Abstract
Background
Medications exhibiting serotonergic properties, such as selective serotonin reuptake inhibitors (SSRIs) antidepressants, opioids, and other antidepressants can induce serotonin syndrome, a rare but potentially life-threatening adverse event.
Aim
This study aims to investigate the risks of serotonin syndrome among different SSRIs and assess the influence of drug-drug interactions with other medications.
Methods
We analyzed the suspected adverse events in the US Food and Drug Administration Adverse Event Reporting System (FAERS) database.
Results
We identified 13,312 reports of serotonin syndrome, 52% of which involved SSRIs (n = 6,921), with reporting odds ratios (RORs) of 24.19. Among the safety reports involving SSRIs, 4,851 cases reported at least one severe outcome. All active substances of the SSRI group were associated with serotonin syndrome, sertraline, and fluoxetine had the most reports, while fluvoxamine had the highest ROR and risk compared to all other SSRIs (ROR: 2.66, 95% confidence interval: 2.33–3.05). The combinations of SSRIs with other drugs with the most reported cases were SSRIs-antidepressants (n = 2,395) and SSRIs-opioids (n = 2,252). The combinations of SSRIs with serotonin-norepinephrine reuptake inhibitors (ROR 25.42) and “other antidepressants” (ROR 22.74) were associated with a signal for serotonin syndrome. The combination SSRIs-opioids was associated with a safety signal, particularly those with higher risk for serotonin syndrome, like tramadol and fentanyl (ROR 41.95).
Conclusion
Close monitoring for symptoms of serotonin syndrome should be considered in patients with depression with a combination of antidepressants, and in those on SSRIs who also require linezolid, monoamine oxidase inhibitors or high-risk opioids, like tramadol, or fentanyl.
Keywords: Selective serotonin reuptake inhibitor antidepressants, Serotonin syndrome, Drug-combinations, Adverse drug reaction, Antidepressant combination
Highlights of the Study
Selective serotonin reuptake inhibitors (SSRIs) have the most reported cases of serotonin syndrome in FAERS database.
When depression and pain coexist, prefer use of SSRIs with opioids that have a lower risk of inducing serotonin syndrome.
Consider close monitoring for symptoms of serotonin syndrome when prescribing SSRIs in combination with other classes of antidepressants.
Introduction
Serotonin syndrome is an adverse drug reaction (ADR), rare but potentially life-threatening, that is induced by medications exhibiting serotonergic properties, such as selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOi), opioid analgesics, antiemetics, illicit drugs, and others [1–3]. Typical symptoms include neuromuscular hyperactivity (myoclonus, tremor, hyperreflexia, and rigidity), autonomic nervous system hyperactivity (hyperthermia, tachycardia, and diaphoresis), and altered mental status (agitation, confusion). Severe cases may result in complications such as seizures, renal or respiratory failure, coma, and death [1, 4, 5]. Serotonin toxicity can result from an overdose of a single drug, the concomitant use of medications with serotonergic properties or pharmacokinetics drug-drug interactions (DDIs) [1, 6–9]. However, diagnosis of serotonin syndrome is challenging because it can be difficult to distinguish from many medical conditions or other adverse drug effects, and this potentially severe adverse drug reaction is often under-reported [1, 2, 7, 10].
Previous findings from the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database showed that serotonin syndrome cases were predominantly associated with SSRI antidepressants, opioids, and other antidepressants, with most cases reported for the SSRIs [11]. This class of antidepressants is the first-line treatment for depression, but in cases of nonresponsive major depression, they are often combined with other antidepressants despite limited studies supporting the effectiveness of this approach [12]. Additionally, patients with depression often have comorbidities requiring further treatments, such as opioid analgesics when depression and pain coexist, even though certain combinations carry a higher risk of serotonin syndrome [13].
