Selective Serotonin Reuptake Inhibitor Monotherapy for Anxiety Disorders in Children and Adolescents with Autism Spectrum Disorder: A Chart Review

Abstract

Objective:

Anxiety disorders are one of the most commonly co-occurring psychiatric diagnoses in youth with autism spectrum disorder (ASD), with a frequency ranging from 22% to 84%.

Methods:

We conducted a chart review of 29 children and adolescents with ASD who had been treated with selective serotonin reuptake inhibitor (SSRI) monotherapy for an anxiety disorder for at least 2 months. Subsequent chart reviews were conducted for the first follow-up visit within 2–6 months (M = 4.2 months) and the visit closest to 9 months posttreatment (ranging from 7 to 12 months; M = 10.5 months). The presence of adverse events (AEs) was examined, and a consensus Clinical Global Impressions Improvement (CGI-I) score was determined.

Results:

Fifty-five percent of patients were given a CGI-I of “improved” or “very much improved” at the 9-month follow-up. Four patients discontinued treatment owing to AEs. Other reported AEs not leading to discontinuation included vivid dreaming, increased emotional lability, and irritability. Responders included a number of patients who had failed previous SSRI trials.

Conclusions:

This study suggests that SSRI treatment should be considered for individuals with ASD and anxiety disorders, even if prior SSRI trials have been unsuccessful.

Introduction

Autism spectrum disorder (ASD) is defined by persistent deficits in social communication and interaction (e.g., reduced social-emotional reciprocity and nonverbal communication), as well as restricted and repetitive behaviors (RRBs)/interests (e.g., repetitive speech, stereotyped hand movements, stereotyped use of objects) (American Psychiatric Association 2013). Recent rigorously controlled global epidemiological studies indicate that ASDs are a growing public health issue worldwide, with median prevalence rates identified in 62 per 10,000 individuals (Elsabbagh et al. 2012).

Anxiety disorders are one of the most commonly co-occurring psychiatric diagnoses in youth with ASD. Between 22% and 84% of those with ASD have been found to have a comorbid anxiety disorder (de Bruin et al. 2007; Simonoff et al. 2008; White et al. 2009; Vasa et al. 2014), and a recent meta-analysis suggests that nearly 40% of children with ASD have a diagnosis of at least one anxiety disorder (van Steensel et al. 2011). The most common forms of anxiety among children with ASD identified by van Steensel et al. (2011) were specific phobia (29.8%), obsessive compulsive disorder (OCD; 17.4%), and social anxiety disorder (16.6%). In fact, some have suggested that high comorbidity is related to overlap in symptom presentation between anxiety disorders, particularly OCD, and the RRBs characteristic of ASD (Hollander et al. 2006; Cath et al. 2008). No matter the type of anxiety disorder, these symptoms often disrupt children's routines at school and in the community and impose hardship and stress for families (e.g., making it difficult to attend community events, shop, or visit friends).

Reviews of the literature suggest that behavioral treatments for anxiety, such as modified cognitive-behavioral therapies, are efficacious but recommend that psychopharmacological interventions should be used cautiously (Vasa et al. 2014, 2016). Although substantial empirical evidence supports the use of selective serotonin reuptake inhibitors (SSRIs) to treat anxiety in typically developing youth (Mohatt et al. 2013), the same conclusions cannot be drawn from investigations of SSRI use to treat anxiety in children and adolescents with ASD. This is due the limited number of empirical and observational studies focusing on the effect of SSRIs on anxiety symptoms in individuals with ASD (Vasa et al. 2014). Of those investigations that have been conducted, there have been no randomized-controlled trials and findings have generally been mixed. Further, there has been a risk of reporting bias and evidence of negative side effects (e.g., behavioral activation, insomnia, akathisia) (McDougle et al. 2000; Couturier and Nicolson 2002; Martin et al. 2003; Williams et al. 2010). Based on the existing literature in this area, guidelines for diagnosis and treatment of anxiety in youth with ASD developed by the Autism Treatment Network/Autism Intervention Research on Physical Health Anxiety Workgroup have suggested that medications for treating anxiety should be prescribed cautiously (Vasa et al. 2016).

