Drug and Non-drug Treatment of Tourette Syndrome

Nathanel       Zelnik
Abstract

Background: Tourette Syndrome (TS) is a neurodevelopmental disorder characterized by multiple repetitive motor and vocal tics. In most patients, its clinical course has a waxing and waning nature and most patients, usually children, will benefit from tolerant environmental and psychoeducation. Patients with more complicated tics, in particular, those with significant comorbidities will require drug therapy.
Objective: The present paper is a mini-review of the current therapeutic arsenal for TS with reference to drug and non-drug management approach.
Methods: A systematic survey of medical literature regarding the treatment decision making and the reported clinical trials or accumulating experience with different medications or other therapeutic modalities which were proven beneficial over the years.
Results: Reviewing the literature indicates that dopamine antagonists, such as haloperidol and pimozoide, are the most reliable agents in terms of treatment response. Due to numerous adverse effects, newer atypical anti-psychotic drugs have been shown effective. Other widely accepted medications include alpha-2 adrenergic agonists, benzamides, dopamine depleting agents, benzodiazepines and dopamine depleting agents. In more selective and intractable cases botulinum toxin, dopamine agonists and cannabinoids should be also considered. Non-pharmacologic therapies reported beneficial effects, which include on the one hand, non-invasive behavioral techniques, such as comprehensive behavior therapy for tics. While on the other hand, in cases with particular protracted pharmaco-resistant tics electric stimulation techniques, such as deep brain stimulation, have been shown to be successful.
Conclusion: Currently, there are numerous multifarious options for treatment of tics and other comorbid symptoms of TS. Nevertheless, treatment options and decision-making algorithms are still a clinical challenge.
Area Covered: A step by step decision-making and various drugs and non-pharmacologic modalities appropriate for the management of TS.
Keywords: Tourette syndrome, tics, ADHD, OCD, treatment, antipsychotic drugs, haloperidol, clonidine, risperidone, aripiprazole, tetrabenazine, cannabinoids, CBIT, deep brain stimulation.
Graphical Abstract

[1] 
Gilbert D. Treatment of children and adolescents with tics and Tourette syndrome. J Child Neurol  2006; 21(8): 690-700.
[http://dx.doi.org/10.1177/08830738060210080401] [PMID: 16970870] 
[2] 
Kerbeshian J, Burd L. Epidemiology and comorbidity: The North Dakota prevalence studies of Tourette syndrome and other developmental disordersTourette syndrome; genetics, neurobiology and treatment Advances in Neurology.  New York: Raven Press 1992; Vol. 58: pp. 67-74.
[3] 
Eapen V, Cavanna AE, Robertson MM. Comorbidities, social impact and quality of life in Tourette syndrome. Front Psychiatry  2016; 7(97): 1-6.
[http://dx.doi.org/10.3389/fpsyt.2016.00097] 
[4] 
Comings DE, Comings BG. A controlled study of Tourette syndrome. I. Attention-deficit disorder, learning disorders, and school problems. Am J Hum Genet  1987; 41(5): 701-41.
[PMID: 2890294] 
[5] 
Bloch MH, Leckman JF. Clinical course of Tourette syndrome. J Psychosom Res  2009; 67(6): 497-501.
[http://dx.doi.org/10.1016/j.jpsychores.2009.09.002] [PMID: 19913654] 
[6] 
Apter A, Pauls DL, Bleich A, et al. An epidemiologic study of Gilles de la Tourette’s syndrome in Israel. Arch Gen Psychiatry  1993; 50(9): 734-8.
[http://dx.doi.org/10.1001/archpsyc.1993.01820210068008] [PMID: 8357298] 
[7] 
Kurlan R, Como PG, Miller B, et al. The behavioral spectrum of tic disorders: a community-based study. Neurology  2002; 59(3): 414-20.
[http://dx.doi.org/10.1212/WNL.59.3.414] [PMID: 12177376] 
[8] 
Robertson MM, Trimble MR, Lees AJ. The psychopathology of the Gilles de la Tourette syndrome. A phenomenological analysis. Br J Psychiatry  1988; 152: 383-90.
[http://dx.doi.org/10.1192/bjp.152.3.383] [PMID: 3167374] 
[9] 
Budman CL, Bruun RD, Park KS, Lesser M, Olson M. Explosive outbursts in children with Tourette’s disorder. J Am Acad Child Adolesc Psychiatry  2000; 39(10): 1270-6.
[http://dx.doi.org/10.1097/00004583-200010000-00014] [PMID: 11026181] 
[10] 
Caine ED, McBride MC, Chiverton P, Bamford KA, Rediess S, Shiao J. Tourette’s syndrome in Monroe County school children. Neurology  1988; 38(3): 472-5.
[http://dx.doi.org/10.1212/WNL.38.3.472] [PMID: 3162295] 
[11] 
Robertson MM, Trimble MR, Lees HJ. Self-injurious behavior and the Gilles de la Tourette’s syndrome: a clinical study and review of the literature. Psychol Med  198(19): 611-25.
[12] 
Erenberg G, Cruse RP, Rothner AD. Tourette syndrome: an analysis of 200 pediatric and adolescent cases. Cleve Clin Q  1986; 53(2): 127-31.
[http://dx.doi.org/10.3949/ccjm.53.2.127] [PMID: 3461891] 
[13] 
Burd L, Freeman RD, Klug KG, Kerbeshian J. Tourette syndrome and learning disabilities. BMC Pediatr  2005; 5(34): 1-6.
[http://dx.doi.org/10.1186/1471-2431-5-34] 
[14] 
Sundaram SK, Huq AM, Wilson BJ, Chugani HT. Tourette syndrome is associated with recurrent exonic copy number variants. Neurology  2010; 74(20): 1583-90.
[http://dx.doi.org/10.1212/WNL.0b013e3181e0f147] [PMID: 20427753] 
[15] 
Clarke RA, Lee S, Eapen V. Pathogenetic model for Tourette syndrome delineates overlap with related neurodevelopmental disorders including Autism. Transl Psychiatry  2012; 2(9)e158
[http://dx.doi.org/10.1038/tp.2012.75] [PMID: 22948383] 
[16] 
Bruun RD, Budman CL. The natural history of Tourette’s syndromeTourette syndrome; genetics, neurobiology and treatment Advances in Neurology.  New York: Raven Press 1992; Vol. 58: pp. 1-6.
