Conditions: Autism Spectrum Disorders Anxiety
Keywords: Autism Spectrum Disorders Anxiety Children Adolescents Buspar Buspirone Pervasive Developmental Disorders
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 9
Healthy volunteers: no

Brief summary:
The main objective of this exploratory 8-week pilot study is to evaluate the safety and efficacy of buspirone for the treatment of anxiety in youth (ages 6-17 years) with autism spectrum disorders. The study results will be used to generate hypothesis for a larger randomized controlled clinical trials with explicit hypotheses and sufficient statistical power.

Detailed description:

Arms:
arm 1: Buspirone administered in tablets twice daily titrated to a maximum daily dose of 60mg for 8 weeks.

Interventions: intervention 1: Buspirone
Intervention descriptions: intervention 1: Children with autism spectrum disorders will receive buspirone treatment for eight weeks. Buspirone will be titrated to the maximum daily dose during the first four weeks of the trial (dose titration phase). Week 4 onwards, subjects will be maintained on maximum achieved dose until the end of the trial (dose maintenance pahe). During the titration phase, total dose will be increased by 10mg at each visit and by 5mg on the 4th day after each visit.

Protocol document:
Prot_SAP_000.pdf: 
Study Protocol: ASD Open-Label Buspirone 
CR 5 RtR 1: Submitted to the IRB 12/14/2017  
Last Modified: 12/14/2017  
 
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NCT01850355 
 
Study Protocol: An open-label trial of buspirone for the treatment of anxiety in 
youth with autism spectrum disorders 
 
Gagan Joshi, MD 
Massachusetts General Hospital 
Clinical and Research Program in Pediatric Psychopharmacology 
 
1. BACKGROUND AND SIGNIFICANCE 
INTRODUCTION 
 
Pervasive developmental disorders (PDD) are lifelong neurodevelopmental 
disorders characterized by core features of impaired communication, socialization, and 
behavioral problems [1]. The term PDD encompasses autistic disorder, Asperger’s 
disorder and PDD-NOS – together also referred to as autism spectrum disorders (ASD). 
An increasingly higher prevalence of ASD is documented in each successive 
epidemiological survey, and ASD is now estimated to affect more than 1% of youth [2].  
 
In addition to the core features of impaired communication, social deficits, and 
repetitive behaviors, youth with ASD manifest comorbid symptoms of anxiety and mood 
dysregulation that contribute to the morbidity and impairment associated with ASD [3-6]. 
In fact, anxiety-related difficulties are so frequently exhibited in children with ASD that 
the DSM-IV highlights anxiety-like responses as a common, ‘‘associated feature’’ of 
autism [7]. 
 
Anxiety is a very common concern in children and adolescents with ASD, with 
recent studies suggesting that nearly half of children with ASD meet criteria for an 
anxiety disorder [8-9], especially social phobia, generalized anxiety disorder, separation 
anxiety, and obsessive-compulsive disorder [10]. 
 
In a study of our clinically referred population of youth with ASD, we observed 
high rates of psychiatric comorbidities [11]. Multiple anxiety disorders (≥2) were present 
in more than half (61%) of the youth with ASD. Among the anxiety disorders, separation 
anxiety disorder, generalized anxiety disorder, and agoraphobia were concurrently 
present in more than a third of the youth with ASD (37%, 35% and 35%, respectively) 
and social phobia in more than a quarter of subjects (28%). 
 
The high rate of comorbidity with anxiety disorders in our youth with ASD is 
consistent with several previous uncontrolled studies that reported equally high 
prevalence rates of anxiety disorder(s) in referred populations of youth with ASD (43–
84%) [8,12-14]. Our findings also concur with previous studies reporting high prevalence 
rates of various specific anxiety disorders [13-16] and higher levels of anxiety symptom 
severity in samples of referred populations with ASD [17-18]. 
 
Underscoring the importance of targeting anxiety symptoms in these youth, 
children with ASD have been found to present with higher rates of anxiety symptoms, 
including social anxiety, than either typically developing children or children with other 
types of impairments (e.g., specific language impairments) [19]. 
 
Child anxiety has been associated with numerous impairments in social and 
academic functioning, including poorer self-image, lower rates of peer acceptance, and 
poorer performance on academic achievement tests [20]. If left untreated in childhood, 
anxiety disorders have been shown to persist through adolescence and adulthood and 
can become more severely impairing [21-23]. Moreover, child anxiety predicts the 
development of later psychiatric comorbidities, including major depression [24], 


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substance use disorders [25], and disruptive behavior disorders [26]. The present 
impairment and risk of future psychopathology and psychosocial dysfunction posed by 
these disorders highlights the importance of finding effective interventions for childhood 
anxiety. 
 
The presence of anxiety symptoms in youth with ASD may be especially 
impairing to their functioning. Such symptoms are associated higher levels of repetitive 
behaviors and poorer social reciprocity in youth with ASD [14]. Anxieties and fears are 
also associated with behavioral problems in youth with ASD at rates higher than those 
found in children with similar mental and chronological ages [19]. Children with ASD may 
also be especially vulnerable to the negative impact of anxiety symptoms, as associated 
avoidance behaviors may further compromise social interactions and limit opportunities 
for the development of appropriate social behaviors and peer relationships. Given the 
high prevalence of anxiety symptoms in children with ASD and the potential for very poor 
outcomes in children who experience these comorbid symptoms, it is important to 
develop effective interventions for these youth. 
 
