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. 2025 Apr 21;31(8):2630–2640. doi: 10.1111/odi.15337

Oral Adverse Effects of Antipsychotic Medications: A Case/Noncase Analysis of EudraVigilance Data

Leire Urien 1, Unax Lertxundi 2, Montserrat Garcia 3, Carmelo Aguirre 1,3, Nerea Jauregizar 1,4, Teresa Morera‐Herreras 1,5,✉
PMCID: PMC12423477  PMID: 40259575

ABSTRACT

Objective

Neuropsychiatric disorders are associated with poor oral health, with antipsychotics as potential contributors. This study aimed to analyse the oral adverse effects of antipsychotics using the EudraVigilance database.

Methods

A case/noncase analysis was conducted to calculate reporting odds ratios (ROR) and assess the disproportionality of oral adverse events.

Results

A total of 5663 reports of oral adverse effects related to antipsychotics were identified. Atypical antipsychotics had a higher overall incidence (5663 vs. 787 for typical), but typical antipsychotics showed stronger associations with specific oral issues (ROR = 2.2 vs. 1.6 for atypical). The most commonly reported effects were disturbances in salivary flow, including xerostomia and hypersalivation. Olanzapine and quetiapine were linked to dry mouth (ROR = 1.8 and 3.0) and tooth loss (ROR = 1.7 and 1.8). Clozapine had the highest number of reports (1619) and ROR (33.1) for hypersalivation. Disproportionality analysis revealed significant associations with orofacial dyskinesia for all antipsychotics, except clozapine. Aripiprazole had the highest ROR (13.7) for orofacial dyskinesia and was linked to a swollen tongue in patients aged ≤ 17 years (12 cases, ROR = 3.6). No sex‐based differences were identified.

Conclusions

Antipsychotics significantly affect oral health, highlighting the need for preventive dental care and interventions to reduce these effects and improve patient well‐being.

Keywords: atypical antipsychotics, drug‐related side effects, EudraVigilance, oral health, pharmacovigilance, typical antipsychotics

1. Introduction

It is well documented that individuals with mental health disorders are at an elevated risk of poor physical health and higher mortality rates compared to the general population (Chan et al. 2023; Momen et al. 2022). In recent years, there has been a growing interest in the oral health of people with mental disorders, given the significant relationship between oral health and overall physical and mental condition, as well as its link to systemic diseases (Denis et al. 2020; Kisely et al. 2015). In this regard, a number of studies have demonstrated that patients with schizophrenia tend to exhibit poorer oral health outcomes, including a higher prevalence of decayed, missing and filled teeth, as well as periodontitis (Arnaiz et al. 2011; Chu et al. 2012; Comparelli et al. 2021; Denis et al. 2019; Hu et al. 2019; Wey et al. 2016). Conversely, it has been documented that individuals diagnosed with bipolar disorder are at an elevated risk of developing dental caries, periodontal disease and occasional gingival lacerations (Sari et al. 2024). Similarly, the literature indicates that the oral health of children with autism spectrum disorders is inferior to that of the general population (Ferrazzano et al. 2020). Additionally, individuals with dementia exhibit a higher prevalence of retained roots, caries and oral soft tissue complications compared to those without dementia (Ho et al. 2023).

The deterioration of oral health in individuals with mental disorders, particularly schizophrenia, has been attributed to a multitude of factors, including unhealthy lifestyles (such as poor oral hygiene habits and substance abuse), systemic conditions (such as obesity, metabolic syndrome, or diabetes) and limited access to dental care (Drake et al. 1998; Henderson et al. 2006; Kebede et al. 2019). Furthermore, it has been proposed that the adverse effects of antipsychotic medication employed for the clinical management of these neuropsychiatric disorders may also contribute to poorer oral health outcomes (Wey et al. 2016).

All first‐generation (typical) and second‐generation (atypical) antipsychotics have been observed to block brain dopaminergic D2 receptors, and their clinical efficacy appears to be similar. However, the safety profiles of these drugs vary considerably (Goff 2014; Lally and MacCabe 2015; Lieberman et al. 2005); UpToDate, 2023). Indeed, adverse effects are specific to each antipsychotic drug, do not conform to first‐ and second‐generation classifications and can range from minor tolerability problems to life‐threatening complications. With the exception of tardive dyskinesia, which is more prevalent in patients treated with first‐generation antipsychotics, adverse effects such as weight gain, extrapyramidal, cardiac, or metabolic effects are not specific to a particular group of antipsychotics (Stroup and Gray 2018). The information on the oral safety of antipsychotics, obtained from the summary of product characteristics (available on the online medication information page (CIMA) of the Spanish Agency for Medicines and Health Products of the Ministry of Health of the Spanish Government; https://cima.aemps.es/cima/publico/home.html), shows that the oral side effects of the most commonly prescribed antipsychotic drugs exhibit considerable variability. Regarding olanzapine, dry mouth has been described as a highly prevalent adverse reaction, whereas hypersalivation has been reported to occur infrequently. In contrast, hypersalivation is a highly prevalent adverse reaction associated with clozapine. With regard to risperidone, reports indicate that dry mouth and toothache occur with high frequency, while tongue oedema is less prevalent. In the case of quetiapine, dry mouth is classified as a very frequent adverse reaction. With regard to aripiprazole, the most frequently reported oral adverse reactions are hypersecretion of saliva. In the case of paliperidone, the most frequently reported adverse reactions are dry mouth and dental pain. Spontaneous reporting systems are regarded as a vital component of postmarketing drug safety monitoring, primarily for the identification of adverse drug reactions. However, following the introduction of a drug to the market, health authorities begin to receive new spontaneous adverse drug reaction reports as a result of increased exposure of patients to the medication over extended periods.

