CHAPTER ELEVEN

Clinical Pharmacology of Nondopaminergic Drugs in Tourette Syndrome Andreas Hartmann*,†,1

*Centre de Re´fe´rence National Maladie Rare: ‘Syndrome Gilles de la Tourette’, De´partement de Neurologie, Poˆle des Maladies du Syste`me Nerveux, Paris, France † Centre de Recherche de l’Institut du Cerveau et de la Moelle Epinie`re, UPMC/INSERM UMR_S975; CNRS UMR 7225, Paris, France 1 Corresponding author: e-mail address: [email protected]

Contents 1. Introduction 2. Alpha2 Receptor Agonists 2.1 Clonidine 2.2 Guanfacine 3. GABA Agonists 4. Cannabinoids 5. Botulinum Toxin 6. Tetrabenazine 7. Nicotine 8. Acetylcholinesterase Inhibitors 9. Immunoglobulins, Plasmapheresis, and Antibiotics 10. Summary and Future Research References

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Abstract Treatment of tics and Gilles de la Tourette syndrome (GTS) by nondopaminergic drugs was initiated more than three decades ago. These approaches were driven by the wish to circumvent antipsychotic-related side effects (metabolic disturbances, parkinsonian syndromes, tardive dyskinesia) or to use these treatments as a valuable add-on therapy in patients at least partially refractory to antipsychotics. In this review, we will therefore discuss the potential value of treating tics with alpha2 receptor agonists, nicotine, tetrabenazine, GABA agonists, botulinum toxin, cannabinoids, and immune modulators (plasmapheresis, intravenous immunoglobulins, antibiotic prophylaxis). Future directions for clinical trials based on our expanding understanding of the pathophysiology of GTS with regard to cholinergic, glutamatergic, and histaminergic neurotransmission will also be briefly outlined.

International Review of Neurobiology, Volume 112 ISSN 0074-7742 http://dx.doi.org/10.1016/B978-0-12-411546-0.00011-1

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1. INTRODUCTION Historically, treatment of tics and Gilles de la Tourette syndrome (GTS) has been based on the use of antipsychotics since the early 1960s. Subsequently, in a reverse-engineering mode, dysfunction of dopaminergic neurotransmission became a center stage hypothesis regarding the pathophysiology of GTS. However, several lines of evidence emerged over the last decades that other neurotransmitter systems are likely involved in the pathophysiology of GTS including noradrenaline, glutamate, serotonin, nicotine, acetylcholine, gamma-aminobutyric acid (GABA) and, most recently, histamine. Therefore, molecules targeting these systems, either as stand-alone or add-on medications to classical antipsychotics, have been actively explored since the late 1970s. Recent reviews have extensively listed all available evidence on tic treatment, in particular the recently published ESSTS guidelines (2011) and we refer to this publication for anyone seeking methodological details on case reports, case series, and clinical trials. These guidelines have made apparent substantial differences in treatment recommendations between European and North American centers (Jankovic & Kurlan, 2011a; Pringsheim et al., 2012; discussed in Jankovic & Kurlan, 2011b; Mu¨ller-Vahl, Roessner, & European Society for the Study of Tourette Syndrome, 2011). Besides obvious differences related to differential availability of drugs, they also reflect different stances on the risks and benefits of using certain pharmacological classes, especially antipsychotics. Indeed, another strong motivation to explore nondopamine-blocking agents in GTS is related to the side effect profile of antipsychotics. Metabolic disturbances are frequent in both children and adults, as well as sedation and cognitive disturbances (Pringsheim & Pearce, 2010). A major concern, especially in North America, relates to possible parkinsonian syndromes and tardive dyskinesia following the use of typical antipsychotics, that is, those with a strong affinity for D2 receptors. However, it appears that the occurrence of motor complications in GTS patients treated by antipsychotics is actually much rarer than previously thought, maybe due to the lower doses used, the underlying pathology, or the patients’ age (Mu¨ller-Vahl & Krueger, 2011). Before discussing specific studies, it should be underlined that controlled, randomized, and double-blind trials are much too scarce in GTS due to the rarity and the regrettable but somewhat understandable lack of interest from pharmaceutical companies in this condition. Unsurprisingly,

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pharmacological treatment of tics is mostly empirical and dominated by case studies or series as well as open-label trials; very few studies fulfill class A evidence criteria, even more so when it comes to nonantipsychotics.

2. ALPHA2 RECEPTOR AGONISTS A group of molecules used for more than three decades in the treatment of tics are alpha2 receptor agonists (e.g., clonidine and guanfacine). Their first identified function was to lower blood pressure and they were therefore used as antihypertensive medication. Subsequently, clonidine and guanfacine became FDA-approved drugs in the treatment of attention deficit hyperactivity disorder (ADHD) in persons aged 6–17, either as monotherapy or as an adjunct to psychostimulants (methylphenidate derivates). Both clonidine and guanfacine stimulate alpha2 receptors in the central nervous system (CNS) which results in decreased cardiac output and peripheral vascular resistance, explaining their antihypertensive properties. Also, they inhibit noradrenaline release from the adrenal medulla and the locus coeruleus resulting in a decrease in sympathetic tone, likely to contribute both to reducing hypertension and hyperactivity. Finally, by binding alpha2 receptors in the prefrontal cortex and thereby strengthening connections in this area, they supposedly increase attention, working memory, impulse control, and decrease distractibility (Arnsten, 2010). Clonidine (formula: C9H9CL2N3) exists in oral form or as a transdermal patch. Dosage for children suffering from ADHD or tics ranges between 3 and 6 mg/kg of body weight, divided into two to four even doses. Guanfacine (formula: C9H9CL2N3O) exists both in standard release and prolonged release forms, with the latter being favored in the treatment of ADHD and tics. Standard dosages range between 1 and 4 mg extendedrelease orally once daily in the morning.

2.1. Clonidine Early reports centered on GTS patients unresponsive to haloperidol but who benefitted from clonidine for tic management (Cohen, Detlor, Young, & Shaywitz, 1980, Cohen, Young, Nathanson, & Shaywitz, 1979). In the same line of thinking used for typical antipsychotics, this therapeutic benefit was interpreted as a sign that the noradrenergic system might be involved, either directly or indirectly, in the genesis of tics and the pathophysiology of GTS.

