ORIGINAL ARTICLE
A D1 Receptor Antagonist, Ecopipam, for Treatment of Tics in Tourette Syndrome Donald L. Gilbert, MD, MS,* Cathy L. Budman, MD,† Harvey S. Singer, MD,‡§ Roger Kurlan, MD,∥ and Richard E. Chipkin, PhD¶ Objectives: Dysregulation of dopaminergic signaling has been hypothesized to underlie the motor and phonic tics in Tourette syndrome (TS). The objective of this trial was to evaluate the safety and ticreducing activity of the selective dopamine D1 receptor antagonist ecopipam in adults with TS. Methods: This was a multicenter, nonrandomized, open-label study of 50-mg ecopipam daily (weeks 1–2) and then 100 mg daily (weeks 3–8), taken orally before bedtime. The primary efficacy end point was the change in the Yale Global Tic Severity Scale (YGTSS) total tic score. Comorbid psychiatric symptoms and premonitory urges were rated; weight, serum metabolic studies, and adverse effects were monitored. Results: Eighteen adults (15 men; 15 white, 2 African American, 1 Asian), with a mean age of 36.2 years (range, 18–63 years), were enrolled, and 15 completed the study. Mean (SD) YGTSS Total Tic score was 30.6 (8.8) at baseline and 25.3 (9.2) at 8 weeks (2-tailed paired t17 = 4.4; P = 0.0004). Mean (SD) YGTSS impairment score was 29.7 (10.9) at baseline and 22.8 (13.7) at final visit (t17 = 2.2; P = 0.04). There was no significant change in premonitory urges or psychiatric symptoms. Mean change in weight was −0.7 kg (P = 0.07). The most commonly reported adverse events were sedation (39%), fatigue (33%), insomnia (33%), somnolence (28%), anxiety (22%), headache (22%), and muscle twitching (22%). Conclusions: In this open-label study in adults with TS, tics were reduced after 8 weeks of treatment with ecopipam. To confirm safety and efficacy, randomized, double blind, placebo-controlled trials are warranted. Key Words: Tourette syndrome, ecopipam, dopamine, D1 receptor, clinical trial (Clin Neuropharm 2014;37: 26–30)
T
ourette syndrome (TS) is a chronic, childhood-onset, hyperkinetic movement disorder characterized by multiple tics that wax and wane in frequency and intensity and that migrate in location over time. Tics are repeated, individually recognizable,
*Division of Neurology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH; †Movement Disorders Center, Department of Psychiatry, North Shore-LIJ Health System, Manhasset, NY; Departments of ‡Neurology, §Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD; ∥Atlantic Neuroscience Institute, Overlook Hospital, Summit, NJ; and ¶Psyadon Pharmaceuticals, Inc, Germantown, MD. Supported by grants from Psyadon Pharmaceuticals, Inc, and Tourette Syndrome Association USA. Conflicts of Interest and Source of Funding: The authors have no conflicts of interest to declare. Presented in part at the 65th Annual Meeting of the American Academy of Neurology, March 19, 2013, San Diego, CA, and at the 166th Annual Meeting of the American Psychiatric Association, May 19, 2013, San Francisco, CA. ClinicalTrials.gov, NCT01244633 Address correspondence and reprint requests to Donald L. Gilbert, MD, MS, Departments of Pediatrics and Neurology, Cincinnati Children’s Hospital Medical Center, ML 2015 - Neurology, 3333 Burnet Ave, Cincinnati OH 45230; E-mail: [email protected] Copyright © 2014 by Lippincott Williams & Wilkins DOI: 10.1097/WNF.0000000000000017
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intermittent movements and phonations sometimes performed in response to specific premonitory urges.1 Tics may be volitionally suppressed, but this is often accompanied by increased salience of a premonitory urge. Tics in a given body area generally do not occur during performance of goal-directed behavior using that same body area. Like other movement disorders, TS may be considered as a basal ganglia circuit disorder,2 involving abnormal signaling in the cortical-striatal-pallidal-thalamo-cortical circuits. Because TS is heterogeneous, it is possible that dysfunctional signaling occurs in different loci in different individuals. According to some models of action selection,3,4 nigrostriatal dopamine “drives” movement in through both dopamine D1 agonism, which activates the excitatory direct pathway, and D2 agonism, which inhibits the inhibitory indirect pathway. Although a unique, tic-related dopaminergic D1 abnormality has not been unequivocally identified with physiological, post-mortem, neuroimaging, or genetic studies,5 the preponderance of evidence supports the theory that dopaminergic dysregulation, either in subcortical nodes6,7 or populations of cerebral cortical neurons,7 underlies tic symptoms in some individuals with TS.8 The clinical implication of this circuit model is that pharmacologic action at dopamine receptors may improve or exacerbate tics. A functional magnetic resonance imaging study demonstrating heightened activity in the D1-mediated pathway in more severe TS9 supports that reduction of dopaminergic signaling via the D1 pathway might reduce tics. Empirically, effects of antagonizing dopaminergic signaling via the D2 indirect pathway is supported by observational10 and clinical trial data.11,12 Fluphenazine, a high-potency D2 receptor with in vitro, but probably not in vivo, D1 blocking activity,13 reduces tics.14,15 However, there are no prior studies investigating whether a selective D1 receptor blocking agent might reduce tics. Ecopipam, a selective antagonist of the dopamine D1 receptor, demonstrates high affinity for D1 receptors in vitro.16,17 Additional studies show that ecopipam is roughly 1000-fold selective for the D1 versus the D2 receptor as well as 100-fold selective versus serotonin receptors (3H-ketanserin) and does not bind at concentrations greater than 700-fold to any of the following sites: adenosine, benzodiazepine, glutamate/AMPA/ kainate, GABA, muscarinic, nicotinic, opiate, α-, or β-adrenergic (Psyadon data on file). Lastly, ecopipam exposure has no agonist, cyclic AMP-mediated effects.18 We report here the results of an open-label clinical trial testing the safety, tolerability, and tic-suppressing effects of ecopipam in adults with TS.