Anxiety disorders are common in typically developing children and adolescents, 
with prevalence rates varying from 6 to 20% [27]. Substantial evidence supports the use 
of selective serotonin reuptake inhibitors (SSRIs) in the treatment of pediatric anxiety 
disorders. SSRIs have emerged as the medications of choice for pediatric anxiety 
disorders based on several controlled trials in youth with moderate to severe anxiety 
symptoms [28-30]. Furthermore, compared to its antidepressant and anti-OCD effects, 
the anti-anxiety efficacy of SSRIs appears greatest in pediatric populations [31]. 
 
Compared to typically developing populations, youth with ASD exhibit a less 
robust response to psychotropic medications, with higher rates of adverse effects to both 
medication and placebo. Such research suggests individuals with ASD may have an 
atypical response to psychotropic medications and higher susceptibility to adverse 
effects [32-35]. 
 
There is increasing empirical support for the use of SSRIs in children with ASD, 
although there also remains a great need for controlled trials of these medications. 
Limited case series and open-label studies have suggested that while SSRIs are 
effective in reducing symptoms of anxiety in youth with ASD, they are less well tolerated 
by youth with ASD. Sertraline is the only SSRI that has been evaluated by an open-label 
trial and found to be effective for the treatment of transition-related anxiety in children 
with autistic disorder [36]. In this trial, Steingard et al. investigated the use of open-label 
sertraline in 9 children with ASD and found that 89% had a positive response in their 
mood and anxiety. Though sertraline was well tolerated at lower doses (<50 mg/day), it 
was associated with behavioral worsening at higher doses. Similarly, in two case series, 
citalopram was found to be effective in treating anxiety but was associated with 
treatment limiting adverse events in nearly a quarter of the youth with ASD [37-38]. 
 
Buspirone is a serotonin (5-HT) receptor type 1A agonist that is widely used as 
an anxiolytic in adults and to treat generalized anxiety disorder in children. Buspirone 
has also been reported to be effective in treating ADHD features in typically developing 
individuals with ADHD [39,40]. 
 
Buspirone appears to be of particular interest for the ASD population because of 
its benign adverse effect profile, including the absence of significant sedative properties 
and complicated interactions with other psychotropic agents. In addition, the serotonin 
agonist activity of the drug may be useful in the treatment of ASD as serotonin 
deregulation is implicated in the etiology of ASD [41-42]. 
 
Limited trials suggest that buspirone is effective in decreasing anxiety and 
irritability/aggression in ASD individuals [43]. More importantly, these limited trials 
suggest that buspirone is well tolerated by the ASD participants.  


Study Protocol: ASD Open-Label Buspirone 
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Rationale 
 
Functionally impairing anxiety is highly prevalent in individuals with ASD. 
Therapeutic options for alleviating anxiety in this population are, at best, limited. 
Buspirone, with its known anxiolytic effect in adults and children, its suggested anxiolytic 
effect in individuals with ASD and anxiety, and its benign adverse effect profile, holds 
promise for the treatment of anxiety in youth with ASD. Buspirone could also be effective 
in treating emotional dysregulation (irritability/aggression) and inattention/hyperactivity, 
which often coexist with ASD. Moreover, as a serotonergic agent, buspirone may be 
effective in improving core features of ASD. 
 
Primary Hypothesis 
Our central hypothesis is that buspirone therapy will be safe, well tolerated, and 
efficacious in the treatment of anxiety in youth with ASD. 
 
Secondary Hypothesis 
Buspirone will be effective in treating core features of ASD and associated features of 
mood dysregulation (irritability/aggression) and ADHD in youth with ASD. 
2. SPECIFIC AIMS 
 
The main objective of this open-label 8-week pilot study is to evaluate the safety 
and efficacy of buspirone for the treatment of anxiety in youth (ages 6-17 years) with 
autism spectrum disorders. The study results will be used to generate hypotheses for a 
larger randomized-controlled trial with explicit hypotheses and sufficient statistical power.  
3. LENGTH OF STUDY 
 
The study will last up to 11 weeks (it could take up to three weeks to schedule 
and complete the initial screening process). Once subjects have completed the 
screening process, they will begin the 8-week open-label phase. Subjects will be 
assessed on measures of efficacy and safety every week for the first 4 weeks (at weeks 
1, 2, 3, and 4) and thereafter biweekly until the end of the study (at weeks 6 and 8). 
4. SOURCE OF SUBJECTS  
We plan to enroll 15 youth in order to achieve the goal of exposing 10 subjects to 
the study medication. We will recruit subjects both internally and externally. Participants 
will be recruited from the pool of existing patients and new referrals to the Pediatric 
Psychopharmacology Program and the Alan and Lorraine Bressler Clinical and 
Research Program for Autism Spectrum Disorders at the MGH, as well as from the Child 
and Adolescent Psychiatry Department at MGH.  
The Bressler clinic is a specialized ambulatory care program, devoted to the 
assessment and treatment of youth and adults with ASD. The patient population served 
by the MGH derives from Boston and its suburbs. Approximately 50% of referrals have 
never been diagnosed or treated. The 3,000 youth that use this clinic make 
approximately 9,000 visits each year. 
If a potential subject’s clinician ascertains that the patient has an interest in study 
participation, the clinician will offer contact information for the study to the patient and/or 
their parent/guardian. The patient and/or their parent/guardian can then contact the 
study coordinator for more information on the study. If the patient's physician is a 


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member of study staff, the patient and his/her family will also be offered the opportunity 
to speak with another study physician who is not their treating clinician to review study 
details and consider participation. Clinical records are not scanned in order to recruit 
subjects. 
 
