Safety Outcomes from a Long-Term,Prospective Study of Sertraline Use in Children and Adolescents: The Sertraline Pediatric Registry for the Evaluation of Safety

Abstract

Objectives:

To describe the Sertraline Pediatric Registry for the Evaluation of Safety (SPRITES) safety results, including adverse events (AEs) (serious and nonserious, including suicide-related events) following long-term treatment with sertraline in children and adolescents aged 6–16 years.

Methods:

SPRITES was a multicenter, prospective, observational study designed to compare cognitive, emotional, and physical development in pediatric patients exposed to sertraline or psychotherapy alone in routine care for up to 3 years. Safety outcomes included AEs collected on the Pediatric Adverse Event Rating Scale and suicidal ideation/behavior (SIB), as assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS). AEs (unadjusted and adjusted for exposure) and C-SSRS data were summarized descriptively, and a marginal structural model (MSM) was applied to the C-SSRS results.

Results:

Between April 2012 and September 2020, 941 patients participated in SPRITES. At baseline, per treating physician discretion, 695 patients were administered sertraline, 243 patients were administered psychotherapy alone, and 3 patients were administered an antidepressant other than sertraline. At postbaseline timepoints, patients receiving sertraline reported higher overall rates of AEs relative to the other antidepressants and nonpharmacologic treatment groups. The most common AEs in the sertraline group were related to psychiatric and gastrointestinal disorders. In all exposure groups, the incidence of AEs and SIB decreased across study timepoints. MSM analyses did not demonstrate an effect of sertraline treatment on new onset or worsening SIB.

Conclusion:

The safety profile of sertraline in a long-term, real-world setting is similar to that of prior pediatric sertraline studies. A greater proportion of AEs and SIB events reported in the sertraline group compared with the nonpharmacologic therapy group is not unexpected given the safety profile of sertraline and observation of baseline differences in psychiatric disease severity between exposure groups. With prolonged sertraline treatment, incidence rates of AEs and SIB events decreased, and worsening of SIB was not observed.

Introduction

The Sertraline Pediatric Registry for the Evaluation of Safety (SPRITES) study was an open-label, observational study of long-term safety and developmental outcomes in patients 6–16 years treated with sertraline (with or without psychotherapy) compared with psychotherapy alone for up to 3 years. The study was conducted to fulfill a postapproval commitment to the European Medicines Evaluation Board and enrolled a total of 941 patients at 44 sites in the United States between April 2012 and September 2020.

Details of the study design, methodology, and baseline demographic/clinical characteristics of patients were previously described (Kolitsopoulos et al., 2021). In addition, results of the primary outcome measures of cognitive, emotional, and physical development following long-term treatment with sertraline were presented in Kolitsopoulos et al. (2023). In brief, aside from a trend for increased weight at higher sertraline doses, the overall results were consistent with normal development, and no significant differences were observed between patients treated with sertraline and those who did not receive any pharmacologic therapy.

The present report summarizes the safety data collected in SPRITES, including adverse events (AEs), serious adverse events (SAEs), and the results of the Columbia-Suicide Severity Rating Scale (C-SSRS) assessments for suicidal ideation and behavior (SIB).

Methods

Study design

SPRITES patients were recruited over a 5-year period from 2012 to 2017 at U.S. centers, including the Child and Adolescent Psychiatry Trials Network (CAPTN) (March et al., 2004). The study enrolled pediatric patients with a mental illness who were deemed eligible for treatment with sertraline based on the clinical judgment of their treatment provider. The baseline visit occurred on or within 45 days of initiating treatment with sertraline or psychotherapy and included routine clinical care and study assessments. Treatment proceeded under real-world clinical settings. The treating physician was provided the FDA-approved sertraline label and could modify treatment, including use of other antidepressants (OA), at any time between, during, or following study visits. Patients were followed for 3 years with postbaseline assessments completed at months 3, 6, 12, 18, 24, 30, and 36. Assessments included documentation of the actual treatment received during the visit interval, primary study outcomes (measures of physical development, psychological development, and pubertal maturation), concomitant medications, compliance with treatment, and safety outcomes, including AEs and systematic assessment of suicidality events. The Copernicus Institutional Review Board (IRB), Western IRB, 24 local IRBs, and Duke University’s Health System IRB approved the study.

To account for nonrandomized allocation to treatment and postbaseline treatment changes, patients were classified into treatment groups (i.e., sertraline, OA, or no pharmacotherapy [NPT]) at baseline and at postbaseline visits according to the actual treatment received as indicated in Table 1.

Table 1.

Treatment Group Definitions—SPRITES

	Time period
Treatment exposure group	Baseline	Postbaseline
Sertraline	Patients who had received sertraline treatment within 45 days of enrollment	Patients who had received sertraline with or without other treatment(s) (e.g., psychotherapy or other antidepressant treatment) since the prior visit
No pharmacotherapy (NPT)	Patients who had received psychotherapy only within 45 days of enrollment and who did not take sertraline or any other antidepressant medication on or within 45 days of enrollment	Patients who had received psychotherapy only or no treatment at all since the prior visit
Other antidepressant (OA)	Patients who had received a non-sertraline antidepressant (with or without psychotherapy) within 45 days of enrollment	Patients who had received a nonsertraline antidepressant (with or without psychotherapy) since the prior visit

SPRITES, Sertraline Pediatric Registry for the Evaluation of Safety.

Safety outcomes

Adverse events

The clinician assessed patients at each study visit for AEs, including signs of clinical worsening, that may have occurred since the last visit. To assist the clinician in this assessment, the 43-item version of the Pediatric Adverse Event Rating Scale (PAERS) was employed. The PAERS is an empirically derived and validated AE monitoring tool, which provides a systematic assessment of common physical and psychiatric AEs (Wehmeier et al., 2008). The scale collects information on the presence of the AE in the past week, severity (mild, moderate, severe, or extreme), relatedness to treatment, impact on function, and outcome of the event. The PAERS was administered as a semistructured interview with the clinician verbally reviewing PAERS items with the child and parent at each visit. An AE was considered serious if it resulted in death or was life-threatening, required inpatient hospitalization or prolongation of hospitalization, resulted in persistent or significant disability/incapacity or congenital anomaly/birth defect.