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An early open-label clinical trial comparing clonidine to antipsychotics suggested a greater efficacy of the latter in treating tics (Shapiro, Shapiro, & Eisenkraft, 1983). Next, a 6-month placebo-controlled crossover study of clonidine versus placebo in 30 GTS patients showed no differences in tic severity or behavior between the two treatment arms (Goetz et al., 1987). Furthermore, when adjusting for dose (0.0075 or 0.015 mg/kg/ day), population (children or adults), dosing schedule (twice or thrice daily), or concomitant use of antipsychotics, no significant difference between placebo and clonidine appeared (Goetz et al., 1987). The first randomized, placebo-controlled double-blind trial on clonidine enrolled 40 GTS patients; the effect of clonidine (3–5 mg/kg/day) versus placebo was evaluated over a 12-week period (Leckman et al., 1991). Clonidine was shown to be more effective than placebo in decreasing tics, hyperactivity, and impulsivity. Subsequently, however, a randomized, double-blind, placebo-controlled study of desipramine (25 mg four times daily) and clonidine (0.05 mg four times daily) for the treatment of ADHD in GTS over 6 weeks revealed that clonidine did not alter tic severity in 34 children aged 7–13 years. A head-to-head trial evaluated risperidone versus clonidine for the treatment of 21 children and adolescents suffering from GTS in an 8-week placebo-controlled double-blind study (Gaffney et al., 2002). Tic reduction measured by the Yale Global Tic Severity Scale (YGTSS) was similar in both conditions (
21% in the risperidone group,
26% in the clonidine group) with comparable sedation in both groups and no extrapyramidal symptoms reported. Metabolic parameters were not evaluated. When given alone or combined with methylphenidate, clonidine improved both tics and ADHD in 136 children in a multicenter, placebo-controlled randomized double-blind clinical trial (Tourette’s Syndrome Study Group, 2002). Clonidine appeared to be especially effective for impulsivity and hyperactivity, whereas methylphenidate appeared more beneficial for inattention. Importantly, tics did not worsen in children treated with methylphenidate alone. Clonidine as an adhesive patch was recently tested in 437 children in a 4-week randomized, double-blind multicenter placebo-controlled trial (Du et al., 2008). Inclusion was based on a Chinese version of the DSMIII with 5% of patients suffering from transient tic disorder, 40% from chronic motor or vocal tics, and 55% from GTS. The dosage of clonidine was adjusted to bodyweight (1.0, 1.5, or 2.0 mg/week). Clonidine significantly reduced tics on the YGTSS scale and the therapeutic response as

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evaluated by the Clinical Global Impression (CGI) scale was higher in the active treatment group, although the placebo response at 47% appears fairly high (69% in the active treatment group). Side effect specific to patch treatment included local skin irritation and problems related to patch displacement. Finally, a recent study compared clonidine with levetiracetam for treating tics in GTS. This study used a 15-week randomized, double-blind, flexible dose crossover protocol in 10 patients, both adults and children (Hedderick, Morris, & Singer, 2009). Clonidine but not levetiracetam treatment resulted in a small reduction in the total tic score of the YGTSS. Adverse reactions of clonidine include sedation, dry mouth, headache, irritability, and midsleep awakening (Du et al., 2008). Blood pressure and pulse should be measured at baseline and monitored during dose adjustment. Specific guidelines for blood pressure monitoring during follow-up have not been established, but regular monitoring of pulse and blood pressure changes, plus symptoms suggestive of cardiovascular problems (e.g., exercise intolerance, dizziness, syncope), is recommended (Daviss et al., 2008). Although blood pressure is generally not a problem with clonidine, patients and families should be educated about the possibility of rebound hypertension, tics, and anxiety with abrupt discontinuation (Bloch, 2008). Although many authors report that the adverse reactions tend to be mild and transient, this view is not fully supported by others (Goetz, 1992; Hedderick et al., 2009; Lichter & Jackson, 1996), especially when moderate-to-severe tics require higher dosage.

2.2. Guanfacine An open-label study of guanfacine in 10 children with GTS (Chappell et al., 1995) and in 25 medication-free children aged 7–16 years (23 males) (Boonyasidhi, Kim, & Scahill, 2005) with GTS þ ADHD revealed a significant decrease in tic severity and improvement in attention. Also, a case report described a 6-year-old boy with GTS treated successfully with guanfacine (Fras, 1996). In controlled trials, guanfacine (1.0 mg/day) compared to placebo was investigated in a randomized, placebo-controlled double-blind study in 34 children suffering from both ADHD and tic disorder over 8 weeks (Scahill et al., 2001). ADHD-related symptoms improved in more than 50% of guanfacine-treated children, whereas none of the placebo-treated children did. Importantly, tic severity decreased by 31% in the guanfacine

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group compared to 0% in the placebo group. Subsequently, guanfacine was shown to be nonsuperior to placebo in a 4-week, double-blind, placebocontrolled study in 24 children with regard to tic reduction and performance-based neuropsychologic measures (Cummings et al., 2002). Whether guanfacine is effective for the treatment of moderate-to-severe tics remains unanswered (Scahill et al., 2006). Also, the suggestion that guanfacine is a better-tolerated alternative to clonidine remains unclear without a direct comparison study (Sandor, 2003). The main side effects of guanfacine are dizziness, drowsiness, confusion, fatigue, headache, hypotension, and depression. Four children with syncopal episodes were reported following guanfacine treatment, probably due to hypotension or bradycardia (King, Harris, Fritzell, & Kurlan, 2006). Constipation and dry mouth are common. Guanfacine, previously approved to treat hypertension in several European countries, has been withdrawn from the market in several of these countries. Guanfacine should be started with 0.5 mg at bedtime and should be increased by 0.5 mg every 5–7 days, if necessary, to a maximum dose of 4 mg/day in a once-a-day or twice-a-day regimen. In conclusion, the efficacy of alpha2 receptor agonists is usually lower than for antipsychotics with comparable sedation. However, guanfacine and clonidine appear to be helpful in managing behavioral problems, especially ADHD (Bloch, Panza, Landeros-Weisenberger, & Leckman, 2009). A recent meta-analysis indeed suggested that alpha2 agonists may have minimal benefit in tic patients without ADHD (Weisman, Qureshi, Leckman, Scahill, & Bloch, 2012). Therefore, we speculate that attenuating ADHD-related symptoms might be one of the keys to explain the decrease in concomitant tics.

