Tics, Twitches and More: How Research Informs Treatment of Tourette’s Disorder and Related Problems John Kenward Memorial C&A Lecture Department of Psychiatry.

Tics, Twitches and More: How Research Informs Treatment of Tourette’s Disorder and Related Problems John Kenward Memorial C&A Lecture Department of Psychiatry University of Chicago April 13, 2017 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 Icahn School of Medicine at Mount Sinai Research Psychiatrist Nathan Kline Institute for Psychiatric Research

Disclosures (Past 12 Months)
American Academy of Child and Adolescent Psychiatry: Honoraria Auspex/Teva: Research Support Catalyst: Research Support Genco Sciences: Advisory Board NIMH/Rutgers/UCSF: Research Support Neurocrine Biosciences: Research Support Shire: Research Support Tourette Association of America: Research Support, Medical Advisory Board, CDC Partnership Off label indications will be discussed

2. Discuss role and impact of psychiatric comorbid disorders
Tics, Twitches and More: How Research Informs Treatment of Tourette’s Disorder and Related Problems Learning Objectives 1. Review relevant epidemiology, genetics, neurobiology and phenomenology of Tourette’s/ tic disorders 2. Discuss role and impact of psychiatric comorbid disorders 3. Update relevant clinical science, including clinical trials with novel agents and behavioral science 4. Apply clinical science to established and potential new treatments in a treatment algorithm

Tourette’s Disorder or Tourette Syndrome
“EVERYTHING IS EXTRAORDINARY IN THIS DISEASE: THE NAME IS RIDICULOUS, ITS SYMPTOMS PECULIAR, ITS CHARACTER EQUIVOCAL, ITS CAUSES UNKNOWN, ITS TREATMENT PROBLEMATICAL…” Georges Gilles De La Tourette, 1885

Tics: Definition and Phenomenology
Tics: Sudden, rapid, repetitive, non-rhythmic, movements or vocalizations which occur in the context of otherwise normal motor activity Characteristics: Change in type, intensity, location Increased by stress, excitement, anxiety, fatigue Temporarily suppressible Reduced by focused activities Preceded by a “premonitory urge” Premonitory urges: Bodily, sensory or mental sensations that precede tics which are temporarily reduced by performance of tics No longer “stereotyped” Clonic: abrupt onset, rapid Dystonic: briefly sustained abnormal posture Tonic: isometric contraction/ abdominal tensing

Types of Phonic (Vocal) Tics:
Types of Motor Tics: Simple: eye blinking, head shaking, shoulder shrugging, abdominal tensing Complex: touching, tapping, squatting skipping, jumping, chewing on clothes, copropraxia (obscene gestures) Types of Phonic (Vocal) Tics: Simple: sniffing, coughing, grunting, throat clearing, snorting, barking, squeaking Complex: spitting, echolalia (repeating others’ words) palilalia (repeating own words), coprolalia (involuntary uttering of obscenities) Copropraxia – genital groping, giving the finger

DSM 5 (2013): Neurodevelopmental Disorders: Motor Disorders: Tic Disorders
Provisional tic disorder: Single or multiple motor tics and/or vocal tics Tics have been present for less than 1 year since first tic onset. Onset is before age 18 years The disturbance is not attributable to the physiological effects of a substance (eg. cocaine) or another medical condition (eg. Huntington’s disease, postviral encephalitis) Criteria have never been met for Tourette’s Disorder or persistent motor or vocal tic disorder. 8

DSM 5 (2013): Neurodevelopmental Disorders: Motor Disorders: Tic Disorders
Persistent (Chronic) motor or vocal tic disorder: Single or multiple motor tics and/or vocal tics have been present during the illness, but not both motor and vocal. The tics may wax and wane in frequency, but have persisted for more than 1 year since first tic onset. Onset is before age 18 years. The disturbance is not attributable to the physiological effects of a substance (eg cocaine) or another medical condition (eg Huntington’s disease, postviral encephalitis) Criteria have never been met for Tourette’s Disorder 9

