Psychological Adverse Events and Associated Safety Profiles of Doxepin: A Pharmacovigilance Study Using VigiBase

Abstract

Background

Doxepin, an antidepressant commonly prescribed for the management of depression and insomnia, has been insufficiently explored regarding its safety. We aimed to determine the overall safety profile of doxepin and evaluate relevant adverse events of special interest (AESIs).

Methods

Utilizing the World Health Organization’s VigiBase from 1967 to 2022, we conducted a disproportionality analysis for AESIs associated with doxepin compared with other tricyclic antidepressants. Reporting odds ratios (RORs) with 95% confidence intervals (CIs) were estimated using multivariable logistic regression analysis. Signals were regarded significant when they met the following criteria: cases ≥ 3, and lower end of the 95% CI of ROR ≥ 1.

Results

Of the 6,827 doxepin-related reports, 3,869 (56.67%) were predominantly reported in women, with a substantial proportion from the middle-aged population. Overall, none of the predefined AESIs met the safety criteria for this analysis. However, among the frequently reported adverse events (AEs) following doxepin administration, safety signal was identified for drug abuse (adjusted ROR, 2.41; 95% CI, 2.06–2.83).

Conclusion

Although no definitive safety signals were detected in our AESI analyses, we identified safety signal for drug abuse. Clinicians should carefully weigh the risks and benefits when prescribing doxepin and emphasize the need for vigilant monitoring of AEs.

Graphical Abstract

INTRODUCTION

In 2017, 258 million people were diagnosed with depression worldwide, approximately 50% increase since 1990, indicating its growing global prevalence.1 With increasing trend of depression prevalence, the World Health Organization (WHO) predicts that major depressive disorder will emerge as the leading cause of global disability by 2030.1,2 In addition, patients with depression are prone to developing associated symptoms, including sleep disorders, suicidality, lethargy, and anxiety.3,4 In particular, insomnia is currently a significant global public health burden.5

Tricyclic antidepressants (TCAs) have been widely deployed across the globe to manage depression. Doxepin, a prominent TCA, treats both depression and insomnia and has Food and Drug Administration (FDA) approval for low-dose treatment of "psychoneurotic patients with depression and/or anxiety."6,7,8 Moreover, it is also the most potent antihistamine of the TCAs in inducing sedation in patients and is more effective than amitriptyline-, diphenhydramine-, and desipramine hydrochloride.9 Reportedly, short-term use of low-dose doxepin enhances sleep quality, maintenance, and duration compared to a placebo.10,11 Additionally, in a recent study, doxepin was found to be more effective in enhancing executive function compared to zolpidem in patient suffering from insomnia disorders.12

Doxepin is widely used to treat patients with depression and insomnia, but data on its safety and efficacy are limited, with unclear risks and benefits.10,13 Several studies have reported an increased incidence of mild adverse events (AEs), such as headache, somnolence, dry mouth and dizziness, as well as severe AEs, such as suicidality, following the administration of doxepin.14,15,16 In addition, previous literature regarding a patient with bipolar disorder suggested the potential for misuse and abuse of doxepin.17 A review of previous studies on doxepin highlights the limited research evaluating the safety and efficacy of doxepin, emphasizing the need for studies with larger sample sizes.13,16,18

Given the limited data on doxepin’s safety, establishing a real-world safety profile and conducting pharmacovigilance studies is critical.19 Therefore, we aimed to investigate the pattern of AEs reported following doxepin use. We conducted an observational pharmacovigilance study using VigiBase to assess doxepin’s safety profile and AEs of special interest (AESI), particularly, suicidality, sleep disturbances, and doxepin-associated drug abuse and dependence.

METHODS

Data source

We used VigiBase, an international pharmacovigilance database maintained by WHO, to identify the safety profiles of the suspected AEs following doxepin administration. It contains individual case safety reports (ICSRs) submitted by participating member states since 1967 as part of the WHO's international drug monitoring program. The database provides access to more than 30 million anonymous reports (as of December 2022) on the safety profiles of various medicines from at least 170 member countries.20 Each AE report includes patient demographic characteristics (sex, age, region, and report source by profession), drug usage information (suspected and concomitant drugs), seriousness, and information linked to the timing of each drug reaction (time-to-onset [TTO]).