Suicidal events

Suicidal ideation (SI) and behavior (SB) were assessed at each study visit using the C-SSRS. The C-SSRS is a validated tool for the prospective assessment of SIB in clinical studies (The Columbia Lighthouse Project, 2016). To establish a baseline reference, the screening and baseline versions of the C-SSRS were completed at the baseline visit. The screening version assessed lifetime prevalence of SI, SB, and nonsuicidal self-injurious behavior (NSSIB), and the baseline version assessed incidence of SI in the 6 months prior to baseline. The C-SSRS completed at postbaseline visits assessed SIB since the patient’s last visit.

If a serious AE (SAE) involved a suicidal event, clinicians completed the C-SSRS as part of the study visit. The determination of whether SIB constituted a serious or nonserious AE was made by the clinician based on their clinical judgment. The protocol instructed clinicians to report the following events as SAEs: development of significant SI, interrupted and preparatory actions toward making a suicide attempt, and any suicide attempts.

Statistical methods

Baseline characteristics, including participant demographics, psychiatric history, and family socioeconomic status, were descriptively summarized by treatment exposure group and compared using Fisher’s exact tests for categorical variables and Kruskal–Wallis tests for continuous variables.

The methods for descriptive summary of AE and C-SSRS data were presented in Kolitsopoulos et al. (2021). Briefly, nonserious AEs, SAEs, and C-SSRS data were summarized by visit and treatment groups for the safety population, which was defined as patients meeting at least one of the following criteria: (1) have AE data available during follow-up, (2) have treatment information available during follow-up, or (3) have a postbaseline C-SSRS assessment. Frequencies of AEs by treatment group and visit based upon raw data (unadjusted for treatment exposure) were calculated and are provided supplementally (Supplementary Tables S1, S2 and S3).

Post hoc summaries of AE incidence rates over the entire study using person-time exposure for each treatment group were completed to account for treatment change from visit to visit. Specifically, AE frequencies were calculated as treatment exposure-adjusted rates for the overall safety population, with exploratory analyses undertaken to examine treatment exposure-adjusted AE rates stratified by primary diagnosis (mood, anxiety, or obsessive-compulsive disorder), age group (ages 6 to <12 years and ages ≥12 years), and sertraline dose level (Supplementary Tables S4a, S4b, S5a, S5b, S6a, and S6b).

A repeated measures marginal structural model (MSM) using a generalized estimating equations approach was used to evaluate new or worsening SI and SB based on the C-SSRS. MSMs use inverse probability weighting to account for potential time-varying confounders, treatment switching, and dropout. The application of the MSM model to the C-SSRS data compared patients who were only treated with sertraline during the study versus patients who never received sertraline during the study (i.e., always exposed versus never exposed).

The “always exposed” group included patients who were taking sertraline at baseline and continued taking it during the interval(s) between the prior visit(s) and the current visit. The “never exposed” group included patients who were not taking sertraline at baseline and remained off sertraline during the interval(s) between the prior visit and the interval covered during their 3-month visit. The model for new onset or worsening SI and SB included variables for the study visit month, exposure group, and interaction between these variables. Additional details on the MSM analysis are available in Kolitsopoulos et al. (2021).

Statistical analyses were conducted using SAS/STAT software, version 9.4 (SAS Institute, Cary, North Carolina), and all tests were two-sided, with α = 0.05. p Values were not adjusted for multiplicity.

Results

Demographics, psychiatric history, C-SSRS data

Demographic, psychiatric history, and baseline C-SSRS data were previously described in Kolitsopoulos et al. (2021). Briefly, 941 patients participated in SPRITES between April 2012 and September 2020 across 44 U.S. sites. At baseline, treating physicians enrolled 696 children and adolescents who were planned to receive sertraline treatment (with or without psychotherapy), and enrolled 245 planned to receive treatment with psychotherapy alone. Almost half (46.0%) of the patients completed the 3-year follow-up, and the proportion of study discontinuations in the baseline sertraline and psychotherapy/NPT groups was comparable, with lost to follow-up being the most common reason for discontinuation.

Baseline demographic characteristics were similar across the sertraline and NPT groups except for age and race; patients in the sertraline group were significantly older than the NPT group, and Asian and Black/African American patients comprised a larger proportion of the sertraline group (Kolitsopoulos et al., 2021).

Baseline clinical characteristics of the sertraline and NPT groups, however, were dissimilar in several ways. Patients in the sertraline group were a more mentally ill study population relative to the NPT group. A greater proportion of children and adolescents in the sertraline group compared with the NPT group had a moderate-to-severe mental illness score on the Clinician-Rated Global Severity of Illness Scale (73.0% vs. 57.6%, respectively; p < 0.001), had a mood disorder (52.1% vs. 32.1%, respectively; p < 0.001), and had received prior treatment with psychotherapy (59.0% vs. 34.2%, respectively; p < 0.001) and psychotropic medications (14.1% vs. 3.3%, respectively; p < 0.001). Baseline C-SSRS data showed that, relative to the NPT group, patients in the sertraline group had a higher lifetime prevalence of SB (5.9% vs. 2.1%, respectively; p = 0.036) and a higher lifetime prevalence of nonsuicidal self-injury behavior (NSSI) (14.4% vs. 8.0%, respectively; p = 0.024).

AE rates by visit and treatment group

All AEs (including serious events) and AEs reported by at least 2% of patients are summarized and tabulated for each study visit by the three treatment groups (Table 2 and Supplementary Table S1, respectively). At each visit, patients were classified to a treatment group based on the actual treatment received during the interim period between the prior visit and the current visit. Up to 30% of patients switched treatments during the study, however. Thus, the patients classified to a particular treatment group comprised both patients who were in that treatment group throughout the interim period as well as patients who switched treatment groups at some point during the interim period. For this reason, it was not possible to establish or compare relatedness to treatment condition across groups.

Table 2.

Overall Adverse Event Frequencies by Visit and Treatment Group in SPRITES—Safety Population^a

	Most recent treatment
Visit timepoint	Sertralinen/N (%)	Other antidepressantsn/N (%)	No pharmacologic therapyn/N (%)
Month 3 (any adverse event)^b	216/622 (34.7)	4/19 (21.1)	61/356 (17.1)
Month 6 (any adverse event)^b	163/516 (31.6)	12/48 (25.0)	48/304 (15.8)
Month 12 (any adverse event)^b	121/426 (28.4)	20/80 (25.0)	48/298 (16.1)
Month 18 (any adverse event)^b	95/335 (28.4)	20/84 (23.8)	33/275 (12.0)
Month 24 (any adverse event)^b	60/289 (20.8)	21/83 (25.3)	33/263 (12.5)
Month 30 (any adverse event)^b	49/240 (20.4)	13/85 (15.3)	24/256 (9.4)
Month 36 (any adverse event)^b	31/207 (15.0)	10/73 (13.7)	26/223 (11.7)

n, number of patients experiencing at least one AE during the visit timepoint interval; N, number of patients in therapy category for the visit interval.