The concomitant use of multiple antidepressants or the combination of drugs that carry a risk of serotonin syndrome is common among older adults, particularly those in nursing homes, which may further increase their risk [14, 15]. However, there is a lack of pharmaco-epidemiological studies which investigate the relationship between serotonin syndrome and drug-drug interactions involving SSRIs, with most of the information coming from case reports [5, 16]. Additionally, even though all SSRIs act by inhibiting serotonin reuptake, they differ in their selectivity for 5HT receptors, leading to varying risks of serotonin syndrome.
In order to improve the appropriate use of medications through a careful evaluation of the benefit-risk ratio, this study aims to investigate the risks of serotonin syndrome among different SSRIs and assess the influence of drug-drug interactions with other central nervous system-affecting medications involved in serotonin toxicity on the risk of developing this potentially severe adverse reaction.
Methods
The FAERS database is a global repository for post-marketing safety reports and pharmacovigilance, using this database provides a warning of potential issues with marketed drugs [17]. Although the FAERS database is useful for assessing the risk of rare and severe adverse events, it can also show increased frequencies of certain adverse events for some drugs in comparison with others. Reports were extracted from inception (January 1, 2004) up to March 31, 2024, through the use of the R package “DiAna (Disproportionality Analyses), a recent tool developed to clean and analyze the FAERS database for signal detection. The package allows the access to a clean database using a drug name standardization among all possibilities (e.g., market names, substance names, alternative names) [18]. We linked the reference name for each drug collected to the relative code at the highest definition level possible according to the Anatomical Therapeutic Chemical (ATC) Classification System. Supplements and non-drug substances were excluded from the analysis. Adverse events are coded according to the Medical Dictionary for Regulatory Activities (MedDRA) terminology, and we detected all adverse events according to the Preferred Terms (PTs) using the definition “serotonin syndrome.”
We detected all SSRI users involved in serotonin syndrome cases through ATC classification (at least one medications classified as N06AB), their sex and age, the role of the drug supposed in the ADR (primary suspect, secondary suspect, or concomitant/interacting) and the consequences of the event (Death, Life Threatening, Hospitalization or Other).
First, we focused on the prevalence of combined use of SSRI with other medications affecting serotonin syndrome to understand the relationship of different drug-drug interaction (DDI). The drug classes investigated as possible interagent were serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic and tetracyclic antidepressants (TCA), other antidepressants, MAOi, opioids (divided into low and high risk), triptans, antiemetics, and antinauseants-5HT3 antagonists and linezolid.
In accordance with the current state of the art, a disproportionality analysis was conducted to analyze potential causal relation between a drug and a suspected adverse drug reaction [19]. The results are mainly presented as reporting odds ratios (RORs), a ratio similar to the odds ratio in case-control studies with their 95% confidence interval, calculated to establish the association between drugs investigated and the occurrences of the ADR reported event. The ROR is calculated comparing cases of serotonin syndrome involving the drug of interest with other ADRs of the same drug, versus cases of serotonin syndrome not related to the drug divided by all reports without exposure and without serotonin syndrome. A signal is considered when the lower limit of the 95% confidence interval of the ROR is greater than one. A higher ROR indicates a stronger relation, and any consideration was accorded to the criteria of Evans [20].
For each drug class a logit model was then assessed to estimate ROR adjusting the results by age and sex. A second comparison (ROR2) was performed by narrowing the focus to SSRI reports only, comparing serotonin syndrome cases for each specific SSRI with serotonin syndrome reports for all other SSRIs.
Moreover, we also calculated the proportional reporting ratio (PRR) for each ADR-drug class pair. The PRR is a statistical measure used to summarize the extent to which a particular adverse event is reported for individuals taking a specific drug compared to the frequency at which the same adverse event is reported for patients taking other drugs or any drug within a specified class. Higher ROR and PRR indicate a stronger relation and any consideration was accorded to the criteria of Evans (ROR or PRR >2, number of cases >4 and Yates’ Chi-Square >4) [20].