While the adverse effects of antipsychotics have been the subject of extensive study, the literature on the oral side effects induced by these agents remains relatively scarce. In light of the significant correlation between oral health and overall well‐being, as well as the incidence of morbidity and mortality, the present study sought to investigate the potential link between antipsychotic medications and oral adverse reactions. This analysis focused on the most commonly prescribed antipsychotics, utilising the centralised European pharmacovigilance database (EudraVigilance) to provide a comprehensive overview. The EudraVigilance database, established by the European Medicines Agency (EMA), manages and analyses reports of suspected adverse drug reactions to medicines from various sources, including pharmaceutical companies (in accordance with their postmarketing obligations, especially after Phase 4 studies), healthcare professionals (such as clinicians, pharmacists and nurses) and patients (Lertxundi et al. 2017).

2. Materials and Methods

2.1. Data Source and Case Extraction

This study used EudraVigilance as the data source, a centralised European database that monitors suspected adverse drug reactions to medicines authorised within the European Economic Area. EudraVigilance was used to identify oral adverse reactions related to antipsychotic drugs, including all reports from the inception of the database until 23 March 2023. A case/noncase study was conducted to investigate the potential association between exposure to antipsychotics and the incidence of oral side effects. The present case/noncase study was carried out at the Basque Country Pharmacovigilance Unit.

Antipsychotics were categorised into two groups: typical (chlorpromazine, levomepromazine, fluphenazine, perphenazine, haloperidol, pericyazine, zuclopenthixol, pimozide, loxapine and clotiapine) and atypical antipsychotics (amisulpride, aripiprazole, asenapine, cariprazine, clozapine, lurasidone, olanzapine, paliperidone, quetiapine, risperidone, sertindole and ziprasidone). A more detailed examination was then conducted of the six most commonly prescribed antipsychotic medications in the public health service providing care to residents of the province of Bizkaia in northern Spain (Bizkaia Mental Health Network), which included olanzapine, clozapine, risperidone, quetiapine, aripiprazole and paliperidone.

Oral adverse reactions (or ‘cases’) were identified using the following preferred terms (from the Medical Dictionary for Regulatory Activities, MedDRA, version 26.0): ‘dental caries’, ‘dry mouth’, ‘gingival recession’, ‘gingival swelling’, ‘lip swelling’, ‘oral discomfort’, ‘oral hypoesthesia’, ‘parotid gland enlargement’, ‘salivary hypersecretion’, ‘submaxillary gland enlargement’, ‘swollen tongue’, ‘tongue discomfort’, ‘tongue movement disturbance’, ‘tooth disorder’, ‘tooth loss’ and ‘toothache’. Noncases were defined as all other adverse drug reaction reports recorded in EudraVigilance during the same period. Exposure was defined as exposure to antipsychotics among both cases and noncases, irrespective of whether the drug was suspected of causing the adverse reaction.

2.2. Data Analysis and Disproportionality Estimation

A descriptive analysis was performed to characterise the data on oral adverse reactions, taking into account both typical and atypical antipsychotics. The analysis was carried out in two stages: first, a general overview of the distribution of the oral reactions was obtained across the two categories of antipsychotics, and second, the distribution was examined for each specific oral adverse reaction under study, considering gender. Subsequently, the analysis was refined to examine the data for each individual antipsychotic.

Subsequently, a case/noncase analysis was performed by calculating the reporting odds ratio (ROR) and its 95% confidence interval (CI) as measures of disproportionality between a drug and an oral adverse drug reaction. The ROR was calculated using a 2‐by‐2 contingency table for each antipsychotic (ROR = ab/cd, where a = case exposed; b = noncase exposed; c = case nonexposed and d = noncase nonexposed). In accordance with the recommendations set forth by the European Medicines Agency, a signal of disproportionate reporting is identified when the following conditions are met: the lower bound of the 95% CI of the ROR is > 1 and the number of individual cases is ≥ 3 (European Medicines Agency n.d.; European Medicines Agency 2017). In order to exclude litigation cases, a process of subgrouping was employed according to the geographical region of reporting (North America, Europe, Japan, the rest of Asia and the rest of the world). In this regard, in EudraVigilance, a drug‐event combination constitutes a signal of disproportionate reporting if the lower bound of the 95% CI of the ROR is above 1 in one region and the number of individual cases is ≥ 3 in the same region (screening for adverse reactions in EudraVigilance).