Part of the difficulty in determining the effectiveness of SSRIs for the treatment of anxiety in ASD is that studies have investigated the effect of SSRIs on a wide range of behavioral targets, including social communication, RRBs, irritability, and hyperactivity. Early hypotheses that fueled use of SSRIs in ASD were that these medications would improve core symptoms of ASD (e.g., social communication), due to evidence of serotonin dysfunction in ASD (Potenza and McDougle 1997; McDougle et al. 2003), and reduce RRBs because RRBs were “reminiscent” of symptoms found in OCD that are often responsive to SSRIs. However, studies have not found SSRIs to improve core social difficulties in youth with ASD. There have been mixed results regarding the impact of SSRIs on RRBs (see Accordino et al. 2016 for review). Among adults with ASD, significant decreases in repetitive thoughts and behaviors have been noted in two placebo-controlled trials (McDougle et al. 1996; Hollander et al. 2012). However, the findings of controlled trials in children with ASD have been inconsistent. Some studies have found reduced RRBs, defined as compulsive behavior (i.e., measured by the Children's Yale-Brown Obsessive-Compulsion Scale; CY-BOCS) (Goodman et al. 1989), after SSRI use (Hollander et al. 2005). Other studies of SSRIs in ASD (including two large-scale randomized-controlled trials) have failed to find reduction in RRBs (McDougle et al. 2000; Autism Speaks 2009; King et al. 2009). Reasons for a differential SSRI response between children and adults may be due to developmental changes in brain serotonin function (McDougle et al. 2000; Accordino et al. 2016).

Currently available research also suggests a mixed picture regarding the ability of SSRIs to improve anxiety symptoms in ASD. Some studies found citalopram to have modest efficacy (Couturier and Nicolson 2002; Namerow et al. 2003), whereas the use of fluvoxamine failed to lead to improvement in anxiety symptoms (Martin et al. 2003). Most studies have been either open-label trials or chart reviews. Methodological shortcomings include the retrospective nature of chart review, use of Clinical Global Impression (CGI) ratings with nonblinded raters, and lack of a clear definition of anxiety symptoms or anxiety disorder types being studied. Such problems make overall conclusions difficult to draw. This brief article summarizes the results of a chart review of 29 children and adolescents with ASD who received monotherapy SSRI treatment for management of symptoms of anxiety for a period of up to 12 months.

Methods

Subjects

Charts from 639 patients from a specialized outpatient clinic serving children and adolescents with ASD and developmental disorders seen between 2008 and 2014 were reviewed. Criteria for selection included a clinical diagnosis of pervasive developmental disorder (autistic disorder, pervasive developmental disorder–not otherwise specified [PDD-NOS], or Asperger's Disorder) and the prescribing of an SSRI. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition Text Revision (DSM-IV-TR) (American Psychiatric Association 2000) diagnostic criteria were used. Diagnoses were made by the treating clinician. Patients taking any other psychotropic medications were excluded. In addition, the SSRI trial needed to be a minimum of 2 months' duration (to provide adequate time to assess clinical efficacy) with a follow-up treatment note discussing response and adverse events (AEs). Target symptoms had to specifically focus on anxiety. Patients who were treated primarily for stereotypic behaviors, aggression, or depression were excluded. For patients who had been involved in more than one SSRI trial, only the results of the most recent trial were included (although reasons for discontinuation of the earlier SSRI were noted). Clinic patients were typically seen at 1–3-month intervals, depending on symptom presentation.

Procedure

After approval from the University of Pittsburgh Institutional Review Board, the following information was gathered from the charts: patient age at the start of the SSRI trial, gender, psychiatric diagnoses, SSRI prescribed, maximum dose, prior history of SSRI trials (including reason for discontinuation, if known), and observed/reported side effects. Two clinicians with experience in the treatment of children and adolescents with ASD (G.T. and B.L.H.) reviewed the chart notes at the baseline visit and provided a consensus Clinical Global Impressions Severity (CGI-S) score. The CGI (Guy 1976) provides a clinician-rated global rating of a study participant's condition before and during medication dosing. It comprises a global severity score (CGI-S) as well as a global improvement score (CGI-I). The CGI-S is based on a 7-point Likert scale ranging from 1 (“normal, not ill”) to 4 (“moderately ill) to 7 (“among the most extremely ill”). The CGI-I is similarly based on a 7-point Likert scale ranging from 1 (“very much improved”) to 4 (“no change”) to 7 (“very much worse”). Subsequent chart reviews were conducted for the first visit within 2–6 months (M = 4.2 months) and the visit closest to 9 months posttreatment (ranging from 7 to 12 months; M = 10.5 months). At that time, a consensus CGI-I was obtained, based on information provided by the prescribing physician. None of the selected patients had been treated by either of the chart reviewers. In addition, information on AEs was obtained. Finally, any information describing prior SSRI trials was obtained along with reasons for discontinuation.

