Psychotropic Drug Prescription in Children and Adolescents: Approved Medications in European Countries and the United States

Abstract

Objectives:

The decision to prescribe a medication and the choice of which one are often complex, particularly in the field of child and adolescent psychiatry where evidence is scarce. The aim of this review is to provide a synthesis of psychotropic drugs approved in children and adolescents for psychiatric indications in several countries.

Methods:

All psychopharmacological treatments used in child and adolescent psychiatry, approved by at least one regulatory agency from Switzerland, the United Kingdom, France, the European Union, or the United States, were considered. A comprehensive review of the summaries of product characteristics was performed.

Results:

A total of 143 psychotropic drugs were included: 47 anxiolytics/hypnotics, 45 antidepressants, 37 antipsychotics, 10 medications for attention-deficit/hyperactivity disorder (ADHD), and 4 mood stabilizers. Only a few of these drugs were approved for use in children or adolescents (38%) at least for a single psychiatric diagnosis in at least one country. The therapeutic class with the lowest rate of approved status was antidepressants (20%), followed by mood stabilizers (25%), anxiolytics/hypnotics (28%), antipsychotics (57%), and medications for ADHD (100%). Important differences in approved diagnoses, ages, and doses were observed between regulatory agencies. Tables presenting drugs for approved diagnoses based on age and regulatory agencies are presented in this article. Drugs classified by regulatory agencies, with complete data on diagnoses, ages, doses, pharmaceutical forms, and particular restrictions, are presented as Supplementary Material.

Conclusion:

This article provides an overview to prescribers with respect to the approved medications in children and adolescents in selected European countries and the United States.

Introduction

Prescription of psychotropic drugs in children and adolescents has increased globally in previous decades. This increase can be attributed to better accessibility of services, lower thresholds for diagnosis and treatment, availability of new-generation medications, such as selective serotonin reuptake inhibitors and atypical antipsychotics, and pharmaceutical marketing (Thomas et al. 2006; Olfson et al. 2012; Meng et al. 2014; Halfdanarson et al. 2017; Kaguelidou et al. 2020).

Randomized-controlled clinical trials are required to demonstrate the efficacy and safety of drugs before marketing authorization. On the basis of the conditions formally evaluated by the manufacturer, the regulatory authorities specify the therapeutic indications and the populations for which the drug is approved. These conditions are described in the summary of product characteristics (SmPC), also known as prescription drug labeling, written principally for health care professionals (Lal and Kremzner 2007).

Children and adolescents are generally not included in clinical trials during drug development. Consequently, relatively few medicines are approved in this population and considerable off-label prescription is used in clinical practice (Czaja and Valuck 2012). Off-label prescription, the use of a pharmaceutical drug outside the conditions specified in the product license, such as therapeutic indication, age, dose, pharmaceutical form, and/or mode of administration (Haw and Stubbs 2007), is legal in many countries, contrary to public opinion, but the prescriber must carefully assess the risk/benefit. The patient should be told the prescription is off-label and the information given meticulously documented.

Due to the absence of examination by the regulatory authorities, off-label use is associated with potentially increased risk of toxicity and fewer established benefits. Furthermore, the costs to the health care system could be increased. Nevertheless, off-label prescription is sometimes the best solution and could provide a pathway for innovation in clinical practice (Radley et al. 2006). More approved indications are generally present with the old drugs compared with the new ones, due to less restrictive criteria some decades ago, and due to the time-lag in approving new agents.

In Switzerland, marketing authorizations of medicines are the responsibility of the Swiss Agency for Therapeutic Products, called Swissmedic (SM) (Swissmedic 2020). In the European Union, the European Medicines Agency (EMA) is responsible for the centralized authorization procedure, which results in a single marketing authorization that is valid in all EU countries. This procedure is compulsory for most innovative medicines, including medicines for rare diseases. The majority of medicines authorized in the European Union, however, do not fall within the scope of the centralized procedure but are authorized by competent national authorities in the Member States.

A marketing authorization can also be obtained simultaneously in several EU countries via the decentralized procedure for drugs that have not yet been authorized in any EU country or via the mutual-recognition procedure for drugs that are already authorized in one EU Member State (EMA 2016). In the United Kingdom, authorization is made by the Medicines and Healthcare Products Regulatory Agency (MHRA) (MHRA 2020), and in France by the National Agency for the Safety of Medicines and Health Products (ANSM) (ANSM 2020). In the United States, the Food and Drug Administration (FDA) gives drug approval (FDA 2020).