Subjects may also be recruited from our department’s screening protocol entitled, 
“A General Screening Protocol for Child and Adolescent Research Studies in the 
Pediatric Psychopharmacology Program”, (#2014-P-001103). After participating in the 
general screening protocol, subjects may be identified as potentially eligible for this 
study and will be contacted via telephone by our study staff within 7 business days to 
assess their interest and to complete a specific phone screen for this study. When a 
member of our study staff telephones the potential subject they will use the already IRB-
approved Buspar OL Telephone script. 5 attempts will be made to reach the potential 
subject before they will be considered uninterested and will not be contacted again by 
our program regarding this study. Participants, and their parent, who meet eligibility 
criteria will then be brought in to meet with a study clinician who will explain the study in 
detail and complete the informed consent process.  
Additionally, subjects who have completed other protocols through our program 
may be eligible to participate in this study, as described in the Study Design section. 
These subjects will only be recruited if they have agreed to be contacted for future 
studies and will be contacted via telephone by a research assistant during the duration 
of our recruitment period. 5 attempts will be made to reach the potential subject before 
they will be considered uninterested and will not be contacted again by our program 
regarding this study. We also plan to recruit through advertising in local and regional 
media via print ads, Internet ads, and advertising posters. Clinical records are not 
scanned in order to recruit subjects. 
5. SUBJECT ENROLLMENT 
 
Informed consent will be obtained prior to the performance of any protocol 
procedures and prior to subjects receiving the study drug. The informed consent and 
assent documents will be used to explain in simple terms the risks and benefits of study 
participation to the subject and/or their parent/guardian. The nature of the study will be 
fully explained to the subject and/or their parent/guardian by a board-certified physician 
who is either the primary investigator or co-investigator. The subject and/or their 
parent/guardian will be encouraged to ask questions pertaining to their participation in 
the study and the subject and/or their parent/guardian may take as much time as they 
feel necessary to consider their participation in the study as well as consult with family 
members or their physician. Participation in this study is voluntary and the subjects 
and/or their parent/guardian may withdraw from the study at any time. The IRB-approved 
informed consent documents will be signed and dated by the subject and the physician 
obtaining consent. 
6. SUBJECT SELECTION CRITERIA 
Inclusion Criteria 
o 
Male or female participants between 6 and 17 years of age 
o 
Fulfills diagnosis of autism spectrum disorders by meeting DSM-IV-TR PDD 
diagnostic criteria of autistic disorder, Asperger’s disorder, or PDD-NOS as 
established by clinical diagnostic interview 
o 
Participants with a score of ≥13 on the Pediatric Anxiety Rating Scale (PARS) 


Study Protocol: ASD Open-Label Buspirone 
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o 
Participants with a score of ≥60 or more on the Anxiety/Depression subscale of 
CBCL and CGI-Anxiety severity of ≥ 4 
o 
Subjects can be taking psychotropic medications if they have been on the medication 
for at least 4 weeks prior to initiating study treatment and if they are on a stable dose, 
provided the medication is not listed in the Concomitant Medications section of the 
protocol. 
o 
Subjects with disruptive behavior disorders, mood, or psychosis will be allowed to 
participate in the study provided they do not meet any exclusionary criteria 
Exclusion Criteria 
o 
I.Q. < 70 
o 
DSM-IV-TR PDD diagnoses of Rett’s disorder, and childhood disintegrative disorder 
o 
History of active seizure disorder (EEG suggestive of seizure activity and/or history 
of seizure in last 1 month) 
o 
Subjects with a medical condition or treatment that will either jeopardize subject 
safety or affect the scientific merit of the study, including: 
o 
Pregnant or nursing females 
o 
Organic brain disorders 
o 
Uncorrected hypothyroidism or hyperthyroidism 
o 
Clinically significant abnormalities on ECG (e.g., QT prolongation, arrhythmia) 
o 
History of renal or hepatic impairment. 
o 
Clinically unstable psychiatric conditions or judged to be at serious suicidal risk 
o 
Current diagnosis of schizophrenia or bipolar disorder 
o 
History of substance use (except nicotine or caffeine) within past 3 months or urine 
drug screen positive for substances of abuse 
o 
Current treatment with medication with primary central nervous system activity (as 
specified in the Concomitant Medication section of the protocol) 
o 
A non-responder or history of intolerance to buspirone, after treatment at an 
adequate dose and duration as determined by the clinician 
o Subjects currently taking monoamine oxidase inhibitors (MAOI) and/or CYP3A4 
inducers or inhibitors including nefazodone, diltiazem, verapamil, erythromaycin, 
itraconazole, or rifampin. 
7. DESIGN 
This proposal seeks to complete an 8-week open-label trial to study the efficacy, 
tolerability, and safety of buspirone for the treatment of the features of anxiety in youth 
with ASD. In this study, we propose to examine ASD youth ages 6-17 years with 
significant anxiety features. 
Outcome measures 
Primary outcome measures: Efficacy will be assessed by reduction in anxiety symptom 
severity as measured by change from baseline on the PARS and CGI-Anxiety-
Improvement scores. Responders are defined as ≥ 30% reduction on the PARS and a 
score ≤ 2 on the improvement subscale of CGI-Anxiety, i.e., “much” or “very much 
improved.” 
Secondary outcome measures will assess the impact of buspirone therapy on the 
following parameters: 
I. Safety and tolerability assessed by monitoring: 
1. For treatment-emergent adverse events 
2. Vital signs (blood pressure, height and weight) 