[17] 
Bloch MH, Peterson BS, Scahill L, et al. Adulthood outcome of tic and obsessive-compulsive symptom severity in children with Tourette syndrome. Arch Pediatr Adolesc Med  2006; 160(1): 65-9.
[http://dx.doi.org/10.1001/archpedi.160.1.65] [PMID: 16389213] 
[18] 
Eapen V, Lees AJ, Lakke JP, Trimble MR, Robertson MM. Adult-onset tic disorders. Mov Disord  2002; 17(4): 735-40.
[http://dx.doi.org/10.1002/mds.10180] [PMID: 12210863] 
[19] 
Leckman JF, Zhang H, Vitale A, et al. Course of tic severity in Tourette syndrome: the first two decades. Pediatrics  1998; 102(1 Pt 1): 14-9.
[http://dx.doi.org/10.1542/peds.102.1.14] [PMID: 9651407] 
[20] 
Kurlan R, Lichter D, Hewitt D. Sensory tics in Tourette’s syndrome. Neurology  1989; 39(5): 731-4.
[http://dx.doi.org/10.1212/WNL.39.5.731] [PMID: 2710364] 
[21] 
Leckman JF, Walker DE, Cohen DJ. Premonitory urges in Tourette’s syndrome. Am J Psychiatry  1993; 150(1): 98-102.
[http://dx.doi.org/10.1176/ajp.150.1.98] [PMID: 8417589] 
[22] 
Harris K, Singer HS. Tic disorders: neural circuits, neurochemistry, and neuroimmunology. J Child Neurol  2006; 21(8): 678-89.
[http://dx.doi.org/10.1177/08830738060210080901] [PMID: 16970869] 
[23] 
Wong DF, Singer HS, Brandt J, et al. D2-like dopamine receptor density in Tourette syndrome measured by PET. J Nucl Med  1997; 38(8): 1243-7.
[PMID: 9255158] 
[24] 
Yeh CB, Lee CS, Ma KH, Lee MS, Chang CJ, Huang WS. Phasic dysfunction of dopamine transmission in Tourette’s syndrome evaluated with 99mTc TRODAT-1 imaging. Psychiatry Res  2007; 156(1): 75-82.
[http://dx.doi.org/10.1016/j.pscychresns.2007.01.003] [PMID: 17716877] 
[25] 
Yoon DY, Gause CD, Leckman JF, Singer HS. Frontal dopaminergic abnormality in Tourette syndrome: A postmortem analysis. J Neurol Sci  2007; 255(1-2): 50-6.
[http://dx.doi.org/10.1016/j.jns.2007.01.069] [PMID: 17337006] 
[26] 
Shapiro AK, Shapiro E. Controlled study of pimozide vs. placebo in Tourette’s syndrome. J Am Acad Child Psychiatry  1984; 23(2): 161-73.
[http://dx.doi.org/10.1097/00004583-198403000-00007] [PMID: 6371107] 
[27] 
Shapiro E, Shapiro AK, Fulop G, et al. Controlled study of haloperidol, pimozide and placebo for the treatment of Gilles de la Tourette’s syndrome. Arch Gen Psychiatry  1989; 46(8): 722-30.
[http://dx.doi.org/10.1001/archpsyc.1989.01810080052006] [PMID: 2665687] 
[28] 
Sallee FR, Nesbitt L, Jackson C, Sine L, Sethuraman G. Relative efficacy of haloperidol and pimozide in children and adolescents with Tourette’s disorder. Am J Psychiatry  1997; 154(8): 1057-62.
[http://dx.doi.org/10.1176/ajp.154.8.1057] [PMID: 9247389] 
[29] 
Bruggeman R, van der Linden C, Buitelaar JK, Gericke GS, Hawkridge SM, Temlett JA. Risperidone versus pimozide in Tourette’s disorder: a comparative double-blind parallel-group study. J Clin Psychiatry  2001; 62(1): 50-6.
[http://dx.doi.org/10.4088/JCP.v62n0111] [PMID: 11235929] 
[30] 
Dion Y, Annable L, Sandor P, Chouinard G. Risperidone in the treatment of tourette syndrome: a double-blind, placebo-controlled trial. J Clin Psychopharmacol  2002; 22(1): 31-9.
[http://dx.doi.org/10.1097/00004714-200202000-00006] [PMID: 11799340] 
[31] 
Cohen DJ, Detlor J, Young JG, Shaywitz BA. Clonidine ameliorates Gilles de la Tourette syndrome. Arch Gen Psychiatry  1980; 37(12): 1350-7.
[http://dx.doi.org/10.1001/archpsyc.1980.01780250036004] [PMID: 6255888] 
[32] 
Leckman JF, Hardin MT, Riddle MA, Stevenson J, Ort SI, Cohen DJ. Clonidine treatment of Gilles de la Tourette’s syndrome. Arch Gen Psychiatry  1991; 48(4): 324-8.
[http://dx.doi.org/10.1001/archpsyc.1991.01810280040006] [PMID: 2009034] 
[33] 
Tourette’s Syndrome study group. Treatment of ADHD in children with tics: a randomized controlled trial. Neurology  2002; 58(4): 527-36.
[http://dx.doi.org/10.1212/WNL.58.4.527] [PMID: 11865128] 
[34] 
Robertson MM, Stern JS. Gilles de la Tourette syndrome: symptomatic treatment based on evidence. Eur Child Adolesc Psychiatry  2000; 9(Suppl. 1): I60-75.
[http://dx.doi.org/10.1007/s007870070020] [PMID: 11140781] 
[35] 
Farag M, Stern JS, Simmons H, Robertson MM. Serial pharmacological prescribing practices for tic management in Tourette syndrome. Hum Psychopharmacol  2015; 30(6): 435-41.
[http://dx.doi.org/10.1002/hup.2495] [PMID: 26299248] 
[36] 
Jankovic J, Orman J. Tetrabenazine therapy of dystonia, chorea, tics, and other dyskinesias. Neurology  1988; 38(3): 391-4.
