# Antipsychotic off-label use in the 21st century: An enduring public health concern

Helene Verdoux

<figure><img src="image_1.png" /></figure>

## To cite this version:

Helene Verdoux. Antipsychotic off-label use in the 21st century: An enduring public health concern. Dialogues in Clinical Neuroscience, 2025, 27 (1), pp.1-12. 10.1080/19585969.2025.2449833. hal-04945343

HAL Id: hal-04945343

https://hal.science/hal-04945343v1

Submitted on 13 Feb 2025

HAL is a multi-disciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

<figure><img src="image_2.png" /></figure>
<figure><img src="image_3.png" /></figure>

REVIEW ARTICLE

<figure><img src="image_4.png" /></figure>

OPEN ACCESS

<figure><img src="image_5.png" /></figure>

Check for updates

# Antipsychotic off-label use in the 21st century: An enduring public health concern

Hélène Verdoux

<figure><img src="image_6.png" /></figure>

University Bordeaux, Inserm, Bordeaux Population Health Research Center, Team Pharmacoepidemiology, UMR 1219, Bordeaux, France

**ABSTRACT**

Soon after the introduction of second-generation antipsychotics, antipsychotic off-label use (OLU) progressively became a common prescribing practice. This evolving practice should be regularly monitored considering the growing number of persons exposed to the adverse effects of antipsychotics. The aim of the present review was to synthesise the literature published over the last 15 years on antipsychotic OLU for mental health symptoms. Observational studies confirm the persisting high rate of antipsychotic OLU prescription in two out of three youths and 30-60% of adults using antipsychotics. Increasing rates of low-dose quetiapine prescriptions for anxiety or sleep symptoms are paradigmatic of the current public health concern regarding antipsychotic OLU. Such prescriptions receive impetus from industry-funded marketing strategies and prescribers' feeling of innocuousness, with a resulting underestimation of the risk of adverse drug reactions (ADR). However, antipsychotic OLU should be neither trivialised nor demonised since it may be the only therapeutic option in persons with resistant psychiatric disorders or serious ADR with labelled drugs. To reduce the populational impact of antipsychotic OLU, it is necessary to better control the influence of the pharmaceutical industry regarding newly marketed drugs and to better inform prescribers and users about the risks associated with OLU prescribing.

**ARTICLE HISTORY**

Received 10 September 2024

Revised 4 November 2024

Accepted 1 January 2025

**KEYWORDS**

Antipsychotic; off-label use; metabolic; marketing

## Introduction

Since the introduction of second-generation antipsychotics (SGA), the growing proportion of persons exposed to antipsychotics has become an acknowledged public health concern (Verdoux et al. 2010; Hálfdánarson et al. 2017). This is mostly due to increased rates of prescribing antipsychotic off-label use (OLU) in youths (Patten et al. 2012; Olfson et al. 2015; Verdoux et al. 2015; Radojčić et al. 2023) and in adults (McKean and Monasterio 2012; Carton et al. 2015; Højlund et al. 2019). A major issue raised by this prescribing practice is the exposure of persons with unapproved indications to the risks of adverse outcomes (Galling et al. 2016; De Hert and Detraux 2018; Verdoux 2018; Ray et al. 2019; Højlund et al. 2021b; Hoekstra and Dietrich 2022; Stogios et al. 2022; Højlund et al. 2023).

OLU encompasses a wide range of situations with respect to OLU criteria (age, diagnosis or contraindications)

as well as to the level of evidence concerning the prescribing practices of old drugs, which are documented by a large body of literature, and the OLU of new drugs, which is documented by only a few small open studies (Martin-Latry et al. 2007; Schröder et al. 2017; Wang et al. 2021; Grabitz et al. 2024). Furthermore, the licenced indications of drugs are rather dependent not only on their pharmacological properties but also on the commercial strategies of pharmaceutical companies. On the one hand, the costs of pre-marketing trials offer little incentive to apply for new marketing authorisations for old drugs, as explained by many between-country variations of approved indications (Zhu et al. 2018). On the other hand, promoting the OLU of newly marketed drugs obviously contributes to enlarging the size of the treated population (Tanne 2010; Roehr 2012; Tanne 2012; Wang et al. 2016; Wang et al. 2017).

Antipsychotic OLU is an enduring but evolving public health problem (Verdoux et al. 2010; Hálfdánarson et al. 2017). The literature on this issue should be

<figure><img src="image_7.png" /></figure>

<figure><img src="image_8.png" /></figure>
<figure><img src="image_9.png" /></figure>

updated regularly to identify signals requiring increased
awareness. The aim of the present review was to syn-
thesise the recent literature on antipsychotic OLU for
mental health symptoms.

Materials and methods

A MEDLINE and PsycINFO search was performed from
2010 through June 2024 using the algorithm 'antipsy-
chotic AND (off-label OR unapproved OR unlicensed)'
to identify articles published in English or French in
peer-reviewed journals. Titles and abstracts of retrieved
citations were screened and selected full-text articles
were assessed for eligibility by the author of the
review. Related references of selected papers as well as
systematic reviews and meta-analyses were also exam-
ined by the author of the review.

First, to explore the frequency and characteristics of
antipsychotic OLU at the level of the population actu-
ally treated, studies meeting the following inclusion
criteria were included: (i) population-based or multi-
centre studies exploring OLU in real-life prescribing
conditions, (ii) exploring antipsychotic OLU targeting
symptoms related to mental health conditions, (iii)
reporting estimates of antipsychotic OLU (incidence or
prevalence rates, prescription data, etc.). Exclusion cri-
teria concerned: (i) studies conducted in mental health
structures for specific populations (Veterans Affairs
facilities, etc.), (ii) studies on OLU for conditions
approved for at least one antipsychotic drug (schizo-
phrenia, bipolar disorder, etc.); (iii) studies on neurode-
generative disorders or non-psychiatric diseases
(cancer, etc.) since distinct reviews would be required
to synthetise the large body of literature addressing
these issues.

Regarding other issues related to antipsychotic OLU
(efficacy, adverse drug reactions (ADR), marketing and
regulatory issues, etc.), prior systematic reviews and
meta-analyses were given precedence over other arti-
cles. Since it was beyond the scope of the present
review to synthesise the findings of all studies assess-
ing the effects of antipsychotics in non-labelled indica-
tions, the search was focused on OLU for conditions
not approved for at least one antipsychotic drug.

Results

Literature search

Ultimately, 51 articles published from 2010 to 2024
were included (Supplementary Figure 1) addressing
the following issues: (i) frequency of OLU in child and
adolescent populations (n=12) (Table 1) or in adult/
all-age populations (n=15) (Table 2), (ii) antipsychotic

OLU in specific mental health conditions (n=7) (anxi-
ety, personality or sleep disorder); (iii) ADR associated
with antipsychotic OLU (n=9), (iv) articles on prescrib-
ers (n=4; (v) marketing and regulatory issues (n=8)
(total number >51 as some articles are quoted in sev-
eral sections).

Frequency and characteristics of antipsychotic OLU

Studies characteristics

Studies were conducted in 14 countries (Table 1): 15
were North-American (USA= 14, Canada = 1), 7
European (UK n=3; Denmark n=1, Germany n=1,
Ireland n=1, Norway n=1; Finland n=1; Germany,
Austria, and Switzerland n=1), 3 Middle-East and Asian
(China n=1, Qatar n=1, Taiwan n=1), and 1 Oceanian
(Australia). Four studies were carried out on data col-
lected before 2000 (Alexander et al. 2011; Comer et al.
2011; Ronsley et al. 2013; Sohn et al. 2016).

Regarding setting and sampling method, most (n=10) of the 12 studies on youths (Table 1) were performed on prescription databases, and the other two were multicentre surveys performed in mental health services (Egberts et al. 2022; Driscoll and McCarthy 2024). Of the 15 studies on adults, most (n=11) were also performed on prescription databases, one in a population-based post-marketing safety cohort survey (Osborne et al. 2016), one in a tertiary psychiatric hospital (Wang et al. 2021), one in a birth cohort (Pirhonen et al. 2022) and one in a random sample of the general population (Radha Krishnan et al. 2024).