^aSafety population: Patients who had (1) PAERS or SAE information available during follow-up, (2) treatment information available during follow-up, or (3) postbaseline C-SSRS assessment.

^bThe AEs counted here are those that had an onset date between the current study timepoint and the preceding study timepoint. For example, AEs reported for month 3 occurred between the baseline visit and the month 3 visit. AEs reported for month 6 occurred between the month 3 visit and the month 6 visit, etc. The most recent treatment corresponding to the AE is the treatment corresponding to the calendar month previous to the calendar month of the AE onset date. The sertraline group is defined as those patients on sertraline only or sertraline and any other treatment. The other antidepressants group is defined as those patients on another antidepressant only or another antidepressant and psychotherapy. The no pharmacologic therapy group is defined as those patients on psychotherapy only or no treatment at all.

AE, adverse event; C-SSRS, Columbia-Suicide Severity Rating Scale; PAERS, Pediatric Adverse Event Rating Scale; SAE, serious adverse events; SPRITES, Sertraline Pediatric Registry for the Evaluation of Safety.

As presented in Table 2, patients who received sertraline had higher overall rates of AEs relative to the OA and NPT groups at all visits, except for month 24 when 25.3% of patients in the OA group experienced AEs compared with 20.8% and 12.5% of patients in the sertraline and NPT groups, respectively. For the sertraline-treated group, the most frequently reported AEs were psychiatric in nature (i.e., anxiety, irritability, depressed mood, hostility, aggression, SI, and intentional self-injury) or gastrointestinal (GI)-related events (i.e., decreased appetite, weight increased, nausea, and abdominal pain) (Supplementary Table S1).

Among the sertraline-treated patients, AEs occurring at a rate of ≥2% and at least twice the proportion of the NPT group included anxiety, irritability, hostility, aggression, intentional self-injury, depressed mood, SI, disturbance in attention, increased weight, insomnia, and headache (Supplementary Table S2). Most AEs were of mild-to-moderate severity and generally declined over time across visits. The most common AEs had frequencies ranging from a peak of 6.4% at month 6 to 1.7% at month 30 (anxiety), 4.7% at month 3 to 1.0% at month 36 (irritability), and 4.0% at month 12 to 0% at month 36 (hostility). The highest proportion of patients experiencing severe or extreme AEs occurred for events of hostility and SI. NSSIB, such as self-mutilation behaviors (e.g., cutting, skin picking, and scratching), comprised the majority (80%) of intentional self-injury events in the sertraline group, which ranged in frequency from 3.1% at month 6 to 1.0% at month 36.

Twelve AEs with onset over 60 days since the last study visit at which treatment information was collected were not included in the AE frequency calculations and are presented in Supplementary Table S7. AEs leading to study discontinuation were not systemically collected in SPRITES. However, for six patients, each of whom was in the sertraline group at baseline, AEs were reported as contributing factors for study discontinuation and are presented in Table 3.

Table 3.

Details for Participants Reporting Adverse Events as Contributing to Study Discontinuation

Patient case^a	Treatment group^b	Adverse event term^c	Serious adverse event	AE severity	Study visit^d	Patient study status
1	Sertraline	Impulsive behavior	No	Moderate	Month 3	Patient/family withdrew consent
1	Sertraline	Disturbance in Attention	No	Moderate	Month 3	Patient/family withdrew consent
2	Sertraline	Irritability	No	Moderate	Month 3	Lost to Follow-up
3	Sertraline	Decreased appetite	No	Mild	Month 3	Patient/family withdrew consent
3	Sertraline	Nausea	No	Mild	Month 6	Patient/family withdrew consent
4	Sertraline	Aggression	Yes	Severe	Month 3	Discontinued; inpatient psychiatric treatment required
		Aggression	Yes	Severe	Unscheduled after month 3
		No Pharmacologic Therapy	Yes	Severe	Unscheduled after month 3
5	Sertraline	Depression	Yes	Severe	Month 3	Patient/family withdrew consent
		Drug ineffective	Yes	Mild	Month 3
		Intentional self-injury	Yes	Moderate	Month 3
		Suicidal Ideation	Yes	Severe	Month 3
		Suicide Attempt	Yes	Severe	Month 3
	Other Antidepressant	Intentional overdose	Yes	Mild	Month 6
		Suicidal ideation	Yes	Mild	Month 6
		Suicide attempt	Yes	Severe	Month 6
6	Other Antidepressant	Suicidal behavior	Yes	Severe	Month 18	Discontinued; SAE and posttraumatic stress disorder
6	Other Antidepressant	Suicidal ideation	Yes	Severe	Month 18	Discontinued; SAE and posttraumatic stress disorder

Each case corresponds to one patient for whom AE(s) were reported as a contributing factor to study discontinuation.

The most recent treatment corresponding to the AE is the treatment corresponding to the calendar month previous to the calendar month of the AE onset date. The sertraline group is defined as those patients on sertraline only or sertraline and any other treatment. The other antidepressants group is defined as those patients on another antidepressant only or another antidepressant and psychotherapy. The no pharmacologic therapy group is defined as those patients on psychotherapy only or no treatment at all.

AEs were tabulated using the Medical Dictionary for Regulatory Activities (MedDRA) version 23.0.

Study visit at which AE first reported on PAERS.

AE, adverse event; PAERS, Pediatric Adverse Event Rating Scale; SAE, serious adverse event.

Serious adverse events

Sertraline-treated patients had higher rates of SAEs compared with the NPT group, except for month 30 when 0.8% of patients in each of these groups experienced SAEs and month 12 when 2.3% of the patients in the sertraline group experienced SAEs compared with 2.7% of patients in the NPT group (Supplementary Table S3).

The most common SAEs across all treatment groups included depression, intentional self-injury, SB, SI, and suicide attempt. One death occurred in the study (a 16-year-old female) that was attributed to complications from a preexisting seizure disorder.

