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Tourette’s Disorder and Tics Child and Adolescent Psychopharmacology

March 5, 2016

Barbara J. Coffey, MD, MS

Professor, Department of Psychiatry

Chief, Tics and Tourette’s Clinical and Research Program

Tourette Association of America Center of Excellence Director of Education in Child and Adolescent Psychiatry

Icahn School of Medicine at Mount Sinai

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: Astra Zeneca, Auspex/Teva, Catalyst, NIMH, Shire, Tourette Association of America, Neurocrine Advisory Board: Genco Sciences, Auspex/Teva Speaker’s Bureau: Tourette Association of America Off-label indications will be discussed

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Tourette’s Disorder and Tics: Learning Objectives

• At the end of this session, the participant should be able to: – Describe a systematic approach to disentangling

tics and psychiatric comorbid symptoms to prioritize targets for treatment

– Interpret relevance of recent research findings for application to treatment of youth with tics and Tourette’s Disorder

– Select approved and off label treatments for Tourette’s and tic disorders

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Tourette’s Disorder and Tics: Overview

1. Overview of Epidemiology, Neurobiology and Comorbidity

2. Challenges of Treating Tics and Psychiatric Symptoms/Disorders

3. Relevant Pharmacotherapy Studies

4. Suggested Treatment Algorithm

5. Summary

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Tics and Tourette’s Disorder: Epidemiology (Scahill, L. et al; Morbidity and Mortality Weekly Report CDC; 2009)

• CDC Prevalence of Diagnosed Tourette’s Disorder

in Youth Age 6-17 in 2007 in US

• National Study of Children’s Health

• 0.3-1% US

• 3x more common in boys than girls

• 2x more frequently diagnosed age 12-17 vs. 6-11

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Prevalence of Lifetime Diagnosis: Tourette Syndrome (parent)

(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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Neurobiological Substrates of TD (Leckman et al; JCAP, 2010; 20 (4); 237-247; McNaught, K, and Mink. J.

Neurology; 2011; 7; 667-676)

• Tics: thought to result from dysfunction in cortical and sub-cortical regions involved in habit formation, including basal ganglia (BG), thalamus and frontal cortex

• Tics, like habits, link sensory cues with motor actions

• Cortico-striatal-thalamic-cortical (CSTC) circuits: are composed of multiple, overlapping but largely parallel circuits that direct information from cortex to sub-cortical structures and back

• Tics represent failure of cortical inhibition of unwanted motor programs generated in the BG

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Cortico-

Striato-

Pallido-

Thalamic

Circuit GLOBUS

PALLIDUS

PUTAMEN

THALAMUS

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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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Non-

specialized

Clinic

Patients

Specialized

Clinic

Patients

Overall

Significance

(N = 92) (N = 103)

Diagnosis N % N % p

Pure TD (Non-

comorbid) 2 2 5 5 .31

Major Depressive

Disorder

45 49 56 54 .49

Any Bipolar Disorder 20 22 16 16 .24

Dysthymia 9 10 4 4 .09

Any Mood Disorder 55 60 59 57 .65

Comorbidity of TD Subjects by Ascertained Site: Mood Disorders

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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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Non-specialized

Clinic Patients

Specialized Clinic

Patients

Overall

Significance

(N = 92) (N = 103)

Diagnosis N % N % p

Panic Disorder 10 11 15 15 .45

Agoraphobia 21 23 27 26 .61

Social Phobia 15 16 5 5 .008

Simple Phobia 25 27 30 30 .73

OCD 19 21 37 36 .021

Separation Anxiety 22 24 39 39 .028

Multiple Anxiety Disorders (2+)

32 35 41 40 .47

Anxiety Disorders

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Diagnostic Evaluation: Tourette’s Disorder and Tics

• 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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The Challenges of Treating Tics!

Roessner,V. et al. Eur Child Adolesc Psychiatry (2011); 20:173-196

……

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TD and Tics: Treatment Overview

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

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

• Behavioral treatment of tics (habit reversal therapy) is now established.

• There are no published studies of combination pharmacotherapy and behavioral treatment of tic disorders/Tourette’s Disorder.