Three out of four studies (74%) concerned OLU of
all antipsychotics (youths n=9, adults n=11) and 7 of
SGA only (youths n=3, adults n=4). The criteria used
to define OLU varied widely from one study to another
(Tables 1 and 2). Approved indications/Summaries of
Product Characteristics were mentioned by 7 studies
(youths n=5, adults n=2). These criteria were applied
more or less stringently from one study to another, i.e.,
approved indications were restricted to those listed for
each antipsychotic or were broadly defined as indica-
tions approved for at least one antipsychotic. Two
studies were restricted to youths with attention-deficit/
hyperactivity disorder (ADHD) (dosReis et al. 2022; Lee
et al. 2022) and one study excluded youths with autism
spectrum disorder (Driscoll and McCarthy 2024). Eight
studies performed in adults excluded varying diagnos-
tic categories: schizophrenia and bipolar disorder were
the most frequently excluded, while other studies also
excluded all mood disorders or dementia (Leslie and
Rosenheck 2012; Citrome et al. 2013; Marston et al.
2014; Driessen et al. 2016; Gjerden et al. 2017; Huang
et al. 2019; Horvitz-Lennon et al. 2021; Wang et al.
2021; Pirhonen et al. 2022; Radojčić et al. 2023).
<figure><img src="image_10.png" /><figcaption>**Table 1.** Studies exploring antipsychotic off-label use (OLU) in children and adolescents.</figcaption></figure>

<table><thead><tr><th>Authors, year</th><th>Country</th><th>Population</th><th>Period</th><th>Diagnosis off-label use criteria</th><th>Main findings</th></tr></thead><tbody><tr><td>Pathak et al. (2010)<br>USA</td><td></td><td>Arkansas Medicaid population<br>Youths &lt;18 yrs with new SGA¹ use (n=11,700)</td><td>2000–2006</td><td>ICD-9²<br>Evidence-based OLU³ (RCT⁴, other trials)</td><td>OLU without strong evidence: 62%<br>OLU without evidence: 41.3% in all diagnoses (ADHD³: 58%; oppositional defiant disorder: 28%; depressive disorder: 28%)</td></tr><tr><td>Ronsley et al. (2013)<br>Canada</td><td></td><td>British Columbia prescription database<br>Youths ≤ 18 yrs with AP⁶ use (2010/11 n=5791)</td><td>1996–2011</td><td>ICD-9<br>No OLU criteria</td><td>Most frequent disorders: depressive disorders (12.8%), ADHD (11.7%), neurotic disorders (11.1%)</td></tr><tr><td>Burcu et al. (2014)<br>USA</td><td></td><td>Maryland Medicaid population<br>Youths 2–17 yrs with SGA use (n=8696)</td><td>2006</td><td>ICD-9<br>No OLU criteria</td><td>ADHD/ DBD⁷: 49.5%<br>Disorders other than psychosis, ASD⁸ and bipolar: 31.8%</td></tr><tr><td>Sohn et al. (2016)<br>USA</td><td></td><td>National Ambulatory Medical Care Survey and National Hospital Ambulatory Medical Care Survey<br>Youths 4–18 yrs with outpatient visits with SGA prescription</td><td>1993–2010</td><td>ICD-9<br>FDA⁹-approved indication</td><td>OLU visits: 65%<br>Most frequent disorders: ADHD (24%), psychoses (14%), disturbances and neurotic disorders (5%)<br>No psychiatric diagnosis: 15%</td></tr><tr><td>Schröder et al. (2017)<br>Germany</td><td></td><td>German statutory health insurance providers<br>Outpatient youths &lt;18 yrs with AP use (2011 n=5459)</td><td>2004–2011</td><td>ICD-10<br>No OLU criteria</td><td>All OLU: 61.0% (2004) to 69.5% (2009); by indication: 42.8% to 66.5%; by age: 11.5% to 13.5%<br>Most frequent disorders: ADHD (52.5%); ASD (19.2%); tic disorder (15.7%)</td></tr><tr><td>Candon et al. (2021)<br>USA</td><td></td><td>Pennsylvania Medicaid-population<br>Youths &lt;22 yrs with AP use (2014 n=7555, 2018 n=3959)</td><td>2014–2018</td><td>ICD-9/10<br>Approved indications: ASD, BP¹⁰, psychosis</td><td>Slight increase in OLU: 44.4% (2014) to 47.3% (2018)<br>Most frequent disorders: ADHD, depression, adjustment disorders, conduct disorders</td></tr><tr><td>dosReis et al. (2022)<br>USA</td><td></td><td>10% random sample of IQVIA PharMetrics® Plus for Academics data<br>Youths 3–18 yrs with ADHD (n=165 794)</td><td>2007–2015</td><td>ICD-9/10<br>No OLU criteria</td><td>Decreased AP use: 4.4% (2007) to 3.4% (2015)<br>Increased co-prescription stimulants-AP for females (19.5% to 28.7%) and youth 15–18 yrs (25.9% to 32.7%)<br>Increased risk of OLU if DBD (OR¹¹=2.5, 95% CI: 2.3, 2.7)</td></tr><tr><td>Egberts et al. (2022)<br>Germany, Austria, and Switzerland</td><td></td><td>Child and adolescent psychiatric centres (n=18)<br>Youths 6–18 yrs with new AP use (n=710) followed up to 6 months after treatment initiation</td><td>2014–2018</td><td>ICD-10<br>SPCs¹²</td><td>OLU: 80.7% of treatment episodes<br>Risk of serious ADR¹³ not significantly different between on-label and OLU (8.7 % vs 7.5 %, p = 0.67)</td></tr><tr><td>Lee et al. (2022)<br>USA</td><td></td><td>IQVIA PharMetrics® Plus for Academics data<br>Youths 5–15 yrs (n=41,098) with ADHD and no DBD at baseline</td><td>2007–2019</td><td>ICD-9/10<br>No indicated diagnosis</td><td>Increased risk of OLU if incident DBD (11.1%) (hazard ratio = 4.6; 95% CI 4.2–5.2) especially in younger males</td></tr><tr><td>Radojčić et al. (2023)<br>UK</td><td></td><td>Clinical Practice Research Datalink (CPRD) Aurum database<br>Youths 3–18 yrs (n=7 217 098)</td><td>2000–2019</td><td>Clinical diagnosis<br>No OLU criteria</td><td>Most frequent diagnoses if 1st prescription: ASD (12.7%), non-affective psychosis (8.6%), anxiety disorders (7.5%), ADHD (7.1%), depression (6.4%), conduct disorders (6.1%)</td></tr><tr><td>Costales et al. (2024)<br>USA</td><td></td><td>Kaiser Permanente Northern California<br>Outpatients youths 10–17 yrs (2021, n=5828):</td><td>2013–2021</td><td>ICD-9/10<br>No FDA-approved indication (ASD, psychosis, BP, Tourette's syndrome)</td><td>OLU in new SGA users ranged from 80.7% (2013) to 69.2% (2019)<br>Increased OLU during COVID-19 pandemic in 10–14 yrs (post-March 2020 slope change = 0.11, p = 0.02)<br>Most frequent diagnoses: depression, anxiety disorders, other mood disorders, ADHD</td></tr><tr><td>Driscoll and McCarthy (2024)<br>Ireland</td><td></td><td>National audit of mental health services<br>Youths &lt; 18 yrs with AP prescription (n=437)</td><td>2021</td><td>Clinical diagnosis<br>ASD excluded<br>No OLU criteria</td><td>Target conditions are more often symptoms (75.5%) than disorders: agitation (25%), irritability (18%), emotional dysregulation (14%)</td></tr></tbody></table>

1. SGA: second-generation antipsychotic; 2. ICD: international classification of diseases; 3. OLU: off-label use; 4. RCT: randomised controlled trial; 5. ADHD: attention-deficit/hyperactivity disorder; 6. AP: antipsychotic; 7. DBD: disruptive behaviour disorder; 8. ASD: autism spectrum disorder; 9. FDA: Food Drug Administration; 10. BP: bipolar disorder; 11. OR: odds ratio; 12. SPCs: Summaries of Product Characteristics; 13. ADR: adverse drug reaction.

