Antidepressants and risk of sudden sensorineural hearing loss: a population-based cohort study | International Journal of Epidemiology | Oxford Academic

Increasing numbers of animal studies have found that sudden sensorineural hearing loss (SSNHL) is related to the mechanism of serotonergic modulation. However, the relationship between antidepressants and SSNHL is unclear in humans. Therefore, this study aimed to evaluate the association between antidepressant use and risk of SSNHL.

Data from 218 466 antidepressant users and 1 116 518 nonusers were obtained from the Taiwan Longitudinal Health Insurance Database. We used propensity-score matching (PSM) and inverse-probability treatment weighting (IPTW) to eliminate any bias. Each patient was tracked for 5 years to ascertain whether or not they were diagnosed with SSNHL. Cox proportional-hazard regression analyses were performed to calculate the SSNHL risk.

Results

The adjusted hazard ratio (aHR) of SSNHL for antidepressant users was 1.36 compared with nonusers in the full cohort study. The aHR for antidepressant users was 1.44 and 1.49 compared with the nonusers in the IPTW and PSM cohorts, respectively. All classes of antidepressants consistently increased the SSNHL risk. Additionally, patients receiving four classes of antidepressants were associated with a much higher SSNHL risk (aHR, 2.05) and those receiving one or two classes of antidepressants had a relatively lower SSNHL risk.

Conclusion

Antidepressants increased SSNHL risk, regardless of their class. Furthermore, patients who took a higher number of antidepressant classes showed an increased risk of developing SSNHL than those who took a lower number of antidepressant classes. Therefore, physicians should estimate the risks and benefits of antidepressant use and avoid prescribing antidepressants concurrently.

This is the first population-based cohort study to evaluate the association between antidepressant use and following incidence of sudden sensorineural hearing loss.

This study found that antidepressants increased sudden sensorineural hearing loss risk, regardless of the antidepressant class, in the full cohort, propensity-score-matched cohort and inverse-probability treatment-weighted cohort.

It was noteworthy that patients who took a higher number of antidepressant classes showed an increased risk of developing sudden sensorineural hearing loss than those who took a lower number of antidepressant classes.

Antidepressant users had a higher risk of sudden sensorineural hearing loss in all documented subgroups.

Physicians should estimate the risks and benefits of antidepressant use and avoid prescribing antidepressants concurrently.

The prevalence of antidepressant use has shown a rapidly growing trend in recent decades. In the USA, antidepressant use increased by nearly 65% over a 15-year period and, in Asia, the prevalence of antidepressant use increased markedly over time., The escalating trend of antidepressant use may be due to the growing number of depressed patients, a broad range of approved indications, growing public awareness and acceptance of newer antidepressants.,, Because antidepressant use has significantly increased, the issue of drug safety needs to be addressed. To date, most antidepressants are recognized as involved in serotonin-related pharmacological mechanisms and increasing animal studies have demonstrated hearing damage related to serotonergic modulation. Thus, it is plausible that antidepressants may contribute to hearing problems in humans.

Sudden sensorineural hearing loss (SSNHL) is defined as a rapid and usually unilateral hearing loss that occurs over a 72-h period. This acute symptom affects 5–20 cases per 100 000 population in the USA. Both sexes and all age groups can be affected., To date, the underlying aetiology of SSNHL remains unclear. Many factors, including chronic otitis media, hyperlipidaemia, hypertension and diabetes mellitus, are considered to play roles in the development of this disease. Recently, increasing evidence has suggested that inappropriate medication exposure might be a common risk factor for SSNHL and many case reports have indicated that antidepressants might induce hearing loss. However, several small clinical studies showed that antidepressants could improve the results of auditory measures and some human studies did not observe an association between antidepressants and hearing loss.

Thus, the findings concerning the relationship between antidepressants and SSNHL in humans are inconsistent. Furthermore, no large, population-based study has comprehensively analysed and evaluated the potential risk of SSNHL according to the different antidepressant classes. To this end, we conducted a population-based cohort study to determine the prevalence of antidepressant use and subsequent risk of SSNHL over 5 years. The use of different classes of antidepressants and the number of classes used were also considered. We further employed propensity-score matching (PSM) and inverse-probability treatment-weighting (IPTW) strategies to eliminate any potential bias.

We obtained data for this cohort study from the Taiwan Longitudinal Health Insurance Database 2005 (LHID2005), which is available to investigators for academic purposes. This large population-based database has national representation and consists of claims data for 2 million individuals randomly selected from the National Health Insurance (NHI) programme in 2005 in Taiwan. The NHI programme was launched in 1995 and provides accessible health services for >99% of Taiwanese citizens. This study was approved by the Institutional Review Board of Tri-Service General Hospital, Taiwan (1–107-05–183).

Study design and participants

This cohort study involved antidepressant users as the study cohort and nonusers as the comparison cohort. The flow diagram for antidepressant users and comparison nonusers is presented in Figure 1. First, we identified patients in the database who received a prescription for antidepressants during ambulatory care visits between 1 January 2001 and 31 December 2010. The study cohort (antidepressant users) included those patients who had ever been exposed to selective serotonin reuptake inhibitors (SSRIs) [fluoxetine, sertraline, citalopram, fluvoxamine, paroxetine and escitalopram; Anatomical Therapeutic Chemical Classification System (ATC) codes N06AB03, N06AB06, N06AB04, N06AB08, N06AB05 and N06AB10, respectively], tricyclic antidepressants (TCAs) (imipramine, dothiepin, clomipramine, maprotiline and amitriptyline; ATC codes N06AA02, N06AA16, N06AA04, N06AA21 and N06AA09, respectively), serotonin–norepinephrine reuptake inhibitors (SNRIs) (venlafaxine, duloxetine and milnacipran; ATC codes N06AX16, N06AX21 and N06AX17, respectively) or other antidepressants (trazodone, bupropion and mirtazapine; ATC codes N06AX05, N06AX12 and N06AX11, respectively). The remaining patients, who did not receive any antidepressants during the study period, were identified as the comparison cohort (nonusers). Then, we excluded patients <20 years old to limit the selected patients to an adult population. We further excluded patients with any medical record of antidepressant use, head injury or SSNHL prior to the index date. Ultimately, the final full cohort sample comprised 218 466 antidepressant users and 1 116 518 nonusers. The date of the first ambulatory care visit when antidepressant treatment was initiated was identified as the index date for each antidepressant user, whereas the index date for each nonuser was defined by randomly selecting one of their visit dates.

Flow diagram for antidepressant users and comparison nonusers

Furthermore, to avoid the influence of confounding factors on our results as well as the biases that commonly occur in observational studies, we employed a PSM strategy (using OneToManyMTCH macro) to obtain between-group balance. The PSM cohort pairs were matched in a 1:1 ratio based on their calculated propensity scores by considering demographic data and co-morbidities, including sex, age, index year, urbanization level, monthly income, diabetes mellitus, hypertension, hyperlipidaemia, chronic otitis media, anxiety and depressive disorder. Then, the PSM cohort in this study comprised 431 916 patients (215 958 antidepressant users and 215 958 matched nonusers).