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3. Electrocardiogram (ECG) 
4. Hematological parameters 
5. For the emergence or worsening of: 
a. Anxiety symptoms assessed by PARS and CGI-Anxiety 
b. Depressive symptoms assessed by CDRS-R and CGI-Depression 
c. Irritability/mania symptoms assessed by YMRS and CGI-Mania 
d. Inattention/hyperactivity symptoms assessed by CGI-ADHD 
e. Repetitive/ritualistic behaviors assessed by CY-BOCS-PDD and CGI-OCD 
II. Core features of ASD assessed by SRS-2, CY-BOCS-PDD, and MGH-SECS-C and -I 
III. Associated features of ASD assessed by YMRS, CDRS-R, and respective CGI-
Improvement subscale 
IV. Cognitive functioning assessed by BRIEF and DANVA 2. 
 
 
This study plans to recruit 15 subjects with ASD between 6-17 years of age with 
clinically significant and functionally impairing features of anxiety as rated by parent 
(significant score on the Child Behavior Checklist [CBCL] subscales for 
anxiety/depression) and clinician (a ≥ 4 on severity subscale of Clinical Global 
Impression Scale [CGI] for anxiety). 
 
We anticipate that subjects may enter this trial following completion of/withdrawal 
from other protocols in our office, and that there may be procedural overlap. So as to not 
burden subjects/parents/guardians with redundant time commitments, we will use the 
following diagnostic data previously collected:  If a subject has completed an evaluation 
with one of the study clinicians within the previous three years or an informant has 
completed the SRS-2 within the six months prior to entrance into this study, subjects will 
not be asked to repeat any overlapping diagnostic procedures. We will use the study 
diagnostic data that had been previously collected so as to not burden the subject with 
redundant time commitments. However, the study clinician will review the interval time 
period to assess for clinically significant medical or psychiatric history, to ensure that the 
subject meets appropriate study entrance criteria.  
 
If the subset of scales assessing intelligence (WASI-II) in the neuropsychological 
battery has been completed within 12 months prior to entrance into this study, subjects 
will not be asked to repeat these procedures. We will use the diagnostic data previously 
collected so as not to burden the subject with redundant time commitments. 
 
Although every effort will be made to encourage subjects to keep regularly 
scheduled appointments, in the event that a subject is unable to come into the office 
within a reasonable timeframe of a scheduled visit, and the treating research clinician 
feels that subject safety will not be jeopardized by doing so, the clinician can conduct the 
visit with the subject and parent/guardian over the phone. The clinician will complete the 
phone visit form for all phone visits that occur. This will ensure that each subject will be 
continuously monitored by the clinician throughout the course of the study despite 
unforeseen scheduling circumstances. The study evaluation visit, the baseline visit or 
the final study visit may be not conducted over the phone. Additionally, phone visits may 
not occur for two consecutive visits.   
 
 
Evaluation and Characterization: Week 99 
 
After providing study information and obtaining IRB-approved informed consent 
and assent, participants will undergo an initial screening assessment consisting of a brief 
demographic interview (collecting information regarding socioeconomic status and 
history of head injury or trauma), psychiatric and medical history, and assessment 


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measures (CBCL, PARS, and CGI-Anxiety). Eligible subjects will be administered a 
detailed assessment battery consisting of diagnostic measures (complete psychiatric 
evaluation including MGH-ASD-SCL), cognitive assessments (WASI-II and DANVA 2), 
measures of psychosocial functioning (SAICA and M-FES), and physical assessment 
measures (complete physical examination including height, vitals, ECG, urine screens, 
and blood tests). Screening (week 99) procedures can occur over 2 days (within the 
three week screening window).  
 
Washout Period 
 
After the screening period, subjects who are currently taking prohibited 
medications (refer top section on the, “Concomitant Medications/Treatments”) must 
discontinue the use of their medication to be eligible for participation in this study. 
Medication washout is recommended by our clinicians to participants, their 
parent/guardian, and current providers – this is done according to a case-by-case 
assessment, considering the duration on drug, the dose, and the adverse effects 
associated with the treatment and effects of stopping that medication/treatment. Our 
office does not take over care for the patient, but remains available during this time 
period. The washout schedule will be discussed with the participant, their 
parent/guardian, and current providers. 
 