MATERIALS AND METHODS Study Subjects All patients fulfilled the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for TS and had a minimum score of 30 on the Diagnostic Confidence Index for TS19 as well as a minimum total tic score of 20 from the Yale
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Clinical Neuropharmacology • Volume 37, Number 1, January/February 2014
Global Tic Severity Scale (YGTSS).20 Ages of the subjects ranged from 18 to 63 years. All subjects had exhibited both motor and phonic tics for more than 5 years. Exclusion criteria included any unstable medical illness, clinically significant electrocardiogram abnormality, a history of myocardial infarction within 6 months, or a history of seizures. Common adult medical problems such as hypertension were allowed. Subjects were also excluded if they had a major depressive episode in the prior 2 years, a history of attempted suicide, current suicidal ideation, schizophrenia, or bipolar disorder. Common TS comorbidities including attention deficit hyperactivity disorder (ADHD), obsessive compulsive disorder (OCD), and generalized anxiety disorder were permitted if symptoms were reasonably well controlled. Concomitant treatment with selective serotonin reuptake inhibitors was permitted if the dose had been stable for at least 4 weeks. Patients were excluded if they were taking medications with tic-suppressing effects or with possible unfavorable interactions with ecopipam such as lithium, psychostimulants, dopamine agonists, or monoamine oxidase inhibitors.
Study Design Planned enrollment was 30 adults. This was a phase 2a, multicenter, single-arm, open-label 8-week clinical trial. The primary objective of this study was to evaluate the safety of ecopipam in adults with TS. The secondary objective was to evaluate clinical activity in suppressing tics. The primary clinical end point was the total tic score of the YGTSS after treatment. The protocol was approved by the institutional review boards at all participating centers.
Clinical Outcomes After eligibility screening, patients were assessed at baseline and every 2 weeks until the final study visit at the end of 8 weeks of ecopipam treatment. Safety end points included frequency of all adverse events (AEs) and serious AEs as well as effects on mood, suicidal ideation, and weight. The YGTSS, which rates motor and phonic tics separately with scores of 0 to 5 for 5 domains (number, frequency, intensity, complexity, and interference), resulting in a maximum possible score of 50, was used to assess tic severity at study onset and end point.20 Secondary tic outcomes were the YGTSS tic impairment scores (0–50) as well as the Clinical Global Impression of Improvement and Severity Scales.21 Attention deficit hyperactivity disorder was evaluated with the Adult Attention Deficit/ Hyperactivity Disorder Self-Report Symptoms (ASRS) checklist, which rates 18 symptoms with scores of 0 to 4 (never, rarely, sometimes, often, very often). On the basis of this, ADHD is considered “highly likely” when greater than 24 and “likely” at 17 to 24.22 Obsessive compulsive disorder was evaluated with the Yale-Brown Obsessive Compulsive Scale,23 in which 5 features (time, interference, distress, resistance, and control) are rated for obsessions and compulsions separately with scores of 0 to 5. Hamilton Depression Rating Scale24 and the Premonitory Urges in TS (PUTS) Scale25 were also used. Adverse event monitoring included interval history, structured diagnostic interviews, the Columbia Suicide Scale,26 physical examination, routine laboratory studies, and electrocardiography.
Safety of Ecopipam in Adults With TS
after the screening. All patients were treated with ecopipam at an initial dose of 50 mg daily by mouth for 2 weeks taken at bedtime, followed by 100 mg daily by mouth for 6 weeks taken at bedtime. At the discretion of the clinician, a dose of 50 mg could be maintained or resumed if AEs were present. In-person assessments occurred every 2 weeks during the treatment.
Statistical Analysis The primary symptom end point was the tic severity as rated by the YGTSS total tic score. All scales were analyzed comparing baseline to end point using paired t test or, if not parametric, a Wilcoxon signed rank test. The primary analysis was intent to treat (ITT) with the last observation carried forward (LOCF). An analysis restricted to subjects who completed the entire study was also performed.
Sample Size Calculation and Planned Interim Analysis Sample size calculation was based on an anticipated YGTSS total tic score group mean at baseline of 26 (of possible 50), with a standard deviation of the change from baseline to end point (final visit or LOCF) of 10. The study was designed to detect a YGTSS total tic reduction of 5 points, which would yield a paired t test statistical significance (P < 0.05) and an approximate open-label effect size of 0.5. No power analysis was done because of the single-treatment design. The protocol included an interim analysis by an independent drug safety monitoring board (DSMB) when 10 subjects had completed. Because of simultaneous and ongoing enrollments, the interim analysis was conducted when 12 subjects had completed. Three dropout subjects were included, so the interim analysis included 15 enrolled subjects. Three additional subjects who had been ongoing during the DSMB review were completed, for a final study population of 18 subjects. Because the interim analysis demonstrated a statistically significant tic reduction, the DSMB recommended early termination of the study. That is, there was no efficacy information to be gained by enrolling additional subjects, and moreover, given the large human experience (>2000 patients) with compound, it was unlikely that substantially different adverse effect data would be identified.
