Introduction
Attention-deficit/hyperactivity disorder (ADHD) carries a significantly increased risk for comorbidity with a wide range of psychiatric disorders (Reale et al., Reference Reale, Bartoli, Cartabia, Zanetti, Costantino and Canevini2017). In particular, ADHD is closely related to depressive disorder, with the latter indicating a 16–26% prevalence in the former (Sonnby, Åslund, Leppert, & Nilsson, Reference Sonnby, Åslund, Leppert and Nilsson2011). Several previous studies have explored this high comorbidity rate as well as the biological linkage or causality and its clinical outcomes (Biederman et al., Reference Biederman, Ball, Monuteaux, Mick, Spencer, McCREARY and Faraone2008; Posner et al., Reference Posner, Siciliano, Wang, Liu, Sonuga-Barke and Greenhill2014; Riglin et al., Reference Riglin, Leppert, Dardani, Thapar, Rice, O'Donovan and Thapar2021). Children with both ADHD and depression have been found to be more impaired in their academic and social functioning than children with ADHD alone (Blackman, Ostrander, & Herman, Reference Blackman, Ostrander and Herman2005). Thus, the American Academy of Pediatrics recommends that clinicians assess children and adolescent patients with newly diagnosed ADHD for depression (Wolraich et al., Reference Wolraich, Hagan, Allan, Chan, Davison, Earls and Disorder2019).
As treatment, adolescents diagnosed with both ADHD and depression concomitantly take ADHD medications and antidepressants according to the clinical guidelines (Cheung et al., Reference Cheung, Zuckerbrot, Jensen, Laraque, Stein, Group and Sarvet2018). Fluoxetine and escitalopram, two types of a selective serotonin reuptake inhibitor (SSRI), are the only antidepressants approved by the US Food and Drug Administration (FDA) for child and adolescent major depressive disorder (MDD) (Boaden, Tomlinson, Cortese, & Cipriani, Reference Boaden, Tomlinson, Cortese and Cipriani2020). In the UK, only fluoxetine is licensed for child and adolescent MDD (Boaden et al., Reference Boaden, Tomlinson, Cortese and Cipriani2020). However, the clinical hurdles for the use of antidepressants are concerns about adverse drug reactions such as suicidal behavior since the ‘black box warning’ issued by the FDA in 2004 (Jick, Kaye, & Jick, Reference Jick, Kaye and Jick2004). In previous research, the risk of suicidal behavior in patients aged 10 to 19 years increased after they began taking antidepressants (Jick et al., Reference Jick, Kaye and Jick2004). Since then, an increasing number of studies have questioned the methodological rigor of the FDA analysis (Fornaro et al., Reference Fornaro, Anastasia, Valchera, Carano, Orsolini, Vellante and De Berardis2019). Further, antidepressants have been associated with an increased rate of manic symptoms, atrial fibrillation, and gastrointestinal symptoms (Fenger-Grøn et al., Reference Fenger-Grøn, Vestergaard, Pedersen, Frost, Parner, Ribe and Davydow2019; Goldsmith, Singh, & Chang, Reference Goldsmith, Singh and Chang2011; Murphy, Segarra, Storch, & Goodman, Reference Murphy, Segarra, Storch and Goodman2008), and the augmentation of a SSRI with a methylphenidate (MPH) is believed to affect serotonin syndrome and MPH addiction (Ishii, Tatsuzawa, Yoshino, & Nomura, Reference Ishii, Tatsuzawa, Yoshino and Nomura2008; Van Waes, Ehrlich, Beverley, & Steiner, Reference Van Waes, Ehrlich, Beverley and Steiner2015). Nonetheless, evidence for the safety evaluation of concomitant ADHD medications and antidepressants use among in adolescents is sparse.
Based on the above, we aimed to evaluate the safety of the concomitant use of SSRIs, the first recommended drug for adolescent depression, in ADHD patients using MPHs through a comparative effectiveness research to establish real-world evidence for such medication use safety. Furthermore, we aimed to execute a head-to-head study comparing the safety outcomes between the SSRI types – fluoxetine and escitalopram.
