Selective serotonin reuptake inhibitors for children with Autism Spectrum Disorder: a systematic review and meta-analysis

doi:10.21203/rs.3.rs-2757603/v1

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Selective serotonin reuptake inhibitors for children with Autism Spectrum Disorder: a systematic review and meta-analysis

https://doi.org/10.21203/rs.3.rs-2757603/v1

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Background

Effects of Selective Serotonin Reuptake Inhibitors (SSRI) for symptoms of autism spectrum disorder (ASD) or comorbid conditions are uncertain. We conducted a systematic review and meta-analyses to determine the efficacy and safety of SSRIs in children with ASD on restricted repetitive behaviors, obsessive-compulsive, anxiety and depressive symptoms, disruptive behaviors, global functioning, and quality of life.

Methods

We searched MEDLINE, EMBASE, CENTRAL, CINAHL, PsycINFO, WHO ICTRP, Clinical.Trials.gov. to retrieve RCT of SSRIs versus placebo in children with ASD that evaluated the outcomes of interest with a validated measurement instrument. Two authors independently extracted data, assessed risk of bias and rated the certainty of evidence.

Results

Seven RCTs with a total of 606 participants were included. The evidence is very uncertain on the effect of SSRIs on restricted-repetitive behaviors and anxiety symptoms in children with ASD, there is low certainty of the evidence suggesting that SSRIs result in little to no effect on obsessive-compulsive symptoms and disruptive behaviors and there is moderate certainty of the evidence that SSRIs likely result in little to no difference in global functioning and a slight increase in adverse events. No studies evaluated depressive symptoms.

Conclusions

The number of studies on this population remains limited, and there is a lack of commonly accepted outcome measures able to identify relevant changes for patients and families.

Protocol registration number:PROSPERO-CRD42020169836

Autism Spectrum Disorder

Pervasive Developmental Disorder

Selective Serotonin Reuptake Inhibitors

Pharmacological treatment

Description of the condition: Autism Spectrum Disorder (ASD) is an umbrella term defining a developmental disability characterized by the presence of two core symptoms: 1-difficulties in social communication and social interaction; and 2-restricted and repetitive behaviors, interests or activities, according to the definition provided by the Diagnostic and Statistical Manual of Mental Disorder – Fifth Edition (DSM-V)(1) and similarly by the International Classification of Disorders – Eleventh Edition (ICD-11(2)). Patients affected by ASD may exhibit different levels of severity and heterogeneous clinical presentations. This definition, introduced in 2013, has encompassed conditions previously identified as Autistic Disorder, Asperger’s Disorder, Pervasive Developmental Disorder Not Otherwise Specified (according to the DSM-IV(3)) and Childhood Autism, Asperger Syndrome, Pervasive Developmental Disorder Unspecified (according to the ICD-10 Revised(4)). In 2014, the prevalence of ASD in the United States was estimated as 1 in every 59 children aged 8 years(5), with worldwide estimates around 1–2% (6, 7), and it is four times more common in males than females. Educational and behavioral interventions that are well-structured, delivered one-to-one and intensively applied within the first 6 years of age have shown to be beneficial in affecting language and cognition(8). Unfortunately, the quality of existing evidence is low and their implementation is often impeded because these techniques are expensive, time consuming, and they are not always available or reimbursable.(9)

As a result, pharmacotherapy is widely used(10) although evidence only supports the treatment of specific co-occurring symptoms or behaviors, such as aggressivity/irritability and hyperactivity. Currently, risperidone and aripiprazole are the only two medications that have shown to be effective(11) and approved to treat severe problem behaviors that occur in about 20–30%(12, 13) of children with ASD. Similarly, methylphenidate(14), atomoxetine(15) and guanfacine(16) can be beneficial for children with an additional diagnosis of Attention Deficit Hyperactivity Disorder (ADHD), occurring in about 28%(17) of children with ASD.