DSM 5 (2013): Neurodevelopmental Disorders: Motor Disorders
Tourette’s Disorder (Tourette Syndrome) Both multiple motor and one or more vocal tics have been present at some time during the illness, although not necessarily concurrently. The tics may wax and wane in frequency but have persisted for more than 1 year since first tic onset. Onset before age 18 years. The disturbance is not attributable to the physiological effects of a substance (eg cocaine) or another medical condition (eg Huntington’s disease, postviral encephalitis) 10

Tourette’s Disorder: Genomics
Familial aggregation long established (Baron et al Am J Hum Gen 1985; 33 (5) MZ twin concordance is ~80 % vs. 25% DZ for all chronic tic disorders Early studies confounded by bilineal transmission and complex phenotypes ~ 40% of clinically referred families with more than one affected child have TD and/or OCD in both maternal and paternal pedigrees Linkage studies through TSA International Consortium for Genetics have not been conclusive to date A GWAS was published in 2012 (Scharf, J. et al; Molecular Psychiatry; 2012; 1-8) Findings in 1285 cases and 4964 controls: no markers achieved a genome wide threshold of significance

Tourette International Collaborative (TIC) Genetics Study

TIC Genetics Team and Methods
International team of experts in TD 10 sites in USA (7 clinical); 6 sites in South Korea (5 clinical); 10 clinical sites in Europe All subjects consent for sharing repository Specific Aims: Recruitment of 1590 individuals with TD over 3 years with focus on simplex trios and multiplex families Whole exome sequencing Search for rare coding mutations shared by affected individuals within families Prioritize any genes for which rare, likely deleterious mutations are shared among affected individuals from more than one family Methods: Consenting subjects complete self-report questionnaire (adapted from TSAICG) Experienced clinician reviews questionnaire and verifies symptoms by direct interview of the subject or parent informant Clinician enters data into online Diagnostic Summary system

TIC Genetics Sites-USA (n=10)
UCSF Connecticut Young Shin Kim Matthew State Bennett Leventhal Iowa Samuel Kuperman Indiana Tatiana Foroud Missouri John Rice New Jersey Gary Heiman Jay Tischfield New York Barbara Coffey Dorothy Grice Connecticut Robert King Ohio Donald Gilbert Pennsylvania Lawrence Brown Washington State Samuel Zinner TIC Genetics Sites-USA (n=10)

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

Tourette’s Disorder: Phenomenology and Course: Remission or Persistence?
Onset: Age 5-6 years. Motor tics usually precede vocal tics. Rostral to caudal and simple to complex progression. Course: “…….The duration of the disorder is usually lifelong, though periods of remission lasting from weeks to years may occur………..”(DSM-IV-TR; 2000) Tic severity: Research in the past decade suggests peak severity occurs at about age years with improvement into adolescence in about half to two thirds of patients (Leckman et al. Pediatrics. 1998; Coffey et al. JNMD. 2004; Bloch et al 2006) 17

Time Course of Tic Severity Ratings (Leckman, Zhang, et al. Pediatrics
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Tourette’s Disorder and Psychiatric Comorbidity: Historical Perspective
Psychiatric comorbid symptoms, such as anxiety and mood symptoms, have long been described in patients with Tourette’s Disorder…. In 1899 in “La Maladies des Tics Convulsif” Georges Gilles de la Tourette first described “fears, phobias and arithmomania.”

CDC Prevalence of Diagnosed TS in Youth Age 6-17 in 2007 in US
Tics and Tourette’s Disorder: Epidemiology (Scahill, L. et al; Morbidity and Mortality Weekly Report CDC; 2009) CDC Prevalence of Diagnosed TS 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 vs. 6-11

Prevalence of Selected Diagnoses Age 6-17 years: Lifetime Diagnosis of Tourette Syndrome, by Parent Report (National Survey of Children's Health, United States, 2007) † Among children ever diagnosed with TS, 79% also had been diagnosed with at least one other selected diagnosis.

