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ADHD, Tics and Tourette’s Disorder Child and Adolescent Psychopharmacology

March 18, 2017

Barbara J. Coffey, MD, MS Professor, Department of Psychiatry

Icahn School of Medicine at Mount Sinai Tourette Association of America Center of Excellence

Chief, Tics and Tourette’s Clinical and Research Program

Research Psychiatrist

Nathan Kline Institute for Psychiatric Research

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Disclosures

My spouse/partner and I have the following relevant financial relationship with a commercial interest to

disclose: Honoraria: American Academy of Child and Adolescent Psychiatry

Research Support: Auspex/Teva, Catalyst, NIMH/Rutgers/UCSF, Shire, Neurocrine Biosciences

Advisory Board: Genco Sciences, Tourette Association of America

Speaker’s Bureau: CDC-Tourette Association of America Partnership Off-label indications will be discussed

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ADHD, Tics and Tourette’s Disorder: Learning Objectives

• At the end of this session, the participant should be able to: – Review evidence for the bidirectional overlap of

ADHD and tic disorders – Describe a systematic approach to disentangling

ADHD and tic disorder symptoms to prioritize target symptoms for treatment

– Interpret relevance of recent research findings for application to treatment of youth and adults with ADHD and tics

– Select approved and off label treatments for comorbid ADHD and tic disorders

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ADHD, Tics and Tourette’s Disorder: Overview

1. Bidirectional Relationship Between ADHD and Tic Disorders

2. Epidemiology Risk Factors, Neurobiology and Comorbidity

3. Challenges of Treating Tics and ADHD

4. Relevant Pharmacotherapy Studies

5. Suggested Guidelines for Treatment and Algorithm

6. Summary

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Epidemiology: Bi-Directional Overlap of ADHD and Tic Disorders

• Rates of tic disorders are higher (10-30%) in children with Attention Deficit Hyperactivity Disorder (ADHD) than in children without ADHD (1-10%) (Spencer T., Biederman, J. Coffey, B. et al.,

Arch Gen Psych; 1999, 56: 842-84)

• ADHD is the most highly prevalent (50-75%) comorbid disorder in clinically referred children with Tourette’s Disorder (TD). (Coffey, B. Biederman, J. et al. J Nerv Ment Dis; 2000;188:583-588; Freeman,

TS International Data base Consortium; Eur Child Adolesc Psych 2007; 16 [suppl; 1];1/15-1/23)

• In a recent large community sample, by parent report, more than 60% of children diagnosed with TD had also been diagnosed with ADHD. (National Survey of Children’s Health Study, US, 2007)

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Gilles de la Tourette Syndrome Robertson et al. (2017)

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A National Profile of Tourette Syndrome (Bitsko, R. et al. (2015) Journal of Behavioral Pediatrics; 35 (5);

317-322)

Method: Data on 65, 540 US children age 6-17 years from the 2011-2012 National Survey of Children’s Health.

Parents reported whether they had ever been told by a clinician that their child had Tourette Syndrome or another neurobehavioral health condition.

Results: 0.19% of US children had TS; average age of diagnosis was 8.1 years.

Compared to those without, children with TS were more likely to have co-occurring neurobehavioral health conditions. Conclusion: TS is characterized by frequent co-occurring neurobehavioral health conditions.

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A National Profile of Tourette Syndrome. (Bitsko, R. et al. (2015) Journal of Behavioral Pediatrics; 35 (5);

317-322)

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Prevalence of Lifetime Diagnosis: Tourette Syndrome

(Scahill, L. et al; Morbidity and Mortality Weekly Report CDC; 2009)

(National Survey of Children's Health, United States, 2007)

•† Selected Diagnoses age 6-17: Among children ever diagnosed with TS, 79% also had been diagnosed with at least one other selected diagnosis.