In order to study the strength of the signal for DDI, we performed Noren’s Omega, a measure of disproportionate reporting, for a drug‐drug‐ADR triplet [21]. For omega, the expected reporting on a drug‐drug‐ADR triplet is based on a model where both drugs add to the baseline risk of the ADR, independently of each other. A positive omega indicates that the two drugs, when taken together, increase the risk of the ADR more than the sum of the risks attributable to each drug in itself. Omega frequentist version comes with a 95% confidence interval. DDI were also evaluated using ROR, considering the two drugs involved as one. All measures do not imply causality of a potential interaction drug-ADR but are a quantitative measure of the deviation in reporting from an assumption of independence.
Results
We identified 13,312 individual case safety reports (ICSRs) of serotonin syndrome within 20 years of post-marketing safety reports in FAERS database, 52% of which involved SSRIs (n = 6,921), among the cases without SSRIs (48%) the drugs which were reported more were SNRIs (n = 1,094, 17.1%), opioids (n = 754, 11.8%) and combination of SNRIs and opioids (n = 666, 10.4%). The ROR for SSRIs and serotonin syndrome was 24.19 (95% confidence interval [CI]: 23.38–25.03). Female cases were more common than male cases, 53.6% vs. 37.1% (9.3% missing or unknown gender). Among the age groups, adults between 40 and 64 years old were those with the most reported cases (n = 2,139, 30.9% of all the total cases). In half of the 6,921 reported cases (50.4%), SSRIs were assessed as the primary suspected drug, and in the other half as the secondary suspected or interacting concomitant drug (see details in Table 1). We also found 540 (7.8%) cases with two concomitant SSRIs, with an ROR of 26.55 (95% CI: 24.33–28.96).
Table 1.
Characteristics of reported cases of serotonin syndrome and SSRIs
| At least one SSRI | SSRIs in combination with | ||||||
|---|---|---|---|---|---|---|---|
| opioids | antidepressants | MAO inhibitors | antiemetics and antinauseants (5HT3 antagonist) | linezolid | triptans | ||
| Total cases, n (%)a | 6,921 (51.99) | 2,252 (16.92) | 2,395 (17.99) | 249 (1.87) | 415 (3.12) | 347 (2.61) | 169 (1.27) |
| Severe outcome, n (%)b | |||||||
| Hospitalization | 4,266 (61.64) | 1,434 (20.72) | 1,515 (21.89) | 141 (2.04) | 286 (4.13) | 178 (2.57) | 83 (1.20) |
| Life threatening | 1,338 (19.33) | 537 (7.76) | 498 (7.19) | 59 (0.85) | 94 (1.36) | 67 (0.97) | 35 (0.51) |
| Death | 587 (8.48) | 187 (2.70) | 155 (2.24) | 52 (0.75) | 11 (0.16) | 25 (0.36) | 16 (0.23) |
| Sex, n (%)b | |||||||
| Female | 3,709 (53.59) | 1,215 (17.56) | 1,221 (17.64) | 111 (1.60) | 210 (3.03) | 165 (2.38) | 128 (1.85) |
| Male | 2,565 (37.06) | 878 (12.69) | 916 (13.24) | 92 (1.33) | 162 (2.34) | 144 (2.08) | 33 (0.48) |
| Missing/unknown | 647 (9.35) | 159 (2.30) | 258 (3.73) | 46 (0.66) | 43 (0.62) | 38 (0.55) | 8 (0.12) |
| Age, n (%)b | |||||||
| 0–17 years | 438 (6.33) | 76 (1.10) | 69 (1.00) | 1 (0.01) | 50 (0.72) | 11 (0.16) | 3 (0.04) |
| 18–39 years | 1,752 (25.31) | 523 (7.56) | 556 (8.03) | 42 (0.61) | 86 (1.24) | 62 (0.90) | 63 (0.91) |
| 40–64 years | 2,139 (30.91) | 818 (11.82) | 808 (11.67) | 42 (0.61) | 135 (1.95) | 125 (1.81) | 55 (0.79) |
| 65–79 years | 986 (14.25) | 370 (5.35) | 400 (5.78) | 51 (0.74) | 77 (1.11) | 57 (0.82) | 20 (0.29) |
| >80 years | 325 (4.70) | 132 (1.91) | 74 (1.07) | 15 (0.22) | 4 (0.06) | 42 (0.61) | 0 |
| Missing | 1,281 (18.51) | 333 (4.81) | 488 (7.05) | 98 (1.42) | 63 (0.91) | 50 (0.72) | 28 (0.40) |
| SSRI role, n (%)b | |||||||
| Primary suspected | 3,491 (50.44) | N/A | N/A | N/A | N/A | N/A | N/A |
| Secondary suspected | 2,229 (32.21) | N/A | N/A | N/A | N/A | N/A | N/A |
| Interacting/concomitant | 1,201 (17.35) | N/A | N/A | N/A | N/A | N/A | N/A |
a% of total ICSR of serotonin syndrome (13,312).