Description of the intervention and how it might work

On the other hand, Selective Serotonin Reuptake Inhibitors (SSRIs) are a class of medication frequently used in clinical practice in children with ASD despite the fact that the evidence-base for their efficacy is still inconclusive. Various SSRIs have been approved from the Food and Drug Administration (USA) for the treatment of major depressive disorder and obsessive-compulsive disorder in non-ASD children, with minor variation of indications/dosage among other countries. In children with ASD, SSRIs are often used off-label in attempt to reduce the frequency and severity of core symptoms, such as repetitive restrictive behaviors (RRBs), or to improve comorbid symptoms, such as anxiety.(18, 19)

Why it is important to do this review

To date, a Cochrane Systematic review published in 2013(20) has examined the efficacy of four SSRIs (fluoxetine, fluvoxamine, fenfluramine and citalopram) in both adult and children populations. The review included 9 randomized controlled trials (RCTs) with a total of 320 patients and explored numerous outcomes. Meta-analysis was possible for only a single outcome, global functioning. The interest on this topic, however, remains high and a few additional RCTs in pediatric populations were published in 2019(21–23). Two recent systematic reviews and meta-analyses(24, 25) evaluated the efficacy of different treatments on RRBs in pediatric and adults patients with ASD and concluded that SSRIs were not associated with a benefit on RRBs compared to placebo. These reviews, however, did not evaluate other patient important outcomes, only one review(24) reported a risk of bias assessment of the included studies, and neither of them applied the Grading of Recommendations Assessment, Development and Evaluation (GRADE) method to rate the certainty of the evidence. An updated and methodologically rigorous systematic review and meta-analysis of RCTs comparing SSRIs versus placebo in pediatric patients with ASD is needed to gain a better understanding of the risks and benefits of this treatment in this specific population and to inform decision-making with the latest best available evidence.

Objectives

We aim to address two key questions in this systematic review: 1) what are the benefits of SSRIs in pediatric population with ASD? and, 2) what are the adverse events (AEs) of SSRIs in children/adolescents with ASD?

We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement(26) (PRISMA) when conducting and reporting this prospectively registered systematic review.

Data Sources and Searches

We searched MEDLINE, EMBASE, The Cochrane Central Register of Controlled Trials (CENTRAL), CINAHL, PsycINFO from inception to the first week of February 2020 and updated the search on March 26th 2021. We did not apply any restrictions based on language, age of participants, publication status or time of publication. Detailed search strategies used for this review are reported in Appendix 1. In MEDLINE (Ovid) the subject specific search strategy was combined with the Cochrane highly sensitive search strategy for identifying randomized trials(27), appropriate adaptations were also applied to the other databases as well.(28, 29)

We reviewed the reference lists of the included trials and any relevant review articles retrieved from the electronic searches to identify any other potentially relevant trials. Efforts were also made to identify unpublished studies, such as those presented only in abstracts. Moreover, we identified ongoing trials using the World Health Organization (WHO) international Trials Registry Platform, Current Controlled Trials (ICTRP) and the Clinical.Trials.gov (CT.gov). Authors of trials were contacted by email to request unpublished data when necessary.

Study Selection

We included RCTs comparing SSRIs versus placebo in children and adolescents (up to 18 years) with a diagnosis of ASD explicitly made according to DSM-V criteria (or equivalent previous definitions according to DSM-IV or ICD-10). We included trials evaluating an oral SSRI, regardless of the compound, dosage, and frequency of administration. Cross-over studies were also eligible for inclusion when an adequate duration of the washout period was reported (considering half-life of the compound and possible carryover effects). Trials including patients with Rett Syndrome or Childhood Disintegrative Disorder were excluded from this review, considering the prognosis, progressive course of disease and potential differences in response to psychoactive treatments.

Two review authors (ET and NJN) independently screened titles and abstracts of articles retrieved by the searches in duplicate. Studies were initially categorized into “possibly relevant” (when meeting the inclusion criteria or when not possible to determine inclusion from title/abstract) and into “excluded” (when clearly not meeting the inclusion criteria). One review author (ET) retrieved copies of all possibly relevant studies. Two review authors (ET and NJN) then independently and in duplicate reviewed the full text of all retrieved studies against the inclusion and exclusion criteria, with disagreements resolved through discussion.

Outcomes

The review addressed the following patient/parent important outcomes(30): restricted repetitive behaviors, obsessive-compulsive symptoms, anxiety symptoms, depressive symptoms, disruptive behaviors, global functioning, quality of life of patient/family, withdrawals due to adverse events (AEs), any AEs.