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TD and ADHD: Neurobiology (Seidman, L. et al; Biol Psychiatry; 2005; 57; 1263-1272; Sukhodolsky, D. et al; Eur Child Adolesc Psychiatry 2007; Leckman, J.

et al; JCAP, 2010; 20 (4); 237-247; Dickstein, S. et al; J Child Psych; 2006: 47: 10. 1051-1062)

• Inhibition is a core deficit in both disorders

• Executive functions abnormalities in both are thought to result from fronto-striatal and frontal-parietal network dysfunction

• TD+ADHD: CTSC misguided neural oscillations may result in basal ganglia disinhibition, worsened by frontal hypoactivity in ADHD.

• Both TD and ADHD tend to improve with time, which may be a result of increased myelinization of prefrontal regions.

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Gilles de la Tourette Syndrome Robertson et al. (2017)

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Tourette Syndrome and Comorbid ADHD: Causes and Consequences. Eur J Pediatr. Malhany, N. Gulisano, M. et al 2014.

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Pre- and Perinatal Complications in Relation to Tourette Syndrome and Co-Occurring OCD and ADHD

(Abdulkadir, M. et al. Journ Psych Res 82 (2016); 126-135)

Aim: To investigate role of pre and perinatal complications in TS, and comorbid OCD and ADHD clinical phenomenology

Method: N= 1113 participants in TIC Genetics study. 586 had chronic tic disorder (CTD) and 527 were unaffected family controls.

Results: Premature birth (OR 1. 72) and morning sickness requiring medical attention (OR 2.57) were associated with CTD. Total number of pre- and peri-natal complications was associated with CTD.

Neonatal complications were related to presence (OR 1.46) and severity (b=2.27) of co-occurring OCD and ADHD severity (b=1.09)

Conclusion: Early exposure to adversity during pregnancy is related to CTD. Exposure at a later stage, at birth or in the neonatal period, is associated with co-occurring OCD and ADHD.

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Pre- and Perinatal Complications in Relation to Tourette Syndrome and Co-Occurring OCD and ADHD

(Abdulkadir, M. et al. Journ Psych Res 82 (2016); 126-135)

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Prenatal Maternal Smoking and Increased Risk for Tourette Syndrome and Chronic Tic Disorders

(Browne, H. et al. JAACAP; 55 (9); (2016); 784-791_

Aim: To assess role of prenatal maternal smoking in risk for TS and chronic tic disorders (CT).

Method: Incidence rates in N= 73, 073 singleton pregnancies from Danish National Birth Cohort; crude and adjusted hazard ratios.

Results: Heavy smoking was associated with 66% increased risk for TS/CT; adjusted hazard ratio was 1.66, 95% (CI 1.17-2.35). Heavy smoking was associated with 2 fold increased risk for TS/CT with comorbid ADHD, and both light and heavy smoking were associated with more than 2 fold increased risk for TS/CT with any non-ADHD psychiatric comorbidity.

Conclusion: Prenatal maternal smoking was associated with increased risk for TS/CT and TS/CT with comorbid psychiatric disorder.

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Prenatal Maternal Smoking and Increased Risk for Tourette Syndrome and Chronic Tic Disorders.

(Browne, H. et al. JAACAP; 55 (9); (2016); 784-791)

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Tourette Syndrome and Comorbid ADHD: Causes and Consequences. Eur J Pediatr Malhany, N. Gulisano, M. et al 2014.

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Familiality of Co-Existing ADHD and Tic Disorders: Evidence from a Large Sibling Study.

(Roessner, V. et al. Frontiers in Psychology; (2016) 7 (1060); 1-8)

Aim: To determine whether ADHD+TD increases risk of ADHD +TD in siblings, and whether this is independent of psychopathology in general.

Method: Based on the IMAGE study; N=3815 individuals in ADHD index patients with comorbid TD (N=262 ADHD +TD) and without TD (N=947).

Results: Comorbid ADHD + TD in index patients increased the risk of both comorbid ADHD +TD and TD in siblings of these index patients.

Conclusion: Co-existence of ADHD + TD may segregate in families. The same holds true for TD (without ADHD). Hence, the segregation of TD (included in both groups) seems to be the determining factor, independent of other behavioral problems.

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Familiality of Co-Existing ADHD and Tic Disorders: Evidence from a Large Sibling Study.