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Comprehensive Behavioral Intervention for Tics Study (CBIT) (Piacentini, J. Woods, D. Scahill et al. JAMA; 2010;303 (19):1929-1937)

Three phases: 1) Awareness training: premonitory

urge/sensation 2) Competing response training 3) Social support

Two parallel studies compared behavior therapy to supportive therapy (PST)

Child study: 126 children (ages 9-17) with TD/CTD; JAMA; 2010

Adult study: 120 children and adults (ages 16+) with TD/CTD: completed; Arch Gen Psych 2012

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Types of Competing Response (Franklin et al. Psychiatr Clin N Am; (2010); 33; 641-655)

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0

10

20

30

40

50

60

52.5%

18.5

%

Responder Status at Week 10: Effect Size 0.68 (CGI-Improvement = 1 or 2) Courtesy of Piacentini, J. AACAP 2009

CBIT PST p < 0.0001

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Bothersome Tics in Patients with Chronic Tic Disorder: Characteristics and Individual Treatment Response to Behavior

Therapy (McGuire, J. et al; 2015; 70; 56-63)

• Design: Young adults and youth were randomly assigned to CBIT or PST.

• Results: At BL, motor tics and tics with urge were more bothersome than vocal tics and those without urge.

• CBIT outperformed PST across tic type and urge presence, but tics with urges at BL had higher severity at post treatment across conditions. Baseline urge presence was associated with tic remission for CBIT but not PST.

• Conclusion: Individual tics respond differently to CBIT relative to PST.

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Bothersome Tics in Patients with Chronic Tic Disorder:

Baseline Sample Demographics

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Bothersome Tics in Patients with Chronic Tic Disorder:

Baseline and Post Treatment Ratings

Fig. 1. Baseline and Post Treatment Severity Ratings on the Hopkins Motor/Vocal Tic Scale by baseline premonitory urge status and treatment condition

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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) – *Aripiprazole (Abilify) (Physicians Desk Reference, 2016) 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. Am J Psych. 1997) Aripiprazole; (Yoo et al 2013) Other interventions – Psychoeducation; referral to the Tourette Association – *Habit reversal therapy (Comprehensive Behavioral

Intervention for Tics) – Individual/ family therapy; educational consultation

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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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A Multicenter, Randomized, Double Blind, Placebo Controlled Study of Aripiprazole in Children And Adolescents With Tourette’s

Disorder (Yoo, H.K. Joung, Y.S. Lee, J.S. et al. J Clinical Psych. 2013; 74 (8) (9); e772-e780)

• Design:10 week RCT in 61 children ages 6-18 • Primary outcome: Change in Total Tic Score (TTS) on YGTSS. • Results: Significant reduction in TTS in aripiprazole group

compared to PBO (-15.0 vs. -9.6 respectively) from baseline to endpoint.

• CGI: 66% active vs. 45% control were much improved. • Adverse effects: No difference in treatment emergent

effects in either group. But metabolic effects (weight, BMI and waist circumference) were significantly greater in aripiprazole group.

• Conclusion: Aripiprazole was efficacious and tolerable in short term treatment of TD in youth.

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Yoo, H.K. et al. 2013

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Yoo, H.K. et al. 2013

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Aripiprazole in Children and Adolescents with Tourette’s Disorder: An Open Label Safety and Tolerability Study (Lyon, G. Samar, S. et al. JCAP; 2009; 19 (6), 623-633)

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Aripiprazole in Children and Adolescents with Tourette’s Disorder: An Open Label Safety and Tolerability Study (Lyon, G. Samar, S. et al. JCAP; 2009; 19 (6), 623-633)

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Aripiprazole in Children and Adolescents with Tourette’s Disorder: An Open Label Safety and Tolerability Study (Lyon, G. Samar, S. et al. JCAP; 2009; 19 (6), 623-633)

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Pharmacological Treatment of Tic Disorders and Tourette Syndrome

(Roessner, V. et al; Neuropharmacology 68; 2013; 143-149)

• Overview of current treatment options; evidence base is still limited.

• Recommendations are based on both scientific evidence and expert opinion.

• In Europe, risperidone and tiapride are first line treatments.

• Aripiprazole and pimozide are second line treatments.

• With comorbid ADHD, atomoxetine, stimulants or clonidine are recommended. If tics are severe, stimulants + risperidone.

• With comorbid OCD, non-OCD or depression, sulpuride is recommended, or in more severe cases, risperidone + SSRI.

