Abstract
Drug-induced mental disorders in children and adolescents are a significant concern, and the relationship between medications and severe mental disorders is not well understood. Utilizing the U.S. Food and Drug Administration’s Adverse Event Reporting System (FAERS), a comprehensive real-world investigation of drug-induced psychiatric disorders in children and adolescents is conducted. We reviewed all adverse event (AE) reports related to mental disorders in children and adolescents in the FAERS database from 2004 to 2024. After data cleansing and standardization, we quantified the statistical association between drugs and mental disorders using the Reporting Odds Ratio (ROR) method. A total of 29,622 AE reports related to drug-induced mental disorders in children and adolescents were identified in the FAERS database, uncovering 252 drugs with positive signals for mental disorders. These medications are primarily used to treat conditions such as Attention Deficit Hyperactivity Disorder (ADHD), psychiatric disorders, acne, asthma, allergic diseases, narcolepsy, contraception, and constipation. Our analysis revealed potential associations between various drugs and mental disorders, with isotretinoin, montelukast, risperidone, methylphenidate, atomoxetine and antidepressants showing higher ROR values, indicating a possible risk of mental disorders. Additionally, we found that some drugs did not explicitly list the risk of mental disorders in their instructions for use.
Keywords: Drug-Induced mental disorders, Children and adolescents, FAERS, Pharmacovigilance, Adverse events
Subject terms: Drug discovery, Psychology
Introduction
Mental disorders in children and adolescents are characterized by a spectrum of mental health conditions that manifest during childhood or adolescence. These disorders may encompass difficulties in emotional, behavioral, cognitive, and social functioning1–3. The WHO predicts that roughly 10 to 20% of the global youth population, including children and adolescents, grapple with mental health issues, with the majority of these conditions manifesting before they reach the age of 14 years4. A comprehensive meta-analysis, which integrated data from 41 studies conducted in 27 different countries, found that around 13.4% of children and adolescents worldwide suffer from mental disorders5. Risk factors for mental disorders in children and adolescents encompass personal characteristics (such as sex, age, ethnicity, and genetic factors) as well as external environmental influences (including family dynamics, societal pressures, and medication use)6–8.
Drug-Induced Mental Disorders in children and adolescents demand vigilant attention. Investigations have demonstrated that steroids, anticonvulsants, quinolone antimicrobials, antimalarial agents, and antiretroviral drugs can elicit psychotic conditions, with the most frequent symptoms being delusions of persecution and auditory hallucinations9–11. A pharmacovigilance study based on the Lareb database in the Netherlands has revealed that between 2003 and 2016, there were a total of 918 reports of adverse drug reactions (ADRs) related to psychiatric disorders in children and adolescents. Among these reports, medications were predominantly focused on drugs used for the treatment of Attention Deficit Hyperactivity Disorder (ADHD), such as methylphenidate and atomoxetine, and asthma medications, including montelukast and fluticasone12. The predisposition to drug-induced mental disorders is multifaceted, encompassing individuals with a history of psychiatric disorders or psychotic episodes, those with cerebral dysfunctions such as brain injury patients, individuals with a history of ethanol or substance misuse, and those exposed to adverse environments like intensive care units who are concurrently suffering from physical comorbidities. The diagnostic process for drug-induced mental disorders is complex and requires a careful evaluation of susceptibility factors.Rapid identification and discontinuation of medications that may precipitate psychiatric disorders in pediatric and adolescent populations are fundamental to clinical management. However, a comprehensive understanding of drug-induced mental disorders to guide clinical practice remains an unmet need in the field. In light of the current context, it is imperative to enhance pharmacovigilance initiatives specifically within the pediatric and adolescent populations. This is crucial for the prompt identification of medications that may trigger psychiatric disorders. Timely action is essential not only for the prevention of such disorders but also for the development of effective therapeutic strategies.
In this study, we reviewed adverse event (AE) records concerning drug-induced mental disorders in children and adolescents, extracted from the FDA’s Adverse Event Reporting System (FAERS) database. We conducted signal detection for all potential drugs associated with drug-induced mental disorders, aiming to summarize the risk characteristics of different medications concerning psychiatric disorders from a pharmacovigilance perspective. This research intends to provide valuable reference information for clinical practice to guide rational medication use and prevent the occurrence of psychiatric disorders.
Materials and methods
Data collection
We Collected AE reports from the FAERS database for a total of 82 quarters, spanning from the first quarter of 2004 to the second quarter of 2024 (https://fis.fda.gov/extensions/FPD-QDE-FAERS/FPD-QDE-FAERS.html).
Data cleaning
We imported the FAERS database data into a PostgreSQL database to establish a local repository and used Python language processing tools to clean and standardize the data. We utilized the Clinical Drug Standard Nomenclature (RxNorm) (https://lhncbc.nlm.nih.gov/MOR/RxTerms/) to standardize all drug names and the Medical Dictionary for Regulatory Activities (MedDRA) v24.0 (https://www.meddra.org/) high-level term (HLT) to standardize adverse events (AEs) and drug indications. We filtered the study population data, selecting “Primary Suspect Drug” and setting the age range to “3–18 years.” We used the high-level terms “Depressive disorders,” “Emotional and mood disturbances NEC(Not Elsewhere Classified),” “Suicidal and self-injurious behavior,” “Anxiety symptoms,” and “Anxiety disorders NEC” for targeted AE queries, collecting adverse events that cause psychiatric disorders in children and adolescents. Duplicate reports were identified and excluded based on the report information.