In the last decade, several articles have published brief tables of psychotropic drugs approved for children and adolescents, limited to antidepressants (Deng et al. 2018), antipsychotics (Caccia et al. 2011; Lee et al. 2018; Mathy and Malchair 2018; Zhu et al. 2018), or some classes of psychotropic drugs (Denizot et al. 2009; Kearns and Hawley 2014; Brauner et al. 2016; Nielsen et al. 2016; Putignano et al. 2019) in different countries: France (Denizot et al. 2009), Italy (Putignano et al. 2019), Denmark (Brauner et al. 2016; Nielsen et al. 2016), Belgium (Mathy and Malchair 2018), the United Kingdom (Caccia et al. 2011; Putignano et al. 2019), the United States (Kearns and Hawley 2014; Deng et al. 2018; Lee et al. 2018; Zhu et al. 2018; Putignano et al. 2019), and China (Deng et al. 2018; Zhu et al. 2018). Furthermore, most of these publications are out of date.

In a recent publication, we reported approved indications for all psychotropic drugs in patients younger than 18 years, but only in Switzerland and without dosing information (Ansermot et al. 2018). To the best of our knowledge, the present publication is the first that reports a comprehensive review of all psychotropic drugs approved in children and adolescents for psychiatric indications in several countries: Switzerland, the European Union, the United Kingdom, France, and the United States. Its aim is to provide an overview to prescribers with respect to the approved medications. This provides, equally and indirectly, knowledge concerning off-label prescription.

Method

Data sources and search strategy

Five therapeutic classes of drugs commonly prescribed in psychiatry in children and adolescents were considered: antidepressants, antipsychotics, anxiolytics/hypnotics, mood stabilizers, and medicines for attention-deficit/hyperactivity disorder (ADHD) (Ansermot et al. 2018). Based on the World Health Organization Collaborating Centre for Drug Statistics Methodology database (WHO 2020), which provides a complete list of internationally available medicines, all psychotropic drugs belonging to these classes were included.

A thorough screening for official SmPC was performed for all these medicines in five databases of drug monitoring agencies: SM for Switzerland (Swissmedic 2020), the EMA for the European Union (EMA 2020; European Commission 2020), the MHRA for the United Kingdom (MHRA 2020), the ANSM for France (ANSM 2020), and the FDA for the United States (FDA 2020). If no SmPC was available on the FDA website, while the status of the medicine was described as marketed, a complementary search was performed on the DailyMed website (DailyMed 2020).

When an SmPC for a drug was not found on one of these websites, meaning that no official evaluation has been performed in this country, the following information was noted in the results “not centrally authorized” for EMA and “not on the official site” for the other regulatory agencies. Medications without any SmPC available in any of the consulted databases were excluded from our research. When several SmPC were present on the same website for the same medicine, which was frequent for generic drugs, all monographs were read and taken into account because the information could vary between manufacturers. More than 1000 SmPC were reviewed in detail for this research. This work was not submitted to the institutional review board, because no patients were involved.

Data selection

All parts of each SmPC were screened for information regarding psychiatric indications for children and adolescents. Indications in somatic medicine, neurology, and anesthesiology, such as nocturnal enuresis for tricyclic antidepressants, epilepsy for mood stabilizers, or premedication for benzodiazepines, were not included in our search. Each approved diagnosis was noted, as well as age categories (or weight), initial doses of the medication, need for divided dosing, progression of dosing, target doses for best therapeutic effects, maximum authorized doses, different routes of administration and drug forms, particular restrictions (second intention or duration of treatment), and contraindications related to age of indication. The data were collected by an author (M.S. or A.O.) and verified independently by a second author (A.O. or N.A.).

Only the diagnoses formally approved for children and adolescents were considered indications, but not those only suggested for use in this population. For example, oral lorazepam use in Switzerland has only a contraindication <12 years, which could suggest an off-label use between 12 and 17 years. However, to be the most exhaustive possible, the suggested uses were pointed out. When the information available in the SmPC was not clear, the marketing authorization holders were contacted.

The original terms used in the official SmPC were reported to describe the indications for each medicine. When, for the same drug in the same database, indications or dosages were different depending on the manufacturers, the differing indications and/or dose ranges were noted and the mention “indications/dosages depending on the SmPC” was added. If a medication had no psychiatric indication in a particular database for either adults or children/adolescents, the note “no psychiatric indication” was written if the drug had a psychiatric indication in at least one other database; otherwise, the drug was excluded. If a drug had a psychiatric indication for adults but not for children/adolescents, the note “no psychiatric indication <18 years” was used if the drug had other indications (nonpsychiatric) for children/adolescents. A medication was considered contraindicated under a certain age (18 years or younger) if it was specified under the Contraindication section of the SmPC.

