# Drugs associated with behavioral addictions: Real world analysis using the WHO pharmacovigilance database

Louis Asselin, Edouard-Jules Laforgue, Mélanie Duval, Bruno Revol, Gwenaëlle Veyrac, Marie Grall-Bronnec, Caroline Victorri-Vigneau

► To cite this version:

Louis Asselin, Edouard-Jules Laforgue, Mélanie Duval, Bruno Revol, Gwenaëlle Veyrac, et al. Drugs associated with behavioral addictions: Real world analysis using the WHO pharmacovigilance database. Therapies, 2025, S0040-5957 (25), pp.00104-0. 10.1016/j.therap.2025.07.002. hal-05392660

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ADDICTOLOGY

# Drugs associated with behavioral addictions: Real world analysis using the WHO pharmacovigilance database

Louis Asselinª, Edouard-Jules Laforgueª,b,c,
Mélanie Duvalª,ᵇ, Bruno Revolᵈ, Gwenaëlle Veyracᵉ,
Marie Grall-Bronnecᶜ,ᵈ, Caroline Victorri-Vigneauª,ᵇ,c,\*

Received 25 February 2025; accepted 21 July 2025

KEYWORDS

Behavioral
addictions;
Pharmacovigilance;
Antipsychotics;
Database

Summary

Objectives. — Behavioral addictions (BA) are a newly recognized diagnostic entity. While some drugs are known to induce BA, some of them remains unknown. The aim of this study was to identify drugs for which B is not listed in the summaries of product characteristics.

Methods. — We conducted a search on Vigibase to identify health professional's cases where drugs are ''suspect'' coded with the following preferred terms: (1) 'behavioral addiction', (2) 'gambling disorder', (3) 'gaming disorder', (4) 'compulsive sexual behavior', (5) 'bulimia nervosa', (6) 'binge eating' and (7) 'compulsive shopping'. We selected drugs ''suspect'' in

<footnote>ª Service de pharmacologie clinique, centre d'évaluation et d'information sur la pharmacodépendance-addictovigilance (CEIP-A), CHU de Nantes, Nantes université, 44000 Nantes, France</footnote>

<footnote>ᵇ Unité de pharmacoépidémiologie, service de pharmacologie clinique, CHU de Nantes, Nantes université, 44000 Nantes, France</footnote>

<footnote>ᶜ Inserm, MethodS in Patients-centered outcomes and HEalth Research (SPHERE), Nantes université, CHU de Nantes, CHU de Tours, université de Tours, 44000 Nantes, France</footnote>

<footnote>ᵈ Service de pharmacosurveillance, addictovigilance, CHU de Grenoble-Alpes, 38000 Grenoble, France</footnote>

<footnote>ᵉ Service de pharmacologie clinique, centre régional de pharmacovigilance, CHU de Nantes, Nantes université, 44000 Nantes, France</footnote>

<footnote>f UIC psychiatrie et santé mentale, CHU de Nantes, Nantes université, 44000 Nantes, France</footnote>

<footnote>* Corresponding author. CEIP-A, CHU de Nantes, 9, quai Moncousu, 44093 Nantes cedex, France.
E-mail address: caroline.vigneau@chu-nantes.fr (C. Victorri-Vigneau).</footnote>
at least five cases for which the summaries of product characteristics do not mention BA. We applied a downward descriptive process (drug only suspect, positive dechallenge, well-documented cases) together with a disproportionality analysis and a PubMed search.

*Results.* — We identified 24 drugs across 7 pharmacological classes: antidepressants, antipsychotics, antiepileptics, benzodiazepines, psychostimulants, antidiabetics and retinoids. Olanzapine was the only accompanied by well-documented cases with positive dechallenges, exhibiting significant disproportionality analysis and associated with publications from the PubMed search.

*Conclusion.* — Our results highlights that several drugs and notably olanzapine are associated with BA. Further research using definitions enabling the diagnosis of addictive disorders for various BA is warranted.

© 2025 The Author(s). Published by Elsevier Masson SAS on behalf of Société française de pharmacologie et de thérapeutique. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

## Abbreviations

ATC anatomical therapeutic chemical

BCPNN Bayesian Confidence Propagation Neural Network

BE binge eating disorder

BN bulimia nervosa

CBS compulsive buying-shopping

CI confidence interval

DSM Diagnostic and Statistical Manual of Mental Disorders

GABA gamma-aminobutyric acid

GD gambling disorder

IC information component

ICD International Statistical Classification of Diseases

MedRA Medical Dictionary for Regulatory Activities

PT preferred terms

SPCs summaries of product characteristics

## Introduction

### Addiction: an evolving concept

Addictions encompass a broad field that can involve both substance use and specific behaviors. They represent complex and multifaceted issues, constituting a major public health challenge for both individuals [1,2] and society [3]. Addiction can be characterized by: (A) recurrent failure to control the behavior, and (B) continuation of the behavior despite significant harmful consequences [1,2]. Addictive processes disrupt three key systems: motivation and reward, emotion regulation and inhibitory control. These factors contribute to the definition of addiction, whether it involves rewarding substances or behaviors.