AE signal detection and analysis
Based on the disproportionality analysis, the reporting odds ratio (ROR) method was employed to calculate the risk signals for target adverse events (AEs). The formula for calculating ROR is ROR = ad/bc, and the 95% confidence interval (CI) was given by elnROR ± 1.96 (1/a + 1/b + 1/c + 1/d)^0.5. Here, a is the number of reports containing both the target drug and the target adverse drug reaction (ADR), b is the number of reports containing the target drug but with other adverse drug reactions, c is the number of reports containing the target adverse drug reaction but with other drugs, d is the number of reports containing other drugs and other adverse drug reactions. Statistical analysis and data processing were conducted using the R programming language. The ROR method was utilized to assess the risk of target AEs associated with the suspect drugs. A positive signal was defined as a ≥ 3a and a lower 95% CI > 1, indicating a statistically significant association between the suspect drug and the target AE. The larger the ROR value, the stronger the correlation and risk signal.We identified primary suspect drugs associated with five categories of psychiatric disorders in children and adolescents aged 3–18 years. The process of data extraction and cleaning is illustrated by a flowchart as shown in Fig. 1.
Fig. 1.
Flow diagram of data extraction and cleaning.
Results
Descriptive analysis
From the first quarter of 2004 to the second quarter of 2024, the FAERS database documented 21,558,935 adverse events. By applying the High-Level Term (HLT) filtering, we identified 29,622 reports closely associated with specific adverse events (AEs). The detailed process is shown in Table 1. Among the 29,622 reports analyzed, key demographic and clinical variables were recorded at varying completeness levels. Gender information was available for 28,941 (97.7%) cases, while the completeness of other variables was detailed in Table 2. The trend in the number of annual adverse event reports is depicted in Fig. 2, with the peak number of reports in 2019, amounting to 2,311 cases, while in 2024, only the first and second quarters’ reports were collected, totaling 1,358 cases. Table 2 details the clinical characteristics of these 29,622 reports. In cases of drug-induced mental disorders in children and adolescents, after excluding cases with missing information, males accounted for 36.94% and females for 33.19%, with a similar gender ratio. The age distribution revealed that the 15–18 age group had the highest number of patients, with 14,971 cases (50.54%); followed by the 11–14 age group, with 7,060 cases (23.83%); the 7–10 age group, with 4,967 cases (16.77%); and the 3–6 age group, with 2,624 cases (8.86%). The median age (Q1, Q3) was 15 years (10.00, 17.00). The primary reporter occupations were primarily pharmacists, physicians, and other health professionals, accounting for 38.01%, and the reports predominantly originated from North America, followed by Europe. According to the characteristics of Table 3, the proportion of serious outcomes for the five types of psychiatric disorders was 79.11%, with the highest proportion of serious outcomes for suicidal and self-injurious behavior, reaching 98.14%, and a relatively high proportion of deaths, at 20.44%.
Table 1.
Top 15 medications associated with mental disorders in children and adolescents by Frequency.
| HLT of depressive disorder | Emotional and mood disturbances NEC | Suicidal and self-injurious behaviour | HLT of Anxiety symptoms | HLT of Anxiety disorders NEC | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Drug name | Number of cases | ROR (95% CI) | Drug name | Number of cases | ROR (95% CI) | Drug name | Number of cases | ROR (95% CI) | Drug name | Number of cases | ROR (95% CI) | Drug name | Number of cases | ROR (95% CI) |
| isotretinoin | 1907 | 18.62(17.59–19.72) | risperidone | 2387 | 14.71(13.97–15.49) | montelukast | 1272 | 7.52(7.05–8.02) | montelukast | 1491 | 12.03(11.31–12.81) | montelukast | 73 | 29.89(22.77–39.24) |
| montelukast | 1023 | 15.39(14.31–16.55) | montelukast | 1403 | 11.14(10.46–11.87) | isotretinoin | 1205 | 3.4(3.19–3.62) | methylphenidate | 818 | 2.66(2.48–2.87) | methylphenidate | 13 | 2.15(1.23–3.75) |
| drospirenone, ethinylestradiol | 171 | 3.48(2.97–4.06) | isotretinoin | 1003 | 3.49(3.27–3.74) | sertraline | 893 | 8.81(8.15–9.53) | isotretinoin | 737 | 2.41(2.23–2.6) | isotretinoin | 12 | 2.01(1.12–3.58) |
| sodium oxybate | 82 | 4.28(3.41–5.36) | atomoxetine | 866 | 3.45(3.21–3.71) | paracetamol | 843 | 4.79(4.45–5.17) | atomoxetine | 677 | 2.56(2.37–2.78) | polyethylene glycol | 10 | 15.19(8.05–28.66) |
| polyethylene glycol | 69 | 3.87(3.03–4.94) | methylphenidate | 761 | 2.48(2.3–2.68) | fluoxetine | 718 | 9.1(8.34–9.93) | drospirenone, ethinylestradiol | 541 | 6.41(5.83–7.05) | citalopram | 7 | 17.69(8.31–37.63) |
| elexacaftor, ivacaftor, tezacaftor | 54 | 2.2(1.67–2.89) | drospirenone, ethinylestradiol | 485 | 5.67(5.14–6.26) | ibuprofen | 600 | 2.25(2.07–2.45) | lisdexamfetamine | 309 | 2.64(2.34–2.97) | fluoxetine | 7 | 4.39(2.07–9.32) |
| paroxetine | 44 | 2.93(2.16–3.97) | lisdexamfetamine | 417 | 3.75(3.38–4.16) | quetiapine | 559 | 5.25(4.78–5.76) | sertraline | 307 | 2.95(2.62–3.32) | lorazepam | 5 | 18.19(7.47–44.3) |