## Frequency and characteristics of antipsychotic OLU in youths

Five of the 12 studies examined trends in antipsychotic OLU over periods ranging from 4 to 8 years. One reported decreasing or stable trends (dosReis et al. 2022). Three reported a slight increase in OLU

(Schröder et al. 2017; Candon et al. 2021) that was restricted to the COVID-19 pandemic period in one study (Costales et al. 2024). Another study examined the incidence of antipsychotic use in youths with ADHD and no disruptive behaviour disorder (DBD) at baseline (Lee et al. 2022). The seven other studies
<figure><img src="image_11.png" /><figcaption>**Table 2.** Studies exploring antipsychotic off-label use (OLU) in adults.</figcaption></figure>

<table><thead><tr><th>Authors, year Country</th><th>Population</th><th>Period</th><th>Diagnosis off-label use criteria</th><th>Main findings</th></tr></thead><tbody><tr><td>Alexander et al. (2011) USA</td><td>IMS Health National Diagnostic and Therapeutic Index<br/>Outpatient visits (n=4800 physicians)</td><td>1995–2008</td><td>Clinical diagnosis<br/>FDA¹-approved indications in 2008</td><td>OLU² all AP³: 74% of AP visits in 1995 (n=4.4 million), 60% in 2008 (n=9.0 million)<br/>OLU SGA⁴: increased from 50% in 1995 to 66% in 2003, before declining to 60% in 2008.<br/>OLU FGA⁵: declined from 78% in 1995 to 67% in 2008</td></tr><tr><td>Comer et al. (2011) USA</td><td>National Ambulatory Medical Care Survey<br/>Psychiatric visits for anxiety disorder (including traumatic stress disorders) (n=4166)</td><td>1996–2007</td><td>ICD⁶-9<br/>FDA-approved indications</td><td>OLU: 48.3% of visits with AP (n=596, 16.7%)<br/>Increased SGA prescriptions from 3.8% (1996–1997) to 20.5% (2006–2007) (OR⁷=5.82, 95% CI = 3.4–9.8, p<0.001)<br/>Decreased FGA prescriptions from 5.8% (1996–1997) to 1.0% (2006–2007) (OR = 0.07, 95% CI = 0.02–0.2, p<0.001)</td></tr><tr><td>Leslie and Rosenheck (2012) USA</td><td>Medicaid Programs in 42 states<br/>AP users (n=372,038)</td><td>2003</td><td>ICD-9<br/>Exclusion SZ⁸, BP⁹</td><td>OLU: 57.6%<br/>Most frequent diagnoses: 'other' mental disorder (35.0%), minor depression (25.4%), major depression (23.2%)<br/>No diagnosis: 18.8%<br/>OLU: 19.6%</td></tr><tr><td>Citrome et al. (2013) USA</td><td>OptumInsight commercial database<br/>Outpatients 18–64 yrs with SGA use (n=18,352)</td><td>2008–2011</td><td>ICD-9<br/>Exclusion SZ, BP, major depression</td><td>Most frequent diagnoses: anxiety disorder (all SGA: around 30%), substance abuse (quetiapine 22.7%)</td></tr><tr><td>Marston et al. (2014) UK</td><td>Primary care database Health Improvement Network (THIN)<br/>AP use (n=47,724)</td><td>2007–2011</td><td>Read code lists<br/>Exclusion psychotic disorder, BP</td><td>OLU: FGA from 27% to 35% by molecule, >50% total; SGA: from 38% to 64% by molecule<br/>Most frequent diagnoses: anxiety, depression, sleep disorders, dementia<br/>No diagnosis: FGA 12–17%</td></tr><tr><td>Driessen et al. (2016) USA</td><td>Random sample of 5% of Medicare beneficiaries<br/>SGA users (n=76,369 in 2012)</td><td>2006–2012</td><td>ICD-9<br/>Exclusion SZ, BP, major depression</td><td>Decline in OLU from 51% (2006) to 45% (2012)<br/>Most frequent diagnoses (2012): dementia (42%), anxiety disorders (14%), minor depression (23%)<br/>Most significant growth in prevalence from 2006 to 2012: hyperkinetic disorder (136%), anxiety disorder (113%), insomnia (102%)</td></tr><tr><td>Osborne et al. (2016) UK</td><td>Population-based post-marketing safety cohort survey<br/>National Health Service database<br/>Quetiapine XL users with prescription by GPs¹⁰ (n=13,276)</td><td>2008–2013</td><td>Survey questionnaire<br/>Clinical indication<br/>no OLU criteria</td><td>OLU: 28.3%<br/>Most frequent diagnoses: psychotic disorder (11.8%) and depression (11.4%)</td></tr><tr><td>Gjerden et al. (2017) Norway</td><td>National prescription database<br/>Outpatients with quetiapine use (n=47,474)</td><td>2004–2015</td><td>ICD-10<br/>Exclusion SZ, mood disorders</td><td>OLU in users with ≥ 2 prescriptions: 60% (2015)<br/>Dose > 200 mg: 5.9% (2015)<br/>Decline (2004–2015) of quetiapine mean dose from 1.58 defined daily dose (SD 8.00) to 0.48 (SD 2.27)</td></tr><tr><td>Huang et al. (2019) Taiwan</td><td>National prescription database<br/>Outpatients with anxiety disorders ≥ 18 years (n=26 235)</td><td>2005–2013</td><td>ICD-9<br/>Exclusion SZ, BP, dementia</td><td>Increase OLU: 8.4% (2005) to 9.1% (2013) (OR= 1.21, 95% CI 1.17–1.25)<br/>Most frequent diagnoses (2013): PTSD¹¹ (24%), OCD¹² (24.4%), panic disorder (18%)</td></tr><tr><td>Bastaki et al. (2021) Qatar</td><td>Major healthcare providers database<br/>Qatari outpatients with AP use (n=9,349)</td><td>2018–2020</td><td>No OLU criteria</td><td>OLU: 69%<br/>Most frequent diagnoses: depression (26%), anxiety disorders 20%</td></tr><tr><td>Højlund et al. (2021b) Denmark</td><td>National prescription database<br/>AP users (n=630 307)</td><td>1997–2018</td><td>ICD-10<br/>No OLU criteria</td><td>OLU without psychiatric, neurological or oncological disorder: 37% of prevalent and 39% of incident use<br/>OLU without SZ/BP: 66% of prevalent and 85% of incident use<br/>OLU without mood and anxiety disorders: 15% of prevalent and 26% of incident use</td></tr><tr><td>Horvitz-Lennon et al. (2021) USA</td><td>Medicaid and Medicare coverage in 4 states<br/>SGA users 18–64 yrs (n=301,367)</td><td>2008–2013</td><td>ICD-10<br/>Exclusion SZ, BP I, severe major depression</td><td>Always OLU: 37% to 42%<br/>No psychiatric diagnosis: 26% to 36%</td></tr></tbody></table>
<figure><img src="image_12.png" /><figcaption>**Table 2. Continued.**</figcaption></figure>

<table><thead><tr><th>Authors, year</th><th>Country</th><th>Population</th><th>Period</th><th>Diagnosis off-label use criteria</th><th>Main findings</th></tr></thead><tbody><tr><td>Wang et al. (2021)<br>China</td><td></td><td>Discharged patients (n=981)<br>from tertiary psychiatric<br>hospitals (n=41)</td><td>2019</td><td>ICD-10<br>Exclusion SZ, BP</td><td>OLU: 63%<br>Most frequent diagnoses: dissociative<br>(conversion) disorder (89.9%), organic<br>mental disorders (81.7%), dementia (79%),<br>OCD (78%)</td></tr><tr><td>Pirhonen et al. (2022)<br>Finland</td><td></td><td>46-year survey of Northern<br>Finland Birth Cohort 1966<br>(n=7071)<br>National prescription database</td><td>2012–2014</td><td>ICD-8/9/10<br>Exclusion SZ, BP</td><td>OLU: 52.4%<br>Most frequent diagnoses: depression (70%),<br>anxiety (40%), substance use disorder (29%)<br>No psychiatric diagnosis: 15%</td></tr><tr><td>Radha Krishnan et al.<br>(2024)<br>Australia</td><td></td><td>Random sample (10%) of the<br>adult Australian population<br>GPs survey Bettering the<br>Evaluation and Care of Health<br>(n=9821 AP prescriptions)</td><td>2005–2021</td><td>Clinical diagnosis<br>No OLU criteria</td><td>OLU: 27%<br>Most frequent diagnoses: psychological<br>disorders other than SZ or BP (20%).<br>6%), neurological disorders (10%)</td></tr></tbody></table>

1. FDA: Food Drug Administration; 2.AP: antipsychotic; 3. OLU: off-label use; 4.SGA: second-generation antipsychotic; 5.FGA: first-generation antipsychotic; 6. ICD: international classification of diseases; 7.OR: odds ratio; 8. SZ: schizophrenia; 9. BP: bipolar disorder; 10. GPs: General Practitioners; 11. PTSD: post-traumatic stress disorder; 12. OCD: obsessive compulsive disorder.

reported data on antipsychotic OLU prevalence (Table 1).

Irrespective of the methods, all studies found a high frequency of antipsychotic OLU in youths. In most studies, antipsychotic OLU was observed in around two out of three antipsychotic users (Table 1). The highest prevalence was observed in a multinational clinical sample with antipsychotic OLU occurring in 80.7% of treatment episodes (Egberts et al. 2022).

SGA OLU predominated in youths and frequently involved drugs with labelled indications in this population (ariprazole, quetiapine, olanzapine or risperidone) (Egberts et al. 2022; Lee et al. 2022; Radojčić et al. 2023; Driscoll and McCarthy 2024).

A German study found that OLU by indication was more frequent than OLU by age (Schröder et al. 2017). The diagnoses most often concerned were ADHD, mood disorders and anxiety disorders. However, as shown by a national audit of Irish mental health services, antipsychotic OLU most often targeted symptoms rather than disorders (Driscoll and McCarthy 2024). A US study using data collected on outpatient visits found that no psychiatric diagnosis was recorded in 15% of visits with SGA prescription (Sohn et al. 2016).

