Normal range (85–114): n=1
|
93±0
|
Borderline intellectual functioning (70–84):
n=2
|
74.0±2.8
|
Mild intellectual disability (50–69):
n=33
|
60.0±5.2
|
Moderate intellectual disability (35–49):
n=18
|
41.4±5.0
|
Severe intellectual disability (20–34):
n=2
|
30±0
|
|
n
|
Sex
|
|
Male
|
68
|
Female
|
34
|
Main psychiatric diagnosis (ICD-10)
|
|
Organic, including symptomatic mental disorders (F0)
|
1
|
Schizophrenia spectrum disorders (F2)
|
6
|
Affective disorders (F3)
|
2
|
Neurotic, stress, and somatoform disorders (F4)
|
3
|
Behavioral disorders with physical disorders and factors
(F5)
|
2
|
Personality and behavioral disorders (F6)
|
3
|
Intelligence disorder (F7)
|
4
|
Developmental disorders (F8)
|
47
|
Behavioral and emotional disorders with onset in childhood
and Adolescence (F9)
|
34
|
Diagnosis of epilepsy
|
22
|
Total number of antipsychotic prescriptions
|
273
|
Pipamperone (on-demand medication)
|
56
|
Risperidone
|
48
|
Aripiprazole
|
44
|
Melperone (on-demand medication)
|
32
|
Zuclopenthixol
|
27
|
Chlorprothixen (on-demand medication)
|
19
|
Quetiapine
|
16
|
Levomepromazine (on-demand medication)
|
11
|
Haloperidol
|
8
|
Olanzapine
|
8
|
Clozapine
|
2
|
Thioridazine
|
2
|
Tiapride
|
1
|
m=mean, SD=standard deviation, IQ=intelligence
quotient.
Frequency of serious adverse drug reactions
Among CAMD, 21.6% (n=22 out of 102), who were treated with one or
more antipsychotic drugs experienced sADRs. [Table 3] shows the severity criterion according to EMA [9]. In 16 cases, the ADR prolonged the
patient’s inpatient stay, and in four cases, the ADR resulted in the
patient’s admission. Two sADRs were life-threatening, and one sADR was
lethal.
Table 3 Description of potentially preventable and
nonpreventable serious adverse drug reactions (sADRs) on
antipsychotic medication and duration.
Patient information (age; main psychiatric/somatic
disorders (ICD-10)
|
Type of sADR
|
Description of sADR
|
Severity criterion according to EMA [9]
|
Suspected antipsychotic(s) (+other suspected
psychotropic drug)
|
Criterion for the preventability of the sADR, according to
Schumock [24]
|
Prolongation of treatment (n=100)
|
8 years; PDD (F8), MR (F71)
|
Cardio-vascular ADRs
|
QTc:460 ms
|
Prolonged stay
|
Zuclopenthixol, (Amphetamine)
|
1
|
8
|
3
|
17 years; EBD (F9), MR (F70), obesity (E66)
|
QTc:480 ms
|
Prolonged stay
|
Zuclopenthixol, Quetiapine
|
1
|
19
|
3
|
5
|
12 years; EBD (F9), MR (F70), congenital malformations of the
heart (Q24), epilepsy (G40), obesity (E66)
|
QTc:550 ms
|
fatal
|
Aripiprazole, (Guanfacine)
|
3
|
–
|
5
|
15 years; PDD (F8), MR (F72)
|
QTc:529 ms
|
Prolonged stay
|
Aripiprazole, Zuclopenthixol, Pipamperone
|
2
|
18
|
3
|
5
|
16 years; schizophrenia (F2), MR (F70)
|
QTc:539 ms
|
Admission to hospital
|
Clozapine
|
6
|
|
16 years; PDD (F8), MR (F71)
|
QTc:479 ms
|
Prolonged stay
|
Aripiprazole, Melperone, Risperidone
|
2
|
|
5
|
14 years; PDD (F8), MR (F70), chromosomal abnormality (Q99),
disorder of ear (H9)
|
EPS
|
Rigor, tremor, akinesia, gaze spasm, tongue or gullet spasm,
akathisia, myoclonus, gait disturbance.