We also performed IPTW in this study. This a novel statistical methodology that eliminated the demographic and co-morbidities imbalances between antidepressant users and nonusers. We initially employed propensity scores to generate weights that were assigned to patients based on the inverse of their probability of receiving treatment. Patients’ sex, age group, urbanization level, monthly income, chronic otitis media, diabetes mellitus, hypertension, hyperlipidaemia, anxiety, depressive disorder, multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis, vasculitis (polyarteritis nodosa, hypersensitivity angiitis, Wegener’s granulomatosis, giant cell arteritis, Buerger’s disease, Takayasu’s arteritis, Kawasaki disease) and Sjogren’s syndrome were all considered for propensity-score calculation. Then, we used stabilized weights that can neutralize the impact of extreme weights on the results.

Outcome measurement and relevant variables

This study attempted to investigate the association between antidepressant use and the risk of SSNHL. Each study subject was individually tracked for a 5-year period from their index date to confirm whether or not they had been diagnosed with SSNHL [International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) code 388.2: sudden hearing loss, unspecified]. Furthermore, we considered several potential confounders, including demographic characteristics and pre-existing co-morbidities. Patients’ sex, age, urbanization level, monthly income, diabetes mellitus, hypertension, hyperlipidaemia, chronic otitis media anxiety, depressive disorders, multiple sclerosis, Sjogren’s syndrome and autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis and vasculitis (including polyarteritis nodosa, hypersensitivity angiitis, Wegener’s granulomatosis, giant cell arteritis, Buerger’s disease, Takayasu’s arteritis and Kawasaki disease) were inputted into the adjustment and weighting models.

Furthermore, to increase the accuracy of the diagnosis for SSNHL in our study, we further carried out a sensitivity analysis and only those who were diagnosed with SSNHL twice or three times were considered as occurrence of an event.

Statistical analysis

We compared the baseline characteristics, including demographic data and co-morbidities, between the antidepressant users and nonusers via standardized differences (SDiffs). Then, Cox proportional-hazards regression models were employed calculate the crude hazard ratios (HRs) and adjusted hazard ratios (aHRs) of SSNHL for the antidepressant users relative to the nonusers in the full cohort study. Stratified Cox proportional-hazards models were applied to the PSM cohort to assess the risk of SSNHL with antidepressant use. The results were presented as HRs along with 95% confidence intervals (95% CIs) and a statistically significant difference was defined as a two-sided p-value < 0.05. Kaplan–Meier survival analyses and log‐rank tests were also performed to plot the SSNHL‐free survival rates for antidepressant users and nonusers, which were compared using log‐rank tests (p ≤ 0.05). All analyses were conducted using SAS 9.4 software (SAS Institute Inc., Cary, NC, USA) and SPSS 21 software (IBM Corp., Armonk, NY, USA).

Results

The distributions of characteristics and co-morbidities between antidepressant users and nonusers are shown in Table 1. In the full cohort (n = 1 334 984), patients receiving antidepressants showed a higher prevalence of diabetes mellitus, hypertension, hyperlipidaemia, and depression and anxiety than nonusers (all SDiffs > 0.1). Additionally, there were significant differences in monthly income and urbanization level between the two groups. After using PSM and IPTW to reduce the bias due to patients’ characteristics and co-morbidities, all baseline characteristics between antidepressant users and nonusers were balanced (all SDiff < 0.1).

Table 1

Baseline characteristics of the study patients

Baseline characteristics of the study patients

Variable Full cohort (n = 1 334 984)


Propensity-score-matched cohort (n = 431 916)


Inverse-probability treatment-weighting (IPTW) cohort


Antidepressant users (n = 218 466)


Nonusers (n = 1 116 518)


SDiff Antidepressant users (n = 215 958)


Nonusers (n = 215 958)


SDiff Antidepressant users


Nonusers


SDiff
% % %
Sex      0.188      0.007      0.021 
 Male  42.5  51.9    49.1  49.1    49.1  49.8   
 Female  57.5  48.1    50.9  50.9    50.9  50.2   
Age group (years)      0.447      0.040      0.045 
 20–34  20.8  36.2    32.3  32.3    32.3  33.6   
 35–49  29.6  33.9    33.9  33.9    33.9  32.9   
 50–64  26.4  19.3    20.7  20.7    20.7  20.4   
 ≥65  23.2  10.7    13.1  13.1    13.1  13.0   
Urbanization level      0.120      0.048      0.048 
 1 (most urbanized)  39.2  39.5    39.2  39.3    39.2  39.6   
 2  26.8  27.8    26.8  26.6    28.5  27.4   
 3  14.2  16.2    14.3  14.3    15.1  16.0   
 4  13.5  11.8    13.5  13.5    12.2  12.1   
 5 (least urbanized)  6.3  4.7    6.3  6.3    4.9  5.0   
Monthly income (NT$)      0.262      0.001      0.045 
 0–18 000  34.0  24.7    33.8  33.9    26.6  26.3   
 18 001–34 999  45.7  45.5    45.8  45.9    46.1  45.4   
 ≥35 000  20.3  29.9    20.4  20.2    27.3  28.3   
Co-morbidities       
 Chronic otitis media  1.0  0.5  0.053  0.9  0.9  0.001  0.6  0.6  0.002 
 Hypertension  35.4  16.8  0.435  35.0  36.0  0.022  20.8  20.1  0.016 
 Diabetes mellitus  20.0  9.0  0.314  19.7  20.3  0.015  11.4  11.0  0.012 
 Hyperlipidaemia  25.9  13.1  0.326  25.5  26.3  0.019  16.1  15.5  0.018 
 Depressive disorder  6.7  1.2  0.289  5.8  5.2  0.027  2.3  2.2  0.005 
 Anxiety  6.2  1.4  0.252  5.6  5.5  0.005  2.4  2.4  0.001 
 Multiple sclerosis  0.03  0.01  0.013  0.02  0.01  0.012  0.01  0.01  0.001 
 Systemic lupus erythematosus  0.19  0.10  0.022  0.19  0.12  0.018  0.12  0.12  0.001 
 Rheumatoid arthritis  0.44  0.28  0.037  0.44  0.30  0.023  0.27  0.27  0.001 
 Vasculitis  0.01  0.005  0.006  0.01  0.004  0.007  0.01  0.01  0.001 
 Sjogren’s syndrome  0.28  0.09  0.045  0.28  0.12  0.035  0.12  0.12  0.001 
Variable Full cohort (n = 1 334 984)


Propensity-score-matched cohort (n = 431 916)


Inverse-probability treatment-weighting (IPTW) cohort


Antidepressant users (n = 218 466)


Nonusers (n = 1 116 518)


SDiff Antidepressant users (n = 215 958)


Nonusers (n = 215 958)


