Efficacy of Low-Dose Buspirone for Restricted and Repetitive Behavior in Young Children with Autism Spectrum Disorder: A Randomized Trial

Efficacy of Low-Dose Buspirone for Restricted and Repetitive Behavior in Young Children with Autism Spectrum Disorder: A Randomized Trial Diane C. Chugani, PhD1,2, Harry T. Chugani, MD1,2,3, Max Wiznitzer, MD4, Sumit Parikh, MD5, Patricia A. Evans, MD, PhD6, Robin L. Hansen, MD7, Ruth Nass, MD8,9, James J. Janisse, PhD10, Pamela Dixon-Thomas, PhD1, Michael Behen, PhD1,2, Robert Rothermel, PhD11, Jacqueline S. Parker, BSc1,2, Ajay Kumar, MD, PhD1,2,3,12, Otto Muzik, PhD1,2,3,12, David J. Edwards, PharmD13, and Deborah Hirtz, MD14, on behalf of the Autism Center of Excellence Network* Objectives To determine safety and efficacy of the 5HT1A serotonin partial agonist buspirone on core autism and associated features in children with autism spectrum disorder (ASD).

Study design Children 2-6 years of age with ASD (N = 166) were randomized to receive placebo or 2.5 or 5.0 mg of buspirone twice daily. The primary objective was to evaluate the effects of 24 weeks of buspirone on the Autism Diagnostic Observation Schedule (ADOS) Composite Total Score. Secondary objectives included evaluating the effects of buspirone on social competence, repetitive behaviors, language, sensory dysfunction, and anxiety and to assess side effects. Positron emission tomography measures of tryptophan metabolism and blood serotonin concentrations were assessed as predictors of buspirone efficacy. Results There was no difference in the ADOS Composite Total Score between baseline and 24 weeks among the 3 treatment groups (P = .400); however, the ADOS Restricted and Repetitive Behavior score showed a time-by-treatment effect (P = .006); the 2.5-mg buspirone group showed significant improvement (P = .003), whereas placebo and 5.0-mg buspirone groups showed no change. Children in the 2.5-mg buspirone group were more likely to improve if they had fewer foci of increased brain tryptophan metabolism on positron emission tomography (P = .018) or if they showed normal levels of blood serotonin (P = .044). Adverse events did not differ significantly among treatment groups. Conclusions Treatment with 2.5 mg of buspirone in young children with ASD might be a useful adjunct therapy to target restrictive and repetitive behaviors in conjunction with behavioral interventions. (J Pediatr 2015;-:---). Trial registration ClinicalTrials.gov: NCT00873509.

A

utism spectrum disorder (ASD) is a neurodevelopmental condition characterized behaviorally by impairment in social communication and the presence of repetitive and restricted behaviors. Current evidence suggests that the risk for ASD is conferred by rare variants in hundreds of genes that converge on networks related to neuronal signaling and development.1 Although there are hundreds of genes that place individuals at risk for autism, it is striking that 30%-50% From the Carman and Ann Adams Department of of individuals with ASD show an elevated concentration of serotonin in the Pediatrics, Wayne State University School of Medicine; blood.2-5 Alterations in serotonin receptors and serotonin synthesis/degradation Children’s Hospital of Michigan; Department of Neurology, Wayne State University School of Medicine, enzymes are involved in the risk for ASD.6 Evidence also exists for altered seroDetroit, MI; Neuroscience Institute, University Hospitals Case Medical Center, Rainbow Babies and Children’s tonin mechanisms in humans and in animal models in which genetic changes Hospital; Cleveland Clinic Neurogenetics & Metabolism, Neuroscience Institute Lerner College of Medicine-Case associated with ASD are not directly related to serotonin function,7-10 as well Western Reserve University, Cleveland, OH; as with environmental exposures linked with ASD, such as in utero exposure Departments of Neurology and Pediatrics, University of 11,12 13 Texas Southwestern Medical Center, Children’s Medical to the anticonvulsant sodium valproate and prenatal viral infections. Center of Dallas, Dallas, TX; Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, Thus, there is strong evidence that serotonin mechanisms may be influenced Department of Pediatrics, University of California Davis, by disparate genetic and environmental risks for ASD. Davis, CA; Departments of Neurology and Child and 1

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3

4

5

6

7

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1-PP ABC ADI-R ADOS ADOS-CTS

1-pyrimidylpiperazine Aberrant Behavior Checklist Autism Diagnostic InterviewRevised Autism Diagnostic Observation Schedule Autism Diagnostic Observation Schedule Composite Total Score

ADOS-RRB ADOS-SA AMT ASD PET RBS SUV

ADOS Restricted and Repetitive Behavior Autism Diagnostic Observation Schedule Social Affect a[11C]methyl-L-tryptophan Autism spectrum disorder Positron emission tomography Repetitive Behaviors ScaleRevised Standard uptake value

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Adolescent Psychiatry, New York University Langone Medical Center, New York, NY; Departments of 10Family Medicine and Public Health Sciences, 11Psychiatry and Behavioral Neurosciences, and 12Radiology, Wayne State University School of Medicine, Detroit, MI; 13 School of Pharmacy, University of Waterloo, Waterloo, Ontario, Canada; and 14National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD *List of members of the Autism Center of Excellent Network is available at www.jpeds.com (Appendix). Supported by the National Institute of Neurological Disorders and Stroke (cooperative agreement 5U01 NS61264). The authors declare no conflicts of interest. 0022-3476/Copyright ª 2015 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/). http://dx.doi.org/10.1016/j.jpeds.2015.11.033

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The present study was designed on the basis of in vivo imaging data in children with ASD that demonstrated a deviation from the normal developmental time course of changes in serotonin synthesis measured by the tryptophan analog a[11C]methyl-L-tryptophan (AMT) on positron emission tomography (PET) imaging.14,15 Because serotonin function is important in postnatal brain development,16 we hypothesized that one approach to the treatment of core features of ASD pharmacologically would be the use of serotonin agonists in children younger than 6 years of age, when their brain serotonin synthesis capacity is lower than in children without ASD. Agonists of the 5HT1A receptor have been shown to improve social function in disparate animal models of ASD.17-19 In the present study, the 5HT1A serotonin partial agonist buspirone was used to target core symptoms during the developmental period of low serotonin synthesis capacity in children with ASD as measured with PET. For this study, we chose the 5HT1A serotonin partial agonist buspirone for a number of reasons. Several small studies of buspirone in older children with autism showed efficacy in some children, with low incidence of adverse events.20-22 Furthermore, buspirone is approved by the Food and Drug Administration for the treatment of anxiety in children, and anxiety increasingly is recognized as a comorbid condition in ASD.23 Previously, we had assessed the disposition of buspirone in 2- to 6-year-old children to establish dosing guidelines for this population.24 Children with a diagnosis of autism received a single, oral dose of buspirone solution (2.5 mg or 5.0 mg). We found plasma concentrations and pharmacokinetic measurements for buspirone and the metabolite 1-pyrimidylpiperazine (1-PP) with 2.5-5.0 mg doses to be similar to values observed in older children receiving 7.5-15.0 mg doses. In the present study, before drug treatment, subjects underwent PET scanning and blood studies to evaluate whether the response to buspirone can be predicted by brain tryptophan metabolism or blood serotonin levels.