3. GABA AGONISTS Recent neuropathological data showed diminished number and aberrant distribution of GABA-ergic interneurons in GTS (Kalanithi et al., 2005; Kataoka et al., 2010), which provides a rationale for the use of GABA agonists in the treatment of tics. However, benzodiazepines, in particular clonazepam (which also acts on the serotonergic system), are much less frequently used for treating tics since their efficacy, so far, seems to be limited and indirect. Also, studies are few and rather old. Baclofen, as discussed below, had a recent renaissance as a potential treatment for alcohol abuse.

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The only benzodiazepine investigated for the treatment of tics is clonazepam (formula: C15H10ClN3O3), a favorite in the treatment of several neuropsychiatric disorders, such as anxiety (panic disorders), orthostatic tremor, REM sleep behavior disorder, and several forms of epilepsy. However, it is only in the latter that it is approved in most countries and accordingly used off-label in most other indications. Clonazepam is a long-acting and highpotency benzodiazepine (elimination half-life: 18–60 h). It binds to the GABAA receptor and acts not by replacing but by enhancing the effects of endogenous GABA. The net effect is an increased influx of chloride ions into neurons resulting in widespread inhibition of synaptic transmission across the CNS (Skerritt & Johnston, 1983). Clonazepam is available in several forms; easiest to titrate is the liquid form with doses usually varying from 0.5 to 2 mg/day. A first, open-label study on seven GTS patients suggested that clonazepam might be an interesting add-on treatment for tics (Gonce & Barbeau, 1977). Clonazepam adjunct to clonidine in seven children and adolescents in an open-label trial reduced tic frequency and severity without affecting comorbid ADHD (Steingard, Goldberg, Lee, & DeMaso, 1994). As with all benzodiazepines, tolerance and adverse reactions including sedation, short-term memory problems, ataxia, and paradoxic disinhibition which often limit the use of clonazepam (Goetz, 1992). Also, the strong addictive potential of GABAA agonists and especially clonazepam must be taken into consideration. In several countries, prescription and use is now severely limited due to abusive recreational use of clonazepam. In contrast to clonazepam, baclofen (formula: C10H12ClNO2) is a GABAB agonist. As a muscle relaxant, it is primarily used to treat spasticity, either orally or by intrathecal delivery. Other, more recent indications include hiccups and alcohol dependence. Tolerance does not seem to occur to a significant degree with baclofen as opposed to GABAA agonists and abuse potential has not been reported. However, withdrawal symptoms can occur after prolonged use and thus necessitate a slow decrease in dose. Baclofen is usually given thrice daily at individual doses ranging between 5 and 20 mg. Baclofen was examined in an open-label study in a large cohort of children with GTS (Awaad, 1999). A total of 250 of 264 patients on baclofen treatment experienced a significant decrease in the severity of tics. Subsequently, a randomized, double-blind 10-week crossover design study (4 weeks per treatment arm þ 2 weeks washout period) involving 10 children suffering from GTS investigated the potential benefits of baclofen

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(3  20 mg daily) on tic reduction (Singer, Wendlandt, Krieger, & Giuliano, 2001). While the CGI score improved significantly in the baclofen arm, the YGTSS tic score did not differ significantly between baclofen and placebo. However, the overall YGTSS score significantly improved in baclofentreated patients which could be attributed to a decrease in the impairment score. The authors concluded that the beneficial effects of baclofen rely on mechanisms different from pure tic reduction. In conclusion, GABA agonists have a very limited role in treating tics to date and if so, rather as add-on than stand-alone medication. Although recent neuropathological data support the use of these molecules to treat tics and associated conditions (depending on the cortico-striato-thalamocortical loop involved, cf. Kataoka et al., 2010), precise pharmacological targeting of GABA-ergic interneurons remains an elusive goal at present. In experimental setting though, a selective activator of striatal GABA-ergic interneurons has been described (IEM-1460, an inhibitor of GluA2-lacking AMPARs) but which requires intraparenchymal injection (Gittis et al., 2011) and is therefore impractical in a clinical setting.

4. CANNABINOIDS From experience, clinicians involved in the care of GTS patients know that many patients report tic reduction when smoking marijuana, and that this improvement is not solely based on sedation. Given the strong interaction of the cannabinoid and dopaminergic systems in the basal ganglia (Ferna´ndez-Ruiz, Herna´ndez, & Ramos, 2010), there is indeed a rationale to investigate the potential use of delta-9-tetrahydrocannabinol (THC), the main active component of marijuana, in the treatment of tics and GTS. THC (formula: C21H30O2) binds to two types of cannabinoid receptors, CB1 and CB2. Only the former is present in the CNS (especially in the basal ganglia, cerebellum, and hippocampus) where it acts as receptor for endocannabinoids such as anandamide and 2-arachidonoyl glyceride. THC has multiple central and peripheral effects such as analgesia and relaxation, the latter being often assumed as the main mechanism of action against tics. However, there are close interactions between the dopaminergic and cannabinoid system, both cortically and subcortically which are more likely underlying antitic activity, although the interaction is probably complex (Kuepper et al., 2010). One of only two Cochrane reviews on the pharmacology of GTS was centered on the use of cannabinoids. Two studies met inclusion criteria

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but the Cochrane review did not support the use of cannabinoids in treating tics (Curtis, Clarke, & Rickards, 2009). The first of these two studies was a randomized crossover trial of THC (5.0, 7.5, or 10.0 mg) in 12 adult GTS patients over 6 weeks (Mu¨ller-Vahl et al., 2002). Significant differences could be observed for complex motor tics on the YGTSS but failed to reach significance for simple motor and vocal tics. There was a significant correlation between tic improvement and maximum 11-OH–THC plasma concentration. No serious adverse reactions occurred. Subsequently, the same group reported a randomized, double-blind placebo-controlled trial over 6 weeks in 24 GTS patients using 10 mg/day of THC versus placebo (Mu¨ller-Vahl et al., 2003a). Despite a high dropout rate (but only one due to treatment-related side effects), significant differences in several observer rating scales, as well as a self-report scale, were noted. No serious adverse reaction occurred and the reported mild adverse reactions were dizziness, tiredness, and dry mouth. Of note, THC treatment did not induce any short- or long-term cognitive deficits which reinforces the notion that THC does not decrease tics through secondary mechanisms such as sedation or decreased general activity (Mu¨ller-Vahl et al., 2003b). In conclusion, targeting the cannabinoid system for treating tics remains an interesting and novel approach. However, the reason why research and clinical trials have stalled over the past decade certainly relates to the fact that THC is considered an addictive substance in most countries with restrictive legislation severely limiting its use, even in a medical setting. Therefore, it is doubtful, at present, whether this therapeutic venue will be further explored in years to come.