(Roessner, V. et al. Frontiers in Psychology; (2016) 7 (1060); 1-8)

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Clinical and Demographic Characteristics of Non-specialized and Specialized Clinic Patients with TD

Non-specialized Clinic patients

(N=92)

Specialized Clinic patients

(N=103)

Overall Significance

Mean SD Mean SD p

Current Age 10.8 3.23 10.8 3.62 0.89

SES 2.0 1.13 2.2 1.24 0.42

N % N % p

Past GAS 47.9 7.50 48.6 7.57 0.54

Current GAS 51.3 7.32 51.9 6.52 0.55

% Male 82 90 81 80 0.06

Informativeness of Structured Diagnostic Interviews in the Identification of Tourette’s Disorder in Referred Youth (Coffey B, Biederman J, Spencer T et al. J Nerv Ment Dis. 2000;Sep;188 (9):583-588)

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Disruptive Behavior Disorders

Non-specialized Clinic Patients

Specialized Clinic Patients

Overall

Significance

(N = 92) (N = 103)

Diagnosis N % N % p

ADHD 76 84 74 72 .053

Conduct Disorder 18 20 14 14 .25

Oppositional Defiant Disorder

63 69 58 57 .91

Any Disruptive Disorder 83 91 86 84 .14

Informativeness of Structured Diagnostic Interviews in the Identification of Tourette’s Disorder in Referred Youth (Coffey B, Biederman J, Spencer T et al. J Nerv Ment Dis. 2000;Sep;188 (9):583-588)

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Course of ADHD and Tic Disorders: What Happens to

Tics in the Context of ADHD Over Time? (Spencer, T. Biederman, J. Coffey, B. et al. Arch Gen Psych 1999, 56: 842-847)

• Design: Prospective ADHD Follow-up • Objective: To evaluate the prevalence and impact of tic

disorders at baseline and at follow-up on the course of ADHD.

• Methods: N=128 boys with ADHD; N=110 controls. Duration of follow-up: 4 years.

• Results: – Proportion of ADHD youth with tics: 34% – Remission rate for tics over 4 years: 65% – Remission rate for ADHD: 20%

• Conclusion: Tic remission rate is independent of ADHD Tic disorders did not impact ADHD course

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Onset of ADHD and Tic Disorders in ADHD Probands

Age in Years 0 5 10 15 20 25

0

ADHD

Tic Disorders

10

20

30

40

50

60

70

80

90

100

Tic Disorders

ADHD

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Offset of ADHD and Tic Disorders in ADHD Probands

Age in Years

0 0 5 10 15 20 25

Tic Disorders

ADHD

10

20

30

40

50

60

70

80

90

100

Tic Disorders

ADHD

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Adults with Tourette Syndrome with and without Attention Deficit Hyperactivity Disorder

(Haddad, A. Umoh, B. Robertson, M. Acta Psychiatr Scand; 2009; 120; 299-307)

• Design: N=80 adults with TS only were compared to 64 with TS+ ADHD in a clinical interview and standardized measures of depression, anxiety and OCD

• Results: No differences noted in tic severity. • TS+ ADHD had significantly more depression, anxiety,

OCD and behavioral problems than TS only. Differences in ADHD family history.

• Conclusion: More overall behavioral problems and psychopathology found in adults with TS+ ADHD vs. TS only is consistent with findings in children.

• ADHD treatment in childhood may prevent development of behavioral problems later in life.

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Haddad, A. et al. 2009

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\ New Insights into Clinical Characteristics of Gilles de la Tourette

Syndrome: Findings in 1032 Patients from a Single German Center (Sambrani, T. et al. Frontiers in Neuroscience. (2016) 10; (415); 1-13)

Aim: Exploration of clinical presentation and comorbidity in TS

Method: Clinical data from a large sample (N=1032) of patients with tic disorders in one setting.

Results: Relevant to ADHD and Tics/Tourette’s Disorder

Tic severity is associated with premonitory urges and number of comorbidities, but not age at onset

Tic severity is higher in patients with comorbid OCD than ADHD

Comorbid ADHD reduces patients’ ability to suppress tics successfully.