Treatment Trial Phase: Weeks 0 through 8 
 
Participants who fulfill the inclusion and exclusion criteria will be treated with 
buspirone for a period of 8 weeks. Subjects will be evaluated at weekly intervals during 
titration phase (4 weeks from baseline) and thereafter every 2 weeks during the 
maintenance phase of the trial. Study visits will have a visit window of +/- 2 days to 
facilitate scheduling. Each visit will assess drug efficacy (CGIs and GAF), tolerability 
(assessing for treatment-emergent adverse-events), and safety (vital signs including 
weight). At baseline, midpoint (week-4), and endpoint, the PARS, MASC, SRS-2, MGH-
SECS-C and -I, BRIEF, CDRS-R, YMRS, CY-BOCS-PDD, and PQ-LES-Q assessment 
measures will be administered. The CBCL will also be administered at weeks 4 and 
8/drop-visit. At endpoint (completion/drop-visit), participants will be reevaluated on 
cognitive (DANVA 2) and physical assessment measures (complete physical 
examination including vitals, ECG, blood tests, and urine screening). 
 
Study Discontinuation 
 
Participants will be withdrawn from the study if they experience significant 
worsening of symptoms, or if the subject or their family decides to withdraw. A subject 
may be withdrawn from the study at any time if any of the following conditions are met: 
 
• 
Worsening of PDD, ADHD, OCD, anxiety, depression, or mania, as reflected by 
respective Clinical Global Improvement score of 6 (Much worse) or 7 (Very Much 
Worse) for 2 visits in a row. 
• 
Subjects who experience intolerable adverse effects, and/or clinically significant 
laboratory values inconsistent with continuation in the study. 
• 
Unstable psychiatric condition that clinically requires 1) a change in stable dose of 
concomitant psychotropic medications or 2) subjects requiring inpatient psychiatric 
admission. 
• 
Emergent suicidality 
• 
Active substance abuse 


Study Protocol: ASD Open-Label Buspirone 
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• 
Pregnancy 
• 
Allergic drug reaction 
• 
Non-compliance (less than 70% compliance for 2 visits or longer) 
• 
Failure to return medication or dosing diary for 2 consecutive visits 
• 
Failure to keep study appointments for more than 2 consecutive visits without 
justification 
• 
Clinical judgment of the investigator 
• 
Withdrawal of consent 
 
 
If study participation is discontinued for safety reasons, participants will be 
offered three follow-up clinical visits, allowing adequate time for appropriate psychiatric 
referrals to treaters in their communities. 
 
 
Study Medication 
 
At each visit, measures of safety and effectiveness will be administered. 
Buspirone will be titrated to the maximum daily dose during the first four weeks of the 
trial (dose titration phase). Week-4 onwards, subjects will be maintained on maximum 
achieved dose till the end of the trial (dose maintenance phase). 
Dose titration phase: Titration of buspirone will follow the flexible titration schedule with 
an option for slower titration, holding at lower dose, or lowering the dose based on 
tolerability and response to buspirone as per clinician judgment. Dose will be adjusted 
upward per titration schedule provided the treatment is well tolerated and the response 
is insufficient (CGI-Improvement>2). 
Dose maintenance phase: During the maintenance phase, buspirone will be maintained 
on the maximum achieved dose. As a one-time option during the maintenance phase, 
the dose of the study medication can be decreased by a maximum of 10 mg based on 
tolerability to buspirone per clinician judgment. 
 
 
 
Buspirone will be administered in divided dosage. During the titration phase, the 
total dose of buspirone will be increased at each visit and on the 4th day after each visit 
by 5 mg. 
 
The study buspirone titration schedule, detailed below, is based on treatment 
guidelines described in the Physicians’ Desk Reference [45]. 
Buspirone Flexible Titration Schedule 
Visit 
 
Week Day 
 
Maximum Total Dose (mg/day) 
1 
 
0 
1 
 
10 
0.5 
5 
 
15 
2 
 
1 
8 
 
25 
1.5 
12 
 
30 
3 
 
2 
15 
 
40 
2.5 
19 
 
45 
4 
 
3 
22 
 
55 
3.5 
26 
 
60 
5 
 
4 
28 
 
Maintained on the maximum achieved dose 
 
Buspirone will be available in four different strengths: 5,10,15, and 30 mg. Ten 
days worth of study medication will be dispensed for weekly visits and 20 days worth of 
medication will be dispensed for biweekly visits. To assess and ensure drug 