Jancovic J.NEJM; 2001. 22

Non-specialized Clinic patients Specialized Clinic patients
Informativeness of Structured Diagnostic Interviews in the Identification of Tourette’s Disorder in Referred Youth (Coffey, B. et al .J. Nerv. Ment. Dis. 2000; Sep;188 (9): ) 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 p Current Age 10.8 3.23 3.62 0.89 SES 2.0 1.13 2.2 1.24 0.42 N % 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 23 23 23

Non-specialized Clinic Patients Specialized Clinic Patients
Comorbidity of TD Subjects by Ascertained Site: Mood Disorders Non-specialized Clinic Patients Specialized Clinic Patients Overall Significance (N = 92) (N = 103) Diagnosis N % p Pure TD (Non-comorbid) 2 5 .31 Major Depressive Disorder 45 49 56 54 .49 Any Bipolar Disorder 20 22 16 .24 Dysthymia 9 10 4 .09 Any Mood Disorder 55 60 59 57 .65

Anxiety Disorders In TD Subjects Non-specialized Clinic Patients Specialized Clinic Patients Overall Significance (N = 92) (N = 103) Diagnosis N % p Panic Disorder 10 11 15 .45 Agoraphobia 21 23 27 26 .61 Social Phobia 16 5 .008 Simple Phobia 25 30 .73 OCD 19 37 36 .021 Separation Anxiety 22 24 39 .028 Multiple Anxiety Disorders (2+) 32 35 41 40 .47

Disruptive Behavior Disorders In TD Subjects Non-specialized Clinic Patients Specialized Clinic Patients Overall Significance (N = 92) (N = 103) Diagnosis N % p ADHD 76 84 74 72 .053 Conduct Disorder 18 20 14 .25 Oppositional Defiant Disorder 63 69 58 57 .91 Any Disruptive Disorder 83 91 86 .14

Lifetime Prevalence, Age of Risk, and Genetic Relationships of Comorbid Psychiatric Disorders in Tourette Syndrome Hirschtritt ME et al. (2015). JAMA Psychiatry; April 2015 Volume 72, Number 4 DESIGN: Cross-sectional structured diagnostic interviews with TS (n = 1374) and TS-unaffected family members (n = 1142). RESULTS; Lifetime prevalence of any psychiatric comorbidity among individuals with TS was 85.7%; 57.7% had 2 or more psychiatric disorders % met criteria for OCD or ADHD. Other disorders, including mood, anxiety, and disruptive behavior, each occurred in approximately 30%. The age of greatest risk for the onset of most comorbid psychiatric disorders was between 4 and 10 years. TS was associated with increased risk of anxiety (odds ratio [OR], 1.4; 95%CI, ; P = .04) independent from comorbid OCD and ADHD; however, high rates of mood disorders (29.8% )may be accounted for by comorbid OCD (OR, 3.7; 95%CI, ; P < .001). CONCLUSION: Psychiatric comorbidities are common among individuals with TS, and most comorbidities begin early in life,

Lifetime Prevalence, Age of Risk, and Genetic Relationships
of Comorbid Psychiatric Disorders in Tourette Syndrome Hirschtritt ME et al. (2015). JAMA Psychiatry; April 2015 Volume 72, Number 4

Lifetime Prevalence, Age of Risk, and Genetic Relationships
of Comorbid Psychiatric Disorders in Tourette Syndrome; Hirschtritt ME et al. (2015). JAMA Psychiatry; April 2015 Volume 72, Number 4

Psychosocial Outcome and Psychiatric Comorbidity in Older Adolescents with Tourette Syndrome (Gorman, D. Thompson, N. Plessen, K. Robertson, M. Leckman, J. and Peterson, B.; Br J Psych; 2010; 197; 36-44) Aim: To compare psychosocial outcome and lifetime comorbidity rates in older adolescents with TD and controls Design: N=65 with TD identified in childhood, and 65 matched community controls, assessed at age 18 Results: Compared with controls, TD individuals had substantially lower CGAS scores and higher rates of ADHD, MDD, and CD (p <0.01). In those with TD, poorer psychosocial outcomes were associated with greater ADHD, OCD and tic severity. Conclusion: Clinically referred youth with TD have impaired psychosocial outcome and high comorbidity rates in late adolescence.