Data Extraction and Quality Assessment

Two review authors (ET, NJN) independently extracted key participant and intervention characteristics, and data on efficacy outcomes and adverse events using pre-developed data extraction forms in duplicate. Reviewers abstracted characteristics of eligible studies, including study design, duration of study, number of centres, study settings, number of patients, age, gender, diagnostic criteria, severity of condition, Intellectual Quotient (IQ), inclusion/exclusion criteria, genetic diagnosis, relevant comorbidities, intervention, comparator, concomitant and previous medications, excluded medications, withdrawals and reasons for discontinuation, efficacy and safety outcomes of interest. We extracted outcome data only when trials measured the outcome of interest with a validated instrument previously described in a peer-review journal and not modified by the authors. Disagreements were resolved by discussion, or if required, by a third author (AI). We attempted to locate the protocol of each included study and contacted the authors of included studies to provide additional data when necessary. After completing data extraction, we contacted authors again to confirm the accuracy of extracted data and we received feedback from three of them(31–33).

Two review authors (ET, NJN) independently assessed the risk of bias of included RCTs in duplicate. Risk of bias assessments were performed for each specific outcome using the Cochrane Risk of Bias tool - RoB 2.0 tool(34), which addresses the following methodological domains: bias arising from randomization process, bias due to deviations from intended interventions, bias due to missing outcome data, bias in measurement of the outcome and bias in selection of the reported result. The risk of bias judgment for each domain is assessed as “low risk”, “high risk” or “some concerns”. Any disagreements in the assessments were resolved by consensus or adjudication by a third review author (AI) when necessary.

Data Synthesis and Analysis

We performed meta-analysis summarizing dichotomous outcomes using risk ratio (RRs) and Risk Difference, with corresponding 95% confidence intervals (CIs). We calculated the absolute estimates of effect by applying relative risk estimates to a baseline risk, for which we pooled control group event rates from the included RCTs. Continuous outcomes were summarized using mean differences (MD) of post scores with corresponding 95% CIs.

Minimal important differences (MIDs) were used to interpret the mean differences between groups for continuous outcomes. We searched the PROMID (Patient Reported Outcomes Minimal Important Difference) database(35), a comprehensive catalog of MIDs for patient-reported outcome measures to retrieve empirically derived MIDs from published anchor-based studies(36). We could only identify a single MID estimate for the Children’s Yale-Brown Obsessive Compulsive Scales modified for pervasive developmental disorders (CYBOCS-PDD(37) rating from 0 to 20, lower score better outcomes; MID: 2 points)(21). In the absence of other MID estimates for the remaining outcome measures of interest, to enhance interpretability of the results, we assumed a 10% reduction in symptoms could represent an acceptable cut-off to appreciate a small but important change (Appendix 6). However, this discretionary threshold is not meant to replace a more appropriate anchor-based estimate of the MID for these outcomes(38) nor to exclude that an accurate MID may be lower or higher than 10%.

We used Review Manager 5 software (RevMan Web, The Cochrane Collaboration, 2019, available at revman.cochrane.org) for the meta-analyses, with the generic inverse-variance random-effects model for continuous outcomes, and Mantel-Haenszel method and random effects for dichotomous outcomes. Forest plots were used for visualization and a two-sided p-value < 0.05 was considered statistically significant. We assessed statistical heterogeneity with the χ² and I² statistics.

Subgroup analysis: We planned to perform three subgroup analyses based on age (< 12 vs 12–18 years), IQ level (≤ 70 vs > 70) and diagnosis of genetic syndrome. Sensitivity analysis: We planned to run sensitivity analysis based on high quality RCTs.

Certainty of the evidence assessments

Two review authors (ET and DP) assessed the certainty of the estimates of effect (quality of evidence) for each outcome using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) method(39), with one author (AI) adjudicating the decision in instances where there were discrepancies. We considered limitations in risk of bias, inconsistency, indirectness, imprecision and publication bias. Certainty in the body of evidence was rated as high (we are very confident that the true effect lies close to that of the estimate of the effect); moderate (the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different); low (the true effect may be substantially different from the estimate of the effect); or very low (the true effect is likely to be substantially different from the estimate of effect)(40). GRADEpro software was used to prepare the Summary of Findings tables, which summarizes the certainty of evidence and the magnitude of effect of the intervention examined for all outcomes(41)^,(42).