Medical dictionary for regulatory activities (MedDRA) provides standardized classification and terminology for drug-related data globally. All identified AEs were coded using preferred terms based on the MedDRA version 24.1. MedDRA provides a hierarchical classification system that includes preferred terms, high-level terms, and system organ class. Preferred terms standardize the representation of specific symptoms or diagnoses in drug AE reporting, while Standardized MedDRA Queries (SMQs) utilize these preferred terms to assemble predefined sets of terms related to specific medical conditions or areas of interest, thereby enabling the identification and analysis of complex medical situations.21

Study drug and data extraction criteria

In this observational, pharmacovigilance study, our study drugs included doxepin, while comparator drugs comprised other TCAs including amoxapine, amitriptyline, clomipramine, imipramine, trimipramine, desipramine, nortriptyline, and protriptyline from VigiBase between January 1, 1967, and December 31, 2022.22 Considering doxepin's application as an antidepressant at higher dosages and the distinct characteristics of antidepressants, the utilization of all other drugs as a comparison group would not provide an appropriate estimation. Consequently, the comparison of doxepin against TCAs, which have analogous clinical uses, was determined to be crucial for conducting comparative analysis. This approach is derived from the active-comparator new-user design of pharmacoepidemiology, with the primary aim of emulating a target randomized controlled trial, thereby positioning the interpretation of the observational study within a similar context.23 This decision underlines our methodological approach, aiming to enhance the precision of safety profile comparisons and ensure clinical relevance of the findings. To ensure internal validity, we excluded duplicated reports, and ICSRs reported as ‘concomitant drugs,’ and ICSRs with no records of suspected AEs from VigiBase (Fig. 1). To mitigate the impact of reverse causation inherent in pharmacovigilance studies, AEs occurring on Day 0 (the date of drug administration) were excluded.

Fig. 1. Flowchart of selection and extraction for reports of doxepin and other TCA drugs.

TCA = tricyclic antidepressant, N = number of reports.

AESIs

Our study was designed to evaluate the potential association of doxepin with AESIs and to investigate its overall safety profile.19 AESIs were predefined based on SMQs from MedDRA version 24.1 and included drug abuse and dependence (e.g., substance use disorders, misuse, dependence, overdose, and withdrawal syndromes), suicide and self-injury, accidents and injuries, lack of efficacy/effectiveness, drug withdrawal, sleep disturbances (e.g., somnolence, narcolepsy, lethargy, and hangover), falls, and fractures. Details of the PT terms included in each SMQ are provided in Supplementary Table 1. The AESIs were identified in advance due to evidence from previous research indicating that medications for insomnia and depression may lead to both mild and severe AEs, including increased risks of sleep disturbances, suicide/self-injury, and accidents and injuries.3,4,10,11,14,15,16,17

Disproportionality analysis

We employed the reporting odds ratio (ROR) statistical method to measure the disproportion of AE reports associated with a specific drug, indicating the relationship between the drug and AEs. Additionally, disproportionality analysis is a validated method used to identify potential safety signals between drugs and AEs in VigiBase.24,25 Through this approach, we assessed the likelihood of doxepin reporting specific AEs more frequently than other drugs within large pharmacovigilance databases like VigiBase.26 This analysis utilizes a case-control approach by comparing the odds of specific AESIs reported for doxepin against the odds of the same AESIs reported for comparator drugs (other TCAs), highlighting the relative frequency of these events within the broader dataset. The denominator used in the analysis represents the total number of AESIs reported for a particular group of drugs. If the proportion of a specific AESI is higher in patients exposed to the study drug (doxepin) than in those not exposed to the drug, this suggests an association between the drug and AESI. To address the challenges of adjusting for external variables and reporting bias in disproportionality analysis, we calculated the adjusted RoR (aROR) with a 95% confidence interval (CI), adjusting for age, sex, region, reporting year, and reporting source profession.