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accountability and compliance, study medication will be returned, counted, and re-
dispensed every visit by the study coordinator. 
Concomitant Medications / Treatments 
A detailed past and present treatment history (pharmacological / non-pharmacological) 
will be taken as part of initial evaluation. Following are the concomitant 
medications/treatments guidelines: 
o 
Participants on stimulant medication must be on a stable dose for at least 2 weeks 
prior to baseline. 
o 
Subjects may take melatonin (up to 3mg) or Benadryl (up to 50 mg) at bedtime as 
needed (prn) for insomnia. 
o 
Non-pharmacological treatments such as supportive individual, family, or group 
therapy will be permitted provided they were in place for a substantial period of time 
(> 1 month) prior to study participation and remain unchanged during the course of 
the trial. 
o 
No new non-pharmacological treatments may be initiated during the course of the 
trial. 
o  Subjects may not take monoamine oxidase inhibitors (MAOI) and CYP3A4 inducers 
or inhibitors including: nefazodone, diltiazem, verapamil, erythromycin, itraconazole, 
rifampin or grapefruit juice 
8. 
ASSESSMENTS (see protocol schedule) 
A. Diagnostic Assessments 
Administered at Week 99 
o 
MGH ASD Symptom Checklist (MGH-ASD-SCL): The spectrum of ASD symptoms 
will be screened by using clinician administered MGH-ASD-SCL. This screening 
instrument adopted items from DSM-IV diagnostic criteria for PDD and assesses for 
the individual core domains and associated features of ASD. 
B. Psychosocial Assessment Measures 
Administered at Week 99 
o 
Social Adjustment Inventory for Children and Adolescents (SAICA): The SAICA is an 
assessment administered to parents that measures social functioning in children 6 to 
18 years old. Content areas include activities, peer relations, family relations, and 
academic performance.  
o 
Moos Family Environment Scale (M-FES): We will use the M-FES as a measure of 
general family conflict. The M-FES assesses the quality of interpersonal relationships 
among family members and consists of 90 true-false items completed by the 
parent(s). The M-FES has high internal and test-retest reliability and population 
norms. Ten aspects of the family environment are assessed, permitting an evaluation 
of the degree of stress in the family environment and of parental discord. In 
divorced/separated families, this instrument will be used to evaluate the biological 
family prior to the divorce, as well as the current family environment. Following 
procedures previously used by our group, families will be categorized into "high" and 
"low" conflict family environments, based upon their scores on the conflict, cohesion, 
and expressiveness subscales. 
Administered Weeks 99, 4 and 8/drop-visit 
o 
Child Behavior Checklist (CBCL): The CBCL is a parent-report measure that 
assesses maladaptive emotional and behavioral problems in children ages 6-18. 
Several subcategories are assessed including social withdrawal, somatic complaints, 


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anxiety and depression, destructive behavior, social problems, thought problems, 
attention problems, aggressive behavior, and delinquent behaviors. 
Administered Weeks 0, 4, and 8/drop-visit 
o 
Pediatric Quality of Life Enjoyment and Satisfaction Questionnaire (PQ-LES-Q): The 
PQ-LES-Q is a self-report measure that assesses quality of life from the point of view 
of the subject. Subjects are instructed to consider each item and indicate their 
response scaled 1-5. 
Administered Weeks 0-8 
o 
DSM-IV Global Assessment of Functioning (GAF): The GAF will assess global 
functioning using a scale from 1 (worst) to 100 (best). This scale will be used at 
baseline to characterize the sample as well as at each visit to assess change. 
 
C. Neuropsychological Battery 
Administered at Week 99 
o 
Wechsler Abbreviated Scale of Intelligence Scale (WASI-II) Vocabulary and Matrix 
Reasoning subtests: This scale meets the demand for a quick reliable measure of 
intelligence in clinical, educational, and research settings and will provide a Full 
Scale IQ. 
 
Administered at Weeks 99 and 8/drop-visit 
3. Assessment of Social Cognition 
o 
Diagnostic Analysis of Nonverbal Accuracy Scale (DANVA 2): Child Faces and Child 
Paralanguages subtests. This assessment consists of 2 tasks of social competence 
assessing participant ability for recognizing feelings expressed through faces and 
paralanguage by children: Both subtests have been standardized and have 
acceptable internal consistency and reliability. This test can be administered for 
testing social competence in children as young as 3 years of age. 
D. Quantitative Scalar Assessments 
Administered Weeks 0-8/drop-visit 
Severity assessment of ADHD, PDD, Psychosis, Mania, Depression, Anxiety, and 
OCD 
o 
NIMH Clinical Global Impression Scale (CGI): The CGI is a measure of illness 
severity, improvement, and efficacy of treatment. The score for severity ranges from 
1 (normal, not at all ill) to 7 (among the most extremely ill subjects). Improvement 
ranges from 1 (very much improved) to 7 (very much worse). And lastly, the 
effectiveness index measures to what extent the subject is experiencing therapeutic 
effects as well as the level of adverse events. The CGI scales will be used for the 
assessment of PDD, ADHD, OCD, psychosis, mania, depression, and anxiety. 
 
Severity assessment of Anxiety 
Administered at screening (Week 99), baseline (Week 0) midpoint (Week 4), & endpoint 
(Week 8/drop-visit) 
o 
Pediatric Anxiety Rating Scale (PARS): The PARS is a clinician-rated scale, to be 
used with parent and children. It has 2 sections: a symptom checklist and severity 
items. The symptom checklist is used to determine the child's repertoire of symptoms 
during the past week. The 7 severity items are used to determine severity of 
symptoms and the PARS total score. The total score for the PARS is derived by 
summing the 7 severity items; total score ranges from 0 to 35. 


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Administered at baseline (Week 0), midpoint (Week 4), and endpoint (Week 8/drop-visit) 
o 
Multidimensional Anxiety Scale for Children (MASC): We will ask all parents and 
children (ages 8-19) to complete the MASC, a 39-item scale, distributed into four 
major factors: physical symptoms, social anxiety, harm avoidance, and separation 
anxiety. It has been shown to distinguish between anxiety and depression, as well as 
among anxiety disorders [44]. 
 