[http://dx.doi.org/10.1212/WNL.38.3.391] [PMID: 3279337] 
[37] 
Kenney CJ, Hunter CB, Mejia NI, Jankovic J. Tetrabenazine in the treatment of Tourette syndrome. J Pediatr Neurol  2007; 5: 9-13.
[38] 
Goetz CG. Clonidine and clonazepam in Tourette syndrome. Adv Neurol  1992; 58: 245-51.
[PMID: 1414629] 
[39] 
Awaad Y. Tics in Tourette syndrome: new treatment options. J Child Neurol  1999; 14(5): 316-9.
[http://dx.doi.org/10.1177/088307389901400508] [PMID: 10342599] 
[40] 
Trimble MR, Whurr R, Brookes G, Robertson MM. Vocal tics in Gilles de la Tourette syndrome treated with botulinum toxin injections. Mov Disord  1998; 13(3): 617-9.
[http://dx.doi.org/10.1002/mds.870130348] [PMID: 9613771] 
[41] 
Gilbert DL, Sethuraman G, Sine L, Peters S, Sallee FR. Tourette’s syndrome improvement with pergolide in a randomized, double-blind, crossover trial. Neurology  2000; 54(6): 1310-5.
[http://dx.doi.org/10.1212/WNL.54.6.1310] [PMID: 10746603] 
[42] 
Anca MH, Giladi N, Korczyn AD. Ropinirole in Gilles de la Tourette syndrome. Neurology  2004; 62(9): 1626-7.
[http://dx.doi.org/10.1212/01.WNL.0000123111.00324.BF] [PMID: 15136698] 
[43] 
Fernández-Jaén A, Fernández-Mayoralas DM, Muñoz-Jareño N, Calleja-Pérez B. An open-label, prospective study of levetiracetam in children and adolescents with Tourette syndrome. Eur J Paediatr Neurol  2009; 13(6): 541-5.
[http://dx.doi.org/10.1016/j.ejpn.2008.12.006] [PMID: 19211282] 
[44] 
Müller-Vahl KR, Schneider U, Koblenz A, et al. Treatment of Tourette’s syndrome with Delta 9-tetrahydrocannabinol (THC): A randomized crossover trial. Pharmacopsychiatry  2002; 35(2): 57-61.
[http://dx.doi.org/10.1055/s-2002-25028] [PMID: 11951146] 
[45] 
Enoch MD, Robin AA. A controlled trial of haloperidol in chronic schizophrenics. J Ment Sci  1960; 106: 1459-67.
[http://dx.doi.org/10.1192/bjp.106.445.1459] [PMID: 13696946] 
[46] 
Sneader W. Drug discovery - a history.  UK: John Wiley & Sons 2005; p. 123.
[http://dx.doi.org/10.1002/0470015535] 
[47] 
Granger B, Albu S. The haloperidol story. Ann Clin Psychiatry  2005; 17(3): 137-40.
[http://dx.doi.org/10.1080/10401230591002048] [PMID: 16433054] 
[48] 
Bruun RD, Shapiro AK, Shapiro E, Sweet R, Wayne H, Solomon GE. A follow-up of 78 patients with Gilles de la Tourette syndrome. Am J Psychiatry  1976; 133: 944-7.
[49] 
Tarsy D, Miyawaki E. Tardive dystonia after neuroleptic treatment of Tourette’s syndrome. J Neurol Neurosurg Psychiatry  1996; 61(1): 119.
[http://dx.doi.org/10.1136/jnnp.61.1.119] [PMID: 8676147] 
[50] 
Muench J, Hamer AM. Adverse effects of antipsychotic medications. Am Fam Physician  2010; 81(5): 617-22.
[PMID: 20187598] 
[51] 
Su YP, Chang CK, Hayes RD, et al. Retrospective chart review on exposure to psychotropic medications associated with neuroleptic malignant syndrome. Acta Psychiatr Scand  2014; 130(1): 52-60.
[http://dx.doi.org/10.1111/acps.12222] [PMID: 24237642] 
[52] 
Ross MS, Moldofsky H. A comparison of pimozide and haloperidol in the treatment of Gilles de la Tourette’s syndrome. Am J Psychiatry  1978; 135(5): 585-7.
[http://dx.doi.org/10.1176/ajp.135.5.585] [PMID: 347954] 
[53] 
Wu CS, Tsai YT, Tsai HJ. Antipsychotic drugs and the risk of ventricular arrhythmia and/or sudden cardiac death: a nation-wide case-crossover study. J Am Heart Assoc  2015; 4(2) e001568
[http://dx.doi.org/10.1161/JAHA.114.001568] [PMID: 25713294] 
[54] 
Gilbert DL, Batterson JR, Sethuraman G, Sallee FR. Tic reduction with risperidone versus pimozide in a randomized, double-blind, crossover trial. J Am Acad Child Adolesc Psychiatry  2004; 43(2): 206-14.
[http://dx.doi.org/10.1097/00004583-200402000-00017] [PMID: 14726728] 
[55] 
Borison RL, Ang L, Chang S, Dysken M, Comaty JE, Davis JM. New pharmacological approaches in the treatment of Tourette syndrome. Adv Neurol  1982; 35: 377-82.
[PMID: 6756088] 
[56] 
Singer HS, Gammon K, Quaskey S. Haloperidol, fluphenazine and clonidine in Tourette syndrome: controversies in treatment. Pediatr Neurosci  1985-1986; 12(2): 71-4.
[http://dx.doi.org/10.1159/000120222] [PMID: 3870139] 
[57] 
Eggers C, Rothenberger A, Berghaus U. Clinical and neurobiological findings in children suffering from tic disease following treatment with tiapride. Eur Arch Psychiatry Neurol Sci  1988; 237(4): 223-9.
[http://dx.doi.org/10.1007/BF00449911] [PMID: 2974416] 
[58] 
Robertson MM, Schnieden V, Lees AJ. Management of Gilles de la Tourette syndrome using sulpiride. Clin Neuropharmacol  1990; 13(3): 229-35.
[http://dx.doi.org/10.1097/00002826-199006000-00005] [PMID: 2357704] 
[59] 
Leucht S, Corves C, Arbter D, Engel RR, Li C, Davis JM. Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis. Lancet  2009; 373(9657): 31-41.