Despite previous descriptions, the inclusion of behavioral addictions in diagnostic classifications like the Diagnostic and Statistical Manual of Mental Disorders (DSM) or International Statistical Classification of Diseases (ICD) is a recent development [4,5]. Indeed, the DSM-5 introduced

non-substance-related addictive disorders, including gambling disorder (GD) in 2013 [5]. Similarly, the ICD-11 included two behavioral addictions: gambling disorder (as in the DSM-5) and gaming disorder since 2019 [4].

To date, no other behavioral addictions have been formally recognized in either the DSM or ICD beyond those mentioned above [4,5]. However, in light of the scientific literature, it appears crucial to acknowledge several other potential behavioral addictions, including sexual addiction [2,6,7], eating disorder with binge eating pattern (i.e., bulimia nervosa [BN] [2,8] and binge eating disorder [BE]) [6,8], and compulsive buying-shopping (CBS) [2,8].

### Drugs and behavioral addictions

Behavioral addictions are complex and underpinned by multiple factors. Among the risk factors for developing behavioral addictions, induction by a substance is of particular concern.

The first cases of drug-induced behavioral addiction, specifically gambling disorder, were reported in the early 2000s among patients treated with dopaminergic agonists for Parkinson's disease [9,10]. As a result, it was subsequently recognized that all dopaminergic agonists, and dopamine replacement therapy more broadly, could potentially lead to behavioral addiction [11–14]. This class effect has been documented for years and is thought to be related to the overstimulation of mesolimbic dopamine pathways [11]. More recently, aripiprazole and brexpiprazole, two dopaminergic receptors partial agonists, has been identified as drugs associated with the development of behavioral addictions [15–17].

Given the association between specific drugs and behavioural addictions, further investigation into these links is essential. The primary objective of this study is to provide an overview of medications reported as 'suspect' in cases of behavioral addiction, utilizing the World Health Organization's global pharmacovigilance database, VigiBase®. Specifically, the study aims to identify drugs for which this
adverse effect is not listed in the summaries of product characteristics (SPCs).

# Methods

## Study design

This pharmacoepidemiologic study aims to identify drugs that are significantly associated with behavioral addiction using the worldwide pharmacovigilance database (VigiBase®) completed with PubMed research for candidate drugs.

## Steering committee

The study was overseen by a steering committee comprising addiction specialists, pharmacologists with expertise in pharmacovigilance, public health physicians, and psychiatrists. This committee has been called upon to oversee the project, at each stage and for each methodological choice.

## Data collection

### VigiBase®

VigiBase® is the World Health Organization's pharmacovigilance database. Established in 1978, it encompasses data from more than 150 countries, representing 99% of the global population. It is the largest pharmacovigilance database in existence, with more than 36 million reports of adverse drug reactions. Drugs within the database are categorized using the anatomical therapeutic chemical (ATC) system, while adverse drug reactions are classified according to the Medical Dictionary for Regulatory Activities (MedDRA).

Adverse event reports can be submitted by healthcare professionals, legal professionals, or patients themselves. Declarations include administrative details (such as age, gender, etc.) and medical information. Drugs involved are assessed for their potential contribution to the reported adverse event and categorized as either "suspect" or "concomitant" [18]. If available, information is also included on dechallenge (i.e., the disappearance of the effect after stopping the suspect drug) and rechallenge (i.e., the reappearance of the effect after re-administration). Ultimately, to enhance the database's quality (as all data for an adverse event are not mandatory), a "VigiGrade" score has been created to assess the quality of declarations. A score above 0.8 is considered indicative of high-quality documentation [19].

### Pubmed® research

Moreover, a Pubmed® bibliographic search encompassed the selected drug's name, the general preferred terms (PT) "behavioural addiction", and any PTs specifically associated with this drug in the reported cases has been conducted. Articles were selected based on their titles and abstracts, with a focus on exploring the potential association between drugs and behavioral addiction. Only articles for which the full text was available were included. Two authors (L.A. and C.V.V.) conducted this research. In cases of disagreement, a third author (E.J.L.) was consulted.

# Methodology

## Search criteria

We selected cases using the PT retained by the steering committee. Selected PT were as follows: (1) "behavioral addiction", (2) "gambling disorder", (3) "gaming disorder", (4) "compulsive sexual behavior", (5) "bulimia nervosa", (6) "binge eating", and (7) "compulsive shopping" and we applied the following research conditions without any restrictions on date or country: (i) the case must be reported by a healthcare professional (physician or pharmacist), (ii) the patient must be aged 12 years or older, and (iii) gender must be specified at the time of reporting.

## Drug selection

We selected drugs from cases, reported as "suspect" at least five cases, for which behavioral dependence is not listed as an adverse effect in either the American or European summaries of product characteristics (SPCs).

## Analysis of selected suspect drugs

For each selected drug, we applied the following downward descriptive process:

* identification of reports where the drug is the only "suspect" (i) among "concomitant" medications (concomitant drugs not known to be responsible for behavioral addictions) or (ii) the only drug present in the case;

* assessment of a positive or negative dechallenge and/or a positive or negative rechallenge;

* analysis of cases with VigiGrade score above 0.8 or those mentioning a published case report in VigiBase®;

* in parallel, a disproportionality analysis with a case-non-case analysis was performed in VigiBase® for each selected drug. The information component (IC) and its 95% confidence interval (CI) were calculated with Bayesian Confidence Propagation Neural Network (BCPNN). A positive IC means that the PT is reported more often than expected, based on all the reports in the database. A lower bound of the 95% CI greater than 0 signifies a significant association between the adverse effect and the drug.