### Frequency and characteristics of antipsychotic OLU in adults

Five of the 15 studies examined trends in antipsychotic OLU over periods ranging from 6 to 13 years. Three reported decreasing trends for all antipsychotics (Driessen et al. 2016) or for first-generation antipsychotics (FGA) only (Alexander et al. 2011; Comer et al. 2011). Three reported increased OLU for all antipsychotics (Huang et al. 2019) or for SGA only (Alexander et al. 2011; Comer et al. 2011). One study reported a temporal decline in quetiapine doses (Gjerden et al. 2017). The

nine other studies reported data on antipsychotic OLU prevalence (Table 2), which was most often around 30–60% but ranged from <10% in patients with anxiety disorders (Huang et al. 2019) to 75% of outpatient visits with antipsychotic prescription (Alexander et al. 2011).

FGA most often concerned by OLU were flupenthixol, haloperidol, levomepromazine, chlorpromazine, pherphenazine and sulpiride while most often concerned SGA were quetiapine, olanzapine and risperidone (Marston et al. 2014; Huang et al. 2019; Bastaki et al. 2021; Højlund et al. 2021a; Wang et al. 2021; Pirhonen et al. 2022; Radha Krishnan et al. 2024).

The psychiatric diagnoses most frequently associated with antipsychotic OLU were mood and anxiety disorders (Table 2). A substantial proportion of users (15% to 42%) had no recorded psychiatric diagnosis (Leslie and Rosenheck 2012; Marston et al. 2014; Højlund et al. 2021a; Horvitz-Lennon et al. 2021; Pirhonen et al. 2022).

### Effects of antipsychotic OLU in specific mental health conditions

#### Anxiety disorders

A systematic review and meta-analysis synthesised the studies published up to 2011 on the effects of SGA in several off-label conditions (Maher et al. 2011). Of the 14 trials assessing the efficacy of SGA in generalised anxiety disorder (GAD), 12 were placebo-controlled and five reported the percentage of responders (at least 50% reduction in Hamilton Anxiety Rating Scale score). The trials assessing the efficacy of olanzapine (n=1) and risperidone (n=1) did not find any significant results. The pooled results of the three quetiapine trials (dose range 50–300 mg/d) showed a 26% increase in positive response at 8 weeks (effect size 0.30). The
<figure><img src="image_13.png" /></figure>

strength of evidence was classified as moderate considering the heterogeneity ($I^2$=78.2%, *p*=0.01) and the fact that all studies were funded by the manufacturers. Of the 16 trials assessing the efficacy of SGA augmentation therapy in antidepressant-resistant obsessive-compulsive disorder (OCD), 10 were placebo-controlled and all reported the percentage of responders (25%-35% reduction on Yale-Brown Obsessive Compulsive Scale). The trials assessing the efficacy of olanzapine (*n*=2) and quetiapine (*n*=5) did not find any significant results. The pooled results of the three risperidone trials (dose range 0.50-2.25 mg/d) showed a 4-fold greater likelihood of response with risperidone (effect size 1.14). The strength of evidence was classified as moderate because of a potential publication bias.

More recently, an umbrella review synthesised 25 systematic reviews (of which 4 included a meta-analysis) up to 2020 investigating the efficacy of antipsychotics in several anxiety disorders (Garakani et al. 2024): GAD (*n*=13), panic disorder (*n*=8), social anxiety disorder (*n*=4), phobias (*n*=6), OCD (*n*=3), and post-traumatic stress disorder (PTSD) (*n*=2). Only one review was found to be of high quality, the others were rated as being of low (*n*=4) or critically low (*n*=20) quality. Efficacy of quetiapine monotherapy in GAD was the only finding with demonstrated evidence. There was no convincing evidence regarding the efficacy of antipsychotics in other disorders.

A study performed on the Taiwan national prescription database (Huang et al. 2019) (Table 2) provided information on real-life antipsychotic prescribing practices in anxiety disorders. A significant increase in antipsychotic OLU rates was observed in adults with anxiety disorders (8.4% in 2005 to 9.1% in 2013, OR= 1.21, 95%CI 1.17-1.25). The increase was more marked in patients with comorbid depression (62%) than in those without depression (20%). The frequency of antipsychotic OLU was higher in patients treated by psychiatrists (15.3%) than in those treated by non-psychiatrists (6.8%). Although increased use concerned all anxiety disorders, the highest prevalence was found for PTSD (24%), OCD (24.4%) and panic disorder (18%). Quetiapine was the most frequently prescribed SGA for patients with anxiety, with increasing rates from 0.3% in 2005-2017 to up to 0.9% in 2011-2013 (OR = 2.98, 95%CI: 2.60-3.42).

## Personality disorders

A systematic review including 57 articles published up to 2011 examined the evidence on SGA efficacy in personality disorders (Rosenbluth and Sinyor 2012). Most studies were open trials with very small samples of

persons with borderline personality disorder (BPD). The authors concluded that there was no evidence regarding the efficacy of SGA OLU on overall illness severity of personality disorders and recommended restricting prescription to persons presenting a comorbid condition with a labelled indication of SGA. However, they highlighted the potential interest of clozapine for reducing self-harm/suicidal behaviour in BPD.

A recent Cochrane review synthesised the findings of RCTs published up to 2022 on the efficacy of FGA (*n*=6) or SGA (*n*=16) in BPD (Stoffers-Winterling et al. 2022). Reduction of anger was significantly greater with antipsychotics vs. placebo (standardised mean difference (SMD) -0.37, 95% CI -0.55 to -0.18; *p*=0.0001). No evidence was found regarding the effects of antipsychotics vs. placebo on BPD symptom severity (SMD -0.18, 95% CI -0.45 to 0.08; *p*=0.18); self-harm (Relative risk (RR) 0.66, 95% CI 0.15 to 2.84; *p*=0.57); suicide-related outcomes (SMD 0.05, 95% CI -0.18 to 0.29; *p*=0.67); psychosocial functioning (SMD 0.05, 95% CI -0.18 to 0.29; *p*=0.67); impulsivity (mean difference (MD) 0.46, 95% CI -12.93 to 13.85; *p*=0.95).

The STAR Network Depot study was carried out on a naturalistic cohort of 449 patients initiating long-acting injectable (LAI) antipsychotic treatment (D'Agostino et al. 2022). Patients were recruited over one year in 35 territorial and university mental health departments in Italy. One out of four patients (26%) was prescribed LAI OLU, of whom 23.7% had a diagnosis of personality disorder.

## Sleep disorders

A systematic review and meta-analysis synthesised the findings up to 2022 of RCTs (*n*=19) and cross-over trials (*n*=2) assessing the effects of quetiapine ≤ 300 mg on sleep quality (Lin et al. 2023). Quetiapine monotherapy was assessed in most trials (*n*=19). Studies were performed in persons with depression (*n*=9), anxiety disorders (*n*=5), other diseases (*n*=5) or healthy persons (*n*=3). All used a standardised measure of sleep quality (most often the Pittsburgh Sleep Quality Index *n*=15). Fewer than half of the trials had a low risk of bias, and three out of four trials were funded by pharmaceutical companies. Sleep quality was significantly improved in the quetiapine group vs. placebo for GAD (SMD -0.59, 95% CI -0.92 to -0.27, high heterogeneity $I^2$ = 92%, *p*<0.00001) and depression (SMD -0.47, 95%CI: -0.66 to -0.28, high heterogeneity $I^2$ = 71%, *p*<0.007) as well as in healthy persons (SMD -1.33, 95%CI -2.12 to -0.54). Improvement in sleep quality was observed at doses 50 mg/day (SMD -0.36, 95%CI -0.60 to -0.11, 150 mg/day (SMD -0.4,
95%CI -0.52 to -0.29), and 300 mg/day (SMD -0.17, 95%CI: -0.31 to -0.04), but not at 25 mg/day (SMD -0.38, 95%CI -1.11 to 0.34)

## ADR associated with antipsychotic OLU

The increased risk of ADR associated with antipsychotic OLU is emphasised by almost all studies. A meta-analysis synthesised the findings of RCTs (n=35) published up to 2019 providing a comparison of metabolic outcomes with SGA OLU vs. placebo (Stogios et al. 2022). The RCTs included adults (18–65 years) with psychiatric diagnoses without a labelled indication for antipsychotics. Across all diagnoses, significantly greater weight gain was found for olanzapine (MD = 3.24 kg, 95% CI 2.57 to 3.90, *p* < 0.00001, I²=63%). Trends in the same direction were identified for risperidone (MD = 0.66 kg, 95% CI -0.09 to 1.40, *p* = 0.08, I² = 57%) and quetiapine (MD = 0.82 kg, 95% CI -0.02 to 1.65, *p* = 0.06, I²=96%). The effects of other SGA on weight could not be determined because of the small number of studies.