SDiff Antidepressant users


Nonusers


SDiff
% % %
Sex      0.188      0.007      0.021 
 Male  42.5  51.9    49.1  49.1    49.1  49.8   
 Female  57.5  48.1    50.9  50.9    50.9  50.2   
Age group (years)      0.447      0.040      0.045 
 20–34  20.8  36.2    32.3  32.3    32.3  33.6   
 35–49  29.6  33.9    33.9  33.9    33.9  32.9   
 50–64  26.4  19.3    20.7  20.7    20.7  20.4   
 ≥65  23.2  10.7    13.1  13.1    13.1  13.0   
Urbanization level      0.120      0.048      0.048 
 1 (most urbanized)  39.2  39.5    39.2  39.3    39.2  39.6   
 2  26.8  27.8    26.8  26.6    28.5  27.4   
 3  14.2  16.2    14.3  14.3    15.1  16.0   
 4  13.5  11.8    13.5  13.5    12.2  12.1   
 5 (least urbanized)  6.3  4.7    6.3  6.3    4.9  5.0   
Monthly income (NT$)      0.262      0.001      0.045 
 0–18 000  34.0  24.7    33.8  33.9    26.6  26.3   
 18 001–34 999  45.7  45.5    45.8  45.9    46.1  45.4   
 ≥35 000  20.3  29.9    20.4  20.2    27.3  28.3   
Co-morbidities       
 Chronic otitis media  1.0  0.5  0.053  0.9  0.9  0.001  0.6  0.6  0.002 
 Hypertension  35.4  16.8  0.435  35.0  36.0  0.022  20.8  20.1  0.016 
 Diabetes mellitus  20.0  9.0  0.314  19.7  20.3  0.015  11.4  11.0  0.012 
 Hyperlipidaemia  25.9  13.1  0.326  25.5  26.3  0.019  16.1  15.5  0.018 
 Depressive disorder  6.7  1.2  0.289  5.8  5.2  0.027  2.3  2.2  0.005 
 Anxiety  6.2  1.4  0.252  5.6  5.5  0.005  2.4  2.4  0.001 
 Multiple sclerosis  0.03  0.01  0.013  0.02  0.01  0.012  0.01  0.01  0.001 
 Systemic lupus erythematosus  0.19  0.10  0.022  0.19  0.12  0.018  0.12  0.12  0.001 
 Rheumatoid arthritis  0.44  0.28  0.037  0.44  0.30  0.023  0.27  0.27  0.001 
 Vasculitis  0.01  0.005  0.006  0.01  0.004  0.007  0.01  0.01  0.001 
 Sjogren’s syndrome  0.28  0.09  0.045  0.28  0.12  0.035  0.12  0.12  0.001 

Baseline characteristics of the study patients

Variable Full cohort (n = 1 334 984)


Propensity-score-matched cohort (n = 431 916)


Inverse-probability treatment-weighting (IPTW) cohort


Antidepressant users (n = 218 466)


Nonusers (n = 1 116 518)


SDiff Antidepressant users (n = 215 958)


Nonusers (n = 215 958)


SDiff Antidepressant users


Nonusers


SDiff
% % %
Sex      0.188      0.007      0.021 
 Male  42.5  51.9    49.1  49.1    49.1  49.8   
 Female  57.5  48.1    50.9  50.9    50.9  50.2   
Age group (years)      0.447      0.040      0.045 
 20–34  20.8  36.2    32.3  32.3    32.3  33.6   
 35–49  29.6  33.9    33.9  33.9    33.9  32.9   
 50–64  26.4  19.3    20.7  20.7    20.7  20.4   
 ≥65  23.2  10.7    13.1  13.1    13.1  13.0   
Urbanization level      0.120      0.048      0.048 
 1 (most urbanized)  39.2  39.5    39.2  39.3    39.2  39.6   
 2  26.8  27.8    26.8  26.6    28.5  27.4   
 3  14.2  16.2    14.3  14.3    15.1  16.0   
 4  13.5  11.8    13.5  13.5    12.2  12.1   
 5 (least urbanized)  6.3  4.7    6.3  6.3    4.9  5.0   
Monthly income (NT$)      0.262      0.001      0.045 
 0–18 000  34.0  24.7    33.8  33.9    26.6  26.3   
 18 001–34 999  45.7  45.5    45.8  45.9    46.1  45.4   
 ≥35 000  20.3  29.9    20.4  20.2    27.3  28.3   
Co-morbidities       
 Chronic otitis media  1.0  0.5  0.053  0.9  0.9  0.001  0.6  0.6  0.002 
 Hypertension  35.4  16.8  0.435  35.0  36.0  0.022  20.8  20.1  0.016 
 Diabetes mellitus  20.0  9.0  0.314  19.7  20.3  0.015  11.4  11.0  0.012 
 Hyperlipidaemia  25.9  13.1  0.326  25.5  26.3  0.019  16.1  15.5  0.018 
 Depressive disorder  6.7  1.2  0.289  5.8  5.2  0.027  2.3  2.2  0.005 
 Anxiety  6.2  1.4  0.252  5.6  5.5  0.005  2.4  2.4  0.001 
 Multiple sclerosis  0.03  0.01  0.013  0.02  0.01  0.012  0.01  0.01  0.001 
 Systemic lupus erythematosus  0.19  0.10  0.022  0.19  0.12  0.018  0.12  0.12  0.001 
 Rheumatoid arthritis  0.44  0.28  0.037  0.44  0.30  0.023  0.27  0.27  0.001 
 Vasculitis  0.01  0.005  0.006  0.01  0.004  0.007  0.01  0.01  0.001 
 Sjogren’s syndrome  0.28  0.09  0.045  0.28  0.12  0.035  0.12  0.12  0.001 
Variable Full cohort (n = 1 334 984)


Propensity-score-matched cohort (n = 431 916)


Inverse-probability treatment-weighting (IPTW) cohort


Antidepressant users (n = 218 466)


Nonusers (n = 1 116 518)


SDiff Antidepressant users (n = 215 958)


Nonusers (n = 215 958)


SDiff Antidepressant users


Nonusers


SDiff
% % %
Sex      0.188      0.007      0.021 
 Male  42.5  51.9    49.1  49.1    49.1  49.8   
 Female  57.5  48.1    50.9  50.9    50.9  50.2   
Age group (years)      0.447      0.040      0.045 
 20–34  20.8  36.2    32.3  32.3    32.3  33.6   
 35–49  29.6  33.9    33.9  33.9    33.9  32.9   
 50–64  26.4  19.3    20.7  20.7    20.7  20.4   
 ≥65  23.2  10.7    13.1  13.1    13.1  13.0   
Urbanization level      0.120      0.048      0.048 
 1 (most urbanized)  39.2  39.5    39.2  39.3    39.2  39.6   
 2  26.8  27.8    26.8  26.6    28.5  27.4   
 3  14.2  16.2    14.3  14.3    15.1  16.0   
 4  13.5  11.8    13.5  13.5    12.2  12.1   
 5 (least urbanized)  6.3  4.7    6.3  6.3    4.9  5.0   
Monthly income (NT$)      0.262      0.001      0.045 
 0–18 000  34.0  24.7    33.8  33.9    26.6  26.3   
 18 001–34 999  45.7  45.5    45.8  45.9    46.1  45.4   
 ≥35 000  20.3  29.9    20.4  20.2    27.3  28.3   
Co-morbidities       
 Chronic otitis media  1.0  0.5  0.053  0.9  0.9  0.001  0.6  0.6  0.002 
 Hypertension  35.4  16.8  0.435  35.0  36.0  0.022  20.8  20.1  0.016 
 Diabetes mellitus  20.0  9.0  0.314  19.7  20.3  0.015  11.4  11.0  0.012 
 Hyperlipidaemia  25.9  13.1  0.326  25.5  26.3  0.019  16.1  15.5  0.018 
 Depressive disorder  6.7  1.2  0.289  5.8  5.2  0.027  2.3  2.2  0.005 
 Anxiety  6.2  1.4  0.252  5.6  5.5  0.005  2.4  2.4  0.001 
 Multiple sclerosis  0.03  0.01  0.013  0.02  0.01  0.012  0.01  0.01  0.001 
 Systemic lupus erythematosus  0.19  0.10  0.022  0.19  0.12  0.018  0.12  0.12  0.001 
 Rheumatoid arthritis  0.44  0.28  0.037  0.44  0.30  0.023  0.27  0.27  0.001 
 Vasculitis  0.01  0.005  0.006  0.01  0.004  0.007  0.01  0.01  0.001 
 Sjogren’s syndrome  0.28  0.09  0.045  0.28  0.12  0.035  0.12  0.12  0.001 