For the six most commonly prescribed antipsychotics in the Bizkaia Mental Health Network, each individual case report pertaining to the oral adverse reactions that met the criteria for generating a signal of disproportionate reporting was extracted. The analysis considered gender (female), age (divided into four categories: ≤ 17 years; 18–64; 65–85 and > 85) and the seriousness of the adverse reaction (expressed as a percentage of serious cases relative to the total number of cases for each drug). The seriousness of each adverse reaction was determined according to the criteria set out by the European Union (Directive 2001/83/EEC), which defines a serious reaction as an adverse reaction that results in death, is life‐threatening, requires hospitalisation or its prolongation, leads to persistent or significant disability, or is a congenital anomaly.

2.3. Ethical Considerations

The study (protocol number 13/23) was approved by the Research Ethics Committee (IRB) of Galdakao‐Usansolo Hospital.

3. Results

3.1. Data Analysed

Over the course of the data collection period (from the inception of the EudraVigilance database until 23 March 2023), the EudraVigilance database received 5663 spontaneous cases of suspected oral adverse reactions related to antipsychotic drugs (Table 1). The female‐to‐male sex ratio was 1:1, with 50.1% of reports from female patients and 49.9% of reports coming from male patients. Of the total number of reports, 787 notifications were related to typical antipsychotic drugs (chlorpromazine, levomepromazine, fluphenazine, perphenazine, haloperidol, pericyazine, zuclopenthixol, pimozide, loxapine and clotiapine), while the remaining 5132 corresponded to atypical antipsychotics (amisulpride, aripiprazole, asenapine, cariprazine, clozapine, lurasidone, olanzapine, paliperidone, quetiapine, risperidone, sertindole and ziprasidone) (Table 1).

TABLE 1.

Disproportionality measures for the association between antipsychotic drugs and the selected oral adverse reactions in EudraVigilance.

Exposure Number of cases Number of noncases ROR (95% CI)
All drugs 134,361 10,840,679 Reference
Typical antipsychotics 787 28,740 2.2 (2.1–2.4)
Atypical antipsychotics 5132 270,281 1.6 (1.5–1.6)
Typical + atypical antipsychotics 5663 289,807 1.6 (1.6–1.7)
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Note: It should be noted that a statistically significant disproportionality was observed in cases reported for both typical and atypical antipsychotics.

Abbreviations: CI, confidence interval; ROR, reporting odds ratio.

3.2. Disproportionality Estimation for All the Antipsychotic Drugs

The observed disproportionality was statistically significant for all the antipsychotic drugs, as well as for atypical and typical antipsychotics, and for the entire set of selected oral adverse reactions. Conversely, although the absolute number of reported cases was higher for the atypical antipsychotic group, the oral adverse reaction association was stronger for typical drugs (ROR 2.2 [95% CI, 2.1–2.4] vs. ROR 1.6 [95% CI, 1.5–1.6]).

Subsequently, the values of the disproportionality estimators for all antipsychotics were analysed separately for typical and atypical drugs, and for each oral adverse reaction, the data were separated by sex. The observed disproportionality was statistically significant for dental caries (typical drugs, male patients), dry mouth (typical and atypical drugs, all patients (males and females)), parotid gland enlargement (atypical drugs, females), salivary hypersecretion (typical and atypical drugs, all patients (males and females)), swollen tongue (typical drugs, male patients) and tongue movement disturbance (typical and atypical drugs, all patients (males and females)) (Table 2). The highest associations were identified for salivary hypersecretion and tongue movement disorders, with respective RORs of 21.2 [95% CI, 20.2–22.1] and 9.0 [95% CI, 7.5–10.9]. The disproportionality analysis did not identify a positive association between antipsychotic drugs and gingival recession, gingival swelling, lip swelling, oral discomfort, oral hypoaesthesia, submaxillary gland enlargement, tongue discomfort, tooth disorder, tooth loss and toothache (Table S1).

TABLE 2.

Disproportionality measures for the association between antipsychotic drugs and each specific oral adverse reaction in EudraVigilance.