Treatment exposure-adjusted rates of AEs

To control for the potential impact of treatment switching and to provide an overall estimate of the frequency of each observed AE under the three treatment conditions, post hoc exposure-adjusted rates per 100 patient-years of follow-up were calculated for all serious and nonserious postbaseline AEs.

Table 4 presents the treatment exposure-adjusted postbaseline AE rates for all AEs where the number of sertraline-treated patients with the AE was ≥5. AEs experienced by at least 100 unique patients across treatment groups included anxiety (n = 127), depressed mood (n = 104), and irritability (n = 102). Sertraline-treated patients had higher overall rates of AEs compared with the OA and NPT groups and experienced the following AEs at an exposure-adjusted rate of ≥2 per 100 participant years of follow-up and at twice the rate in the NPT group: aggression, anxiety, decreased appetite, diarrhea, fatigue, hostility, impulsive behavior, insomnia, intentional self-injury, irritability, and weight increased. The treatment exposure-adjusted rate per 100 participant years for SI in the sertraline group was 5.9 as compared with rates of 4.7 and 3.4 in the OA- and NPT-treated groups, respectively. Suicidal behavior and suicide attempt rates in the sertraline- and NPT-treated groups were ≤1 and in the OA group were 2.1 and 0.5, respectively.

Table 4.

Treatment Exposure-Adjusted Rates of Postbaseline Adverse Events (per 100 Participant Years) Reported in SPRITES—Safety Population

Adverse event term	Sertraline (N = 620) n (r)	Other antidepressants (N = 146) n (r)	No pharmacologic therapy (N = 548) n (r)
Anxiety	90 (8.5)	6 (3.1)	31 (3.9)
Depressed mood	65 (6.2)	8 (4.2)	31 (3.9)
Irritability	67 (6.4)	10 (5.2)	25 (3.2)
Suicidal ideation	62 (5.9)	9 (4.7)	27 (3.4)
Hostility	66 (6.3)	4 (2.1)	22 (2.8)
Headache	44 (4.2)	5 (2.6)	23 (2.9)
Disturbance in attention	41 (3.9)	6 (3.1)	22 (2.8)
Weight increased	42 (4)	7 (3.6)	9 (1.1)
Abdominal pain	35 (3.3)	3 (1.6)	15 (1.9)
Intentional self-injury	43 (4.1)	3 (1.6)	7 (0.9)
Insomnia	37 (3.5)	3 (1.6)	8 (1)
Affect lability	29 (2.8)	3 (1.6)	13 (1.7)
Decreased appetite	32 (3)	1 (0.5)	12 (1.5)
Fatigue	30 (2.8)	3 (1.6)	8 (1)
Aggression	28 (2.7)	4 (2.1)	4 (0.5)
Nausea	20 (1.9)	4 (2.1)	8 (1)
Diarrhea	21 (2)	1 (0.5)	8 (1)
Impulsive behavior	22 (2.1)	1 (0.5)	4 (0.5)
Vomiting	15 (1.4)	3 (1.6)	6 (0.8)
Acne	16 (1.5)	0 (0)	6 (0.8)
Dizziness	17 (1.6)	2 (1)	3 (0.4)
Suicidal behavior	9 (0.9)	4 (2.1)	6 (0.8)
Weight decreased	11 (1)	2 (1)	5 (0.6)
Depression	13 (1.2)	1 (0.5)	3 (0.4)
Increased appetite	10 (0.9)	0 (0)	7 (0.9)
Suicide attempt	11 (1)	1 (0.5)	3 (0.4)
Akathisia	9 (0.9)	1 (0.5)	2 (0.3)
Dry mouth	7 (0.7)	2 (1)	3 (0.4)
Apathy	9 (0.9)	1 (0.5)	1 (0.1)
Euphoric mood	8 (0.8)	1 (0.5)	1 (0.1)
Rash	7 (0.7)	1 (0.5)	2 (0.3)
Hypersomnia	6 (0.6)	0 (0)	3 (0.4)
Panic attack	5 (0.5)	3 (1.6)	1 (0.1)
Tachyphrenia	5 (0.5)	2 (1)	2 (0.3)
Tic	7 (0.7)	0 (0)	2 (0.3)
Pharyngitis streptococcal	5 (0.5)	1 (0.5)	2 (0.3)
Contusion	6 (0.6)	0 (0)	1 (0.1)
Enuresis	6 (0.6)	1 (0.5)	0 (0)
Intentional overdose	5 (0.5)	1 (0.5)	1 (0.1)
Drug ineffective	6 (0.6)	0 (0)	0 (0)
Hypersensitivity	5 (0.5)	0 (0)	0 (0)

n, number of participants reporting at least one occurrence of the event; r, exposure-adjusted rate per 100 participant years of follow-up; N, the number of participants who were exposed to the corresponding treatment at least once postbaseline.

AEs where the number of sertraline participants with the event is less than 5 are not included in this table.

AE terms are presented in order of most to least frequent based on the total number of unique participants with the event across all three treatment exposure groups.

AEs were tabulated using the Medical Dictionary for Regulatory Activities (MedDRA) version 23.0.

AEs, adverse events; SPRITES, Sertraline Pediatric Registry for the Evaluation of Safety.

Table 5 presents the treatment exposure-adjusted postbaseline SAE rates for SAEs experienced by at least two unique patients across the three treatment groups. SAEs of SI, SIB, and suicide attempt were reported in at least 10 patients across treatment groups. The exposure-adjusted rate per 100 participant years of follow-up for SI SAEs was 3.2 in the sertraline group compared with 2.2 in the NPT group and 3.6 in the OA group. Rates of SB and suicide attempt SAEs in the sertraline and NPT groups were both ≤1 and in the OA group were 2.1 and 0.5, respectively.

Table 5.