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Table 1 Roessner, V et al. (2013) 36

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Perceptions of Treatment for Tics Among Young People with Tourette Syndrome and Their Parents: A Mixed Methods Study

(Cuenca, J. et al. 2015; BMC Psychiatry; 15:46)

Design: Interviews of 42 young people with TS and mixed methods online survey of 295 patients through TA (Tourette’s Action)

Results: Health professionals have limited knowledge of TS and treatment. Medication was common treatment, but many adverse effects were described and was a common reason for discontinuation. Aripiprazole was viewed most positively.

Access to behavioral treatment was limited, despite the fact that 76% of parents wanted this for their child. Managing the urge to tic was an important outcome of treatment.

Conclusion: Results suggest a need for more training in identification and management of TS.

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Table 1 – Cuenca, J. et al. (2015)

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39 Table 3 – Cuenca, J. et al. (2015)

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Serial Pharmacological Prescribing Practices for Tic Management in Tourette Syndrome

(Farag, M. et al. Hum Psychopharmacol Clin Exp; 2015; 30; 435-441)

Design: Patients are frequently treated serially with agents in search for optimal treatment. 400 consecutive TS patients were reviewed over 10 year period.

Results: 225 of 400 (56%) were prescribed medication. Last drug used may be proxy measure of some benefit.

Most commonly prescribed were aripiprazole, clonidine, risperidone and sulpiride.

Number of drugs tried ranged from one to 8.

Conclusion: The data suggest that pharmacological treatment of tics is difficult. Even after several trials, there may be potential benefit in trying other options.

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Figure 1. Order of drug prescribing and frequency of the top five medications used to reduce tics. Farag et al. (2015)

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Why Do We Need Novel/New Pharmacological Treatments of Tourette’s Disorder?….

Current treatments are ineffective and/or intolerable in many patients

Off label treatments are more frequently prescribed than dopamine D2 receptor antagonists in the US

Beyond dopamine………

Potential New Treatments:

Novel formulation of existing agents

Histaminergic Agents

GABAergic Agents

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Guanfacine in Children with Tic Disorders: A Multi-Site Study

(Scahill, L. Coffey, B. and Murphy, T. 2012)

• Guanfacine is commonly used to treat tics in children with Tourette’s Disorder, but the extended release formulation has not been evaluated for this outcome.

• Overall goal: to determine whether extended release guanfacine (GXR) warrants further study in a large scale trial.

• Immediate-release guanfacine is frequently used in children with TD, but dosing, time to effect and adverse effects with GXR are unknown.

• This was a multi-site, randomized, double-blind, placebo-controlled, parallel-group design, followed by an 8-week extension for subjects who show positive response to guanfacine in the double-blind phase.

• Subjects who were randomly assigned to placebo and did not show improvement were offered 8-week, open-label treatment with GXR.

• Objectives • Primary Aim: To evaluate the benefit of flexibly dosed, extended release

guanfacine GXR) on tic severity in 42 children with Tourette’s Disorder as measured by the Total Tic score of the YGTSS.

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N Engl J Med 2010;362:1901-8.

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The histaminergic system in the human brain

Haas H L et al. Physiol Rev 2008;88:1183-1241

©2008 by American Physiological Society

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Histamine synthesis and metabolism

Haas H L et al. Physiol Rev 2008;88:1183-1241

©2008 by American Physiological Society

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The Two-Generation Pedigree and Results of Haplotype Analysis

Ercan-Sencicek et al., 2010

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“A 6-Month, Multicenter, Randomized, Safety, Tolerability, Pharmacokinetic, and Preliminary Efficacy Study of AZD5213 in Adolescents with Tourette’s Disorder”

AZD5213 is a novel histamine H3 receptor inverse agonist that shows promise for the potential treatment of a variety of indications, including TD.

Histaminergic neurotransmission in the brain is mediated by four

histamine receptors (H1-H4). Both H2 and H3 receptors are significantly enriched in human striatum.

The H3 receptor acts as 1) a presynaptic auto-receptor on histaminergic

projection neurons; 2) a presynaptic heteroreceptor on non-histaminergic neurons that regulates a variety of neurotransmitters, including dopamine, serotonin, norepinephrine, and acetylcholine; and 3) as a postsynaptic receptor, especially enriched in striatum, co-localized with D1 and D2 receptors.

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“A 6-Month, Multicenter, Randomized, Safety, Tolerability, Pharmacokinetic, and Preliminary Efficacy Study of AZD5213 in Adolescents with Tourette’s Disorder”

Inverse agonists of the presynaptic H3 auto-receptor, such as AZD5213, increase both synthesis and release of histamine by blocking the inhibitory effects of activation of the H3 auto-receptor.