ROR is a ratio similar in concept to odds ratio in case-control studies and defined as the odds of exposure among reported cases of depression relative to the odds of exposure among reported non-cases (controls) [20].

## Bibliographic search

The general PT 'behavioral addiction' was utilized in all searches on Pubmed®, with additional PTs when relevant to the drug being investigated in VigiBase® cases. The PT found in the cases, and thus included in the search equation together on PubMed® with "(Drug, for example 'olanzapine') AND ((behavioral addiction) OR', are "(gambling disorder) OR (gaming disorder) OR (compulsive sexual behavior) OR (bulimia nervosa) OR (binge eating) OR (compulsive buying)); Filters: Humans, English, French". Searches for all study types had been performed on April 2024 with no time limit.
<table><caption>**Table 1** Description of cases and preferred terms retained from VigiBase selection.</caption><thead><tr><th colspan="2">Cases (total n = 1038)</th></tr></thead><tbody><tr><td>Drugs</td><td>n (% on 1038)</td></tr><tr><td>619</td><td></td></tr><tr><td>Gender</td><td></td></tr><tr><td>Male</td><td>566 (54.5%)</td></tr><tr><td>Age (years old)</td><td></td></tr><tr><td>12–17</td><td>34 (3.3%)</td></tr><tr><td>18–44</td><td>372 (35.8%)</td></tr><tr><td>56–65</td><td>477 (46.0%)</td></tr><tr><td>65–74</td><td>123 (11.8%)</td></tr><tr><td>> 75</td><td>32 (3.1%)</td></tr><tr><td>Provenance</td><td></td></tr><tr><td>Europe</td><td>724 (69.7%)</td></tr><tr><td>Including France</td><td>296 (28.5%)</td></tr><tr><td>North America</td><td>205 (24.2%)</td></tr><tr><td>Other</td><td>109 (10.5%)</td></tr><tr><td>Preferred term</td><td></td></tr><tr><td>Gambling disorder</td><td>575 (55.4%)</td></tr><tr><td>Compulsive buying-shopping</td><td>185 (17.8%)</td></tr><tr><td>Bulimia nervosa</td><td>159 (15.3%)</td></tr><tr><td>Binge eating</td><td>130 (12.5%)</td></tr><tr><td>Compulsive sexual behavior</td><td>55 (5.3%)</td></tr><tr><td>Behavioral addiction</td><td>20 (1.9%)</td></tr><tr><td>Gaming disorder</td><td>2 (0.2%)</td></tr></tbody></table>

# Results

## Population characteristics

The description of the cases retained after research for PT in VigiBase® is detailed in Table 1.

## Drug selection

Among the 619 drugs, only 43 were "suspect" in at least five cases. The full distribution of these drugs is illustrated in Fig. 1. Drugs are 16 dopaminergic agonists (37%), 10 antidepressants (23%), 5 dopaminergic antagonists (12%), 3 antiepileptics (7%), 2 partial agonists (5%), 2 benzodiazepines or related drugs (5%), 2 psychostimulants (5%), 1 retinoid (2%), 1 antidiabetic (2%), and 1 other central nervous system drug (2%). The 3 most frequently "suspect" drugs were pramipexole (n = 249; 24%), aripiprazole (n = 221; 21%), and ropinirole (n = 117; 11%), which together accounted for over half of all adverse reaction reports (Fig. 1a).

After analyzing the US and European summary of product characteristics (SPCs), 24 medications were retained for which behavioral addiction is not found in the SPCs. These included: 10 antidepressants (42%), 5 dopamine antagonists (21%), 3 antiepileptics (13%), 2 benzodiazepines or related drugs (8%), 2 psychostimulants (8%), 1 retinoid (4%), and 1 antidiabetic (4%). The three most frequently encountered drugs were olanzapine (n = 25), mirtazapine (n = 15), and quetiapine (n = 13) (Fig. 1b).

## Analysis of "suspect" drugs

Table 1 presents the findings from the stepwise descriptive analysis of the 24 drugs flagged as "suspect" at least 5 times for which behavioral addiction is not found in the SPCs. For each drug, it outlines the type of effect reported in cases from VigiBase®, the presence or absence of positive or negative dechallenge, the disproportionality analysis, and the outcomes of the PubMed® search.

## Antipsychotics

Antipsychotics are detailed in Table 1.

Out of the 25 cases where olanzapine was "suspect", it was the only "suspect" drug 9 times (with concomitant medication present). Among these, there were 3 cases with positive dechallenge and VigiGrade > 0.8 (1 BE and 2 BN). Moreover, it was the only drug prescribed in 4 cases, with one case showing positive dechallenge and VigiGrade > 0.8 (1 CSB). The $CI_{0.25}$ for olanzapine was significant ($CI_{0.25}$ = 2.69 [2.08; 3.19]).

Clozapine was identified as a "suspect" drug in 8 cases. However, no case documented a positive dechallenge. The statistical analysis for clozapine showed no significant findings ($CI_{0.25}$ = -0.37 [-1.54; 0.46]).