|
Prolonged stay
|
Aripiprazole
|
2
|
11
|
3
|
16 years; PDD (F8), MR (F72), microcephaly (Q02), disorders
of refraction and accommodation (H52)
|
Prolonged stay
|
Quetiapine, Aripiprazole, Melperone, (Lorazepam,
Melatonine)
|
1
|
|
2
|
5
|
19 years; schizophrenia (F2), MR (F71), Di George syndrome
(D82), scoliosis (M41)
|
Prolonged stay
|
Haloperidol
|
3
|
12
|
15 years; EBD (F9), MR (F70), congenital malformations of
heart (Q24)
|
Prolonged stay
|
Zuclopenthixol
|
2
|
2
|
3
|
15 years; adjustment disorder (F4), MR (F70), Di George
syndrome (D82), epilepsy (G40), congenital malformations of
cardiac septa (Q21)
|
Prolonged stay
|
Risperidone, Melperone
|
1
|
|
5
|
13 years; PDD (F8), MR (F71), disorders related to short
gestation and low birth weight (P07), microcephaly (Q02),
spastic diplegic cerebral palsy (G80), cerebral cysts
(G93)
|
Prolonged stay
|
Zuclopenthixol
|
2
|
4
|
3
|
17 years, MR (F71), schizophrenia (F2)
|
Epileptic seizure
|
Epileptic seizure
|
Prolonged stay
|
Clozapine, Aripiprazole
|
5
|
|
14 years; EBD (F9), MR (F70), disorders of refraction and
accommodation (H52)
|
Gastrointestinal ADR
|
Nausea, vomiting, abdominal pain with diarrhea
|
Admission to hospital
|
Quetiapine, (+Sertraline)
|
1
|
|
5
|
11 years; EBD (F9), MR (F70)
|
Prolonged stay
|
Aripiprazole
|
2
|
|
14 years; EBD (F9), MR (F70), epilepsy (G40)
|
Increased salivation
|
Prolonged stay
|
Thioridazine, Risperidone
|
1
|
19
|
3
|
16 years; habit and impulse disorders (F6), MR (F7), epilepsy
(G40),
|
Prolonged stay
|
Pipamperone, Melperone, Aripiprazole
|
1
|
|
5
|
8 years; EBD (F9), MR (F71), abnormal results of function
studies of the central nervous system (EEG) (R94)
|
Prolonged stay
|
Zuclopenthixol, (Valproate),
|
1
|
7
|
3
|
17 years; schizophrenia (F2), MR (F70), epilepsy (G40),
microcephaly (Q02), chromosomal abnormality (Q99),
atrioventricular and right fascicular block (I44, I45)
|
Weight change
|
Weight gain (>10 kg)
|
Prolonged stay
|
Olanzapine
|
not avoidable
|
|
17 years; habit and impulse disorders (F6), MR (F72),
drug-induced obesity (E66), congenital malformations of
cardiac septa (Q21)
|
Blood count change
|
Liver value increase
|
Admission to hospital
|
Pipamperone, Risperidone
|
5
|
|
14 years; MR (F71), other congenital malformations of the
heart (Q24)
|
Aplastic anemia
|
Admission to hospital
|
Zuclopenthixol, Melperone, Tiapride, (Lamotrigine)
|
1
|
|
3
|
life-threatening
|
5
|
11 years; PDD (F8), MR (F71), cerebral cysts (G93.0)
|
Psychiatric ADR
|
(auto-) aggression
|
life-threatening
|
Aripiprazole, (Oxcarbazepine)
|
1
|
|
ICD-10=International Statistical Classification of Diseases and
Related Health Problems 10th Revision; EMA=European Medicine
Agency, (s)ADR=(serious) adverse drug reaction, EPS:
extrapyramidal symptoms, PDD: pervasive developmental disorder, MR:
mental retardation, EBD: emotional and behavioral disorders, QTc:
frequency-corrected QT interval according to Bazett.
Of sADRs, 95% (n=21) were somatic symptoms, and one was a
psychiatric event. QTc prolongation and EPS were the most frequent sADR. The
frequency of the affected organ systems and the type of sADR are shown in [Table 3].
Antipsychotics linked to suspected serious adverse drug reactions
One hundred two patients received a total of 273 antipsychotic drug
prescriptions. For 37 prescriptions, sADRs were reported ([Table 2]). The drug with the highest
absolute number of suspected sADRs was the third-generation antipsychotic
aripiprazole (9 sADRs in 44 patients on aripiprazole; 20.5%).