Methods
Study design and database
This is a retrospective observational cohort study, which used a nationwide administrative claims database in South Korea [Health Insurance Review and Assessment service (HIRA)] from Jan 2016 to Mar 2021. The HIRA database contains complete health information for the Korean population, including anonymized personal identifiers, demographics, diagnoses, and information on medical procedures and medications in the national reimbursement lists. The HIRA database was standardized to Observational Medical Outcomes Partnership common data model (OMOP–CDM) version 5.3.
The study protocol was pre-specified before execution and registered with the EU Post-Authorization Studies register under EUPAS44893 (see Supplement 1). According to this protocol, the study package for the entire process was released in an online repository for transparency of analyses (https://github.com/ABMI/Assure). Analyses of de-identified data were performed in accordance with local laws and regulation and with approval from respective scientific and ethics committees (Ajou University Medical Center Institutional Review Board: AJIRB-MED-EXP-21-88).
Study population and exposure
All detailed code lists are presented in Table S1 (see Supplement 2). For the study population, we identified adolescent (aged 10–19 years) MPH users with ADHD and depressive disorder diagnoses. To avoid any bias from database left censoring, we excluded patients who had been enrolled in the database for less than 1 year before the index date. Patients who had non-stimulant ADHD prescriptions (atomoxetine, bupropion, clonidine) were also excluded. The population was divided into four study groups: the MPH-only group, MPH plus SSRIs group (SSRI group), MPH plus fluoxetine group (fluoxetine group), and MPH plus escitalopram group (escitalopram group). As described in the study protocol (see Supplement 1), we also performed a sertraline analysis. However, we could not execute a confounder adjustment due to the small sample size, so it was excluded from this study.
The MPH-only group was defined as patients who were prescribed an MPH for the first time according to their medical history. This group was limited to antidepressant-naïve patients only. The SSRI group was defined as patients who were exposed to both an MPH and a SSRI for the first time in their treatment, to the exclusion of those prescribed antidepressants other than SSRIs. The fluoxetine and escitalopram groups were defined as patients who were prescribed fluoxetine or escitalopram only without other SSRIs in the SSRI group. The schematic visualization for the study groups is presented in the Figure S1 (see Supplement 3).
The index date was defined as the date of first MPH prescription for the MPH-only group. For the SSRI, fluoxetine, and escitalopram groups, it was defined the date of first concomitant prescription of a MPH and any SSRI, fluoxetine, or escitalopram, respectively.
Outcomes and follow-up
All outcomes were defined based on their diagnostic codes according to SNOMED-CT classification (Table S1 in the Supplement 2). The primary outcomes were neuropsychiatric events, which included psychosis, tic disorder, mania, sleep disorder, suicide, and ADHD-related hospitalization. ADHD-related hospitalization was defined as any hospitalization with the presence of an ADHD diagnosis and individual psychotherapy without hospitalization in the previous 2 weeks. The secondary outcomes were arrhythmia, hypertension, seizure, traumatic injury, tremor, headache, and gastrointestinal events (abdominal pain, constipation, nausea/vomiting). All study outcomes were limited to new-onset events in the database except traumatic injury, gastrointestinal events, and ADHD-related hospitalization. We also validated our results through analysis, using respiratory tract infection as a negative control outcome.
Patients were followed up to the last date of assigned treatment [as treated (AT) approach], the date of last observation in the database, the date of occurrence of the endpoint, and the date of censoring. Each treatment was considered continued if the patient received their new prescription within 30 days of the last date of the previous prescription. Treatment discontinuation was defined as the last prescription at which no more prescriptions were given within 30 days, and the discontinued date was defined as the 30 days after the last administration (the grace period of 30 days). Censoring events were defined as events wherein patients were exposed to another therapy (i.e. patients in the MPH-only group were considered censored when exposed to a SSRI and the SSRI group was considered censored when the SSRI or MPH treatment were discontinued).