The potential benefit of H3-receptor inverse agonists in TD is further

supported by several observations: (1) the identification of a mutation in the gene for L-histidine decarboxylase (HDC); the rate-limiting enzyme in the synthesis of histamine) in a family in which a father and his eight children were affected by TD, (2) the finding that HDC-/- mice exhibit traits relevant to features of TD, including exaggerated stimulant-induced locomotor and stereotypic movements (proposed as a model of human tics) as well as increased anxious-type behavior, and (3) multiple clinical reports of antihistamine-induced exacerbation of tic symptoms.

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AZD5213 Study Objectives (Phase II)

• Overall Objective: Obtain information critical to understanding AZD5213 while minimizing burden to patients, caregivers, and sites

The right assessments, administered judiciously and carefully

Study design “fit-to-purpose”

• Specific Objectives: Understand safety, tolerability, PK, efficacy.

• Safety and Tolerability

– Standard assessments - physical and neurological exams, labs, vitals, ECG, AEs, concomitant medIcations.

– Population- and drug-specific assessments: C-SSRS, CDRS-R, MOS-Sleep.

• Pharmacokinetics (Part 1 of Study)

– Single- and multiple-dose PK. Efficacy (Part 2 of Study)

– YGTSS, PUTS, CGI-TS, CY-BOCS.

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I see glutamate!

How do we know what’s inside?

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Evidence to Support a Role

for Alterations in GABA and Glutathione (GSH) in TD

• There is evidence that GABA, the major CNS inhibitory neurotransmitter, is reduced in patients with TD

• Glutamate dysregulation in TD may be associated with decreased glutathione (GSH)

• GSH depletion results in abnormal movements in rodents

– ECC Syndrome

• Clinical evidence: NAC, a GSH precursor, may be beneficial in TD-related disorders such as trichotillomania

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Proton MRS Reveals Striatal and Anterior Cingulate GABA Deficits in Adolescents with Tourette’s

Disorder Vilma Gabbay1,2, M.D., M.S.; Barbara Coffey1,2, M.D.; Xiangling Mao3, M.S.; Benjamin Ely1, B.S.; Aviva Panzer1, B.S.; James Babb4, Ph.D.; Nora Weiduschat3, Ph.D.; Dikoma C. Shungu3, Ph.D.

1NYU School of Medicine, NYU Child Study Center; 2Nathan S. Kline Institute for Psychiatric Research; 3Radiology, Weill Cornell Medical College; 4Radiology, NYU School of Medicine

CONCLUSIONS

Our finding of decreased GABA levels in adolescent TD is potentially

consistent with a pathophysiological role for dysregulated striatal and ACC

neurotransmitter function, and provides further evidence for possible

dysfunction of the central GABAergic system in TD. Follow-up studies

should examine GABA levels in larger groups as well as other regions

implicated in TD.

RESULTS

Concentrations of GABA:

ACC GABA/w was significantly decreased in adolescents with TD vs. HC in

both the striatum (t = -2.47, p = 0.025) and the ACC (t = -2.71, p = 0.011).

AIMS AND HYPOTHESES

Aims: To analyze striatal and ACC GABA concentrations using proton

magnetic resonance spectroscopy (1H MRS) in: a) psychotropic-medication-

free adolescents with TD; and b) HC.

Hypotheses: Adolescents with TD would have significantly decreased ACC

and striatal GABA compared to HC.

REFERENCES 1. Kalanithi PS, Zheng W, Kataoka Y, DiFiglia M, Grantz H, Saper CB, Schwartz ML, Leckman JF,

Vaccarino FM. Altered parvalbumin-positive neuron distribution in basal ganglia of individuals with

Tourette syndrome. Proc Natl Acad Sci 102,13307-13312 (2005).

2. Veliskova J, Moshe SL. Sexual dimorphism and developmental regulation of substantia nigra function.

Ann Neurol 50, 596-601 (2001).

3. Kataoka Y, Kalanithi PS, Grantz H, Schwartz ML, Saper C, Leckman JF, Vaccarino FM. Decreased

number of parvalbumin and cholinergic interneurons in the striatum of individuals with Tourette

syndrome. J Comp Neurol 518: 277-91 (2010).

4. Peterson BS, Staib L, Scahill L, Zhang H, Anderson C, Leckman JF, Cohen DJ, Gore JC, Albert J,

Webster R. Regional brain and ventricular volumes in Tourette syndrome. Arch Gen Psychiatry 58: 427-

40 (2001).