Vol. -, No. Autism Diagnostic Observation Schedule (ADOS)26 via use of the revised algorithms27 with the following cutoff scores for the ADOS: Module 1, no words cutoff = 14; Module 1, some words cutoff = 10; Module 2, younger cutoff = 8; Module 2, older cutoff = 8; Module 3, cutoff = 7. Exclusion criteria were the presence or history of neurologic disorders, including seizure disorders, phenylketonuria, tuberous sclerosis complex, Rett syndrome, Fragile X syndrome, Down syndrome, and traumatic brain injury, and other medical or behavioral problems that required medications that are centrally active. Additional exclusion criteria were renal or hepatic disease, treatment with drugs known to alter the activity of CYP3A4, use of centrally acting drugs during the 6 weeks before or during the study, and previous treatment for periods longer than 2 weeks with buspirone or selective serotonin reuptake inhibitors. Participants who used a stable dose of melatonin for sleep before entry into the study were allowed to continue use during the study.

Methods

Treatment Buspirone hydrochloride U.S.P. (Fermion, Espoo, Finland) or placebo dissolved in Orasweet (2.5 mg/mL or 5.0 mg/ mL; Paddock Laboratories Inc, Minneapolis, Minnesota) was administered once per day in the evening for the first week of treatment and thereafter twice a day, approximately 12 hours apart, for 23 weeks during the placebo-controlled phase. Patients who received buspirone during the first phase were continued on the same dose during the second phase. Patients receiving placebo were randomized to 2.5 mg or 5.0 mg buspirone for the 24-week second phase. Within each site, participants were randomized in blocks for age groups (2 to <4 years and 4 to <6 years) to treatment groups of 2.5 mg, 5 mg, or placebo. Drug compliance, as assessed by measuring the volume of unused drug, showed that for 61% of the subjects there was 100% compliance, 27% had compliance between 90% and 100%, 7% had compliance between 80% and 90%, and 4% had less than 80% compliance. All site personnel were blinded to treatment during both phases of treatment. A medical monitor at a different site not involved in the enrollment of participants evaluated the adverse events.

The study and was conducted at 6 academic medical centers: Wayne State University School of Medicine, Children’s Hospital of Michigan; Case Western Reserve University, Rainbow Babies Hospital; University of Texas Southwestern; Cleveland Clinic Foundation; University of California Davis; and New York University School of Medicine. All study-site institutional review boards approved the study, and written informed consent was obtained for each participant from at least 1 parent or legal guardian. The National Institutes of Neurological Disorders and Stroke established a Data and Safety Monitoring Board to monitor the trial. Participants (N = 166, 2 to <6 years) with ASD were included based on criteria from the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision, the Autism Diagnostic Interview-Revised (ADI-R),25 and the

Efficacy Measures Efficacy measures assessed at baseline, 24 weeks, and 48 weeks included scores derived from several measures, including the ADOS, Vineland Adaptive Behavior Scales-Second Edition,28 Aberrant Behavior Checklist (ABC),29,30 Repetitive Behaviors Scale-Revised (RBS),31 Sensory Profile Scale,32 Leiter Parent-Report,33 and the Children’s Yale Brown Obsessive Compulsive Scale, Modified for Pervasive Developmental Disorders.34 Global cognitive functioning was measured at baseline by the use of either the Mullen Scales of Early Learning35 or the Differential Abilities Scales-Second Edition.36 Clinicians who completed research training were required to demonstrate 90% reliability with a consensuscoded protocol of an ADI-R recording and 80% reliability with a consensus coded protocol of a Module 1 or 2 and

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- 2015 Module 3 ADOS recording. Every third ADOS was reviewed for fidelity, and clinicians were given written feedback regarding the fidelity of their administrations and coding. PET Scan Protocol and Image Data Analyses PET studies with the tracer AMT were performed before treatment with the use of an EXACT/HR whole-body positron tomography (CTI/Siemens, Knoxville, Tennessee) at Children’s Hospital of Michigan as previously described.14 The calculation of the unidirectional uptake rate constant for AMT (K-complex) was obtained via the Patlak graphical approach.37 Standard uptake value (SUV) images were used to determine whether there were focal regions of increased AMT uptake. A nuclear medicine physician blinded to treatment results assessed each SUV scan and tabulated the location(s) of increased AMT uptake. For comparison with outcome, the data were coded from 0 to 3 to indicate the number of regions of focal increased tracer uptake in each participant. Furthermore, visual analyses for focal AMT uptake were verified by semiquantitative assessment in basal ganglia and thalamus by obtaining mean SUV bilaterally for manually defined regions of interest. Adverse Events and Laboratory Measures Adverse events were assessed monthly with the Safety Monitoring Uniform Report Form and once between monthly visits using a structured interview. Pulse, blood pressure, and weight were measured monthly. A physical examination was conducted at baseline, 4, 24, 28, and 48 weeks. Hematology, renal function, and liver function laboratory tests, and buspirone and 1-PP levels were measured at 4, 12, 24, 28, 36, and 48 weeks as described previously.24 Mean buspirone levels for cases in which drug was detected were 0.14  0.24 ng/mL for the 2.5-mg group and 0.22  0.55 ng/mL for the 5.0-mg group. Mean 1-PP levels for cases in which drug was detected were 0.78  0.87 ng/mL for the 2.5-mg group and 1.08  1.22 ng/mL for the 5.0-mg group. Blood for serotonin concentration was collected at baseline and assayed by high-pressure liquid chromatography by ARUP Laboratories (Salt Lake City, Utah; coefficient of variation = 8.9, normal range less than 220 ng/mL). Statistical Analyses To assess the primary outcome of the impact of buspirone on the ADOS Composite Total Score (ADOS-CTS), we performed a 3  2 mixed-design ANOVA with the 3 treatment groups as between-subjects factors and the 2 assessment time points (baseline and 24 weeks) as the within-subjects factor. Secondary outcomes included social competence and deviance (ADOS Social Affect [ADOS-SA] score, Vineland socialization domain, ABC scale II), language competence and deviance (Vineland communication domain, ABC scale V), repetitive behavior (ADOS Restricted and Repetitive Behavior [ADOS-RRB] score, RBS total score, Children’s Yale Brown Obsessive Compulsive Scale, Modified for Pervasive Developmental Disorders total score), anxiety