Statistical analysis
All variables were denoted as frequency and percentage. Propensity score (PS) was calculated for estimating empirical equipoise which can assess feasibility of comparison (Alexander et al., Reference Alexander, Patrick, Lauer, Hornbrook, Marin, Platt and Schneeweiss2013) and adjusting the effects of bias from confounders between the two study groups. We defined two groups as comparable when their empirical equipoise was greater than 70%. We used L1 regularized logistic regression to estimate the PS including all the available characteristics in the database. All variables were dichotomized, and all missing variables were considered not present. Study groups were matched in 1:1 pair based on the PS and an absolute standardized mean difference (aSMD) was assessed to describe the balance of covariate distribution. For all outcomes, the incidence rates (IR) were estimated. The Cox proportional hazards model was used to develop an outcome model for calculating hazard ratios (HRs) with 95% confidence intervals (CI). Only the treatment was included as a covariate of the Cox model. The Kaplan–Meier curve and Log-rank tests were used to derive cumulative incidence and compare between-group differences. p < 0.05 was defined as statistically significant. A subgroup analysis was performed to determine whether the results differed according to sex.
Sensitivity analyses
We conducted sensitivity analysis in the following analytic settings: PS adjustment method, follow-up strategy, and study population. We varied PS adjustment methods from 1:1 PS matching to 1: maximum (1: n) matching or stratification with 5 strata. We also varied our follow-up strategy to intention-to-treat (ITT) for estimating the effect of being assigned to a given treatment regardless of non-adherence (Smith, Coffman, & Hudgens, Reference Smith, Coffman and Hudgens2021). In the ITT strategy, patients were limited to those observed for 1 year and followed up to the study period (1 year) or the occurrence of the outcome. Additionally, we varied two definitions related to the study groups. First, we included only patients who were simultaneously prescribed an MPH and a SSRI; however, in the sensitivity analysis, we permitted a 30-day gap between MPH and SSRI. The index date was based on the first prescription of SSRI, with the MPH prescription falling within 30 days before the first SSRI prescription. Second, to assess the generalizability of our results, we expanded our study groups from MPH users to patients who used ADHD medications including MPHs, atomoxetine, bupropion, and clonidine.
All analyses were performed using R, version 4.1.0, and its open-source statistical packages, including the Observational Health Data Sciences and Informatics analytic packages.
Results
Cohort characteristics
This analysis covered 9663 patients, 6746 of whom were assigned to the SSRI groups and 2917 to the MPH-only group (Fig. 1; Table S1 in the Supplement 3). The SSRI groups were divided into the escitalopram group (n = 3364) and the fluoxetine group (n = 2381). The study group pairs were compatible for comparison with empirical equipoise of above 70% (Figure S3 in the Supplement 2).
Fig. 1. Flow diagram between the SSRI and the MPH-only groups.
The baseline characteristics of the overall study population before and after propensity score matching are reported in Table 1. After propensity score matching, all baseline characteristics between the MPH-only and SSRI groups among 2650 matched pairs were balanced (all aSMD <0.10; Table 1). The male proportions between these groups were 56.6 and 57.9%, respectively. Anxiety disorder was a common comorbidity in both groups, at 28.6 and 28.4%, respectively. Anticholinergics and antipsychotics were the most commonly prescribed medications for both groups (26.5 and 27.5% for anticholinergics; 21.9 and 22.8% for antipsychotics). The mean dose of initial methylphenidate prescription was 17.4 ± 15.1 mg and 17.4 ± 12.7 mg in the SSRI and MPH-only groups, respectively (aSMD < 0.01).
Table 1. Comparisons of baseline characteristics, comorbidities, and concomitant drugs in adolescent ADHD patients with depression after propensity score matching
ADHD, attention-deficit/hyperactivity disorder; PS, propensity score; MPH, methylphenidate; SSRI, selective serotonin reuptake inhibitor; aSMD, absolute standardized mean difference; FLX, fluoxetine; ECP, escitalopram.
In the comparison within SSRI types – the fluoxetine group v. the escitalopram group – all baseline characteristics were balanced (all aSMD <0.10; Table 1). Specifically, the male proportions were 47.3% and 47.7% for the fluoxetine and escitalopram groups, respectively. Anxiety disorder was 24.6 and 23.7%, and anticholinergics and antipsychotics were commonly prescribed between these groups as well. Anxiolytics accounted for 15.9 and 14.0% for each group. The mean dose of initial methylphenidate prescription was 16.2 ± 11.2 and 16.7 ± 12.1 mg in the fluoxetine and escitalopram groups, respectively (aSMD = 0.04).