Results

Table 1 depicts group demographic information (mean age, gender) as well as diagnoses, SSRIs prescribed and mean dose, days on medication, and the number of individuals on prior medication trials. Subjects in the chart review were 29 youth aged 4–20 years at the time of enrollment (mean age 13.28). Thirteen were diagnosed with Asperger's disorder, seven with autistic disorder, and nine with PDD-NOS. Approximately two-thirds (19) were antidepressant naive, and 17 of these had no prior psychopharmacological trials whatsoever. Eighteen of the 29 subjects were male. Among the 12 preadolescents (those aged 4–12 years), only 3 (25%) were female; whereas among the 17 adolescents (ages 13 and older), 8 (47%) were female. All the antidepressant trials in this chart review were with an SSRI, either fluoxetine (14), sertraline (9), or citalopram (6). Subgroups are analyzed later by using only descriptive statistics, due to the small sample size and the possibility of type II errors.

Table 1.

Group Demographic Measures

Variable	N = 29
Age in years, mean (SD)	13.28 (4.11)
Gender, n (%)
Male	18 (62.1)
Female	11 (37.9)
ASD diagnosis, n (%)
Autism	7 (24.1)
Asperger's	13 (44.8)
PDD-NOS	9 (31.0)
Non-ASD diagnosis, n (%)
Anxiety	25 (86.2)
Depression	6 (20.7)
Disruptive behavior	5 (17.2)
Obsessive compulsive	7 (24.1)
ADHD	3 (10.3)
Other diagnosis^a	3 (10.3)
SSRI prescribed and dose, n (%)/mean (SD)
Fluoxetine	14 (48.3)/21.57 mg (10.26)
Sertraline	9 (31.0)/53.19 mg (34.07)
Citalopram	6 (20.7)/25.00 mg (11.83)
Days on medication, mean (SD)	293.55 (76.53)
Previous medication trial, n (%)	12 (41.4)

Other diagnoses include one case of Adjustment Disorder with Mixed Anxiety and Depressed Mood, one case of Fragile X, and one case of an eating disorder.

ADHD, attention-deficit/hyperactivity disorder; ASD, autism spectrum disorder; PDD-NOS, pervasive developmental disorder–not otherwise specified; SD, standard deviation; SSRI, selective serotonin reuptake inhibitor.

Table 2 provides individual participant information. Participants ranged on initial CGI-S scores from 4 to 7 with a mean score of 5.1. Twenty of the 29 patients had improvement in their CGI-I scores (a score of 1 or 2) and 5 had a CGI-I score of 3 at the initial 2–6-month postbaseline review. Of the remaining four patients, two had a worsening course and the remaining two displayed no meaningful improvement in anxiety. Despite such concerns, all patients remained on their prescribed SSRI (although some experienced dose changes). On conducting the chart review between 7 and 12 months postbaseline, it was determined that four patients either switched or stopped their SSRI medication. Of the remaining 25 patients, 16 displayed CGI-I scores of 1 or 2, indicating a positive response to the SSRI. Five patients were given CGI-I scores of 3 (indicating minimal improvement), and four patients showed either no change or a worsening of anxiety symptoms. Thus, 55.2% of the patients were given a CGI-I score of “1” or “2” (indicating a positive SSRI response) over a 7–12-month period on the same SSRI.

Table 2.