Table 2 shows the incidence and HRs for SSNHL during the 5-year follow-up period among selected patients. The main findings indicate that the incidence rates of SSNHL per 1000 person-years within the 5-year study period were 0.74 (95% CI, 0.68–0.79) and 0.44 (95% CI, 0.42–0.46) for antidepressant users and nonusers in the full cohort, respectively. The Cox proportional-hazard regression analyses revealed that the aHR of SSNHL for antidepressant users was 1.36 (95% CI, 1.25–1.48) compared with nonusers after adjusting for characteristics and co-morbidities. We further performed an IPTW analysis and the IPTW-aHR for antidepressant users was 1.44 (95% CI, 1.37–1.52) compared with nonusers. In the PSM cohort, the aHR for SSNHL among antidepressant users was 1.49 (95% CI, 1.32–1.66) compared with the matched nonusers. Additionally, the Kaplan–Meier survival analyses with log-rank tests consistently indicated that antidepressant users had an obviously lower SSNHL-free survival rate than nonusers (all log-rank tests: p < 0.001) in the full cohort, the PSM cohort and the IPTW cohort (Figure 2).

Sudden sensorineural hearing loss-free survival rates for antidepressant users and the nonusers. (A) Full cohort; (B) propensity-score-matched (PSM) cohort; (C) inverse-probability treatment-weighted (IPTW) cohort.

Sudden sensorineural hearing loss-free survival rates for antidepressant users and the nonusers. (A) Full cohort; (B) propensity-score-matched (PSM) cohort; (C) inverse-probability treatment-weighted (IPTW) cohort.

Table 2

Incidence and hazard ratios for sudden sensorineural hearing loss during the 5-year follow-up period among selected patients

Incidence and hazard ratios for sudden sensorineural hearing loss during the 5-year follow-up period among selected patients

Presence of sudden sensorineural hearing loss Full cohort study


Propensity-score-matched cohort


Antidepressant users (n = 218 466) Nonusers (n = 1 116 518) Antidepressant users (n = 215 958) Nonusers (n = 215 958)
Five-year follow-up period         
 No. of patients with sudden sensorineural hearing loss (%)  796 (0.36)  2403 (0.22)  784 (0.36)  550 (0.25) 
 Total follow-up (person-years)  1 045 706  5 445 938  1 033 829  1 035 541 
 Incidence rate per 1000 person-years (95% CI)  0.74 (0.68–0.79)  0.44 (0.42–0.46)  0.76 (0.71–-0.81)  0.53 (0.49–0.58) 
 Crude HR (95% CI)  1.73 (1.59–1.87)  1.00  1.44 (1.29–1.61)  1.00 
 Adjusted HR (95% CI)  1.36 (1.25–1.48),c  1.00  1.49 (1.32–1.66),c  1.00 
 IPTW crude HR (95% CI)  1.73 (1.59–1.87)  1.00  –  – 
 IPTW adjusted HR (95% CI)  1.44 (1.37–1.52),c  1.00  –  – 
Presence of sudden sensorineural hearing loss Full cohort study


Propensity-score-matched cohort


Antidepressant users (n = 218 466) Nonusers (n = 1 116 518) Antidepressant users (n = 215 958) Nonusers (n = 215 958)
Five-year follow-up period         
 No. of patients with sudden sensorineural hearing loss (%)  796 (0.36)  2403 (0.22)  784 (0.36)  550 (0.25) 
 Total follow-up (person-years)  1 045 706  5 445 938  1 033 829  1 035 541 
 Incidence rate per 1000 person-years (95% CI)  0.74 (0.68–0.79)  0.44 (0.42–0.46)  0.76 (0.71–-0.81)  0.53 (0.49–0.58) 
 Crude HR (95% CI)  1.73 (1.59–1.87)  1.00  1.44 (1.29–1.61)  1.00 
 Adjusted HR (95% CI)  1.36 (1.25–1.48),c  1.00  1.49 (1.32–1.66),c  1.00 
 IPTW crude HR (95% CI)  1.73 (1.59–1.87)  1.00  –  – 
 IPTW adjusted HR (95% CI)  1.44 (1.37–1.52),c  1.00  –  – 

CI, confidence interval; HR, hazard ratio; IPTW, inverse probability of treatment weighting.

Adjustment for sex, age group, urbanization level, monthly income, chronic otitis media, diabetes mellitus, hypertension, hyperlipidaemia, anxiety, depressive disorder, multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis, vasculitis and Sjogren’s syndrome.

P < 0.05;

Incidence and hazard ratios for sudden sensorineural hearing loss during the 5-year follow-up period among selected patients

Presence of sudden sensorineural hearing loss Full cohort study


Propensity-score-matched cohort


Antidepressant users (n = 218 466) Nonusers (n = 1 116 518) Antidepressant users (n = 215 958) Nonusers (n = 215 958)
Five-year follow-up period         
 No. of patients with sudden sensorineural hearing loss (%)  796 (0.36)  2403 (0.22)  784 (0.36)  550 (0.25) 
 Total follow-up (person-years)  1 045 706  5 445 938  1 033 829  1 035 541 
 Incidence rate per 1000 person-years (95% CI)  0.74 (0.68–0.79)  0.44 (0.42–0.46)  0.76 (0.71–-0.81)  0.53 (0.49–0.58) 
 Crude HR (95% CI)  1.73 (1.59–1.87)  1.00  1.44 (1.29–1.61)  1.00 
 Adjusted HR (95% CI)  1.36 (1.25–1.48),c  1.00  1.49 (1.32–1.66),c  1.00 
 IPTW crude HR (95% CI)  1.73 (1.59–1.87)  1.00  –  – 
 IPTW adjusted HR (95% CI)  1.44 (1.37–1.52),c  1.00  –  – 
Presence of sudden sensorineural hearing loss Full cohort study


Propensity-score-matched cohort


Antidepressant users (n = 218 466) Nonusers (n = 1 116 518) Antidepressant users (n = 215 958) Nonusers (n = 215 958)
Five-year follow-up period         
 No. of patients with sudden sensorineural hearing loss (%)  796 (0.36)  2403 (0.22)  784 (0.36)  550 (0.25) 
 Total follow-up (person-years)  1 045 706  5 445 938  1 033 829  1 035 541 
 Incidence rate per 1000 person-years (95% CI)  0.74 (0.68–0.79)  0.44 (0.42–0.46)  0.76 (0.71–-0.81)  0.53 (0.49–0.58) 
 Crude HR (95% CI)  1.73 (1.59–1.87)  1.00  1.44 (1.29–1.61)  1.00 
 Adjusted HR (95% CI)  1.36 (1.25–1.48),c  1.00  1.49 (1.32–1.66),c  1.00 
 IPTW crude HR (95% CI)  1.73 (1.59–1.87)  1.00  –  – 
 IPTW adjusted HR (95% CI)  1.44 (1.37–1.52),c  1.00  –  – 

CI, confidence interval; HR, hazard ratio; IPTW, inverse probability of treatment weighting.

Adjustment for sex, age group, urbanization level, monthly income, chronic otitis media, diabetes mellitus, hypertension, hyperlipidaemia, anxiety, depressive disorder, multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis, vasculitis and Sjogren’s syndrome.

