1. Child, Adolescent & Adult Psychiatrist
Effective Treatments for Psychiatric Problems in Adolescents & Young Adults with 22q11DS
Prof. Doron Gothelf, M.D.
Child, Adolescent & Adult Psychiatrist
Tel Aviv University

2. In A Nutshell
About two-thirds of individuals with 22q11DS cope with at least one psychiatric disorder
There are effective treatments for psychiatric disorders in 22q11DS

3. Common Psychiatric Disorders in 22q11DS
ADHD 40%
Anxiety disorders 50%
Depressive disorders 20%
Psychotic disorders 30%
Autism spectrum disorders (14%-45%)

4. ADHD in 22q11DS
Diagnosed in about half of children with 22q11DS and in only 13% of older adults.

5. ADHD: Symptoms of Intattention
Sustain attention for few minutes only
Avoids tasks requiring sustained concentration
Easily distracted
Frequently dreamy
Careless mistakes
Fail to follow instructions and to finish tasks
Difficulty organizing
Often loses things
forgetful

6. ADHD: Symptoms of Hyperactivity
Often leaves seat in classroom
Acts as if “driven by a motor”
Fidgets hands and feet
Difficulty engaging in activities quietly
Runs about and climbs excessively
Talks excessively

7. ADHD: Symptoms of Impulsivity
Blurts out answers
Difficulty awaiting turn
Butts into conversations or games

8. Subtypes of ADHD
Inattentive presentation: at least 6 of 9 symptoms of inattention (very common)
Hyperacitve-Impulsive presentation: at least 6 of 9 symptoms of hyperactivity and impulsivity (not- common)
Combined presentation (common)

9. Medications for ADHD
Elevates brain catecholamines (dopamine, norepinephrine) levels

10. Most Effective ADHD Medications
Short Acting
Ritalin-IR 4 hours
Focalin 4 hours
Adderall/Attent 6 hours
Medium
Ritalin-LA 8 hours
Ritalin-SR 8 hours
Focalin-XR hours
Long Acting
Concerta 12 hours
Vyvanse 13 hours

11. Ritalin-IR in 22q11DS: Study 1 An Open-Label Study
Open label 4 weeks study showed effectiveness and safety of ritalin 0.3 mg/kg in 22q11DS:
9 of 12 children with VCFS (75%) significantly improved
Duration of clinical effect was 3.2 ± 1.4 hours
None of the children
Experienced psychotic or manic exacerbations
discontinued ritalin
Gothelf et al J Clin Psychiatry 2003

12. Ritalin-IR in 22q11DS: Study 2
34 children with VCFS aged 5 to 20 years (mean 11yrs; Males=20, Females=14)
Subjects were randomly assigned to receive ritalin (n=22) or placebo (n=12)
Ritalin dosage- 0.5 mg/kg
Green et al., J Child Adolesc Psychopharmacol, 2011

13. Improvement of ADHD Symptoms Following 6 Months of Ritalin Treatment* * * *
40% reduction in severity of ADHD symptoms

14. Ritalin Also Improved Prefrontal Cognitive Functioning Compared to Placebo

15. Rate (%) of Ritalin’s Side Effects in 22q11DS

16. Ritalin’s Side Effects in 22q11DS
At least one side effect reported in all subjects
No psychotic symptoms
No manic or hypomanic exacerbation

17. Ritalin in 22q11DS: Cardiac Safety
Before Ritalin
On Ritalin
P value
Heart rate
82.4 ± 13.5
87.9 ± 17.8
<0.05
Diastolic BP
60.6 ± 8.4
64.6 ± 6.9
Systolic BP*
108.1 ± 11.2
108.7 ± 7.9 NS
QTc
0.40 ± 0.02
* An increase in systolic BP above 95th percentile occurred in 2 children

18. Ritalin is effective and safe in 22q11DS
The only medication studied for the treatment of ADHD in 22q11DS is the short-acting Ritalin
Ritalin is effective and safe in 22q11DS
Before initiation of ritalin treatment evaluation by a cardiologist is recommended-
Echocardiogram
EKG
Heart rate and blood pressure

19. Treatment of Anxiety Disorders and Depression
SSRI Medication
Cognitive-Behavioral Therapy
1 retrospective study
In 22q11DS
No data in 22q11DS

20. Common Anxiety Disorders in VCFS
Specific Phobias
Separation-anxiety disorder
Social anxiety disorder/Selective mutism
Obsessive-compulsive disorder