Additionally, to account for potential shifts in prescribing patterns and doxepin usage over time, we stratified the analyses into three reporting periods. Although selective serotonin reuptake inhibitors (SSRIs) were introduced in late 1980s, we considered the time required for their widespread clinical use and set 1990 as the stratification point of analysis. We then implemented additional stratification point considering an indication expansion of low-dose doxepin for insomnia in 2010. Therefore, we categorized the reporting periods as follows: pre-SSRIs era (before 1989), post SSRIs era (1990–2010), indication expansion of doxepin (after 2011).

Statistical analysis

We conducted a descriptive analysis of the demographic characteristics of ICSRs, specifically age, sex, region of patients, reporting source by profession, and serious AEs. The age group was divided into six subgroups: < 18, 18–44, 45–64, 65–74, > 75 years, and unknown age. Serious AEs were categorized based on the criteria defined by the WHO-Uppsala Monitoring Centre (UMC) as death, life-threatening, caused/prolonged hospitalization, other, and unknown.

We selected the top 20 AEs following doxepin administration based on the frequency of the preferred terms. We evaluated the aROR with a 95% CI using multivariable logistic regression, adjusting for age group, sex, region, reporting year, reporting source by profession, and serious AEs. To identify potential signals, we considered an AE as a signal when the lower limit of the CI for aROR was ≥ 1.27 Additionally, we then assessed whether the identified AEs were included in the labeling information provided by the Ministry of Food and Drug Safety (MFDS) of Korea. Additionally, following MedDRA criteria, we selected AESIs alongside SMQs to cover a wider range of conditions and conducted further disproportionality analyses.

TTO is the time interval between doxepin administration (doxepin start date) and the AE onset.28 TTO was measured in days and calculated using ICSRs with available TTO data (ICSRs with TTO values of ≤ 0 were excluded from this analysis).29 To assess TTO, we divided the data into five subgroups: day 1–7, and days 8–30, 31–90 and post-day 90, and conducted TTO analysis for six groups of AESIs (suicide/self-injury; sleep disturbances; lack of efficacy/effectiveness; drug abuse and dependence; accidents and injuries; and drug withdrawal). Additionally, we conducted a supplementary TTO analysis of TCA groups to compare the patterns between doxepin and other TCA groups (Supplementary Fig. 1). All statistical analyses were conducted using the SAS software (version 9.4; SAS Institute Inc., Cary, NC, USA).

RESULTS

Baseline characteristics of ICSRs

A total of 33,188,305 ICSRs were reported to VigiBase between 1967 and 2022. Among these, 74,877 ICSRs were associated with TCAs, with 6,827 and 68,050 reports on doxepin and other TCAs, respectively (Fig. 1). Among the reports of doxepin, the highest proportions of reported AEs were observed in the 45–64 age group, and female patients accounted for a larger number of ICSRs than male patients. In addition, the most frequently reported ICSRs for doxepin originated in the Americas (56.79%). In terms of the reporting group, physicians accounted for the highest reporting frequency of doxepin-related AEs, with 6,077 reports (89.01%). The most frequently reported serious AE were unknown (54.42%), followed by death (17.37%), others (7.98%), caused/prolonged hospitalization (7.73%), and life-threatening events (1.49%; Table 1).

Table 1. Baseline characteristics of ICSRs related to doxepin and other TCAs use in VigiBase.