The other antipsychotics included quetiapine (13 cases), risperidone (12 cases), and paliperidone (8 cases). Among these, only risperidone has a well-documented case of a positive dechallenge of CSB. Disproportionality analyses for these three drugs yielded significant results: $IC_{0.25}$ (quetiapine) = 1.79 [0.90; 2.47]; $IC_{0.25}$ (risperidone) = 1.45 [0.52; 2.15] and $IC_{0.25}$ (paliperidone) = 2.14 [0.97; 2.97].

The bibliographic search by antipsychotic molecule on PubMed® is detailed in Table 2. After removal of duplicates, 7 articles were identified linking antipsychotics with behavioral addiction.

Stogios conducted a scoping review exploring patterns of disturbed eating in psychosis and highlighted the evidence that antipsychotic treatment may induce binge eating or other related compulsive eating behaviors [21].

Three studies concerned clozapine and olanzapine. One randomized double-blind study [22] compared abnormal eating behavior using a standardized scale in thirty patients with schizophrenia, schizophreniform or schizoaffective disorder treated by either clozapine or olanzapine. In both treatment groups, the number of patients reporting food craving and BE episodes or both increased over time; the likelihood to experience food craving at any time showed a trend to be higher in the olanzapine group compared to clozapine. The likelihood to experience BE episodes at any time was numerically but not statistically significant higher in the olanzapine group than in the clozapine group. These results suggest that both olanzapine and clozapine are associated with increase in food craving and BE episodes.

Gebhardt [23] examined the association between eating disorders prior the use of clozapine or olanzapine and after initiation in 64 patients. The authors concluded that these treatments may exacerbate pre-existing binge eating or trigger full-blown eating disorders.

Theisen et al. explored the BE symptomatology and onset of disorders previous or during antipsychotic treatment in
a