[http://dx.doi.org/10.1016/S0140-6736(08)61764-X] [PMID: 19058842] 
[60] 
Borison RL, Pathiraja AP, Diamond BI, Meibach RC. Risperidone: clinical safety and efficacy in schizophrenia. Psychopharmacol Bull  1992; 28(2): 213-8.
[PMID: 1381102] 
[61] 
Marder SR. Risperidone: Clinical development: North American results. Clin Neuropharmacol  1992; 15(Suppl. 1 Pt A): 92A-3A.
[http://dx.doi.org/10.1097/00002826-199201001-00049] [PMID: 1379883] 
[62] 
Lombroso PJ, Scahill L, King RA, et al. Risperidone treatment of children and adolescents with chronic tic disorders: a preliminary report. J Am Acad Child Adolesc Psychiatry  1995; 34(9): 1147-52.
[http://dx.doi.org/10.1097/00004583-199509000-00011] [PMID: 7559308] 
[63] 
Bruun RD, Budman CL. Risperidone as a treatment for Tourette’s syndrome. J Clin Psychiatry  1996; 57(1): 29-31.
[PMID: 8543544] 
[64] 
Lim LKYS. Shin SYM. Risperidone versus Haloperidol in the treatment of Tourette’s syndrome and chronic vocal or motor tic disorder in Korea. Eur Neuropsychopharmacol  2006; 16: 5527.
[http://dx.doi.org/10.1016/S0924-977X(06)70729-5] 
[65] 
Sandor P, Stephens RJ. Risperidone treatment of aggressive behavior in children with Tourette syndrome. J Clin Psychopharmacol  2000; 20(6): 710-2.
[http://dx.doi.org/10.1097/00004714-200012000-00025] [PMID: 11106151] 
[66] 
McCracken JT, McGough J, Shah B, et al. Research units on pediatric psychopharmacology autism network. Risperidone in children with autism and serious behavioral problems. N Engl J Med  2002; 347(5): 314-21.
[http://dx.doi.org/10.1056/NEJMoa013171] [PMID: 12151468] 
[67] 
Chappell PB, Leckman JF, Riddle MA. The pharmacological treatment of tic disorders. Child Adolesc Psychiatr Clin N Am  1995; 4: 197-216.
[http://dx.doi.org/10.1016/S1056-4993(18)30457-7] 
[68] 
Budman CL, Gayer A, Lesser M, Shi Q, Bruun RD. An open-label study of the treatment efficacy of olanzapine for Tourette’s disorder. J Clin Psychiatry  2001; 62(4): 290-4.
[http://dx.doi.org/10.4088/JCP.v62n0412] [PMID: 11379844] 
[69] 
McCracken JT, Suddath R, Chang S, Thakur S, Piacentini J. Effectiveness and tolerability of open label Olanzapine in children and adolescents with TS. J Child Adolesc Psychopharmacol  2008; 18: 501-8.
[70] 
Copur M, Arpaci B, Demir T, Narin H. Clinical effectiveness of quetiapine in children and adolescents with Tourette’s syndrome: a retrospective case-note survey. Clin Drug Investig  2007; 27(2): 123-30.
[http://dx.doi.org/10.2165/00044011-200727020-00005] [PMID: 17217317] 
[71] 
Mukaddes NM, Abali O. Quetiapine treatment of children and adolescents with Tourette’s disorder. J Child Adolesc Psychopharmacol  2003; 13(3): 295-9.
[http://dx.doi.org/10.1089/104454603322572624] [PMID: 14642017] 
[72] 
Sallee FR, Kurlan R, Goetz CG, et al. Ziprasidone treatment of children and adolescents with Tourette’s syndrome: a pilot study. J Am Acad Child Adolesc Psychiatry  2000; 39(3): 292-9.
[http://dx.doi.org/10.1097/00004583-200003000-00010] [PMID: 10714048] 
[73] 
Blair J, Scahill L, State M, Martin A. Electrocardiographic changes in children and adolescents treated with ziprasidone: a prospective study. J Am Acad Child Adolesc Psychiatry  2005; 44(1): 73-9.
[http://dx.doi.org/10.1097/01.chi.0000145372.61239.bb] [PMID: 15608546] 
[74] 
Jaffe E, Trémeau F, Sharif Z, Reider R. Clozapine in tardive Tourette syndrome. Biol Psychiatry  1995; 38(3): 196-7.
[http://dx.doi.org/10.1016/0006-3223(95)00218-6] [PMID: 7578666] 
[75] 
Allison DB, Casey DE. Antipsychotic-induced weight gain: a review of the literature. J Clin Psychiatry  2001; 62(Suppl. 7): 22-31.
[PMID: 11346192] 
[76] 
Davies L, Stern JS, Agrawal N, Robertson MM. A case series of patients with Tourette’s syndrome in the United Kingdom treated with aripiprazole. Hum Psychopharmacol  2006; 21(7): 447-53.
[http://dx.doi.org/10.1002/hup.798] [PMID: 17029306] 
[77] 
Budman C, Coffey BJ, Shechter R, et al. Aripiprazole in children and adolescents with Tourette disorder with and without explosive outbursts. J Child Adolesc Psychopharmacol  2008; 18(5): 509-15.
[http://dx.doi.org/10.1089/cap.2007.061] [PMID: 18928415] 
[78] 
Yoo HK, Choi SH, Park S, Wang HR, Hong JP, Kim CY. An open-label study of the efficacy and tolerability of aripiprazole for children and adolescents with tic disorders. J Clin Psychiatry  2007; 68(7): 1088-93.
[http://dx.doi.org/10.4088/JCP.v68n0717] [PMID: 17685747] 
[79] 
Murphy TK, Mutch PJ, Reid JM, et al. Open label aripiprazole in the treatment of youth with tic disorders. J Child Adolesc Psychopharmacol  2009; 19(4): 441-7.
[http://dx.doi.org/10.1089/cap.2008.0149] [PMID: 19702496] 
[80] 
Lyon GJ, Samar S, Jummani R, et al. Aripiprazole in children and adolescents with Tourette’s disorder: an open-label safety and tolerability study. J Child Adolesc Psychopharmacol  2009; 19(6): 623-33.