ORIGINAL ARTICLES (composite of ABC scale I and Leiter Emotion regulation score), and sensory processing (Sensory Profile, Multisensory score) by use of the same statistical analysis as the primary objective. Measures were analyzed separately and as composites. Brain and blood serotonin biomarker predictor analyses included K-complex values and the number of focally increased AMT SUV based on AMT PET imaging and blood serotonin concentration measured at baseline. For outcomes that showed an improvement attributable to treatment with buspirone, the change from baseline to 24 weeks was calculated as an improvement score. Each of the outcome variables was analyzed separately. To determine whether improvement was related to K-complex, number of regions of focally increased AMT uptake and blood serotonin, bivariate analyses, and linear multiple regression were performed. Statistical analysis for adverse events was grouped into classes, differences between the groups were tested with the Fisher exact test. The SAS program Proc freq (SAS Institute Inc, Cary, North Carolina) was used with the option of exact chisq.

Results Enrollment for the study began on July 14, 2009, and was completed on January 8, 2013. Two hundred ten children were consented and assessed for eligibility into the study, and 166 eligible children were enrolled in the study and randomized to 3 treatment groups: 2.5 mg buspirone (n = 54), 5.0 mg buspirone (n = 55), and placebo (n = 57) (Figure 1; available at www.jpeds.com). Twenty-four participants (14%) discontinued the study during the treatment phase (adverse event [n = 12, 6 in the placebo group, 3 in the 2.5-mg group, 3 in the 5.0-mg group], withdrew consent [n = 3], lost to follow-up [n = 3], started exclusionary medication [n = 2], clinical decision [n = 2], participant moved [n = 1], time commitments [n = 1]). Outcome data could not be obtained for 11 of 24 subjects who discontinued early because families declined to return for the final visit testing or were lost to follow-up (3 in the 2.5-mg group, 3 in the 5.0-mg group, and 5 in placebo group). Of the 142 participants who completed the first phase of the trial, 138 were rerandomized to the second phase (Figure 1). The 2.5-mg, 5.0-mg, and placebo groups showed no significant differences at baseline in sex, age, ethnicity or race, ADOS, ADI-R, Vineland Adaptive Scale age equivalents, and Mullen Scales of Early Learning or Differential Abilities Scales-Second Edition (Table I). Efficacy

ADOS-CTS, ADOS-SA, and ADOS-RRB Scores. For the main outcome measure, there was significant improvement with time (P = .002) but no difference in the change in ADOS-CTS scores between baseline and 24 weeks among the 3 treatment groups (P = .400; Table II). For the secondary outcomes, the ADOS-SA scores showed significant improvement with time (P = .006) but no

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Table I. Participant demographics and baseline group characteristics Characteristics Sex, n (%) Female Male Age, 2 to <4 y n Mean (SD) Age, 4 to <6 y n Mean (SD) Ethnicity, n (%) Hispanic or Latino Not Hispanic or Latino Unknown or not reported Race American Indian or Alaskan Asian Black or African American Hawaiian or Pacific Islander White More than one race Unknown or not reported ADOS Module 1: no words n Mean (SD) ADOS Module 1: some words n Mean (SD) ADOS Module 2: Younger n Mean (SD) ADOS Module 2: Older n Mean (SD) ADOS Module 3: Total n Mean (SD) ADI-R-A n Mean (SD) ADI-R-B (Verbal) n Mean (SD) ADI-R-B (Non-Verbal) n Mean (SD) ADI-R-C n Mean (SD) Differential Abilities Scale score n Mean (SD) Mullen Scales of Early Learning n Mean (SD)

2.5 mg (n = 54)

5.0 mg (n = 55)

Placebo (n = 57)

P value

8 (15) 46 (85)

11 (20) 44 (80)

10 (18) 47 (82)

.779

25 2.5 (0.51)

23 27 (0.49)

25 2.7 (0.48)

.475

29 4.4 (0.50)

32 4.5 (0.51)

32 4.3 (0.46)

.129

9 (17) 44 (81) 1 (2)

3 (5) 52 (95) 0 (0)

4 (7) 53 (93) 0 (0)

.237

1 (2) 1 (2) 17 (31) 1 (2) 31 (57) 2 (4) 1 (2)

0 (0) 0 (0) 18 (33) 1 (2) 31 (56) 5 (9) 0 (0)

0 (0) 1 (2) 16 (28) 1 (2) 35 (61) 2 (4) 2 (4)

.718

20 21.9 (3.29)

22 20.5 (2.97)

27 21.7 (3.86)

.358

22 17.5 (4.70)

23 17.3 (3.44)

18 18.8 (4.49)

.468

7 14.4 (3.64)

4 15.3 (4.65)

9 14.4 (5.59)

.956

0 0

3 15.7 (3.79)

2 23.0 (1.41)

.087

5 12.4 (6.19)

3 16.3 (3.21)

1 8.0

.413

54 19.3 (4.73)

55 18.4 (5.21)

57 19.1 (4.52)

.621

22 16.5 (4.07)

22 15.1 (3.35)

24 15.6 (2.95)

.398

32 11.7 (2.12)

33 11.8 (2.05)

33 11.6 (2.24)

.889

54 5.7 (2.38)

55 5.5 (2.33)

57 5.9 (2.05)

.739

4 71.8 (40.62)

3 65.3 (33.62)

4 63.8 (36.88)

.952

33 62.5 (18.80)

34 64.6 (23.90)

35 65.2 (21.73)

.862

difference between treatment groups (P = .865). In contrast, the ADOS-RRB scores showed a significant time by treatment effect (P = .006). There was evidence of an improvement in the 2.5-mg group (P = .003), and the 5.0-mg group (P = .122), and the placebo group (P = .346) showed no change over time (Figure 2, A).