RESULTS Twenty-three patients were screened. The ITT group comprised 18 patients who met entry criteria, gave consent, and started study medication. Three patients withdrew from the study because of AEs. Thus, 15 subjects completed the study protocol (completers). Baseline characteristics of the subjects are summarized in Table 1. The population included adults with common health problems such as hypertension (medications on file) as well as stably treated psychiatric problems such as anxiety, OCD, and ADHD. Three subjects were prescribed citalopram; one subject, buspirone. There was concomitant medication use for acute problems such as pain or infection.
Clinical Outcomes Treatment The study was a monotherapy trial; that is, all subjects were withdrawn from all other tic-suppression drugs at least 7 days before and neuroleptics at least 2 weeks before screening. The baseline, first-dose visit occurred at a mean of 2 weeks © 2014 Lippincott Williams & Wilkins
Using the LOCF, the mean (SD) YGTSS tic reduction at the time of the interim analysis was 5.3 (9.0) in the ITT (n = 18) and 5.9 (9.0) in the completer (n = 15) analyses (Fig. 1; Table 2). Reductions in the YGTSS total, motor, and vocal tic severity scores occurred. Post hoc analysis showed reduction in the www.clinicalneuropharm.com
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TABLE 1. Demographics of Study Sample
No. Sex, M:F Race White African American Asian/Pacific Islander Age, mean (SD), y Age, (min, max), y Prior use of D2 receptor blockers
All (Intent to Treat)
Completers Only
18 15:3
15 12:3
15 2 1 36 (15) 18, 63 13
12 2 1 35 (15) 18, 63 10
F, female; M, male.
YGTSS at the first treatment visit (t17 = −4.9; P = 0.0001), which persisted for the remainder of the study (Fig. 1). Impairment scores and Clinical Global Impression of Severity also improved. Premonitory urges (PUTS) and depression scores did not change, and there was no report of development of suicidal ideation. Symptom scores of ADHD were in the diagnostic range in most cases at baseline (Table 2): “highly likely” range for 13, “likely” for 3, subthreshold for 2. The mean reduction in ASRS was 13%. Post hoc ITT comparisons involving only those participants with ASRS scores in the highly likely range (mean [SD], 39.1 [8.9]) showed a mean 16% reduction by the final visit (P = 0.06). Baseline OCD scores were low: none or subclinical symptoms for 10, mild for 4, moderate for 4. Posttreatment OCD ratings did not change.
Safety Outcomes There were no serious AEs reported in this study. Non– serious AEs were rated mild to severe. Four subjects experienced 9 AEs rated as severe. Two, both in their 50s, discontinued participation early: one for insomnia and the other for somnolence, decreased appetite, and cold sweats. The remaining 2 subjects completed the study. One had jitteriness and sedation. This individual remained on the initial, 50-mg dose for 4 weeks, rather than 2. The other had a rib fracture on day 24 of the study and a panic attack on day 37. Fourteen subjects experienced AEs rated as mild to moderate. The most common of these were sedation (39%), fatigue (33%), insomnia (33%), somnolence (28%), anxiety (22%), headache (22%), and muscle twitching (22%). One subject was noted to develop akathisia. There were no clinically meaningful laboratory abnormalities identified at screening or treatment week 8 related to study participation (data on file). One subject had systolic hypertension at both visits. One subject had an electrocardiogram abnormality at treatment week 8, judged as not clinically significant by an independent cardiologist. Body weight did not increase.
Ecopipam is a selective D1 antagonist.27,28 Postmortem human brain tissue studies demonstrated the affinity of ecopipam for D1 receptors localizing to caudate, putamen, and cortical regions.29 Positron emission tomographic imaging showed 100 mg administered orally results in 70% D1 receptor occupancy,30 comparable with that seen in positron emission tomographic studies with D2-selective antagonists.31 Effects of ecopipam on behaviors that may be relevant to TS, particularly locomotor activity32 and motivation/reward responses,33 have been studied extensively in rodents and primates. The obvious limitation of this study is the open-label design. In a prior study, positive results from an open-label study of levetiracetam34 were not later replicated in a double-blind study.35 In contrast, positive results from an open-label study of risperidone36 were supported by multiple subsequent doubleblind trials.12,37 A recent meta-analysis showed that placebo effects in tic disorders may be of small magnitude, particularly in adults.38 The fact that 13 of 18 participants had previously taken one or more neuroleptics supports that the benefit of ecopipam could be clinically important. Comparing the tic reduction in this study with those in D2 antagonist studies39 is problematic because most prior clinical trials involve children and adolescents, not adults. It would be of interest to determine whether the effect size of ecopipam on YGTSS would be greater in younger patients. The decision to include in the present study patients with typical comorbidities allowed us to recruit a representative sample of adult patients.40 This also provided the opportunity to explore whether ecopipam might affect comorbid symptoms. Regarding OCD, our sample had predominantly mild symptoms. The “floor effect” made determining whether ecopipam could improve OCD symptoms impossible. There was no worsening of ADHD symptoms that were prevalent and moderately severe in this cohort. The finding that ecopipam did not affect the urge to tic, as assessed by the PUTS scale, holds scientific interest. The salience and strength of the tic urge captured by the PUTS may involve failure to filter out particular sensations, which, in turn, compel
DISCUSSION Pharmacologic antagonism of the dopamine D1 receptor is a novel approach to tic reduction in TS. In this first study, tic severity was reduced after open-label treatment with the D1 antagonist ecopipam. During the treatment, there was no worsening of ADHD or OCD and no weight gain. The safety and tolerability results suggest the potential utility of ecopipam in adults with TS and support the need for double-blind, placebo-controlled studies.