Characteristics		No. of ICSRs (%)
		Doxepin (n = 6,827)	Other TCAs (n = 68,050)
Age group, yr
	< 18	111 (1.63)	2,690 (3.95)
	18–44	1,807 (26.47)	20,260 (29.77)
	45–64	2,074 (30.38)	20,391 (29.96)
	65–74	721 (10.56)	7,488 (11.00)
	≥ 75	523 (7.66)	5,572 (8.19)
	Unknown	1,591 (23.30)	11,649 (17.12)
Sex group
	Male	2,258 (33.07)	21,560 (31.68)
	Female	3,869 (56.67)	41,678 (61.25)
	Unknown	700 (10.25)	4,812 (7.07)
Region
	European	1,960 (28.71)	25,630 (37.66)
	Region of the Americas	3,877 (56.79)	27,565 (40.51)
	Western Pacific	966 (14.15)	9,191 (13.51)
	Eastern Mediterranean	6 (0.09)	692 (1.02)
	South-East Asia	18 (0.26)	4,604 (6.77)
	African Region	0 (0.00)	368 (0.54)
Report source by professions
	Physician	6,077 (89.01)	64,316 (94.51)
	Pharmacist	198 (2.90)	1,524 (2.24)
	Other health professional	82 (1.20)	473 (0.70)
	Lawyer	266 (3.90)	573 (0.84)
	Consumer or other non-health professional	204 (2.99)	1,164 (1.71)
	Unknown	0 (0.00)	0 (0.00)
Serious adverse event
	Death	1,186 (17.37)	5,273 (7.75)
	Life threatening	102 (1.49)	1,227 (1.80)
	Caused/prolonged hospitalization	528 (7.73)	5,941 (8.73)
	Others	545 (7.98)	5,267 (7.74)
	Unknown	4,466 (54.42)	50,342 (73.98)

ICSRs = individual case safety reports, TCA = tricyclic antidepressant.

Detected signals for doxepin by preferred terms and labeling

We used VigiBase preferred term codes to identify significant safety signals for doxepin. We identified the top 20 most frequently reported AEs for doxepin using preferred term codes. Significant potential safety signals with doxepin are presented with the aROR. Among the top 20 most frequently reported AEs, suicide (completed suicide and suicide attempt), toxicity to various agents, and sleep disturbances (somnolence and insomnia) were predominantly reported. Ten AEs met the aROR criteria (lower CI ≥ 1), including completed suicide (aROR, 1.79; 95% CI, 1.63–1.97), toxicity to various agents (aROR, 1.79; 95% CI, 1.60–1.99), death (aROR, 1.64; 95% CI, 1.45–1.85), drug ineffective (aROR, 1.37; 95% CI, 1.21–1.55), overdose (aROR, 1.57; 95% CI, 1.37–1.80), suicide attempt (aROR, 2.17; 95% CI, 1.87–2.52), drug abuse (aROR, 2.41; 95% CI, 2.06–2.83). Most of the frequently reported AEs were documented in MFDS drug labels. 5 out of 10 were not listed in the Korean drug label; drug ineffective, overdose, drug abuse, cardiac arrest, cardio-respiratory arrest (Table 2).

Table 2. Detected signals and labeling information on frequent AEs following doxepin.

No.	AEs (PT)	No. of AEs	aRORa (95% CI)	Signalb (Y, N)	Drug label in Koreac (Y, N)
1	Completed suicide	603	1.79 (1.63–1.97)	Y	Y
2	Toxicity to various agents	438	1.79 (1.60–1.99)	Y	Y
3	Death	328	1.64 (1.45–1.85)	Y	Y
4	Somnolence	326	1.05 (0.93–1.18)	N	Y
5	Drug ineffective	294	1.37 (1.21–1.55)	Y	N
6	Dizziness	251	0.85 (0.74–0.97)	N	Y
7	Overdose	247	1.57 (1.37–1.80)	Y	N
8	Suicide attempt	217	2.17 (1.87–2.52)	Y	Y
9	Drug abuse	203	2.41 (2.06–2.83)	Y	N
10	Cardiac arrest	174	1.78 (1.51–2.11)	Y	N
11	Weight increased	168	1.31 (1.12–1.55)	Y	Y
12	Dry mouth	163	0.51 (0.43–0.59)	N	Y
13	Insomnia	159	1.08 (0.92–1.28)	N	Y
14	Headache	159	0.84 (0.71–0.98)	N	Y
15	Fatigue	158	1.12 (0.95–1.33)	N	Y
16	Pruritus	158	1.08 (0.92–1.28)	N	Y
17	Nausea	150	0.79 (0.67–0.93)	N	Y
18	Confusional state	150	0.69 (0.59–0.82)	N	Y
19	Rash	150	0.63 (0.54–0.75)	N	N
20	Cardio-respiratory arrest	149	1.74 (1.45–2.08)	Y	N