5. BOTULINUM TOXIN Botulinum toxin (BTX) is a neurotoxin produced by the bacterium Clostridium botulinum. BTX blocks neuromuscular transmission by decreasing acetylcholine release from presynaptic terminals by targeting SNARE25, synaptobrevin, or syntaxin, resulting in muscle paralysis. Accordingly, BTX is used in medical conditions where sustained and abnormal muscle contraction occurs, such as dystonia. In medical settings, BTX is used in two forms, type A and type B, the latter being used less commonly (usually in case of antibody production against BTX-A). BTX injections are reversible and last 3–4 months on average. Therefore, they need to be repeated regularly to maintain therapeutic benefit.

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Apart from dystonic syndromes, BTX has strong potential to treat isolated tics by weakening the muscles necessary for tic expression. BTX allows a targeted and limited intervention on localized (noncomplex) and potentially dangerous tics, especially those of the neck. Importantly, BTX also appears beneficial to treat disabling vocal tics. Finally, one intriguing observation concerns the fact that tic suppression by BTX over several months or years seems to diminish premonitory sensations, sometimes until complete tic extinction, potentially as the result of interfering with a sensory reflex arc necessary for the perpetuation of tics. Kwak, Hanna, and Jankovic (2000) injected 35 GTS patients with BTX into the site of their most problematic tics. Response to BTX was based on a 0–4 clinical rating scale (0, no improvement, to 4, marked improvement in both severity and function). Questionnaires were administered to evaluate patients’ impressions of overall efficacy and degree of benefit with premonitory sensations. The mean peak effect response treated in 115 sessions was 2.8 (range, 0–4); the mean duration of benefit was 14.4 weeks (maximum, 45 weeks); and the mean latency to onset of benefit was 3.8 days (maximum, 10 days). Twenty-one (84%) of 25 patients with premonitory sensations derived marked relief of these symptoms (mean benefit, 70.6%). The authors concluded that BTX injections are an effective and well tolerated treatment of tics and also provides relief of premonitory sensations. Subsequently, in a randomized, placebo-controlled double-blind crossover trial, 18 GTS patients were treated with BTX (Marras, Andrews, Sime, & Lang, 2001). A video rating scale showed a 39% reduction in tics following BTX administration compared to a 6% increase in the placebo group. Premonitory urges also diminished in the BTX group whereas they increased in the placebo group. Surprisingly, patients did not report an overall benefit from the active treatment on the CGI scale, possibly because only a selected subset of tics could be treated in each patient. Regarding simple (but disabling) motor tics, BTX injections in 15 consecutive patients resulted in good or moderate efficacy on tics in 89% of patients, with good long-term efficacy. Premonitory sensations were present in 53% of patients and resolved after BTX injections. Interestingly, complete remission of tics occurred in three patients (20%) with a maximum followup of 10 years (Rath, Tavy, Wertenbroek, van Woerkom, & de Bruijn, 2010). BTX injections into the vocal cords can be considered in the presence of important vocal tics. A first report in 1996 (Scott, Jankovic, & Donovan, 1996) described a 13-year-old boy suffering from coprolalia who was

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successfully treated with unilateral BTX injections into the vocal cords. Interestingly, premonitory sensations also diminished in this patient. A further, positive case report was published in 1998 (Trimble et al., 1998). The only case series to date on the use of BTX to treat vocal tics included 30 patients. Repeated BTX injections into both vocal cords over 12 months resulted in improvement in 93% of patients, with 50% becoming tic free; hypophonia was the major side effect reported in 80% of patients (Porta, Maggioni, Ottaviani, & Schindler, 2004). Premonitory sensations diminished from 53% to 20%. In conclusion, BTX injections are a helpful addition to systemic drug administration or as a stand-alone approach when patients complain of simple but disabling motor or vocal tics. Also, the decrease and even extinction of premonitory sensations after repeated BTX injections deserves further study. Finally, the observation by Marras et al. (2001) that tic decrease did not correlate with a subjectively perceived overall benefit should also be investigated further, for instance by using recent quality of life scales specifically designed for GTS patients (Cavanna et al., 2008).

6. TETRABENAZINE Tetrabenazine (TBZ; formula: C19H27NO3) is a monoamine depletor (vesicular monoamine transporter type 2 inhibitor) and works by promoting the early metabolic degradation of monoamines, especially dopamine. Its action, in contrast to antipsychotics is thereby pre- rather than postsynaptic. Its main medical use concerns hyperkinetic movement disorders, in particular hemiballismus, tardive dyskinesia, and Huntington disease (chorea). For the latter, it is approved in several countries and used off-label for other indications, including tics. Compared to typical antipsychotics, it offers the potential advantage of not inducing tardive dyskinesia. TBZ is therefore especially favored in North America for the treatment of tics in GTS since tardive dyskinesia are a particularly feared side effect when using antipyschotics; note, however, that TBZ can induce parkinsonian syndromes (Jankovic & Kurlan, 2011a; Pringsheim et al., 2012). Also, TBZ compares favorably to antipsychotics in terms of metabolic side effects, especially weight gain (Ondo, Jong, & Davis, 2008). Jankovic, Glaze, and Frost (1984) reported on nine GTS patients treated with TBZ over more than 6 months. Only two patients showed no response