Administered at baseline (Week 0), midpoint (Week 4), and endpoint (Week 8/drop-visit) 
Severity assessment of Autism Spectrum Disorder – Core Features 
o 
Social Responsiveness Scale-Second Edition (SRS-2): The SRS-2 is a 65-item 
rating scale completed by the parent or guardian. This scale measures the severity 
of autism spectrum symptoms as they occur in natural social settings. 
o 
MGH Social-Emotional Competence Scale [Clinician-Rated Measure] (MGH-SECS-
C): Severity of ASD will be assessed by administering the clinician rated MGH-
SECS-C. This is a 37-item scale that assesses for the severity of core and 
associated symptoms of ASD in a Likert scale from 0 to 8. 
o 
MGH Social-Emotional Competence Scale [Informant-Rated Measures] (MGH-
SECS-I): is a 37-item scale that assesses for the severity of core and associated 
symptoms of ASD in a Likert scale from 0 to 6. This scale is to be completed by the 
parent or guardian measuring the severity of autism spectrum symptoms as they occur 
in natural social settings. 
Severity assessment of Executive Function Deficits 
o 
Behavior Rating Inventory of Executive Function (BRIEF): An 86-item rating scale to 
assess level of executive function deficits. 
Severity assessment of Compulsive/Repetitive Behaviors 
o 
Children’s Yale Brown Obsessive Compulsive Scale modified for PDD (CY-BOCS-
PDD): CY-BOCS is a clinician-rated 10-item scale (total range from 0 to 40), with 
subtotals for obsessions (items 1-5) and compulsions (items 6-10). The CY-BOCS 
includes a Symptom Checklist of over 60 examples of obsessions and compulsions. 
CY-BOCS-PDD is modified and validated version of CY-BOCS for use in children 
with PDD. CY-BOCS-PDD consists of following modifications: 1) the Obsessions 
checklist and severity scales are dropped because of the well-known cognitive and 
communication limitations in this population, 2) the compulsions checklist is retained 
from the original CY-BOCS and expanded to include repetitive behaviors commonly 
seen in children with PDD, 3) given that parents are the primary informant for 
children with PDD, selective alterations are made on the probes for Compulsion 
severity items. 
Severity assessment of Depression 
o 
Children’s Depression Rating Scale-Revised (CDRS-R): The CDRS-R is modeled 
after the Hamilton Depression Rating Scale for adults, and assesses the presence 
and severity of depressive symptoms in children ages 6 and older. It includes 
questions relevant to youth, such as questions about school, family, and peer 
functioning. We will administer this measure to parents and directly to the child. 17 
symptom areas associated with depression are assessed. It has been widely used in 
treatment outcome studies of childhood depression and BPD. 
Severity assessment of Mania symptoms 
o 
Young Mania Rating Scale (YMRS): The YMRS is an 11-item interview which 
queries the core symptoms of mania in the child, including elevated mood, irritability, 
psychomotor agitation, hypersexuality, and aggressive behavior. The YMRS score 


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ranges from 0-60. Questions are asked about the last week. We will administer this 
measure separately to parents and children. Originally designed for use with bipolar 
adults, the YMRS has recently been adapted for use with children. The YMRS has 
shown acceptable internal consistency and good discriminative validity. It is 
considered one of the best available instruments for assessing pediatric mania, and 
has been widely used in phenomenologic and treatment outcome studies of youth 
with BPD. 
E. Safety Assessment Measures 
Administered Weeks 0-8/drop-visit 
o 
Adverse Experiences: We will record any adverse health events experienced during 
the study, along with duration, severity, cause, treatment, and outcome. 
o 
Vital Signs: Blood pressure, pulse, and weight 
 
Completed at screening (Week 99) and endpoint (Week 8/drop-visit) 
o 
Physical Examination 
o 
Blood Tests: Comprehensive metabolic panel including complete blood count, total 
electrolyte count, liver function test, thyroid function test, and random glucose levels 
o 
Urine Drug Screen (for subjects ≥12 years old)  
o 
Urine Pregnancy Test (for menstruating female subjects 
o 
ECG 
9. DATA ANALYSIS 
 
Considering our open-label single group design, we will rely on comparisons of 
the participants’ performances at baseline (week 0) prior to the initiation of treatment 
relative to their scores at the last assessment (week 8). Thus, statistics for paired 
samples will be utilized. This design largely protects against the bias introduced by 
confounding factors. That is, since the same participants are tested on two occasions, all 
static confounding factors are perfectly balanced, and can have no impact on the 
findings. Bias can still result from time-varying factors that are not associated with the 
outcomes, but we are confident that any such factors will have a minimal impact on this 
study, considering the duration of the trial. Specifically, we will employ Wilcoxon signed 
rank tests for continuous or discrete outcome measures, and McNemar’s test for binary 
outcomes. These tests are free from assumptions regarding the distribution of the 
outcome variables, which is appropriate since the scales we are proposing to utilize are 
not considered to have Gaussian distributions, and will not be amenable to parametric 
methods. 
 
10. 
SAFETY 
 
The principal investigator (PI) will be responsible for the safety of all research 
subjects. The PI will supervise all study activities including ratings, laboratory tests, and 
vital signs. Consistent with good clinical practice, safety will be monitored by each 
subject's assigned clinician at each study visit. This clinician will be available 24 hours a 
day by page. 
 
If a subject is withdrawn from the study due to adverse events, lack of response, 
or as a decision by the clinician, they will be offered open treatment for three months, 
giving adequate time for appropriate psychiatric care to be arranged. 
 