[http://dx.doi.org/10.1089/cap.2009.0035] [PMID: 20035580] 
[81] 
Wenzel C, Kleimann A, Bokemeyer S, Müller-Vahl KR. Aripiprazole for the treatment of Tourette syndrome: a case series of 100 patients. J Clin Psychopharmacol  2012; 32(4): 548-50.
[http://dx.doi.org/10.1097/JCP.0b013e31825ac2cb] [PMID: 22722499] 
[82] 
Yoo HK, Joung YS, Lee JS, et al. A multicenter, randomized, double-blind, placebo-controlled study of aripiprazole in children and adolescents with Tourette’s disorder. J Clin Psychiatry  2013; 74(8): e772-80.
[http://dx.doi.org/10.4088/JCP.12m08189] [PMID: 24021518] 
[83] 
Ghanizadeh A, Haghighi A. Aripiprazole versus risperidone for treating children and adolescents with tic disorder: a randomized double blind clinical trial. Child Psychiatry Hum Dev  2014; 45(5): 596-603.
[http://dx.doi.org/10.1007/s10578-013-0427-1] [PMID: 24343476] 
[84] 
Burris KD, Molski TF, Xu C, et al. Aripiprazole, a novel antipsychotic, is a high-affinity partial agonist at human dopamine D2 receptors. J Pharmacol Exp Ther  2002; 302(1): 381-9.
[http://dx.doi.org/10.1124/jpet.102.033175] [PMID: 12065741] 
[85] 
Jordan S, Koprivica V, Chen R, Tottori K, Kikuchi T, Altar CA. The antipsychotic aripiprazole is a potent, partial agonist at the human 5-HT1A receptor. Eur J Pharmacol  2002; 441(3): 137-40.
[http://dx.doi.org/10.1016/S0014-2999(02)01532-7] [PMID: 12063084] 
[86] 
Gerasch S, Kanaan AS, Jakubovski E, Müller-Vahl KR. Aripiprazole improves associated comorbid conditions in addition to tics in adult patients with Gilles de la Tourette syndrome. Front Neurosci  2016; 10: 416.
[http://dx.doi.org/10.3389/fnins.2016.00416] [PMID: 27672358] 
[87] 
Ben Djebara M, Worbe Y, Schüpbach M, Hartmann A. Aripiprazole: a treatment for severe coprolalia in “refractory” Gilles de la Tourette syndrome. Mov Disord  2008; 23(3): 438-40.
[http://dx.doi.org/10.1002/mds.21859] [PMID: 18067182] 
[88] 
Sallee F, Kohegyi E, Zhao J, et al. Randomized, double-blind, placebo-controlled trial, demonstrates the efficacy and safety of oral aripiprazole for the treatment of Tourette’s disorder in children and adolescents. J Child Adolesc Psychopharmacol  2017; 27(9): 771-81.
[http://dx.doi.org/10.1089/cap.2016.0026] [PMID: 28686474] 
[89] 
Cohen DJ, Young JG, Nathanson JA, Shaywitz BA. Clonidine in Tourette’s syndrome. Lancet   1979; 2(8142): 551-3.
[http://dx.doi.org/10.1016/S0140-6736(79)91614-3] [PMID: 89558] 
[90] 
Cohen DJ, Riddle MA, Leckman JF. Pharmacotherapy of Tourette’s syndrome and associated disorders. Psychiatr Clin North Am  1992; 15(1): 109-29.
[http://dx.doi.org/10.1016/S0193-953X(18)30260-0] [PMID: 1549543] 
[91] 
Goetz CG, Tanner CM, Wilson RS, Carroll VS, Como PG, Shannon KM. Clonidine and Gilles de la Tourette’s syndrome: double-blind study using objective rating methods. Ann Neurol  1987; 21(3): 307-10.
[http://dx.doi.org/10.1002/ana.410210313] [PMID: 3300518] 
[92] 
Singer HS, Brown J, Quaskey S, Rosenberg LA, Mellits ED, Denckla MB. The treatment of attention-deficit hyperactivity disorder in Tourette’s syndrome: a double-blind placebo-controlled study with clonidine and desipramine. Pediatrics  1995; 95(1): 74-81.
[PMID: 7770313] 
[93] 
Song PP, Jiang L, Li XJ, et al. The efficacy and tolerability of the clonidine transdermal patch in the treatment for children with tic disorders: a prospective, open, single-group, self-controlled study. Front Neurol  2017; 8: 32.
[http://dx.doi.org/10.3389/fneur.2017.00032] [PMID: 28280480] 
[94] 
Posey DJ, McDougle CJ. Guanfacine and guanfacine extended release: treatment for ADHD and related disorders. CNS Drug Rev  2007; 13(4): 465-74.
[http://dx.doi.org/10.1111/j.1527-3458.2007.00026.x] [PMID: 18078429] 
[95] 
Chappell PB, Riddle MA, Scahill L, et al. Guanfacine treatment of comorbid attention-deficit hyperactivity disorder and Tourette’s syndrome: preliminary clinical experience. J Am Acad Child Adolesc Psychiatry  1995; 34(9): 1140-6.
[http://dx.doi.org/10.1097/00004583-199509000-00010] [PMID: 7559307] 
[96] 
Whittington C, Pennant M, Kendall T, et al. Practitioner Review: Treatments for Tourette syndrome in children and young people - a systematic review. J Child Psychol Psychiatry  2016; 57(9): 988-1004.
[http://dx.doi.org/10.1111/jcpp.12556] [PMID: 27132945] 
[97] 
Jankovic J, Glaze DG, Frost JD Jr. Effect of tetrabenazine on tics and sleep of Gilles de la Tourette’s syndrome. Neurology  1984; 34(5): 688-92.
[http://dx.doi.org/10.1212/WNL.34.5.688] [PMID: 6584743] 
[98] 
Jankovic J, Beach J. Long-term effects of tetrabenazine in hyperkinetic movement disorders. Neurology  1997; 48(2): 358-62.
[http://dx.doi.org/10.1212/WNL.48.2.358] [PMID: 9040721] 
[99] 
Porta M, Sassi M, Cavallazzi M, Fornari M, Brambilla A, Servello D. Tourette’s syndrome and role of tetrabenazine: review and personal experience. Clin Drug Investig  2008; 28(7): 443-59.