AEs = adverse events, PT = preferred term, aROR = adjusted reporting odds ratio, CI = confidence interval.

^aAdjusted for age group, sex, region, reporting year, and report source by profession.

^bEvaluated as signal when the lower limit of the CI for reporting odds ratio was ≥ 1.

^cAEs were assessed whether the AE is included in the labeling information in the Ministry of Food and Drug Safety of Korea.

Association between doxepin and AESIs

The data are primarily composed of preferred term codes, but to cover a broader range of conditions, we carefully selected relevant preferred term codes as the basis for using SMQs. A disproportionality analysis was conducted in VigiBase using ICSRs associated with AESIs following doxepin administration (Fig. 2). In this analysis, four of the predefined AESIs met criteria for signal detection; drug abuse and dependence (aROR, 1.66; 95% CI, 1.56–1.77), suicide/self-injury (aROR, 1.81; 95% CI, 1.69–1.95), hangover (aROR, 2.46; 95% CI, 1.24–4.86), lack of efficacy/effectiveness (aROR, 1.14; 95% CI, 1.03–1.25). Stratified analyses by reporting period showed that suicide/self-injury (SMQ) was consistently significant across all periods, with an aROR of 3.70 (95% CI, 2.42–5.64) for pre-SSRIs era (before 1989), 1.65 (95% CI, 1.47–1.85) for post SSRIs era (1990–2010), and 1.79 (95% CI, 1.63–1.97) for indication expansion of doxepin (after 2011) (Supplementary Table 2).

Fig. 2. Disproportionality analysis for AESIs following doxepin in VigiBase (overall reporting period).

AESI = adverse event of special interest, aROR = adjusted reporting odds ratio, CI = confidence interval, SMQ = standardized medical dictionary for regulatory activities query.

^aAESIs were defined as SMQs in VigiBase.

^bAdjusted for age group, sex, region, reporting year, and report source by profession.

^cSMQs utilize these preferred terms to assemble predefined sets of terms related to specific medical conditions or areas of interest, thereby enabling the identification and analysis of complex medical situations.

TTO analysis

In the TTO analysis of AESIs, only AESIs with available TTO information were included: 127/1,297 suicide/self-injury cases, 160/533 sleep disturbances cases, 42/515 lack of efficacy/effectiveness cases, 77/1,462 drug abuse and dependence cases, 128/232 accident and injuries cases, and 35/92 drug withdrawal cases were informative. Specifically, sleep disturbances were predominantly reported between days 1–7 following doxepin administration. Similarly, among the 77 cases of drug abuse and dependence and the 127 cases of suicide/self-injury, 36 (46.75%), 60 (47.24%) occurred on day 1–7, respectively. However, the majority of AESIs, such as lack of efficacy/effectiveness, accidents and injuries, and drug withdrawal, were observed 91 days after doxepin administration (Fig. 3). The results of TTO patterns of TCA groups showed that the overall patterns were similar, particularly during the initial 1–7 days. For suicide and self-injury, the TTO pattern for doxepin was largely consistent with that of other TCAs.

Fig. 3. Time-to-event onset (TTO) for AESIs following doxepin in VigiBase.

DISCUSSION

In this study, we evaluated the safety profile of AEs following doxepin administration in the general population since 1967, using the spontaneous AE reporting database from the WHO-UMC, VigiBase. Four predefined AESIs met the safety criteria, such as drug abuse and dependence, suicide/self-injury, hangover, and efficacy/effectiveness. Completed suicide, toxicity to various agents, death, somnolence and drug ineffective were the frequently reported AEs following doxepin administration.