ABSTRACT

Background: Converging lines of evidence derived from postmortem1 and

animal2 studies implicate γ-aminobutyric acid (GABA), the major inhibitory

neurotransmitter in the central nervous system, in the pathophysiology of

Tourette’s disorder (TD), an inherited neuropsychiatric disorder of childhood

onset characterized by multiple motor and at least one vocal tic. Our aims

were to assess anterior cingulate cortex (ACC) and striatal GABA in

adolescents with TD and healthy controls (HC).

Methods: Ten medically healthy adolescents with TD and 22 HC subjects,

ages 12-17, were enrolled in the study. GABA levels were assessed via

proton MR spectroscopy at 3T using the standard J-editing difference

method, and expressed semi-quantitatively as ratios relative to the

unsuppressed voxel tissue water (w). ANCOVA compared GABA between

groups controlling for age and gender. GABA levels were obtained in the

ACC of 10 TD and 22 HC subjects, and in the striatum of 10 TD and 10 HC

subjects.

Results: We found significantly decreased mean GABA levels in TD

subjects compared to HC both in the ACC (2.41 x 10-3 ± 0.29 x 10-3 vs. 2.63

x 10-3 ± 0.028 x 10-3, p = 0.011) and in the striatum (3.18 x 10-3 ± 0.56 x

10-3 vs. 3.75 x 10-3 ± 0.51 x 10-3, p = 0.025). These findings provide the

first direct in vivo evidence of GABA alterations in fronto-striatal circuits in

TD.

Conclusions: Our findings support a role for GABA in the pathophysiology

of TD.

Table 1. Clinical and Demographic Characteristics of Adolescents with TD

and HC

Characteristic Adolescents with TD (N = 10) Healthy Controls (N=22)

Age 14.75 ± 2.19 15.13 ± 1.57

Gender (Female/Male) 3 / 7 (30% / 70%) 16 / 6 (73% / 27%)

YGTSS Scores 31.3 ± 9.8 0

Mean ACC GABA/w 2.41 x 10-3 ± 0.29 x 10-3 2.63 x 10-3 ± 0.028 x 10-3

Mean Striatal GABA/w 3.18 x 10-3 ± 0.56 x 10-3 3.75 x 10-3 ± 0.51 x 10-3 (N=10)

Figure 2. Striatal and ACC GABA/w measures for adolescents with TD and HC

INTRODUCTION

Fronto-striatal alterations have been documented in TD; however, the

mechanisms involved and the role of specific

neurochemical/neurotransmitter dysfunction in TD is still unknown. New

research directions suggest that decreased GABA activity plays a role in the

development of TD. To date, no study has examined this system directly in

patients with TD.

Several postmortem studies of TD patients identified altered and decreased

parvalbumin-positive neuron distribution in the basal ganglia, a change

which is consistent with alterations in GABAergic neurons.3 As such, we

selected the striatum (Figure 1B), a core structure of the basal ganglia, as

one of our regions of interest. Studies have also documented volumetric

abnormalities of the frontal white and gray matter in TD;4 consequently, we

also sought to examine GABA levels in the ACC (Figure 1A).

METHODS

Subjects: Ten adolescents with TD and 22 HC were enrolled. Diagnosis of

TD was established with the Schedule for Affective Disorders and

Schizophrenia for School-Age Children – Present and Lifetime Version (K-

SADS-PL), and severity of tics was assessed by the Yale Global Tic Severity

Scale (YGTSS). All participants were right-

Figure 1. Images of [A] the ACC voxel and [B] the striatal voxel. [C] PRESS 1H MR spectra with editing rf

pulse [a] off and [b] on. Note that with the editing pulse off, a standard PRESS spectrum is obtained, which

yields high quality spectra for N-acetylaspartate (NAA), creatine (CR), and choline (CHO). [D] The

difference of the spectra in [C] showing (a) the detected GABA and Glx peaks, with (b-d) best-fit model

curves and residuals, which yield the areas under the peaks and concentrations. The data were acquired in 15

min using TE/TR 68/1500 ms, and 240 interleaved excitations (total 580) with editing pulse on or off.

C D

CONFLICTS OF INTERST

All authors declare no conflicts.

handed, were psychotropic medication-free, had negative day-of-scan urine

toxicology, and the TD group had YGTSS scores > 10. GABA levels were

obtained in the ACC of 10 TD and 22 HC subjects, and in the striatum of 10

TD and 10 HC subjects.