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at all, but drowsiness occurred in two-thirds of patients and Parkinsonism and oculogyric crisis in one patient, respectively. In a retrospective chart review of 77 GTS patients (mean age: 15 years), 80% improved in functioning and tic-related symptoms following TBZ treatment over 2 years (Porta et al., 2008). Also, these authors suggested that TBZ might be a valuable add-on treatment in 120 comedicated patients based on CGI improvement in 76% of patients. Adverse reactions included drowsiness/fatigue (36.4%), nausea (10.4%), depression (9.1%), insomnia (7.8%), and akathisia/parkinsonism (6.5%), but these symptoms improved with reduction in dosage. Weight gain was less pronounced in doses of comparable efficacy than under treatment with antipsychotics and most patients who switched from an antipsychotic drug to TBZ subsequently lost weight. Finally, a report about two patients with GTS who developed tardive dystonia after treatment with antipsychotic agents is worth mentioning. The dystonic movements persisted after the offending drugs were stopped and improved with TBZ (Singh & Jankovic, 1988), in line with TBZ as a recommended treatment for tardive dyskinesia (Chen, Ondo, Dashtipour, & Swope, 2012). In conclusion, TBZ is definitely an interesting treatment option in patients who suffer from metabolic disturbances and/or tardive dyskinesia following antipsychotic use. As to the use of TBZ as a first- or second-line treatment, opinions differ between European and North American centers. Therefore, head-to-head randomized, controlled double-blind studies are sorely needed to answer this question. Finally, the role of TBZ as an addon medication to antipsychotics or non-dopamine-blocking agents equally awaits elucidation in carefully designed clinical trials.

7. NICOTINE Nicotine (formula: C10H14N2) is a parasympathomimetic alkaloid which binds to nicotinic acetylcholine receptors in the CNS. Its actions are complex as it is both a stimulant and a relaxant, and stimulates the presynaptic release of most major neurotransmitters in the brain. With regard to its antipsychotic potentiating effects (see below), the mechanism(s) of action remain unclear. In 1989, Sanberg et al. reported that nicotine potentiates haloperidolinduced hypokinesia in rats and went on to treat 10 GTS nonadult patients with 2 mg nicotine gums as adjunct to ongoing haloperidol treatment (Sanberg et al., 1989). Improvement was noted in 80% of children treated,

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but the vast majority discontinued the nicotine gum because of side effects (bitter taste and nausea). Subsequently, in the first controlled study, it was shown in 19 GTS patients that, when associated with haloperidol, nicotine gums potentiated the effects of the antipsychotic, whereas nicotine gum alone offered only transient benefit, compared to placebo (McConville et al., 1992). A randomized, controlled double-blind trial of transdermal nicotine (7 mg/24 h) compared to placebo with adjunct haloperidol (individual optimal dose) was performed in 70 GTS patients over 33 days (Silver et al., 2001). The study design called for a 50% decrease of haloperidol after 6 days, and after 2 weeks, the patch was discontinued. On the CGI, nicotine was significantly more efficient than placebo, but these changes were only partially reflected by the YGTSS. Side effects (nausea, vomiting) of nicotine treatment were frequent (71% of patients) with a dropout rate of 20%. The authors concluded that nicotine was effective in potentiating the effects of haloperidol but its regular use was limited by side effects; however, its use might be confined to a p.r.n. basis. In conclusion, the rationale to use nicotine as a stand-alone medication in treating tics and GTS is weak. However, as adjunct to typical antipsychotics, nicotine might have some worth, although side effects, especially in children and adult nonsmokers, probably limit its use. Moreover, it is intriguing to note that the addictive potential of nicotine in nonsmokers, present even in pharmacological preparations (gum or patch), is not adequately discussed in the literature.

8. ACETYLCHOLINESTERASE INHIBITORS Based on the aforementioned work on reduced numbers of striatal cholinergic interneurons (Kataoka et al., 2010), increasing cerebral acetylcholine concentrations might offer therapeutic benefits in tics and GTS. Acetylcholine (formula: C7NH16Oþ 2 ) binds to nicotinic and muscarinic receptors in the peripheral and CNS. Its metabolizing enzyme, acetylcholinesterase, which converts acetylcholine into choline and acetate, can be inhibited by drugs such as donepezil and rivastigmine which are best known in the treatment of Alzheimer disease where a prominent deficit in cholinergic neurotransmission from the nucleus basalis of Meynert to the cortex can be observed. In the striatum, cholinergic interneurons respond to salient environmental stimuli with stereotyped responses which are temporally aligned with the responses of nigral dopaminergic neurons (Goldberg &

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Reynolds, 2011). In rodents, cocaine-induced motor stereotypies, which are often considered as tic equivalents, can be arrested by increasing cholinergic transmission in the prefrontal territory of the dorsal striatum since dopaminergic and cholinergic systems appear to counterbalance each other at the striatal level (Aliane, Pe´rez, Bohren, Deniau, & Kemel, 2011). Therefore, increasing cholinergic tone may reciprocally decrease dopaminergic tone in the striatum, similarly to antipsychotics, albeit through a different mechanism. Finally, in the cortex, acetylcholine acts through nicotinic receptors to excite inhibitory interneurons, which further dampen down cortical activity (Gulledge, Park, Kawaguchi, & Stuart, 2007). First reports using physostigmine, a peripherally and centrally acting, reversible acetylcholinesterase inhibitor, suggested that it might decrease tics in small case series (Stahl & Berger, 1981; Tanner, Goetz, & Klawans, 1982). In subsequent studies, because of its exclusively central action, donepezil was favored. Hoopes (1999) reported on two patients treated with low-dose donepezil over 8 months who experienced sustained (but nonquantified) tic reduction. Tolerance appeared to be good. Niederhofer (2006) treated an 18-year-old woman suffering from GTS with 10 mg donepezil per day over 2 weeks: YGTSS score decreased by 34% and began to rise again about 1 week after discontinuing therapy which fits with donepezil’s half-life of about 70 h. Tolerance was not specifically mentioned. Cubo et al. (2008) conducted an open-label, dose escalating (from 2.5 to 5.0 to 10.0 mg/day) 14-week trial on 20 GTS patients (age 8–14), followed by a 4-week washout period. YGTSS total tic score decreased by 34% after 14 weeks, exactly as reported by Niederhofer (2006) but, surprisingly, remained stable at the week 18 visit. However, tolerance was poor with 65% of children experiencing adverse effects (irritability, gastrointestinal symptoms, headache, sedation, nightmares, urinary incontinence, and dizziness) at 5.0 and 10.0 mg, and a 50% dropout rate. In conclusion, raising striatal and possibly cortical cholinergic transmission is an interesting therapeutic lead in GTS and supported by recent human potsmortem data. However, tolerance of donepezil, at least above 5.0 mg/day, seems to be poor in children and adolescents, but maybe better in adults. Therefore, a next logic step would be to test the potential effects of centrally acting acetylcholinesterase inhibitors in adults with tics refractory to antipsychotics, either as stand-alone or add-on medication, in randomized controlled trials. Finally, as for GABA, specifically targeting cholinergic interneurons would be the ideal but yet unaccessible choice.