| medroxyprogesterone | 41 | 4.72(3.43–6.5) | polyethylene glycol | 258 | 9.04(7.86–10.41) | lisdexamfetamine | 478 | 3.47(3.14–3.82) | fluoxetine | 223 | 2.71(2.36–3.11) | carbamazepine | 4 | 3.85(1.43–10.34) |
| interferon beta | 37 | 2.4(1.73–3.34) | guanfacine | 118 | 3.28(2.71–3.97) | bupropion | 423 | 8.69(7.77–9.73) | polyethylene glycol | 207 | 6.73(5.78–7.84) | ciprofloxacin | 4 | 9.2(3.42–24.78) |
| doxycycline | 33 | 2.83(1.99–4.02) | paroxetine | 111 | 4.06(3.32–4.95) | paroxetine | 330 | 13.34(11.65–15.29) | paroxetine | 169 | 6.61(5.59–7.82) | paroxetine | 3 | 5.33(1.7–16.67) |
| finasteride | 29 | 41.65(25.81–67.22) | amphetamine aspartate, amphetamine sulfate, dextroamphetamine saccharate, dextroamphetamine sulfate | 88 | 3.36(2.69–4.19) | promethazine | 282 | 67.14(53.33–84.53) | olanzapine | 168 | 2.78(2.37–3.26) | clarithromycin | 3 | 5.18(1.66–16.2) |
| citalopram | 25 | 2.28(1.53–3.4) | oxycodone | 83 | 2.14(1.71–2.67) | escitalopram | 250 | 11.66(10.01–13.58) | bupropion | 154 | 3.15(2.66–3.72) | oxycodone | 3 | 3.99(1.28–12.48) |
| dexmethylphenidate | 25 | 2.84(1.9–4.25) | dexmethylphenidate | 81 | 5.25(4.14–6.65) | metformin | 243 | 9.71(8.35–11.28) | sodium oxybate | 112 | 2.99(2.46–3.64) | gabapentin | 3 | 7.26(2.32–22.72) |
| duloxetine | 20 | 2.32(1.48–3.62) | triptorelin | 63 | 4.62(3.54–6.03) | alprazolam | 221 | 6.97(5.99–8.11) | citalopram | 79 | 3.95(3.12–5) | |||
| varenicline | 17 | 14.77(8.66–25.19) | trofinetide | 55 | 3.52(2.66–4.66) | venlafaxine | 220 | 12.59(10.67–14.84) | amphetamine aspartate, amphetamine sulfate, dextroamphetamine saccharate, dextroamphetamine sulfate | 74 | 2.74(2.15–3.48) | |||
| lurasidone hydrochloride | 17 | 2.12(1.31–3.45) | venlafaxine | 48 | 2.41(1.79–3.24) | citalopram | 206 | 10.67(9.04–12.59) | diphenhydramine | 74 | 2.58(2.03–3.28) | |||
Only 13 medications are associated with anxiety disorders.
Table 2.
Patient characteristics on Drug-Induced mental disorders in children and Adolescents.
| Demographic variables | Cases, n (%) | |
|---|---|---|
| Gender | Male | 15,243(51.46) |
| Female | 13,698(42.24) | |
| Missing | 681(2.30) | |
| Age Group(year) | [3–6] | 2624(8.86) |
| [7–10] | 4967(16.77) | |
| [11–14] | 7060(23.83) | |
| [15–18] | 14,971(50.54) | |
| Age(year) | Mean(SD) | 13.28 (4.06) |
| Median(Q1,Q3) | 15.00 (10.00, 17.00) | |
| Reporters’ occupations | Consumer or non-health professional | 9772(33.00) |
| Physician | 7675(25.91) | |
| Other health professional | 6861(23.16) | |
| Lawyer | 1951(6.58) | |
| Pharmacist | 1146(3.87) | |
| Missing | 2217(7.48) | |
| Continent | North America | 18,295(61.76) |
| Europe | 7892(26.64) | |
| Missing | 1793(6.05) | |
| Asia | 949(3.20) | |
| South America | 328(1.11) | |
| Oceania | 290(0.98) | |
| Africa | 75(0.25) | |
Fig. 2.
Trend Graph of Annually Reported Adverse Event Numbers for Five Drug-Related Mental Disorders from 2004 to Q1-Q2 of 2024.
Table 3.
Outcome characteristics of reported cases with Drug-Induced mental disorders in children and Adolescents.
| Outcome | TOTAL | Depressive disorders | Emotional and mood disturbances NEC | Suicidal and self-injurious behaviour | Anxiety symptoms | Anxiety disorders NEC | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Cases Reported (N) | Percentage (%) | Cases Reported (N) |
Percentage (%) | Cases Reported (N) |
Percentage(%) | Cases Reported (N) |
Percentage(%) | Cases Reported (N) |
Percentage(%) | Cases Reported (N) |
Percentage (%) | |
| Non-Serious | 6187 | 20.89 | 739 | 14.48 | 4255 | 42.92 | 264 | 1.86 | 1793 | 21.22 | 16 | 8.12 |
| Serious | 23,435 | 79.11 | 4366 | 85.52 | 5659 | 57.08 | 13,914 | 98.14 | 6657 | 78.78 | 181 | 91.88 |
| Serious-Death | 2973 | 12.69 | 117 | 2.68 | 111 | 1.96 | 2844 | 20.44 | 221 | 3.32 | 5 | 2.76 |
| Serious-Life Threatening | 2270 | 9.69 | 410 | 9.39 | 331 | 5.85 | 1836 | 13.2 | 584 | 8.77 | 20 | 11.05 |
| Serious-Disability | 1367 | 5.83 | 535 | 12.25 | 507 | 8.96 | 485 | 3.49 | 773 | 11.61 | 51 | 28.18 |
| Serious-Hospitalization | 8888 | 37.93 | 1188 | 27.21 | 1286 | 22.72 | 6119 | 43.98 | 2527 | 37.96 | 44 | 24.31 |
| Serious-Congenital Anomaly | 34 | 0.1 | 5 | 0.11 | 5 | 0.09 | 9 | 0.06 | 14 | 0.21 | 1 | 0.55 |
| Serious-Required Intervention | 319 | 1.36 | 96 | 2.2 | 94 | 1.66 | 173 | 1.24 | 131 | 1.97 | 4 | 2.21 |
| Serious-Other | 15,712 | 67.05 | 3529 | 80.83 | 4506 | 79.63 | 8315 | 59.76 | 4714 | 70.81 | 147 | 81.22 |
Disproportionality analysis
In accordance with the ROR criteria, a total of 252 drugs with positive signals for psychiatric disorders were unearthed. Based on the frequency of adverse event reports, Table 1 provides a summary of the top 15 medications associated with five categories of psychiatric disorders in pediatric and adolescent patients. Among the 252 drugs identified with positive psychiatric disorder signals, isotretinoin and montelukast exhibited the strongest associations with depressive disorders (ROR 18.62 and ROR 15.39, respectively). Finasteride showed the highest ROR (41.65). Among emotional and mood disturbances, risperidone and montelukast had relatively high ROR values (14.71 and 11.14, respectively). In suicidal and self-injurious behaviour, montelukast, promethazine and paroxetine had relatively high ROR values (7.52, 67.14 and 13.34, respectively). Montelukast had the highest ROR values in both Anxiety symptoms and Anxiety disorders. These suggests a potentially strong signal for psychiatric effects.