Outcome assessment
The risks of all the outcomes were not significantly different between the SSRI and MPH-only groups (Table 2; Fig, 2). Specifically, the incidence rates were 37.59/1000 PYs and 36.63/1000 PYs [HR 1.04 (0.66–1.65)], respectively for psychosis, 0.89/1000 PYs and 2.13/1000 PYs for suicide, and 23.26/1000 PYs and 12.91/1000 PYs [HR 1.85 (0.95–3.80)] for ADHD-related hospitalization. Detailed number of events, person-years and incidence rates are presented in Table S2 (see Supplement 3). The negative control outcome did not show statistical significance in any analysis setting including sensitivity analyses.
Fig. 2. Forest plots of outcome estimates from analyses which compared the SSRI v. the MPH-only groups and the fluoxetine v. the escitalopram groups. Red shading is neuropsychiatric events, and the red dot and line means statistically significant.
Table 2. Risk of outcome events between the SSRI and the MPH-only group or between the fluoxetine and escitalopram groups
MPH, methylphenidate; SSRI, selective serotonin reuptake inhibitor; FLX, fluoxetine; ECP, escitalopram; §Incidence rate were calculated as case per 1000 person-years; HR, hazard ratio; CI, 95% confidence interval; ‡statistically significant; †Hospitalization indicates a hospitalization with the presence of an ADHD diagnosis; Negative control outcome indicates respiratory tract infection.
In the comparison between SSRI types, there were significant differences in tic disorder (Table 2; Fig. 2). The fluoxetine group showed lower risk of tic disorder than the escitalopram group [IR 41.72/1000PYs, 71.80/1000 PYs, respectively; HR 0.60 (0.37–0.95)]. Suicide and hypertension could not be assessed due to no outcome in the study groups. The remaining outcomes did not show any statistically significant differences.
In the subgroup analyses, all the comparisons between the SSRI and MPH-only male subgroups showed no significant differences; however, there was a significant difference in tic disorder between the fluoxetine and escitalopram male groups [HR 0.35 (0.17–0.65)] (Fig. S3; Table S4, S5 in the Supplement 3). For the female subgroup, there were significant differences in ADHD-related hospitalization [HR 6.14 (1.13–114.03)] and nausea and vomiting [HR 4.4 (1.45–19.01)] between the SSRI and MPH-only groups (Table S3 in the Supplement 3). Unlike the male subgroup, there was no difference in the risk of tic disorder between the fluoxetine and escitalopram female subgroups [HR 0.73 (0.30–1.72); Fig. 3].
Fig. 3. Comparison of tic disorder between the fluoxetine and escitalopram groups. (a) Results of sensitivity analyses for tic disorder (Red dot and line means statistically significant) (b) Kaplan-Meier plot for tic disorder between fluoxetine and escitalopram groups (c) Kaplan-Meier plot for tic disorder in the male subgroup (d) Kapan-Meier plot for tic disorder in the female subgroup. MPH, methylphenidate; SSRI, selective serotonin reupdate inhibitor; AT, as treated; PS, propensity score; ITT, intention-to-treat; ADHD, attention-deficit/hyperactivity disorder; CI, 95% confidence interval.
Sensitivity analyses
Balances between the study groups in all the sensitivity analyses are presented in Figure S3 and S4 (see Supplement 3). In all analyses, the maximum value of aSMD was under 0.10. The overall sensitivity analysis results are shown in Table S6 and S7 (see Supplement 3). For the comparison between SSRI and MPH-only groups, no consistent results were confirmed by the various sensitivity analysis settings.
Between the fluoxetine and the escitalopram groups, however, the fluoxetine group showed a lower risk of tic disorder than the escitalopram group with consistency and significance (Table S7 in the Supplement 3). Figure 3 shows the results of sensitivity and subgroup analyses for tic disorder.
Discussion
In this nationwide retrospective cohort study, we extensively compared the risk of neuropsychiatric, cardiovascular, and other safety outcomes according to the presence or types of SSRIs use in adolescent ADHD patients with depressive disorder. We found that the concomitant use of MPHs and SSRIs showed safe profiles in the study population. In the head-to-head comparison for fluoxetine and escitalopram, most of the differences in safety were not significant. However, the risk of tic disorder was significantly higher in the escitalopram than the fluoxetine group with consistency in all analytic settings.