Adverse reaction Type of antipsychotic Sex Number of cases Number of noncases ROR (95% CI)
Dental caries
Typical Male 9 15,272 2.4 (1.2–4.6)
Dry mouth
Typical Male 99 15,182 2.3 (1.9–1.8)
Females 149 12,946 2.7 (2.3–3.2)
All cases 252 29,239 2.4 (2.1–2.7)
Atypical Male 462 140,224 1.2 (1.1–1.3)
Females 714 120,830 1.4 (1.3–1.5)
All cases 1201 274,212 1.2 (1.1–1.3)
Typical + atypical Male 540 149,432 1.3 (1.2–1.4)
Females 822 128,454 1.5 (1.4–1.6)
All cases 1389 291,612 1.3 (1.3–1.4)
Parotid gland enlargement
Atypical Females 24 121,520 2.2 (1.5–3.3)
All cases 42 275,371 1.5 (1.1–2.0)
Typical + atypical Females 26 129,250 2.2 (1.5–3.3)
All cases 44 292,957 1.5 (1.1–2.0)
Salivary hypersecretion
Typical Male 225 15,056 18.0 (15.7–20.6)
Females 153 12,942 20.0 (17.0–23.6)
All cases 386 29,105 19.7 (17.8–21.9)
Atypical Male 1505 139,181 20.4 (19.0–21.7)
Females 1050 120,494 19.1 (17.8–20.6)
All cases 2616 272,797 20.0 (19.1–21.0)
Typical + atypical Male 1616 148,353 21.7 (20.2–23.1)
Females 1138 128,138 20.1 (18.87–21.6)
All cases 2821 290,180 21.2 (20.2–22.1)
Swollen tongue
Typical Male 37 15,244 1.67 (1.2–2.3)
Tongue movement disturbance
Typical Male 17 15,264 21.0 (12.8–34.4)
Females 7 13,088 8.0 (3.8–16.9)
All cases 24 29,467 13.6 (9.0–20.4)
Atypical Male 50 140,636 1.7 (5.0–10.5)
Females 58 121,486 8.0 (6.1–10.6)
All cases 120 275,293 8.3 (6.8–10.1)
Typical + atypical Male 61 149,911 9.3 (7.0–12.5)
Females 62 129,214 8.1 (6.2–10.6)
All cases 135 292,866 9.0 (7.5–10.9)
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Note: The table shows the drugs that meet the criteria for generating a disproportionate reporting signal (the lower bound of the 95% CI of the ROR is > 1 and the number of individual cases is ≥ 3).

Abbreviations: CI, confidence interval; ROR, reporting odds ratio.

3.3. Disproportionality Estimation for the Most Commonly Prescribed Antipsychotics in the Bizkaia Mental Health Network

As illustrated in Figure S1, disproportionality measures were extracted for each of the six selected drugs, representing the most widely prescribed atypical antipsychotics within the Bizkaia Mental Health Network during the study period. The disproportionality analysis revealed statistically significant differences for dental caries (aripiprazole and olanzapine), dry mouth and tooth loss (olanzapine and quetiapine), parotid gland enlargement (clozapine), salivary hypersecretion (all drugs), swollen tongue (aripiprazole) and altered tongue movement (all drugs except clozapine). The disproportionality analysis did not identify a positive association between these antipsychotic drugs and the other oral adverse reactions examined (Table S2).

Subsequently, a comprehensive analysis was conducted to ascertain the disproportionality estimators for the specific drugs and oral adverse events that met the criteria for generating a signal of disproportionate reporting (Table 3). It is noteworthy that aripiprazole, clozapine and olanzapine were the antipsychotic drugs most frequently associated with oral adverse reactions. The highest risks were reported for salivary hypersecretion and tongue movement disturbances. With regard to salivary hypersecretion, a significant association was identified for all six drugs under analysis, with a slightly higher frequency observed in males than in females and a mean age of patients of 42 ± 1.7 years (mean ± SD). It should be noted that clozapine demonstrated the highest ROR value for salivary hypersecretion (ROR 33.1 [95% CI, 31.3–35.0]) among the antipsychotic drugs under investigation. With regard to tongue movement disturbances, the highest risk was identified with aripiprazole (ROR 13.7 [95% CI, 9.3–20.1]), followed by risperidone (ROR 9.4 [95% CI, 6.3–13.9]), with no notable differences between sexes.

TABLE 3.

The total number of adverse reactions reported in the EudraVigilance database for drugs that meet the criteria for generating a signal of disproportionate reporting, along with the general characteristics of these cases.