Isotretinoin (1907 cases, ROR 18.62, 95% CI 17.59–19.72) is the most common drug associated with depressive disorders, followed by montelukast (1023 cases, ROR 15.39, 95% CI 14.31–16.55), drospirenone-ethinylestradiol (171 cases, ROR 3.48, 95% CI 2.97–4.06), sodium oxybate (82 cases, ROR 4.28, 95% CI 3.41–5.36), polyethylene glycol (69 cases, ROR 3.87, 95% CI 3.03–4.94), elexacaftor-ivacaftor-tezacaftor (54 cases, ROR 2.20, 95% CI 1.67–2.89), paroxetine (44 cases, ROR 2.93, 95% CI 2.16–3.97), medroxyprogesterone (41 cases, ROR 4.72, 95% CI 3.43–6.5), interferon beta (37 cases, ROR 2.4, 95% CI 1.73–3.34), and doxycycline (44 cases, ROR 2.83, 95% CI 1.99–4.02), among others. Additionally, finasteride (29 cases, ROR 41.65, 95% CI 25.81–67.22) and varenicline (17 cases, ROR 14.77, 95% CI 8.66–25.19) exhibit elevated ROR values (Table 1).
Risperidone (2387 cases, ROR 14.71, 95% CI 13.97–15.49) is the most commonly associated drug with emotional and mood disturbances, followed by montelukast (1403 cases, ROR 11.14, 95% CI 10.46–11.87), isotretinoin (1003 cases, ROR 3.49, 95% CI 3.27–3.74), atomoxetine (866 cases, ROR 3.45, 95% CI 3.21–3.71), methylphenidate (761 cases, ROR 2.48, 95% CI 2.3–2.68), drospirenone-ethinylestradiol (485 cases, ROR 5.67, 95% CI 5.14–6.26), lisdexamfetamine (417 cases, ROR 3.75, 95% CI 3.38–4.16), polyethylene glycol (258 cases, ROR 9.04, 95% CI 7.86–10.41), guanfacine (118 cases, ROR 3.28, 95% CI 2.71–3.97), and paroxetine (111 cases, ROR 4.06, 95% CI 3.32–4.95), among others (Table 1).
Montelukast (1272 cases, ROR 7.52, 95% CI 7.05–8.02) is the most common drug associated with suicidal and self-injurious behavior, followed by isotretinoin (1205 cases, ROR 3.4, 95% CI 3.19–3.62), sertraline (893 cases, ROR 8.81, 95% CI 8.15–9.53), paracetamol (843 cases, ROR 4.79, 95% CI 4.45–5.17), fluoxetine (718 cases, ROR 9.1, 95% CI 8.34–9.93), ibuprofen (600 cases, ROR 2.25, 95% CI 2.07–2.45), quetiapine (559 cases, ROR 5.25, 95% CI 4.78–5.76), lisdexamfetamine (478 cases, ROR 3.47, 95% CI 3.14–3.82), bupropion (423 cases, ROR 8.69, 95% CI 7.77–9.73), and paroxetine (330 cases, ROR 13.34, 95% CI 11.65–15.29), among others. Furthermore, promethazine (282 cases, ROR 67.14, 95% CI 53.33–84.53) demonstrates a notably high ROR value (Table 1).
Montelukast (1491 cases, ROR 12.03, 95% CI 11.31–12.81) is the most frequently implicated medication in inducing anxiety symptoms, followed by methylphenidate (818 cases, ROR 2.66, 95% CI 2.48–2.87), isotretinoin (737 cases, ROR 2.41, 95% CI 2.23–2.60), atomoxetine(677 cases, ROR 2.56, 95% CI 2.37–2.78), drospirenone-ethinylestradiol (541 cases, ROR 6.41, 95% CI 5.83–7.05), lisdexamfetamine (309 cases, ROR 2.64, 95% CI 2.34–2.97), sertraline (307 cases, ROR 2.95, 95% CI 2.62–3.32), fluoxetine (223 cases, ROR 2.71, 95% CI 2.36–3.11), polyethylene glycol (207 cases, ROR 6.73, 95% CI 5.78–7.84), and paroxetine (169 cases, ROR 6.61, 95% CI 5.59–7.82), among others (Table 1).
Montelukast (73 cases, ROR 29.89, 95% CI 22.77–39.24) is the most commonly associated drug with anxiety disorders, followed by methylphenidate (13 cases, ROR 2.15, 95% CI 1.23–3.75), isotretinoin (12 cases, ROR 2.01, 95% CI 1.12–3.58), polyethylene glycol (10 cases, ROR 15.19, 95% CI 8.05–28.66), citalopram (7 cases, ROR 17.69, 95% CI 8.31–37.63), fluoxetine (7 cases, ROR 4.39, 95% CI 2.07–9.32), lorazepam (5 cases, ROR 18.19, 95% CI 7.47–44.3), carbamazepine (4 cases, ROR 3.85, 95% CI 1.43–10.34), ciprofloxacin (4 cases, ROR 9.2, 95% CI 3.42–24.78), and paroxetine (3 cases, ROR 5.33, 95% CI 1.7–16.67), among others (Table 1).