According to the FDA label for doxepin, initially approved in the United States as Silenor in 1969, the most frequently reported treatment-emergent AEs included somnolence/sedation and nausea, both of which consistently aligned with the AE reporting patterns published in the FDA label for doxepin.30 AEs like somnolence, weight increased, headache, dizziness and dry mouth showed patterns similar to our results. However, it's noteworthy that while the label contained warnings and precautions related to "sleep-driving," our results indicated a notably low frequency of reporting, ultimately yielding inconclusive findings in this regard.

Notably, completed suicide was the most frequently reported AE, aligning with previous case reports associating suicide with doxepin.31,32 In our investigation, suicide met the safety signal criteria for the disproportionality analysis when defined as both preferred term (completed suicide: aROR, 1.79; 95% CI, 1.63–1.97; and suicide attempt: aROR, 2.17; 95% CI, 1.87–2.52) and SMQ (suicide/self-injury: aROR, 1.81; 95% CI, 1.69–1.95). A previous study reported that suicide may be attributed to an overdose of antidepressants, underscoring the necessity for physicians to inform patients about these risks when prescribing antidepressants and to ensure appropriate monitoring throughout the course of treatment. Additionally, the elevated occurrence of early-onset suicide/self-injury cases within the first 1–7 days underscores the importance of vigilant monitoring. A supplementary TTO analysis comparing doxepin to other TCA groups revealed similar patterns, particularly during the first 1–7 days. This trend suggests that the early reporting of severe AESIs may be influenced by the critical nature of these events rather than differences in drug safety profiles. However, these findings of TTO analysis should be interpreted with caution due to potential reporting bias. Given that the y-axis represents the proportion of reported AEs rather than occurred AEs, this does not imply a direct association between doxepin use and the rapid onset of suicide/self-injury. Specifically, suicide-related events are more likely to be reported within the first 7 days compared to later periods (e.g., beyond 7, 30, or 90 days).33

Historically, doxepin was administered at higher doses, primarily for the treatment of severe depression, which may have contributed to the observed increase in AEs during the initial treatment phases. The initial stages of antidepressant therapy are known to be critical, with a potential risk of suicide and self-injury, as symptoms may temporarily worsen before the therapeutic effects of the medication become apparent.34,35 This phenomenon is linked to the pharmacological mechanism of doxepin, a TCA, which functions by inhibiting the reuptake of serotonin and norepinephrine to increase their availability in the synaptic cleft.30 While this mechanism is effective in alleviating depressive symptoms over time, it may transiently exacerbate anxiety, agitation, or suicidal ideation, particularly in younger populations or patients with pre-existing anxiety disorders or a history of suicide attempts. Similar findings in the literature indicate that TCAs may increase the risk of suicidal ideation during the early treatment period.36,37 Therefore, close monitoring during this period is essential to mitigate these risks.33,34 Further studies are warranted to elucidate the underlying mechanisms driving these observations and to enhance the understanding of doxepin's safety profile in the context of evolving prescribing patterns and reporting behaviors.

Previous studies have underscored doxepin's association with a high mortality rate, often linked to addiction and overdose when antidepressants were the cause of death.36,37,38,39 Given that TCAs are more toxic than other classes of antidepressants and previous research have indicated that doxepin is two to three times more toxic than amitriptyline,40,41,42 monitoring for abuse of doxepin is necessary. In our study, intentional overdose surfaced as a frequently reported event and was identified as a signal, which could potentially lead to fatal situations. Although amitriptyline is reportedly the most abused TCA in previous literature, doxepin has been shown to antagonize muscarinic receptors at twice the potency of amitriptyline when compared at an equivocal noradrenaline reuptake inhibition dose, indicating a heightened potential for abuse.17,42 The potential for drug abuse should be monitored carefully, especially doxepin’s expanded use for insomnia. However, our TTO analysis should be interpreted with caution because of the substantial number of drug abuse and dependence cases that occurred on day 1 to 7. Stratified analyses by reporting period showed a notable increase in drug abuse and dependence cases in indication expansion of doxepin (after 2011), which may be attributed to the expanded use of low-dose doxepin as a sleep aid following its FDA approval for insomnia (Supplementary Table 2). Given the potential of TCAs to induce dependence, overdose, and even hangovers, it is imperative that physicians exercise careful consideration when prescribing or dispensing psychoactive medications. Further studies are warranted to confirm the association between doxepin administration and AEs.