When a drug was not approved for children or adolescents, different notations were regularly observed in the SmPC to describe the status in this population, sometimes varying between different SmPC for the same drug on the same website or even inside the same SmPC. A subjective priority ranking was decided upon to assure reporting only the highest level term during data collection: “must not be used” > “only for adults” > “not indicated” > “not approved” > “should not be used” > “not recommended” > “not studied” > “not evaluated” > “not established” > “no data available.” If nothing was specified in the SmPC for children and adolescents, we noted “no information in the SmPC about <18 years.” As the article focuses only on psychiatric treatment of children and adolescents, a possible absence of indication for adults was not reported in our results.

Results

A total of 143 different psychotropic drugs or combinations were reviewed in detail for indications in children and adolescents in the official drug databases of 5 regulatory agencies (SM, EMA, MHRA, ANSM, and FDA): 45 antidepressants, 37 antipsychotics, 47 anxiolytics or hypnotics/sedatives, 4 mood stabilizers, and 10 medications for ADHD. Complete information on these drugs is provided in Supplementary Tables S1–S5.

Among these medicines, only 54 (38%) are approved for use in patients younger than 18 years for at least one diagnosis in at least one database: 9 (20%) antidepressants, 21 (57%) antipsychotics, 13 (28%) anxiolytics or hypnotics/sedatives, 1 (25%) mood stabilizer, and 10 (100%) medications for ADHD (Tables 1–5).

Table 1.

Antidepressants Approved in Children and Adolescents for Psychiatric Indications

Drug	Major depressive disorders	Obsessive-compulsive disorders	Other
Tricyclic antidepressants
Amitriptyline	≥16 years (MHRA)
Amitriptyline	<18 years (ANSM)
Clomipramine		≥10 years (SM, ANSM, FDA)
Nortriptyline	In adolescents (MHRA)
Selective serotonin reuptake inhibitors
Escitalopram	≥12 years (FDA)
Fluoxetine	≥8 years (MHRA, ANSM, FDA)	≥7 years (FDA)
Fluoxetine + olanzapine			Depressive episodes in bipolar I disorder≥10 years (FDA)
Fluvoxamine		≥8 years (SM, MHRA, ANSM, FDA)
Sertraline		≥6 years (SM, MHRA, ANSM, FDA)
Serotonin and norepinephrine reuptake inhibitor
Duloxetine			Generalized anxiety disorder ≥7 years (FDA)

For detailed information, including doses (Supplementary Table S1). If the formulation is not specified in the table, the indications correspond to an oral form only.

ANSM, National Agency for the Safety of Medicines and Health Products; FDA, Food and Drug Administration; MHRA, Medicines and Healthcare Products Regulatory Agency; SM, Swissmedic.

Table 2.

Antipsychotics Approved in Children and Adolescents for Psychiatric Indications

Drug	Schizophrenia and/or psychotic disorders	Manic and/or mixed episodes in bipolar disorders	Agitation and/or behavioral problems including in autism and intellectual disability	Other
Typical antipsychotics
Chlorpromazine	≥1 year oral/inj (MHRA)		≥1 year oral/inj (MHRA^a)≥3 years (ANSM)≥6 months oral/inj (FDA)
Cyamemazine			≥3 years (ANSM)
Haloperidol	≥13 years (SM, MHRA, ANSM)≥3 years (FDA)		≥6 years (SM^a, MHRA^a, ANSM^a)≥3 years (FDA)	Tics ≥10 years (SM, MHRA, ANSM), ≥3 years (FDA)
Levomepromazine			<18 years (MHRA)≥3 years (ANSM)
Loxapine	≥15 years (ANSM)		≥15 years inj (ANSM)
Pimozide	≥12 years (MHRA)		≥6 years (ANSM^a)	Tics ≥6 years (ANSM), ≥12 years (FDA)
Pipamperone			≥5 years (ANSM)
Prochlorperazine	≥2 years oral/inj (FDA)
Promazine	≥12 years (SM)
Sulpiride			≥6 years (ANSM^a)
Thioridazine	<18 years (FDA)
Tiapride				Tics ≥7 years (SM), ≥6 years (ANSM)
Trifluoperazine	≥6 years (MHRA, FDA)		≥3 years (MHRA)
Zuclopenthixol			In children depot (ANSM)
Atypical antipsychotics
Aripiprazole	≥13 years (SM, FDA)≥15 years (EMA, MHRA, ANSM)	≥13 years (SM, EMA, MHRA, ANSM)≥10 years (FDA)	≥6 years (FDA^a)	Tourette disorder ≥6 years (FDA)
Asenapine		≥10 years (FDA)
Lurasidone	≥13 years (EMA, FDA)			Depressive episodes in bipolar I disorder ≥10 years (FDA)
Olanzapine	≥13 years (FDA)	≥13 years (FDA)
Paliperidone	≥15 years (EMA)≥12 years (FDA)
Quetiapine	≥13 years (SM, FDA)	≥10 years (SM, FDA)
Risperidone	≥13 years (FDA)	≥15 years (SM)≥ 10 years (FDA)	≥5 years (SM,^a MHRA,^a ANSM,^a FDA^a)

For detailed information, including doses (Supplementary Table S2). If the formulation is not specified in the table, the indications correspond to an oral form only.