A summary of indications for drug-induced mental disorders in children and adolescents is presented in Table 4. The top ten indications corresponding to the five categories of drug-induced mental disorders are as follows: ADHD (5575 cases), Acne (2246 cases), Asthma (1929 cases), Depression (1585 cases), Bipolar Disorder (608 cases), Anxiety (589 cases), Autism Spectrum Disorder (533 cases), Oppositional Defiant Disorder (ODD, 476 cases), Affective Disorder (456 cases), and Multiple Allergies (375 cases). For drug-induced depressive disorders, the top ten indications are Acne (1280 cases), Asthma (676 cases), ADHD (563 cases), Acne cystic (188 cases), Hypersensitivity (135 cases), Multiple Allergies (125 cases), Narcolepsy (87 cases), Contraception (83 cases), Anxiety (71 cases), and Rhinitis allergic (63 cases). Regarding emotional and mood disturbances induced by medication, the leading indications are ADHD (3307 cases), Asthma (874 cases), Acne (699 cases), Oppositional defiant disorder (ODD, 430 cases), Depression (408 cases), Bipolar Disorder (397 cases), Autism Spectrum Disorder (393 cases), Affective Disorder (379 cases), Anxiety (251 cases), and Constipation (216 cases). The top ten indications for medication-induced Suicidal and self-injurious behaviour are ADHD (1268 cases), Depression (1126 cases), Asthma (858 cases), Acne (735 cases), Anxiety (328 cases), Major Depression (197 cases), Suicide Attempt (173 cases), Hypersensitivity (161 cases), Bipolar Disorder (148 cases), and Multiple Allergies (135 cases). For medication-induced anxiety symptoms, the top ten indications are ADHD (1543 cases), Asthma (955 cases), Acne (588 cases), Depression (426 cases), Contraception (187 cases), Multiple Allergies (178 cases), Constipation (176 cases), Hypersensitivity (140 cases), Narcolepsy (119 cases), and Anxiety (108 cases). Lastly, for medication-induced anxiety disorders, the top ten indications are Asthma (54 cases), ADHD (22 cases), Acne (9 cases), Constipation (9 cases), Multiple Allergies (8 cases), Bipolar Disorder (8 cases), Depression (8 cases), Anxiety (6 cases), Suicidal Depression (6 cases), and Urinary Tract Infection (4 cases).
Table 4.
Indications for Drug-induced mental disorders in children and Adolescents.
| Total | Depressive disorders | Emotional and mood disturbances NEC | ||||||
|---|---|---|---|---|---|---|---|---|
| Indications | Cases Reported (N) |
Percentage (%) | Indications | Cases Reported (N) |
Percentage (%) | Indications | Cases Reported (N) |
Percentage (%) |
| Attention deficit hyperactivity disorder | 5575 | 23.46 | Acne | 1280 | 27.48 | Attention deficit hyperactivity disorder | 3307 | 28.36 |
| Acne | 2246 | 9.45 | Asthma | 676 | 14.51 | Asthma | 874 | 7.49 |
| Asthma | 1929 | 8.12 | Attention deficit hyperactivity disorder | 563 | 12.09 | Acne | 699 | 5.99 |
| Depression | 1585 | 6.67 | Acne cystic | 188 | 4.04 | Oppositional defiant disorder | 430 | 3.69 |
| Bipolar disorder | 608 | 2.56 | Hypersensitivity | 135 | 2.9 | Depression | 408 | 3.5 |
| Anxiety | 589 | 2.48 | Multiple allergies | 125 | 2.68 | Bipolar disorder | 397 | 3.4 |
| Autism spectrum disorder | 533 | 2.24 | Narcolepsy | 87 | 1.87 | Autism spectrum disorder | 393 | 3.37 |
| Oppositional defiant disorder | 476 | 2 | Contraception | 83 | 1.78 | Affective disorder | 379 | 3.25 |
| Affective disorder | 456 | 1.92 | Anxiety | 71 | 1.52 | Anxiety | 251 | 2.15 |
| Multiple allergies | 375 | 1.58 | Rhinitis allergic | 63 | 1.35 | Constipation | 216 | 1.85 |
| others | 9395 | 39.52 | others | 1387 | 29.43 | others | 4308 | 37.41 |
| Suicidal and self-injurious behaviour | Anxiety symptoms | Anxiety disorders NEC | ||||||
|---|---|---|---|---|---|---|---|---|
| Indications | Cases Reported (N) |
Percentage(%) | Indications | Cases Reported (N) |
Percentage(%) | Indications | Cases Reported (N) |
Percentage(%) |
| Attention deficit hyperactivity disorder | 1268 | 16.49 | Attention deficit hyperactivity disorder | 1543 | 20.84 | Asthma | 54 | 27.98 |
| Depression | 1126 | 14.64 | Asthma | 955 | 12.9 | Attention deficit hyperactivity disorder | 22 | 11.4 |
| Asthma | 858 | 11.16 | Acne | 588 | 7.94 | Acne | 9 | 4.66 |
| Acne | 735 | 9.56 | Depression | 426 | 5.75 | Constipation | 9 | 4.66 |
| Anxiety | 328 | 4.27 | Contraception | 187 | 2.53 | Multiple allergies | 8 | 4.15 |
| Major depression | 197 | 2.56 | Multiple allergies | 178 | 2.4 | Bipolar disorder | 8 | 4.15 |
| Suicide attempt | 173 | 2.25 | Constipation | 176 | 2.38 | Depression | 8 | 4.15 |
| Hypersensitivity | 161 | 2.09 | Hypersensitivity | 140 | 1.89 | Anxiety | 6 | 3.11 |
| Bipolar disorder | 148 | 1.92 | Narcolepsy | 119 | 1.61 | Depression suicidal | 6 | 3.11 |
| Multiple allergies | 135 | 1.76 | Anxiety | 108 | 1.46 | Urinary tract infection | 4 | 2.07 |
| others | 2560 | 33.06 | others | 2984 | 39.64 | others | 59 | 30.63 |
*Indications/Number of Indication Records
Medication duration of drug-induced mental disorders in children and dolescents
The duration of medication use of drug-induced mental disorders in children and adolescents was calculated (see Table 5, with the unit being days), and the median total duration of medication use was 24 (1, 160) days. The median duration of medication use was 24 days (IQR: 1–160 days). Most cases had short-term medication exposure, with 6,650 cases using the drug for only one day. However, 2,005 cases exceeded 721 days, suggesting prolonged exposure in a subset of patients (Table 5).