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Blood draw: A topical anesthetic cream (EMLA) will be offered to subjects before blood 
draws. The dose of EMLA cream will not exceed administration guidelines based on 
subject age and weight. Subjects with sensitivity to local topical anesthetics will not 
receive EMLA cream.  If an infection does occur, it will be treated. 
Study Medication: Safety will be monitored through treatment-emergent adverse events 
and measuring change in vital signs through laboratory analyses. All adverse events will 
be recorded. A subject may be dropped from the study or dosage may be decreased 
and timing of medication changed at any time due to adverse events. All adverse events 
will be reported to the PHRC according to PHRC guidelines. 
11. CONFIDENTIALITY 
 
All research-related records, initiated as a result of a subject’s participation in this 
study that reveal the subject’s identity, will remain confidential except as may be 
required by law. While the results of the clinical laboratory blood testing will become part 
of a subject’s Massachusetts General Hospital medical record, they will not link the 
subject to participation in any research. Subjects will only be contacted regarding future 
studies if they indicate that they are interested in being contacted by initialing in the 
specific section of the consent form. 
 
When voice recordings are used, they will be labeled with the subjects’ code name 
and number, and only the study coordinator and study clinicians will have access to the 
recordings.  These recordings will be used to monitor the completeness of study 
evaluations and the similarities and differences between different raters.  These 
recordings will be saved securely using a password-protected database and maintained 
for 1 year after completion of the study for the purpose of verifying data and maintaining 
study reliability and will then be deleted after this time. 
12. RISKS AND DISCOMFORTS 
Blood Draw: There may be some discomfort during the blood draws. Subjects may 
have a bruise and/or bleeding at the needle site. Occasionally a subject may feel faint 
when blood is drawn. Rarely, an infection may develop. If an infection does occur, it can 
be treated. EMLA cream will be regularly offered to any subject to numb the site of the 
draw.  
Study Medication - Buspirone: The most common side effects reported with use of 
buspirone are: nausea, vomiting, headache, dizziness, drowsiness, fatigue, weakness, 
numbness, nervousness, lightheadedness, upset stomach, stomach pain, constipation, 
diarrhea, dry mouth, difficulty sleeping, depression, and excitement. 
Other side effects include: skin rash, itching, fast or irregular heartbeat, blurred vision, 
and unusual movements of the head or neck muscles. 
All subjects will be closely monitored for serious adverse reactions and drug-drug 
interactions with any ongoing concomitant medications. All serious unexpected adverse 
experiences of a research subject will be reported to PHRC. 
13. POTENTIAL BENEFITS 
 
There may be no direct benefit to subjects participating in this study. Potential 
benefits to the participants include education about ASD, a trial of medication that could 


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14
be continued after the study, and the opportunity to contribute to medical science and 
thus help others with ASD. 
 
 


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Protocol Schedule 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Evaluation Titration 
Maintenance 
Week 
99 
0  
1  
2  
3  
4  
6  
8 
Day 
 
0 5 8 12 15 19 22 26 29 36 43 50 57 
Buspirone Dosing (Total mg/day) 
 
10 15 25 30 40 45 55 60 *** *** *** *** *** 
Consenting (Parent & Subject) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic Interview 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Psychiatric Evaluation & Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Vital Signs (BP, pulse & weight) 
X 
X  
X  
X  
X  
X  
X  
X 
Urine pregnancy test (menstruating females) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Urine drug screen (subjects ≥12 years old) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Hematological tests 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Cognitive Tasks 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Neuropsychological Battery*  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
DANVA-2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Clinician Rated Scales 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MGH-ASD-SCL 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
PARS 
X 
X  
 
 
 
 
 
 
X  
 
 
X 
CGI** 
X 
X  
X  
X  
X  
X  
X  
X 
GAF 
 
X  
X  
X  
X  
X  
X  
X 
Adverse Event Log 
 
X  
X  
X  
X  
X  
X  
X 
Concomitant Medication Log 
 
X  
X  
X  
X  
X  
X  
X 
CY-BOCS-PDD 
 
X  
 
 
 
 
 
 
X  
 
 
X 
MGH-SECS-C 
 
X  
 
 
 
 
 
 
X  
 
 
X 
CDRS-R 
 
X  
 
 
 
 
 
 
X  
 
 
X 
YMRS 
 
X  
 
 
 
 
 
 
X  
 
 
X 
Patient/Parent-Rated Scales 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SAICA 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
M-FES 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBCL 
X 
 
 
 
 
 
 
 
 
X  
 
 
X 
MASC 
 
X  
 
 
 
 
 
 
X  
 
 
X 
SRS-2 
 
X  
 
 
 
 
 
 
X  
 
 
X 
BRIEF-Parent 
 
X  
 
 
 
 
 
 
X  
 
 
X 
MGH-SECS-I 
 
X  
 
 
 
 
 
 
X  
 
 
X 
PQLESQ 
 
X  
 
 
 
 
 
 
X  
 
 
X 
*Please see Section 8 (Assessments) for details. 
**CGIs: (Only CGI-Anxiety completed at wk. 99) PDD, PDD-SI, PDD-SC, PDD-M, Anxiety, ADHD, OCD, 
Psychosis, Depression, Mania 
***Maximum achieved dose 
 


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16
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