Comparison of Lifetime Psychiatric Disorders in the Tourette Syndrome group and Community controls
Gorman, BJ Psych, 2010

Mount Sinai / Presentation Slide / December 5, 2012

TD and Psychiatric Comorbid Disorders: Diagnostic Evaluation
A comprehensive, detailed history with observations derived from multiple sources is the cornerstone of evaluation of patients with TD and psychiatric comorbid disorders. Tics may be suppressed during the initial examinations. Parents may not be aware of OCD symptoms, since children often keep symptoms hidden (worries, rituals). ADHD symptoms, often present, may mask underlying tic and OCD symptoms.

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

2) Competing response training 3) Social support
Comprehensive Behavioral Intervention for Tics Study (CBITS) (Piacentini, J. Woods, D. Scahill, L. et al. JAMA; 2010; 303 (19): ) Three phases: 1) Awareness training 2) Competing response training 3) Social support Two parallel studies compared behavior therapy to supportive therapy (ST) Child study: 126 children (ages 9-17) with TD/CTD; JAMA; 2010 Adult study: 120 children and adults (ages 16+) with TD/CTD: Arch Gen Psych 2012 37

Design: Randomized, observer-blind, controlled trial
Comprehensive Behavioral Intervention for Tics Study (CBITS) (Piacentini, J. Woods, D. Scahill, L. et al. JAMA; 2010; 303 (19): ) Design: Randomized, observer-blind, controlled trial of 126 children recruited December 2004 through May 2007 age 9-17 years, with impairing Tourette’s or chronic tic disorder N=61 Randomly assigned to 8 sessions during 10 weeks BT N=65 control treatment supportive therapy and education Responders received 3 monthly booster sessions Reassessed at 3 and 6 months following treatment. Intervention: Comprehensive behavioral intervention. Main Outcome Measures: Yale Global Tic Severity Scale; CGI 38

CI, 15.1-19.1]) from baseline to end point
Comprehensive Behavioral Intervention for Tics Study (CBITS) (Piacentini, J. Woods, D. Scahill, L. et al. JAMA; 2010; 303 (19): ) Results: Behavioral intervention led to a significantly greater decrease on YGTSS (24.7 [95% confidence interval {CI}, ] to 17.1 [95% CI, ]) from baseline to end point compared with the control treatment (24.6 [95% CI, ] to 21.1 [95% CI, ]) (P.001; difference between groups, 4.1; 95% CI, ) (effect size=0.68). Significantly more children receiving BT compared with control were rated as very much improved or much improved on the CGI–Improvement (52.5% vs 18.5%, respectively; P.001; number needed to treat=3). Treatment gains were durable, with 87% of available responders to BT exhibiting continued benefit 6 months following treatment. Conclusion: A comprehensive behavioral intervention, compared with supportive therapy and education, resulted in greater improvement in symptom severity among children with Tourette and chronic tic disorder. 39

Behavior Therapy for Children with Tourette Disorder: A Randomized Controlled Trial. Piacentini, J. et al. JAMA. 2010;303(19): Mount Sinai / Presentation Slide / December 5, 2012

Responder Status at Week 10: Effect Size 0
Responder Status at Week 10: Effect Size 0.68 (CGI-Improvement = 1 or 2) Courtesy of Piacentini, J. AACAP 2009 CBIT PST p < 42

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

Treatment of Tourette’s Disorder: Overview
Only formally approved (labeled) pharmacotherapy treatments for TD: D2 dopamine antagonists: conventional neuroleptics Haloperidol (Haldol) and pimozide (Orap) (Physicians Desk Reference, 2016) *Aripiprazole (Yoo et al; 2013) 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) Other interventions Psychoeducation; referral to the Tourette Association of America (Bayside, New York) *CBIT (Comprehensive Behavioral Intervention for Tics: Habit reversal therapy) Individual and family therapy; Educational consultation 46

Medication Range of daily dosing Haloperidol 0.25-4.0mg Pimozide
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): doi: /dot ). Medication Range of daily dosing Haloperidol mg Pimozide mg Risperidone mg Aripiprazole mg Clonidine mg Guanfacine

Stimulants and Tics: The Historical Perspective
Case series published in JAMA 1982 reported that stimulants precipitated TS in 15 patients Pharmaceutical labeling states tics and/or family history of tic/Tourette’s are a contraindication for use of stimulants (Physicians Desk Reference, 2017) Older studies: Long term methylphenidate treatment did not worsen tics in children with ADHD and multiple tic disorders (Castellanos, F.X. 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) 49

Stimulants and Tics: What Is the Evidence Base for the Risk of Tics in Association with Stimulants?
50

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); ) 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). 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.