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

b

<figure><img src="image_5.png" /><figcaption>**Figure 1.** "Suspect" drugs reported in the selected cases. a: drugs 'suspect' of behavioral addictions reported at least 5 times on VigiBase; b: drugs 'suspect' of behavioral addictions reported at least 5 times in VigiBase, and for which behavioral addictions are not listed as an adverse reaction in the US or European SPCs.</figcaption></figure>
<table><caption>Table 2 Results of the downward descriptive process.</caption><thead><tr><th rowspan="2">Drugs<sup>a</sup></th><th rowspan="2">N</th><th rowspan="2">Preferred terms (PT)<sup>b</sup></th><th colspan="2">Only drug ‘‘suspect’’<sup>c</sup></th><th colspan="2">Single drug ‘‘suspect’’<sup>d</sup></th><th rowspan="2">Disproportionality</th><th colspan="2">Pubmed® search</th></tr><tr><th>N</th><th>Dechallenge+</th><th>N</th><th>Dechallenge+</th><th>S/N</th><th>Article linking drug to behavioral addictions</th></tr></thead><tbody><tr><td>Olanzapine</td><td>25</td><td>BE/BN/CS/CSB/GD</td><td>9</td><td>1 BE/1 BN/1 BN<sup>e</sup></td><td>4</td><td>1 CS/1 CSB<sup>e</sup></td><td>2.69 [2.08; 3.19]</td><td>6/153</td><td>1 scoping review [21]: antipsychotics in general<br>3 studies clozapine and olanzapine [22–24] including 1 randomized double blind [22] 3 case reports: olanzapine [25,26], clozapine [27]</td></tr><tr><td>Quetiapine</td><td>13</td><td>BE/BN/CS/GD</td><td>2</td><td>1 BN</td><td>2</td><td>1 BE</td><td>1.79 [0.90; 2.47]</td><td>0/68</td><td></td></tr><tr><td>Risperidone</td><td>12</td><td>BE/BN/CSB/GD</td><td>1</td><td>1 CSB</td><td>2</td><td>0</td><td>1.45 [0.52; 2.15]</td><td>0/115</td><td></td></tr><tr><td>Clozapine</td><td>8</td><td>BE/BN/CS/CSB/GD</td><td>0</td><td>0</td><td>4</td><td>0<sup>g</sup></td><td>-0.37 [-1.54; 0.46]</td><td>5/184</td><td></td></tr><tr><td>Paliperidone</td><td>8</td><td>BE/BN/GD</td><td>1</td><td>0</td><td>3</td><td>0</td><td>2.14 [0.97; 2.97]</td><td>0/10</td><td></td></tr><tr><td>Mirtazapine</td><td>15</td><td>BE/BN/CS/CSB/GD</td><td>3</td><td>1 CS/1 CSB</td><td>2</td><td>1 BN</td><td>2.73 [1.91; 3.37]</td><td>0/56</td><td></td></tr><tr><td>Duloxetine</td><td>11</td><td>BE/CS/CSB/GD</td><td>2</td><td>0<sup>f</sup></td><td>0</td><td>0</td><td>2.00 [1.03; 2.73]</td><td>0/41</td><td></td></tr><tr><td>Escitalopram</td><td>11</td><td>BA/BE/BN/CS/CSB/GD</td><td>4</td><td>1 BN/1 BN/1 CS</td><td>2</td><td>0</td><td>2.11 [1.13; 2.84]</td><td>0/83</td><td></td></tr><tr><td>Fluoxetine</td><td>10</td><td>BE/BN/CS/GD</td><td>1</td><td>1 BN</td><td>5</td><td>1 BN/1 CS-GD<sup>e</sup></td><td>1.80 [0.77; 2.55]</td><td>0/387</td><td></td></tr><tr><td>Venlafaxine</td><td>10</td><td>BE/CS/CSB/GD</td><td>2</td><td>1 BE/1 GD</td><td>0</td><td>0</td><td>1.70 [0.67; 2.45]</td><td>0/80</td><td></td></tr><tr><td>Bupropion</td><td>7</td><td>BE/CS/CSB/GD</td><td>2</td><td>0</td><td>0</td><td>0</td><td>1.76 [0.50; 2.63]</td><td>0/660</td><td></td></tr><tr><td>Sertraline</td><td>7</td><td>BE/BN/GD</td><td>1</td><td>1 GD</td><td>1</td><td>0</td><td>1.06 [-0.20; 1.94]</td><td>0/124</td><td></td></tr><tr><td>Amitriptyline</td><td>5</td><td>BE/BN</td><td>2</td><td>1 BE</td><td>1</td><td>1 BN</td><td>0.95 [-0.58; 1.95]</td><td>0/31</td><td></td></tr><tr><td>Paroxetine</td><td>5</td><td>BE/CS/CSB/GD</td><td>0</td><td>0</td><td>2</td><td>1 CSB</td><td>0.99 [-0.54; 1.98]</td><td>0/83</td><td></td></tr><tr><td>Vortioxetine</td><td>5</td><td>BE/BN/CS</td><td>1</td><td>0</td><td>3</td><td>1 BE/1 BN</td><td>2.47 [0.94; 3.46]</td><td>0/8</td><td></td></tr><tr><td>Pregabalin</td><td>9</td><td>BA/BE/BN/CS/GD</td><td>1</td><td>0</td><td>2</td><td>0</td><td>0.87 [-0.22; 1.66]</td><td>0/77</td><td></td></tr></tbody></table>
<table><caption>Table 2 (Continued)</caption><thead><tr><th rowspan="2">Drugs<sup>a</sup></th><th rowspan="2">N</th><th rowspan="2">Preferred terms (PT)<sup>b</sup></th><th colspan="2">Only drug ‘‘suspect’’<sup>c</sup></th><th colspan="2">Single drug ‘‘suspect’’<sup>d</sup></th><th rowspan="2">Disproportionality</th><th colspan="2">Pubmed® search</th></tr><tr><th>N</th><th>Dechallenge+</th><th>N</th><th>Dechallenge+</th><th>S/N</th><th>Article linking drug to behavioral addictions</th></tr></thead><tbody><tr><td>Valproic acid</td><td>7</td><td>BE/BN</td><td>2</td><td>0</td><td>1</td><td>0</td><td>0.81 [-0.45; 1.69]</td><td>0/69</td><td></td></tr><tr><td>Topiramate</td><td>6</td><td>BE/BN/CS</td><td>0</td><td>0</td><td>5</td><td>0</td><td>1.87 [0.49; 2.80]</td><td>0/246</td><td></td></tr><tr><td>Zolpidem</td><td>12</td><td>BE/BN/CS/CSB/GD</td><td>4</td><td>1 BE/1 GD</td><td>5</td><td>1 BN/1 BN</td><td>2.36 [1.43; 3.06]</td><td>0/62</td><td></td></tr><tr><td>Oxazepam</td><td>5</td><td>BA/BN</td><td>0</td><td>0</td><td>0</td><td>0</td><td>2.20 [0.67; 3.19]</td><td>0/18</td><td></td></tr><tr><td>Lisdexamfetamine</td><td>9</td><td>BE/CSB/GD</td><td>4</td><td>4 BE</td><td>2</td><td>1 BE/1 GD</td><td>3.65 [2.55; 4.44]</td><td>0/127</td><td></td></tr><tr><td>Methylphenidate</td><td>8</td><td>BE/BN/CSB/GD</td><td>1</td><td>1 GD</td><td>3</td><td>1 GD</td><td>2.61 [1.44; 3.44]</td><td>0/331</td><td></td></tr><tr><td>Isotretinoin</td><td>7</td><td>BN</td><td>1</td><td>0</td><td>6</td><td>0</td><td>1.33 [0.07; 2.20]</td><td>1/3</td><td>1 observational study [29]</td></tr><tr><td>Semaglutide</td><td>7</td><td>BE/BN</td><td>5</td><td>0</td><td>2</td><td>0</td><td>2.42 [1.16; 3.29]</td><td>0/12</td><td></td></tr></tbody></table>

BA: behavioral addiction; BE: binge eating; BN: bulimia nervosa; CS: compulsive shopping; CSB: compulsive sexual behavior; GD: gambling disorder; S: number of selected articles; N: number of abstracts retrieved using the criteria described in the methodology.

a Drugs ‘‘suspect’’ at least 5 times, with no mention of behavioral addiction as an adverse reaction in the American and European Summaries of Product Characteristics (SPCs).

b Corresponding PTs identified in the cases.