Table 5.
Medication duration associated with Drug-induced mental disorders in children and Adolescents.
| Time variable | Mean (SD) | Median (IQR) | Frequency |
|---|---|---|---|
| Total Duration | 246.65 (2133.39) | 24 (1, 160) | 15,370 |
| Segmented Statistics | |||
| 1 Days | 1.00 (0.04) | 1 (1, 1) | 6650 |
| 2 Days | 2.00 (0.00) | 2 (2, 2) | 414 |
| 3 Days | 3.00 (0.00) | 3 (3, 3) | 279 |
| 4–7 Days | 5.51 (1.15) | 6 (4, 7) | 806 |
| 8–14 Days | 11.02 (2.21) | 11 (9, 13) | 945 |
| 15–30 Days | 22.63 (5.04) | 22 (18, 28) | 1695 |
| 31–60 Days | 41.80 (9.50) | 40 (33, 49) | 1773 |
| 61–90 Days | 73.32 (9.63) | 72 (64, 82) | 988 |
| 91–120 Days | 103.34 (9.50) | 103 (93, 112) | 735 |
| 121–150 Days | 134.50 (9.87) | 134 (125, 144) | 572 |
| 151–180 Days | 163.69 (9.91) | 161 (154, 173) | 469 |
| 181–270 Days | 218.27 (26.47) | 215 (194, 243) | 824 |
| 271–360 Days | 311.88 (27.12) | 309 (287, 335) | 496 |
| 361–720 Days | 494.53 (109.38) | 481 (392, 580) | 1440 |
| 721- Days | 1731.16 (6556.66) | 1311 (946, 1899) | 2005 |
Discussion
This study utilized real-world data from the FAERS pharmacovigilance database to conduct a comprehensive assessment of adverse events associated with drug-induced mental disorders in children and adolescents. We described the clinical characteristics of these adverse events and identified the medications most closely associated with pediatric and adolescent drug-induced mental disorders.
We identified 29,622 reports of drug-induced mental disorders adverse events in the population aged 3–18 years. Notably, these psychiatric disorder adverse events were predominantly concentrated in the 12–18 age group, with a median age (Q1, Q3) of 15 (10.00, 17.00). This finding suggests that adolescence may be a high-risk period for drug-induced psychiatric disorders, necessitating particular attention. A study indicates that the burden of mental disorders increases with age across different age groups. Specifically, in the 10–14 age group, the disability-adjusted life years (DALYs) for conduct disorders and attention-deficit/hyperactivity disorder (ADHD) are the highest, followed by a gradual decline13. This phenomenon may be associated with the rapid physiological and psychological changes during adolescence, a period during which an individual’s neurodevelopment, hormonal levels, and pressures from the social environment can all potentially impact mental health14. Furthermore, the manifestations of drug-induced mental disorders in children and adolescents may differ from those observed in adults. This population may be more susceptible to the effects of medications, leading to the onset of psychiatric disorders. This increased vulnerability could be related to their stage of brain development, particularly during the maturation of the prefrontal cortex, which is intimately associated with functions such as impulse control and decision-making15. Abnormalities in neurotransmitters such as norepinephrine, serotonin, and dopamine are considered to be the foundation for the development of psychiatric disorders16,17. Medications may induce psychiatric disorders due to their impact on neurotransmitters.
By analyzing data from the FAERS, we investigated the onset time of drug-induced mental disorders in children and adolescents. The study found that the median onset time was 24 days, with over half of the cases developing within this timeframe. Statistical analysis of the onset time revealed a higher number of cases within the first 1–3 days, potentially associated with acute drug reactions. As time progressed, the number of cases decreased, but there was an increase in the 31–90 day period, possibly related to long-term drug effects or individual sensitivities. Notably, even after prolonged medication use exceeding 721 days, there were 2005 cases reported, indicating that the risk of long-term medication remains. These findings underscore the necessity for stringent monitoring of medication use in children and adolescents, particularly the need for rapid assessment and intervention for patients with acute onset, as well as continuous monitoring for those on long-term medication to prevent mental health issues.
The study identified that the primary indications associated with drug-induced mental disorders in children and adolescents are Attention Deficit Hyperactivity Disorder (ADHD), psychiatric disorders, acne, asthma, allergic diseases, narcolepsy, contraception, and constipation.The study found that some medications do not explicitly state the risk of inducing psychiatric disorders in children and adolescents within their package inserts.
Children and adolescents with ADHD reported a total of 5,575 cases of drug-induced mental disorders, which ranked first among the indications for emotional and mood disorders, suicidal and self-injurious behaviors, and anxiety states. The medications implicated may include methylphenidate, dexmethylphenidate (d-threo-methylphenidate), lisdexamfetamine, and atomoxetine. All four drugs detected signals for emotional and mood disturbances, anxiety symptoms, or anxiety disorders. Specifically, lisdexamfetamine showed signals for suicidal and self-injurious behavior, while dexmethylphenidate was associated with various signals for depressive disorders. The study suggests that adverse reactions in the nervous system may occur following ADHD medication treatment18–20. Mosholder et al. reported a prevalence of psychiatric symptoms of 1.5% following exposure to ADHD medications (compared to 0% for placebo)21. Marco Pozzi et al.22 noted that in the FAERS database, reports of adverse events related to emotional symptoms associated with ADHD medications were predominantly attributed to atomoxetine, accounting for 50.7% of the reports, followed by methylphenidate with 32.5%, and lisdexamfetamine with 14.2%. For all medications, irritability, anxiety, obsessive thinking, depressive mood, and euphoria scores were all significantly associated with ROR23.