Cohen SC et al. (2015). J Am Acad Child Adolesc Psychiatry

Figure 1. TIC AND OCD SEVERITY OVER TIME Box plots comparing tic and obsessive-compulsive disorder (OCD) symptom severity at the time of initial assessment in childhood (time 1) and follow-up in early adulthood (time 2). Tic symptom severity scores were measured by the Yale Global Tic Severity Scale 7 and are reported for all 46 subjects with Tourette syndrome. Bloch: Arch Pediatr Adolesc Med, Volume 160 (1).January –69

Tics and Obsessive Compulsive Disorder (OCD): Bidirectional Overlap
Patients with OCD have about a 7% lifetime risk of Tourette’s Disorder and 20% risk of tics. Obsessive compulsive symptoms or full obsessive compulsive disorder (OCD) have been reported in 20-60% of patients with Tourette’s Overlapping neuroanatomic structures: CSTC pathways (Cohen, D. and Leckman, J. 1994, 33: 2-15 JAACAP)

Usual Dose Range (mg/day)
Medications used in the Treatment of OCD: Empirical Support and Dosing Guidelines Empirical Support Medication Child Adult Starting Dose (mg) Usual Dose Range (mg/day) Clomipramine A 25-50 Fluoxetine 5-20 10-60 Sertraline 50-250 Fluvoxamine 50-350 Paroxetine B 5-10 Citalopram 20-60 Escitalopram* 10-20 * Not well studied in OCD, presumed to be similar in efficacy to citalopram. Scahill et al. 2006

Mount Sinai / Presentation Slide / December 5, 2012

Guanfacine in Children with Tic Disorders: A Multi-Site Study (Scahill, L. Coffey, B. and Murphy, T. 2012) Guanfacine is commonly used for the treatment of tics in children with Tourette’s Disorder, but the new extended release formulation has not been evaluated for this outcome. 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 is a multi-site, randomized, double-blind, placebo-controlled, parallel-group design, followed by an 8-week extension for subjects who show positive response to GXR in the double-blind phase. Subjects who are randomly assigned to placebo and do not show improvement will be offered 8-week, open-label treatment with GXR. Objectives Primary Aim: To evaluate the benefits of flexibly dosed GXR on tic severity in children with TD as measured by the Total Tic score of the YGTSS. Results are pending and will be available soon!! 59

How do we know what’s inside?
I see glutamate!

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

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 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 x 10-3 ± x 10-3, p = 0.011) and in the striatum (3.18 x 10-3 ± 0.56 x vs 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. RESULTS B 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 Mean ACC GABA/w 2.41 x 10-3 ± 0.29 x 10-3 2.63 x 10-3 ± 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) 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). C D 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). 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. Figure 2. Striatal and ACC GABA/w measures for adolescents with TD and HC 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. 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. 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, (2005). 2. Veliskova J, Moshe SL. Sexual dimorphism and developmental regulation of substantia nigra function. Ann Neurol 50, (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: (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: (2001). 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- CONFLICTS OF INTERST All authors declare no conflicts.

Overview: GABAergic Pharmacotherapy
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 (VFDs) 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

GABA-AT Inhibitor Platform
GABA-AT inhibitors have No receptor dependency No addictive liability No dose tolerance Minimal side effects Neuronal Excitability Seizures (IS) Craving Inhibit GABA-AT Stored Brain GABA Brain Dopamine Addictive Behavior Correct HypoGABAergic Signaling Disorders Other CNS Indications

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 medication; normal intelligence. Study design: 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.