c Only drug ‘‘suspect’’ with ‘‘concomitant’’ with number of cases and dechallenge positive per PT reported. In bold, cases with vigiGrade > 0.8.

d Single drug ‘‘suspect’’ without ‘‘concomitant’’ with number of cases and dechallenge positive per PT reported. In bold, cases with vigiGrade > 0.8.

e Related poster congress abstract on Vigibase.

f Negative dechallenge on cases with vigiGrade > 0.8.

g Negative dechallenge on cases with cases with vigiGrade < 0.8.
74 adolescent and young adult patients treated with clozapine or olanzapine [24]. They found a broad spectrum of BE symptomatology (12.2% of the patients fulfilled criteria for BED and 4.1% for BN) with only a minority (1/5) reporting BE episodes prior to initial antipsychotic treatment. The authors concluded that clozapine/olanzapine may induce BE episodes and full-blown eating disorders which may have predictive value for weight gain.

Three case reports have been identified. Wu described the case of a woman with history of BN that developed resurgence of BN within five weeks after olanzapine initiation. BN resolved with reducing the dose, with remission following dose reduction [25]. This case is also found in our VigiBase search. Stefanou described the case of a 29-year-old man diagnosed with schizophrenia who developed CSB and paraphilia 1.5 months after initiation of olanzapine, with complete remission following withdrawal [26]. Brewerton reported a case of worsening BN six weeks after clozapine initiation in a patient with schizoaffective disorder [27].

## Antidepressants

In total, 12 well-documented cases with a positive dechallenge (5 with selective serotonin reuptake inhibitor (escitalopram, fluoxetine, paroxetine, sertraline), 1 with serotonin and norepinephrin reuptake inhibitor (venlafaxine), 1 with tricyclic (amitriptyline), 3 with mirtazapine and 2 with vortioxetine). In 4 of these cases, the antidepressant is the only medication present. Fluoxetine was identified as the only medication involved, including 1 well-documented case of CSB and GD with an associated conference abstract in VigiBase® [28]. Disproportionality analysis for fluoxetine showed positive results (CI<sub>0.25</sub> = 1.80 [0.77; 2.55]). Duloxetine had one well-documented case of negative dechallenge, it should be noted that for some antidepressants, the disproportionality is negative. Disproportionality analysis was negative for sertraline (CI<sub>0.25</sub> = 1.06 [-0.20; 1.94]), amitriptyline (CI<sub>0.25</sub> = 0.95 [-0.58; 1.95]), and paroxetine (CI<sub>0.25</sub> = 0.99 [-0.54; 1.98]). However, a single case of gambling disorder was reported for sertraline, and one case of binge eating for amitriptyline showed positive dechallenge and a VigiGrade score > 0.8 on VigiBase®.

However, no significant PubMed® findings were identified for any antidepressant.

## Antiepileptics

Pregabalin, valproic acid, and topiramate were each implicated, though none had cases with positive dechallenge, and the PubMed® search yielded no results. Disproportionality analysis was negative for pregabalin (CI<sub>0.25</sub> = 0.87 [-0.22; 1.66]) and valproic acid (CI<sub>0.25</sub> = 0.81 [-0.45; 1.69]), but positive for topiramate (CI<sub>0.25</sub> = 1.87 [0.49; 2.80]).

## Benzodiazepines and related drugs

Zolpidem was reported as a suspect drug in 12 instances, including 4 cases where it was the only suspect drug (alongside concomitant medications), among which 1 well-documented case of BE was noted. It was the only drug implicated in 5 cases, including one well-documented case of BN. Disproportionality analysis showed a positive association

(CI<sub>0.25</sub> = 2.36 [1.43; 3.06]). For oxazepam, there are no cases where it is the only 'suspect' medication. The PubMed search did not find any relevant results for benzodiazepines and related substances.

## Psychostimulants

Only methylphenidate had a well-documented case of gambling disorder (GD) with a positive dechallenge. Lisdexamfetamine (CI<sub>0.25</sub> = 3.65 [2.55; 4.44]) and methylphenidate (CI<sub>0.25</sub> = 2.61 [1.44; 3.44]) showed a positive disproportionality score. However, the PubMed® search did not find any relevant results.

We found 7 cases with isotretinoin. Despite the absence of cases with a positive dechallenge on VigiBase®, disproportionality analysis was positive (CI<sub>0.25</sub> = 1.33 [0.07; 2.20]). A 2023 study analyzing the VigiBase® international pharmacovigilance database was conducted in 2023 and concluded that there was a significant positive association between isotretinoin and BN in children and adolescents [29].

Semaglutide was found in 7 cases, none with positive dechallenge. The PubMed® search did not find any relevant results despite a positive disproportionality.

## Discussion

Our research in Vigibase® highlights that several drugs from different pharmacological classes are associated with terms of behavioral addiction. The methodology employed does not allow for a clear distinction between symptoms and formal diagnoses, notably due to the late definition of behavioral addictions diagnoses in classifications. Indeed, definitions have enabled the diagnosis of addictive disorders for various behavioral addictions by assessing all the criteria; however, in clinical practice, clinicians more commonly encounter symptoms of these disorders particularly symptoms of bingeing and compulsions.