P < 0.05;

P < 0.01;

P < 0.001.

We employed the PSM cohort for further analyses (Table 3). We evaluated the association between the classes of antidepressants and the risk of SSNHL during the 5-year follow-up period. The incidence rates of SSNHL per 1000 person-years within the 5-year follow-up period were 0.65, 0.86, 0.83, 0.76 and 0.53 for SSRI users, TCA users, SNRI users, other-antidepressant users and the matched nonusers, respectively (data not shown). The findings revealed that SSRIs, TCAs, SNRIs and other-antidepressant users were associated with a 1.36-fold (95% CI, 1.16–1.58), 1.55-fold (95% CI, 1.37–1.76), 1.79-fold (95% CI, 1.40–2.30) and 1.45-fold (95% CI, 1.27–1.67) increased risk of SSNHL after adjustments when compared with nonusers. Additionally, Kaplan–Meier survival analysis indicated that users of SSRIs, TCAs, SNRIs and other antidepressants had a distinctly lower SSNHL-free survival rate than nonusers (all log-rank tests: p < 0.05) (Figure 3). All antidepressant classes consistently increased the risk of SSNHL.

Sudden sensorineural hearing loss-free survival rates among the propensity-score-matched (PSM) cohort. (A) Patients ever receiving selective serotonin reuptake inhibitors (SSRIs); (B) patients ever receiving tricyclic antidepressants (TCAs); (C) patients ever receiving serotonin–norepinephrine reuptake inhibitors (SNRIs); (D) patients ever receiving other antidepressants.

Sudden sensorineural hearing loss-free survival rates among the propensity-score-matched (PSM) cohort. (A) Patients ever receiving selective serotonin reuptake inhibitors (SSRIs); (B) patients ever receiving tricyclic antidepressants (TCAs); (C) patients ever receiving serotonin–norepinephrine reuptake inhibitors (SNRIs); (D) patients ever receiving other antidepressants.

Table 3

Antidepressant use and risk of sudden sensorineural hearing loss, classified by antidepressant classes, numbers of antidepressant classes, sex, age group and co-morbidities

Antidepressant use and risk of sudden sensorineural hearing loss, classified by antidepressant classes, numbers of antidepressant classes, sex, age group and co-morbidities

Variables Propensity-score-matched cohort study


Crude HR (95% CI) Adjusted HR (95% CI),b
Antidepressant classes     
 Patients ever receiving SSRIs  1.22 (1.05–1.41)  1.36 (1.16–1.58) 
 Patients ever receiving TCAs  1.63 (1.44–1.84)  1.55 (1.37–1.76) 
 Patients ever receiving SNRIs  1.57 (1.23–2.01)  1.79 (1.40–2.30) 
 Patients ever receiving other antidepressants  1.43 (1.25–1.65)  1.45 (1.27–1.67) 
 Nonusers  1.00  1.00 
Numbers of antidepressant classes     
 Patients receiving 1 class of antidepressants  1.42 (1.26–1.59)  1.42 (1.26–1.60) 
 Patients receiving 2 classes of antidepressants  1.35 (1.12–1.62)  1.37 (1.14–1.64) 
 Patients receiving 3 classes of antidepressants  1.70 (1.31–2.21)  1.80 (1.38–2.34) 
 Patients receiving 4 classes of antidepressants  1.83* (1.12–3.01)  2.05 (1.25–3.38) 
 Nonusers  1.00  1.00 
Subgroups (antidepressant users vs matched nonusers)     
 Sex     
  Male  1.37 (1.16–1.59)  1.37 (1.17–1.60) 
  Female  1.49 (1.29–1.74)  1.51 (1.30–1.76) 
 Age group (years)     
  20–34  1.55* (1.10–2.17)  1.55* (1.10–2.17) 
  35–49  1.61 (1.29–2.00)  1.60 (1.29–2.00) 
  50–64  1.43 (1.19–1.72)  1.45 (1.21–1.73) 
  ≥65  1.28* (1.04–1.56)  1.28* (1.04–1.57) 
 Co-morbidities     
  Hypertension     
   Yes  1.33 (1.14–1.56)  1.34 (1.15–1.57) 
   No  1.54 (1.32–1.78)  1.53 (1.32–1.78) 
  Diabetes mellitus     
   Yes  1.31 (1.08–1.59)  1.32 (1.08–1.61) 
   No  1.49 (1.31–1.70)  1.50 (1.32–1.71) 
  Hyperlipidaemia     
   Yes  1.42 (1.19–1.68)  1.42 (1.20–1.69) 
   No  1.45 (1.26–1.67)  1.45 (1.26–1.67) 
Variables Propensity-score-matched cohort study


Crude HR (95% CI) Adjusted HR (95% CI),b
Antidepressant classes     
 Patients ever receiving SSRIs  1.22 (1.05–1.41)  1.36 (1.16–1.58) 
 Patients ever receiving TCAs  1.63 (1.44–1.84)  1.55 (1.37–1.76) 
 Patients ever receiving SNRIs  1.57 (1.23–2.01)  1.79 (1.40–2.30) 
 Patients ever receiving other antidepressants  1.43 (1.25–1.65)  1.45 (1.27–1.67) 
 Nonusers  1.00  1.00 
Numbers of antidepressant classes     
 Patients receiving 1 class of antidepressants  1.42 (1.26–1.59)  1.42 (1.26–1.60) 
 Patients receiving 2 classes of antidepressants  1.35 (1.12–1.62)  1.37 (1.14–1.64) 
 Patients receiving 3 classes of antidepressants  1.70 (1.31–2.21)  1.80 (1.38–2.34) 
 Patients receiving 4 classes of antidepressants  1.83* (1.12–3.01)  2.05 (1.25–3.38) 
 Nonusers  1.00  1.00 
Subgroups (antidepressant users vs matched nonusers)     
 Sex     
  Male  1.37 (1.16–1.59)  1.37 (1.17–1.60) 
  Female  1.49 (1.29–1.74)  1.51 (1.30–1.76) 
 Age group (years)     
  20–34  1.55* (1.10–2.17)  1.55* (1.10–2.17) 
  35–49  1.61 (1.29–2.00)  1.60 (1.29–2.00) 
  50–64  1.43 (1.19–1.72)  1.45 (1.21–1.73) 
  ≥65  1.28* (1.04–1.56)  1.28* (1.04–1.57) 
 Co-morbidities     
  Hypertension     
   Yes  1.33 (1.14–1.56)  1.34 (1.15–1.57) 
   No  1.54 (1.32–1.78)  1.53 (1.32–1.78) 
  Diabetes mellitus     
   Yes  1.31 (1.08–1.59)  1.32 (1.08–1.61) 
   No  1.49 (1.31–1.70)  1.50 (1.32–1.71) 
  Hyperlipidaemia     
   Yes  1.42 (1.19–1.68)  1.42 (1.20–1.69) 
   No  1.45 (1.26–1.67)  1.45 (1.26–1.67) 

CI, confidence interval; HR, hazard ratio; SSRIs, selective serotonin reuptake inhibitors; TCAs, tricyclic antidepressants; SNRIs, serotonin–norepinephrine reuptake inhibitors; Others, other antidepressants (including trazodone, mirtazapine and bupropion).

Adjustment for sex, age group, urbanization level, monthly income, chronic otitis media, diabetes mellitus, hypertension, hyperlipidaemia, anxiety, depressive disorder, multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis, vasculitis and Sjogren’s syndrome.