[http://dx.doi.org/10.2165/00044011-200828070-00006] [PMID: 18544005] 
[100] 
Kenney C, Hunter C, Jankovic J. Long-term tolerability of tetrabenazine in the treatment of hyperkinetic movement disorders. Mov Disord  2007; 22(2): 193-7.
[http://dx.doi.org/10.1002/mds.21222] [PMID: 17133512] 
[101] 
Ondo WG, Jong D, Davis A. Comparison of weight gain in treatments for Tourette syndrome: tetrabenazine versus neuroleptic drugs. J Child Neurol  2008; 23(4): 435-7.
[http://dx.doi.org/10.1177/0883073807307108] [PMID: 18192650] 
[102] 
Jancovic J, Jimenez-Shahed J, Budman C, et al. Deutetrabenazine in tics associated with Tourette syndrome. Termor Other Hyperkinet Mov  2016; 6:  422 e.
[103] 
Drtilkova I, Balaotikova B, Lemanova H, Zak J. Therapeutic effects of clonidine and clonazepam in children with tic syndrome. Homeost Health Dis  1994; 35: 296.
[104] 
Merikangas JR, Merikangas KR, Kopp U, Hanin I. Blood choline and response to clonazepam and haloperidol in Tourette’s syndrome. Acta Psychiatr Scand  1985; 72(4): 395-9.
[http://dx.doi.org/10.1111/j.1600-0447.1985.tb02628.x] [PMID: 3865498] 
[105] 
Singer HS, Wendlandt J, Krieger M, Giuliano J. Baclofen treatment in Tourette syndrome: a double-blind, placebo-controlled, crossover trial. Neurology  2001; 56(5): 599-604.
[http://dx.doi.org/10.1212/WNL.56.5.599] [PMID: 11245709] 
[106] 
Greenfield LJ Jr. Molecular mechanisms of antiseizure drug activity at GABAA receptors. Seizure  2013; 22(8): 589-600.
[http://dx.doi.org/10.1016/j.seizure.2013.04.015] [PMID: 23683707] 
[107] 
Jankovic J, Jimenez-Shahed J, Brown LW. A randomised, double-blind, placebo-controlled study of topiramate in the treatment of Tourette syndrome. J Neurol Neurosurg Psychiatry  2010; 81(1): 70-3.
[http://dx.doi.org/10.1136/jnnp.2009.185348] [PMID: 19726418] 
[108] 
Yang CS, Zhang LL, Zeng LN, Huang L, Liu YT. Topiramate for Tourette’s syndrome in children: a meta-analysis. Pediatr Neurol  2013; 49(5): 344-50.
[http://dx.doi.org/10.1016/j.pediatrneurol.2013.05.002] [PMID: 24139534] 
[109] 
Awaad Y, Michon AM, Minarik S. Use of levetiracetam to treat tics in children and adolescents with Tourette syndrome. Mov Disord  2005; 20(6): 714-8.
[http://dx.doi.org/10.1002/mds.20385] [PMID: 15704204] 
[110] 
Smith-Hicks CL, Bridges DD, Paynter NP, Singer HS. A double blind randomized placebo control trial of levetiracetam in Tourette syndrome. Mov Disord  2007; 22(12): 1764-70.
[http://dx.doi.org/10.1002/mds.21615] [PMID: 17566124] 
[111] 
Hedderick EF, Morris CM, Singer HS. Double-blind, crossover study of clonidine and levetiracetam in Tourette syndrome. Pediatr Neurol  2009; 40(6): 420-5.
[http://dx.doi.org/10.1016/j.pediatrneurol.2008.12.014] [PMID: 19433274] 
[112] 
Yang CS, Zhang LL, Lin YZ, Guo Q. Sodium valproate for the treatment of Tourette׳s syndrome in children: a systematic review and meta-analysis. Psychiatry Res  2015; 226(2-3): 411-7.
[http://dx.doi.org/10.1016/j.psychres.2014.08.058] [PMID: 25724485] 
[113] 
Neglia JP, Glaze DG, Zion TE. Tics and vocalizations in children treated with carbamazepine. Pediatrics  1984; 73(6): 841-4.
[PMID: 6587312] 
[114] 
Sotero de Menezes MA, Rho JM, Murphy P, Cheyette S. Lamotrigine-induced tic disorder: report of five pediatric cases. Epilepsia  2000; 41(7): 862-7.
[http://dx.doi.org/10.1111/j.1528-1157.2000.tb00254.x] [PMID: 10897158] 
[115] 
Marras C, Andrews D, Sime E, Lang AE. Botulinum toxin for simple motor tics: a randomized, double-blind, controlled clinical trial. Neurology  2001; 56(5): 605-10.
[http://dx.doi.org/10.1212/WNL.56.5.605] [PMID: 11245710] 
[116] 
Porta M, Maggioni G, Ottaviani F, Schindler A. Treatment of phonic tics in patients with Tourette’s syndrome using botulinum toxin type A. Neurol Sci  2004; 24(6): 420-3.
[http://dx.doi.org/10.1007/s10072-003-0201-4] [PMID: 14767691] 
[117] 
Rath JJ, Tavy DL, Wertenbroek AA, van Woerkom TC, de Bruijn SF. Botulinum toxin type A in simple motor tics: short-term and long-term treatment-effects. Parkinsonism Relat Disord  2010; 16(7): 478-81.
[http://dx.doi.org/10.1016/j.parkreldis.2009.11.011] [PMID: 20034838] 
[118] 
Gilbert DL, Dure L, Sethuraman G, Raab D, Lane J, Sallee FR. Tic reduction with pergolide in a randomized controlled trial in children. Neurology  2003; 60(4): 606-11.
[http://dx.doi.org/10.1212/01.WNL.0000044058.64647.7E] [PMID: 12601100] 
[119] 
Cianchetti C, Fratta A, Pisano T, Minafra L. Pergolide improvement in neuroleptic-resistant Tourette cases: various mechanisms causing tics. Neurol Sci  2005; 26(2): 137-9.
[http://dx.doi.org/10.1007/s10072-005-0448-z] [PMID: 15995832] 
[120] 
Benarroch E. Endocannabinoids in basal ganglia circuits: Implications for Parkinson disease. Neurology  2007; 69(3): 306-9.