There is a lack of published data on the medication safety of concomitant MPH and SSRI use for adolescent patients. In our study, suicide showed no definite risk observed between the SSRI and the MPH-only groups. Our results align with Chen et al.'s nationwide longitudinal study, in which they observed no risk of suicidal behavior related to ADHD medication, both before and after adjustment for antidepressants (Chen et al., Reference Chen, Sjölander, Runeson, D'Onofrio, Lichtenstein and Larsson2014). Although antidepressants were reported to have an effect on suicide (Jick et al., Reference Jick, Kaye and Jick2004), a study found that ADHD diagnosis was not influenced by the impact of SSRI initiation on suicide risk (Lagerberg et al., Reference Lagerberg, Fazel, Sjölander, Hellner, Lichtenstein and Chang2022). Further, impulsivity associated with suicide was related to unintentional accident outcomes such as fractures (Chen et al., Reference Chen, Yang, Liao, Kuo, Liang, Huang and Lin2017).21 As with suicide risk, we did not find differences in traumatic injury risk between SSRI and MPH-only groups.
Our finding of no difference in the risk of new-onset manic symptoms between MPH–SSRI combination use, and MPH-only use are consistent with those of Chang, Saxena, Howe, and Simeonova (Reference Chang, Saxena, Howe and Simeonova2010). Stimulants and SSRIs should be carefully prescribed for adolescents with risk factors, such as a history of antidepressant-induced-mania, psychosis, and a family history of bipolar disorder (Goldsmith et al., Reference Goldsmith, Singh and Chang2011). The pharmacological mechanism of MPHs is associated with the risk of psychotic symptoms and disorders (Tost, Alam, & Meyer-Lindenberg, Reference Tost, Alam and Meyer-Lindenberg2010). However, antidepressants have possible beneficial effects on psychosis (Bykowsky et al., Reference Bykowsky, Harrisberger, Schmidt, Smieskova, Hauke, Egloff and Borgwardt2019). Although our study did not explore these possible protective effects, the results showed no difference in the risk of psychosis between the concomitant use of MPHs and SSRIs and the use of MPH only.
For sleep disorder, sleep initiation and maintenance are affected by antidepressants; that is, some antidepressants can improve sleep (Wilson & Argyropoulos, Reference Wilson and Argyropoulos2005), while others may worsen sleep disorders like REM sleep disorder and nightmares (Wichniak, Wierzbicka, Walęcka, & Jernajczyk, Reference Wichniak, Wierzbicka, Walęcka and Jernajczyk2017). In our study, the concomitant use of MPHs and SSRIs showed no sleep disorder risk.
Our study also showed no significant difference in tic disorder between MPH-only and SSRIs groups. MPHs have been reported to have an effect on tic symptoms in children with ADHD, but tic symptoms induced by SSRIs are a rare adverse effect (Gadow, Sverd, Sprafkin, Nolan, & Ezor, Reference Gadow, Sverd, Sprafkin, Nolan and Ezor1995; Kayhan, Uguz, Kayhan, & Toktaş, Reference Kayhan, Uguz, Kayhan and Toktaş2014). Similarly, MPHs have been linked to risk of seizure and headache (Man et al., Reference Man, Lau, Coghill, Besag, Cross, Ip and Wong2020; Pan et al., Reference Pan, Jonsson, Şahpazoğlu Çakmak, Häge, Hohmann, Nobel Norrman and Bölte2022), while antidepressants generally have a low risk (Montgomery, Reference Montgomery2005; Walker, Walker, Robertson, & Stansfeld, Reference Walker, Walker, Robertson and Stansfeld1998). In this study, the concomitant use of MPHs and SSRIs did not show higher seizure or headache risk than MPH-only use. On the other hand, both antidepressants and MPHs have been associated with drug-induced tremor (Frei & Truong, Reference Frei and Truong2022). However, our findings showed that no difference in the risk of tremor between the SSRI and MPH-only groups. Since drug-induced tremor shows dose-dependent exacerbation, further studies considering SSRI doses are needed (Baizabal-Carvallo & Morgan, Reference Baizabal-Carvallo and Morgan2022).