We screened a total of 1893 unique records (after 661 duplicates were removed) identified from the five electronic databases. No additional records were identified through other sources. Details of the process of screening and selecting studies for inclusion in the review are presented in Fig. 1. Overall, there were a total of 7 included trials (corresponding to 13 publications), 34 excluded articles, and 5 registered protocols awaiting classification. Details on trials excluded at full-text and on studies awaiting classification are reported respectively in Appendix 2 and Appendix 4.

Of the seven included studies, three studies tested fluoxetine(21, 22, 43), one citalopram(44), two sertraline(23, 45) and one fluvoxamine(46), and the comparator was placebo in each case. Five studies used a parallel design(22, 23, 44, 45, 47), and two a crossover design(43, 46). Both studies with crossover designs observed a washout period compatible with the recommended length for the specific SSRI. However, because of a possible period effect in the Hollander(43) study, we pulled data in the meta-analysis only from the first period of treatment. No data was extracted from the Sugie(48) study because results were only presented for genotypes rather than as treatment-placebo comparison. Authors from three(21, 32, 45) studies provided us with additional unpublished data. The Greiss Hess(45) study included participants with Fragile X, however, we considered only the subgroup of patients with ASD. Unpublished data were collected on global functioning (dichotomus(21, 32, 45) and continuous results(45)), disruptive behaviours(32) and adverse events(45).

We did not perform the planned subgroup and sensitivity analyses because of the limited data available for meta-analysis. To assess publication bias we searched databases for protocols of unpublished studies(49) but did not construct a funnel plot due to the small number of studies included in the analyses.

Characteristics of included studies are presented in Appendix 3.

Risk of bias of included studies: The allocation sequence was randomly generated and it was concealed in four studies with no apparent baseline imbalances(22, 44, 45, 48). In one study there was no information about the randomization process but no baseline imbalances were reported(50). In another study, although random sequence generation was adequate and allocation was concealed, some baseline imbalances were likely due to chance(51). Finally, in one study no details on allocation sequence concealment were reported and the two groups appear unbalanced for various baseline characteristics(23). Risk of bias due to deviation from the intended interventions was low in five of the seven included studies(22, 45, 47, 48, 50), while in one study there were some concerns about the possibility of patients and study personnel being aware of the intervention(44) and in another study(23) there were some concerns because Intention-to-Treat (ITT) analysis was conducted for the primary outcomes but not specified for the outcomes of our interest. Risk of bias due to missing outcome data was detected in three studies: two studies had differential and high dropout rates that led to some concerns(22) and high risk(47); for one study(50) there were some concerns because of a 11% of drop-outs that were not included in the ITT analysis and four studies were at low risk(23, 44, 45, 48). Risk of bias in measurement of the outcome was judged low in all included studies. Finally, risk of bias for selective reporting was low in five studies(22, 23, 44, 45, 47) for which trial registrations were available as well as details on prespecified outcomes. Whereas, for one study(50) the protocol didn’t provide any detail on outcomes, and for another study the protocol was not available and the analysis reported effectiveness only for genetic subgroups(48). Details on risk of bias assessment of the included studies are reported in Appendix 3 and associated plots in Fig. 2 and Fig. 3. When risk of bias has been found to be different for different outcomes in the same study, the judgment has been reported in the specific domain along with the outcome (underscored in Appendix 3).

1-Restricted Repetitive Behaviors

Two studies(21, 44) reported restricted repetitive behaviours measured with the Repetitive Behavior Scale-Revised (RBS-R). However, while King 2009(44) reported the mean differences for the 5 subscales, Reddihough 2019(21) reported only the total score. Pooling the total scores was possible by imputing the SD from Reddihough 2019(21).

Pooling data from two RCTs(44, 51) including 230 participants, treated for 12–16 weeks, showed a MD -3.24 in restricted repetitive behaviours on the RBS-R score with the use of SSRIs (_95%CI -14.91, 8.43; I² = 74%; MID − 12.9 points; Analysis 1). Owing to concerns of serious risk of bias, inconsistency and imprecision, the evidence is very uncertain about the effect SSRIs in children with ASD on Restricted Repetitive Behaviors (Summary of Findings, Table 1).