Individual Participant Information

ASD diagnosis	Anxiety diagnoses and other diagnoses	Age	Gender	Baseline SSRI	Maximum dose, mg	Prior trials	Baseline CGI-S	Timepoint 1 (2–6 months)	Timepoint 2 (7–12 months)	Side effects (none unless noted)
Asperger's disorder	Generalized anxiety disorder	20	M	Fluoxetine	Possibly 40 (unknown)	Escitalopram	4	3	Disc. Med.	A
						Bupropion
						Lorazepam
Asperger's disorder	Adjustment disorder with mixed anxiety and depressed mood	17	M	Fluoxetine	20	Sertraline	5	2	2
Asperger's disorder	Generalized anxiety disorder	16	F	Fluoxetine	20	Paroxetine	5	2	1
Asperger's disorder	Anxiety disorder NOS; depressive disorder NOS	8	M	Fluoxetine	10	None	5	2	2	B
Autistic disorder	Anxiety disorder NOS; disruptive behavior disorder NOS	14	F	Sertraline	20	Fluoxetine	4	1	3
Autistic disorder	Anxiety disorder NOS; disruptive behavior disorder NOS; depressive disorder NOS	13	M	Citalopram	15	None	5	2	6
Asperger's disorder	OCD	17	M	Sertraline	50	None	5	2	1
PDD-NOS	Anxiety disorder NOS	10	M	Sertraline	10	None	4	2	5	C
Autistic disorder	Anxiety disorder NOS	12	M	Fluoxetine	28	None	4	3	3	D
PDD-NOS	Anxiety disorder due to a medical condition; Fragile X syndrome	9	M	Citalopram	40	Guanfacine	5	4	1
PDD-NOS		9	M	Citalopram	40	Fluoxetine	5	4	1
PDD-NOS	Anxiety disorder NOS; major depressive disorder; eating disorder NOS	19	F	Fluoxetine	40	None	5	2	2
PDD-NOS	Anxiety disorder NOS; OCD	11	F	Fluoxetine	20	None	5	4	4
PDD-NOS	OCD; disruptive behavior disorder NOS	12	F	Fluoxetine	30	None	5	2	3
PDD-NOS	Anxiety disorder NOS; depressive disorder NOS; disruptive behavior disorder NOS	18	F	Fluoxetine	20	Escitalopram	4	2	2
Autistic disorder	Specific phobia	15	M	Fluoxetine	20	Aripiprazole	5	6	Disc. Med.	E
Asperger's disorder	Separation anxiety disorder; OCD	6	M	Sertraline	80	None	6	2	2
Autistic disorder	Anxiety disorder NOS	8	M	Citalopram	20	Escitalopram	5	2	3
						Aripiprazole Sertraline
						Buspirone
Autistic disorder	Panic disorder with agoraphobia	4	F	Fluoxetine	8	None	6	2	1
PDD-NOS	ADHD inattentive type; depressive disorder NOS; “Anxiety/Depression”^a	19	M	Fluoxetine	20	None	4	2	1
Asperger's disorder	Generalized anxiety disorder	11	M	Sertraline	50	None	5	2	1
Asperger's disorder	Panic disorder without agoraphobia; anxiety disorder NOS	12	M	Fluoxetine	20	Lorazepam	6	2	1
Asperger's disorder	Panic disorder without agoraphobia; anxiety disorder NOS	12	M	Fluoxetine	20	Diphenhydramine	6	2	1
Autistic disorder	Disruptive behavior disorder NOS; unspecified anxiety disorder; trichotillomania	13	F	Fluoxetine	6	None	5	2	2
Asperger's disorder	Rule out social phobia; ADHD inattentive subtype; transient Tic disorder	13	M	Citalopram	15	None	5	2	3
Asperger's disorder	Anxiety disorder NOS	17	F	Citalopram	20	None	6	2	1
Asperger's disorder	Generalized anxiety disorder; depressive disorder NOS	15	F	Sertraline	100	None	6	2	1
PDD-NOS	Separation anxiety disorder; anxiety disorder NOS; ADHD NOS	9	M	Sertraline	18.75	Mirtazapine	6	3	Disc. Med.	F
						Sertraline
						Aripiprazole
						Risperidone
						See A
Asperger's disorder	Anxiety disorder NOS	17	M	Sertraline	100	None	6	3	4
PDD-NOS	Anxiety disorder NOS	17	M	Citalopram	40	Sertraline	4	3	2
Asperger's disorder	OCD	13	F	Sertraline	50	Fluoxetine	7	5	Disc. Med.	G
Asperger's disorder	OCD	13	F	Sertraline	50	Sertraline	7	5	Disc. Med.	G

A = Vivid dreams.

B = Possible activation.

C = Irritability.

D = Moodiness and crying.

E = Strange behavior (sitting in house and placing blanket on head).

F = Whininess and frustration.

G = Agitation.

Medical chart does not specifically diagnose an anxiety disorder, but treatment notes indicate concerns with “anxiety/depression.”