[http://dx.doi.org/10.1212/01.wnl.0000267407.79757.75] [PMID: 17636069] 
[121] 
Koppel BS. Cannabis in the treatment of dystonia, dyskinesias and tics. Neurotherapeutics  2015; 12(4): 788-92.
[http://dx.doi.org/10.1007/s13311-015-0376-4] [PMID: 26271953] 
[122] 
Müller-Vahl KR, Kolbe H, Schneider U, Emrich HM. Cannabinoids: possible role in patho-physiology and therapy of Gilles de la Tourette syndrome. Acta Psychiatr Scand  1998; 98(6): 502-6.
[http://dx.doi.org/10.1111/j.1600-0447.1998.tb10127.x] [PMID: 9879795] 
[123] 
Müller-Vahl KR, Schneider U, Prevedel H, et al. Delta 9-tetrahydrocannabinol (THC) is effective in the treatment of tics in Tourette syndrome: a 6-week randomized trial. J Clin Psychiatry  2003; 64(4): 459-65.
[http://dx.doi.org/10.4088/JCP.v64n0417] [PMID: 12716250] 
[124] 
Curtis A, Clarke CE, Rickards HE. Cannabinoids for Tourette’s syndrome. (review) Cochrane Database Syst Rev 2009; (4):  CD006565
[PMID: 19821373] 
[125] 
Nicolson R, Craven-Thuss B, Smith J, McKinlay BD, Castellanos FX. A randomized, double-blind, placebo-controlled trial of metoclopramide for the treatment of Tourette’s disorder. J Am Acad Child Adolesc Psychiatry  2005; 44(7): 640-6.
[http://dx.doi.org/10.1097/01.chi.0000163279.39598.44] [PMID: 15968232] 
[126] 
Chappell PB, Leckman JF, Scahill LD, Hardin MT, Anderson G, Cohen DJ. Neuroendocrine and behavioral effects of the selective kappa agonist spiradoline in Tourette’s syndrome: a pilot study. Psychiatry Res  1993; 47(3): 267-80.
[http://dx.doi.org/10.1016/0165-1781(93)90084-T] [PMID: 8396784] 
[127] 
Stahl SM, Berger PA. Physostigmine in Tourette syndrome: Evidence for cholinergic underactivity. Am J Psychiatry  1981; 138(2): 240-2.
[http://dx.doi.org/10.1176/ajp.138.2.240] [PMID: 6935977] 
[128] 
McConville BJ, Fogelson MH, Norman AB, et al. Nicotine potentiation of haloperidol in reducing tic frequency in Tourette’s disorder. Am J Psychiatry  1991; 148(6): 793-4.
[PMID: 1817466] 
[129] 
Dursun SM, Reveley MA. Differential effects of transdermal nicotine on microstructured analyses of tics in Tourette’s syndrome: an open study. Psychol Med  1997; 27(2): 483-7.
[http://dx.doi.org/10.1017/S0033291796003984] [PMID: 9089841] 
[130] 
Strassnig M, Riedel M, Müller N. Electroconvulsive therapy in a patient with Tourette’s syndrome and co-morbid Obsessive Compulsive Disorder. World J Biol Psychiatry  2004; 5(3): 164-6.
[http://dx.doi.org/10.1080/15622970410029930] [PMID: 15346542] 
[131] 
Dhossche DM, Reti IM, Shettar SM, Wachtel LE. Tics as signs of catatonia: electroconvulsive therapy response in 2 men. J ECT  2010; 26(4): 266-9.
[http://dx.doi.org/10.1097/YCT.0b013e3181cb5f60] [PMID: 21155151] 
[132] 
Vanderwalle V, van der Linden C, Groenewegen HJ, Caemaert J. Stereotactic treatment of Gilles de LaTourette syndrome by high frequency stimulation of thalamus. Lancet  1999; 353: 724.
[http://dx.doi.org/10.1016/S0140-6736(98)05964-9] 
[133] 
Visser-Vandewalle V, Temel Y, Boon P, et al. Chronic bilateral thalamic stimulation: a new therapeutic approach in intractable Tourette syndrome. Report of three cases. J Neurosurg  2003; 99(6): 1094-100.
[http://dx.doi.org/10.3171/jns.2003.99.6.1094] [PMID: 14705742] 
[134] 
Servello D, Porta M, Sassi M, Brambilla A, Robertson MM. Deep brain stimulation in 18 patients with severe Gilles de la Tourette syndrome refractory to treatment: the surgery and stimulation. J Neurol Neurosurg Psychiatry  2008; 79(2): 136-42.
[http://dx.doi.org/10.1136/jnnp.2006.104067] [PMID: 17846115] 
[135] 
Porta M, Brambilla A, Cavanna AE, et al. Thalamic deep brain stimulation for treatment-refractory Tourette syndrome: two-year outcome. Neurology  2009; 73(17): 1375-80.
[http://dx.doi.org/10.1212/WNL.0b013e3181bd809b] [PMID: 19858459] 
[136] 
Shahed J, Poysky J, Kenney C, Simpson R, Jankovic J. GPi deep brain stimulation for Tourette syndrome improves tics and psychiatric comorbidities. Neurology  2007; 68(2): 159-60.
[http://dx.doi.org/10.1212/01.wnl.0000250354.81556.90] [PMID: 17210901] 
[137] 
Cannon E, Silburn P, Coyne T, O’Maley K, Crawford JD, Sachdev PS. Deep brain stimulation of anteromedial globus pallidus interna for severe Tourette’s syndrome. Am J Psychiatry  2012; 169(8): 860-6.
[http://dx.doi.org/10.1176/appi.ajp.2012.11101583] [PMID: 22772329] 
[138] 
Kefalopoulou Z, Zrinzo L, Jahanshahi M, et al. Bilateral globus pallidus stimulation for severe Tourette’s syndrome: a double-blind, randomised crossover trial. Lancet Neurol  2015; 14(6): 595-605.
[http://dx.doi.org/10.1016/S1474-4422(15)00008-3] [PMID: 25882029] 
[139] 
Deeb W, Rossi PJ, Porta M, et al. The international deep brain registry and data base for Gilles de la Tourette syndrome: How does it work? Front Neurosci  2016; 10: 170.