2-Obsessive-Compulsive Symptoms

Four studies(21, 22, 44, 50) reported measures of obsessive-compulsive behaviours. However, Hollander 2005(50) used a version of the CYBOCS modified by the investigators recording only compulsive symptoms, and therefore was not included in the meta-analysis.

Pooling data from the 3 RCTs(44, 51, 52) including 413 participants, treated for 12–16 weeks, showed a MD -0.10 in obsessive-compulsive symptoms on the CYBOCS-PDD score with the use of SSRIs (_95%CI -1.57, 1.37; I² = 74%; MID − 2 points; Analysis 2). Due to serious concerns of risk of bias and inconsistency, there is low certainty evidence that suggests that use of SSRIs in children with ASD results in little to no difference in obsessive-compulsive symptoms (Summary of Findings, Table 1).

3-Anxiety Symptoms

Two studies(21, 23) reported anxiety symptoms using two different scales. Potter 2019(23) reported results from the Preschool Anxiety Scale-Revised (PAS-R) in 47 young children (2–6 years) treated for 26 weeks with a low dose of sertraline (MD 3.34; _95%CI -3.78, 10.46; MID − 13.6 point). Reddihough 2019(21) instead used the Spence Children Anxiety Scale (SCAS) and reported the results on 106 older children (7.5–18 years) treated for 16 weeks with a moderate dose of fluoxetine (MD -4.12; _95%CI -10.84, 2.60; MID − 11.4 point). Considering the serious concern of risk of bias, inconsistency and imprecision, the evidence is very uncertain about the effect of SSRIs in children with ASD on anxiety symptoms (Summary of Findings, Table 1).

4-Depressive Symptoms

None of the included studies reported any measure of depressive symptoms in children and adolescents with ASD.

5-Disruptive Behaviors

Three studies(21, 23, 44) reported maladaptive behaviours using the Aberrant Behavior Checklist - Community Version (ABC-CV) checklist and we reported the irritability subscale that mainly measures disruptive behaviours.

Pooling data from three RCTs(21, 32, 44) (published and unpublished) including 276 participants treated for 12–26 weeks, showed a MD 0.20 in disruptive behaviours measured with the Irritability Subscale of ABC-CV with the use of SSRIs (_95%CI -2.00, 2.40; I² = 0%; MID − 4.5 points; Analysis 3). Because of serious concerns of risk of bias and imprecision, there is low certainty evidence that suggests that use of SSRIs in children with ASD results in little to no difference in disruptive behaviours (Summary of Findings, Table 1).

6-Global Functioning

All of the included studies used some version of the Clinical Global Impression – Improvement scale (CGI-I) to measure change in global functioning. However, Sugie 2005(46), in a cross-over trial including 18 patients, presented the CGI scale results for different genotypes only, therefore it was not possible to determine the post-treatment score for the two groups.

Collecting additional unpublished data allowed us to pool both dichotomous results (responders defined as “much improved” or “very much improved”), as well as continuous results.

Pooling data from five RCTs(23, 31, 44, 51, 52) including 491 participants, treated for 12–26 weeks, showed a RR of 0.99 (_95%CI 0.73, 1.36; I² = 32%) in the number of responders at the CGI-I score with the use of SSRIs, corresponding to an absolute effect of 0 more participants improving per 100 using SSRIs (from 9 less to 12 more, Analysis 4). Because of the serious concern of risk of bias, there is moderate certainty evidence that suggests that SSRIs in children with ASD probably result in little to no difference in the number of patients showing an improvement in global functioning (Summary of Findings, Table 1).

An additional analysis pooling continuous data on the CGI-I scale from four RCTs(32, 43, 45, 51) including 226 participants showed comparable results (Analysis 5).

7-Quality of Life

Only one(52) RCT reported quality of life measured with the Caregiver Strain Questionnaire (CSQ) for a group of 121 participants treated for 14 weeks (MD 0.00; _95%CI -0.27, 0.27; MID − 0.5 point). Because of serious concerns of indirectness and imprecision, there is low certainty evidence that suggests that SSRIs may not increase nor reduce parent's quality of life (Summary of Findings, Table 1).