Adverse reaction Number of cases Number of noncases ROR (95% CI) Age (years) median (interquartile range) Sex (%F) Seriousness (%)
Dry mouth
Olanzapine 264 41,340 1.8 (1.6–2.0) 49.0 (35.0–62.0) 54.9 67.8
Quetiapine 474 43,508 3.0 (2.8–3.3) 52.0 (38.3–63.0) 65.4 71.9
Dental caries
Aripiprazole 19 33,102 1.8 (1.2–2.9) 37.0 (26.0–52.0) 57.9 73.7
Olanzapine 21 41,583 1.6 (1.0–2.5) 40.0 (29.0–50.0) 61.9 95.2
Tooth loss
Olanzapine 21 41,583 1.7 (1.1–2.6) 44.5 (38.5–58.0) 57.1 100
Quetiapine 23 43,959 1.8 (1.2–2.6) 56.0 (49.0–66.0) 60.9 91.3
Parotid gland enlargement
Clozapine 35 88,530 3.9 (2.8–5.4) 41.0 (25.0–48.0) 54.3 77.1
Salivary hypersecretion
Aripiprazole 286 32,835 12.8 (11.4–14.4) 40.0 (56.0–57.0) 47.2 76.9
Clozapine 1619 86,946 33.1 (31.3–35.0) 41.0 (30.0–52.0) 36.9 83.6
Olanzapine 226 41,378 8.0 (7.0–9.1) 44.0 (30.3–60.0) 42.9 85.8
Paliperidone 149 20,074 10.7 (9.1–12.6) 43.0 (30.0–56.5) 38.4 76.5
Quetiapine 157 43,825 5.2 (4.4–6.1) 44.0 (27.8–59.5) 41.4 86.6
Risperidone 472 45,809 15.5 (14.1–17.0) 41.0 (24.0–60.0) 43.0 83.5
Swollen tongue
Aripiprazole 98 33,023 1.4 (1.2–1.8) 30.0 (19.5–45.0) 55.1 84.7
Tongue movement disturbance
Aripiprazole 27 33,094 13.7 (9.3–20.1) 41.5 (20.0–54.8) 44.4 85.2
Olanzapine 17 41,587 6.7 (4.2–10.9) 50.0 (23.0–65.0) 47.1 100.0
Paliperidone 5 20,218 4.0 (1.7–9.7) 34.0 (24.0–53.5) 60.0 40.0
Quetiapine 22 43,960 8.3 (5.4–12.7) 57.0 (47.3–70.3) 59.1 72.7
Risperidone 26 46,255 9.4 (6.3–13.9) 38.0 (24.5–64.0) 50.0 84.6
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Abbreviations: % F, percentage of females; % Seriousness, percentage of serious cases; CI, confidence interval; ROR, reporting odds ratio.

The estimated age‐stratified values of the disproportionality estimators for the six drugs and oral adverse events were subsequently analysed (Table 4). Significant disproportionality was identified for the adverse effect of dry mouth and quetiapine across all age groups, as well as for dry mouth and olanzapine across all age groups except for those aged over 85 years. Furthermore, a significant association was identified in all age groups when analysing salivary hypersecretion for the six drugs. It is noteworthy that the statistical significance of disproportionality was observed exclusively in the group of individuals aged ≤ 17 years for swollen tongue and aripiprazole. Additionally, positive associations between tongue movement disturbances and all the drugs studied except clozapine were identified, with variable results across the different age groups. Finally, disproportionality results were obtained for patients under 65 years of age for dental caries and tooth loss, which were similar to those observed for parotid gland enlargement and clozapine.

TABLE 4.

The total number of adverse reactions reported in the EudraVigilance database for drugs that meet the criteria for generating a signal of disproportionate reporting stratified by age.

Age (years) ≤ 17 18–64 65–85 > 85
Adverse reaction Cases Noncases ROR (95% CI) Cases Noncases ROR (95% CI) Cases Noncases ROR (95% CI) Cases Noncases ROR (95% CI)
Dry mouth
Olanzapine 7 1874 4.1 (1.9–8.5) 177 26,2610 1.7 (1.5–2.0) 40 4882 1.9 (1.4–2.5) 3 677 1.5 (0.5–4.7)
Quetiapine 8 2144 4.1 (2.0–8.2) 292 26,626 2.9 (2.6–3.3) 65 5877 2.5 (2.0–3.2) 14 1573 3.0 (1.8–5.2)
Dental caries
Aripiprazole 3 3035 3.7 (1.2–11.5) 10 19,061 1.7 (0.9–3.1) 0 — — 0 — —
Olanzapine 0 — — 19 26,768 2.3 (1.4–3.5) 0 — — 0 — —
Tooth loss
Olanzapine 0 — — 13 26,774 1.9 (1.1–3.2) 0 — — 0 — —
Quetiapine 0 — — 10 26,908 1.4 (0.8–2.6) 3 5941 1.4 (0.4–4.2) 0 — —
Parotid gland enlargement
Clozapine 3 1276 3.7 (1.2–11.5) 26 63,622 5.0 (3.4–7.4) 1 — — 0 — —
Salivary hypersecretion
Aripiprazole 21 3017 5.0 (3.3–7.8) 194 18,877 13.8 (11.9–15.9) 28 2303 22.5 (15.4–32.8) 2 — —
Clozapine 49 1230 29.6 (22.1–39.6) 1254 62,394 36.4 (34.1–38.9) 95 7490 24.3 (19.7–29.9) 4 461 14.7 (5.4–39.7)
Olanzapine 11 1870 4.2 (2.3–7.7) 160 26,627 8.0 (6.8–9.3) 30 4892 11.3 (7.9–16.3) 4 676 10.22 (3.8–27.6)
Paliperidone 3 428 5.0 (1.6–15.6) 102 12,548 10.6 (8.7–12.9) 18 1032 32.0 (20.0–51.1) 2 — —
Quetiapine 8 2144 2.7 (1.3–5.4) 106 26,812 5.2 (4.3–6.3) 18 5926 5.6 (3.5–8.9) 5 1582 5.5 (2.3–13.3)
Risperidone 64 4797 10.1 (7.8–13.0) 267 25,015 14.5 (12.8–16.5) 74 5847 24.2 (19.1–30.6) 18 2037 16.4 (10.1–26.7)
Swollen tongue
Aripiprazole 12 3026 3.6 (2.1–6.4) 53 19,018 1.2 (0.9–1.6) 8 2323 1.5 (0.8–3.1) 0 — —
Tongue movement disturbance
Aripiprazole 3 3035 9.7 (3.1–30.9) 12 19,059 9.9 (5.6–17.6) 3 2328 25.8 (8.2–81.3) 0 — —
Olanzapine 0 — — 12 26,775 7.0 (3.9–12.5) 2 — — 1 — —
Paliperidone 0 — — 5 12,645 6.1 (2.5–14.7) 0 — — 0 — —
Quetiapine 0 — — 13 26,905 7.6 (4.4–13.2) 6 5938 20.8 (9.2–47.2) 1 — —
Risperidone 3 4858 6.1 (1.9–19.2) 13 25,269 8.7 (5.1–14.9) 3 5918 10.1 (3.2–31.8) 3 2052 21.1 (6.3–70.4)
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Note: It should be noted that there are cases of unknown age, which results in the total number of cases stratified by the four age groups being lower than the total number of cases (Table 3).