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FIGURE 1. Time course of tic severity during the study for individual patients taking ecopipam. Thick line is group mean. © 2014 Lippincott Williams & Wilkins
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Clinical Neuropharmacology • Volume 37, Number 1, January/February 2014
Safety of Ecopipam in Adults With TS
TABLE 2. Clinical Rating Scales for Intention to Treat and Study Completors All Participants, ITT (n = 18)
YGTSS total tic Motor Phonic YGTSS impairment PUTS CGI improvement CGI severity ADHD ASRS OCD YBOCS total Obsession Compulsion HAM-D Depression
Baseline Mean SD 30.6 8.8 16.2 4.5 14.4 5.9 29.7 10.9 24.6 7.1 — — 4.7 1.0 33.0 12.6 7.8 8.0 3.4 4.3 4.3 4.0 3.1 2.3
Study Completors (n = 15)
End Mean 25.3 13.7 11.6 22.8 25.1 −1.2 3.9 28.6 8.1 3.7 4.4 3.4
SD 9.2 4.2 6.8 13.7 6.2 1.2 1.2 14.2 7.5 4.5 3.8 3.1
P 0.0004 0.0004 0.0056 0.0407 NS 0.0043 0.0137 0.11 NS NS NS NS
Baseline Mean SD 30.3 8.7 16.2 4.5 14.1 6.0 29.7 11.4 25.0 6.7 — — 74.6 1.0 33.1 13.7 9.1 8.1 4.1 4.4 5.0 4.1 2.9 2.3
End Mean 24.4 13.7 10.7 20.3 25.4 −1.3 3.7 28.3 9.0 3.9 5.0 3.4
SD 9.3 4.6 6.8 12.9 5.9 1.2 1.2 15.3 7.7 4.7 3.8 3.1
P 0.0008 0.0014 0.0046 0.0161 NS 0.0068 0.0137 0.14 NS NS NS NS
CGI, clinical global impression; HAM-D, Hamilton Depression Rating Scale; NS, not statistically significant (all of these are P values > 0.2); YBOCS, Yale Brown Obsessive Compulsive Scale. Bold designates significant (p < .05).
performance of the tic. The tic that is performed in response to an urge may then be executed like purposeful movements via the direct cortico-striatal, D1-influenced pathway. Thus, the observation that ecopipam improves tics without reducing urges may support a “downstream” mechanism of action. That is, while taking ecopipam, patients with TS may sense an urge just as strongly but feel able to resist performing their tics more successfully. The AE profile of ecopipam seen in patients with TS is comparable with that reported previously.41 Adverse effects were mild to moderate and primarily affected the central nervous or gastrointestinal systems. No clinically significant hepatic, renal, or cardiovascular AEs were reported. Unlike D2 antagonists, there was no increase in body weight.41 Overall, patient retention in the study was comparable with that seen in clinical trials of other drugs used to TS.12,42,43 Extrapolating adverse effects and efficacy to a pediatric population requires some caution because 5 participants were in their 50s or 60s. Should ecopipam’s efficacy be confirmed in double-blind trials, active comparator studies with D2 receptor blockers would be valuable. Certain individuals with TS might respond more selectively to one class. Issues of D1 versus D2 activity have also arisen with regard to variable results using dopamine agonists for tic suppression.44–46 Overlap in efficacy could also occur because D2 antagonists may “indirectly” suppress tics via a more broadly inhibited motor state, as the one that occurs in drug-induced parkinsonism, whereas D1 antagonists may have more a “direct” tic-suppressing activity via circuits underlying selected and habitual actions.
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CONCLUSIONS In conclusion, this first study of ecopipam for TS suggests promise for tic suppression. The absence of common neuroleptic adverse effects of weight gain47 and those of drug-induced movement disorders48 support larger controlled trials.
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ACKNOWLEDGMENTS The authors thank the clinical research team at each site for their careful work and the participating patients for their efforts. © 2014 Lippincott Williams & Wilkins
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41. Astrup A, Greenway FL, Ling W, et al. Randomized controlled trials of the D1/D5 antagonist ecopipam for weight loss in obese subjects. Obesity (Silver Spring) 2007;15:1717–1731. 42. Budman CL, Gayer A, Lesser M, et al. An open-label study of the treatment efficacy of olanzapine for Tourette’s disorder. J Clin Psychiatry 2001;62:290–294. 43. Dion Y, Annable L, Sandor P, et al. Risperidone in the treatment of Tourette syndrome: a double-blind, placebo-controlled trial. J Clin Psychopharmacol 2002;22:31–39. 44. Black KJ, Mink JW. Response to levodopa challenge in Tourette syndrome. Mov Disord 2000;15:1194–1198. 45. Gilbert DL, Dure L, Sethuraman G, et al. Tic reduction with pergolide in a randomized controlled trial in children. Neurology 2003;60:606–611. 46. Kurlan R, Crespi G, Coffey B, et al. A multicenter randomized placebo-controlled clinical trial of pramipexole for Tourette’s syndrome. Mov Disord 2012;27:775–778. 47. Zuddas A, Zanni R, Usala T. Second generation antipsychotics (SGAs) for non-psychotic disorders in children and adolescents: a review of the randomized controlled studies. Eur Neuropsychopharmacol 2011;21:600–620. 48. Wonodi I, Reeves G, Carmichael D, et al. Tardive dyskinesia in children treated with atypical antipsychotic medications. Mov Disord 2007;22:1777–1782.