Our analysis allows to narrow down the search to include only the most thoroughly documented cases: the only drugs suspected with positive dechallenge, a VigiGrade score above 0.8 and an analysis of disproportionality. Additionally, bibliographic analysis allowed for comparison of these cases with scientific literature. This process culminated in reducing the initial count of 619 suspect to 1: olanzapine.

These results should be interpreted with caution, as the number of cases is very small and the literature does not provide conclusive data. Most of the articles identified in the PubMed® search exhibited a low level of evidence [30], as they primarily consist of case reports and observational studies. Among these, only one article was a randomized double-blind study [22]. Moreover, the presence of cases in VigiBase® as well as case reports depends on the duration of the drugs' market availability and the number of countries in which they are marketed.

## Strength and limitation

A key strength of this study is the utilization of VigiBase®, the world's largest pharmacovigilance database. Despite variability in reporting quality, our methodology aimed to address this issue by prioritizing cases with comprehen-
sive administrative details, a positive dechallenge when the drug is the only 'suspect', a viGiGrade > 0.8, and reported by healthcare professionals. This approach was designed to ensure specificity and reliability. However, VigiBase® has inherent limitations, notably the absence of clinical details or the clinical progression of reported cases. This underscores the importance of healthcare professionals providing comprehensive information regarding adverse drug reactions, enabling more effective utilization of the pharmacovigilance data. There is an apparent overrepresentation of French reports even though VigiBase® is a global database. This may reflect active national reporting practices by French healthcare professionals, which could contribute to this pattern. The overrepresentation of French reports, as observed in our analysis, is consistent with the literature, which highlights similar patterns for high-income countries and the United States [31,32]. Disproportionality analysis offers two significant advantages: it enables the examination of adverse events in real-world practice, including those with rare or very rare frequencies, aligning well with the objectives of this study [33]. However, disproportionality analysis has some limitations. A positive signal of disproportionality does not refer to a causal link. We set a minimum threshold of five cases to retain only drugs with a more consistent reporting pattern. Although the literature does not validate a clear cut-off, and the minimum generally accepted is three for disproportionality analysis. Lower thresholds have been associated with less stable estimates and an increased risk of false positives due to random variability in spontaneous reports. By choosing a threshold of five, we aimed to improve the specificity of our findings and reduce noise from isolated or weakly documented signals. This conservative choice, while potentially reducing sensitivity, was deemed appropriate in the context of our stringent case selection criteria, which also included the presence of a positive dechallenge, a VigiGrade score above 0.8, and a single suspected drug. These combined measures were intended to prioritize the reliability of the associations over the exhaustiveness of signal detection.

Another limitation of this study concerns the selec-
tion of PTs utilized in the VigiBase® research. Not all PTs
employed are officially recognized as behavioral addictions,
and there remains ongoing debate regarding the classifi-
cation of these disorders in international standards. The
steering committee aimed to minimize misclassification
and to align the research with current scientific under-
standing. Moreover, our stringent selection criteria likely
reduced sensitivity, potentially excluding valid cases. Addi-
tionally, certain PT exhibit symptom overlap; for instance,
"hypersexuality" and CSB share clinical similarities, making
accurate differentiation between the two symptoms chal-
lenging. Consequently, cases of sexual addiction may have
been reported under "hypersexuality".

Nonetheless, we identified olanzapine as a drug for which
our rigorous and specific methodology allows a possible asso-
ciation with behavioral addictions to be questioned. We
acknowledge that this analysis, based on PTs closest to
behavioral addictions, the most detailed cases reported only
by healthcare professionals, and inclusion of cases with pos-
itive dechallenge, certainly allows us to be specific but not
sensitive.

Link between dopaminergic antagonists and behavioral addictions

We found in VigiBase®, associated with antipsychotics, cases of eating disorders and sexual addictions and we have selected articles mainly with olanzapine.

The literature is very rich regarding eating-related dis-
order among patients with schizophrenia, with or without
antipsychotics but lacks conclusive evidence on the role
of antipsychotics. Firstly, heterogeneous methodologies and
confounding factors (socio-economic status) makes a pre-
cise evaluation of eating behavior disorders difficult [21].
Secondly, increased appetite is a possible consequence of
antipsychotic but intrinsic illness-related effects on eat-
ing behaviors remain poorly understood. However, the
specificity of our cases selection (reported by health-
care professionals) avoids the misclassification of increased
appetite — commonly observed with antipsychotics and
likely driven by a distinct pharmacological mechanism —
under the PT BN. Patients with schizophrenia who are
antipsychotic-naïve may have a higher intake of calorie
dense foods than the general population [21] and epi-
demiological review have suggested that approximatively
10% of patients with schizophrenia suffer for binge eat-
ing episodes or night eating syndromes, five times higher
than in the general population [34]. Nevertheless, antipsy-
chotics may not only induce weight gain and obesity
through increase appetite, but also binge eating episodes
and full-blown eating disorders including compensatory
behaviors. All the articles we have selected, as well as
the cases found in VigiBase®, support the hypothesis that
second-generation antipsychotics (olanzapine, clozapine,
quetiapine, risperidone, palipéridone) may induce binge
eating episodes or related compulsive eating disorders. The
two factors, pathology and treatment, seem intertwined:
in the study of Theisen, 12.2% of the patients fulfilled
criteria for BED and 4.1% for BN, with only a minority
that had developed binge eating episodes prior to initial
antipsychotic treatment [24]. In addition, Gebhardt high-
lighted a recurrence or deterioration of binge eating-related
disorders [23].