Treatment Exposure-Adjusted Rates of Postbaseline Serious Adverse Events Reported in SPRITES—Safety Population

Serious adverse event term	Sertraline (N = 620) n (r)	Other antidepressants (N = 146) n (r)	No pharmacologic therapy (N = 548) n (r)
Suicidal ideation	34 (3.2)	7 (3.6)	17 (2.2)
Suicidal behavior	9 (0.9)	4 (2.1)	6 (0.8)
Suicide attempt	11 (1)	1 (0.5)	3 (0.4)
Intentional self-injury	8 (0.8)	0 (0)	1 (0.1)
Depression	6 (0.6)	1 (0.5)	1 (0.1)
Intentional overdose	4 (0.4)	1 (0.5)	1 (0.1)
Aggression	4 (0.4)	0 (0)	0 (0)
Overdose	3 (0.3)	0 (0)	1 (0.1)
Depressed mood	3 (0.3)	0 (0)	0 (0)
Abdominal pain	2 (0.2)	0 (0)	0 (0)
Appendicitis	2 (0.2)	0 (0)	0 (0)
Concussion	2 (0.2)	0 (0)	0 (0)
Homicidal ideation	1 (0.1)	0 (0)	1 (0.1)

SAEs are presented in order of most to least frequent based upon the total number of unique participants who experienced the event across all treatment exposure groups.

Table lists SAEs experienced by at least two unique patients across treatment groups.

SAEs experienced by one unique participant across all three treatment exposure groups include in the sertraline group: agitation, anemia, anticholinergic syndrome, arthralgia, conversion disorder, diarrhea, dizziness, drug ineffective, dysmenorrhea, hostility, hypersomnia, iron deficiency anemia, mental status changes, nausea, postconcussion syndrome, pyelonephritis acute, self-injurious ideation, substance-induced psychotic disorder, syncope, and vomiting; in the OA group: pneumonia; and in the NPT group: anger, anxiety, behavior disorder, emotional disorder, liver function test increased, psychotic disorder, and serotonin syndrome.

AEs were tabulated using the Medical Dictionary for Regulatory Activities (MedDRA) version 23.0.

AEs, adverse events; NPT, no pharmacotherapy; OA, other antidepressants; SAEs, serious adverse events; SPRITES, Sertraline Pediatric Registry for the Evaluation of Safety.

Post hoc analyses of treatment exposure-adjusted AE rates stratified by baseline diagnosis and age group

Given recent reports suggesting there may be differences in the tolerability of SSRIs according to the disorder being treated (Boaden et al., 2020; Tini et al., 2022), exposure-adjusted AE rates per 100 participant years were further explored when stratified by primary baseline diagnosis (i.e., mood, anxiety, or obsessive-compulsive disorder). As shown in Supplementary Tables S4a and S4b, patients with a primary diagnosis of a mood disorder generally had higher rates of AEs than those with an anxiety disorder or OCD, while patients with an anxiety disorder diagnosis had higher rates than those with OCD. This pattern is similar regardless of treatment (sertraline or NPT) and is true for both physical and psychiatric AEs as well as harm-related AEs, including SIBs. Notable exceptions to this pattern were observed among OCD patients treated with sertraline, who had higher rates of dizziness, impulsive behavior, and akathisia compared with mood and anxiety disorder patients treated with sertraline (i.e., dizziness: 2.2, 1.6, 3.5; akathisia: 0.8, 0.7, 2.8; impulsive behavior: 1.8, 1.7, and 3.5, for mood, anxiety, and OCD, respectively).

Treatment exposure-adjusted AE rates were also examined when stratified by baseline age group (child [6 to <12 years] vs. adolescent [≥12 years]). As shown in Supplementary Tables S5a and S5b, children in the sertraline group tended to have lower rates of physical AEs than adolescents. However, children treated with sertraline had higher rates than adolescents of attentional disturbance (5.2 vs. 2.6) and GI symptoms such as diarrhea (2.5 vs. 1.2), vomiting (1.9 vs. 0.9), and increased appetite (1.5 vs. 0.4).

While overall rates of psychiatric AEs were similar across age groups in both treatment exposure groups, sertraline-treated children had higher rates of irritability (8.1 vs. 4.7), hostility (8.3 vs. 4.3), affect lability (4 vs. 1.5), and impulsive behavior (3.5 vs. 0.8) compared to sertraline-treated adolescents. In contrast, adolescents manifested higher rates of depression (0.2 vs. 2.3) and harm-related behaviors (5.6 vs. 12), including SI (4.2 vs. 7.5) and intentional self-injury (1.9 vs. 6.2).

Dose-related effects on tolerability

To examine possible dose-related effects on tolerability, the incidence of (nonexposure adjusted) postbaseline AEs was stratified by sertraline dose level. In this post hoc analysis, the percentages of patients who had an AE while exposed to a specific sertraline dose category were determined. The sertraline dose levels were: 0.1 to <25 mg/day, 25 to <50 mg/day, 50 to <75 mg/day,75 to <100 mg/day, and ≥100 mg/day.

As shown in Supplementary Tables S6a and S6b, total physical and total psychiatric AEs (excluding harm-related AEs) increased from the 0.1 to <25 mg/day dose level to the 25 to <50 mg/day dose level but appear to plateau at subsequent dose levels. Among physical AEs, there was a higher incidence of weight increase at the highest dose level of ≥100 mg/day (as previously reported in Kolitsopoulos et al., 2023). Among psychiatric AEs, the incidence of anxiety, aggression, and impulsive behavior increased in a dose-related manner over the first three dose levels (i.e., anxiety: 3.6% to 6% to 6.3%; aggression: 0.9% to 1.5% to 2.5%; impulsive behavior: 0.4% to 1.3% to 1.6%) but thereafter decreased in frequency. The clearest dose-related increase occurred for harm-related AEs (which ranged from 2.7% at the lowest dose level to 8.5% at the highest dose level), with similar dose-related increases observed for SI and intentional self-injury. Of note, the overall rate for harm-related AEs in the sertraline group appeared comparable to that observed in the NPT group.

SI and behavior as assessed by the C-SSRS

Throughout the study, the postbaseline incidence of SIB, as assessed by C-SSRS, remained below <11% across all treatment groups in the safety population. The incidence ranged from 10.8% at month 3 to 3.5% at month 36, demonstrating a marked decline over time (Table 6). The frequency of reported SI and SB decreased across all timepoints in all exposure groups and remained highest in the OA group. A greater proportion of patients in the sertraline group compared with the NPT group experienced SI at most timepoints, with SI ranging from 11.5% at month 3 to 4.6% at month 18 in the sertraline group and from 8.2% at month 6 to 0.6% at month 36 in the NPT group. The incidence of SB in the sertraline and NPT groups remained less than 2% across all study timepoints. The proportion of patients reporting postbaseline NSSIB and self-injurious behavior of unknown intent was ≤4.2% and ≤0.6%, respectively, with higher frequencies in the sertraline group as compared with the NPT group.