8-Adverse Events

Withdrawal due to adverse events

Three studies(33, 44, 52) reported the number of withdrawals due to adverse events and one study(23) provided us with unpublished data (Analysis 6a). One additional study reported no withdrawal due to adverse events in both arms (Greiss Hess 2016(31) unpublished data for the subgroup of 32 participants with ASD). Similarly, there were no discontinuation due to adverse events reported in the publication of the two cross-over studies: Hollander 2005(50) (44 participants) and Sugie 2005(46) (19 participants). Those results, excluded from the meta-analysis of RRs, were included in an additional analysis of Risk Difference (Analysis 6b) obtaining comparable results.

Pooling data from 4 RCTs(21, 32, 44, 52) including 511 participants, treated for 12–26 weeks, showed a RR of 1.14 (_95%CI 0.64 to 2.04, I² = 0%) in the number of withdrawals due to AEs with the use of SSRIs, corresponding to an absolute effect of 1 more event per 100 people using SSRIs (from 3 less to 8 more). Because of serious concern of risk of bias, there is moderate certainty evidence that suggests that SSRIs probably result in a slight increase of discontinuation due to adverse events (Summary of Findings, Table 1).

Any adverse events

Adverse events were inconsistently described among studies. The most commonly reported adverse events were gastrointestinal disorders, activation/hyperactivity, sleep disorders, and agitation/irritability, mainly of mild or moderate level of severity. Among the few serious adverse events reported there were four cases of suicidal ideation, three with placebo(33, 50) and one with SSRI(52), and one case of seizure with SSRI(53) requiring emergency hospitalization.

Pooling data from five RCTs(21, 32, 44, 45, 52) (both published and unpublished data) including 543 participants, treated for 12–26 weeks, showed a RR of 1.05 (_95%CI 0.95, 1.15; I² = 0%; Analysis 7) in the number of participants experiencing at least one adverse event with the use of SSRIs, corresponding to an absolute effect of 3 more participants experiencing adverse events per 100 people using SSRIs (from 4 less to 11 more). Because of serious concern of risk of bias, there is moderate certainty evidence that suggests that SSRIs in children with ASD probably result in a slight increase of adverse events (Summary of Findings, Table 1).

Summary of main results and certainty of the evidence

The number of studies conducted on the use of SSRIs in ASD remain limited, however among the few rigorous studies that have been completed and reported to date on children, our findings are consistent. Compared to the previous review(20), four additional studies with rigorous methodology were conducted in the pediatric population.

Overall, the evidence does not suggest a benefit of SSRIs for patient/parent important outcomes in pediatric population with ASD, and there is evidence that they may cause harm. However, the certainty of the evidence available for the various outcomes is not homogeneous. There is very low certainty evidence for restricted repetitive behaviors and anxiety symptoms, whereas the certainty of the evidence for obsessive-compulsive symptoms, disruptive behaviours and quality of life is low and suggests little to no difference in these outcomes with the use of SSRIs. In contrast, there is moderate certainty evidence that SSRIs probably result in no difference in global functioning and in slight increase of adverse events in children with ASD. Finally, there is no data available for depressive symptoms on ASD children treated with SSRIs.

Decision about the use of SSRIs in specific conditions that may co-occur with autism needs to be made balancing the potential harm/benefit in each individual case. Shared decision-making and transparent presentation of the current evidence along with its limitation is essential.

Overall completeness and applicability of evidence

Our review focused on children and adolescents with ASD, considering age and neurodevelopmental level as a potential factor of differential response to this class of drug. For this reason, our findings cannot directly extend to different ages and a similar review of the evidence is also needed in the adult population. Moreover, relevant variations in the clinical profile of ASD patients, such as IQ and global functioning, or comorbidity and syndromic diagnosis may influence the effect of SSRIs. Similarly, the identification of a minimum baseline level of targeted symptoms and establishing reliable and sensible measures to detect changes is crucial in evaluating treatment efficacy. Lastly, different dosages and duration of treatment may play a relevant role in adding an extra layer of heterogeneity. We could not explore these factors as planned through subgroup analyses due to paucity of evidence available. Future high-quality trials addressing these additional considerations may improve understanding about whether there is a role for the use of SSRIs in children with ASD.