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9. IMMUNOGLOBULINS, PLASMAPHERESIS, AND ANTIBIOTICS One of the most promising but also controversial pathophysiological models of GTS concerns the PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections) hypothesis. According to this model, tic genesis might be due to the production of antineuronal antibodies directed against the basal ganglia resulting from a cross-reactivity with A group streptococci (Martino, Dale, Gilbert, Giovannoni, & Leckman, 2009). Accordingly, plasmapheresis or intravenous immunoglobulins (IVIG) to remove the damaging antibodies from the circulation have been proposed as acute treatments for PANDAS. As a prophylaxis against streptococcal infection and thus antineuronal antibody production, antibiotic therapy (especially amoxicillin) has been put forward. Plasmapheresis is an extracorporeal therapy whereby antibodies are removed from blood circulation. This is achieved by first separating blood cells from plasma; the blood cells are reinfused, whereas plasma is first filtered for disease-causing antibodies and then returned to blood circulation. As such, it is used in a wide variety of autoimmune disorders. Note, however, that additional immunosuppressive therapy is usually necessary for longterm management of these disorders. As plasmapheresis, IVIG infusion is also a rapid, short-term intervention aimed at reducing autoantibody load, with similar indications in the field of autoimmune diseases. IVIG contains the pooled, polyvalent IgG extract from the plasma of more than 1000 blood donors. The precise mechanism action of IVIG is not firmly established but likely involves the formation of immune complexes that activate Fc receptors on dendritic cells, thereby mediating anti-inflammatory effects. IVIG’s effects last between 2 weeks and 3 months with reinfusions, if necessary, that need to be repeated accordingly. The administered dose is 1–2 g/kg bodyweight. Amoxicillin is a moderate spectrum beta-lactam antibiotic favored to combat streptococcal infections, that is, pharyngitis and endocarditis. It is well absorbed orally; dosage and treatment duration must be tailored to the type of infection. Although usually well tolerated, allergic reactions after amoxicillin use occur and can be life threatening. In the initial and seminal paper, improvements in obsession and compulsion scores were detected after IVIG treatment in 50 PANDAS patients; however, tics remained unaltered compared to placebo (Swedo et al., 1998).

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Perlmutter et al. (1999) observed significant improvement on tics and obsessive–compulsive behavior following either plasma exchange or IVIG in 30 children (plasmapheresis, IVIG, or placebo in 10 children each), with a mean improvement of 49% on the Tourette syndrome unified rating scale. In contrast, Hoekstra, Minderaa, and Kallenberg (2004) investigated the effect of IVIG (1 g/kg on two consecutive days) in a double-blind randomized placebo-controlled study in 30, mostly adult patients with a DSM-IVvalidated diagnosis of tic disorder and found no difference between IVIG and placebo regarding tic severity. Penicillin prophylaxis was evaluated in 37 children meeting PANDAS criteria in an 8-month double-blind, crossover study (4 months twice daily 250 mg penicillin V p.o. and 4 months placebo). No differences in tic severity could be detected when comparing both treatment groups (Garvey et al., 1999). In conclusion, the rationale for using IVIG, plasmapheresis, and antibiotic prophylaxis in the treatment of tics, especially outside a PANDAS setting, remains weak. Also, these approaches are either invasive and costintense (IVIG and plasmapheresis) or potentially harmful on a long-term basis (antibiotic prophylaxis). Yet, the immunological hypothesis of tic genesis deserves further investigation (http://emtics.eu), possibly resulting in more targeted, less invasive, and less costly treatment approaches.

10. SUMMARY AND FUTURE RESEARCH At least from a European perspective (Rickards, Cavanna, & Worrall, 2012), nondopaminergic drugs have not fulfilled the expectation that they might replace antipsychotics in terms of efficacy for treating tics. However, in case of mild tics and especially in the presence of ADHD, clonidine remains a worthwhile treatment option. BTX also deserves mention for the treatment of isolated but disabling simple motor and vocal tics. All other approaches discussed in this review (TBZ, GABA agonists, THC, nicotine, and immune response modulation) display scarce evidence as stand-alone medications and/or are limited by costs/side effect profile. However, in case of severe tics at least partially refractory to antipsychotics, a pragmatic view encourages to try these molecules as add-on medication before resorting to deep brain stimulation (Mu¨ller-Vahl, 2013). In the occurrence of disabling antipsychotic-related side effects (metabolic disturbances, parkinsonian syndromes, tardive dyskinesia), they can also be tried as stand-alone medications, bearing in mind that cognitive-behavioral therapy is now increasingly becoming an attractive option for patients wishing or needing