ADHD, attention-deficit/hyperactivity disorder; ASD, autism spectrum disorder; CGI-S, Clinical Global Impressions Severity; OCD, obsessive compulsive disorder; PDD-NOS, pervasive developmental disorder–not otherwise specified; SSRI, selective serotonin reuptake inhibitor.

Adverse events

Seven of the patients or caregivers reported side effects that were felt to possibly relate to the SSRI. Of these, four discontinued their medication before the conclusion of the 7–12-month mark; the remaining three who reported side effects continued treatment. Side effects included vivid dreaming, increased emotional lability, and irritability. In general, the medication was well tolerated, with only a single report of possible activation and two reports of increased irritability or agitation.

Prior SSRI use

Ten of the patients in this chart review had participated in a prior SSRI trial, and all had been discontinued due to AEs or poor response. Of these individuals, five were deemed to be responders (CGI-I of 1 or 2 at 12 months). AEs were reported by three of the five nonresponders.

Age

The sample was split into two groups: ≤12 years of age and ≥13 years of age. This split in age was used to examine the possibility that adolescents and children might respond differentially. Among the younger group, 50% (6 out of 12) were deemed to be clinical responders. Conversely, among the older group, 59% (10 out of 17) were given a CGI-I score of 1 or 2.

ASD severity

Of the seven individuals with a diagnosis of autistic disorder, only 2 (29%) were found to be clinical responders. Conversely, 69% with a diagnosis of Asperger's disorder (9 of 13 individuals) were found to be responders and 67% of those with a diagnosis of PDD-NOS (6 of 9 individuals) were deemed to be clinical responders.

Baseline CGI-S

Of the individuals with a baseline CGI-S score of 4, 43% (3 of 7) were deemed to be responders. Conversely, of the individuals with a baseline CGI-S score ≥5, 59% (13 of 22) were rated as responders to treatment.

Discussion

The current chart review adds to the available literature on the efficacy of SSRI treatment for children and adolescents with ASD. Unlike many of the prior studies of SSRIs in the ASD population, the focus of this chart review was exclusively on treating anxiety disorders. The overall response rate of 55% suggests that a good number of families of children and adolescents placed on SSRIs for the treatment of anxiety report clinically significant symptom improvement. In general, those who responded well after 2–6 months of treatment continued to do well at the 7–12-month assessment. In addition, AEs were relatively low, with 4 of 29 (14%) individuals discontinuing SSRI treatment due to side effects. The chart review was limited to those receiving SSRI monotherapy, thereby eliminating possible interactions with other medications. As a result, only 29 charts were identified out of well over a 100 charts of individuals prescribed SSRIs in combination with other concomitant psychotropic medications.

The findings suggest that children and adolescents who may have failed an earlier SSRI trial for anxiety might still benefit from a trial with an alternative SSRI. In this case, 50% of those who were not SSRI-naive were deemed to be treatment responders. There was also a trend for those rated with more severe anxiety at baseline to be more responsive than those rated with mild anxiety at baseline. In terms of age, response rates appeared to be slightly higher for teenagers than for younger children with ASD (possibly due to developmental changes in brain serotonin function, resulting in greater serotonin maturity). Finally, the fact that almost half of the adolescents (those ages 13 and older) in the sample were female (vs. only one quarter among the preadolescents) suggests that internalizing disorders, such as anxiety, may be more frequently reported among older versus younger girls with ASD.

In terms of ASD severity, it appears that those with more severe symptoms (i.e., diagnoses of autistic disorder) were the least responsive to SSRI treatment. A diagnosis of autistic disorder not only indicates greater symptom severity but also could be associated with more limited language and greater difficulty related to symptom severity and treatment response. It is also possible that diagnosing anxiety disorders in individuals with more severe ASD is more challenging for clinicians and that there is a greater risk of incorrectly attributing behaviors of concern as symptoms of anxiety. Future prospective studies of SSRIs should assess the impact of ASD symptom severity on treatment response.