ABC-CV	Aberrant Behavior Checklist - Community Version
AEs	Adverse Events
ASD	Autism Spectrum Disorders
CGI-I	Clinical Global Impression - Improvement scale
CSQ	Caregiver Strain Questionnaire
CYBOCS-PDD	Children’s Yale-Brown Obsessive Compulsive Scales modified for pervasive developmental disorders
DSM-5	Diagnostic and Statistical Manual of Mental Disorders - 5
GRADE	Grading of Recommendations Assessment, Development and Evaluation
ICD-10	International Classification of Diseases 11th Revision
ICTRP	International Trials Registry Platform, Current Controlled Trials
IQ	Intelligence Quotient
ITT	Intention-to-Treat
MID	Minimal Important Difference
PAS-R	Preschool Anxiety Scale - Revised
PRISMA	Preferred Reporting Items for Systematic Reviews and Meta-Analyses
PROMID	Patient Reported Outcomes Minimal Important Difference
RBS-R	Repetitive Behavior Scale - Revised
RCT	Randomized Controlled Trial
RRB	Repetitive Restrictive Behavior
SCAS	Spence Children Anxiety Scale
SSRI	Selective Serotonin Reuptake Inhibitors
WHO	World Health Organization

ETHICS APPROVAL AND CONSENT TO PARTICIPATE:

Not applicable

CONSENT FOR PUBLICATION:

Not appliable

AVAILABILITY OF DATA AND MATERIALS:

Data analyzed in this systematic review are publicly available from the included studies. Any additional data retrieved from authors are included in this manuscript and appendices.

COMPETING INTERESTS:

The authors declare that they have no competing interests.

FUNDING:

No funding was secured for this study.

AUTHORS’ CONTRIBUTIONS:

E.T. conceptualized and designed the study, E.T. and N.N. conducted Title/Abstract and Full-Text screening, Risk of Bias assessment and data extraction, E.T. and D.P. assessed the certainty of the evidence by applying the GRADE method, E.T. carried out the analyses and drafted the initial manuscript. D.P. and T.D. performed the critical review, and technical editing of the manuscript and provided methodological supervision. T.N. supervised and reviewed search strategies. O.C. provided content expert feedback and critical editing of the manuscript for important intellectual content. A.I. provided methodological supervision and expert feedback. All authors reviewed and approved the manuscript.

ACKNOWLEDGEMENTS:

Thank you to Francesca Orsini for providing unpublished data for Reddihough 2019 and to Hazel Maridith Barlahan Biag for provided unpublished data for Potter 2019 and Greiss Hess 2016. Thank you also to Naito Ryo for assisting in translating Sugie 2001 from Japanese.

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Table 1. Summary of findings