Secondary Measures. There was a significant time by treatment effect on the RBS total score (P = .017; Table II). The 2.5-mg group showed improvement (P < .001), and 4

the placebo (P = .197) and 5.0-mg (P = .437) groups showed no significant change during the treatment period. At baseline, however, the 2.5-mg group was significantly worse on the RBS than the 5.0-mg (P = .002) and placebo (P = .040) groups, but at 24 weeks these groups were no longer statistically different (P = .082 and P = .405, respectively). The Anxiety Composite showed a significant time by treatment effect (P = .041; Table II). For the Anxiety Composite score, the 2.5-mg group (P < .001) and the placebo group (P = .004) showed improvement, and Chugani et al

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ORIGINAL ARTICLES

Table II. ADOS Results and Secondary Outcomes Placebo, baseline

Placebo, 24 wk

2.5 mg, baseline

2.5 mg, 24 wk

ADOS-CTS

19.6 (0.6)

18.3 (0.7)

ADOS-SA

15.0 (0.5)

ADOS-RRB

4.7 (0.3)

18.6 (0.7) .039 14.1 (0.6) .069 4.4 (0.3) .346 72.4 (1.7) .255 11.0 (1.1) .001 69.7 (2.2) .418 3.9 (0.5) .682 34.2 (3.2) .197 11.2 (0.6) .143 0.242 (0.1) .004 66.7 (3.6) .678

16.2 (0.7) .009 13.3 (0.6) .242 3.5 (0.03) .003 70.4 (1.7) .228 12.1 (1.1) .001 68.2 (2.3) .052 4.1 (0.5) .288 38.0 (3.3) <.001 11.1 (0.6) .052 0.118 (0.1) <.001 59.6 (3.6) .750

Social Competence (Vineland socialization domain)

70.4 (1.5)

Social deviance (ABC scale II)

14.2 (1.2)

Language Competence (Vineland communication domain) Language deviance (ABC Subscale V)

68.5 (2.2)

Repetitive behavior (RBS total)

36.7 (3.5)

Compulsive behaviors (CYBOCS total score)

11.9 (0.6)

Anxiety composite score (ABC subscale I, Leiter emotion regulation) Sensory processing (Sensory Profile Multisensory score)

3.8 (0.5)

0.008 (0.1) 65.4 (3.7)

13.9 (0.5) 4.4 (0.3) 68.7 (1.5) 15.3 (1.2) 65.5 (2.2) 4.4 (0.5) 46.9 (3.5) 12.1 (0.6) 0.536 (0.1) 58.6 (3.8)

5.0 mg, baseline 18.4 (0.6) 14.2 (0.5) 4.1 (0.3) 71.0 (1.5) 11.8 (1.2) 70.6 (2.2) 3.7 (0.5) 31.5 (3.5) 11.5 (0.6) 0.014 (0.1) 67.2 (3.7)

5.0 mg, 24 wk 17.9 (0.7) .431 13.4 (0.6) .063 4.6 (0.3) .122 72.3 (1.7) 10.6 (1.1) .218 72.7 (2.2) .119 3.5 (0.4) .728 29.9 (3.3) .437 10.7 (0.6) .104 0.120 (0.1) .214 68.1 (3.5) .776

Significance time by treatment .400 .002 .865 .006 .006 .154 .982 .057 .204 <.001 .709 .013 .579 .560 .017 <.001 .936 .004 .041 <.001 .995 .557

CYBOCS, Children’s Yale Brown Obsessive Compulsive Scale, Modified for Pervasive Developmental Disorders. Values are mean (SD), and P value unless otherwise stated. Bold values indicate statistical significance.

there was no significant improvement in the 5.0-mg (P = .214) group. Similar to the RBS score, the 2.5-mg group was significantly worse at baseline for the Anxiety Composite compared with the 5.0-mg and placebo groups. None of the other measures showed significant time by treatment effects.

Brain AMT PET and Plasma Serotonin as Predictors of Drug Response. Whole-brain serotonin synthesis capacity (K-complex) and presence of focal regions showing elevated AMT SUV in basal ganglia, thalamus, cerebellum, and brainstem were assessed on AMT PET scans, which were acquired in 119 of the study participants, 39 of whom were in the 2.5-mg buspirone group. The whole-brain serotonin synthesis (K-complex) ranged from 0.003 to 0.008 g/mL in the 119 children. In the 2.5-mg buspirone group, the mean K-complex was 0.00581 g/mL for those who improved on the ADOS-RRB and 0.00539 g/mL for those who did not show an improvement (P = .399). For the entire sample having a PET scan (N = 119), 65 showed at least 1 focal region with increased AMT uptake. Focal abnormalities were present in basal ganglia (N = 27), thalamus (N = 24), cerebellum (N = 27), and brainstem (N = 26) (Figure 2, B and D). The 2.5-mg buspirone group was coded as 0 (n = 16), 1 (n = 13), 2 (n = 7), and 3 (n = 3), according to the number of focal increases present in each child. The mean SUV for focal increases in basal ganglia was 0.509  0.095 SD, and the mean SUV was 0.489  0.086 SD for the contralateral region. For the thalamus, increased focal regions had a mean SUV of 0.519  0.091 compared with the contralateral side, with a mean SUV of 0.499  0.087. In subjects with no focal

increases of AMT uptake, mean SUVs for basal ganglia (left: 0.467  0.081, right: 0.471  0.083) and thalamus (left: 0.471  0.087, right: 0.473  0.085) were similar to regions with lower AMT SUV in cases with asymmetry. In a bivariate analysis, the number of focal increases of AMT SUV in the 2.5-mg group was significantly related to improvement on the ADOS-RRB score (r = 0.38, P = .018, n = 39). Fewer focal abnormalities were associated with more improvement (Figure 2, B). Elevated blood serotonin concentration was defined as greater than 220 ng/mL by the clinical laboratory. For the entire sample, N = 60 showed elevated blood serotonin (Figure 2, C). When a t test was used to compare improvement in the ADOS-RRB score for elevated (n = 19) or nonelevated plasma serotonin (n = 31) subjects in the 2.5-mg buspirone group, the subjects with normal blood serotonin concentrations were significantly more likely to improve on the ADOS-RRB score than those with elevated blood serotonin (t = 2.066, P = .044, n = 50). In a multiple regression analysis predicting improvement on the ADOS-RRB (n = 39), the number of focal increases in AMT SUV remained a significant predictor (P = .025), but dichotomous blood serotonin did not (P = .117). The sample size for the multiple regression was smaller because blood serotonin cases in the multiple regression included only those patients who had PET scans, and this may account for less power to detect an effect of blood serotonin as a significant predictor. Adverse Events There was no significant difference in occurrence of any adverse events among the 3 groups (P = .145; Table III

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Figure 2. A, Estimated marginal means for the ADOS-RRB Scale at baseline and after 24 weeks for the 3 treatment groups. B, Improvement in the 2.5 mg group was significantly related to the number of brain regions showing focal increases in AMT SUVs. C, Distribution of blood serotonin concentration. D, AMT SUV Images. The left column displays images from a child with no focal increases in tracer SUV. The other 3 columns show images from children with focally increased tracer uptake denoted by arrows in basal ganglia, thalamus, brainstem and cerebellum. Rt, right; Lt, left.