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A D1 Receptor Antagonist, Ecopipam, for Treatment of Tics in Tourette Syndrome Donald L. Gilbert, MD, MS,* Cathy L. Budman, MD,† Harvey S. Singer, MD,‡§ Roger Kurlan, MD,∥ and Richard E. Chipkin, PhD¶ Objectives: Dysregulation of dopaminergic signaling has been hypothesized to underlie the motor and phonic tics in Tourette syndrome (TS). The objective of this trial was to evaluate the safety and ticreducing activity of the selective dopamine D1 receptor antagonist ecopipam in adults with TS. Methods: This was a multicenter, nonrandomized, open-label study of 50-mg ecopipam daily (weeks 1–2) and then 100 mg daily (weeks 3–8), taken orally before bedtime. The primary efficacy end point was the change in the Yale Global Tic Severity Scale (YGTSS) total tic score. Comorbid psychiatric symptoms and premonitory urges were rated; weight, serum metabolic studies, and adverse effects were monitored. Results: Eighteen adults (15 men; 15 white, 2 African American, 1 Asian), with a mean age of 36.2 years (range, 18–63 years), were enrolled, and 15 completed the study. Mean (SD) YGTSS Total Tic score was 30.6 (8.8) at baseline and 25.3 (9.2) at 8 weeks (2-tailed paired t17 = 4.4; P = 0.0004). Mean (SD) YGTSS impairment score was 29.7 (10.9) at baseline and 22.8 (13.7) at final visit (t17 = 2.2; P = 0.04). There was no significant change in premonitory urges or psychiatric symptoms. Mean change in weight was −0.7 kg (P = 0.07). The most commonly reported adverse events were sedation (39%), fatigue (33%), insomnia (33%), somnolence (28%), anxiety (22%), headache (22%), and muscle twitching (22%). Conclusions: In this open-label study in adults with TS, tics were reduced after 8 weeks of treatment with ecopipam. To confirm safety and efficacy, randomized, double blind, placebo-controlled trials are warranted. Key Words: Tourette syndrome, ecopipam, dopamine, D1 receptor, clinical trial (Clin Neuropharm 2014;37: 26–30)
T
ourette syndrome (TS) is a chronic, childhood-onset, hyperkinetic movement disorder characterized by multiple tics that wax and wane in frequency and intensity and that migrate in location over time. Tics are repeated, individually recognizable,
*Division of Neurology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH; †Movement Disorders Center, Department of Psychiatry, North Shore-LIJ Health System, Manhasset, NY; Departments of ‡Neurology, §Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD; ∥Atlantic Neuroscience Institute, Overlook Hospital, Summit, NJ; and ¶Psyadon Pharmaceuticals, Inc, Germantown, MD. Supported by grants from Psyadon Pharmaceuticals, Inc, and Tourette Syndrome Association USA. Conflicts of Interest and Source of Funding: The authors have no conflicts of interest to declare. Presented in part at the 65th Annual Meeting of the American Academy of Neurology, March 19, 2013, San Diego, CA, and at the 166th Annual Meeting of the American Psychiatric Association, May 19, 2013, San Francisco, CA. ClinicalTrials.gov, NCT01244633 Address correspondence and reprint requests to Donald L. Gilbert, MD, MS, Departments of Pediatrics and Neurology, Cincinnati Children’s Hospital Medical Center, ML 2015 - Neurology, 3333 Burnet Ave, Cincinnati OH 45230; E-mail: [email protected] Copyright © 2014 by Lippincott Williams & Wilkins DOI: 10.1097/WNF.0000000000000017
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intermittent movements and phonations sometimes performed in response to specific premonitory urges.1 Tics may be volitionally suppressed, but this is often accompanied by increased salience of a premonitory urge. Tics in a given body area generally do not occur during performance of goal-directed behavior using that same body area. Like other movement disorders, TS may be considered as a basal ganglia circuit disorder,2 involving abnormal signaling in the cortical-striatal-pallidal-thalamo-cortical circuits. Because TS is heterogeneous, it is possible that dysfunctional signaling occurs in different loci in different individuals. According to some models of action selection,3,4 nigrostriatal dopamine “drives” movement in through both dopamine D1 agonism, which activates the excitatory direct pathway, and D2 agonism, which inhibits the inhibitory indirect pathway. Although a unique, tic-related dopaminergic D1 abnormality has not been unequivocally identified with physiological, post-mortem, neuroimaging, or genetic studies,5 the preponderance of evidence supports the theory that dopaminergic dysregulation, either in subcortical nodes6,7 or populations of cerebral cortical neurons,7 underlies tic symptoms in some individuals with TS.8 The clinical implication of this circuit model is that pharmacologic action at dopamine receptors may improve or exacerbate tics. A functional magnetic resonance imaging study demonstrating heightened activity in the D1-mediated pathway in more severe TS9 supports that reduction of dopaminergic signaling via the D1 pathway might reduce tics. Empirically, effects of antagonizing dopaminergic signaling via the D2 indirect pathway is supported by observational10 and clinical trial data.11,12 Fluphenazine, a high-potency D2 receptor with in vitro, but probably not in vivo, D1 blocking activity,13 reduces tics.14,15 However, there are no prior studies investigating whether a selective D1 receptor blocking agent might reduce tics. Ecopipam, a selective antagonist of the dopamine D1 receptor, demonstrates high affinity for D1 receptors in vitro.16,17 Additional studies show that ecopipam is roughly 1000-fold selective for the D1 versus the D2 receptor as well as 100-fold selective versus serotonin receptors (3H-ketanserin) and does not bind at concentrations greater than 700-fold to any of the following sites: adenosine, benzodiazepine, glutamate/AMPA/ kainate, GABA, muscarinic, nicotinic, opiate, α-, or β-adrenergic (Psyadon data on file). Lastly, ecopipam exposure has no agonist, cyclic AMP-mediated effects.18 We report here the results of an open-label clinical trial testing the safety, tolerability, and tic-suppressing effects of ecopipam in adults with TS.