Proportionately, the first-generation antipsychotic zuclopenthixol was most
frequently associated with sADRs (7 sADRs in 27 patients on zuclopenthixol;
25.9%). Fifteen Patients with sADR (68.2%) were administered
more than one psychotropic drug.
Potential preventability of serious adverse drug reactions
According to the Schumock score, 95.5% (n=21) of the sADRs
(n=22) were potentially preventable (see [Table 3]). In 11 of these cases, no TDM
was performed (criterion 3). In 11 cases, avoidance of the interaction with
co-medication could have prevented the sADR (criterion 5). In 10 cases, the
antipsychotic drug linked to the sADR was not considered appropriate for the
clinical condition of the patient (criterion 1). A dosing error was observed in
seven patients (criterion 2). One patient showed a too-high serum level
(criterion 6).
Prolongation of treatment by serious adverse drug reactions and estimation of
cost savings due to therapeutic drug monitoring
For 16 patients, prolongation of the hospital stay due to a sADR was documented.
In total, 246 ‘prolongation days’ until the complete resolution
of sADR symptoms were documented. For 11 of those patients, sADRs were judged as
‘potentially preventable through TDM’ based on Schumock
criterion 3 (n=11). For nine patients, the prolongation of their stay
resulted from a sADR, which could have been prevented with TDM, with a total of
100 prolongation days. Our findings indicate that the use of TDM could have
reduced patient stays by 100 days for a total of nine patients (with 9 of 22
sADR recorded; 40.9%), resulting in potential savings of approximately
€40,000.
Discussion
Frequency and nature of serious adverse drug reactions under antipsychotic
treatment
In our study, around 20% of CAMD treated with antipsychotics for various
psychiatric disorders suffered at least one sADR. This reflects the high
vulnerability of ADRs in this group of pediatric patients and underlines the
need for highly standardized therapy surveillance.
EPS and QTc prolongation were the most frequently observed sADRs. Interestingly,
in the TDM Vigil study [25], psychiatric
(not somatic) sADRs were most frequently reported. In our sample, psychiatric
sADRs were very rare. One possible explanation is that psychiatric sADRs are
harder to recognize in patients with multiple disabilities due to impairments of
those patients in introspection and communication. Furthermore, in contrast to
the prospective TDM vigil study, our investigation relied on retrospective
excerpts from routine documentation. It is also possible that psychiatric ADRs
are documented less frequently since they may be attributed to the underlying
disability. It is, however, likely that CAMD are more prone to somatic ADRs
[8].
The first-generation antipsychotic zuclopenthixol, which is not licensed for
pediatric use, was most frequently associated with a sADR relative to
prescription frequency. Notably, conducting TDM for this substance was not
possible in our laboratory during the observation period, which may also have
contributed to the high rate of sADR under zuclopenthixol treatment.
The purely descriptive results of our study suggest that typical antipsychotics,
like zuclopenthixol, may be unsuitable for pediatric patients, and
second-generation atypical antipsychotics may be preferable, as recommended in
guidelines [26]. However, this
retrospective study was not suitable or intended to investigate the tolerability
profile of different antipsychotics. Further prospective studies are needed to
confirm the results.
Assessment of preventability of serious adverse drug reactions by therapeutic
drug monitoring
Eleven patients who experienced a sADR did not undergo TDM. TDM is based on the
assumption that there is a relationship between serum concentration and the
clinical effects of a drug. The upper limit of the therapeutic range, if
exceeded, warns of the occurrence of ADRs. However, TDM in pediatric patients is
limited by the fact that reference ranges are defined for adults and are mostly
not validated for children and adolescents and their specific indications.
Nevertheless, that TDM with the knowledge on adult reference ranges is valuable
also in minors shows a representative example of our sample: A 16-year-old
patient with schizophrenia (ICD-10 F2) was treated with clozapine
(750 mg/day) and suffered from a prolonged QTc ([Table 3]). The measured clozapine drug
level (796 ng/mL) lay clearly above the reference range for
adults (300–600 ng/mL) [21]. The dose was reduced, and the patient recovered. An association
between serum concentration and ADRs has been demonstrated for clozapine [27]
[28], haloperidol [29],
olanzapine [30]
[31], risperidone [32]
[33], and ziprasidone [34], for
example.