Conclusion: TS +OCD may be a more severe form of TS, and ADHD might be conceptualized as a separate problem.

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New Insights into Clinical Characteristics of Gilles de la Tourette Syndrome: Findings in 1032 Patients from a Single German Center (Sambrani,T. et al. Frontiers in Neuroscience. (2016) 10; (415); 1-13)

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New Insights into Clinical Characteristics of Gilles de la Tourette Syndrome: Findings in 1032 Patients from a Single German Center

(Sambrani,T. et al. Frontiers in Neuroscience. (2016) 10; (415); 1-13)

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New Insights into Clinical Characteristics of Gilles de la Tourette Syndrome: Findings in 1032 Patients from a Single German Center.

(Sambrani et al. Frontiers in Neuroscience. (2016) 10; (415); 1-13)

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Diagnostic Evaluation: Tics and ADHD

• Structured diagnostic interviews, such as the Children's Schedule for Affective Disorders and Schizophrenia (K-SADS) can improve classification and assessment of comorbidity.

• Standardized rating scales have improved diagnostic reliability in research studies; helpful in clinical care.

• The Yale-Global Tic Severity Scale (YGTSS) (Leckman, Riddle, Hardin, Ort, Swartz, Stevenson, et al., 1989) is considered the “gold standard.” The YGTSS assesses domains of: tic number, frequency, intensity, complexity and interference (0-50), and tic related impairment (0-50).

• SNAP and Conners (Parent and Teacher) are helpful for quantitative evaluation of ADHD symptoms.

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Tics/Tourette’s Disorder: Pharmacotherapy Overview

Only formally approved (labeled) treatments for TD:

– D2 dopamine antagonists: conventional neuroleptics

– Haloperidol (Haldol) and pimozide (Orap)

(Physicians Desk Reference, 2017)

Haloperidol: effective for tics, superior to placebo

(Shapiro et al. 1968, 1978)

Pimozide: effective for tics, superior to placebo and haloperidol

(Shapiro et al. 1983, 1984; Sallee et al; 1997)

Aripiprazole: effective for tics, superior to placebo (Yoo et al 2013)

Other interventions

– Psychoeducation; referral to the Tourette Syndrome Association

– **Habit reversal therapy (Comprehensive Behavioral Intervention for Tics)

– Individual and family therapy

– Educational consultation

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The Challenges of Treating Tics! Roessner et al. Eur Child Adolesc Psychiatry (2011); 20:173-196

What’s new in treatment of tics? Rounding up the usual suspects………

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Trends in Psychopharmacological Treatment of Tic Disorders in Children and Adolescents in Germany. Bachmann, C. et al; Eur Child Adolesc Psychiatry 2014;D0I 10.1007/s00787-014-0563-6

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TD/Tics + ADHD: Treatment Overview

• Pharmacotherapy is cornerstone.

• Tics: Most patients with mild tic symptoms need only monitoring, education, and guidance.

• ADHD: Since ADHD symptoms are more likely to persist and cause significant functional impairment, treatment is usually necessary.

• Behavioral treatment of tics (Comprehensive Behavioral Intervention for Tics (CBIT)) is now established.

• There are no published studies of comorbid ADHD and tic disorders of combination pharmacotherapy and behavioral treatment.

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Daily Doses of Frequently Prescribed Tic Medications (Egolf, A. Coffey, B. Current Pharmacotherapeutic Approaches to the Treatment of Tourette Syndrome:

Drugs Today; 2014 Feb; 50 (2):159-79. doi: 10.1358/dot.2014.50.2.2097801).

Medication Range of daily dosing

Haloperidol 0.25-4.0mg

Pimozide 0.5-8.0mg

Risperidone 0.125-3.0mg

Aripiprazole 1.0-15.0mg

Clonidine 0.025-0.4mg

Guanfacine 0.25-4.0mg

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ADHD and Tics/TD: Can We Treat with Stimulants?