These drugs are approved in autism and/or intellectual disability, but are not necessarily all exclusive to this type of population.

ANSM, National Agency for the Safety of Medicines and Health Products; depot, long-acting injection; EMA, European Medicines Agency; FDA, Food and Drug Administration; MHRA, Medicines and Healthcare Products Regulatory Agency; inj, short-acting injection; SM, Swissmedic.

Table 3.

Anxiolytics and Hypnotics/Sedatives Approved in Children and Adolescents for Psychiatric Indications

Drug	Anxiety	Sleep disorders and/or insomnia	Other
Benzodiazepine anxiolytics
Bromazepam	<18 years (SM)
Chlordiazepoxide	≥6 years (FDA)
Clobazam	≥3 years (SM)
Clorazepate	≥9 years (SM)≥6 years (ANSM)		Alcohol withdrawal ≥6 years (ANSM)
Diazepam	≥6 months oral/inj (SM)≥1 year rectal (MHRA)≥6 years (ANSM)≥6 months (FDA)		Agitation ≥6 months oral/inj (SM), ≥1 year rectal (MHRA)Alcohol withdrawal ≥6 months oral/inj (SM), ≥6 years (ANSM), ≥6 months (FDA)Night terrors/somnambulism <18 years (MHRA)
Prazepam	≥3 years (SM)≥12 years (ANSM)		Agitation ≥3 years (SM)
Other anxiolytics
Hydroxyzine	<18 years (FDA)	≥3 years (ANSM)
Meprobamate	≥6 years (FDA)
Other hypnotics/sedatives
Chloral hydrate		<18 years (SM)	Excitation <18 years (SM)
Chloral hydrate		≥2 years (MHRA)	Excitation <18 years (SM)
Diphenhydramine		≥2 years (SM)
Diphenhydramine		≥16 years (MHRA)
Doxylamine		≥12 years (SM, FDA)
Melatonin		In autism spectrum disorders or Smith-Magenis syndrome ≥2 years (SM, EMA)In ADHD ≥6 years (MHRA)
Pentobarbital		<18 years inj (FDA)

For detailed information, including doses (Supplementary Table S3). If the formulation is not specified in the table, the indications correspond to an oral form only.

ADHD, attention-deficit/hyperactivity disorder; ANSM, National Agency for the Safety of Medicines and Health Products; EMA, European Medicines Agency; FDA, Food and Drug Administration; inj, short-acting injection; MHRA, Medicines and Healthcare Products Regulatory Agency; SM, Swissmedic.

Table 4.

Mood Stabilizers Approved in Children and Adolescents for Psychiatric Indications

Drug	Acute phase and prophylaxis of bipolar disorders	Combination with antidepressants for resistant depression	Severe chronic aggressiveness
Lithium	≥12 years (SM)	≥12 years (SM)	≥12 years (SM)
Lithium	≥7 years (FDA)	≥12 years (SM)	≥12 years (SM)

For detailed information, including doses (Supplementary Table S4). If the formulation is not specified in the table, the indications correspond to an oral form only.

FDA, Food and Drug Administration; SM, Swissmedic.

Table 5.

Medications for Attention-Deficit/Hyperactivity Disorder Approved in Children and Adolescents for Psychiatric Indications

Drug	ADHD	Refractory hyperkinetic states
Nonamphetamine psychostimulants
Dexmethylphenidate	≥6 years (SM, FDA)
Methylphenidate	≥6 years (SM, MHRA, ANSM)
Methylphenidate	≥6 years oral/transdermal (FDA)
Amphetamine psychostimulants
Amphetamine	≥6 years (FDA)
Amphetamine mixed salts + dextroamphetamine mixed salts	≥6 years (FDA)
Dexamphetamine	≥6 years (MHRA)	≥3 years (MHRA)
Lisdexamfetamine	≥6 years (SM, MHRA, FDA)
Methamphetamine	≥6 years (FDA)
Nonpsychostimulants
Atomoxetine	≥6 years (SM, MHRA, FDA)
Clonidine	≥6 years (FDA)
Guanfacine	≥6 years (SM, EMA, FDA)

For detailed information, including doses (Supplementary Table S5). If the formulation is not specified in the table, the indications correspond to an oral form only.