Age- or indication-specific therapeutic reference ranges for children and
adolescents have also been proposed for antipsychotics, e. g., for
tiapride in the treatment of tic disorders [35], risperidone in the treatment of children and adolescents with
impulsive-aggressive behavior [36] and
schizophrenia, and pipamperone in children and adolescents with conduct disorder
[37]. No TDM studies have been
conducted specifically for CAMD. This critical topic warrants further
research.
Sixty-eight percent of patients with documented sADRs were being treated
polypharmacologically. Polypharmacology is the only indication for TDM
specifically recommended for CAMD in the current guidelines [26]. In four patients, both Schumock
criterion 5 (interaction) and criterion 3 (no TDM) were fulfilled. For example,
a QTc prolongation occurred in a 15-year-old patient treated with
zuclopenthixol, aripiprazole, and pipamperone ([Table 3]). As all these antipsychotics have the potential to cause
concentration-dependent QTc-prolongation [38], and a TDM would have been strongly indicated. Our results
confirm the importance of TDM if polypharmacy is necessary.
Cost-saving potential of therapeutic drug monitoring
In addition to enhancing patient safety and treatment efficacy, TDM has the
potential to reduce unnecessary healthcare costs. Shortening hospital stays
through TDM-guided antidepressant therapy has previously been shown in studies
with adult patients [20]
[39]. The estimation in our study supports
the premise that TDM has significant cost-saving potential by reducing the
frequency of sADRs and therefore preventing prolonged inpatient treatment in
this particular patient population. Additionally, other indications for TDM,
e. g., problems with adherence or relapse prevention [16]
[17], have great potential for savings. The potential cost savings
calculated in this study are approximately €40,000 for a 2-year survey
period, including 102 CAMD on antipsychotics. Therefore, the use of TDM can
optimize pharmacotherapy to prevent and shorten inpatient stays. This
health-economic benefit becomes even clearer when the costs of a serum
concentration determination (25€ for physicians in Germany) are compared
with the daily rate of inpatient psychiatric treatment, which is more than 15
times higher in most specialized child and adolescent psychiatric clinics.
Limitations
The results of this study must be evaluated in the context of the limitations of
a retrospective study. All data were based on the available routine case
documentation. Thus, poor or biased documentation may have affected results.
However, the department has previously participated in pharmacovigilance drug
RCTs (TDM-VIGIL), having substantially improved the standards for documentation
on drug treatment. Furthermore, as this was a monocentric study and only
prescription patterns and drug monitoring of one highly specialized clinic were
evaluated. Thus, these results may not be generalizable to other settings.
The causal relationship between sADR and antipsychotic treatment was assessed
using WHO criteria [23]. None of the cases
had been classified as a ‘probable’ or ‘certain’
causal relationship. Therefore, most cases had only a ‘possible’
causal relationship to antipsychotic therapy. Accordingly, other causes
(e. g., severe chronic somatic disorders) could also be responsible for
the occurrence of severe events. However, the assessment using WHO criteria is a
standardized process, which is also used in pharmacovigilance practice in the
EU. In some cases, more than one antipsychotic or other psychotropic drugs were
suspected of causing the sADR.
It is also not known whether TDM could have actually prevented sADRs. We do not
possess information on whether the reason for the sADR was an overdose or a drug
interaction. A further limitation is the lack of age- and indication-specific
therapeutic reference ranges.
Regarding the role of TDM in the prolongation of stays and cost-saving potential,
results have to be interpreted carefully. The duration of inpatient stay may
also have depended on other factors not recorded in this study (e. g.,
symptom aggravation irrespective of medication). Also, in some cases, TDM was
not the only fulfilled criterion of preventability. So, preventability by TDM
and, thus, the cost-saving potential of TDM may have been overestimated.
Moreover, the calculation of the cost savings was based only on rounded rough
estimates. However, the lowest estimated value for the special clinic’s
average base daily rate per patient was used. Nowadays, the daily rates are
already significantly higher. In addition, there are still the costs of TDM to
consider, which are, however, comparatively low.
Conclusion
sADRs in CAMD are frequent and a reason for concern. Many of those sADRs may be
potentially preventable through TDM. It is therefore recommended that TDM is
implemented in daily clinical practice for this particularly vulnerable group of
minors in order to increase medication safety while reducing healthcare costs.
Prospective studies are needed to confirm our results regarding the frequency and
type of sADRs as well as the benefits of TDM.