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nonpharmacologic approaches in treating tics (van de Griendt, Verdellen, van Dijk, & Verbraak, 2013). Future clinical studies should go hand in hand with an increased understanding of the pathophysiology of tics and GTS, particularly with regard to immune modulation (Elamin, Edwards, & Martino, 2013) and the potential roles of the glutamatergic (Singer, Morris, & Grados, 2010) and histaminergic (Fernandez et al., 2012) transmission systems, so far under-appreciated as therapeutic targets. More specifically, glutamate as the most abundant excitatory neurotransmitter in the CNS has received surprisingly little attention in the GTS literature so far. Glutamate interacts strongly with the dopaminergic system (probable cotransmission, i.e., dopaminergic neurons are able to release glutamate, cf. Sulzer et al., 1998), for instance within cortico-striato-thalamocortical circuits which play an important role in GTS pathophysiology. However, it remains unclear to date whether GTS is associated with a hyper- or hypoglutamatergic state (Singer et al., 2010). Glutamate antagonists, that is, riluzole, and agonists, that is, D-Serine, are currently tested in clinical trials (ClinicalTrials.gov NCT01018056). Also, several pathophysiological studies on glutamate and GTS are underway within a European research program (http://www.ts-eurotrain.eu/index.php/the-project/ project-plan/workpackage3). With regard to histamine, a recent linkage analysis identified the L-histidine decarboxylase (HDC) gene in a large family with most members suffering from GTS (Ercan-Sencicek et al., 2010). HDC codes for the ratelimiting enzyme in histamine synthesis. The mutation appears to be loss of function resulting in decreased histamine synthesis. However, the role of this mutation in larger cohorts remains to be verified. A recent case study reported on a patient suffering both from GTS and narcolepsy who was treated by an inverse agonist of the H3 receptor (BF2.649 or tiprolisant or pitolisant, Bioprojet Ltd, France) which raises histaminergic neurotransmission (Hartmann, Worbe, & Arnulf, 2011). H3 receptor reverse agonists increase wakefulness and therefore represent newer alternatives to modafinil or methylphenidate derivatives to treat narcolepsy and related conditions with increased daytime sleepiness. In this patient, BF2.649 (5–40 mg/day) decreased daytime sleepiness without increasing tics as had been the case with prior trials of psychostimulants. Therefore, H3 receptor reverse agonists are worth testing in nonnarcoleptic GTS patients with special attention to comorbid ADHD which might also be improved by this therapeutic approach. Controlled trials have not been registered on ClinicalTrials.gov to date.

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REFERENCES Aliane, V., Pe´rez, S., Bohren, Y., Deniau, J. M., & Kemel, M. L. (2011). Key role of striatal cholinergic interneurons in processes leading to arrest of motor stereotypies. Brain, 134, 110–118. Arnsten, A. F. (2010). The use of alpha-2A adrenergic agonists for the treatment of attentiondeficit/hyperactivity disorder. Expert Review of Neurotherapeutics, 10, 1595–1605. Awaad, Y. (1999). Tics in Tourette syndrome: New treatment options. Journal of Child Neurology, 14(5), 316–319. PubMed PMID: 10342599. Bloch, M. H. (2008). Emerging treatments for Tourette’s disorder. Current Psychiatry Reports, 10, 323–330. Bloch, M. H., Panza, K. E., Landeros-Weisenberger, A., & Leckman, J. F. (2009). Metaanalysis: Treatment of attention-deficit/hyperactivity disorder in children with comorbid tic disorders. Journal of the American Academy of Child and Adolescent Psychiatry, 48, 884–893. Boon-yasidhi, V., Kim, Y. S., & Scahill, L. (2005). An open-label, prospective study of guanfacine in children with ADHD and tic disorders. Journal of the Medical Association of Thailand, 88(Suppl. 8), S156–S162. Cavanna, A. E., Schrag, A., Morley, D., Orth, M., Robertson, M. M., Joyce, E., et al. (2008). The Gilles de la Tourette syndrome-quality of life scale (GTS-QOL): Development and validation. Neurology, 7, 1410–1416. Chappell, P. B., Riddle, M. A., Scahill, L., Lynch, K. A., Schultz, R., Arnsten, A., et al. (1995). Guanfacine treatment of comorbid attention-deficit hyperactivity disorder and Tourette’s syndrome: Preliminary clinical experience. Journal of the American Academy of Child and Adolescent Psychiatry, 34, 1140–1146. Chen, J. J., Ondo, W. G., Dashtipour, K., & Swope, D. M. (2012). Tetrabenazine for the treatment of hyperkinetic movement disorders: A review of the literature. Clinical Therapeutics, 34, 1487–1504. Cohen, D. J., Detlor, J., Young, J. G., & Shaywitz, B. A. (1980). Clonidine ameliorates Gilles de la Tourette syndrome. Archives of General Psychiatry, 37, 1350–1357. Cohen, D. J., Young, J. G., Nathanson, J. A., & Shaywitz, B. A. (1979). Clonidine in Tourette’s syndrome. Lancet, 2, 551–553. Cubo, E., Ferna´ndez, Jae´n A., Moreno, C., Anaya, B., Gonza´lez, M., & Kompoliti, K. (2008). Donepezil use in children and adolescents with tics and attention-deficit/ hyperactivity disorder: An 18-week, single-center, dose-escalating, prospective, openlabel study. Clinical Therapeutics, 30, 182–189. Cummings, D. D., Singer, H. S., Krieger, M., Miller, T. L., & Mahone, E. M. (2002). Neuropsychiatric effects of guanfacine in children with mild tourette syndrome: A pilot study. Clinical Neuropharmacology, 25(6), 325–332. PubMed PMID:12469007. Curtis, A., Clarke, C. E., & Rickards, H. E. (2009). Cannabinoids for Tourette’s Syndrome. Cochrane Database of Systematic Reviews4CD006565. Daviss, W. B., Patel, N. C., Robb, A. S., McDermott, M. P., Bukstein, O. G., Pelham, W. E., Jr., et al. (2008). Clonidine for attention-deficit/hyperactivity disorder: II. ECG changes and adverse events analysis: Journal of the American Academy of Child and Adolescent Psychiatry, 47(2), 189–198. http://dx.doi.org/10.1097/chi.0b013e31815d9ae4. PubMed PMID: 18182964. Du, Y. S., Li, H. F., Vance, A., Zhong, Y. Q., Jiao, F. Y., Wang, H. M., et al. (2008). Randomized double-blind multicentre placebo-controlled clinical trial of the clonidine adhesive patch for the treatment of tic disorders. Australian and New Zealand Journal of Psychiatry, 42, 807–813. Elamin, I., Edwards, M. J., & Martino, D. (2013). Immune dysfunction in Tourette syndrome. Behavioural Neurology, 27, 23–32.