ADHD, attention-deficit/hyperactivity disorder; ANSM, National Agency for the Safety of Medicines and Health Products; EMA, European Medicines Agency; FDA, Food and Drug Administration; MHRA, Medicines and Healthcare Products Regulatory Agency; SM, Swissmedic.

For the treatment of major depressive disorders, four antidepressants are approved: amitriptyline (MHRA ≥16 years, ANSM <18 years), nortriptyline (MHRA in adolescents), escitalopram (FDA ≥12 years), and fluoxetine (MHRA, ANSM, and FDA ≥8 years) (Table 1). Lithium is approved in combination with antidepressants for resistant depression (SM ≥12 years) (Table 4).

For obsessive-compulsive disorders, four antidepressants are indicated: clomipramine (SM, ANSM, and FDA ≥10 years), fluoxetine (FDA ≥7 years), fluvoxamine (SM, MHRA, ANSM, and FDA ≥8 years), and sertraline (SM, MHRA, ANSM, and FDA ≥6 years) (Table 1).

Fourteen antipsychotics are indicated for schizophrenia and/or psychotic disorders: chlorpromazine (MHRA ≥1 year), haloperidol (SM, MHRA, and ANSM ≥13 years, FDA ≥3 years), loxapine (ANSM ≥15 years), pimozide (MHRA ≥12 years), prochlorperazine (FDA ≥2 years), promazine (SM ≥12 years), thioridazine (FDA <18 years), trifluoperazine (MHRA and FDA ≥6 years), aripiprazole (SM and FDA ≥13 years, EMA, MHRA, and ANSM ≥15 years), lurasidone (EMA and FDA ≥13 years), olanzapine (FDA ≥13 years), paliperidone (EMA ≥15 years, FDA ≥12 years), quetiapine (SM and FDA ≥13 years), and risperidone (FDA ≥13 years) (Table 2).

For the treatment of manic and/or mixed episodes in bipolar disorders, five antipsychotics are approved: aripiprazole (SM, EMA, MHRA, and ANSM ≥13 years, FDA ≥10 years), asenapine (FDA ≥10 years), olanzapine (FDA ≥13 years), quetiapine (SM and FDA ≥10 years), and risperidone (SM ≥15 years, FDA ≥10 years) (Table 2). Among the mood stabilizers, only lithium is approved for the acute phase and maintenance in bipolar disorders (SM ≥12 years, FDA ≥7 years) (Table 4). For the treatment of depressive episodes in bipolar I disorder, the fluoxetine/olanzapine combination (FDA ≥10 years) and lurasidone (FDA ≥10 years) are approved (Tables 1 and 2).

Eight antipsychotics have an indication for agitation or behavioral problems not specified or associated with psychotic disorders: chlorpromazine (ANSM ≥3 years, FDA ≥6 months), cyamemazine (ANSM ≥3 years), haloperidol (FDA ≥3 years), levomepromazine (MHRA <18 years, ANSM ≥3 years), loxapine (ANSM ≥15 years), pipamperone (ANSM ≥5 years), trifluoperazine (MHRA ≥3 years), and zuclopenthixol (ANSM in children) (Table 2).

Six antipsychotics also have a more precise indication for behavioral problems in autism or intellectual disability, but are not necessarily all exclusive to this type of population: chlorpromazine (MHRA ≥1 year), haloperidol (SM, MHRA, and ANSM ≥6 years), pimozide (ANSM ≥6 years), sulpiride (ANSM ≥6 years), aripiprazole (FDA ≥6 years), and risperidone (SM, MHRA, ANSM, and FDA ≥5 years). Some benzodiazepines also have an indication for agitation: diazepam (SM ≥6 months, MHRA ≥1 year) and prazepam (SM ≥3 years) (Table 3). Lithium is also approved for the treatment of severe chronic aggressiveness (SM ≥12 years) (Table 4).

Eight drugs are indicated for treating anxiety: bromazepam (SM <18 years), chlordiazepoxide (FDA ≥6 years), clobazam (SM ≥3 years), clorazepate (SM ≥9 years, ANSM ≥6 years), diazepam (SM and FDA ≥6 months, MHRA ≥1 year, ANSM ≥6 years), prazepam (SM ≥3 years, ANSM ≥12 years), hydroxyzine (FDA <18 years), and meprobamate (FDA ≥6 years) (Table 3). Among the antidepressants, only duloxetine (FDA ≥7 years) is approved for generalized anxiety disorder (Table 1).