Table 6.

Columbia-Suicide Severity Rating Scale by Visit and Treatment Group in SPRITES—Safety Population^a

Time point parameter, n/N (%)	Sertraline^b	Other antidepressants^b	No pharmacologic therapy^b	All patients
3 months
Suicidal behavior and/or ideation	64/557 (11.5)	2/3 (66.7)	14/178 (7.9)	80/738 (10.8)
Suicidal ideation	64/557 (11.5)	2/3 (66.7)	14/178 (7.9)	80/738 (10.8)
Suicidal behavior	9/557 (1.6)	2/3 (66.7)	2/178 (1.1)	13/738 (1.8)
Self-injurious behavior, no suicidal intent	25/557 (4.5)	1/3 (33.3)	3/178 (1.7)	29/738 (3.9)
Self-injurious behavior, intent unknown	2/557 (0.4)	0/3 (0.0)	2/178 (1.1)	4/738 (0.5)
6 months
Suicidal behavior and/or ideation	42/478 (8.8)	9/36 (25.0)	14/171 (8.2)	65/685 (9.5)
Suicidal ideation	41/478 (8.6)	9/36 (25.0)	14/171 (8.2)	64/685 (9.3)
Suicidal behavior	8/478 (1.7)	2/36 (5.6)	0/171 (0.0)	10/685 (1.5)
Self-injurious behavior, no suicidal intent	23/478 (4.8)	4/36 (11.1)	2/171 (1.2)	29/685 (4.2)
Self-injurious behavior, intent unknown	4/478 (0.8)	0/36 (0.0)	0/171 (0.0)	4/685 (0.6)
12 months
Suicidal behavior and/or ideation	32/383 (8.4)	8/59 (13.6)	10/145 (6.9)	50/587 (8.5)
Suicidal ideation	32/383 (8.4)	8/59 (13.6)	10/145 (6.9)	50/587 (8.5)
Suicidal behavior	5/383 (1.3)	0/59 (0.0)	2/145 (1.4)	7/587 (1.2)
Self-injurious behavior, no suicidal intent	12/383 (3.1)	1/59 (1.7)	1/145 (0.7)	14/587 (2.4)
Self-injurious behavior, intent unknown	1/383 (0.3)	0/59 (0.0)	0/145 (0.0)	1/587 (0.2)
18 months
Suicidal behavior and/or ideation	14/304 (4.6)	12/73 (16.4)	10/149 (6.7)	36/526 (6.8)
Suicidal ideation	14/304 (4.6)	12/73 (16.4)	10/149 (6.7)	36/526 (6.8)
Suicidal behavior	0/304 (0.0)	0/73 (0.0)	0/149 (0.0)	0/526 (0.0)
Self-injurious behavior, no suicidal intent	11/304 (3.6)	1/73 (1.4)	0/149 (0.0)	12/526 (2.3)
Self-injurious behavior, intent unknown	0/304 (0.0)	0/73 (0.0)	0/149 (0.0)	0/526 (0.0)
24 months
Suicidal behavior and/or ideation	15/263 (5.7)	6/71 (8.5)	8/139 (5.8)	29/473 (6.1)
Suicidal ideation	15/263 (5.7)	6/71 (8.5)	8/139 (5.8)	29/473 (6.1)
Suicidal behavior	1/263 (0.4)	1/71 (1.4)	1/139 (0.7)	3/473 (0.6)
Self-injurious behavior, no suicidal intent	10/263 (3.8)	1/71 (1.4)	0/139 (0.0)	11/473 (2.3)
Self-injurious behavior, intent unknown	1/263 (0.4)	0/71 (0.0)	0/139 (0.0)	1/473 (0.2)
30 months
Suicidal behavior and/or ideation	11/218 (5.0)	4/65 (6.2)	7/149 (4.7)	22/432 (5.1)
Suicidal ideation	11/218 (5.0)	4/65 (6.2)	7/149 (4.7)	22/432 (5.1)
Suicidal behavior	1/218 (0.5)	0/65 (0.0)	0/149 (0.0)	1/432 (0.2)
Self-injurious behavior, no suicidal intent	9/218 (4.1)	0/65 (0.0)	1/149 (0.7)	10/432 (2.3)
Self-injurious behavior, intent unknown	0/218 (0.0)	0/65 (0.0)	0/149 (0.0)	0/432 (0.0)
36 months
Suicidal behavior and/or ideation	10/205 (4.9)	4/64 (6.3)	1/162 (0.6)	15/431 (3.5)
Suicidal ideation	10/205 (4.9)	4/64 (6.3)	1/162 (0.6)	15/431 (3.5)
Suicidal behavior	1/205 (0.5)	0/64 (0.0)	0/162 (0.0)	1/431 (0.2)
Self-injurious behavior, no suicidal intent	5/205 (2.4)	3/64 (4.7)	1/162 (0.6)	9/431 (2.1)
Self-injurious behavior, intent unknown	0/205 (0.0)	0/64 (0.0)	0/162 (0.0)	0/431 (0.0)

n, number of participants reporting at least one occurrence of the event; N, the number of participants who were exposed to the corresponding treatment at least once postbaseline.

^aSafety population: Patients who had PAERS or SAE information available during the follow-up, had treatment information available during follow-up, or had a postbaseline C-SSRS assessment.

^bThe treatment categories for a given postbaseline visit were based on treatment since the previous visit. The sertraline group was defined as those patients on sertraline only or sertraline and any other treatment. The other antidepressants group was defined as those patients on another antidepressant only or another antidepressant and psychotherapy. The no pharmacologic therapy group was defined as those patients on psychotherapy only or no treatment at all.

C-SSRS, Columbia-Suicide Severity Rating Scale for Children; PAERS, Pediatric Adverse Event Rating Scale; SAE, serious adverse event; SPRITES, Sertraline Pediatric Registry for the Evaluation of Safety.

Table 7 presents results from the post hoc MSM analysis of C-SSRS data, which accounted for treatment switching and dropouts. A comparison of the subgroup of patients who were only treated with sertraline (i.e., always exposed) with those who never received sertraline (i.e., never exposed) showed no statistically significant effect of sertraline treatment on SIB across all postbaseline visits.

Table 7.