b% of ICSR of SSRIs and serotonin syndrome (6,921).
Among the safety reports involving SSRIs, 4,851 cases (70.1%) reported at least one severe outcome due to serotonin syndrome, such as hospitalization, life threatening event or death (see details in Table 1). All active substances belonging to the SSRI group were associated with serotonin syndrome, with ROR values ranging from 10.70 to 32.20. Among these, sertraline and fluoxetine had the most reports of serotonin syndrome, while fluvoxamine had the highest ROR (32.20, 95% CI: 28.15–36.83) and the highest risk compared to all other SSRIs (ROR: 2.66, 95% CI: 2.33–3.05) (Table 2), also after adjusting the analysis for age and sex (adjusted ROR: 27.14 [95% CI: 23.51–31.35].
Table 2.
SSRI active substances
| Number cases | ROR (95% CI) | Adjusted ROR (95% CI)a | ROR2 (95% CI) | Adjusted ROR2 (95% CI)a | |
|---|---|---|---|---|---|
| Sertraline | 1,874 | 13.22 (12.58–13.88) | 11.93 (11.29–12.60) | 0.93 (0.88–0.98) | 0.91 (0.86–0.97) |
| Fluoxetine | 1,582 | 17.01 (16.14–17.94) | 14.93 (14.07–15.84) | 1.32 (1.25–1.39) | 1.28 (1.20–1.36) |
| Citalopram | 1,385 | 13.18 (12.46–13.93) | 12.55 (11.80–13.35) | 0.98 (0.92–1.04) | 1.01 (0.94–1.08) |
| Paroxetine | 1,303 | 16.63 (15.70–17.61) | 15.76 (14.78–16.80) | 1.30 (1.22–1.38) | 1.34 (1.25–1.44) |
| Escitalopram | 1,158 | 10.70 (10.07–11.37) | 8.84 (8.24–9.50) | 0.78 (0.73–0.83) | 0.70 (0.65–0.75) |
| Fluvoxamine | 223 | 32.20 (28.15–36.83) | 27.14 (23.51–31.35) | 2.66 (2.33–3.05) | 2.41 (2.09–2.79) |
aAdjusted for age and sex.
The combinations of SSRIs with other classes of drugs that had the most reported cases of serotonin syndrome were SSRI-antidepressant (n = 2,395) and SSRI-opioid (n = 2,252). In contrast, the combinations of SSRI with linezolid, an antibacterial with mild MAO inhibitory activity, and MAOi showed the highest values of statistical variables for drug-drug interaction (DDI) signals, indicating a stronger signal for serotonin syndrome (Table 3).
Table 3.