Data Acquisition and Analysis: All in vivo brain GABA spectra were

recorded in 15 min. from single 2.5x2.5x3.0-cm3 ACC and 1.5x2.0x3.0-cm3

striatal voxels on a GE 3.0 T “EXCITE” MR system, using the standard J-

edited spin echo difference method and an eight-channel phased-array head

coil with TE/TR 68/1500 ms and 240 interleaved excitations (580 total).

Figure 1 illustrates the editing method and the resulting difference spectrum,

which includes a co-edited glutamate+glutamine (Glx) resonance. The areas

under the GABA and Glx peaks were obtained by frequency-domain spectral

fitting (Figure 1D) and expressed as ratios relative to the area of

simultaneously acquired unsuppressed voxel tissue water (w) peaks. Mean

GABA/w values in each voxel for the two groups were compared using rank-

based analysis of covariance, with age and gender as covariates.

B

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Overview: GABAergic Pharmacotherapy

• CPP-109 is Catalyst’s version of vigabatrin • Vigabatrin, also known as gamma-vinyl-GABA (GVG)

– Analogue of the inhibitory neurotransmitter GABA • Orally available, small chiral molecule • Racemic version marketed worldwide since 1986 as Sabril® and Sabrilex®

to treat infantile spasms and epilepsy • U.S NDA approved in August 2009

• Generally well tolerated, safe and effective – Visual field defects (VFD’s) primary safety issue

• No visual field defects observed in short term studies of 9-12 weeks in cocaine & methamphetamine dependent subjects

– Managed in U.S. through REMS program

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Vigabatrin in Patients with Treatment Resistant Tourette’s Disorder: A Proof of Concept Study

Barbara J. Coffey, M.D. M.S., Jonathan Brodie, MD. Ph.D.

• Methods: Open label, proof of concept study for adults with treatment resistant Tourette’s Disorder.

• Inclusion criteria: Age between 18 and 50 years; full DSM-IV-TR diagnostic criteria for TD; failure to respond to an adequate trial of clonidine, guanfacine, and a typical and atypical neuroleptic medications; normal intelligence.

• Study design: The trial lasted 10 weeks and included 9 visits.

Vigabatrin was initiated at a dose of 500 mg for the first 3 days, and increased to 500 mg bid at week 1, 1000 mg bid at week 2 and 1500 mg bid at week 3.

• Subjects were maintained on 1500 mg bid for weeks 3-7, and tapered and discontinued during week 8. A follow up visit occurred at week 10.

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Table 1. Demographic and Clinical Characteristics of the sample

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Vigabatrin in Patients with Treatment Resistant Tourette’s Disorder: A Proof of Concept Study

Barbara J. Coffey, M.D. M.S., Jonathan Brodie, MD. Ph.D.

• Results: Thirty-three subjects were screened for the study, and 4 were enrolled (Table 1).

• All 4 subjects experienced a reduction in YGTSS total tic, tic related impairment and global severity scores at weeks 3, 4, and 6 following titration to the maximum dose at week 3 (p <0.01) (Figure 1).

• Improvement in CGI-Tics and GAF scores were also observed at weeks 3, 4 and 6 (p <0.01).

• In general, vigabatrin was well tolerated; daytime tiredness was the most common adverse effect.

• There were no major ophthalmological adverse effects, nor evidence of suicidality or increase in abnormal movements.

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Figure 1. Changes from baseline to endpoint on YGTSS

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Vigabatrin in Patients with Treatment Resistant Tourette’s Disorder: A Proof of Concept Study

Barbara J. Coffey, M.D. M.S., Jonathan Brodie, MD. Ph.D.

• Conclusion: Preliminary results suggest a small signal that vigabatrin may reduce tics in some treatment resistant patients with Tourette’s Disorder.

• Vigabatrin was generally well tolerated. • Significant ophthalmological adverse effects may not

appear at short term treatment and dosage of 1500 mg bid. • Limitations include the small sample size and the open

label design. Results of this proof of concept study may encourage implementation of larger, controlled studies of vigabatrin as a treatment option for tic reduction in Tourette’s Disorder.

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SD-809 in Treatment of Tourette’s Disorder in Adolescents: Aims and Methods

(j. Jancovic, D. Stamler, B. Coffey et al 2015)

• Background: SD-809 (deutetrabenazine), an inhibitor of vesicular monoamine transporter type 2 (VMAT2), depletes presynaptic DA and may have utility in treatment of various hyperkinetic movement disorder,s including tics.