Drugs that meet the criteria for generating a disproportionate reporting signal for each age group (i.e., the lower limit of the 95% CI of ROR is > 1 and the number of individual cases is ≥ 3) are highlighted in red.

4. Discussion

This pharmacovigilance study aimed to identify antipsychotic drugs suspected of inducing different oral adverse reactions using a case/noncase approach. To the best of our knowledge, this is the first study to address this objective using this methodology. It should be noted that the present study was not designed to conclude on the risk of oral adverse reactions based on the results, but rather to provide an increased probability of reporting.

A statistically significant disproportionality was identified in cases reported to EudraVigilance, both for typical and atypical antipsychotics. It is noteworthy that, despite the higher number of reports for atypical antipsychotics, our findings indicated a higher disproportionality for oral adverse reactions in patients treated with typical drugs. The discrepancy in the number of notifications between the two groups can be attributed to the higher clinical utilisation or primary prescription of atypical versus typical antipsychotics (Ågren 2021). Zhou et al. have recently proposed an antipsychotic drug categorisation by mechanism that extends beyond the division into typical and atypical agents. This incorporates a third category of agents, namely third‐generation dopamine D2 partial agonists, which includes aripiprazole and other drugs. This classification attempts to include data on receptor systems other than dopamine D2. While the typical versus atypical categorisation is mainly based on affinities for the D2 receptor, this is not entirely representative. A more targeted strategy would be to group drugs that share specific mechanisms based on affinities for one or more receptors, which could explain the underlying mechanisms of both the therapeutic and adverse effects of these agents (Zhou et al. 2022).

In accordance with the prevailing approach in clinical practice, subsequent case/noncase analyses were conducted on the most commonly prescribed drugs within the Mental Health Network of Bizkaia (all of which were atypical antipsychotics). Of all the oral adverse reactions studied, those related to the modification of salivary flow (both sialorrhea and xerostomia) are of particular note in terms of the number of notifications. Indeed, when each antipsychotic drug was analysed individually, it was observed that all of them induce salivary hypersecretion, although some also produce dry mouth. These two reactions can be considered to be opposites (e.g., the antipsychotics olanzapine and quetiapine). This heightened incidence of reporting for dry mouth and salivary hypersecretion was observed across all age groups. Xerostomia is associated with the anticholinergic and/or sympathomimetic effects of certain drugs and is linked to an elevated risk of dental caries and subsequent tooth loss (Iorgulescu 2009). Furthermore, the lack of saliva may precipitate periodontal disease, characterised by the loss of bone attachment, which, in turn, promotes tooth loss (Hu et al. 2019; Phipps and Stevens 1995). The aforementioned evidence may explain why, in this study, olanzapine and quetiapine, both of which have a marked anticholinergic profile (Lexicomp n.d.), were found to show statistically significant disproportionality for both dry mouth and tooth loss. Furthermore, it has been reported that 65% of cases of dry mouth related to quetiapine have been observed in women.

Excessive salivation, or sialorrhea, is often considered a mild condition. However, it can lead to significant discomfort for those affected, reducing their self‐esteem and confidence. This, in turn, can exacerbate social exclusion and contribute to the stigmatisation of this group (Maher et al. 2016; Qurashi et al. 2015). While reduced salivary flow (hyposalivation) is typically linked to oral infections and halitosis, certain medications can increase the viscosity of saliva, which may create the sensation of excessive salivation. This can cause discomfort, as well as the paradoxical feeling of dry mouth. Additionally, increased saliva may impair speech, and there is an associated risk of life‐threatening aspiration pneumonia linked to excessive salivation (Schoretsanitis et al. 2021).