Some studies suggest an association between MPH–SSRI concomitant use and arrhythmia and raise concerns about this combination. Moreover, antidepressant treatment has been associated with a higher risk of atrial fibrillation (Fenger-Grøn et al., Reference Fenger-Grøn, Vestergaard, Pedersen, Frost, Parner, Ribe and Davydow2019). However, there was no significant difference in the risk of arrhythmia and hypertension between the SSRI and MPH-only groups. Furthermore, because hypertension is more common in people over the age of 55 years, results related to hypertension risk require confirmation through a study considering other age groups (Wang et al., Reference Wang, Yuan, Zheng, Pan, Wang, Zhao and Xue2020).
Further, our findings showed no difference in the risk of gastrointestinal symptoms between MPH–SSRI concomitant use and MPH alone. Although antidepressants increase the risks of gastrointestinal symptoms, such symptoms are usually transient (Murphy et al., Reference Murphy, Segarra, Storch and Goodman2008).
For ADHD-related hospitalization, we found no difference between SSRIs and MPH-only groups. Previous studies on co-morbid ADHD and obsessive-compulsive disorder suggest that treating both disorders concurrently can be beneficial (Cabarkapa, King, Dowling, & Ng, Reference Cabarkapa, King, Dowling and Ng2019). We found that SSRIs do not exacerbate ADHD symptoms, although we could not identify whether it was beneficial to treat comorbidity or not. Overall, our findings suggest that the concomitant use of SSRIs and MPHs is not significantly riskier than MPHs alone for neuropsychiatric, cardiovascular, and other safety issues.
Our subgroup analysis by sex showed no difference in most safety outcomes in females using SSRIs and MPHs together, except for the increased risk of nausea and vomiting and ADHD-related hospitalization. Consistent with our finding on nausea and vomiting, Romero-Acosta et al., found that girls reported more somatic symptoms such as stomach-ache than did boys (Romero-Acosta et al., Reference Romero-Acosta, Canals, Hernández-Martínez, Penelo, Zolog and Domènech-Llaberia2013). However, gastrointestinal symptoms are usually transient. In addition, because outcome counts for ADHD-related hospitalization in female group were less than 10, it was challenging to determine whether the concomitant use of MPHs and SSRIs was risky or not. Sex differences in the symptoms of ADHD are well documented in the literature (Arnett et al., Reference Arnett, Pennington, Willcutt, DeFries and Olson2015). However, with respect to ADHD medication safety, previous studies considering sex differences are limited (Kok, Groen, Fuermaier, & Tucha, Reference Kok, Groen, Fuermaier and Tucha2020). Sex-related differences in pharmacokinetics, immunological, and hormonal factors might be a potential explanation, but still, further studies are needed to confirm our results.
A previous study reported no significant difference between fluoxetine and escitalopram treatments with regard to efficacy and adverse events (Patris et al., Reference Patris, Bouchard, Bougerol, Charbonnier, Chevalier, Clerc and Høpfner Petersen1996). Similarly, except tic disorder, we observed no difference in the risk of adverse events between escitalopram and fluoxetine groups (Oh, Zupan, Gross, & Toth, Reference Oh, Zupan, Gross and Toth2009). Tic disorder is a rare adverse event of SSRI whose pathophysiology is imperfectly known, although an indirect dopaminergic inhibition through serotoninergic mediation has been proposed (Altindag, Yanik, & Asoglu, Reference Altindag, Yanik and Asoglu2005). In our study, the fluoxetine group showed a lower risk of tic disorder than the escitalopram group, and other sensitivity analyses showed consistent results. In line with our finding, Revet et al., showed the possibility of an opposite direction of association for tic disorder between fluoxetine and escitalopram, although there was no statistical significance (Revet et al., Reference Revet, Montastruc, Roussin, Raynaud, Lapeyre-Mestre and Nguyen2020). Contrary to escitalopram, fluoxetine antagonizes 5-HT2C receptors (Opal et al., Reference Opal, Klenotich, Morais, Bessa, Winkle, Doukas and Dulawa2014; Pogorelov et al., Reference Pogorelov, Rodriguiz, Cheng, Huang, Schmerberg, Meltzer and Wetsel2017). Considering that tic disorder is related to dopamine, dopamine action through 5-HT2C receptors may have caused a difference between fluoxetine and escitalopram. Specifically, a rodent study showed that 5-HT2C receptor antagonists might be efficacious in treating movement disorders caused by dopamine signaling and in potentiating the antidepressant and anxiolytic effects of SSRIs by reducing anxiety and depression-like behavior (Demireva et al., Reference Demireva, Suri, Morelli, Mahadevia, Chuhma, Teixeira and Ansorge2020). Overall, there is no difference in most of the adverse events between fluoxetine and escitalopram when used in combination with a MPH, but further studies on tic disorder are needed to verify this.