Among the top 20 medications, those prescribed for pediatric and adolescent patients with psychiatric disorders, the drugs implicated in reports of drug-induced mental disorders adverse events may include selective serotonin reuptake inhibitors (SSRIs) such as sertraline, paroxetine, fluoxetine, citalopram, and escitalopram; serotonin-norepinephrine reuptake inhibitors (SNRIs) like venlafaxine and duloxetine; atypical antidepressants (bupropion); monoamine oxidase inhibitors (MAOIs) (viloxazine); atypical antipsychotics (risperidone, paliperidone, quetiapine, olanzapine); and benzodiazepines (alprazolam). These medications are primarily associated with suicidal and self-injurious behaviors, anxiety symptoms or anxiety disorders, and emotional and mood disorders. Among these, there were a total of 4,101 cases of suicidal and self-injurious behaviors AE, with 2,397 cases involving SSRIs, 333 cases involving SNRIs (venlafaxine), 423 cases involving the atypical antidepressant bupropion, 727 cases involving atypical antipsychotics (559 cases of quetiapine, 168 cases of olanzapine), and 221 cases involving the benzodiazepine alprazolam. SSRIs are prone to induce suicidal and self-injurious behaviors, which is consistent with findings from randomized controlled trials (RCTs). The study found that there is an increased risk of new-onset suicidal ideation and behaviors in children and adolescents in the SSRI treatment group23. A meta-analysis specifically highlighted that, compared to placebo and five other antidepressant medications (escitalopram, imipramine, duloxetine, fluoxetine, and paroxetine), venlafaxine is significantly associated with an increased risk of suicidal behavior or ideation24. The prescribing information for quetiapine, olanzapine, and alprazolam does not mention adverse reactions of suicidal and self-injurious behaviors. In this study, we collected reports of 559 cases of quetiapine, 168 cases of olanzapine, and 221 cases of alprazolam associated with suicidal and self-injurious behavior adverse events, which warrants close monitoring in clinical practice. A total of 1,286 cases of anxiety symptoms or anxiety disorders adverse events were reported, with 863 cases involving SSRIs, 101 cases involving SNRIs, 154 cases involving the atypical antidepressant bupropion, and 168 cases involving the atypical antipsychotic olanzapine. Previous studies have found that the use of antidepressants in children and adolescents can lead to activation symptoms, including hyperactivity, irritability, insomnia, disinhibition, restlessness, agitation, and anxiety24–27. During the first 2 or 3 weeks of treatment, the activation tendency is more pronounced28. The early emergence of activation adverse effects in children and adolescents should take into account the impact of cytochrome (CYP) enzymes, drug interactions, and phenotypic transformations on the pharmacokinetics of antidepressant medications. CYP activity varies during development, and genetic variations in these enzymes can significantly affect the exposure (area under the curve [AUC]), maximum concentration (CMAX), and half-life (t½) of several commonly used SSRIs in adolescents, leading to pharmacokinetically related adverse events29. In children and adolescents, anxiety symptoms induced by antidepressant medications overlap with the core symptoms of the treated conditions, complicating the identification of treatment-related anxiety symptoms. Therefore, it is crucial to assess symptoms before initiating treatment, and to reduce the occurrence of related adverse reactions during the treatment process through dose adjustments and slower titration29.
Pediatric patients with acne reported a total of 2,246 cases of drug-induced mental disorders adverse events, involving the drug isotretinoin. Signals for all five types of psychiatric disorders were detected, with the ROR (95% CI) for depressive disorders, emotional and mood disturbance, suicidal and self-injurious behaviors, anxiety symptoms, and anxiety disorders being 18.62 (17.59–19.72), 3.49 (3.27–3.74), 3.4 (3.19–3.62), 2.41 (2.23–2.60), and 2.01 (1.12–3.58), respectively. The study suggests that isotretinoin may be associated with depression, emotional disorders, suicidal tendencies, and anxiety symptoms, although this relationship is controversial30. Some studies have also found that at the population level, there is no increased risk of suicide or mental illness among users of isotretinoin, but there may be a low risk of suicide attempts within 2 to 4 years after treatment. The psychological distress caused by severe acne may be a contributing factor to suicide or depression during the patient’s medication period, rather than isotretinoin itself16,31. Therefore, further research is needed to elucidate the relationship between isotretinoin and psychiatric disorders. Clinicians should provide comprehensive psychodermatological care for patients with acne and monitor for signs of psychological distress during isotretinoin treatment.
Pediatric patients with asthma reported a total of 1,929 cases of drug-induced mental disorders adverse events. The medications involved may include montelukast and beclomethasone. Montelukast was associated with signals for all five types of psychiatric disorders, with the ROR (95% CI) for depressive disorders, Emotional and mood disturbances, suicidal and self-injurious behaviors, anxiety symptoms, and anxiety disorders being 15.39 (14.31–16.55), 11.14 (10.46–11.87), 7.52 (7.05–8.02), 12.03 (11.31–12.81), and 29.89 (22.77–39.24), respectively. Recent research has found a potential association between montelukast and neuropsychiatric adverse reactions in children and adolescents, including depression, sleep disturbances, and suicidal ideation32,33. Montelukast may affect the central nervous system by disrupting the glutathione detoxification system in the brain, as well as modulating neurotransmitter and neurosteroid pathways, particularly those involved in the regulation of the hypothalamic-pituitary-adrenal (HPA) axis32.