available at www.jpeds.com). Overall, there was no significant difference in the occurrence of adverse events in the second phase of the study among the treatment groups, including those who were on placebo during the first 24 weeks and subsequently started the drug, compared with those who were taking the drug for the full 48 weeks (P = .600; Table IV available at www.jpeds.com). This finding suggests that long-term treatment with buspirone up to 48 weeks is not associated with increased adverse events. It is notable that there were no differences between the placebo and treatment groups in behavioral activation side effects that have been reported with selective serotonin reuptake inhibitors.38

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Discussion Analyses of the main study outcome indicate that even though buspirone treatment in young children with ASD does not result in decreased overall symptoms of autism as measured by the ADOS-CTS, secondary outcome measures demonstrate significant improvement in repetitive and restricted behaviors on the ADOS-RRB score in children with ASD taking 2.5 mg of buspirone. Buspirone is a 5HT1A partial agonist at both the presynaptic somatodendritic autoreceptors as well as postsynaptic receptors.39-42 A body of literature in animal models has indicated that when used in low doses, 5HT1A agonists preferentially Chugani et al

- 2015 activate presynaptic autoreceptors, whereas greater doses are required to stimulate the postsynaptic receptors.43-46 Thus, the dose dependency for the actions of 5HT1A agonists is attributable to different effects at presynaptic and postsynaptic receptors. This finding is illustrated in studies in rats, where low doses of the 5HT1A agonist 8-OHDPAT specific for the presynaptic receptor suppress locomotion47,48 and greater doses actually increase locomotion.44,49 Similarly, a low dose (1 mg/kg) of buspirone, but not a greater dose (2.0 mg/kg), attenuated apomorphine-induced locomotor stereotypy in rats.50 Buspirone also shows dose dependency in improving social behaviors in animal models of ASD. For example, female prairie voles injected with 8 mg/kg buspirone displayed partner preference, whereas those administered saline or 30 mg/kg buspirone failed to show partner preference.18 Furthermore, buspirone (2 mg/kg) was shown to increase social behavior in the black and tan, brachyuric autism mouse model.17 On the basis of these studies, we suggest that preferential stimulation of the presynaptic autoreceptor could explain why the 2.5-mg buspirone group but not the 5.0-mg buspirone group showed improvement on repetitive and restricted behaviors in our study. In addition to activity at the 5HT1A receptor, buspirone also has activity at the dopamine D2 receptor at greater doses.29,45,46 Activity of buspirone at the D2 receptor may be responsible for loss of the drug effect on stereotyped behavior at the greater dose. Thus, the development of new 5HT1A agonists without D2 activity might be more effective in treating stereotypy, as well as social symptoms and anxiety. A recent report of a new orally active phenylaminotetralinchemotype dual 5HT1A and 5HT7 receptor partial agonist was effective in decreasing motor stereotypy and increasing social interactions with greater efficacy at greater doses in multiple mouse models.51 There are several limitations with regard to the study and its outcome. The first is that the ADOS, the tool used to measure the main outcome, was not designed to measure improvement in the severity of ASD. The ADOS is considered the gold standard for the diagnosis of ASD, and it has been shown to provide stability of diagnosis over time.52 Indeed, several recent studies have demonstrated the diagnostic stability of ADOS in children as young as 15 months of age.53,54 Our study included children as young as 2 years of age. The stability of diagnosis for ASD was demonstrated to be high in toddlers, and there was change with time in the ADOS-SA and -RRB scores.54 Thus, in that study, SA scores tended to improve at a follow-up of at least 12 months, and the RRB scores tended to worsen. The SA scores in our study also improved at 24 weeks’ follow-up in all treatment groups, but this improvement did not differ significantly among the treatment groups. The detection of a drug effect on the ADOS-SA might be hindered by the tendency for this measure to improve in this age group regardless of treatment. For the ADOS-RRB scores, the placebo group and 5.0-mg buspirone groups showed either no change or tended to worsen, consistent with the report of age-related worsening in this domain. In

ORIGINAL ARTICLES contrast, the 2.5-mg buspirone group showed a significant improvement on the ADOS-RRB at 24 weeks (Figure 2, A). Buspirone has long been approved for the treatment of anxiety in children and adults. Several studies have found a relationship between restricted and repetitive behaviors and anxiety.55,56 Determining anxiety in young children with developmental delays relies on the observation of behavior from which inferences of mood states are drawn. Our anxiety composite included not only symptoms of anxiety but also other mood states and regulation of affect. In the present study, there was evidence for improvement on the anxiety composite with 2.5 mg of buspirone, although the placebo group also showed significant improvement for anxiety. In addition, our study sample represents children for whom the etiology of their ASD is not known. We had no genetic measures that could be used to compare outcome with genetic risk or drug metabolism, although children with known genetic disorders such as tuberous sclerosis complex and Fragile X were excluded. Our results, which show high blood serotonin concentrations in ASD, are consistent with the body of literature on blood serotonin and ASD.58 The group with elevated blood serotonin concentrations in our study was significantly less likely to improve on the ADOS-RRB score. We also found that fewer focal increases of AMT SUV were significantly related to more improvement on the ADOS-RRB score in the 2.5-mg buspirone group. Focal abnormalities shown on AMT PET scans in subjects with ASD were first reported as an asymmetry of AMT uptake in thalamus, dentate nucleus of the cerebellum, and frontal cortex.15 Studies on brain tissue obtained at resective surgery from patients without autism but with tuberous sclerosis complex and intractable epilepsy or from patients with brain tumors who had undergone AMT PET scanning revealed that increased AMT uptake may represent tryptophan metabolism by the kynurenine pathway (which is related to brain inflammation) rather than the pathway for serotonin synthesis.57,59 In the current study, semiquantitative analyses support our visual assessment that the asymmetries in basal ganglia and thalamus represent increased tryptophan metabolism, because the mean SUV from cases with no asymmetry had values that were closer to values of the lower side in cases who did show asymmetry. This observation is intriguing in light of accumulating evidence for a role of brain inflammation in ASD, as has been reported in both imaging and neuropathology studies.60-62 Thus, the brain regions showing focally increased AMT SUV may represent tryptophan metabolism by the kynurenine pathway and brain inflammation. If that were the case, and fewer focal increases of tryptophan metabolism are related to more improvement in restricted and repetitive behavior with 2.5 mg of buspirone treatment, a greater number of focal increases may potentially be a predictor of more improvement in ASD in future studies that use anti-inflammatory treatments. Restricted and repetitive behaviors in ASD have been reported to interfere with learning and lead to family stress.56 Recent research indicates that early behavioral intervention