Our study has several strengths. Firstly, to our knowledge, this is the first study to evaluate the safety profile of doxepin using VigiBase. As the world's largest database of drug AEs, VigiBase includes extensive data collected from various countries, enabling us to provide a comprehensive and global analysis of doxepin's safety. Furthermore, since VigiBase is derived from real patient experiences, it can include rare AEs that are difficult to identify in the short term or effects from long-term use, thereby offering reliable real-world evidence. Secondly, our research provides new insights through disproportionality analysis of AEs following doxepin administration. The analysis through VigiBase allows us to expand existing knowledge on doxepin and reveal its safety profile compared to other TCAs in the same class. This contribution can aid in the improvement of clinical usage guidelines for doxepin. Additionally, by enhancing the understanding of doxepin's safety profile, we provide important information to healthcare professionals and patients, assisting them in making informed decisions regarding medication choices.

On the other hand, this study has several limitations. First, not all AEs were reported to the WHO-UMC, resulting in a lack of information in VigiBase owing to the spontaneous reporting nature of the database. Under-reporting AEs may limit the generalizability of our findings. Second, because this database contains spontaneously reported AEs, it is difficult to ascertain the history of diseases, and concomitant drug information and the gender disparity in ICSR could potentially affect the results of the study. Third, we were unable to account for differences in indications by dosage due to limited dosing information in VigiBase (e.g., variability in dosing units and insufficient detail). Future studies warrant further investigation into whether the safety signals identified in our study differ by doxepin dosage, enabling more comprehensive safety monitoring. Fourth, our study's design, descriptive analysis in nature, inherently precludes hypothesis testing, and the disproportionality analysis used in this study only assesses the statistical disproportionality of AEs as a signal, which limits our capacity to establish causal relationships between doxepin use and its associated AEs. Moreover, due to the vulnerability to effects such as underreporting and notorious bias in pharmacovigilance studies, it should be interpreted with caution, unlike the risk estimates from other study designs. Lastly, the analysis of 'TTO' in this study has limitations due to missing data. The absence of such data can significantly impact the interpretation of the study results, reflecting the inherent limitations of spontaneous adverse drug reaction reporting systems. It should also be noted that for the TTO analysis in this study, AEs occurring on day 0 were excluded to mitigate the effects of reverse causality inherent in pharmacovigilance studies, potentially affecting the selection bias of the results. To elucidate the causal relationship between doxepin administration and AEs, further observational or experimental studies are warranted.

Our study underscores the critical need for a comprehensive assessment of the safety profile of doxepin, given its extensive use in treating depression and insomnia. Several psychological AEs, including completed suicide emerged as safety signals in our AESI analyses. The importance of clinical decision-making that carefully considering the risks and benefits of prescribing psychoactive medications such as doxepin and the need for thorough monitoring after doxepin administration. Further epidemiological studies are warranted to elucidate the precise association between doxepin administration and AEs.

SUPPLEMENTARY MATERIALS

Supplementary Table 1

Terms in the standardized MedDRA classification version 24.1

Supplementary Table 2

Disproportionality analysis for AESIs following doxepin in VigiBase by reporting periods (pre-SSRIs era [before 1989], post SSRIs era [1990–2010], indication expansion of doxepin [after 2011])

Supplementary Fig. 1

Time-to-event onset (TTO) comparison between Doxepin and other TCAs in VigiBase.