Overall, SSRIs were well tolerated by the children and adolescents in this study. The response rate of 55% was consistent with some prior reports (both controlled and uncontrolled trials) of SSRIs targeting RRBs and broader symptom complexes (DeLong et al. 2002; Hollander et al. 2006), but higher than that reported by other chart reviews (Henry et al. 2006, 2009). For example, in an open-label trial of 129 children with ASD (ages 2–8 years) treated with fluoxetine targeting core features of ASD, Delong et al. (2002) reported that 69% were responders. Conversely, in the Henry et al. (2006, 2009) chart reviews, the targets were defined more broadly to include anxiety, perseverations, aggression, or mood symptoms. In Henry et al. (2006), the CGI scale was used to rate clinical response for 89 children and adolescents with a DSM-IV diagnosis of PDD who were receiving SSRI treatment. It was found that 44.9% of the children received CGI-I ratings of “much improved” and were considered to be responders. However, 35.4% of the cohort reported adverse side effects. A subsequent chart review was conducted by Henry et al. (2009) with similar sample characteristics (n = 22), but it was designed to assess the effectiveness of a second trial of SSRI after an initial treatment failure. In this second study, the same CGI-I rating of “much improved” was assigned to 31.8% of the sample, with 68.2% demonstrating adverse side effects.

The current study's findings also differed considerably from the results of three randomized-controlled trials, all of which targeted RRBs in children with ASD (McDougle et al. 2000; Autism Speaks 2009; King et al. 2009). King et al. (2009) reported a citalopram response rate of 32.9% versus a placebo response rate of 34.2% in a placebo-controlled randomized trial to treat RRBs. Similar negative findings have been reported in two other RCTs (McDougle et al. 2000; Herscu et al., in press). In contrast, in a controlled trial of 34 children (ages 5–16 years) with ASD and RRBs treated with fluoxetine, 56% received a CGI-I of “much improved” or “very much improved” (Hollander et al. 2005). The 55% response rate reported in this study is similar to that of Hollander et al. (2005), although treatment targets were defined somewhat differently.

Limitations

The most significant study limitation was that this was a retrospective chart review of only 29 children and adolescents. The information available to the CGI raters was inconsistent, including the limited use of any standardized questionnaires. The sample included individuals who were SSRI naive as well as those who had previously failed an SSRI trial. Participants were prescribed a range of SSRIs, rather than limiting the chart review to a single SSRI. In addition, dosing and titration practices differed across the prescribing physicians. As this was only a chart review, no specific information on intelligence quotient (other than that the patient may have had intellectual disability) and its potential impact on response was able to be assessed. The impact of cognitive functioning level on SSRI response is an area for future exploration. In addition, ASD diagnoses were based on information contained in the medical record and participants had not necessarily been diagnosed by using gold standard assessment practices. Similarly, there were no standardized measures to assess anxiety and participants represented a wide range of anxiety diagnoses, including anxiety disorder NOS, generalized anxiety disorder, OCD, and panic disorder. Finally, our criteria for study inclusion were 2 months of SSRI treatment and a follow-up clinic visit within 2–6 months after initiation of SSRI treatment. Therefore, it is possible that some individuals experienced side effects or simply discontinued medication (possibly due to lack of efficacy) and chose not to return for a follow-up visit. As a result, our reported response rate (which does not include such individuals) could be inflated.

Conclusions

This chart review of 29 children and adolescents with ASD treated with SSRI monotherapy for anxiety disorders found 55% of the sample to be clinical responders at the 4- and 9-month follow-up. Overall, the SSRIs were well tolerated. Although this chart's review findings suggest that SSRI treatment should be a consideration for individuals with ASD and anxiety disorders, even if prior SSRI trials have been unsuccessful, results from other studies suggest this be done with caution.

Clinical Significance

Although the literature remains highly inconsistent, the results of the current chart review suggest that consideration should be given to using SSRIs to treat anxiety symptoms in this population. This study documented a 55% response rate to SSRI treatment, an adequate AE profile, and no reports of activation. Also of note was a 50% response rate for individuals who had failed prior SSRI trials. This is a higher response rate than suggested by prior studies of SSRI retrial (Henry et al. 2009), suggesting that it might be reasonable to consider a second SSRI if an initial trial proves unsuccessful. Finally, it appears that for adolescents (vs. children), individuals with less severe ASD symptoms and those with more severe anxiety-related symptoms are the most likely to evidence a positive response to SSRI treatment.

Footnotes

Disclosures

The authors have received research funding from the following: Dr. Handen: Curemark, Neuropharm, Lilly, Forest, Bristol Myers Squibb, Roche, Pediamed, and Pfizer. Dr. Laughlin: Moderna Therapeutics, Inc., Dr. Thorkelson, Dr. Turner, and Ms. Ober report no biomedical financial interests or potential conflicts of interest.

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