P < 0.05;

Antidepressant use and risk of sudden sensorineural hearing loss, classified by antidepressant classes, numbers of antidepressant classes, sex, age group and co-morbidities

Variables Propensity-score-matched cohort study


Crude HR (95% CI) Adjusted HR (95% CI),b
Antidepressant classes     
 Patients ever receiving SSRIs  1.22 (1.05–1.41)  1.36 (1.16–1.58) 
 Patients ever receiving TCAs  1.63 (1.44–1.84)  1.55 (1.37–1.76) 
 Patients ever receiving SNRIs  1.57 (1.23–2.01)  1.79 (1.40–2.30) 
 Patients ever receiving other antidepressants  1.43 (1.25–1.65)  1.45 (1.27–1.67) 
 Nonusers  1.00  1.00 
Numbers of antidepressant classes     
 Patients receiving 1 class of antidepressants  1.42 (1.26–1.59)  1.42 (1.26–1.60) 
 Patients receiving 2 classes of antidepressants  1.35 (1.12–1.62)  1.37 (1.14–1.64) 
 Patients receiving 3 classes of antidepressants  1.70 (1.31–2.21)  1.80 (1.38–2.34) 
 Patients receiving 4 classes of antidepressants  1.83* (1.12–3.01)  2.05 (1.25–3.38) 
 Nonusers  1.00  1.00 
Subgroups (antidepressant users vs matched nonusers)     
 Sex     
  Male  1.37 (1.16–1.59)  1.37 (1.17–1.60) 
  Female  1.49 (1.29–1.74)  1.51 (1.30–1.76) 
 Age group (years)     
  20–34  1.55* (1.10–2.17)  1.55* (1.10–2.17) 
  35–49  1.61 (1.29–2.00)  1.60 (1.29–2.00) 
  50–64  1.43 (1.19–1.72)  1.45 (1.21–1.73) 
  ≥65  1.28* (1.04–1.56)  1.28* (1.04–1.57) 
 Co-morbidities     
  Hypertension     
   Yes  1.33 (1.14–1.56)  1.34 (1.15–1.57) 
   No  1.54 (1.32–1.78)  1.53 (1.32–1.78) 
  Diabetes mellitus     
   Yes  1.31 (1.08–1.59)  1.32 (1.08–1.61) 
   No  1.49 (1.31–1.70)  1.50 (1.32–1.71) 
  Hyperlipidaemia     
   Yes  1.42 (1.19–1.68)  1.42 (1.20–1.69) 
   No  1.45 (1.26–1.67)  1.45 (1.26–1.67) 
Variables Propensity-score-matched cohort study


Crude HR (95% CI) Adjusted HR (95% CI),b
Antidepressant classes     
 Patients ever receiving SSRIs  1.22 (1.05–1.41)  1.36 (1.16–1.58) 
 Patients ever receiving TCAs  1.63 (1.44–1.84)  1.55 (1.37–1.76) 
 Patients ever receiving SNRIs  1.57 (1.23–2.01)  1.79 (1.40–2.30) 
 Patients ever receiving other antidepressants  1.43 (1.25–1.65)  1.45 (1.27–1.67) 
 Nonusers  1.00  1.00 
Numbers of antidepressant classes     
 Patients receiving 1 class of antidepressants  1.42 (1.26–1.59)  1.42 (1.26–1.60) 
 Patients receiving 2 classes of antidepressants  1.35 (1.12–1.62)  1.37 (1.14–1.64) 
 Patients receiving 3 classes of antidepressants  1.70 (1.31–2.21)  1.80 (1.38–2.34) 
 Patients receiving 4 classes of antidepressants  1.83* (1.12–3.01)  2.05 (1.25–3.38) 
 Nonusers  1.00  1.00 
Subgroups (antidepressant users vs matched nonusers)     
 Sex     
  Male  1.37 (1.16–1.59)  1.37 (1.17–1.60) 
  Female  1.49 (1.29–1.74)  1.51 (1.30–1.76) 
 Age group (years)     
  20–34  1.55* (1.10–2.17)  1.55* (1.10–2.17) 
  35–49  1.61 (1.29–2.00)  1.60 (1.29–2.00) 
  50–64  1.43 (1.19–1.72)  1.45 (1.21–1.73) 
  ≥65  1.28* (1.04–1.56)  1.28* (1.04–1.57) 
 Co-morbidities     
  Hypertension     
   Yes  1.33 (1.14–1.56)  1.34 (1.15–1.57) 
   No  1.54 (1.32–1.78)  1.53 (1.32–1.78) 
  Diabetes mellitus     
   Yes  1.31 (1.08–1.59)  1.32 (1.08–1.61) 
   No  1.49 (1.31–1.70)  1.50 (1.32–1.71) 
  Hyperlipidaemia     
   Yes  1.42 (1.19–1.68)  1.42 (1.20–1.69) 
   No  1.45 (1.26–1.67)  1.45 (1.26–1.67) 

CI, confidence interval; HR, hazard ratio; SSRIs, selective serotonin reuptake inhibitors; TCAs, tricyclic antidepressants; SNRIs, serotonin–norepinephrine reuptake inhibitors; Others, other antidepressants (including trazodone, mirtazapine and bupropion).

Adjustment for sex, age group, urbanization level, monthly income, chronic otitis media, diabetes mellitus, hypertension, hyperlipidaemia, anxiety, depressive disorder, multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis, vasculitis and Sjogren’s syndrome.

P < 0.05;

P < 0.01;

We then assessed the relationship between the numbers of classes of antidepressants used (numbers of combination use) and the risk of SSNHL among the PSM cohort (Table 3). Compared with nonusers, those patients who received four classes of antidepressants were associated with a higher risk of SSNHL (aHR, 2.05), followed by those who received three classes (aHR, 1.80) and then those who received one and two classes (aHR, 1.42 and 1.37, respectively). Kaplan–Meier survival analysis also indicated that SSNHL risk was obviously increased if patients received three or four classes of antidepressants (log-rank test: p < 0.001) (Figure 4).

Sudden sensorineural hearing loss-free survival rates among propensity-score-matched (PSM) cohort: numbers of antidepressant classes

Sudden sensorineural hearing loss-free survival rates among propensity-score-matched (PSM) cohort: numbers of antidepressant classes

Subgroup analyses were also performed. The assessment of SSNHL risk according to sex, age group and co-morbidity status are shown in Table 3. Among both men and women, antidepressant users had a higher risk for SSNHL compared with nonusers (males: HR, 1.37 and females: HR, 1.51). Antidepressant users in all age groups had a higher risk of SSNHL compared with nonusers (all p< 0.05). Among the comorbid and non-comorbid patients, antidepressant users had a higher risk for SSNHL compared with nonusers (all p< 0.05).

The findings remained robust during the sensitivity analyses (Table 4). Notably, the risk of SSNHL was evidently increased among antidepressant users compared with nonusers by limiting those who were diagnosed with SSNHL twice or three times (aHR, 1.58 and 1.62, respectively) during the 5-year study period.