Combinations of SSRIs and other drugs
| Cases, n | ROR | Omega | PRR | Chi2 Yates | |
|---|---|---|---|---|---|
| SSRIs and opioids | |||||
| SSRI alone | 4,669 | 15.52 (14.97 to 16.08) | 15.37 | 40,766.62 | |
| Opioid alone | 2,497 | 3.30 (3.16 to 3.44) | 3.29 | 3,236.58 | |
| SSRI and OPIOID | 2,252 | 21.90 (20.93 to 22.93) | 0.50 (0.44 to 0.56) | 21.54 | 36,664.40 |
| With high-risk opioids (tramadol, fentanyl, pethidine, dextromethorphan, tapentadol, and methadone) | |||||
| SSRI alone | 5,169 | 15.54 (15.00 to 16.09) | 15.40 | 42,605.86 | |
| Opioid high-risk alone | 1,932 | 6.30 (6.00 to 6.61) | 6.27 | 7,317.00 | |
| SSRI and opioid high risk | 1,752 | 41.95 (39.86 to 44.15) | 1.25 (1.18 to 1.32) | 40.56 | 58,722.97 |
| With low-risk opioids (codeine, oxycodone, morphine, buprenorphine, oxymorphone, and hydromorphone) | |||||
| SSRI alone | 5,985 | 22.02 (21.27 to 22.78) | 21.76 | 65,307.86 | |
| Opioid low risk alone | 951 | 1.53 (1.43 to 1.63) | 1.53 | 159.54 | |
| SSRI and opioid low risk | 936 | 10.61 (9.93 to 11.34) | −0.45 (−0.54 to −0.36) | 10.52 | 7,496.65 |
| SSRI and antidepressants | |||||
| With SNRIs | |||||
| SSRI alone | 6,232 | 20.74 (20.05 to 21.46) | 20.53 | 61,614.09 | |
| SNRI alone | 2,918 | 13.94 (13.38 to 14.53) | 13.80 | 27,073.21 | |
| SSRI and SNRI | 689 | 25.42 (23.52 to 27.46) | 0.11 (0.003 to 0.22) | 24.86 | 14,953.33 |
| With “others” (bupropion, mirtazapine, trazodone, vortioxetine, agomelatine, mianserine, oxitriptane, triptofan, nefazodone) | |||||
| SSRI alone | 5,281 | 17.25 (16.66 to 17.87) | 17.09 | 48,289.68 | |
| “Other” alone | 1,773 | 8.40 (7.99 to 8.84) | 8.35 | 9,948.22 | |
| SSRI and “other” | 1,640 | 22.74 (21.59 to 23.96) | 0.16 (0.095 to 0.24) | 22.33 | 29,306.69 |
| With TCAs | |||||
| SSRI alone | 6,418 | 21.98 (21.24 to 22.74) | 21.74 | 65,830.79 | |
| TCA alone | 722 | 6.88 (6.34 to 7.41) | 6.84 | 3,401.36 | |
| SSRI and TCA | 503 | 17.64 (16.12 to 19.30) | −0.078 (−0.20 to 0.048) | 17.37 | 7,458.98 |
| SSRIs and other classes | |||||
| With antiemetics and antinauseants (5HT3 antagonists) | |||||
| SSRI alone | 6,506 | 22.34 (21.60 to 23.12) | 22.10 | 67,069.22 | |
| 5HT3 antagonist alone | 493 | 3.17 (2.89 to 3.47) | 3.16 | 699.98 | |
| SSRI and 5HT3 antagonist | 415 | 17.60 (15.94 to 19.42) | 0.23 (0.09 to 0.37) | 17.33 | 6,175.99 |
| With linezolid | |||||
| SSRI alone | 6,574 | 21.83 (21.10 to 22.58) | 21.60 | 65,424.10 | |
| Linezolid alone | 407 | 20.82 (18.85 to 23.00) | 20.44 | 7,284.63 | |
| SSRI and linezolid | 347 | 392.90 (346.98 to 444.90) | 3.19 (3.03 to 3.34) | 287.40 | 96,268.10 |
| With MAO inhibitors | |||||
| SSRI alone | 6,672 | 22.53 (21.77 to 23.31) | 22.29 | 67,719.55 | |
| MAOi alone | 289 | 19.81 (17.61 to 22.28) | 19.46 | 4,938.64 | |
| SSRI and MAOi | 249 | 124.15 (108.75 to 141.73) | 1.86 (1.69 to 2.04) | 111.22 | 26,607.50 |
| With triptans | |||||
| SSRI alone | 6,752 | 23.46 (22.68 to 24.28) | 23.21 | 70,758.53 | |
| Triptan alone | 277 | 5.04 (4.47 to 5.67) | 5.02 | 869.16 | |
| SSRI and triptan | 169 | 15.49 (13.29 to 18.05) | −0.11 (−0.33 to 0.11) | 15.28 | 2,214.44 |
The combinations of SSRIs with SNRIs and with “other antidepressants” were associated with a signal for serotonin syndrome, with ROR values of 25.42 (23.52–27.46) and omega 0.11, and ROR of 22.74 (21.59–23.96) and omega 0.16, respectively. Instead, the combination of SSRIs with tricyclic and TCAs was not associated with an increased signal.