For the treatment of sleep disorders and insomnia, five drugs are approved: hydroxyzine (ANSM ≥3 years), diphenhydramine (SM ≥2 years and MHRA ≥16 years), doxylamine (SM and FDA ≥12 years), chloral hydrate (SM <18 years, MHRA ≥2 years), and pentobarbital (FDA <18 years) (Table 3). Melatonin is approved specifically in children and adolescents for insomnia in autism spectrum disorders or the Smith-Magenis syndrome (SM and EMA ≥2 years) and for insomnia in ADHD (MHRA ≥6 years). The only indicated medicine for the treatment of night terrors and somnambulism is diazepam (MHRA <18 years).

To treat tics or Tourette disorder, four antipsychotics are approved: haloperidol (SM, MHRA, and ANSM ≥10 years, FDA ≥3 years), pimozide (ANSM ≥6 years, FDA ≥12 years), tiapride (SM ≥7 years, ANSM ≥6 years), and aripiprazole (FDA ≥6 years) (Table 2).

The drugs indicated for the treatment of ADHD are dexmethylphenidate (SM and FDA ≥6 years), methylphenidate (SM, MHRA, ANSM, and FDA ≥6 years), amphetamine (FDA ≥6 years), dexamphetamine (MHRA ≥6 years), lisdexamfetamine (SM, MHRA, and FDA ≥6 years), methamphetamine (FDA ≥6 years), a combination of amphetamine mixed salts with dextroamphetamine mixed salts (FDA ≥6 years), atomoxetine (SM, MHRA, and FDA ≥6 years), clonidine (FDA ≥6 years), and guanfacine (SM, EMA, and FDA ≥6 years) (Table 5).

Discussion

In the present work, all psychotropic drugs from the main therapeutic classes registered in at least one database of the five regulatory agencies in Europe and the United States were reviewed in detail for psychiatric indications in children and adolescents. Our results show that only 33% of the available medicines are officially approved in children (6 months to 11 years) for at least one psychiatric indication in at least one country and this slightly increases to 38% in adolescents (12–17 years).

The decision to prescribe a drug and the choice of drug are often complex; the risk/benefit should be carefully evaluated, particularly in children and adolescents. This article seeks to provide an overview to prescribers with respect to the approved medications. More than 20 diagnoses commonly observed in children and adolescents have at least one medicine approved by at least one regulatory agency. The choice of a psychopharmacological treatment should preferably fall among drugs that already have an indication for children or adolescents in the prescriber's country. When no drugs are approved for a particular diagnosis in the prescriber's country, authorization in another country could represent an indication to prescribe it.

Nevertheless, some approved drugs may no longer be recommended for best clinical practice, particularly the medications used for several decades. Thus, the choice of the drug should also be based primarily on the most recent national or international treatment guidelines or expert opinions. Many treatment guidelines are regularly published and updated; they are not presented and discussed here, as it is outside the scope of this article. However, to illustrate the problematic gap between the official indications and current treatment guidelines, the pharmacological treatment of major depressive disorders is discussed.

In Switzerland, for example, no antidepressant is approved for the treatment of major depressive disorders. If an antidepressant is required for a patient, the prescriber should choose a medication that is approved in another country, such as fluoxetine (MHRA, ANSM, and FDA ≥8 years) or escitalopram (FDA ≥12 years). The National Institute for Health and Care Excellence (NICE) guideline recommends using fluoxetine as the first-line pharmacological treatment of depression in children and adolescents, and to use sertraline or citalopram as second line (NICE 2019). Sertraline and citalopram are approved for the treatment of depression in adults, but not in children and adolescents. Sertraline is approved for the treatment of obsessive-compulsive disorders in children ≥6 years (SM, MHRA, ANSM, and FDA), which is not the case for citalopram.

In the meta-analysis of Cochrane, there was a statistically significant reduction in depressive symptoms with fluoxetine, escitalopram, and sertraline, compared with placebo, but a statistically significant increase in the remission rate was observed only with fluoxetine (Hetrick et al. 2012). In the meta-analysis of Cipriani et al. (2016) fluoxetine, escitalopram, and sertraline were statistically more effective than placebo in the pairwise analyses, but in the network analyses, only fluoxetine was statistically significantly more effective. Despite some tricyclic antidepressants still being approved by some authorities in children and adolescents for historical reasons, they should no longer be used for the treatment of depression in this population (NICE 2019), because they have not been shown to be effective and are less tolerated than selective serotonin reuptake inhibitors (Weller and Weller 2000; Hazell and Mirzaie 2013).