In our study, we found that clozapine was associated with the highest number of cases of salivary hypersecretion (1619) and the highest ROR for this and all oral adverse reactions analysed (33.1). These results are consistent with those of recent studies, which also highlight hypersalivation as a very common adverse effect of clozapine. Specifically, two studies showed that hypersalivation occurred in 74.6% (n = 465/623) and 92.3% (n = 120/130) of cases respectively (Sanagustin et al. 2023; van der Horst et al. 2023). The authors identified a significant correlation between age and the incidence of clozapine‐induced hypersalivation, with each 10‐year increase in age associated with a 21% reduction in the likelihood of experiencing hypersalivation (van der Horst et al. 2023). In accordance with these findings, another recent retrospective cohort study has demonstrated that clozapine‐induced hypersalivation was reported with greater frequency in younger patients (aged less than 55 years) compared to older patients (aged 55 years or above) (Groenewald and Kok 2024). The age‐stratified analysis of the six most commonly prescribed antipsychotics, including clozapine, also revealed a significant association between salivary hypersecretion and all age groups. The absolute number of reported cases for clozapine was higher in the 18‐ to 64‐year‐old age group. Furthermore, our findings are in line with those from a disproportionality analysis of data from VigiBase (the World Health Organisation global Individual Case Safety Report database), which reported that sialorrhea was disproportionately more common with clozapine than with other antipsychotics, with a total of 2732 cases and a reporting odds ratio (ROR) of 3.60 (95% CI, 3.41–3.79) (Man et al. 2020).

The main treatment for clozapine‐induced hypersalivation is anticholinergic drugs (Fornaro et al. 2023). This represents a paradoxical adverse effect of clozapine, given that the drug is a potent anticholinergic agent. However, the precise mechanism underlying this effect remains unclear. One hypothesis suggests that it may be a combination of α2‐adrenoceptor antagonism (Corrigan et al. 1995) and muscarinic M4 receptor agonism (Zorn et al. 1994), as well as the reduction of laryngeal peristalsis via muscarinic M2 and M3 receptor antagonism (Praharaj et al. 2006).

Furthermore, disproportionality analysis revealed statistically significant differences for parotid gland enlargement (ROR = 3.9) in addition to the aforementioned findings for clozapine. Parotid gland swelling and inflammation (parotitis) is a rare and less frequently reported side effect of clozapine. It has been associated with hypersalivation (Brodkin et al. 1996; Robinson et al. 1995; Saguem et al. 2015). Indeed, it has been postulated that sustained hypersalivation may result in the inflammation of the salivary glands, leading to the formation of calculi and parotitis (Robinson et al. 1995).

In terms of extrapyramidal adverse effects, the disproportionality analysis indicated statistically significant discrepancies for all antipsychotic medications under investigation, with the exception of clozapine, in the induction of orofacial dyskinesia (assessed as the oral adverse effect of tongue movement disturbance). Of the drugs under consideration, aripiprazole was associated with the highest number of reported cases (27) and the highest ROR (13.7). Additionally, a statistically significant association was observed between aripiprazole and an increased risk of dystonia (evaluated as swollen tongue). It is noteworthy that the age‐stratified analysis demonstrated a significant association between aripiprazole use and adverse effects in patients aged ≤ 17 years, specifically in children and adolescents (n = 12). In 58% of the cases involving aripiprazole in this age group, the indication was bipolar disorder. The remaining 8.3% were associated with autism, while the indication in the remaining cases was not specified. In this regard, it has been proposed that the disparate pharmacological profiles, characterised by the antagonistic effects on dopaminergic D2 and serotonergic 5‐HT2A receptors, may underpin the observed differences in the prevalence of movement disorders among antipsychotic agents (Martino et al. 2018).

Although subtle, sex differences in the number of notifications were observed for clozapine and paliperidone, which were found to induce salivary hypersecretion. This was reported predominantly in male patients. In contrast, olanzapine‐induced dental caries, quetiapine‐induced dry mouth and paliperidone‐induced tongue movement disturbance or quetiapine‐induced tooth loss were more frequently reported in female patients. In terms of the severity of the adverse reactions reported, the study demonstrates that the majority of cases were serious. The adverse reaction with the lowest percentage of serious cases was dry mouth, with 64.8% of cases for olanzapine and 71.9% for quetiapine classified as serious. It is noteworthy that all cases of involuntary tongue movement (n = 17) and tooth loss (n = 21) reported with olanzapine were classified as serious according to the criteria set forth by the European Union (Directive 2001/83/EEC).