• Old studies suggested that stimulants increase tics, (Lowe

et al. 1980) and pharmaceutical labeling states tics are a contraindication for stimulants (PDR, 2015)

• Long term methylphenidate treatment did not worsen

tics in children with ADHD and multiple tic disorders (Castellanos et al, 1997)

• More recent studies demonstrated that some TD

patients with significant ADHD may be candidates for methylphenidate (MPH) when no other treatments have been effective (Gadow, Nolan, Sverd. 1992; Gadow et al. 2007)

Stimulants and Tics: The Historical Perspective

How it all got started…..... With 15 cases in a case series!!!! Stimulant Medications Precipitate Tourette's Syndrome

(T. Lowe; D. Cohen; J. Detlor; M. Kremenitzer; B. Shaywitz. JAMA 1982;247:1168-1169)

Pharmaceutical labeling states tics and/or family history of

tics/Tourette’s are a contraindication for use of stimulants (Physicians Desk Reference, 2017)

RITALIN (methylphenidate hydrochloride) HOW SUPPLIED Tab: (Ritalin) 5mg, 10mg*, 20mg*; Tab, SR: (Generic) 10mg, (Ritalin-SR)

20mg *scored CONTRAINDICATIONS Marked anxiety, tension, agitation, glaucoma, motor tics or family

history or diagnosis of Tourette's syndrome. .

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Meta-Analysis: Treatment of Attention Deficit Hyperactivity Disorder in

Children with Comorbid Tic Disorders

• Aim: To determine relative efficacy of medications to treat

ADHD and tic symptoms in children with both TD and ADHD.

• Design: PubMed search for all double blind, RCTs in children with ADHD and tics using random effects meta-analysis with standardized mean difference as primary outcome for effect size.

• Results: N=9 studies (x-over or parallel) with 477 subjects. N=6 medications: dextroamphetamine, methylphenidate, alpha 2 agonists (clonidine and guanfacine), desipramine, atomoxetine, and deprenyl.

(Bloch, M. Panza, K. Landeros-Weisenberger, A. and Leckman, J. JAACAP. 2009; 48 (9);884-893)

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• Results: Methylphenidate, alpha 2 agonists, desipramine, and atomoxetine showed efficacy in improving ADHD symptoms in children with comorbid tics.

• Alpha agonists and atomoxetine significantly improved comorbid tics

• Supra-therapeutic doses of dextroamphetamine increase tics.

• There is no evidence that methylphenidate worsened tic severity in the short term.


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Meta-Analysis: Effectiveness of medication in treating ADHD and tic disorders

Bloch, M 2009

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• Conclusion: Methylphenidate seems to offer the best and most immediate improvement of ADHD and does not seem to worsen tics.

• Alpha agonists offer the best combination of improvement in both tics and ADHD symptoms.

• Atomoxetine and desipramine provide additional evidence based treatment of ADHD in children with comorbid tics.

• Supra-therapeutic doses of dextroamphetamine should be avoided.


53

The Latest? Meta Analysis: Risk of Tics Associated with Stimulant Use in Randomized, Placebo-Controlled Trials

(Cohen, S. Mulqueen, J. Ferracioli-Oda, E. Stuckelman, Z. Coughlin, C, Leckman, J. Bloch, M. JAACAP; 2015; 54(9); 728-736)

Design: Meta-analysis of RCTs of stimulants in treatment of ADHD

Results: N=22 studies with 2385 children with ADHD.

New onset or worsening of tics were commonly reported with stimulants (5.7%) and placebo groups (6.5%).

Risk of new onset or tic worsening associated with stimulants was similar to that of placebo (risk ratio=0.99, p=.962).

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What Is The Latest? Meta Analysis: Risk of Tics Associated with Stimulant Use in Randomized, Placebo-Controlled Trials

(Cohen, S. Mulqueen, J. Ferracioli-Oda, E. Stuckelman, Z. Coughlin, C, Leckman, J. Bloch, M. JAACAP; 2015; 54(9); 728-736)

Results: Stimulant type, dose, duration and age did not affect risk.

Cross over studies were associated with a significantly greater risk than parallel group trials.

Conclusion: There is no evidence for support of an association between new onset or worsening of tics with stimulant use in patients with ADHD.