• Aims: explore safety, tolerability and preliminary efficacy of SD-809 in adolescents with moderate to severe tics associated with Tourette syndrome (TS).

• Methods: In an open-label design, TS patients (age 12-17 years) were titrated over 6 weeks to a dose up to 36 mg/day. The titration phase was followed by a maintenance phase at this dose for 2 weeks.

• An independent, blinded rater assessed tic severity using the Yale Global Tic Severity Scale (YGTSS) and tic impact using the TS-Clinical Global Impression (TS-CGI).

• Safety was assessed by monitoring adverse events (AEs), vital signs, physical examination, 12-lead ECGs, clinical laboratory tests and safety scales.

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SD-809 in Tourette Syndrome

• 23 adolescent patients (mean age 16 years; range: 12-18) with moderate-to-severe tics associated with TS

• Open-label treatment x 8 weeks (dosage: 6-36 mg/day)

• Mean dose at Week 8 = 32.0 mg (Range: 18-36 mg)

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SD-809 in Treatment of Tourette Syndrome in Adolescents: Results

• 23 patients received SD-809 and had at least 1 post-baseline YGTSS assessment.

• Mean (SD) YGTSS Total Tic score at baseline was 31.6 (7.9) which decreased by 11.6 (8.2) at endpoint, a 37.6% reduction in tic severity (p<0.0001).

• PGIC results at week 8 indicated that more than 75% of subjects described themselves as much or very much improved, compared to before treatment.

• Mean dose at endpoint was 32.1 mg/day. • One week after withdrawal of SD-809, statistically significant increases were

observed in a number of YGTSS component scores. • No serious or severe AEs were reported. One subject withdrew from the

study for an AE of irritability that was unrelated to study drug.

• Conclusion: SD-809 was well tolerated and associated with clinically meaningful improvement in tic severity. Results support further development of SD-809 for treatment of TS.

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SD-809 in Tourette syndrome

• Treatment-Emergent Adverse Events: 15/23 (65.2%) • Most common AEs were headache, fatigue, irritability and somnolence • None serious or severe

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Comorbid Disorder(s) Optimally Treated but Tics Still Problematic

CBIT: Habit Reversal Therapy Alpha Agonist

Effective Intolerable or

Inadequate

Monitor Aripiprazole

Risperidone Alpha-Agonist + Atypical

Antipsychotic

Effective

Effective

Monitor

Monitor

Intolerable or Inadequate

Intolerable or Inadequate

Haloperidol or Pimozide

Tics/TD Treatment

Algorithm Level 1

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Adequate Trial(s) of •Alpha-Agonist

•Atypical Antipsychotic •Typical Antipsychotic

•And Combinations But Intolerable Adverse Effects or

Inadequate Benefit

Fluphenazine

Effective

Monitor

Intolerable or Inadequate

Anticonvulsants •Topiramate

•Levetiracetam

Clonazepam Vigabatrin

Pramipexole Baclofen

rTMS DBS

Tics/TD Treatment

Algorithm Level 2

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Summary: Tourette’s Disorder and Tics

• Treatment of tics is indicated when tics cause distress and/or impairment

• Psychiatric comorbid disorders (ADHD, OCD, mood and anxiety) should be comprehensively evaluated and usually need treatment

• CBIT (Habit reversal therapy) has an established evidence base and is suggested as first line treatment for mild-moderate tics

• Aripiprazole is now approved for treatment of Tourette’s Disorder • Pharmacological treatment of tics is difficult. Even after several

trials, there may be potential benefit in trying other options. • Novel treatments, including extended release guanfacine, an H3

receptor inverse agonist, GABAergic agents and VMAT inhibitor are under investigation and are promising… but more studies are needed…..

• Stay tuned!!

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• Icahn School of Medicine at Mount Sinai Tics and Tourette’s Clinical and Research Program/Division of Tics, OCD and Related Disorders (DTOR)

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

• 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 • Laura Ibanez, B.A. Research Coordinator

Blanca Garcia-Delgar, M.D. Visiting Research Fellow • Maxwell Luber, B.A. Research Assistant • Natasha Kostek, B.S Clinical Coordinator • NYU School of Medicine Collaborators: F. Xavier Castellanos, M.D. Jonathan Brodie, M.D. Ph.D.