Among the top 20 medications, those prescribed for allergic diseases in children and adolescents reported drug-induced mental disorders adverse events primarily associated with cetirizine, promethazine, and diphenhydramine. Cetirizine mainly revealed signals for various types of depression (12 cases, ROR 2.62, 95% CI 1.47–4.68). The prescribing information for this drug notes that it can cause adverse reactions such as anxiety, depression, and emotional agitation, which should be taken into consideration in clinical practice. Promethazine mainly revealed signals for suicidal and self-injurious behaviour (282 cases, ROR 67.14, 95% CI 53.33–84.53) and anxiety symptoms (54 cases, ROR 4.75, 95% CI 3.56–6.3). Diphenhydramine mainly revealed signals for suicidal and self-injurious behaviour (169 cases, ROR 5.37, 95% CI 4.54–6.36) and anxiety symptoms (74 cases, ROR 2.58, 95% CI 2.03–3.28). The prescribing information for promethazine and diphenhydramine does not record these emotional disorders. Reports on antihistamines causing suicide and anxiety are relatively scarce. Pinar Guzel Ozdemir et al. reported that cetirizine and hydroxyzine seem to have a negative impact on emotional states34. F SABON35 reported a case of a patient who committed suicide while concurrently taking quinine, promethazine, and aspirin. The analysis suggests that the central nervous system depressant effects of quinine and promethazine, combined with the toxicity of aspirin, may have collectively contributed to the suicidal act. Given the widespread clinical use of antihistamines, these findings warrant closer examination in further studies.
In this study, medications implicated in narcolepsy may include sodium oxybate, as well as compound formulations of calcium oxybate- magnesium oxybate- potassium oxybate-amphetamine. Sodium oxybate was associated with depressive disorders signals (82 cases, ROR 4.28, 95% CI 3.41–5.36) and anxiety symptoms (112 cases, ROR 2.99, 95% CI 2.46–3.64), which are not documented in the prescribing information.
In this study, among the top 20 medications implicated in the five categories of drug-induced mental disorders, newly identified risk signals include elexacaftor- ivacaftor-tezacaftor (54 cases, ROR 2.2, 95% CI 1.67–2.89) associated with depressive disorders, polyethylene glycol causing depressive disorders (69 cases, ROR 3.87, 95% CI 3.03–4.94), emotional and mood disturbances (258 cases, ROR 9.04, 95% CI 7.86–10.41), anxiety symptoms (207 cases, ROR 6.73, 95% CI 5.78–7.84), and anxiety disorders (10 cases, ROR 15.19, 95% CI 8.05–28.66); doxycycline inducing depressive disorders (33 cases, ROR 2.83, 95% CI 1.99–4.02); paracetamol (843 cases, ROR 4.79, 95% CI 4.45–5.17), ibuprofen (600 cases, ROR 2.25, 95% CI 2.07–2.45), metformin (243 cases, ROR 9.71, 95% CI 8.35–11.28), amlodipine (206 cases, ROR 5.72, 95% CI 4.91–6.67), and tramadol (169 cases, ROR 3.79, 95% CI 3.22–4.46) associated with suicidal and self-injurious behaviour signals; carbamazepine inducing anxiety disorders (4 cases, ROR 3.85, 95% CI 1.43–10.34) signals. While these findings still require extensive clinical research for validation, they should nonetheless be of significant concern to the public.
While our study provides a comprehensive overview of medications with potential risks of mental disorders in children and adolescents from a pharmacovigilance perspective, it is not without its inherent limitations. Firstly, ROR does not establish causation, only association. These findings indicate potential associations between these drugs and mental disorders. Secondly, FAERS is a spontaneous reporting system, and results should be interpreted with caution due to potential biases and underreporting. Data is based on voluntary reporting, which may introduce reporting bias. Thirdly, confounding factors such as patient gender, age, race, comorbidities, and concomitant medications significantly impact the occurrence of adverse events, but there is currently a lack of recognized practices to eliminate the influence of these factors. The relationship between medications and adverse events still requires further validation. In the future, our research will integrate electronic health records and prospective cohort designs to validate these findings.
Conclusions
This study utilized the FAERS database to conduct a comprehensive analysis of adverse events associated with drug-induced mental disorders in children and adolescents. The research revealed a wide array of suspected medications, encompassing drugs used to treat a variety of conditions including attention deficit hyperactivity disorder, psychiatric disorders, acne, asthma, allergic diseases, narcolepsy, contraception, and constipation. Isotretinoin, montelukast, risperidone, methylphenidate, atomoxetine, and antidepressants demonstrated elevated ROR values. It is noteworthy that the risks of psychiatric disorders associated with several high-risk medications have not been explicitly labeled in the prescribing information for children and adolescents.Our findings highlight the need for stricter monitoring of high-risk medications such as isotretinoin, montelukast, and antidepressants. It is necessary that clinicians should assess psychiatric risk factors before prescribing and conduct regular follow-ups, especially in adolescents.Monitoring can timely detect adverse reactions to mental disorders, intervene early, and avoid the occurrence of serious adverse reactions to mental disorders.
Acknowledgements
This study was performed using the FDA Adverse Event Reporting System (FAERS)database that was provided by the FDA. The information, results, or interpretation of the current study do not represent any opinion of the FDA.
Author contributions
Linlin Tang, Lijuan Teng, and Qian Li contributed to the study concept and design. Linlin Tang, Hui Li, and Qian Li contributed to acquisition of data. Linlin Tang, Hui Li, Chuanhua Ding, Xue Zhao, and Lijuan Teng contributed to analysis and interpretation of data. Linlin Tang and Lijuan Teng contributed to drafting of the manuscript. Linlin Tang and Hui Li contributed to statistical analysis. Linlin Tang and Qian Li are co-first authors. All authors have read and approved the manuscript.
Funding
This work was supported by the Natural Science Foundation of Shandong Province of China (ZR2022LSW016).
Data availability
Data for pharmacovigilance studies can be collected from the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) and can be obtained through the FAERS Quarterly Data Extract Files (https://fis.fda.gov/extensions/FPD-QDE-FAERS/FPD-QDE-FAERS.html).
Declarations
Competing interests
The authors declare no competing interests.
Consent for publication
Not applicable.
Consent to participate
Not applicable.
Ethics
Institutional review board approval was waived for this study because FAERS is a public anonymized database.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Linlin Tang and Qian Li have equally contributed this work.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Data for pharmacovigilance studies can be collected from the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) and can be obtained through the FAERS Quarterly Data Extract Files (https://fis.fda.gov/extensions/FPD-QDE-FAERS/FPD-QDE-FAERS.html).