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Practical Tips on Treating ADHD and TD with Stimulants

• Methylphenidates (MPH) are recommended

• Initiate treatment with very low doses: for example, for prepubertal children:

• Start with 2.5 mg bid

• Titrate to 5 mg AM, 2.5 mg PM

• Increase to 5 mg bid

• If tolerated, switch to 10mg equivalent long- acting delivery system, ie extended release MPH 10 mg or 18 mg OROS

• For adolescents, MPH can be initiated at 10 mg and titrated upward gradually.

• If tics increase along the way, if ADHD symptoms have improved, hold the dose and monitor, or temporarily reduce the dose and titrate back upward.

• Guanfacine or clonidine can be added if tic increase is sustained.

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Systematic Review: Pharmacological Treatment of Tic Disorders: Efficacy of Antipsychotic and Alpha 2 Agonist Agents

• Design: Meta-analysis of RCTs in treatment of chronic tic disorders and examination of moderators

• Results: Significant benefit of antipsychotics vs. placebo. SMD=0.58. No significant difference in efficacy of risperidone, pimozide, haloperidol and ziprasidone.

• Significant benefit of alpha 2 agonists vs. placebo. Significant moderating effect of comorbid ADHD.

• With comorbid ADHD SMD:0.68. No ADHD: 0.15.

• Conclusion: Significant benefits of both medication types, but alpha 2 agonists may have minimal benefit in patients without ADHD.

(Weisman, H. Qureshi, I. Leckman, J. Scahill, L. Bloch, M. Neuroscience and Biobehavioral

Reviews; 2013; 37; 1162-1171)

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Rizzo, R. Gulisano, M. et al. Tourette Syndrome and Comorbid ADHD: Current Pharmacological Treatment Options. Eur Jour Ped Neurology; 2013; 17; 421-428.

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Evidence Based ADHD/Tics/TD Treatment Algorithm

ADHD + TD or Persistent Tic Disorder

ADHD Primary Tics Primary

Alpha Agonist Stimulant (MPH)

Effective

Monitor

Tics Increase

Add Alpha-Agonist or Switch to Atomoxetine

Effective

Monitor

Intolerable or Inadequate

Consider atomoxetine +stimulant or pramipexol

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Summary: ADHD, Tics and Tourette’s Disorder

**There is bi-directional overlap of ADHD and Tic Disorders, including common neural substrates and phenomenology.

1. Prevalence of ADHD in TD in clinically referred samples is 50-75%, and tics in ADHD patients 10-30%.

2. ADHD symptoms persist, but tic symptoms tend to remit over time. 3. Much of the associated psychopathology (behavioral, neurocognitive) in

Tourette’s Disorder is secondary to ADHD. 4. An alpha agonist is recommended as initial pharmacotherapy for ADHD + tics

when tics are the primary issue. 5. Methylphenidate is effective in treatment of ADHD in children with ADHD and

tics, and does not increase tics in the short run. 6. To date there is no data regarding behavioral treatment for ADHD + TS; targeted

combined treatment studies are needed. 7. A randomized, controlled trial of extended release guanfacine in TD will be

published this year. 8. Tune in next year!!!

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• Icahn School of Medicine at Mount Sinai Tics and Tourette’s Clinical and Research Program

• Wayne Goodman, M.D. Former Professor and Chair, Department of Psychiatry, Icahn School of Medicine at Mount Sinai

Director, Division of Tics, OCD and Related Problems • Vilma Gabbay, M.D. M.S Associate Professor, Department of Psychiatry, Director, Pediatric Mood and Anxiety and Disorders Clinical Research Program • Dorothy Grice, M.D. Professor, Department of Psychiatry, Director, Pediatric OCD Program • Ariz Rojas, Ph.D. Assistant Professor, Department of Psychiatry • Maxwell Luber, B.A. Research Coordinator • Melissa Fluehr, B.A. Clinical Coordinator • Saniya Saleem, B.A. Research Intern • NYU School of Medicine Collaborators: F. Xavier Castellanos, M.D. Jonathan Brodie, M.D. Ph.D. Nathan Kline Institute Collaborators: Russell Tobe, M.D.

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