US-Style Off-Label Psychiatric Prescribing Is Spreading to Europe’s Children

Off-label prescription of psychiatric drugs in the United States began to take off in the 1990s.  Children and adolescents are disproportionately exposed to this practice despite a lack of evidence for its benefits and little information about the long term effects in underage populations. What is known is this: off-label prescribing exposes children to a number of harms, including increased risk of suicide, insomnia, tardive dysphoria, withdrawal, death, “brain atrophy,” diabetes, and metabolic, endocrine, and motor dysfunction.

This prescribing practice, largely pioneered in the US, has spread as a consequence of the globalization of psychiatric practices. While ethical and legal frameworks limited off-label prescribing in Europe, this risky practice is becoming more common, especially for children and adolescents. A recent study published in Child and Adolescent Psychiatry and Mental Health provides new evidence for this trend.

The current work finds that off-label prescriptions of antidepressants and antipsychotics for children and adolescents were common in Austria, Germany, and Switzerland. In total, 67% of all prescriptions for antidepressants and antipsychotics given to included service users were off-label. This research, led by Regina Taurines from the University Hospital of Wuerzburg, additionally finds that severity of symptoms was not associated with off-label prescriptions. The authors report:

“In this prospective naturalistic study, 66.9% of all documented psychotropic treatments (55.2% for antidepressants, 81.7% for antipsychotics) were ‘off-label’, i.e. only about one third of the drug treatment episodes in the studied child and adolescent psychiatric population were administered according to the approved indication, in the approved age group, or according to the licensed treatment duration in case of risperidone. “

The aim of this research was to investigate the frequency of off-label prescribing of antidepressants and antipsychostics for people under the age of 18 in Austria, Switzerland, and Germany. Additionally, the authors wanted to explore factors associated with off-label prescription of these drugs.

Methodology

The authors used data from the TDM-VIGIL study collected between October 2014 and December 2018. Service user data from 10 university hospitals, seven child and adolescent psychiatric state hospitals, and one private practice was stored in an online database. Child and adolescent psychiatrists coded diagnoses according to the ICD-10. Symptoms severity was measured using the Clinical Global Impression Scale for Severity. This inventory has clinicians rate symptom severity in the past week on a scale from 0 (“not accessed”) to 7 (“among the most extremely ill”). Off-label use was defined based on the summary of product characteristics in Germany.

The authors sorted off-label prescriptions into 4 categories:

• Off-label by age – age of service user was not within the age range for which the drug was licensed
• Off-label by indication – drug was not licensed to treat service user’s symptoms or diagnosis
• Off-label by treatment duration – treatment duration was longer than licensed short-term indication (this was specific to a 6 week indication for risperidone in the current study).
• Off-label by age and indication – drug was not approved for the age and symptoms/diagnosis of the service user

Results

In total, 700 adolescents and children were included in the current work. These participants experienced a total of 1,265 drug treatment episodes. They were followed for between 55 and 241 days. Follow up averaged 5.1 months. The majority of participants were girls (66.6%) and were treated as inpatients (77.4%).

Two thirds of drug treatment episodes (66.8%) were off-label. 55.2% of treatment episodes for antidepressants were off-label compared to 81.7% for antipsychotics. Off-label use by age was most common (39.5% of all off-label treatment episodes), followed by off-label use by indication (35.1%), and off-label use by both age and indication (25.3%). About 0.1% of off-label treatment episodes were due to exceeding the recommended treatment duration of risperodone.

Antidepressants

Off-label use of antidepressants was a bit higher in service users 12 years old and older (55.5%) than in those under 12 (50.0%). Off-label use by age was most common (51.1%) followed by indication (37.4%), and both age and indication (11.5%). The authors note that only 1.6% of off-label by age treatment episodes occurred in service users under the age of 12.

Fluoxetine, the most frequently prescribed antidepressant, was given off-label in 16.1% of fluoxetine treatment episodes. The second most commonly prescribed antidepressant, sertraline, was administered off-label in 66.2% of sertraline treatment episodes. Some antidepressants, including escitalopram and citalopram, are not approved for use in children and adolescents. This means 100% of treatment episodes involving these drugs were off-label. Mirtazapine and agomelatine were also both prescribed 100% off-label.

Diagnoses of depressive episodes and obsessive compulsive disorder were linked to reduced off-label use of antidepressants, as these drugs are licensed to treat these symptoms. Suicidality at admission and a high number of drug treatment episodes was linked to increased off-label prescriptions. Severity of symptoms, age, and sex was not associated with off-label prescriptions of antidepressants.

Antipsychotics

Off-label use of antipsychotics was nearly equal between those 12 years old and older (81.6%) and those under 12 (83.3%). Off-label use by age and indication (30.6% of off-label treatment episodes) was most common, followed by indication alone (27.1%), and age alone 24.1%). 7.3% of off-label treatment episodes with antipsychotics involved service users under the age of 12.

Second generation antipsychotics (SGA) were more frequently prescribed off label (92% of all SGA prescriptions) compared to typical antipsychotics (36.9%). SGAs quetiapine and olanzapine are not licensed for use on minors in Germany, which means they were prescribed 100% off-label.

As antipsychotics are licensed to treat psychosis, schizophrenia spectrum disorder diagnoses were linked to reduced off-label antipsychotic prescriptions. Receiving treatment in a university hospital was associated with an increased likelihood of off-label antipsychotic prescription. Similar to antidepressants, severity of symptoms, age, and sex was not associated with off-label prescriptions of antipsychotics.

Limitations

The authors acknowledge several limitations to the current work. As many of the participants received specialized treatment at university hospitals and inpatient settings, generalizability to populations receiving less specialized treatment, or treatment in other settings, is limited. Doseage was not considered as a factor in the current work. German indications were used to determine off-label treatment in Switzerland where indication may be different. The study was not designed to investigate safety of efficacy of off-label versus on-label prescriptions. Additionally, these findings came exclusively from three German-speaking countries, limiting generalizability to other child and adolescent populations.

Off-Label Prescribing and Industry Influence

Off-label prescribing is largely driven by corrupt industry practices. While off-label marketing is mostly illegal in the United States, the pharmaceutical industry has slithered around these regulations using “key opinion leaders.” This practice involves targeting corruptible researchers and academics, then paying them to promote off-label uses of industry products. These “key opinion leaders” can then conduct biased continuing medical education seminars, contribute industry propaganda to textbooks, and publish research ghost written by industry agents to legally promote off-label prescription of psychiatric drugs.

One prominent example of this type of corruption was Joseph Biederman, a Harvard professor of psychiatry that collected $1.6 million of undisclosed payments from the pharmaceutical industry. His research created the pediatric bipolar diagnosis and opened up a new market for industry products, exposing children to harmful drugs in the process. These kinds of tactics are now being employed to open up new markets for pharmaceutical industry products all over the world.

While the authors of the current work argue that off-label prescribing in European children may be the result of too few incentives for companies to test drugs for use in pediatric populations, framing this practice as one that sells industry products without having to prove safety or efficacy may be more accurate.

****

Taurines, R., Gerlach, M., Correll, C. Et al. (2025). Off-label drug use in children and adolescents treated with antidepressants and antipsychotics: Results from a prospective Multicenter Trial. Child and Adolescent Psychiatry and Mental Health, 19(1). (Link)