The therapeutic class with the lowest rate of approved status in child and adolescent psychiatry is antidepressants (20%), which are mainly indicated for a major depressive disorder (only 9%) and obsessive-compulsive disorders (only 9%). This low rate is probably due to the increased risk of suicide-related behavior (suicidal thoughts and suicide attempt) and hostility (predominantly aggression, oppositional behavior, and anger) observed in clinical studies in young patients (Hammad et al. 2006; Hetrick et al. 2012; Cipriani et al. 2016). A black box warning about the emergence of suicidal behavior has been included in the drug labeling of all antidepressants since 2004. This warning has to be taken into account and informed about, particularly when an off-label antidepressant is prescribed.

Only 28% of the anxiolytics/hypnotics have an indication for children and adolescents, mainly anxiety (17%) or sleep disorders (13%), but also agitation or excitation for some of them (6%). Among the mood stabilizers, only lithium is authorized in child and adolescent psychiatry. Antipsychotics have a higher level of approval (57%) and are mainly indicated for schizophrenia or psychotic disorders (38%), followed by agitation or behavioral problems not specified or present in psychotic disorders, autism or intellectual disability (32%), manic or mixed episodes in bipolar disorders (14%), and tics (11%). The highest approval rate is for medications for ADHD (100%), a pathology that typically starts during childhood.

The low proportion of approved medications in children and adolescents, linked to the limited number of clinical trials conducted during drug development, occurs for multiple reasons: (1) ethical and legal considerations concerning protection of vulnerable populations; (2) difficulties in obtaining informed consent for underage patients; (3) developmental concerns; (4) necessity of considering each age category separately (neonates, infants, children, and adolescents); (5) blood sampling or other painful medical examinations during clinical trials; (6) difficulties in developing formulations appropriate for children; (7) small sample sizes compared with the adult population; (8) expense; and (9) low financial incentives for the pharmaceutical companies due to low numbers of potentially treated patients (Cuzzolin et al. 2003; Czaja and Valuck 2012; Tanemura et al. 2019).

Different regulations have been introduced by the authorities to provide incentives for the manufacturers to initiate new clinical trials in children and adolescents, such as the FDA Modernization Act, the Best Pharmaceuticals for Children Act, and The Pediatric Research Equity Act in the United States (Bourgeois and Hwang 2017), or the Paediatric Investigation Plan in the European Union (EMA 2021).

The lack of authorization for children and adolescents does not necessarily mean that the medication is inappropriate or that there is a lack of evidence. It only means that the evidence of efficacy and safety necessary for inclusion in the label has not been submitted or approved by the regulatory authorities. There may be data from nonrandomized-controlled clinical trials supporting possible effectiveness, or the manufacturer may choose not to apply for new labeling despite sufficient evidence (Cuzzolin et al. 2003; Czaja and Valuck 2012; Putignano et al. 2019). In the United States, the law allows some unapproved drugs to be marketed if they meet the criteria of generally being recognized as safe and effective or grandfathered (FDA 2021).

The regulatory agency with the highest number of psychotropic drugs with at least one SmPC available in its database (with or without indications in patients <18 years) is the FDA (n = 103), followed by SM (n = 84), MHRA (n = 77), ANSM (n = 75), and EMA (n = 21). The low number of SmPC available for EMA is explained by the fact that only a few psychotropic drugs have been approved via the centralized procedure, which was not possible before 1995 (EMA 2016). When only psychiatric indications in patients younger than 18 years are considered, the regulatory agency that approved the most drugs and diagnoses, respectively, is the FDA (n = 36 and 50), followed by SM (n = 24 and 36), ANSM (n = 22 and 29), MHRA (n = 20 and 32), and EMA (n = 5 and 6).

Important differences in the official drug monographs among the various drug agencies are also observed concerning the type of approved diagnoses, ages, and doses.

The minimum age authorized for use of these drugs varies based on the pathology being treated, for example: 3–6 years for severe behavioral problems (even 6 months for chlorpromazine), 3–12 years for anxiety (even 6 months for diazepam), 2–16 years for sleep disorders, 6 years for ADHD treatments, 6–10 years for obsessive-compulsive disorders, 6–12 years for tics, 7–12 years for lithium treatment, 8–16 years for major depressive disorders, 10–15 years for manic episodes in bipolar disorders, and 12–15 years for schizophrenia (even less for some old antipsychotics).

