Specifying and Treating Anxiety in Autism Research

Approximately 40%-80% of children and adolescents with autism spectrum disorder (ASD) exhibit
clinically significant anxiety symptoms. These symptoms are associated with increased social
deficits, depression, irritability, and stereotyped and self-injurious behaviors. Children
and adolescents with anxiety also frequently avoid potentially stressful situations, thereby
missing opportunities to learn important new skills. Despite the significant consequences of
anxiety symptoms, several critical treatment-relevant issues remain unresolved. First, there
is a lack of clarity about how to differentiate ASD and anxiety symptoms. Second, little is
known about how anxiety manifests in those with ASD and intellectual disability (ID). Third,
the neural substrates of anxiety in ASD are poorly understood. The overarching goal of this
project is to investigate these open issues in order to make interventions more precise, more
personalized, and more likely to promote positive outcomes -- an objective consistent with
the National Institutes of Health (NIH), the Roadmap, Precision Medicine, and Research Domain
Criteria Project (RDoC) Initiatives and the Interagency Autism Coordinating Committee (IACC)
Strategic Plan, Chapter 4.

While there is no doubt that anxiety is a very serious issue for those with ASD, what to do
about this problem is less clear. The search for empirically-validated treatments has begun
with multiple small trials providing promising evidence that selective serotonin reuptake
inhibitors (SSRIs) and cognitive behavior therapy (CBT) might reduce anxiety in those with
ASD. However, this work is in its early stages. There is a great need for large, rigorously
designed trials that validate the effectiveness of both medication and CBT, as well as
functional neuroimaging studies that identify neural predictors of treatment efficacy and
markers of therapy-induced change. Such work holds the potential to help answer the questions
posed above and to assist the field in developing more personalized treatments. In Project 1
of the Center for the Development of Phenotype-Based Treatments of Autism Spectrum Disorder,
we leverage the large, well-characterized UC Davis MIND Institute Autism Phenome Project
(APP) cohort to conduct a comparative efficacy trial in N=132 participants (ages 8-12 years)
with ASD and clinically significant anxiety.

Inclusion Criteria:

1. Outpatient boys and girls with ASD between ages 8-12 years at consent.

2. Meets criteria for a diagnosis of ASD.

3. Meets criteria for clinically significant anxiety symptoms as defined by a minimum
score of 14 on the PARS Severity Scale.

4. The child has a Full Scale and Verbal Comprehension IQ greater than 50 as assessed on
the Wechsler Abbreviated Scales of Intelligence.

5. Subjects with co-morbid depression, tic disorder or disruptive behavior disorders will
be acceptable as long as the anxiety symptoms are considered the primary mental health
problem (i.e., most impairing/distressing). (a) Eligibility will be guided by the
following principle: For subjects presenting with comorbid symptomology, the co-morbid
conditions cannot be sufficiently severe to: 1) warrant immediate treatment or require
a change in an otherwise stable psychosocial treatment regimen for that disorder, or
2) potentially interfere with the child's ability to comply with the study assessment
and treatment batteries. (b) Preliminary determination of acceptable eligibility will
be made by the PI with consultation with clinical co-Investigators on the project. (c)
Finally, each potential subject will be presented and discussed at weekly team
meetings.

6. The use of stable stimulant or alpha-agonist medications will be allowed if the dose
has been consistent for 8 weeks and the family and treating psychiatrist affirm there
is no plan to alter the dose or change medication in the foreseeable future.

Exclusion criteria:

1. Receiving concurrent psychotherapy, social skills training that include homework, or
behavioral interventions (e.g., applied behavior analysis). Families will have the
option of discontinuing such services to enroll in the study. Other non-medication
interventions will be allowed but we will document type and dose. This includes
academic tutoring, occupational therapy, speech therapy, school counseling that is no
more than 60 minutes per week in duration, school aides, and social skills training
groups that do not include homework and are no more than 60 minutes/week in duration.
Families of youth with ASD often have a variety of adjunctive services of this nature
that they do not want to give up, and given the limited documentation of the efficacy
of such interventions for social and emotional outcomes, it is deemed important to
permit families to retain them in the service of recruiting a representative sample.
If a potential participant is receiving non-allowed psychosocial treatments
(psychotherapy, social skills training with homework, ABA) at the time of the phone
evaluation and wishes to discontinue these treatments to enter the study, the patient
will be asked to discuss this option with their clinician to determine whether
termination would be safe and in the child's best interest. In addition, we will
obtain the patient's written consent to contact their treating clinician to determine
the appropriateness of study participation. We will not influence the decision
patients make with their clinician. If non-allowed psychosocial treatments are
discontinued, Gate B assessments will not be conducted until 1 month following
termination.

2. Child has failed a previous trial of sertraline judged adequate in dose (100mg/daily)
and duration (at least 6 weeks) or child has a history of intolerance to sertraline.
Subject has failed two previous SSRI (other than sertraline) trials judged adequate in
dose (of 30mg/daily citalopram or paroxetine; 20mg/daily of escitalopram; 20mg/daily
fluoxetine, 100mg/daily of fluvoxamine) and duration (6 weeks).

3. Biological Treatments: Recent treatment with psychotropic medication within 12 weeks
of study entry for antidepressants and within 6 weeks for neuroleptics. No new
alternative medications, nutritionals or therapeutic diets within 6 weeks of study
enrollment.

4. Established Treatment changes: Any change in medication dosage (e.g., stimulant, alpha
agonist) within 8 weeks before study enrollment will result in exclusion from the
study. Any medications (e.g., stimulant) that the child is on must remain stable
during treatment. If a potential participant is taking non-allowed psychotropic
medication (antidepressants, antipsychotics) at the time of the phone evaluation and
wishes to discontinue this medication to enter the study, the patient will be asked to
discuss this option with their prescribing physician to determine whether medication
discontinuation would be safe and in the child's best interest. In addition, we will
obtain the patient's written consent to contact their treating clinician to determine
the appropriateness of study participation. We will not influence the decision
patients make with their prescribing physician. All pharmacotherapy recommendations
will be made in consultation with the study physician. As described in Exclusion
criterion 3, a specified waiting period would be required before the Gate B assessment
should patients choose to discontinue non-allowed medications to enter the study.

5. Current clinically significant suicidality or (b) individuals who have engaged in
suicidal behaviors within 6 months will be excluded and referred for appropriate
clinical intervention.

6. Child has failed an adequate trial of CBT for anxiety within the previous 2 years (at
least 10 sessions over a period of less than 1 year conducted by a licensed provider
of CBT). This will be determined through records review and speaking with the
clinician if appropriate.

7. Lifetime DSM-5 bipolar disorder, schizophrenia or schizoaffective disorder as assessed
by all forms of information (i.e., clinical history, data from the ADIS-IV, etc.).

8. Child has a major neurological disorder or medical illness that requires a prohibited
episodic or chronic systemic medication or that would interfere with study
participation (e.g., frequent hospitalizations, frequent school absences).

9. Child pregnancy as indicated by history or positive pregnancy test.

10. Inability to safely swallow study mediation after pill swallowing education.

11. Contraindications to MRI (i.e. claustrophobia, extreme sensitivity to noise, metal in
the body).

12. Excess motion during scanning even after 2-3 training sessions.