ADR induced by antipsychotic OLU in children and adolescents are of great concern, especially regarding metabolic ADR which can lead to dramatic increase in body mass index (Hoekstra and Dietrich 2022). A multinational study included youths (6–18 years, n=710) followed up 6 months after antipsychotic initiation (Egberts et al. 2022). The frequency of serious ADR rated with the Paediatric Adverse Event Rating Scale was not significantly different between on-label and OLU antipsychotics (8.7% vs 7.5%, *p* = 0.67).

Several studies specifically addressed ADR related to quetiapine OLU. Meta-analyses and systematic reviews reported a higher risk of weight gain, hypertriglyceridaemia, high-fasting glucose increase, sedation and hyperprolactinaemia with quetiapine vs. placebo (Garakani et al. 2022; Lin et al. 2023). A population-based study performed on Danish health registers explored the risk of diabetes associated with low-dose quetiapine (25–50 mg) (Højlund et al. 2021b). New quetiapine users ≥18 years (n=54 616) without severe mental illness (SMI) were matched with new users of selective serotonin reuptake inhibitors. The cumulative incidence of type 2 diabetes (first diagnosis/antidiabetic medication/haemoglobin A1C (HbA1C) ≥6.4%) did not differ between the two groups (incidence rate ratios (IRR) for as-treated 0.99; 95%CI 0.87 to 1.13; for intention to treat 0.92, 95%CI 0.84 to 1.00). Sensitivity analyses showed that higher cumulative doses were associated with an increased risk of diabetes when persons using higher tablet strengths (>50 mg as proxy

for higher daily doses) were included (OR 1.44, 95%CI, 1.13–1.84).

Another study on the same population examined the impact of initiating low-dose quetiapine on HbA1c, triglyceride and cholesterol levels (Højlund et al. 2023). Metabolic monitoring before and after initiation was performed in a very small proportion of newly eligible quetiapine users (n=31 208) ranging from 1.2% for fasting triglycerides to 9.3% for total cholesterol. No significant increase in HbA1c level was found after quetiapine initiation in the total sample (β=0.999, 95%CI 0.997 to 1.002), but an increase was observed in patients with normal level at baseline vs. those with prediabetic or diabetic HbA1c levels before initiation (β=1.006 vs. β=0.999/0.971; *p* < 0.001). Initiation of low-dose quetiapine was associated with decreased levels of total cholesterol (β=0.993, 95%CI 0.98 to 0.996), low-density lipoprotein cholesterol (β=0.984, 95%CI 0.977 to 0.990), high-density lipoprotein cholesterol (β=0.982, 95%CI 0.98 to 0.99) and with increased levels of fasting triglycerides (β=1.04, 95%CI 1.027 to 1.072).

A Swedish population-based study was carried out in adults ≥ 18 years with ≥2 prescriptions of low-dose olanzapine (≤ 5 mg/d) and/or quetiapine (≤ 75 mg/d) (Berge et al. 2022). Persons with SMI or a prescription of antipsychotics or cardiometabolic drugs were excluded. The risk of cardiometabolic mortality was similar in persons exposed to low doses of olanzapine or quetiapine vs. those unexposed to antipsychotics (hazard ratio (HR) 0.86, 95% CI 0.64 to 1.15). However, the risk varied with duration of exposure: it was significantly lower for those treated for <6 months (HR 0.56, 95% CI 0.37 to 0.87) and significantly higher for those treated for 6–12 months (HR 1.89, 95% CI 1.22 to 2.92), suggesting that a selection bias may lead to more antipsychotic prescription to persons with lower cardiometabolic risk profiles.

An audit of 270 New Zealand general practitioners in 2015–2016 found that metabolic monitoring was seldom performed in quetiapine users: only 2.3% of them had full monitoring, while 68% had partial monitoring and 29.7% no monitoring at all (Huthwaite et al. 2018).

## Studies on prescribers

A non-industry funded survey mailed to 300 Italian psychiatrists (67% response rate) explored SGA OLU (Aguglia et al. 2021). Although most reported SGA OLU (very often: 16.7%, often: 33.4% or occasionally:
<figure><img src="image_14.png" /></figure>

34.7%), only half of them routinely required users' informed consent before SGA initiation. The main motives for SGA OLU were literature evidence (51.5%), non-response (37.2%) or ADR (11.9%) with labelled drugs, or indications from other regulatory agencies such as the Food and Drug Administration (FDA). Patient preference was mentioned only by 1.5% of participants.

A study performed on a 20% random sample of the Danish population investigated quetiapine prescribing trends from 2001–2020 (Højlund et al. 2022). Although the study did not provide a quantitative estimate of quetiapine OLU, several indicators suggested that these prescribing practices increased in GPs' prescriptions over the study period. In 2020, half (53%) of quetiapine prescriptions were initiated by GPs, especially in elderly patients (20% in those ≤17 years vs. 72% in those aged ≥80 years). The mean dose of quetiapine was 43 mg/d in users aged ≥ 80 years.

A qualitative study on 15 Canadian GPs found they did not consider quetiapine as a first-line treatment and restricted its use to patients unresponsive to other drugs and/or presenting with complex psychosocial needs in order to ‘keep patient functioning’ (Kelly et al. 2018). Quetiapine was preferred to benzodiazepines because it was considered as non-addictive. Most participants considered low-dose quetiapine as safe and were not aware of mechanisms of action or of guidelines especially regarding monitoring. Quetiapine use was influenced by the prescribing practices of other colleagues, but prescribers did not consider that promotion from pharmaceutical companies impacted their prescribing practices.

A survey including 16 prescribers investigated the reasons for not discontinuing long-term antipsychotic OLU in persons with neurodevelopmental disorders (de Kuijper and Hoekstra 2017). Of the 3,299 persons living in residential facilities in the Netherlands, 29.6% used antipsychotics, most often (95%) prescribed for more than one year for off-label indications. According to the prescribers, half (51%) of these long-term prescriptions could be discontinued. A higher likelihood of discontinuation was associated with prescription for challenging behaviour. Non-discontinuation was most often based on the prescriber's decision but lack of consent of the legal representative was also frequent (up to 30% in some facilities). Differences in attitudes and beliefs of settings' staff were identified by the authors as impacting prescribing patterns and decisions of physicians not to discontinue OLU use.

## Impact of marketing and regulatory issues

Several pharmaceutical companies have been convicted in the USA for marketing antipsychotic OLU (Tanne 2010, 2012; Wang et al. 2016; Wang et al. 2017). The companies promoted antipsychotic OLU in a range of unapproved uses, such as dementia in elderly people, schizophrenia and bipolar disorder in youths, depression, anxiety disorders, and insomnia. The promotion strategies included influencing the narrative of company speakers, sponsoring medical educational programs, conducting studies on unapproved uses, ghost-writing articles, providing child psychiatrists and general practitioners with free samples of the drug, and rewarding prescribers with lucrative consulting agreements (Tanne 2010, 2012; Roehr 2012).

The impact of findings obtained by small exploratory studies on OLU rates has been addressed by a systematic meta-epidemiological review (Grabitz et al. 2024). Half of the 176 studies reporting efficacy outcomes for quetiapine in unapproved indications over the period 1995–2022 were industry-funded. A positive efficacy endpoint was found by 87% of the 147 exploratory studies and 72% of the 29 confirmatory studies. According to the authors, ‘clinical agnosticism’ encouraging OLU is induced by small exploratory studies: they suggest that a drug might be effective in unapproved indications even if evidence of efficacy from controlled studies is lacking. Indeed, the authors identified nine clinical practice guidelines recommending the use of quetiapine in indications only documented by exploratory studies, such as PTSD and eating disorders.

The characteristics of antipsychotic OLU in a given country are directly related to the decisions of national regulatory agencies, since approved indications for a given drug vary widely from one country to another (Zhu et al. 2018). However, the agencies' decisions after first market authorisation have a more limited impact on antipsychotic OLU. A study carried out on the Optum Research Database assessed trends in antipsychotic OLU rates after FDA approval in 2009 of supplemental indications in youths for olanzapine and quetiapine and non-approval of expanding indications for ziprasidone (Wang et al. 2016). After the FDA decisions, no significant differences were found in the rates of new prescriptions in youths compared to adults favouring drugs with new indications and cautioning against ziprasidone. Another study performed on the same database found no reduction in olanzapine OLU after settlements for illegal promotion of this drug in OLU indications (Wang et al. 2017).
<figure><img src="image_15.png" /></figure>

Conversely, a slight reduction in antipsychotic OLU in youths was observed in the year following the implementation of a state Medicaid peer-review authorisation programme (5–9 years: 88.4 to 85.7%; 10 to 17 years: 74.2% to 71.8) (Pennap et al. 2018). This programme was based upon a review of new antipsychotic prescriptions by clinical pharmacists on the basis of clinical criteria such as age, diagnosis, target symptom severity, medication dosage, monitoring criteria, etc.