MATERIALS AND METHODS Study Subjects All patients fulfilled the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for TS and had a minimum score of 30 on the Diagnostic Confidence Index for TS19 as well as a minimum total tic score of 20 from the Yale
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Clinical Neuropharmacology • Volume 37, Number 1, January/February 2014
Global Tic Severity Scale (YGTSS).20 Ages of the subjects ranged from 18 to 63 years. All subjects had exhibited both motor and phonic tics for more than 5 years. Exclusion criteria included any unstable medical illness, clinically significant electrocardiogram abnormality, a history of myocardial infarction within 6 months, or a history of seizures. Common adult medical problems such as hypertension were allowed. Subjects were also excluded if they had a major depressive episode in the prior 2 years, a history of attempted suicide, current suicidal ideation, schizophrenia, or bipolar disorder. Common TS comorbidities including attention deficit hyperactivity disorder (ADHD), obsessive compulsive disorder (OCD), and generalized anxiety disorder were permitted if symptoms were reasonably well controlled. Concomitant treatment with selective serotonin reuptake inhibitors was permitted if the dose had been stable for at least 4 weeks. Patients were excluded if they were taking medications with tic-suppressing effects or with possible unfavorable interactions with ecopipam such as lithium, psychostimulants, dopamine agonists, or monoamine oxidase inhibitors.
Study Design Planned enrollment was 30 adults. This was a phase 2a, multicenter, single-arm, open-label 8-week clinical trial. The primary objective of this study was to evaluate the safety of ecopipam in adults with TS. The secondary objective was to evaluate clinical activity in suppressing tics. The primary clinical end point was the total tic score of the YGTSS after treatment. The protocol was approved by the institutional review boards at all participating centers.
Clinical Outcomes After eligibility screening, patients were assessed at baseline and every 2 weeks until the final study visit at the end of 8 weeks of ecopipam treatment. Safety end points included frequency of all adverse events (AEs) and serious AEs as well as effects on mood, suicidal ideation, and weight. The YGTSS, which rates motor and phonic tics separately with scores of 0 to 5 for 5 domains (number, frequency, intensity, complexity, and interference), resulting in a maximum possible score of 50, was used to assess tic severity at study onset and end point.20 Secondary tic outcomes were the YGTSS tic impairment scores (0–50) as well as the Clinical Global Impression of Improvement and Severity Scales.21 Attention deficit hyperactivity disorder was evaluated with the Adult Attention Deficit/ Hyperactivity Disorder Self-Report Symptoms (ASRS) checklist, which rates 18 symptoms with scores of 0 to 4 (never, rarely, sometimes, often, very often). On the basis of this, ADHD is considered “highly likely” when greater than 24 and “likely” at 17 to 24.22 Obsessive compulsive disorder was evaluated with the Yale-Brown Obsessive Compulsive Scale,23 in which 5 features (time, interference, distress, resistance, and control) are rated for obsessions and compulsions separately with scores of 0 to 5. Hamilton Depression Rating Scale24 and the Premonitory Urges in TS (PUTS) Scale25 were also used. Adverse event monitoring included interval history, structured diagnostic interviews, the Columbia Suicide Scale,26 physical examination, routine laboratory studies, and electrocardiography.
Safety of Ecopipam in Adults With TS
after the screening. All patients were treated with ecopipam at an initial dose of 50 mg daily by mouth for 2 weeks taken at bedtime, followed by 100 mg daily by mouth for 6 weeks taken at bedtime. At the discretion of the clinician, a dose of 50 mg could be maintained or resumed if AEs were present. In-person assessments occurred every 2 weeks during the treatment.
Statistical Analysis The primary symptom end point was the tic severity as rated by the YGTSS total tic score. All scales were analyzed comparing baseline to end point using paired t test or, if not parametric, a Wilcoxon signed rank test. The primary analysis was intent to treat (ITT) with the last observation carried forward (LOCF). An analysis restricted to subjects who completed the entire study was also performed.
Sample Size Calculation and Planned Interim Analysis Sample size calculation was based on an anticipated YGTSS total tic score group mean at baseline of 26 (of possible 50), with a standard deviation of the change from baseline to end point (final visit or LOCF) of 10. The study was designed to detect a YGTSS total tic reduction of 5 points, which would yield a paired t test statistical significance (P < 0.05) and an approximate open-label effect size of 0.5. No power analysis was done because of the single-treatment design. The protocol included an interim analysis by an independent drug safety monitoring board (DSMB) when 10 subjects had completed. Because of simultaneous and ongoing enrollments, the interim analysis was conducted when 12 subjects had completed. Three dropout subjects were included, so the interim analysis included 15 enrolled subjects. Three additional subjects who had been ongoing during the DSMB review were completed, for a final study population of 18 subjects. Because the interim analysis demonstrated a statistically significant tic reduction, the DSMB recommended early termination of the study. That is, there was no efficacy information to be gained by enrolling additional subjects, and moreover, given the large human experience (>2000 patients) with compound, it was unlikely that substantially different adverse effect data would be identified.