Presence of sudden sensorineural hearing loss Propensity-score-matched cohort study


Antidepressant users (n = 218 466) Nonusers (n = 1 116 518)
Receiving a SSNHL diagnosis within the 5-year study period     
 Crude HR (95% CI)  1.44 (1.29–1.61)  1.00 
 Adjusted HR (95% CI)  1.49 (1.32–1.66),b  1.00 
Receiving >2 SSNHL diagnoses within the 5-year study period     
 Crude HR (95% CI)  1.53 (1.31–1.77)  1.00 
 Adjusted HR (95% CI)  1.58 (1.36–1.85),b  1.00 
Receiving >3 SSNHL diagnoses within the 5-year study period     
 Crude HR (95% CI)  1.57 (1.31–1.88)  1.00 
 Adjusted HR (95% CI)  1.62 (1.35–1.95),b  1.00 
Presence of sudden sensorineural hearing loss Propensity-score-matched cohort study


Antidepressant users (n = 218 466) Nonusers (n = 1 116 518)
Receiving a SSNHL diagnosis within the 5-year study period     
 Crude HR (95% CI)  1.44 (1.29–1.61)  1.00 
 Adjusted HR (95% CI)  1.49 (1.32–1.66),b  1.00 
Receiving >2 SSNHL diagnoses within the 5-year study period     
 Crude HR (95% CI)  1.53 (1.31–1.77)  1.00 
 Adjusted HR (95% CI)  1.58 (1.36–1.85),b  1.00 
Receiving >3 SSNHL diagnoses within the 5-year study period     
 Crude HR (95% CI)  1.57 (1.31–1.88)  1.00 
 Adjusted HR (95% CI)  1.62 (1.35–1.95),b  1.00 

CI, confidence interval; HR, hazard ratio; SSNHL, sudden sensorineural hearing loss.

Adjustment for sex, age group, urbanization level, monthly income, chronic otitis media, diabetes mellitus, hypertension, hyperlipidaemia, anxiety, depressive disorder, multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis, vasculitis and Sjogren’s syndrome.

P < 0.05;

Presence of sudden sensorineural hearing loss Propensity-score-matched cohort study


Antidepressant users (n = 218 466) Nonusers (n = 1 116 518)
Receiving a SSNHL diagnosis within the 5-year study period     
 Crude HR (95% CI)  1.44 (1.29–1.61)  1.00 
 Adjusted HR (95% CI)  1.49 (1.32–1.66),b  1.00 
Receiving >2 SSNHL diagnoses within the 5-year study period     
 Crude HR (95% CI)  1.53 (1.31–1.77)  1.00 
 Adjusted HR (95% CI)  1.58 (1.36–1.85),b  1.00 
Receiving >3 SSNHL diagnoses within the 5-year study period     
 Crude HR (95% CI)  1.57 (1.31–1.88)  1.00 
 Adjusted HR (95% CI)  1.62 (1.35–1.95),b  1.00 
Presence of sudden sensorineural hearing loss Propensity-score-matched cohort study


Antidepressant users (n = 218 466) Nonusers (n = 1 116 518)
Receiving a SSNHL diagnosis within the 5-year study period     
 Crude HR (95% CI)  1.44 (1.29–1.61)  1.00 
 Adjusted HR (95% CI)  1.49 (1.32–1.66),b  1.00 
Receiving >2 SSNHL diagnoses within the 5-year study period     
 Crude HR (95% CI)  1.53 (1.31–1.77)  1.00 
 Adjusted HR (95% CI)  1.58 (1.36–1.85),b  1.00 
Receiving >3 SSNHL diagnoses within the 5-year study period     
 Crude HR (95% CI)  1.57 (1.31–1.88)  1.00 
 Adjusted HR (95% CI)  1.62 (1.35–1.95),b  1.00 

CI, confidence interval; HR, hazard ratio; SSNHL, sudden sensorineural hearing loss.

Adjustment for sex, age group, urbanization level, monthly income, chronic otitis media, diabetes mellitus, hypertension, hyperlipidaemia, anxiety, depressive disorder, multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis, vasculitis and Sjogren’s syndrome.

P < 0.05;

P < 0.01;

This study found that antidepressants increased SSNHL risk, regardless of the antidepressant class, in the full cohort, PSM cohort and IPTW cohort. It was noteworthy that patients who took a higher number of antidepressant classes showed an increased risk of developing SSNHL compared with those who took a lower number of antidepressant classes. Additionally, antidepressant users had a higher risk of SSNHL in all documented subgroups. Ours is the first population-based study to investigate the relationship between antidepressants and subsequent SSNHL.

We found a relationship between antidepressant use and subsequent SSNHL. To date, very few studies have investigated this relevant issue. Some prior findings were consistent with our study. For instance, some case reports indicated that antidepressants might induce hearing loss. However, a small clinical trial indicated that citalopram treatment could positively impact central auditory measures in elderly patients. Some biological mechanisms that explain the association between antidepressants and otological side effects might support our research findings.,,, A prior study demonstrated that serotonin shows a bias for one input pathway in the dorsal cochlear nucleus by simultaneously enhancing excitability in the principal cells and in a pathway-specific feedforward inhibitory interneuron. Eventually, serotonin enhances signalling from the multisensory input and decreases input from auditory nerve fibres. Because most antidepressants are recognized as involved in serotonin-related pharmacological mechanisms, it was plausible that antidepressants might contribute to the incidence of SSNHL. One the other hand, some previous studies found that serotonin modulation could inhibit the acoustic pathways., One study demonstrated that serotonin inhibited the spontaneous activity and the tone-evoked activity in neurons of the cochlear nucleus. Davis et al. reported inhibition of the acoustic startle reflex in response to a serotonin infusion in the lateral ventricle. Therefore, these underlying mechanisms also provide explanations for the relationship between antidepressants and SSNHL.

Nevertheless, the results from other studies were inconsistent., A prospective, randomized study involving 39 patients (>60 years old, without moderate or severe depression) showed no clinical effect with citalopram use in central auditory tests during a 6-month period. Additionally, one investigation indicated no significant difference for pure-tone averages between depressed woman receiving SSRIs and those who did not receive SSRIs. However, due to the relatively small sample sizes, limited statistical power, short follow-up time, restricted study population, single antidepressant exposure and unbalanced co-morbidities, the relevant findings in prior studies may conflict with our study results.

Additionally, our findings indicated that the risk of SSNHL was raised with the use of increasing numbers of antidepressant classes. Patients who received four classes of antidepressants were significantly associated with a 2-fold increased risk of SSNHL. Even though the underlying reasons for this association remain unclear, a prior study indicated that polypharmacy might result in complicated drug interactions or cumulative toxicity and further increase the risk of adverse reactions. Nevertheless, we observed that patients who received one class (aHR, 1.42) or two classes (aHR, 1.37) had a relatively low risk of SSNHL. Consequently, we recommend that physicians avoid the concurrent prescription of antidepressants.

The subgroup analysis indicated that, compared with nonusers, SNRIs, TCAs, other antidepressants (including trazodone, mirtazapine and bupropion) and SSRIs increased the risk of SSNHL by 79%, 55%, 45% and 36%, respectively. SNRI users (aHR, 1.79) had the highest risk of SSNHL compared with the users of the other classes. An explanation for this phenomenon was that SNRIs might cause vasoconstriction and this appears to be related to the potency of norepinephrine effects., For example, cocaine, which is involved in regulating the norepinephrine transporter, prevents the reuptake of amines at the presynaptic receptor level and induces vasospasm, which is thought to lead to cochlear anoxia., Therefore, it was plausible that TCA users also had a higher risk of SSNHL.