21. Separation Anxiety Disorder
Excessive anxiety concerning separation from parents accompanied by-
Fear of possible illness or harm befalling the parents or himself when without the parents
Insisting to sleep in the parents’ bad
Refusal to go to school

22. Social Anxiety Disorder/Selective Mutism
Marked and persistent fear of social and/or performance situations such as:
Speaking in front of colleagues classmates
talking with teacher or other adults unless he/she knows them very well
Shy with peers

23. Obsessive-Compulsive Disorder
Common OCD themes
Disgust of dirt, fear of contamination accompanied by compulsions of washing
Doubt and checking
Aggressive obsessions
Hoarding
Repetitive questions

24. SelectiveSerotonin-Reuptake Inhibitors (SSRIs): Mechanism of Action

25. SSRIs in Individuals with 22q11DS: A Retrospective Study
Age range 11 to 41 years
Mean duration of treatment 41.3 months (range months)
21 subjects treated with an SSRI medication (13 with Flouxetine (prozac) 20-60mg/day)
10 for depressive disorders
6 for anxiety disorders
5 for OCD

26. SSRIs in Individuals with 22q11DS
21 subjects treated with an SSRI medication (13 with Flouxetine (prozac) 20-60mg/day)
10 for depressive disorders
6 for anxiety disorders
5 for OCD
Dori et al; J Child Adolesc Psychopharmacol, 2015

27. Response to Treatment with SSRIs in 22q11DS

28. SSRI Medications: Adverse Events in the 22q11DS Sample
2 (7.6%)
Fatigue
1 (3.8%)
Irritability
Hypomania GI
Dry mouth

29. Treatment of Psychotic Disorders

30. 22q11DS Retrospective Antipsychotic Trials
Naïve
Age (yr)
Mean
Range N
Males/Females
Ref. 0% 31
19-42 20
11/9
Butcher 2015 32
19-70 28
12/16
Verhoeven & Egger 2015
53% 24
11-41
19 (30 trials)
11/8
Dori 2017
Butcher et al. British Journal of Psychiatry 2015; Verhoeven & Egger Pharmacopsychiatry 2015; Dori et al. Journal of Child & Adolescent Psychopharmacoloy, 2017.

31. 22q11DS Antipsychotic Trials
Other Medications
Antipsychotic Studied
Ref.
Antipsychotics 30%
Depalept ??
Clozapine
250 (50-425)
Butcher 2015
Risperidone 21%
Depalept 29%
140 (75-300)
Seroquel
170 ( )
Verhoeven & Egger 2015
Antiepileptics 40%
Antidepressants 30%
Methylphenidate 5%
Antipsychotics 5%
Benzodiazepines 47%
Various antipsychotics
Dori 2017

32. 22q11DS Antipsychotic Trials
Side Effects
Response Rate
Treatment
Duration
Ref.
Drowsiness 75%
Weight gain 50%
Hypersalivation 50%
Seizures 44%
Parkinsonism 25%
Neutropenia 15%
85%
6.2 yrs
Butcher 2015
Not mentioned
75%
0.9->5 yrs
Verhoeven & Egger 2015
Akathisia/Parkinson 26%
Weight gain 14%
Drowsiness 9%
Seizures 6%
50%
3.4 yrs
Dori 2017

33. Potential Novel-Specific Treatments in 22q11.2DS
Metyrosine
SAMe 33

34. Metyrosine (Demser) Reduces the synthesis of dopamine
Improvement in neuropsychiatric symptoms in 4 of 5 treated patients
Potential side effects: drowsiness, hypotension, extrapyramidal symptoms
A potential treatment for 22q11DS refractory psychosis
Graf et al Neurology :410–416; Carandang & Scholten Journal of Child & Adolescent Psychopharmacology 2007 34

35. Conclusions
It is important to diagnose and treat psychiatric disorders in 22q11DS because they have a negative effect on the quality of life, development and risk for the later evolution of psychosis
Evaluation by a psychiatrist skilled in developmental disabilities is recommended for all individuals with 22q11DS
The critical periods for evaluation are-
During transition to elementary school
Transition to adolescence
Frequent evaluations during adolescence and up to age 25 years

36. Summary: Psychiatric Treatments in 22q11DS
ADHD
stimulants (e.g., ritalin, concerta)
Anxiety disorders and depression
Cognitive-behavioral therapy
SSRI medications (e.g., prozac)
Psychotic disorders
Antipsychotics
If 2 antipsychotics fail clozapine should be initiated