The combination of SSRI with opioids was associated with a safety signal for serotonin syndrome, particularly the combination with opioids with the higher risk for serotonin syndrome, such as tramadol and fentanyl, which had an ROR of 41.95 (95% CI: 39.86–44.15), PRR of 40.56 and omega 1.25. Finally, the combination of SSRI with linezolid was the interaction with the highest safety signal for serotonin syndrome, with ROR of 392.90 (95% CI: 346.98–444.90) and omega shrinkage of 3.19. Further information on ROR values of every class evaluated has been given in Table 3.
Discussion
In accordance with our previous study, SSRIs were found to be the medications with the highest number of individual case safety reports for serotonin syndrome, accounting for more than half of the reports in the FAERS database [11]. In our previous analysis of FAERS, beyond confirming high RORs for well-known high-risk drugs such as MAOIs, linezolid, opioids, and other antidepressants, we also detected a safety signal for drug classes with an uncertain risk, including triptans and 5-HT3 antagonists (antiemetics and antinauseants). Based on these findings, we decided to focus our analysis on combinations of SSRIs with other medication classes that pose both established and uncertain risks for serotonin syndrome [11]. We found that about 70% of these ICSRs reported a severe adverse outcome, the majority of which required hospitalization and about 8% resulted in death. Additionally, we found more reported cases in females than in males. Among age groups, adults between 40 and 64 years old accounted for the most reported cases of serotonin syndrome, representing more than 30% of the total.
Our study found that sertraline is the SSRI with the highest number of case reports, while the risk of serotonin syndrome is highest for fluvoxamine compared to other SSRIs. Despite its lower selectivity for serotonin relative to norepinephrine compared to citalopram, escitalopram, or sertraline, and having the lowest number of reported cases, fluvoxamine seems to carry the highest risk of serotonin syndrome among SSRIs [22].
We also found that the combination of SSRIs with SNRIs or “other antidepressants” (including bupropion, mirtazapine, and trazodone) is associated with a higher risk of serotonin syndrome, while no interaction was found for the combination with tricyclic or TCAs. SSRIs are often combined with other antidepressants, but review on combining antidepressants warn that several combinations have a low benefit-risk ratio and should be avoided [12, 23]. Furthermore, our findings suggest that the concomitant use of an SSRI with another antidepressant should be carefully monitored due to the increased risk of serotonin syndrome.