This resurgence was also found in case reports [25].

It appears necessary to mention clozapine due to the
discrepancy in the findings. In fact, despite the absence
of any cases on VigiBase® and a negative disproportional-
ity analysis, clozapine is the second drug with the most
articles selected on Pubmed®, after olanzapine. Addition-
ally, the five articles found for clozapine overlapped with
those found for olanzapine [22–24,35], including the ran-
domized clinical trial suggesting both may contribute to
the recurrence of BE episodes and BN [22]. However,
clozapine is known to induce obsessive-compulsive disor-
ders, which shares clinical characteristics with behavioral
addictions [36,37].

The reward system plays a well-established role to
the development and maintenance of addictive behaviors,
attributed to the direct or indirect impact of psychotropic
substances on dopaminergic neurons [38–40]. In substance
addiction, there is a disruption of homeostasis, resulting
in a rearrangement of the mesocorticolimbic pathway,
which fosters the development and persistence of addic-
tive behaviors [38–40]. Additionally, it is important to
acknowledge that addiction is a complex phenomenon from
a neurobiological perspective, involving alterations in other
neurotransmitters or systems such as serotonin, opioid
peptides, and the gamma-aminobutyric acid (GABA) sys-
tem [38,40]. Similarities between substance and behavioral
addiction, particularly in the dysregulation of the meso-
corticolimbic pathway and monoamines like dopamine and
serotonin [41–43].

Moreover, antagonism of 5HT<sub>2A</sub> and 5HT<sub>2C</sub> receptors enhances presynaptic dopamine release in dopaminergic pathways. This mechanism is supposed to counteract the D2 receptor antagonism of antipsychotic. The serotoniner- gic system could be involved in clozapine and olanzapine associated binge eating because both drugs affect sero- toninergic transmission as an antagonist with high affinity for all 5HT<sub>2A</sub> receptors [22]. This serotonergic mechanism has also been mentioned to explain the sexual behav- ior disorders associated with antipsychotics and a possible underlying mechanism for occurrence of hypersexuality in patients with olanzapine monotherapy [26]. In patients with primary hypersexual disorders, pathological alterations in brain regions of the reward system have been reported [44]. Olanzapine is the medication that stands out in our selection among antipsychotics; this may be due to olanza- pine having a less dopamine (D<sub>2</sub>) and high serotonin (5HT<sub>2A</sub>) receptors affinity than risperidone with a low ratio D<sub>2</sub>/5HT<sub>2A</sub> of 2 [45].

Antidepressants

Despite the large number of PubMed® search results for,
no relevant articles were found supporting a link between
behavioral addictions and antidepressants. However, one
article was found for an antidepressant that did not come up
in the VigiBase search: citalopram. Cuomo reported the case
of a 58-year-old woman with major depression who devel-
oped a pathological gambling during citalopram treatment
with a reduction in gambling compulsions when reducing the
medication [46].

Zolpidem

Our PubMed® search for zolpidem yielded one notable case report describing compulsive shopping and binge eating, accompanied by partial or complete anterograde amnesia. However, based on the clinical descriptions provided in the article, there remains a possibility that these behaviors may not strictly qualify as behavioral addictions. The pathological behaviors are often accompanied by total or partial amnesia, suggesting potential parasomnias such as sleep-related eating disorders [4].

Zolpidem, binds to GABA-A receptors [47] and no clear pathophysiological mechanism has been established linking it to behavioural addictions. Nonetheless, zolpidem is known for paradoxical effects, including instances with euphoric or stimulating effects [47]. Moreover, zolpidem transiently improved increased blood flow to the frontal cortex [48]. Taken together, could behavioral addictions, then, be construed as a paradoxical outcome of zolpidem use or secondary to increased blood flow of bilateral frontal lobes?

Our pharmacoepidemiological study aimed to identify
drugs ‘‘suspect’’ of inducing behavioral addictions. Among
the drugs investigated, olanzapine emerged as a notable
candidate. Further research using definitions enabling the
diagnosis of addictive disorders for various behavioral
addictions by assessing all the criteria is warranted, and
adverse drug reactions should be continuously reported to
pharmacovigilance services to ascertain a specific causal
relationship. This collective endeavor is crucial for offering a
more comprehensive overview of established and emerging
adverse drug reactions, thus enhancing our understanding of
drug-related risks.

Funding

None.

Authors’ contributions

L.A.: formal analysis; writing – original draft.

E.J.L.: analysis, review and editing.

M.D.: methodology review and editing.

B.R.: project administration, methodology, review and editing.

G.V.: review and editing.

M.G.B.: review and editing.

C.V.V: project administration, formal analysis; writ-
ing – original draft.

Availability of data and materials

The datasets presented in this article are not readily avail-
able because data from this study is derived from the
VigiBase®, the WHO global pharmacovigilance database
composed of individual case safety reports (ICSR).

Disclosure of interest

The authors declare that they have no competing interest.

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