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in young children is effective in improving socialization, language skills, and adaptive behavior, as measured on the Vineland Scales and IQ as measured with the Mullen Scales of Early Learning, but not in improvement on the ADOS or on the Repetitive Behavior Scale.63 The present study has shown that low-dose buspirone reduced restricted and repetitive behaviors in young children with ASD. Therefore, this treatment might be considered for further exploration as a useful adjunct therapy to target restrictive and repetitive behavior in conjunction with early behavioral intervention, which has been shown to be effective in improving socialization, language skills and adaptive behavior, to provide therapeutic coverage for the full range of autism core features and adaptive skills in young children with ASD. n Submitted for publication Jun 15, 2015; last revision received Oct 5, 2015; accepted Nov 11, 2015. Reprint requests: Diane C. Chugani, PhD, Nemours—AI DuPont Hospital for Children, 1600 Rockland Road, ARB 291, Wilmington, DE 19803. E-mail: [email protected]

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- 2015 37. Muzik O, Chugani DC, Chakraborty P, Mangner T, Chugani HT. Analysis of [C-11]alpha-methyl-tryptophan kinetics for the estimation of serotonin synthesis rate in vivo. J Cereb Blood Flow Metab 1997;17:659-69. 38. King BH, Hollander E, Sikich L, McCracken JT, Scahill L, Bregman JD, et al. Lack of efficacy of citalopram in children with autism spectrum disorders and high levels of repetitive behavior: citalopram ineffective in children with autism. Arch Gen Psychiatry 2009;66:583-90. 39. Gozlan H, El Mestikawy S, Pichat L, Glowinski J, Hamon M. Identification of presynaptic serotonin autoreceptors using a new ligand: 3H-PAT. Nature 1983;305:140-2. 40. Pompeiano M, Palacios JM, Mengod G. Distribution and cellular localization of mRNA coding for 5-HT1A receptor in the rat brain: correlation with receptor binding. J Neurosci 1992;12:440-53. 41. Sprouse JS, Aghajanian GK. Responses of hippocampal pyramidal cells to putative serotonin 5-HT1A and 5-HT1B agonists: a comparative study with dorsal raphe neurons. Neuropharmacology 1988;27:707-15. 42. Verge D, Daval G, Marcinkiewicz M, Patey A, el Mestikawy S, Gozlan H, et al. Quantitative autoradiography of multiple 5-HT1 receptor subtypes in the brain of control or 5,7-dihydroxytryptamine-treated rats. J Neurosci 1986;6:3474-82. 43. Blier P, Lista A, De Montigny C. Differential properties of pre- and postsynaptic 5-hydroxytryptamine1A receptors in the dorsal raphe and hippocampus: I. Effect of spiperone. J Pharmacol Exp Ther 1993;265:7-15. 44. Chen NH, Reith ME. Monoamine interactions measured by microdialysis in the ventral tegmental area of rats treated systemically with (+/ )-8-hydroxy-2-(di-n-propylamino)tetralin. J Neurochem 1995;64: 1585-97. 45. Peroutka SJ. Selective interaction of novel anxiolytics with 5hydroxytryptamine1A receptors. Biol Psychiatry 1985;20:971-9. 46. Shireen E, Haleem DJ. Motor effects of buspirone: relationship with dopamine and serotonin in the striatum. J Coll Physicians Surg Pak 2005;15:753-6. 47. Carey RJ, DePalma G, Damianopoulos E, Hopkins A, Shanahan A, Muller CP, et al. Dopaminergic and serotonergic autoreceptor stimulation effects are equivalent and additive in the suppression of spontaneous and cocaine induced locomotor activity. Brain Res 2004;1019:134-43. 48. Carey RJ, Depalma G, Damianopoulos E, Muller CP, Huston JP. The 5-HT1A receptor and behavioral stimulation in the rat: effects of 8-OHDPAT on spontaneous and cocaine-induced behavior. Psychopharmacology (Berl) 2004;177:46-54. 49. Mignon L, Wolf WA. Postsynaptic 5-HT(1A) receptors mediate an increase in locomotor activity in the monoamine-depleted rat. Psychopharmacology (Berl) 2002;163:85-94.

ORIGINAL ARTICLES 50. Ikram H, Haleem DJ. Attenuation of apomorphine-induced sensitization by buspirone. Pharmacol Biochem Behav 2011;99:444-50. 51. Canal CE, Felsing DE, Liu Y, Zhu W, Wood JT, Perry CK, et al. An orally active phenylaminotetralin-chemotype serotonin 5-HT7 and 5-HT1A receptor partial agonist that corrects motor stereotypy in mouse models. ACS Chem Neurosci 2015;6:1259-70. 52. Lord C, Risi S, DiLavore PS, Shulman C, Thurm A, Pickles A. Autism from 2 to 9 years of age. Arch Gen Psychiatry 2006;63:694-701. 53. Chawarska K, Klin A, Paul R, Macari S, Volkmar F. A prospective study of toddlers with ASD: short-term diagnostic and cognitive outcomes. J Child Psychol Psychiatry 2009;50:1235-45. 54. Guthrie W, Swineford LB, Nottke C, Wetherby AM. Early diagnosis of autism spectrum disorder: stability and change in clinical diagnosis and symptom presentation. J Child Psychol Psychiatry 2013;54: 582-90. 55. Gotham K, Bishop SL, Hus V, Huerta M, Lund S, Buja A, et al. Exploring the relationship between anxiety and insistence on sameness in autism spectrum disorders. Autism Res 2013;6:33-41. 56. Rodgers J, Glod M, Connolly B, McConachie H. The relationship between anxiety and repetitive behaviours in autism spectrum disorder. J Autism Dev Disord 2012;42:2404-9. 57. Batista CE, Juhasz C, Muzik O, Kupsky WJ, Barger G, Chugani HT, et al. Imaging correlates of differential expression of indoleamine 2,3-dioxygenase in human brain tumors. Mol Imaging Biol 2009;11:460-6. 58. Gabriele S, Sacco R, Persico AM. Blood serotonin levels in autism spectrum disorder: a systematic review and meta-analysis. Eur Neuropsychopharmacol 2014;24:919-29. 59. Chugani DC, Muzik O. Alpha[C-11]methyl-L-tryptophan PET maps brain serotonin synthesis and kynurenine pathway metabolism. J Cereb Blood Flow Metab 2000;20:2-9. 60. Suzuki K, Sugihara G, Ouchi Y, Nakamura K, Futatsubashi M, Takebayashi K, et al. Microglial activation in young adults with autism spectrum disorder. JAMA Psychiatry 2013;70:49-58. 61. Vargas DL, Nascimbene C, Krishnan C, Zimmerman AW, Pardo CA. Neuroglial activation and neuroinflammation in the brain of patients with autism. Ann Neurol 2005;57:67-81. 62. Morgan JT, Chana G, Pardo CA, Achim C, Semendeferi K, Buckwalter J, et al. Microglial activation and increased microglial density observed in the dorsolateral prefrontal cortex in autism. Biol Psychiatry 2010;68: 368-76. 63. Dawson G, Rogers S, Munson J, Smith M, Winter J, Greenson J, et al. Randomized, controlled trial of an intervention for toddlers with autism: the Early Start Denver Model. Pediatrics 2010;125:e17-23.