## Discussion

The recent literature on antipsychotic OLU confirms the persisting high prevalence of these prescribing practices. Increased rates of antipsychotic OLU became a source of concern soon after the introduction of SGA, especially in youths (Zito et al. 2000; Verdoux et al. 2010; Patten et al. 2012; Olfson et al. 2015; Hálfdánarson et al. 2017). Three decades later, antipsychotic OLU rates are still very high, since two out of three youths and 30–60% of adults using antipsychotics have no labelled indications. However, there may be a ceiling effect as some studies are reporting stable or decreasing trends of antipsychotic OLU rates (Driessen et al. 2016; dosReis et al. 2022).

The reasons for OLU in the recent literature are comparable to those reported by older studies (Olfson et al. 2015; Verdoux et al. 2015). Regarding OLU by indication or age, changes are mostly related to decisions made by regulatory agencies that authorise supplemental indications rather than to modifications of prescribing practices. The most frequent diagnoses are still ADHD, mood and anxiety disorders in youths, and mood and anxiety disorders in adults. In both populations, a substantial proportion of antipsychotic users (15–40%) have no recorded psychiatric diagnosis (Leslie and Rosenheck 2012; Marston et al. 2014; Sohn et al. 2016; Højlund et al. 2021a; Horvitz-Lennon et al. 2021; Pirhonen et al. 2022).

The most striking change in recent years concerns the growing body of literature on quetiapine OLU (Tanne 2010; Osborne et al. 2016; Gjerden et al. 2017; Huthwaite et al. 2018; Kelly et al. 2018; Huang et al. 2019; Højlund et al. 2021b; Berge et al. 2022; Højlund et al. 2022; Højlund et al. 2023; Lin et al. 2023; Garakani et al. 2024; Grabitz et al. 2024). A consistent and widespread finding is that rates of low-dose quetiapine OLU are increasing for anxiety or sleep symptoms in persons without a SMI or psychiatric disorder.

Quetiapine prescribing trends may be viewed as paradigmatic to illustrate the multifactorial determinants of antipsychotic OLU. These prescribing practices are

undoubtedly facilitated by the illegal promotion of OLU by pharmaceutical companies through sponsored medical educational programs, exploratory studies on unapproved uses, the ghost-writing of articles, etc. (Tanne 2010; Wang et al. 2016; Grabitz et al. 2024). Guidelines recommending the use of quetiapine in indications documented only by exploratory studies also contribute to OLU (Garakani et al. 2024; Grabitz et al. 2024). Attitudes of prescribers leading to a feeling of innocuousness and extension of perceived indications also favour OLU (Verdoux et al. 2010; Huthwaite et al. 2018; Kelly et al. 2018; Højlund et al. 2022). Prescribing low-dose quetiapine may be viewed as a common practice for anxiety or sleep symptoms. Prescribers may consider that quetiapine is less risky than drugs with labelled indications such as benzodiazepines; because they underestimate the risk of adverse events and are not aware of the need for metabolic monitoring (Marston et al. 2014; Hoekstra and Dietrich 2022; Højlund et al. 2022; Stogios et al. 2022; Højlund et al. 2023). Furthermore, prescribers are often unaware that they may be responsible for the legal consequences of ADR induced by antipsychotic OLU (Martin-Latry et al. 2007).

As illustrated by the case of quetiapine, there is little doubt regarding the need to reduce antipsychotic OLU as a first-line strategy in persons without SMI because of its detrimental benefit-risk ratio. However, antipsychotic OLU may be necessary in some psychiatric conditions (Wang et al. 2021; Driscoll and McCarthy 2024). These situations have characteristics mirroring those described for the case of quetiapine. They mostly concern persons with resistant psychiatric disorders or presenting with serious ADR with labelled drugs. The potential clinical benefits clearly predominate over the financial benefits for the drug company. The prevalence of antipsychotic OLU for resistant disorders is not documented.

Antipsychotic OLU may be regarded as a spectrum of prescribing practices, with low-dose quetiapine as the first-line treatment of sleep symptoms at the one end, and at the other, clozapine as a fifth- or even tenth-line treatment in refractory and severe personality (Rosenbluth and Sinyor 2012) or neurodevelopmental disorders (Verdoux et al. 2024). A common point between these two opposite situations is that evidence-based studies may also be lacking for OLU prescriptions motivated by resistance. However, in such cases it should be borne in mind that 'there will always be individuals that achieve significant improvement from a therapy despite limited controlled evidence' (Faden and Citrome 2019).
<figure><img src="image_16.png" /></figure>

## Conclusion

Although OLU is common in most medical specialties, it is highly prevalent in psychiatry owing to the lack of clear diagnostic boundaries and limited pathophysiological knowledge (Martin-Latry et al. 2007; Verdoux 2018; Wang et al. 2021). Addressing the influence of the pharmaceutical industry on the OLU prescription of newly marketed drugs is a clear public health priority. OLU may also be reduced by making prescribers more aware of industry marketing practices, especially regarding the limitations of industry-sponsored exploratory studies (Wang et al. 2017; Grabitz et al. 2024).

However, antipsychotic OLU should be neither trivialised nor demonised, as it remains the only therapeutic option in several clinical conditions. Due to the high cost and complexity of conducting RCTs, not all potential indications can be tested, especially in resistant psychiatric disorders or youth/adolescent populations, where RCTs are particularly challenging.

The literature is scarce regarding patients' opinions on antipsychotic OLU. Users need to be informed not only about the benefits but also about the risks associated with OLU (Huthwaite et al. 2018; Kelly et al. 2018). Close relatives and legal representatives of the most vulnerable patients also need to be aware of when and why antipsychotics should be initiated or discontinued in non-labelled indications (de Kuijper and Hoekstra 2017). Further studies are required regarding the stigma potentially associated with antipsychotic use in non-psychotic conditions, especially in youths (King and Voruganti 2002).

## Acknowledgments

The authors thank Ray Cooke for supervising the English of this manuscript.

## Disclosure statement

The author reports that there are no competing interests to declare.

## ORCID

Hélène Verdoux http://orcid.org/0000-0003-2948-3782

## References

* Aguglia A, Serafini G, Nebbia J, Salvi V, Martinotti G, Corbo M, Signorelli MS, Mineo L, Mencacci C, Di Sciascio G, et al. 2021. Off-label use of second-generation antipsychotics in borderline personality disorder: a survey of Italian psychiatrists. J Pers Disord. 35(3):321-335. doi: 10.1521/pedi_2019_33_445.

* Alexander GC, Gallagher SA, Mascola A, Moloney RM, Stafford RS. 2011. Increasing off-label use of antipsychotic medications in the United States, 1995-2008. Pharmacoepidemiol Drug Saf. 20(2):177-184. doi: 10.1002/pds.2082.

* Bastaki K, El Anbari M, Ghuloum S, Jithesh PV. 2021. Prescription pattern and off-label use of antipsychotics in a middle eastern population. Front Pharmacol. 12:753845. doi: 10.3389/fphar.2021.753845.

* Berge J, Abri P, Andell P, Movahed P, Ragazan DC. 2022. Associations between off-label low-dose olanzapine or quetiapine and cardiometabolic mortality. J Psychiatr Res. 149:352-358. doi: 10.1016/j.jpsychires.2021.11.023.

* Burcu M, Zito JM, Ibe A, Safer DJ. 2014. Atypical antipsychotic use among Medicaid-insured children and adolescents: duration, safety, and monitoring implications. J Child Adolesc Psychopharmacol. 24(3):112-119. doi: 10.1089/cap.2013.0094.

* Candon M, Shen S, Fadeyibi O, Smith JL, Rothbard A. 2021. Trends in antipsychotic prescribing for approved and un-approved indications to Medicaid-enrolled youth in Philadelphia, Pennsylvania between 2014 and 2018. BMC Psychiatry. 21(1):524. doi: 10.1186/s12888-021-03533-3.

* Carton L, Cottencin O, Lapeyre-Mestre M, Geoffroy PA, Favre J, Simon N, Bordet R, Rolland B. 2015. Off-label prescribing of antipsychotics in adults, children and elderly individuals: a systematic review of recent prescription trends. Curr Pharm Des. 21(23):3280-3297. doi: 10.2174/1381612821666150619092903.

* Citrome L, Kalsekar I, Guo Z, Laubmeier K, Hebden T. 2013. Diagnoses associated with use of atypical antipsychotics in a commercial health plan: a claims database analysis. Clin Ther. 35(12):1867-1875. doi: 10.1016/j.clinthera.2013.09.006.