Columbia-Suicide Severity Rating Scale Positive^a or Worsening Suicidal Ideation or Behavior—MSM Summary (Safety Populationb)

Endpoint^a visit	Always treated with sertraline^c n/N (%)	Never treated with sertraline^c n/N (%)	Odds ratio(95% CI)	p ^d
C-SSRS: Positive or worsening suicidal ideation or behavior^c				0.753
3 months	34/533 (6.4)	8/157 (5.1)	1.1 (0.4, 2.8)
6 months	24/422 (5.7)	7/123 (5.7)	0.9 (0.3, 2.6)
12 months	16/328 (4.9)	4/89 (4.5)	0.9 (0.3, 2.9)
18 months	8/246 (3.3)	1/69 (1.4)	3.4 (0.7, 16.4)
24 months	4/197 (2.0)	3/59 (5.1)	0.5 (0.1, 2.0)
30 months	4/154 (2.6)	1/49 (2.0)	1.6 (0.3, 9.2)
36 months	3/134 (2.2)	2/46 (4.3)	1.5 (0.3, 7.6)

Positive suicidal ideation or behavior at a given postbaseline visit was defined as a patient reporting no suicidal ideation and no suicidal behavior at the baseline visit and then reporting any suicidal ideation or behavior at the given postbaseline visit. Any postbaseline visit where these criteria were met counted as separate instances of positive suicidal ideation or behavior.

Safety Population: Patients who had PAERS or SAE information available during the follow-up, had treatment information available during follow-up, or had a postbaseline C-SSRS assessment.

The objective of this analysis was to compare the likelihood of having a positive or worsening suicidal ideation or behavior event at each visit between the Always vs. Never Exposed to Sertraline exposure categories. Patients corresponding to the “Always” group were those patients who were on sertraline at baseline and were still on sertraline for at least their month 3 visit. The visits included for “Always” patients were those visits where the patient had not yet stopped taking sertraline since their baseline visit. Patients corresponding to the “Never” group were those patients who were not on sertraline at baseline and were still not on sertraline for at least their month 3 visit. The visits included for “Never” patients were those visits where the patient had not yet started taking sertraline since their baseline visit.

The p value is from an overall test across all visits.

CI, confidence interval; C-SSRS, Columbia-Suicide Severity Rating Scale for Children; MSM, marginal structural model; PAERS, Pediatric Adverse Event Rating Scale; SAE, serious adverse event.

Discussion

While the primary objective of SPRITES was to evaluate the effect of sertraline on child and adolescent physical and psychological development, the study also provided an opportunity for treating physicians in the community to report safety data on long-term, real-world use of the medicine. The most common AEs reported in the sertraline group were psychiatric and GI in nature, including behavioral activation-related AEs, such as disturbance in attention, impulsive behavior, insomnia, and irritability. No new or unexpected safety signal was identified over the course of this 3-year study, and, importantly, there was no increase in rates of suicidality over time.

The sertraline safety profile observed in SPRITES is consistent with that observed in shorter-term pediatric studies of sertraline (Rynn et al., 2015; Tini et al., 2022; Wagner et al., 2003; Walkup et al., 2008). For example, in a pooled analysis of two multicenter, randomized, controlled trials of the efficacy and safety of 10 weeks of sertraline treatment for major depressive disorder in patients 6–17 years of age, AEs occurring in sertraline-treated patients at a frequency greater than 2% and at least twice that in placebo-treated patients were primarily GI-related: insomnia (19.8%), diarrhea (15.1%), anorexia (10.5%), vomiting (9.3%), agitation (8.1%), urinary incontinence (7.0%), and purpura (5.8%) in children (n = 86) and vomiting (7.8%) and diarrhea (6.8%) in adolescents (n = 103) (Wagner et al., 2003).

Similarly, results from the Child/Adolescent Anxiety Multimodal Study (CAMS), which assessed AEs in pediatric patients with anxiety disorders receiving CBT, sertraline, combination CBT and sertraline, or placebo across a 12-week period, showed significantly higher rates of fatigue, insomnia, sedation, activation AEs (including restlessness, disinhibition, and increased motor activity), and worsening or emergence of trouble sleeping and feeling bloated in the sertraline groups compared to the CBT group (Rynn et al., 2015). Taken together, the AEs occurring most frequently in sertraline-treated pediatric patients in SPRITES appear comparable to those reported in prior shorter-term sertraline studies. Other publications have documented similar patterns of AEs (Mills and Strawn, 2020; Posner et al., 2007; Solmi et al., 2020; Tini et al., 2022).

Moreover, the observation in sertraline-treated patients of decreasing incidence of AEs, including suicidality and activation-related events, across the 3-year follow-up period extends findings from a limited number of publications reporting AE chronology with acute SSRI treatment in youth. In CAMS, analysis of physical symptoms in sertraline-treated patients showed a reduction of these AEs across the 12-week treatment phase (Rynn et al., 2015) and statistically significant decreases from baseline at week 12 in the frequency of GI (abdominal pain, dry mouth, and nausea) and behavioral activation events (insomnia and restlessness) (Strawn et al., 2023).

The post hoc analyses provide additional evidence that there may be differences in tolerability of sertraline across diagnostic groups as well as age groups, as previously reported (Boaden et al., 2020; Rynn et al, 2015). In the present study, regardless of treatment assignment, children and adolescents with primary mood disorder diagnoses had higher rates of AEs, including self-harming behaviors than patients with primary anxiety disorders or OCD. There were also differences in the sertraline tolerability profile between children and adolescents. In the present study, children in the sertraline group tended to have lower rates of physical AEs compared with adolescents, while sertraline-treated children had higher rates of specific types of (but not overall) psychiatric AEs (i.e., irritability, impulsive behavior, disturbance in attention). Not surprisingly, higher rates of depression and suicidality were reported in adolescents treated with sertraline. The underlying factors contributing to these clinically important differences warrant further research, as they may not be related in any straightforward manner to dose and serum exposure of sertraline (Tini et al, 2022). In fact, the post hoc analysis for dose effects of sertraline did not show marked dose–response relationships for AEs, other than possibly for self-harmful behaviors. This observation, however, is confounded by the fact that children and adolescents with higher levels of suicidality are likely to receive higher doses of sertraline.

