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

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

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

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

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

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

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

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)

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

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 10 hours Long Acting Concerta 12 hours Vyvanse 13 hours

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

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

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

Ritalin Also Improved Prefrontal Cognitive Functioning Compared to Placebo

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

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

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

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

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

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

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

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

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

SelectiveSerotonin-Reuptake Inhibitors (SSRIs): Mechanism of Action

SSRIs in Individuals with 22q11DS: A Retrospective Study Age range 11 to 41 years Mean duration of treatment 41.3 months (range 1.5-233 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

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

Response to Treatment with SSRIs in 22q11DS

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

Treatment of Psychotic Disorders

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.

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 (200-600) Verhoeven & Egger 2015 Antiepileptics 40% Antidepressants 30% Methylphenidate 5% Antipsychotics 5% Benzodiazepines 47% Various antipsychotics Dori 2017

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 0.1-17.7 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 0.1-19.4 Dori 2017

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

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 2001 57:410–416; Carandang & Scholten Journal of Child & Adolescent Psychopharmacology 2007 34

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

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