* Comer JS, Mojtabai R, Olfson M. 2011. National trends in the antipsychotic treatment of psychiatric outpatients with anxiety disorders. Am J Psych. 168(10):1057-1065. doi: 10.1176/appi.ajp.2011.11010087.

* Costales B, Slama NE, Penfold RB, Nugent JR, Spalding SR, Sterling SA, Iturralde E. 2024. On- and off-label atypical antipsychotic prescription trends across a nine-year period among adolescents pre- to post-COVID-19. Acad Pediatr. 24(6):995-1000. doi: 10.1016/j.acap.2024.03.003.

* D'Agostino A, Aguglia A, Barbui C, Bartoli F, Carrà G, Cavallotti S, Chirico M, Ostinelli EG, Zangani C, Martinotti G, et al. 2022. Off-label long acting injectable antipsychotics in real-world clinical practice: a cross-sectional analysis of prescriptive patterns from the STAR Network DEPOT study. BMC Psych. 22(1):442. doi: 10.1186/s12888-022-04071-2.

* De Hert M, Detraux J. 2018. The urgent need for optimal monitoring of metabolic adverse effects in children and youngsters who take on-label or off-label antipsychotic medication. JAMA Psychiatry. 75(8):771-772. doi: 10.1001/jamapsychiatry.2018.1080.

* de Kuijper GM, Hoekstra PJ. 2017. Physicians' reasons not to discontinue long-term used off-label antipsychotic drugs in people with intellectual disability. J Intellect Disabil Res. 61(10):899-908. doi: 10.1111/jir.12385.

* dosReis S, Saini J, Hong K, Reeves G, Spence OM. 2022. Trends in antipsychotic use for youth with attention-deficit/ hyperactivity disorder and disruptive behavior disorders. Pharmacoepidemiol Drug Saf. 31(7):810-814. doi: 10.1002/pds.5445.

* Driessen J, Baik SH, Zhang Y. 2016. Trends in off-label use of second-generation antipsychotics in the medicare
<figure><img src="image_17.png" /></figure>

population from 2006 to 2012. Psychiatr Serv. 67(8):898-903. doi: 10.1176/appi.ps.201500316.

Driscoll DJO, McCarthy S. 2024. Antipsychotic prescribing: national findings of children and adolescents attending mental health services in Ireland. Eur Child Adolesc Psychiatry. 33(11):3861-3870. doi: 10.1007/s00787-024-02428-4.

Egberts KM, Gerlach M, Correll CU, Plener PL, Malzahn U, Heuschmann P, Unterecker S, Scherf-Clavel M, Rock H, Antony G, et al. 2022. Serious adverse drug reactions in children and adolescents treated on- and off-label with antidepressants and antipsychotics in clinical practice. Pharmacopsychiatry. 55(5):255-265. doi: 10.1055/a-1716-1856.

Faden J, Citrome L. 2019. Resistance is not futile: treatment-refractory schizophrenia – overview, evaluation and treatment. Expert Opin Pharmacother. 20(1):11-24. doi: 10.1080/14656566.2018.1543409.

Galling B, Roldán A, Nielsen RE, Nielsen J, Gerhard T, Carbon M, Stubbs B, Vancampfort D, De Hert M, Olfson M, et al. 2016. Type 2 diabetes mellitus in youth exposed to antipsychotics: a systematic review and meta-analysis. JAMA Psych. 73(3):247-259. doi: 10.1001/jamapsychiatry.2015.2923.

Garakani A, Buono FD, Salehi M, Funaro MC, Klimowicz A, Sharma H, Faria CGF, Larkin K, Freire RC. 2024. Antipsychotic agents in anxiety disorders: an umbrella review. Acta Psychiatr Scand. 149(4):295-312. doi: 10.1111/acps.13669.

Garakani A, Freire RC, Buono FD, Thom RP, Larkin K, Funaro MC, Salehi M, Perez-Rodriguez MM. 2022. An umbrella review on the use of antipsychotics in anxiety disorders: a registered report protocol. PLoS One. 17(6):e0269772. doi: 10.1371/journal.pone.0269772.

Gjerden P, Bramness JG, Tvete IF, Slørdal L. 2017. The antipsychotic agent quetiapine is increasingly not used as such: dispensed prescriptions in Norway 2004-2015. Eur J Clin Pharmacol. 73(9):1173-1179. doi: 10.1007/s00228-017-2281-8.

Grabitz P, Saksone L, Schorr SG, Schwietering J, Bittlinger M, Kimmelman J. 2024. Research encouraging off-label use of quetiapine: a systematic meta-epidemiological analysis. Clin Trials. 21(4):418-429. doi: 10.1177/17407745231225470.

Hálfdánarson Ó, Zoëga H, Aagaard L, Bernardo M, Brandt L, Fusté AC, Furu K, Garuoliené K, Hoffmann F, Huybrechts KF, et al. 2017. International trends in antipsychotic use: a study in 16 countries, 2005-2014. Eur Neuropsychopharmacol. 27(10):1064-1076. doi: 10.1016/j.euroneuro.2017.07.001.

Hoekstra PJ, Dietrich A. 2022. First do no harm: use off-label antipsychotic medication in children and adolescents with great caution. Eur Child Adolesc Psychiatry. 31(1):1-3. doi: 10.1007/s00787-022-01950-7.

Højlund M, Andersen JH, Andersen K, Correll CU, Hallas J. 2021a. Use of antipsychotics in Denmark 1997-2018: a nation-wide drug utilisation study with focus on off-label use and associated diagnoses. Epidemiol Psychiatr Sci. 30:e28. doi: 10.1017/s2045796021000159.

Højlund M, Lund LC, Andersen K, Correll CU, Hallas J. 2021b. Association of low-dose quetiapine and diabetes. JAMA Netw Open. 4(5):e213209. doi: 10.1001/jamanetworkopen.2021.3209.

Højlund M, Pottegård A, Johnsen E, Kroken RA, Reutfors J, Munk-Jørgensen P, Correll CU. 2019. Trends in utilization and dosing of antipsychotic drugs in Scandinavia: comparison of 2006 and 2016. Br J Clin Pharmacol. 85(7):1598-1606. doi: 10.1111/bcp.13945.

Højlund M, Rasmussen L, Olesen M, Munk-Olsen T, Pottegård A. 2022. Who prescribes quetiapine in Denmark? Br J Clin Pharmacol. 88(9):4224-4229. doi: 10.1111/bcp.15388.

Højlund M, Støvring H, Andersen K, Correll CU, Hallas J. 2023. Impact of low-dose quetiapine-use on glycosylated hemoglobin, triglyceride and cholesterol levels. Acta Psychiatr Scand. 147(1):105-116. doi: 10.1111/acps.13515.

Horvitz-Lennon M, Volya R, Hollands S, Zelevinsky K, Mulcahy A, Donohue JM, Normand ST. 2021. Factors associated with off-label utilization of second-generation antipsychotics among publicly insured adults. Psychiatr Serv. 72(9):1031-1039. doi: 10.1176/appi.ps.202000381.

Huang CW, Chiu YW, Chen PJ, Yu NW, Tsai HJ, Chang CM. 2019. Trends and factors in antipsychotic use of outpatients with anxiety disorders in Taiwan, 2005-2013: a population-based study. Psychiatry Clin Neurosci. 73(8):501-507. doi: 10.1111/pcn.12861.

Huthwaite M, Tucker M, McBain L, Romans S. 2018. Off label or on trend: a review of the use of quetiapine in New Zealand. N Z Med J. 131(1474):45-50.

Kelly M, Dornan T, Pringsheim T. 2018. The lesser of two evils: a qualitative study of quetiapine prescribing by family physicians. CMAJ Open. 6(2):E191-e196. doi: 10.9778/cmajo.20170145.

King C, Voruganti LN. 2002. What's in a name? The evolution of the nomenclature of antipsychotic drugs. J Psychiatry Neurosci. 27:168-175.

Lee H, Zhang C, Rose R, dosReis S. 2022. Pediatric off-label antipsychotic use for attention-deficit/hyperactivity disorder. Clin Ther. 44(9):e83-e90. doi: 10.1016/j.clinthera.2022.07.011.

Leslie DL, Rosenheck R. 2012. Off-label use of antipsychotic medications in Medicaid. Am J Manag Care. 18(3):e109-117-e117.

Lin CY, Chiang CH, Tseng MM, Tam KW, Loh EW. 2023. Effects of quetiapine on sleep: a systematic review and meta-analysis of clinical trials. Eur Neuropsychopharmacol. 67:22-36. doi: 10.1016/j.euroneuro.2022.11.008.