Our study used a population-based cohort study using claims data. Despite randomized controlled trials (RCTs) being the gold standard, advantages of the cohort study such as larger samples and longer follow-up time could be an alternative to RCTs. Considering confounding factors as the limitation of the cohort study, we applied large-scale propensity score adjustments including one-to-one propensity score matching, variable-ratio propensity score matching, and propensity score stratification to reduce the effects of confounding factors.
Limitations
This study has some limitations. First, we did not perform a clinical evaluation considering ADHD type and severity or depressive disorder at baseline. This was because capturing the symptoms of ADHD or depressive disorder directly was challenging due to the nature of the claims data. This limitation may have led to a bias in the difference in disease severity at baseline. However, by including the incident diagnosis of depressive disorder in both groups, we conducted the study with an empirical equipoise of more than 70% between the groups. In addition, we attempted to minimize the confounding bias by introducing a large-scale propensity score, which we calculated using all the variables we could capture, and a negative control outcome to validate our results.
Second, since this was a code-based analysis, the possibility of errors due to misclassification of variables cannot be ruled out. However, this is a limitation of all retrospective observational studies using database. Therefore, we evaluated the overall consistency of the results by performing analyses with the strictest definitions and various sensitivity settings. For example, in the study group definition, we confirmed whether the overall results were consistent through analysis by changing the MPH-user group to the ADHD-medication-user group and by changing the interval between MPH and SSRI from 0 to 30 days. In addition, the definition of most outcomes is also limited to incident cases, and only outcomes that could occur repeatedly for independent reasons were allowed. Also, adverse events not reaching the status of a case were not captured. Despite the above limitations, this remains the first large-scale retrospective cohort study to evaluate the safety of concomitant SSRI and MPH use in adolescents diagnosed with both ADHD and depressive disorder.
Conclusion
In conclusion, our findings suggest no difference in the risk of neuropsychiatric, cardiovascular, and other adverse events between the concomitant use of MPHs and SSRIs and MPH-only use. Considering this result, SSRIs may be a favorable treatment option for mood symptoms in ADHD patients using MPHs. Moreover, we found no difference in most of adverse events between fluoxetine and escitalopram in terms of SSRI selection, but caution may be required for tic disorder. Further collaborative investigations are still needed to clarify the association with each safety outcome according to ethnicity.
Supplementary material
The supplementary material for this article can be found at https://doi.org/10.1017/S0033291723000120.
Acknowledgements
This work was supported by the Health Insurance Review and Assessment Service (HIRA). The views expressed are those of the authors and not necessarily those of the HIRA. This research was also funded by the Bio Industrial Strategic Technology Development Program (20003883, 20005021) funded By the Ministry of Trade, Industry & Energy (MOTIE, Korea) and a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health &Welfare, Republic of Korea (grant number: HR16C0001).
Financial support
The funder of the study had no role in the study design, data collection, data analysis, data interpretation, or writing of the manuscript and had no access to the raw data. The main authors had full access to all the data and had the final responsibility for the decision to submit for publication.
Conflict of interest
CK received consulting fees from IQVIA. RWP reports grants from the Ministry of Trade, Industry & Energy (MOTIE, Korea), the Ministry of Health & Welfare (Korea), and AstraZeneca. DPA reports grants from Amgen, Chesi-Taylor, Novartis, and UCB Biopharma. All other authors declare no competing interests.