Similarly, a safety signal has been detected for the combinations of SSRI with high-risk opioids. Opioids carry varying risks of serotonin syndrome, with some, as highlighted in the Australian Prescriber [13], such as tramadol, pethidine, dextromethorphan, fentanyl, tapentadol, and methadone, known to have a high risk of inducing serotonin syndrome [11]. This study found a higher risk of serotonin syndrome only when SSRIs were combined with high-risk opioids, while the combination with low-risk opioids showed no safety signal. These results should be considered when depression and pain coexist, and low-risk opioids should be preferred. In clinical practice, SSRIs are recommended as first-line treatment for patients with depression, while tramadol is a second-line option for painful conditions. Therefore, co-prescription of these medications is likely common, because depression and pain often coexist. Approximately one-third of people with depression suffer from painful conditions, and the chronic use of opioids increases the risk of new onset of depression [24]. Additionally, depressive symptoms are associated with higher rates of self-reported opioid misuse in patients with no history of substance abuse [25]. In light of the close relationship between opioids and antidepressants, close monitoring for symptoms of serotonin syndrome should be considered, especially when high-risk opioids are used.
The primary strength of this study lies in its novelty as the first large-scale pharmacoepidemiological analysis using a comprehensive database of spontaneously reported adverse drug reactions to investigate the role of drug-drug combinations in the risk of serotonin syndrome. There is a general lack of epidemiological studies examining the relationship between serotonin syndrome and drug-drug interactions, with only a few pharmacovigilance studies specifically addressing SSRIs and serotonin syndrome. For example, one study analyzed data from the French pharmacovigilance system, identifying 203 cases of serotonin syndrome and analyzing only 125 of these cases based on clinical diagnostic criteria. Approximately 60% of these cases resulted from pharmacodynamic drug-drug interactions, most frequently involving SSRIs and opioids [26]. Another study queried the FAERS database to identify records of serotonin syndrome due to drug interactions where linezolid was listed as a suspect drug, uncovering 669 cases, with half of these involving citalopram [27]. Analyzing ICSR databases, like FAERS, can provide valuable insights for understanding and assessing the impact of drug-drug interactions in clinical practice [28]. In our study, we utilized data from one of the largest adverse event reporting systems available. Moreover, by incorporating all available records, we aimed to mitigate selection bias, although it’s important to note that underreporting or selective reporting cannot be completely ruled out [29].
Limitations, common to pharmacovigilance studies, include the lack of systematic recording of drug exposure duration or doses, which hinders our ability to assess the role of higher medication doses in relation to the observed outcomes [30]. Another limitation is the inability to correlate the negative outcomes described in our analysis (hospitalization, life-threatening events, and death) directly with the serotonin syndrome reported as the suspected drug adverse event. Additionally, the FAERS database does not allow for the assessment of the incidence of serotonin syndrome, so the higher number of cases reported for fluoxetine and sertraline could be attributed to a longer duration of data collection. Finally, due to its inherent limitations and inability to infer causality, our results should be interpreted as a signal warranting further investigation.
Conclusion
Our study found that sertraline was the SSRI with the highest number of reported cases of serotonin syndrome, while the strongest signal was found for fluvoxamine compared to other SSRIs. The combinations associated with a higher risk of serotonin syndrome were SSRIs with other antidepressants, except with tricyclic or TCAs, with high-risk opioids, such as tramadol, tapentadol, or fentanyl, and with linezolid and MAOi. A close monitoring for symptoms of serotonin syndrome should be considered in patients with depression when a combination of antidepressants is prescribed, and in those on SSRIs who also require linezolid, MAOi or high-risk opioids.
Statement of Ethics
Institutional review board approval was not required because FAERS is an anonymized database open to pharmacovigilance centers.
Conflict of Interest Statement
The authors have no conflicts of interest directly relevant to the content of this manuscript.
Funding Sources
No funding was received for conducting this study.
Author Contributions
Chiara Elli and Luca Pasina designed the study, interpreted data, and wrote the manuscript; Alessio Novella conducted and interpreted statistical analyses. All the authors critically revised the manuscript and approved its final version.
Funding Statement
No funding was received for conducting this study.
Data Availability Statement
The data are openly available in the FDA Adverse Event Reporting System Public Dashboard at https://openvigil.sourceforge.net/.
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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
The data are openly available in the FDA Adverse Event Reporting System Public Dashboard at https://openvigil.sourceforge.net/.