With respect to the C-SSRS data, the observation that a greater proportion of patients in the sertraline group experienced SIB as compared with the NPT group was anticipated given baseline differences between groups in age, disease severity, and SIB history. It is of interest that SI and SB decreased across study timepoints in the sertraline group. These data were further corroborated in a post hoc analysis that did not support an association between sertraline and higher reporting of SI and SB on the C-SSRS. While this study was not powered to assess suicidality as a primary outcome, frequencies of SIB observed in the sertraline group in SPRITES (11.5%–4.6%) were comparable to those observed in prior short-term SNRI/SSRI studies in children and adolescents that used the C-SSRS to prospectively assess SIB (Atkinson et al., 2019; Findling et al., 2017, 2018).

The present study had limitations that were previously described (Kolitsopoulos et al., 2023). To summarize, the study did not have balanced baseline characteristics between treatment groups due to lack of randomization, which is inherent in observational studies. Consistent with real-world practice, the sertraline group was composed of patients with greater baseline disease severity and lifetime SIB. Treatment switching postbaseline was not completed at random, as patients were channeled into the treatment group deemed appropriate by their treating physician. As a result, it was not possible to ascertain relatedness of an AE to treatment condition across exposure groups.

As noted, the study was not powered to detect treatment differences in AE and C-SSRS outcomes, and the small sample size of the OA group makes comparisons difficult. Limitations of the MSM analysis include the potential for unmeasured confounding, for instance, in the predictors of SIB at baseline. Although sensitivity analyses were not performed to assess the impact of unmeasured confounding, accounting for such factors is unlikely to change the result given the analysis p value (0.753). Given the real-world design (e.g., 6-month data collection intervals, postbaseline treatment switches, patient-reported estimates of dosing compliance), analysis populations defined for the MSM did not account for the effect of intermittent dosing. Consequently, the “Always exposed” population may have included patients with variable or subtherapeutic sertraline exposure levels, which could affect tolerability data.

Additionally, prior research has linked CYP2C19 and CYP2CB6 metabolizer status with sertraline exposure levels and tolerability in pediatric patients (Poweleit et al., 2019, 2024; Strawn et al., 2019). However, as SPRITES did not include clinical genotyping, assessment of the relationship between sertraline pharmacogenomics and AE and SIB events could not be explored. Last, the above-described design elements precluded evaluation of sertraline-withdrawal-emergent events—a topic on which further data in pediatric patients is needed (Khan et al., 2023).

Additional areas for future investigation include further evaluation of the time course of treatment-related AEs, diagnostic-related differences in tolerability, and predictors of treatment switching and suicide-related events in sertraline-treated youth.

Conclusion

The primary objective of SPRITES was to determine whether long-term treatment with sertraline affected children’s growth and development; a particular strength of the study was that it provided structured assessments of long-term outcomes and tolerability in children taking sertraline. As previously reported (Kolitsopoulos et al., 2023), aside from a trend for increased weight at higher doses of sertraline, the overall results were consistent with normal development, and no significant differences in growth and development were observed between the youth treated with sertraline and those who did not receive any pharmacologic therapy. The present study, summarizing the safety data from the SPRITES study, demonstrates that the safety profile of long-term treatment with sertraline is consistent with results of prior, shorter-term pediatric sertraline studies and extends observations from acute studies suggesting improved tolerability across the sertraline treatment timeframe. No new or unexpected safety signal was identified with prolonged treatment of children with sertraline, and, of note, there was no increase in rates of suicidality over time.

Clinical Significance

SSRIs are generally regarded as the first-line medication treatment for pediatric mood and anxiety disorders. In children, the SSRI, sertraline, is approved for treatment of OCD only, and is widely prescribed off-label for treatment of other mental health conditions. The efficacy and safety of sertraline treatment in children has been assessed in several acute studies, although there is limited published data on the tolerability of sertraline for extended treatment timeframes. While the main objective of the current study was to assess long-term treatment with sertraline on physical and psychological development in children, the inclusion of structured safety assessments provided a unique opportunity to evaluate tolerability of sertraline over a 3-year follow-up period. Results show that the safety profile of prolonged sertraline treatment in a real-world setting is consistent with outcomes from prior, acute studies in youth and extend the observation from short-term studies of improved tolerability across the course of sertraline treatment.

Footnotes

Acknowledgments

The authors thank the pediatric participants of SPRITES; the investigators, coordinators, and additional site staff who took part in the study; and the Pfizer Medical, Worldwide Safety and Regulatory employees: Cynthia DeLuise, Tanya Russell, Omar Ahmed, Sarah Dubrava, Lisa Falato, and Nancy Sherman. Joann Munting was an employee of ExecuPharm, who was a paid contractor to Pfizer in the management of SPRITES. John March, John Curry, Mary Creed, Kristy Vaughan, Sara Taylor, Jennifer Murphy, and Eliza Sgherza are (in some cases, were previously) employees of Duke Clinical Research Institute, which received financial support in the management of this study. The authors also thank Kristina Marschall for her contribution to review of the article and Venkata Satya Sai Minnikanti, from Viatris, Bengaluru, India, for his contribution to the medical editorial review of the article.

Authors’ Contributions

F.K. participated in the design of the study. S.B., F.K., S.R., L.L., P.C., J.O., W.B., S.N.C., and Y.L. were involved with scientific/logistical/operational decisions, assisted with drafting of the study statistical analysis plan, interpreted the data, and were involved with article writing. S.H. also took part in drafting the article. All authors read and approved the final article.

Data Availability

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

Author Disclosure Statement

W.B., P.C., L.L., and S.R. are full-time employees and stock shareholders of Pfizer. W.B. and S.R. are also stock shareholders of Viatris. At the time of study conduct, F.K. and J.O. were full-time employees and stock shareholders of Pfizer, and S.N.C. was a full-time employee of Duke University/Duke Clinical Research Institute. S.B. and Y.L. are employees of Duke University/Duke Clinical Research Institute. S.H. is an employee of Viatris and a stock shareholder of Viatris and Pfizer. Currently, F.K. is affiliated with Gilead Sciences, Inc., Clinical Data Science—Real World Evidence in Parsippany, New Jersey; J.O. is with Lehman College, Bronx, New York; and S.N.C. is with Ann and Robert H. Lurie Children’s Hospital of Chicago, Northwestern University Feinberg School of Medicine.

Supplementary Material

Supplementary Table S1

Supplementary Table S2

Supplementary Table S3

Supplementary Table S4

Supplementary Table S5

Supplementary Table S6

Supplementary Table S7

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