RESULTS Twenty-three patients were screened. The ITT group comprised 18 patients who met entry criteria, gave consent, and started study medication. Three patients withdrew from the study because of AEs. Thus, 15 subjects completed the study protocol (completers). Baseline characteristics of the subjects are summarized in Table 1. The population included adults with common health problems such as hypertension (medications on file) as well as stably treated psychiatric problems such as anxiety, OCD, and ADHD. Three subjects were prescribed citalopram; one subject, buspirone. There was concomitant medication use for acute problems such as pain or infection.
Clinical Outcomes Treatment The study was a monotherapy trial; that is, all subjects were withdrawn from all other tic-suppression drugs at least 7 days before and neuroleptics at least 2 weeks before screening. The baseline, first-dose visit occurred at a mean of 2 weeks © 2014 Lippincott Williams & Wilkins
Using the LOCF, the mean (SD) YGTSS tic reduction at the time of the interim analysis was 5.3 (9.0) in the ITT (n = 18) and 5.9 (9.0) in the completer (n = 15) analyses (Fig. 1; Table 2). Reductions in the YGTSS total, motor, and vocal tic severity scores occurred. Post hoc analysis showed reduction in the www.clinicalneuropharm.com
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TABLE 1. Demographics of Study Sample
No. Sex, M:F Race White African American Asian/Pacific Islander Age, mean (SD), y Age, (min, max), y Prior use of D2 receptor blockers
All (Intent to Treat)
Completers Only
18 15:3
15 12:3
15 2 1 36 (15) 18, 63 13
12 2 1 35 (15) 18, 63 10
F, female; M, male.
YGTSS at the first treatment visit (t17 = −4.9; P = 0.0001), which persisted for the remainder of the study (Fig. 1). Impairment scores and Clinical Global Impression of Severity also improved. Premonitory urges (PUTS) and depression scores did not change, and there was no report of development of suicidal ideation. Symptom scores of ADHD were in the diagnostic range in most cases at baseline (Table 2): “highly likely” range for 13, “likely” for 3, subthreshold for 2. The mean reduction in ASRS was 13%. Post hoc ITT comparisons involving only those participants with ASRS scores in the highly likely range (mean [SD], 39.1 [8.9]) showed a mean 16% reduction by the final visit (P = 0.06). Baseline OCD scores were low: none or subclinical symptoms for 10, mild for 4, moderate for 4. Posttreatment OCD ratings did not change.
Safety Outcomes There were no serious AEs reported in this study. Non– serious AEs were rated mild to severe. Four subjects experienced 9 AEs rated as severe. Two, both in their 50s, discontinued participation early: one for insomnia and the other for somnolence, decreased appetite, and cold sweats. The remaining 2 subjects completed the study. One had jitteriness and sedation. This individual remained on the initial, 50-mg dose for 4 weeks, rather than 2. The other had a rib fracture on day 24 of the study and a panic attack on day 37. Fourteen subjects experienced AEs rated as mild to moderate. The most common of these were sedation (39%), fatigue (33%), insomnia (33%), somnolence (28%), anxiety (22%), headache (22%), and muscle twitching (22%). One subject was noted to develop akathisia. There were no clinically meaningful laboratory abnormalities identified at screening or treatment week 8 related to study participation (data on file). One subject had systolic hypertension at both visits. One subject had an electrocardiogram abnormality at treatment week 8, judged as not clinically significant by an independent cardiologist. Body weight did not increase.
Ecopipam is a selective D1 antagonist.27,28 Postmortem human brain tissue studies demonstrated the affinity of ecopipam for D1 receptors localizing to caudate, putamen, and cortical regions.29 Positron emission tomographic imaging showed 100 mg administered orally results in 70% D1 receptor occupancy,30 comparable with that seen in positron emission tomographic studies with D2-selective antagonists.31 Effects of ecopipam on behaviors that may be relevant to TS, particularly locomotor activity32 and motivation/reward responses,33 have been studied extensively in rodents and primates. The obvious limitation of this study is the open-label design. In a prior study, positive results from an open-label study of levetiracetam34 were not later replicated in a double-blind study.35 In contrast, positive results from an open-label study of risperidone36 were supported by multiple subsequent doubleblind trials.12,37 A recent meta-analysis showed that placebo effects in tic disorders may be of small magnitude, particularly in adults.38 The fact that 13 of 18 participants had previously taken one or more neuroleptics supports that the benefit of ecopipam could be clinically important. Comparing the tic reduction in this study with those in D2 antagonist studies39 is problematic because most prior clinical trials involve children and adolescents, not adults. It would be of interest to determine whether the effect size of ecopipam on YGTSS would be greater in younger patients. The decision to include in the present study patients with typical comorbidities allowed us to recruit a representative sample of adult patients.40 This also provided the opportunity to explore whether ecopipam might affect comorbid symptoms. Regarding OCD, our sample had predominantly mild symptoms. The “floor effect” made determining whether ecopipam could improve OCD symptoms impossible. There was no worsening of ADHD symptoms that were prevalent and moderately severe in this cohort. The finding that ecopipam did not affect the urge to tic, as assessed by the PUTS scale, holds scientific interest. The salience and strength of the tic urge captured by the PUTS may involve failure to filter out particular sensations, which, in turn, compel
DISCUSSION Pharmacologic antagonism of the dopamine D1 receptor is a novel approach to tic reduction in TS. In this first study, tic severity was reduced after open-label treatment with the D1 antagonist ecopipam. During the treatment, there was no worsening of ADHD or OCD and no weight gain. The safety and tolerability results suggest the potential utility of ecopipam in adults with TS and support the need for double-blind, placebo-controlled studies.