Table 1. Demographic and Clinical Characteristics of the sample

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. One subject still remains on the medication and is doing well two years out without adverse effects

Vigabatrin in Patients with Treatment Resistant Tourette’s Disorder: A Proof of Concept Study Figure 1. Changes from baseline to endpoint on YGTSS

Vigabatrin was generally well tolerated.
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 in short term treatment and dosage of 1500 mg bid. Limitations include the very small sample size and open label design. Results of this small proof of concept study may encourage implementation of larger, controlled studies of vigabatrin as a treatment option for tic reduction in Tourette’s Disorder.

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 disorders, including tics. Aims: Explore safety, tolerability and preliminary efficacy of SD-809 in adolescents with tics associated with Tourette Syndrome (TS). Methods: In an open-label design, TS patients (age years) were titrated over 6 weeks to a dose up to 36 mg/day. Titration phase was followed by a maintenance phase at this dose for 2 weeks. An independent, blinded rater assessed tic severity with the Yale Global Tic Severity Scale (YGTSS) and tic impact with 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.

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: mg) _

SD-809 in Treatment of Tourette Syndrome in Adolescents: Results
N= 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.

SD-809 in Treatment of Tourette Syndrome in Adolescents: Results
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. A large Phase II/III global trial will take place soon.

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

CBIT (Habit Reversal Therapy) Alpha-Agonist + Atypical Antipsychotic
Tics Primary Target CBIT (Habit Reversal Therapy) Alpha 2 Agonist Effective Intolerable or Inadequate Monitor Aripiprazole Alpha-Agonist + Atypical Antipsychotic Haloperidol Pimozide Suggested Tics/TD Treatment Algorithm: Tics Primary

Alpha 2 Agonist or Stimulant
TD + ADHD Alpha 2 Agonist or Stimulant Effective Monitor Intolerable or Inadequate Stimulant Stimulant + Alpha Agonist Atomoxetine TD + ADHD Suggested Treatment Algorithm: Tics and/or ADHD Primary

Suggested Treatment Algorithm
TD + Anxiety/OCD CBT and/or SSRI Effective Monitor Intolerable or Inadequate Clonazepam SSRI + clonazepam SSRI + neuroleptic Vigabatrin? Baclofen? TD + Anxiety/OCD Suggested Treatment Algorithm Anxiety/OCD Primary

Summary: Tics, Twitches and More: How Research Informs Treatment of Tourette’s Disorder and Related Problems Tourette’s Disorder has a complex phenomenology and heterogeneous phenotype Psychiatric comorbid disorders (ADHD, OCD, mood and anxiety disorders) may start early in life and need comprehensive evaluation. Older adolescents may be at risk for greater psychiatric comorbidity, poorer outcome and depression One of the largest clinical trials to date in children with tics/Tourette’s demonstrated that CBIT was effective, durable and without significant adverse effects. Thus this is the first line recommended treatment. Only 3 medications are labeled for treatment of Tourette’s in the US, and all are neuroleptics. Off label alpha 2 agonists are recommended for first line pharmacotherapy given neuroleptics’ potential for adverse effects. Stimulants may be used judiciously in patients with TD + ADHD There is some evidence for GABA deficits in the striatum and ACC in individuals with Tourette’s Disorder Novel treatments, including GABAergic and VMAT 2 inhibitor agents may be promising…. but more investigation is needed….. 82

Associate Professor, Department of Psychiatry,
Acknowledgements: Icahn School of Medicine at Mount Sinai Tics and Tourette’s Clinical and Research Program Wayne Goodman, M.D. Professor and Former 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 Maxwell Luber, B.A.Research Coordinator Melissa Fluehr, B.A. Clinical Coordinator NYU School of Medicine Collaborators: F. Xavier Castellanos, M.D. Jonathan Brodie, M.D. Ph.D. NKI Collaborator: Russell Tobe, M.D.

Tics, Twitches and More: How Research Informs Treatment of Tourette’s Disorder and Related Problems John Kenward Memorial C&A Lecture Department of Psychiatry.

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Tics, Twitches and More: How Research Informs Treatment of Tourette’s Disorder and Related Problems John Kenward Memorial C&A Lecture Department of Psychiatry.

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Presentation on theme: "Tics, Twitches and More: How Research Informs Treatment of Tourette’s Disorder and Related Problems John Kenward Memorial C&A Lecture Department of Psychiatry."— Presentation transcript:

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