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 hy- pothesized to underlie the motor and phonic tics in Tourette syndrome (TS). The objective of this trial was to evaluate the safety and tic- reducing 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 en- rolled, 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 t 17 = 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 (t 17 = 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, hyper- kinetic movement disorder characterized by multiple tics that wax and wane in frequency and intensity and that migrate in lo- cation over time. Tics are repeated, individually recognizable, intermittent movements and phonations sometimes performed in response to specific premonitory urges. 1 Tics may be voli- tionally suppressed, but this is often accompanied by increased salience of a premonitory urge. Tics in a given body area gener- ally 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, neu- roimaging, or genetic studies, 5 the preponderance of evidence supports the theory that dopaminergic dysregulation, either in subcortical nodes 6,7 or populations of cerebral cortical neu- rons, 7 underlies tic symptoms in some individuals with TS. 8 The clinical implication of this circuit model is that phar- macologic action at dopamine receptors may improve or exac- erbate tics. A functional magnetic resonance imaging study demonstrating heightened activity in the D1-mediated pathway in more severe TS 9 supports that reduction of dopaminergic signal- ing via the D1 pathway might reduce tics. Empirically, effects of antagonizing dopaminergic signaling via the D2 indirect pathway is supported by observational 10 and clinical trial data. 11,12 Flu- phenazine, 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 re- ceptor blocking agent might reduce tics. Ecopipam, a selective antagonist of the dopamine D1 re- ceptor, demonstrates high affinity for D1 receptors in vitro. 16,17 Additional studies show that ecopipam is roughly 1000-fold se- lective 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 TS 19 as well as a minimum total tic score of 20 from the Yale *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 ‡Neurol- ogy, §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: Donald.gilbert@cchmc.org Copyright © 2014 by Lippincott Williams & Wilkins DOI: 10.1097/WNF.0000000000000017 ORIGINAL ARTICLE 26 www.clinicalneuropharm.com Clinical Neuropharmacology • Volume 37, Number 1, January/February 2014 Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.