Very low ages are approved for some drugs used for several decades, chlorpromazine for schizophrenia (MHRA ≥1 year), for example, which is not the case with newer drugs. Prescribers should be cautious about using these old drugs in young children, as the approval criteria might have been less restrictive in the past. For some other old drugs, the approved ages are not clear, for example, thioridazine for schizophrenia (FDA <18 years) or nortriptyline for major depressive disorder (MHRA in adolescents).

The low rate of psychotropic medications approved in underage patients observed in our review, especially for certain therapeutic classes, is in line with the high rate of off-label prescriptions observed in this population. In adolescents hospitalized in a Swiss psychiatric university hospital, the prevalence of off-label psychotropic drug prescriptions was 68% in 2014 (Ansermot et al. 2018). In Germany, using claims data, the annual share of off-label prescription in 2011 was 36% for antidepressants (Schroder et al. 2017a) and 62% for antipsychotics (Schroder et al. 2017b). Antipsychotics were mainly prescribed to manage aggressive and impulsive behaviors, which raises concerns, since the efficacy and safety of these drugs have not been sufficiently investigated in these indications (Schroder et al. 2017b).

In a cross-sectional study in Denmark, 32% of psychopharmacological prescriptions were off-label in a child and adolescent psychiatric setting in 2014 (Brauner et al. 2016). In the United States, a cross-sectional study in ambulatory care settings found that 91% of antidepressants prescribed for children and adolescents were off-label from 2000 to 2006 (Lee et al. 2012). A systematic review of prescription trends showed that between 36% and 93% of antipsychotics were prescribed off-label in children and adolescents (Carton et al. 2015). These high rates of off-label prescription use highlight the need for additional clinical studies in children and adolescents to evaluate the safety and clinical efficacy of these drugs.

An important part of this work was to carefully standardize the information that is often presented differently among SmPC, particularly for old drugs, without modifying its accuracy. Differences among SmPC from different manufacturers for the same drug in the same database were also observed. In addition, some discrepancies between different parts of a single SmPC were also observed for some drugs. For example, some tricyclic antidepressants were not approved for patients younger than 18 years in the FDA labels, but were suggested for use for adolescents under the Dosage and Administration section. When the approved indications, ages, or dosages were not clear, the marketing authorization holders were contacted to obtain more precise information. However, in most cases, the manufacturers referred only to the SmPC without additional information.

Limitations

The first limitation of this work is that the SmPC from only five regulatory agencies were reviewed, namely, those of Switzerland, France, the United Kingdom, the European Union, and the United States. Prescribers from other countries should first consider drugs and official information approved in their own country. However, when no drug is indicated for a particular diagnosis, or when the approved drugs are not suitable for a particular patient, the present article can help prescribers choose a drug based on the approval status in other countries. The second limitation is that the recommendations certified by national and international drug monitoring authorities are regularly evolving; new studies could be performed with new data on efficacy or toxicity, which could change the approved diagnoses, ages, or doses. New drugs with potential indications in children and adolescents will also probably be marketed in the future.

The third limitation is that despite every effort being made to ensure the accuracy of this information, an error, inaccuracy, or misinterpretation of the official data cannot be totally excluded, particularly for some drugs where the approved diagnoses, ages, or doses were not clearly formulated in the SmPC. The authors decline any responsibility for use of the information provided in this article. Prescribers must always refer to current information on official websites.

Conclusion

Our review shows that only a few psychotropic medications are officially approved for use in children or adolescents for a psychiatric indication, particularly for some therapeutic classes such as antidepressants, which is in line with the high rate of off-label prescriptions observed in this population. Significant differences are observed among the various regulatory agencies concerning approved diagnoses, ages, and doses. These results highlight the need for additional clinical studies in children and adolescents to evaluate the safety and efficacy of these drugs.

Clinical Significance

This article provides an overview for prescribers with respect to the approved psychotropic medications in children and adolescents for psychiatric indications in several countries. The choice of a psychopharmacological treatment should preferably fall among medications that already have an indication for children or adolescents in the prescriber's country. When no drugs are approved for a particular diagnosis, the present article can help prescribers choose a drug based on the approval status in other countries. However, the approved drugs are not necessarily the best treatments, particularly those used for several decades. The most recent clinical practice guidelines should be considered before a drug is prescribed.

Footnotes

Disclosures

M.S., A.O., K.J.P., C.B.E., and N.A. declare no conflicts of interest regarding the publication of this article. C.B.E. received honoraria for conferences or teaching CME courses from Janssen-Cilag, Lundbeck, Otsuka, Sandoz, Servier, Sunovion, Vifor-Pharma, and Zeller in the past 3 years.

Supplementary Material

Supplementary Table S1

Supplementary Table S2

Supplementary Table S3

Supplementary Table S4

Supplementary Table S5

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