Maher AR, Maglione M, Bagley S, Suttorp M, Hu JH, Ewing B, Wang Z, Timmer M, Sultzer D, Shekelle PG. 2011. Efficacy and comparative effectiveness of atypical antipsychotic medications for off-label uses in adults: a systematic review and meta-analysis. JAMA. 306(12):1359-1369. doi: 10.1001/jama.2011.1360.

Marston L, Nazareth I, Petersen I, Walters K, Osborn DP. 2014. Prescribing of antipsychotics in UK primary care: a cohort study. BMJ Open. 4(12):e006135. doi: 10.1136/bmjopen-2014-006135.

Martin-Latry K, Ricard C, Verdoux H. 2007. A one-day survey of characteristics of off-label hospital prescription of psychotropic drugs. Pharmacopsychiatry. 40(3):116-120. doi: 10.1055/s-2007-977713.

McKean A, Monasterio E. 2012. Off-label use of atypical antipsychotics: cause for concern? CNS Drugs. 26(5):383-390. doi: 10.2165/11632030-000000000-00000.

Olfson M, King M, Schoenbaum M. 2015. Treatment of young people with antipsychotic medications in the United States. JAMA Psych. 72(9):867-874. doi: 10.1001/jamapsychiatry.2015.0500.

Osborne V, Davies M, Layton D, Shakir SAW. 2016. Utilisation of extended release quetiapine (Seroquel XL™): results from an observational cohort study in England. Eur Psychiatry. 33(1):61-67. doi: 10.1016/j.eurpsy.2015.12.004.
<figure><img src="image_18.png" /></figure>

Pathak P, West D, Martin BC, Helm ME, Henderson C. 2010. Evidence-based use of second-generation antipsychotics in a state Medicaid pediatric population, 2001-2005. *Psychiatr Serv.* 61(2):123-129. doi: 10.1176/ps.2010.61.2.123.

Patten SB, Waheed W, Bresee L. 2012. A review of pharmac- epidemiologic studies of antipsychotic use in children and adolescents. *Can J Psych.* 57(12):717-721. doi: 10.1177/ 070674371205701202.

Pennap D, Burcu M, Safer DJ, Zito JM. 2018. The impact of a state medicaid peer-review authorization program on pe- diatric use of antipsychotic medications. *Psychiatr Serv.* 69(3):293-299. doi: 10.1176/appi.ps.201700177.

Pirhonen E, Haapea M, Rautio N, Nordström T, Turpeinen M, Laatikainen O, Koponen H, Silvan J, Miettunen J, Jääskeläinen E. 2022. Characteristics and predictors of off-label use of antipsychotics in general population sam- ple. *Acta Psychiatr Scand.* 146(3):227-239. doi: 10.1111/ acps.13472.

Radha Krishnan RP, Harrison C, Buckley N, Raubenheimer JE. 2024. On- and off-label utilisation of antipsychotics in Australia (2000-2021): retrospective analysis of two medi- cation datasets. *Aust N Z J Psychiatry.* 58(4):320-333. doi: 10.1177/00048674231210209.

Radojičić MR, Pierce M, Hope H, Senior M, Taxiarchi VP, Trefan L, Swift E, Abel KM. 2023. Trends in antipsychotic prescrib- ing to children and adolescents in England: cohort study using 2000-19 primary care data. *Lancet Psych.* 10(2):119- 128. doi: 10.1016/s2215-0366(22)00404-7.

Ray WA, Stein CM, Murray KT, Fuchs DC, Patrick SW, Daugherty J, Hall K, Cooper WO. 2019. Association of an- tipsychotic treatment with risk of unexpected death among children and youths. *JAMA Psych.* 76(2):162-171. doi: 10.1001/jamapsychiatry.2018.3421.

Roehr B. 2012. Marketing of antipsychotic drugs targeted doctors of Medicaid patients, report says. BMJ. 345(oct2 2):e6633-e6633. doi: 10.1136/bmj.e6633.

Ronsley R, Scott D, Warburton WP, Hamdi RD, Louie DC, Davidson J, Panagiotopoulos C. 2013. A population-based study of antipsychotic prescription trends in children and adolescents in British Columbia, from 1996 to 2011. *Can J Psych.* 58(6):361-369. doi: 10.1177/070674371305800608.

Rosenbluth M, Sinyor M. 2012. Off-label use of atypical antipsy- chotics in personality disorders. *Expert Opin Pharmacother.* 13(11):1575-1585. doi: 10.1517/14656566.2011.608351.

Schröder C, Dörks M, Kollhorst B, Blenk T, Dittmann RW, Garbe E, Riedel O. 2017. Extent and risks of antipsychotic off-label use in children and adolescents in Germany be- tween 2004 and 2011. *J Child Adolesc Psychopharmacol.* 27(9):806-813. doi: 10.1089/cap.2016.0202.

Sohn M, Moga DC, Blumenschein K, Talbert J. 2016. National trends in off-label use of atypical antipsychotics in children and adolescents in the United States. *Medicine (Baltimore).* 95(23):e3784. doi: 10.1097/md.0000000000003784.

Stoffers-Winterling JM, Storebø OJ, Pereira Ribeiro J, Kongerslev MT, Völlm BA, Mattivi JT, Faltinsen E, Todorovac A, Jørgensen MS, Callesen HE, et al. 2022. Pharmacological

interventions for people with borderline personality disor- der. *Cochrane Database Syst Rev.* 11(11):Cd012956. doi: 10.1002/14651858.CD012956.pub2.

Stogios N, Smith E, Bowden S, Tran V, Asgarioozbehani R, McIntyre WB, Remington G, Siskind D, Agarwal SM, Hahn MK. 2022. Metabolic adverse effects of off-label use of second-generation antipsychotics in the adult population: a systematic review and meta-analysis. *Neuropsychopharmacology.* 47(3):664-672. doi: 10.1038/s41386-021-01163-7.

Tanne JH. 2010. AstraZeneca pays $520m fine for off label marketing. BMJ. 340 apr29 3):c2380-c2380. doi: 10.1136/ bmj.c2380.

Tanne JH. 2012. Johnson & Johnson pays $181m for mislead- ing marketing of risperidone. BMJ. 345 (sep03 1):e5916- e5916. doi: 10.1136/bmj.e5916.

Verdoux H, Pambrun E, Cortaredona S, Tournier M, Verger P. 2015. Antipsychotic prescribing in youths: a French community-based study from 2006 to 2013. *Eur Child Adolesc Psych.* 24(10):1181-1191. doi: 10.1007/s00787-014-0668-y.

Verdoux H, Quiles C, de Leon J. 2024. Clozapine for persons with neurodevelopmental disorders: a systematic review and expert recommendations for clinical practice.

Verdoux H, Tournier M, Bégaud B. 2010. Antipsychotic pre- scribing trends: a review of pharmaco-epidemiological studies. *Acta Psychiatr Scand.* 121(1):4-10. doi: 10.1111/j. 1600-0447.2009.01425.x.

Verdoux H. 2018. Safety of psychotropic medicines: contribu- tion from observational evidence. *Epidemiol Psychiatr Sci.* 27(6):531-536. doi: 10.1017/s2045796018000276.

Wang B, Franklin JM, Eddings W, Landon J, Kesselheim AS. 2016. Did FDA decision making affect anti-psychotic drug prescribing in children?: a time-trend analysis. *PLoS One.* 11(3):e0152195. doi: 10.1371/journal.pone.0152195.

Wang B, Studdert DM, Sarpatwari A, Franklin JM, Landon J, Kesselheim AS. 2017. The effect of federal and state off-label marketing investigations on drug prescribing: the case of olanzapine. *PLoS One.* 12(4):e0175313. doi: 10.1371/journal.pone.0175313.

Wang J, Jiang F, Yang Y, Zhang Y, Liu Z, Qin X, Tao X, Liu T, Liu Y, Tang YL, et al. 2021. Off-label use of antipsychotic medications in psychiatric inpatients in China: a national real-world survey. *BMC Psych.* 21(1):375. doi: 10.1186/ s12888-021-03374-0.

Zhu X, Hu J, Sun B, Deng S, Wen Y, Chen W, Qiu C, Shang D, Zhang M. 2018. Comparison of unlicensed and off-label use of antipsychotics prescribed to child and adolescent psychiatric outpatients for treatment of mental and be- havioral disorders with different guidelines: the China Food and Drug Administration Versus the FDA. *J Child Adolesc Psychopharmacol.* 28(3):216-224. doi: 10.1089/ cap.2017.0079.

Zito JM, Safer DJ, dosReis S, Gardner JF, Boles M, Lynch F. 2000. Trends in the prescribing of psychotropic medica- tions to preschoolers. *JAMA.* 283(8):1025-1030. doi: 10.1001/jama.283.8.1025.