There were many advantages to our study. First, this was the first and largest sample cohort study to investigate the association between antidepressant use and the subsequent risk of SSNHL. We were able to detect rare outcomes when comparing our results with prior literature. Additionally, our cohort study design was able to demonstrate the causal and temporal connection between antidepressants and SSNHL. Second, our main findings were validated via three different strategies, including full cohorts with adjustments, a PSM model and an IPTW design. Thus, the confounders and biases could be eliminated and the relevant findings were considered robust. Third, this study used a rigorous, physician-diagnosed disease (ICD-9-CM code 388.2: sudden hearing loss, unspecified) as our outcome’s definition. Most prior studies only employed self-assessment questionnaires.

Nevertheless, there were several study limitations that merit mention. First, the LHID2005 database did not record the use of over-the-counter drugs. Second, there was no detailed information on the family history of SSNHL, laboratory data (such as lipid profiles or low folate levels), lifestyles factors (a diet rich in fresh vegetables, smoking status and alcohol consumption) and noise exposure, which are prognostic factors of SSNHL. Third, we did not exclude patients who had used concomitant medications that might affect hearing. However, we did consider the history of co-morbidities and many medications that might affect hearing could have been prescribed for the documented co-morbidities in this study. We used adjustments, IPTW and PSM strategies to eliminate the potential effects. Fourth, it was still unclear whether the SSNHL was unilateral or bilateral in this study. From the diagnosis code of SSNHL, it cannot be directly determined whether the affected ear is unilateral or bilateral. However, in general, SSNHL is usually unilateral and, less often, bilateral. Autoimmune inner-ear disease may be an exception in which bilateral involvement is common at onset. Nevertheless, we have taken autoimmune diseases into consideration in our regression model, so the effect is minimal.

Conclusion

In conclusion, this study has shown that antidepressant users might have a significantly higher SSNHL risk than nonusers. Additionally, all antidepressant classes were found to consistently increase the risk of SSNHL. It was also noteworthy that patients who took a higher number of antidepressant classes showed an increased risk of developing SSNHL than those who took a lower number of antidepressant classes. Therefore, clinicians should be cautious when prescribing antidepressants and avoid prescribing several antidepressants concurrently for those patients with co-morbidities and potential hearing problems.

Author Contributions

Study conception and design: P.-X.Z., L.-T.K., I.-H.L. and J.-H.S. Statistical analysis: P.-X.Z. and L.-T.K. Interpretation of the data: P.-X.Z., L.-T.K., I.-H.L., K.-W.C. and C.-B.Y. Drafting of the manuscript: P.-X.Z., L.-T.K. and J.-H.S. Contributions to the final version of the manuscript were made by all authors and all of them had full access to the data and can take responsibility for the integrity of the data and the accuracy of the data analysis.

We thank Po-Ting Lin for assisting with the literature review and creating the published tables. This study was approved by the Institutional Review Board of Tri-Service General Hospital, Taiwan (1–107-05–183). Data sharing is not applicable to this article. Data used in this study are handled and stored by the Health and Welfare Data Science Center. Interested researchers can obtain the data through formal application to the Health and Welfare Data Science Center, Department of Statistics, Ministry of Health and Welfare, Taiwan (http://dep.mohw.gov.tw/DOS/np-2497-113.html).

Conflict of interest

Antidepressant use among persons aged 12 and over: United States

.

NCHS Data Brief

 

Trends, correlates, and disease patterns of antidepressant use among elderly persons in Taiwan

.

Soc Psychiatry Psychiatr Epidemiol

 

2015

;

Prevalence, correlates, and disease patterns of antidepressant use in Taiwan

.

Utilization of antidepressants in Taiwan: a nationwide population-based survey from 2000 to 2009

.

Pharmacoepidemiol Drug Saf

 

2012

;

Trends of polypharmacy and prescription patterns of antidepressants in Asia

.

J Clin Psychopharmacol

 

2018

;

WHO. mhGAP Intervention Guide for Mental, Neurological and Substance Use Disorders in Non-Specialized Health Settings: Mental Health Gap Action Programme (mhGAP): Version 2.0. Geneva: World Health Organization

 

2016

.

M
Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015

.

Lancet

 

Utilization, price, and spending trends for antidepressants in the US Medicaid Program

.

Res Social Adm Pharm

 

Antidepressant use in 27 European countries: associations with sociodemographic, cultural and economic factors

.

Br J Psychiatry

 

2015

;

Serotonergic modulation of sensory representation in a central multisensory circuit is pathway specific

.

Cell Rep

 

Serotonergic regulation of excitability of principal cells of the dorsal cochlear nucleus

.

J Neurosci

 

5-HT(1A) receptor subtype mRNA expression in cochlear nucleus

.

Clinical practice guideline: sudden hearing loss

.

Otolaryngol Head Neck Surg

 

Sudden sensorineural hearing loss

.

Early identification of idiopathic sudden sensorineural hearing loss

.

Serum fatty acids and cardiovascular risk factors in sudden sensorineural hearing loss: a case-control study

.

Ann Otol Rhinol Laryngol

 

2010

;

Risk factors for sudden deafness: a case-control study

.

Auris Nasus Larynx

 

Metabolic syndrome increases the risk of sudden sensorineural hearing loss in Taiwan: a case-control study

.

Otolaryngol Head Neck Surg

 

2015

;

BR.
Clinical study to evaluate the association between sensorineural hearing loss and diabetes mellitus in poorly controlled patients whose hba1c >8

.

Indian J Otolaryngol Head Neck Surg

 

Characteristics and prognosis of idiopathic sudden sensorineural hearing loss in aged people: a retrospective study

.

Acta Otolaryngol

 

Higher risk of developing sudden sensorineural hearing loss in patients with chronic otitis media

.

JAMA Otolaryngol Head Neck Surg

 

2015

;

Sensorineural hearing loss associated with bupropion use

.

Clin Pediatr (Phila)

 

Ototoxic reaction associated with use of nortriptyline hydrochloride: case report

.

Rapid ascending sensorimotor paralysis, hearing loss, and fatal arrhythmia in a multimorbid patient due to an accidental overdose of fluoxetine

.

Case Rep Neurol Med

 

2017

;

Serotonin reuptake inhibitors in auditory processing disorders in elderly patients: preliminary results

.

The effect of citalopram versus a placebo on central auditory processing in the elderly

.

Selective serotonin reuptake inhibitors treatment effects on auditory measures in depressed female subjects

.

Eur J Pharmacol

 

2005

;

Performing a 1:N case-control match on propensity score

.

Serotonin modulates auditory information processing in the cochlear nucleus of the rat

.

Neurosci Lett

 

Excitatory and inhibitory effects of serotonin on sensorimotor reactivity measured with acoustic startle

.

MW
Cerebrovascular, cardiovascular, and mortality events in new users of selective serotonin reuptake inhibitors and serotonin norepinephrine reuptake inhibitors: a propensity score-matched population-based study

.

J Clin Psychopharmacol

 

2017

;

Cooperative action of APJ and α1A-adrenergic receptor in vascular smooth muscle cells induces vasoconstriction

.

Sudden bilateral sensorineural hearing loss after intravenous cocaine injection: a case report and review of the literature

.

Considerations on the physiopathological mechanism of inner ear damage induced by intravenous cocaine abuse: cues from a case report

.

Auris Nasus Larynx

 

2009

;

Prenatal IV cocaine: alterations in auditory information processing

.

Pei-Xun Zhong, I-Hsun Li contributed equally to this study.

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