[http://dx.doi.org/10.3389/fnins.2016.00170] [PMID: 27199634] 
[140] 
Martinez-Ramirez D, Jimenez-Shahed J, Leckman JF, et al. Efficacy and safety of deep brain stimulation in Tourette syndrome. The international Tourette syndrome deep brain stimulation public database and registry. JAMA Neurol  2018; 75(3): 353-9.
[http://dx.doi.org/10.1001/jamaneurol.2017.4317] [PMID: 29340590] 
[141] 
McClintock SM, Reti IM, Carpenter LL, et al.  Consensus recommendations
for the clinical application of repetitive transcranial
magnetic stimulation (rTMS) in the treatment of depression. J Clin
Psychiatry 2018; 79(1): pii: 16cs10905.
[142] 
Mantovani A, Leckman JF, Grantz H, King RA, Sporn AL, Lisanby SH. Repetitive transcranial stimulation of the supplementary motor area in the treatment of Tourette syndrome: report of two cases. Clin Neurophysiol  2007; 118(10): 2314-5.
[http://dx.doi.org/10.1016/j.clinph.2007.07.011] [PMID: 17709291] 
[143] 
Landeros-Weisenberger A, Mantovani A, Motlagh MG, et al. Randomized sham controlled double-blind trial of repetitive transcranial magnetic stimulation for adults with severe Tourette syndrome. Brain Stimul  2015; 8(3): 574-81.
[http://dx.doi.org/10.1016/j.brs.2014.11.015] [PMID: 25912296] 
[144] 
Azrin NH, Nunn RG. Habit-reversal: A method of eliminating nervous habits and tics. Behav Res Ther  1973; 11(4): 619-28.
[http://dx.doi.org/10.1016/0005-7967(73)90119-8] [PMID: 4777653] 
[145] 
Miltenberger RG, Fuqua RW, Woods DW. Applying behavior analysis to clinical problems: Review and analysis of habit reversal. J Appl Behav Anal  1998; 31(3): 447-69.
[http://dx.doi.org/10.1901/jaba.1998.31-447] [PMID: 9757583] 
[146] 
Woods DW, Twohig MP, Flessner CA, Roloff TJ. Treatment of vocal tics in children with Tourette syndrome: investigating the efficacy of habit reversal. J Appl Behav Anal  2003; 36(1): 109-12.
[http://dx.doi.org/10.1901/jaba.2003.36-109] [PMID: 12723873] 
[147] 
Himle MB, Woods DW, Piacentini JC, Walkup JT. Brief review of habit reversal training for Tourette syndrome. J Child Neurol  2006; 21(8): 719-25.
[http://dx.doi.org/10.1177/08830738060210080101] [PMID: 16970874] 
[148] 
Bolton D, Perrin S. Evaluation of exposure with response-prevention for obsessive compulsive disorder in childhood and adolescence. J Behav Ther Exp Psychiatry  2008; 39(1): 11-22.
[http://dx.doi.org/10.1016/j.jbtep.2006.11.002] [PMID: 17207457] 
[149] 
Verdellen CW, Hoogduin CA, Kato BS, Keijsers GP, Cath DC, Hoijtink HB. Habituation of premonitory sensations during exposure and response prevention treatment in Tourette’s syndrome. Behav Modif  2008; 32(2): 215-27.
[http://dx.doi.org/10.1177/0145445507309020] [PMID: 18285507] 
[150] 
Verdellen C, van de Griendt J, Hartmann A, Murphy T. ESSTS Guidelines Group. European clinical guidelines for Tourette syndrome and other tic disorders. Part III: behavioural and psychosocial interventions. Eur Child Adolesc Psychiatry  2011; 20(4): 197-207.
[http://dx.doi.org/10.1007/s00787-011-0167-3] [PMID: 21445725] 
[151] 
Woods DW, Piacentini JC, Chang S, et al. Managing Tourette’s syndrome: A Behavioral Intervention for Children and Adults. New York: Oxford University Press 2008.
[152] 
Piacentini J, Woods DW, Scahill L, et al. Behavior therapy for children with Tourette disorder: a randomized controlled trial. JAMA  2010; 303(19): 1929-37.
[http://dx.doi.org/10.1001/jama.2010.607] [PMID: 20483969] 
[153] 
Sukhodolsky DG, Woods DW, Piacentini J, et al. Moderators and predictors of response to behavior therapy for tics in Tourette syndrome. Neurology  2017; 88(11): 1029-36.
[http://dx.doi.org/10.1212/WNL.0000000000003710] [PMID: 28202705] 
[154] 
Pringsheim T, Marras C. Pimozide for tics in Tourette’s syndrome. Cochrane Database Syst Rev 2009; (2):  CD006996
[PMID: 19370666] 
[155] 
Roessner V, Plessen KJ, Rothenberger A, et al. ESSTS Guidelines Group. European clinical guidelines for Tourette syndrome and other tic disorders. Part II: pharmacological treatment. Eur Child Adolesc Psychiatry  2011; 20(4): 173-96.
[http://dx.doi.org/10.1007/s00787-011-0163-7] [PMID: 21445724] 
[156] 
Castellanos FX, Giedd JN, Elia J, et al. Controlled stimulant treatment of ADHD and comorbid Tourette’s syndrome: effects of stimulant and dose. J Am Acad Child Adolesc Psychiatry  1997; 36(5): 589-96.
[http://dx.doi.org/10.1097/00004583-199705000-00008] [PMID: 9136492] 
[157] 
Murphey TK, Lewin AB, Storch AE, Stock S. American Academy of Child and Adolescent Psychiatry (AACAP), Committee on Quality Issues (CQI). Practice parameter for the assessment and treatment of children and adolescents with tic disorders. J Am Acad Child Adolesc Psychiatry  2013; 52: 1341-59.
[158] 
Rodrigo L, Alvarez N, Fernandez-Bustillo E, Salag-Puig J, Huerta M, Hernandez-Lahoz C. Efficacy of Gluten-free diet in Gilles de la Tourette syndrome: a pilot study. Nutrients  2018; 10: 573.
Cite As
Current Drug Therapy

Drug and Non-drug Treatment of Tourette Syndrome

Abstract

Graphical Abstract