It is important to acknowledge the limitations of the study. Firstly, it should be noted that underreporting represents an inherent limitation of this specific type of pharmacovigilance study. Indeed, the reporting rates of adverse drug reactions can vary depending on several factors, including the specific drug in question, the severity of the reaction, the timing of the reaction's onset, the qualifications of the primary source reporting it, the source or geographic origin of the report and even the time that has passed since the drug's commercial launch (Hazell and Shakir 2006). Secondly, the MedDRA terminology employed may be lacking in semantic accuracy, and some disorders may have been misclassified. Thirdly, it is important to note that the case/no case approach is an observational and exploratory analysis that is useful for detecting potential signals but does not prove a causal relationship. It should be noted that the ROR provides an estimate of the risk of reports rather than the actual risk of an adverse drug reaction (Montastruc et al. 2011). A number of different types of reporting bias have been identified, including the previously mentioned underreporting, the Weber effect (a tendency for serious events to be reported more frequently than nonserious events) and notoriety bias. It should be noted that the study does not allow for the control of other potential risk factors, such as lifestyle, the intake of other drugs or previous disease, which may interact with the results and influence the conclusions drawn. It should be noted that while the database contains information on the indication for which antipsychotic drugs were prescribed, in some cases this information is missing or not specified. As a result, it is not possible to establish accurate percentages of drug indication. It is possible that some antipsychotics were prescribed to patients who were already at an elevated risk of experiencing these adverse effects. In the case of clozapine, it is important to consider the high estimated ROR for salivary hypersecretion (ROR = 33.1), with 1619 cases, in the context of the drug's frequent prescription to schizophrenic patients in a more severe state, which is expected to result in a greater number of complications and comorbidities, which in turn will lead to a higher number of oral adverse effects (cases). However, this will also result in a greater number of other reactions (noncases) than the adverse reaction of interest, which could affect the ROR in an unpredictable manner (increasing or decreasing it). Finally, another limitation of this study was that due to the large number of cases analysed, it was not possible to extract the corresponding information on time to onset for further analysis. This constraint may have impacted our ability to explore potential temporal patterns in the occurrence of adverse events.

Conversely, this study also possesses a number of notable strengths. The study employed data from EudraVigilance, the principal pharmacovigilance database, which is a system designed to monitor the adverse effects of medications and to facilitate the detection of potential pharmacovigilance signals. The aforementioned reports are employed for the purposes of monitoring the benefits and risks associated with the development of medicinal products, as well as for the monitoring of their safety once they have been authorised within the European Economic Area. The monitoring of drug safety enables the identification of rare adverse effects in uncontrolled settings. Moreover, with professional access to EudraVigilance, information not accessible to the public can also be analysed, including dosage and a brief clinical history. Furthermore, in the present pharmacovigilance study, we commenced with highly general information extracted from the EudraVigilance database, focusing on all oral adverse reaction reports and oral antipsychotic drugs. We then narrowed the search and analysis down to the six most prescribed antipsychotic drugs in a real‐life setting.

5. Conclusions

The disproportionality observed in the European database EudraVigilance indicates that both typical and atypical antipsychotic drugs are associated with oral adverse reactions, with those related to altered salivary flow (hypersalivation or dry mouth) being the most frequently reported. A detailed analysis indicates that olanzapine and quetiapine are prone to developing xerostomia and tooth loss, whereas clozapine is the drug with the highest risk of hypersalivation and parotitis. Furthermore, this study demonstrates that all antipsychotics tested, with the exception of clozapine, are associated with extrapyramidal adverse effects, such as orofacial dyskinesia.

In conclusion, the findings of this study indicate that patients undergoing treatment with antipsychotic drugs are at an increased risk of developing oral diseases, many of which are likely to be associated with the adverse effects of these agents on oral health. In light of the pivotal role of oral health in the overall well‐being and quality of life of individuals with neuropsychiatric disorders, it is imperative to prioritise the provision of comprehensive and multidisciplinary care that encompasses oral exploration, examination of the parotid glands and targeted preventive measures (oral hygiene, specific brushing techniques, etc.).

Author Contributions

Leire Urien: data curation, formal analysis, writing – original draft. Unax Lertxundi: investigation, writing – review and editing. Montserrat Garcia: data curation, formal analysis, investigation, writing – review and editing. Carmelo Aguirre: investigation, writing – review and editing. Nerea Jauregizar: conceptualization, investigation, supervision, writing – review and editing. Teresa Morera‐Herreras. conceptualization, investigation, supervision, writing – review and editing.

Ethics Statement

This study was approved by the institutional review board of Galdakao‐Usansolo Hospital.

Conflicts of Interest

The authors declare no conflicts of interest.

Supporting information

Data S1.

ODI-31-2630-s001.docx (217.4KB, docx)

Acknowledgements

We would like to express our gratitude to Raphaelle Bidgood for her assistance with language editing and her valuable comments on the manuscript.

Funding: The authors received no specific funding for this work.

Nerea Jauregizar and Teresa Morera‐Herreras should be considered shared last authors.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Data S1.

ODI-31-2630-s001.docx (217.4KB, docx)

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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