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Appendix Members of the Autism Center of Excellence Network include: Wayne State University School of Medicine and Children’s Hospital of Michigan (Detroit, MI): Huiyuan Jiang, MD, Lalitha Sivaswamy, MD, Ginger Steinhilber, RN, Kristin Kennedy, RN, Kathy Pawlik, CNP, Ruth Roeder, PNP, Monica Malian, Hailey Turner, Amira Hanna, Jamie Katusin, Deanna Supula, RN, Stacey Halverson, William Guy, Nore Gjolaj, Thomas Mangner, PhD, Pulak Chakraborty, PhD, Angela Wigeluk, Gregory Patterson, Andrew Mosqueda, Melissa Burkett, Anna DeBoard, RN, Jane Cornett, RN, Mei-li Lee, Xin Lu, Catherine Germain, Marianne Majkowski, DO, Beth French, PNP, Amy Stolinski, Suzi Naguib, PhD, Courtney Wolfe-Christensen, PhD, Sara Taylor, Jamal Ameli, Julie Kemp McQueeney, Michelle Rubinlicht, Bethany Gorka, Erin Zacharski; Case Western Reserve University (Cleveland, OH): Jeffrey L. Blumer, PhD, MD, Kathleen Maxwell, RN, Catherine Tasi, RN, Philip Toltzis, MD, Jolee Kalic, RN, Dianne Morus, RRT, Jany Paulett, Bonnie Rosolowski, RRT, Michael Banchy, RPh, Kathryn Westlake, RPh, Barbara Calabro, CCRP, Carol Tacket, CCRP, Ina Adkins, RN, Kenneth Buchheit, RN, Kathryn Hepper, RN David Speicher, MD, Susan Bergant, RN, Jennifer Haky, Mary Beth Frohnapfel, RN, Cindy Schaefer, RN, Allison Browning; Cleveland Clinic (Cleveland, OH): Roberta Bauer, MD, Rebecca Embacher, Julie Knapp, PhD, Stephanie Levy, Diane Davies, Donna Lach, John Petrich, Rph, MS, Sharon Kreischer, Patty Blubaugh; University of Texas Southwestern (Dallas, TX): Mary Ann Morris, Carolyn Garver, Mariam Andersen, Meredith Greene, Amanda Richards, Maria Rocha, Ruth Merryman, Sailaja Golla, MD, Alan Lorenzen, Julie Long Sherrod, Paulette Perryman, Kara Lorduy; University of California, Davis (Davis, CA): Kathleen Angkustsiri, MD, Lauren Back Plumer, MD, Mary Jacena Siy Leigh, MD, Susan C. Bacalman, MSW, MD, Dorcas Liriano Roa, PhD, Kushma Govindappa, MD, Gayatri Mahajan, MD, Erika Bickel, Norman Brule, Emma Hare, Nadir Sarwary, Dominique Cargill, Joyce Lee, Smiley Hom, Dennis Steindorf, Mandy Pietrykowski, Kindra Root, Sarah Coffey, Elise Phelps Hanzel, PhD Adriana Santana, Clara Ramirez, Stefanie Berci, Nielsen Gabriel; New York University (New York, NY): Glenn Hirsch, MD, Elizabeth Roberts, PsyD, Amanda Zwilling, Resham Gellatly, Dana Levy, PsyD, Sandi Lee, RPh, Jennifer Rodman, Amira Hanna, Nora Oberfield, Susan Friedland; University of Michigan (Ann Arbor, MI): Catherine Lord, PhD (current affiliation Department of Psychology, and Center for Autism and the Developing Brain, New York-Presbyterian Hospital, Weill Cornell Medical College, Columbia University College of Physicians and Surgeons); Altarum Institute (Rockville, MD): Rene Kozloff, RN, PhD, Celeste Crouse, Stephanie Millen, Alex J. Coımbre, BA, MPS, CCRA, Kelly L. McCarter, MA, LPC MHSP. Medical Monitor—David Posey, MD (Indiana University School of Medicine, Indianapolis, IN).

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ORIGINAL ARTICLES Figure 1. CONSORT diagram. DSM-IV-TR, Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision; IVRS, Interactive Voice Response System.

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Table III. Treatment emergent adverse events during first 24 wk A-2.5 mg (n = 54)

B-5.0 mg (n = 55)

Subjects

C-Placebo (n = 57)

Subjects

Subjects

Body system and preferred term

n*

(%)

Events

n*

(%)

Events

n*

(%)*

Events

P value*

All adverse events Psychiatric disorders Aggression Sleep disorder Initial insomnia Agitation Terminal insomnia Affect lability Abnormal behavior Anxiety Respiratory disorders Cough Sinus congestion Rhinorrhea Nasal congestion Epistaxis General disorders Pyrexia Irritability Gastrointestinal disorders Vomiting Diarrhea Constipation Infections and infestations Ear infection Upper respiratory tract infection Nasopharyngitis Nervous system disorders Psychomotor hyperactivity Somnolence Nutrition disorders Decreased appetite Increased appetite Skin disorders Rash Injury, poisoning, and procedural Renal and urinary disorders Eye disorders Immune system disorders Investigations Musculoskeletal disorders Ear and labyrinth disorders

52 42 23 14 9 7 5 8 5 6 38 25 12 15 9 4 38 31 10 32 20 18 5 32 11 6 6 26 15 7 25 17 11 18 8 7 6 7 5 1 5 7

(96) (78) (43) (26) (17) (13) (9) (15) (9) (11) (70) (46) (22) (28) (17) (7) (70) (57) (19) (59) (37) (33) (9) (59) (20) (11) (11) (48) (28) (13) (46) (31) (20) (33) (15) (13) (11) (13) (9) (2) (9) (13)