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FIGURE 1. Time course of tic severity during the study for individual patients taking ecopipam. Thick line is group mean. © 2014 Lippincott Williams & Wilkins
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Clinical Neuropharmacology • Volume 37, Number 1, January/February 2014
Safety of Ecopipam in Adults With TS
TABLE 2. Clinical Rating Scales for Intention to Treat and Study Completors All Participants, ITT (n = 18)
YGTSS total tic Motor Phonic YGTSS impairment PUTS CGI improvement CGI severity ADHD ASRS OCD YBOCS total Obsession Compulsion HAM-D Depression
Baseline Mean SD 30.6 8.8 16.2 4.5 14.4 5.9 29.7 10.9 24.6 7.1 — — 4.7 1.0 33.0 12.6 7.8 8.0 3.4 4.3 4.3 4.0 3.1 2.3
Study Completors (n = 15)
End Mean 25.3 13.7 11.6 22.8 25.1 −1.2 3.9 28.6 8.1 3.7 4.4 3.4
SD 9.2 4.2 6.8 13.7 6.2 1.2 1.2 14.2 7.5 4.5 3.8 3.1
P 0.0004 0.0004 0.0056 0.0407 NS 0.0043 0.0137 0.11 NS NS NS NS
Baseline Mean SD 30.3 8.7 16.2 4.5 14.1 6.0 29.7 11.4 25.0 6.7 — — 74.6 1.0 33.1 13.7 9.1 8.1 4.1 4.4 5.0 4.1 2.9 2.3
End Mean 24.4 13.7 10.7 20.3 25.4 −1.3 3.7 28.3 9.0 3.9 5.0 3.4
SD 9.3 4.6 6.8 12.9 5.9 1.2 1.2 15.3 7.7 4.7 3.8 3.1
P 0.0008 0.0014 0.0046 0.0161 NS 0.0068 0.0137 0.14 NS NS NS NS
CGI, clinical global impression; HAM-D, Hamilton Depression Rating Scale; NS, not statistically significant (all of these are P values > 0.2); YBOCS, Yale Brown Obsessive Compulsive Scale. Bold designates significant (p < .05).
performance of the tic. The tic that is performed in response to an urge may then be executed like purposeful movements via the direct cortico-striatal, D1-influenced pathway. Thus, the observation that ecopipam improves tics without reducing urges may support a “downstream” mechanism of action. That is, while taking ecopipam, patients with TS may sense an urge just as strongly but feel able to resist performing their tics more successfully. The AE profile of ecopipam seen in patients with TS is comparable with that reported previously.41 Adverse effects were mild to moderate and primarily affected the central nervous or gastrointestinal systems. No clinically significant hepatic, renal, or cardiovascular AEs were reported. Unlike D2 antagonists, there was no increase in body weight.41 Overall, patient retention in the study was comparable with that seen in clinical trials of other drugs used to TS.12,42,43 Extrapolating adverse effects and efficacy to a pediatric population requires some caution because 5 participants were in their 50s or 60s. Should ecopipam’s efficacy be confirmed in double-blind trials, active comparator studies with D2 receptor blockers would be valuable. Certain individuals with TS might respond more selectively to one class. Issues of D1 versus D2 activity have also arisen with regard to variable results using dopamine agonists for tic suppression.44–46 Overlap in efficacy could also occur because D2 antagonists may “indirectly” suppress tics via a more broadly inhibited motor state, as the one that occurs in drug-induced parkinsonism, whereas D1 antagonists may have more a “direct” tic-suppressing activity via circuits underlying selected and habitual actions.
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CONCLUSIONS In conclusion, this first study of ecopipam for TS suggests promise for tic suppression. The absence of common neuroleptic adverse effects of weight gain47 and those of drug-induced movement disorders48 support larger controlled trials.
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ACKNOWLEDGMENTS The authors thank the clinical research team at each site for their careful work and the participating patients for their efforts. © 2014 Lippincott Williams & Wilkins
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41. Astrup A, Greenway FL, Ling W, et al. Randomized controlled trials of the D1/D5 antagonist ecopipam for weight loss in obese subjects. Obesity (Silver Spring) 2007;15:1717–1731. 42. Budman CL, Gayer A, Lesser M, et al. An open-label study of the treatment efficacy of olanzapine for Tourette’s disorder. J Clin Psychiatry 2001;62:290–294. 43. Dion Y, Annable L, Sandor P, et al. Risperidone in the treatment of Tourette syndrome: a double-blind, placebo-controlled trial. J Clin Psychopharmacol 2002;22:31–39. 44. Black KJ, Mink JW. Response to levodopa challenge in Tourette syndrome. Mov Disord 2000;15:1194–1198. 45. Gilbert DL, Dure L, Sethuraman G, et al. Tic reduction with pergolide in a randomized controlled trial in children. Neurology 2003;60:606–611. 46. Kurlan R, Crespi G, Coffey B, et al. A multicenter randomized placebo-controlled clinical trial of pramipexole for Tourette’s syndrome. Mov Disord 2012;27:775–778. 47. Zuddas A, Zanni R, Usala T. Second generation antipsychotics (SGAs) for non-psychotic disorders in children and adolescents: a review of the randomized controlled studies. Eur Neuropsychopharmacol 2011;21:600–620. 48. Wonodi I, Reeves G, Carmichael D, et al. Tardive dyskinesia in children treated with atypical antipsychotic medications. Mov Disord 2007;22:1777–1782.
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