SSRIs compared to placebo in children with ASD
Patient or population: children with ASD Setting: outpatients Intervention: SSRI Comparison: placebo
Outcomes	Anticipated absolute effects^* (95% CI)		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Outcomes	Risk without SSRI	Risk with SSRI	Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Restricted repetitive behaviors assessed with: RBS-R Scale from: 0 to 129 (worse) follow up: range 12 weeks to 16 weeks	The mean restricted repetitive behaviors ranged from 28-36 points	MD 3.24 points lower (14.91 lower to 8.43 higher)	-	230 (2 RCTs)	⨁◯◯◯ VERY LOW ^a,b,c	The evidence is very uncertain about the effect SSRIs in children with ASD on Restricted Repetitive Behaviors
Obsessive-Compulsive symptoms assessed with: CYBOCS-PDD Scale from: 0 to 20 (worse) follow up: range 12 weeks to 16 weeks	The mean obsessive-Compulsive symptoms ranged from 10-13 points	MD 0.1 points lower (1.57 lower to 1.37 higher)	-	413 (3 RCTs)	⨁⨁◯◯ LOW ^d,e	SSRIs may result in little to no difference on Obsessions-Compulsions in children with ASD
Anxiety symptoms assessed with: different scales (PAS-R, SCAS) follow up: range 16 weeks to 26 weeks	Studies showed inconsistent effects - an increase and also a reduction in anxiety symptoms			153 (2 RCTs)	⨁◯◯◯ VERY LOW ^c,f,g	The evidence is very uncertain about the effect of SSRIs in children with ASD on anxiety symptoms
Depressive symptoms - not reported	-	-	-	-	-	None of the included studies reported any measure of depressive symptoms in children with ASD
Disruptive behaviours assessed with: ABC-CV irritability subscale Scale from: 0 to 45 follow up: range 12 weeks to 26 weeks	The mean disruptive behaviours ranged from 9-13 points	MD 0.2 points higher (2 lower to 2.4 higher)	-	276 (3 RCTs)	⨁⨁◯◯ LOW ^h,i	SSRIs may result in little to no difference in disruptive behaviors
Global functioning assessed with: CGI-I (much or very much improved) follow up: range 12 weeks to 26 weeks	32 per 100	32 per 100 (23 to 44)	RR 0.99 (0.73 to 1.36)	491 (5 RCTs)	⨁⨁⨁◯ MODERATE ^h	SSRIs probably result in little to no difference in the number of patients showing an improvement in global functioning
Quality of life (parents) assessed with: CSQ Scale from: 0 to 5 follow up: 14 weeks	The mean quality of life (parents) was 2.7 points	MD 0 points (0.24 lower to 0.24 higher)	-	155 (1 RCT)	⨁⨁◯◯ LOW ^i,j	SSRIs (fluoxetine) may not increase nor reduce parent's quality of life
Discontinuation due to adverse events follow up: range 12 weeks to 26 weeks	8 per 100	9 per 100 (5 to 16)	RR 1.14 (0.64 to 2.04)	511 (4 RCTs)	⨁⨁⨁◯ MODERATE ^d	SSRIs probably result in a slight increase of discontinuation due to adverse events
Any adverse events follow up: range 12 weeks to 26 weeks	74 per 100	77 per 100 (70 to 85)	RR 1.05 (0.95 to 1.15)	543 (5 RCTs)	⨁⨁⨁◯ MODERATE ^k	SSRIs probably result in a slight increase in adverse events
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; MD: Mean difference; RR: Risk ratio
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

Explanations

a. Risk of bias across studies mainly due to missing data

b. statistical inconsistency (I2=74%, chi-squared p=0.05), partially related to different compounds and doses

c. Substantial imprecision due to a small number of participants and wide CIs including appreciable benefit/harm and no effect

d. Risk of bias due to missing data (high drop-out rate in two studies accounting for more than 50% of the weight)

e. Substantial heterogeneity not due to chance, both qualitative (likely because of different subpopulation and dose) and quantitative (I2 of 74%, (p=0.02) and visual inspection)

f. Serious concern of risk of bias mainly due to missing data

g. Serious concern of clinical inconsistency related to different ages, different compounds and doses, and different duration of the treatment

h. Risk of bias due to problem with deviation from intended intervention and missing data

i. Serious concerns of imprecision due to the small sample size

j. Serious concerns of indirectness due to selection of a specific subpopulation (only AD with mild severity)

k. Serious concern of risk of bias mainly due to missing data

No competing interests reported.

FORESTPLOTS.docx
Analysis 1. Restricted Repetitive Behaviors (Mean difference for the RBS-R) Analysis 2. Obsessive-Compulsive Symptoms (Mean difference for the CYBOCS-PDD) Analysis 3. Disruptive Behaviors (Mean difference for the ABC-Irritability subscale) Analysis 4. Global Functioning (Number of responders at the CGI-I) Analysis 5. Global Functioning (Mean difference for the CGI-I) Analysis 6a. Withdrawal due to adverse events (RR) Analysis 6b. Withdrawal due to adverse events (RD) Analysis 7. Participants experiencing at least one adverse event (RR)
SSRIinASDAppendices25.04.2023.docx

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Selective serotonin reuptake inhibitors for children with Autism Spectrum Disorder: a systematic review and meta-analysis

Status:

Version 1

Abstract

Figures

Background

Objectives

Methods

Data Sources and Searches

Study Selection

Outcomes

Data Extraction and Quality Assessment

Data Synthesis and Analysis

Certainty of the evidence assessments

Results

1-Restricted Repetitive Behaviors

2-Obsessive-Compulsive Symptoms

3-Anxiety Symptoms

4-Depressive Symptoms

5-Disruptive Behaviors

6-Global Functioning

7-Quality of Life

8-Adverse Events

Withdrawal due to adverse events

Any adverse events

Conclusions

Abbreviations

Declarations

References

Table

Additional Declarations

Supplementary Files

Status:

Version 1