617 119 30 16 9 8 6 9 5 6 118 48 19 19 16 8 74 47 10 78 28 27 8 69 12 14 9 46 16 15 34 20 11 22 8 12 10 10 6 4 5 7

55 46 15 19 10 7 13 7 1 3 38 23 19 17 5 3 37 24 14 37 23 22 15 22 6 3 4 26 12 6 23 11 16 16 8 6 7 5 3 8 2 3

(100) (84) (27) (35) (18) (13) (24) (13) (2) (5) (69) (42) (35) (31) (9) (5) (67) (44) (25) (67) (42) (40) (27) (40) (11) (5) (7) (47) (22) (11) (42) (20) (29) (29) (15) (11) (13) (9) (5) (15) (4) (5)

608 115 19 26 12 7 15 10 2 4 134 44 38 28 9 3 75 42 17 115 36 30 23 40 6 4 7 36 13 8 29 13 16 23 11 7 8 5 4 8 2 4

53 41 22 13 11 10 5 4 9 1 41 28 18 15 9 7 38 29 15 37 22 20 10 29 8 12 6 26 18 4 22 13 11 19 7 8 7 2 6 5 5 1

(93) (72) (39) (23) (19) (18) (9) (7) (16) (2) (72) (49) (32) (26) (16) (12) (67) (51) (26) (65) (39) (35) (18) (51) (14) (21) (11) (46) (32) (7) (39) (23) (19) (33) (12) (14) (12) (4) (11) (9) (9) (2)

633 119 25 19 14 11 7 4 13 1 137 49 30 25 11 16 80 50 19 88 28 28 15 62 8 26 9 41 21 4 26 15 11 28 10 9 9 5 7 5 9 1

.1455 .3392 .2183 .3826 .9674 .7578 .0481 .4035 .0261 .0927 .9765 .7277 .3370 .8861 .4601 .4411 .9135 .3581 .5635 .6818 .9019 .7737 .0468 .1323 .3971 .0460 .8019 .9804 .5102 .5600 .7088 .3662 .4329 .8735 .9220 .9171 1.0000 .1779 .6494 .0493 .4597 .0500

*Each subject is counted only once per preferred term, at the greatest severity.

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Table IV. Adverse events during wk 25-48 D-2.5 mg (n = 46)

E-5.0 mg (n = 46)

Subjects

Subjects

Placebo-2.5 mg (n = 23) Subjects

Placebo-5.0 mg (n = 23) Subjects

Body system and preferred term

n*

(%)

Events

n*

(%)

Events

n*

(%)

Events

n*

(%)

Events

P value

All adverse events Respiratory disorders Cough Sinus congestion Rhinorrhea Nasal congestion Epistaxis Psychiatric disorders Aggression Sleep disorder Initial insomnia Abnormal behavior Terminal insomnia Agitation Affect lability Anxiety Gastrointestinal disorders Vomiting Diarrhea Constipation General disorders Pyrexia Irritability Fatigue Infections and infestations Ear infection Upper respiratory tract infection Nervous system disorders Psychomotor hyperactivity Headache Skin and subcutaneous tissue disorders Rash Metabolism and nutrition disorders Decreased appetite Increased appetite Injury, poisoning, and procedural complications Investigations Ear and labyrinth disorders Eye disorders Musculoskeletal and connective tissue disorders

43 31 24 14 4 7 2 26 11 8 4 2 3 4 1 2 25 12 13 5 22 17 7 0 26 6 4 15 5 5 15 10 9 6 4 7 6 1 1 1

(93) (67) (52) (30) (9) (15) (4) (57) (24) (17) (9) (4) (7) (9) (2) (4) (54) (26) (28) (11) (48) (37) (15) (0) (57) (13) (9) (33) (11) (11) (33) (22) (20) (13) (9) (15) (13) (2) (2) (2)

353 75 31 18 6 7 2 53 16 9 4 3 3 6 1 2 46 17 14 6 36 28 7 0 53 7 8 24 6 6 21 11 14 7 5 10 7 1 1 1

42 32 26 15 13 6 0 26 12 7 7 2 3 3 5 1 28 18 12 8 25 23 4 2 24 7 6 13 5 2 9 3 11 6 7 7 6 6 2 1

(91) (70) (57) (33) (28) (13) (0) (57) (26) (15) (15) (4) (7) (7) (11) (2) (61) (39) (26) (17) (54) (50) (9) (4) (52) (15) (13) (28) (11) (4) (20) (7) (24) (13) (15) (15) (13) (13) (4) (2)

409 104 42 25 17 10 0 65 17 12 8 2 3 3 5 1 71 26 15 18 40 31 4 2 39 9 11 23 5 5 11 3 17 6 10 9 10 7 2 1

23 16 10 8 6 3 3 15 5 4 3 4 3 0 1 2 13 9 2 4 16 13 3 1 11 7 4 7 5 1 7 3 7 4 5 3 3 1 3 3

(100) (70) (43) (35) (26) (13) (13) (65) (22) (17) (13) (17) (13) (0) (4) (9) (57) (39) (9) (17) (70) (57) (13) (4) (48) (30) (17) (30) (22) (4) (30) (13) (30) (17) (22) (13) (13) (4) (13) (13)

212 51 17 13 9 6 3 33 10 5 3 5 3 0 1 2 24 14 2 4 27 19 4 1 22 8 7 12 8 1 9 4 12 5 7 3 4 1 6 3

21 12 8 5 6 2 1 18 7 5 3 6 3 4 1 3 11 6 6 3 10 5 6 3 9 3 3 6 3 2 5 2 6 3 2 2 1 2 0 1

(91) (52) (35) (22) (26) (9) (4) (78) (30) (22) (13) (26) (13) (17) (4) (13) (48) (26) (26) (13) (43) (22) (26) (13) (39) (13) (13) (26) (13) (9) (22) (9) (26) (13) (9) (9) (4) (9) (0) (4)

182 36 15 6 10 3 1 50 10 5 3 8 3 4 2 3 24 7 7 5 18 7 7 3 22 3 8 10 3 2 6 2 6 3 2 2 1 2 0 1

.6006 .5275 .3379 .8051 .0704 .9545 .0926 .2868 .9156 .9256 .7799 .0112 .5812 .1945 .3963 .2271 .7608 .4580 .2901 .8154 .2709 .0576 .3021 .0926 .5860 .3299 .7571 .9731 .6247 .6988 .5193 .1887 .7525 .9692 .4356 .9422 .7683 .2078 .1620 .1820

*Each subject is counted only once per preferred term, at the greatest severity.

Efficacy of Low-Dose Buspirone for Restricted and Repetitive Behavior in Young Children with Autism Spectrum Disorder: A Randomized Trial

9.e4