Clinical Pharmacology of Nondopaminergic Drugs

369

Ercan-Sencicek, A. G., Stillman, A. A., Ghosh, A. K., Bilguvar, K., O’Roak, B. J., Mason, C. E., et al. (2010). L-histidine decarboxylase and Tourette’s syndrome. The New England Journal of Medicine, 362(20), 1901–1908. http://dx.doi.org/10.1056/ NEJMoa0907006. Epub 2010 May 5. PubMed PMID: 20445167; PubMed Central PMCID: PMC2894694. Fernandez, T. V., Sanders, S. J., Yurkiewicz, I. R., Ercan-Sencicek, A. G., Kim, Y. S., Fishman, D. O., et al. (2012). Rare copy number variants in Tourette syndrome disrupt genes in histaminergic pathways and overlap with autism. Biological Psychiatry, 71, 392–402. Ferna´ndez-Ruiz, J., Herna´ndez, M., & Ramos, J. A. (2010). Cannabinoid-dopamine interaction in the pathophysiology and treatment of CNS disorders. CNS Neuroscience and Therapeutics, 16, e72–e91. Fras, I. (1996). Guanfacine for Tourette’s disorder. Journal of the American Academy of Child and Adolescent Psychiatry, 35, 3–4. Gaffney, G. R., Perry, P. J., Lund, B. C., Bever-Stille, K. A., Arndt, S., & Kuperman, S. (2002). Risperidone versus clonidine in the treatment of children and adolescents with Tourette’s syndrome. Journal of the American Academy of Child and Adolescent Psychiatry, 41, 330–336. Garvey, M. A., Perlmutter, S. J., Allen, A. J., Hamburger, S., Lougee, L., Leonard, H. L., et al. (1999). A pilot study of penicillin prophylaxis for neuropsychiatric exacerbations triggered by streptococcal infections. Biological Psychiatry, 45, 1564–1571. Gittis, A. H., Leventhal, D. K., Fensterheim, B. A., Pettibone, J. R., Berke, J. D., & Kreitzer, A. C. (2011). Selective inhibition of striatal fast-spiking interneurons causes dyskinesias. Journal of Neuroscience, 31, 15727–15731. Goetz, C. G. (1992). Clonidine and clonazepam in Tourette syndrome. Advances in Neurology, 58, 245–251. Goetz, C. G., Tanner, C. M., Wilson, R. S., Carroll, V. S., Como, P. G., & Shannon, K. M. (1987). Clonidine and Gilles de la Tourette’s syndrome: Double-blind study using objective rating methods. Annals of Neurology, 21, 307–310. Goldberg, J. A., & Reynolds, J. N. (2011). Spontaneous firing and evoked pauses in the tonically active cholinergic interneurons of the striatum. Neuroscience, 198, 27–43. Gonce, M., & Barbeau, A. (1977). Seven cases of Gilles de la Tourette’s syndrome: Partial relief with clonazepam: A pilot study. Canadian Journal of Neurological Sciences, 4, 279–283. Gulledge, A. T., Park, S. B., Kawaguchi, Y., & Stuart, G. J. (2007). Heterogeneity of phasic cholinergic signaling in neocortical neurons. Journal of Neurophysiology, 97, 2215–2229. Hartmann, A., Worbe, Y., & Arnulf, I. (2011). Increasing histamine neurotransmission in Gilles de la Tourette syndrome. Journal of Neurology, 259, 375–376. Hedderick, E. F., Morris, C. M., & Singer, H. S. (2009). Double-blind, crossover study of clonidine and levetiracetam in Tourette syndrome. Pediatric Neurology, 40, 420–425. Hoekstra, P. J., Minderaa, R. B., & Kallenberg, C. G. (2004). Lack of effect of intravenous immunoglobulins on tics: A double-blind placebo-controlled study. Journal of Clinical Psychiatry, 65, 537–542. Hoopes, S. P. (1999). Donepezil for Tourette’s disorder and ADHD. Journal of Clinical Psychopharmacology, 19(4), 381–382. PubMed PMID: 10440471. Jankovic, J., Glaze, D. G., & Frost, J. D., Jr. (1984). Effect of tetrabenazine on tics and sleep of Gilles de la Tourette’s syndrome. Neurology, 34, 688–692. Jankovic, J., & Kurlan, R. (2011a). Tourette syndrome: Evolving concepts. Movement Disorders, 26, 1149–1156. Jankovic, J., & Kurlan, R. (2011b). Treatment of tics in patients with Tourette syndrome: Recommendations according to the European Society for the Study of Tourette Syndrome (author reply). Movement Disorders, 26, 2448.

370

Andreas Hartmann

Kalanithi, P. S., Zheng, W., Kataoka, Y., DiFiglia, M., Grantz, H., Saper, C. B., et al. (2005). Altered parvalbumin-positive neuron distribution in basal ganglia of individuals with Tourette syndrome. Proceedings of the National Academy of Sciences of the United States of America, 102, 13307–13312. Kataoka, Y., Kalanithi, P. S., Grantz, H., Schwartz, M. L., Saper, C., Leckman, J. F., et al. (2010). Decreased number of parvalbumin and cholinergic interneurons in the striatum of individuals with Tourette syndrome. Journal of Comparative Neurology, 518, 277–291. King, A., Harris, P., Fritzell, J., & Kurlan, R. (2006). Syncope in children with Tourette’s syndrome treated with guanfacine. Movement Disorders, 21, 419–420. Kuepper, R., Morrison, P. D., van Os, J., Murray, R. M., Kenis, G., & Henquet, C. (2010). Does dopamine mediate the psychosis-inducing effects of cannabis? A review and integration of findings across disciplines. Schizophrenia Research, 121, 107–117. Kwak, C. H., Hanna, P. A., & Jankovic, J. (2000). Botulinum toxin in the treatment of tics. Archives of Neurology, 57, 1190–1193. Leckman, J. F., Hardin, M. T., Riddle, M. A., Stevenson, J., Ort, S. I., & Cohen, D. J. (1991). Clonidine treatment of Gilles de la Tourette’s syndrome. Archives of General Psychiatry, 48, 324–328. Lichter, D. G., & Jackson, L. A. (1996). Predictors of clonidine response in Tourette syndrome: Implications and inferences. Journal of Child Neurology, 2, 93–97. Marras, C., Andrews, D., Sime, E., & Lang, A. E. (2001). Botulinum toxin for simple motor tics: A randomized, double-blind, controlled clinical trial. Neurology, 56, 605–610. Martino, D., Dale, R. C., Gilbert, D. L., Giovannoni, G., & Leckman, J. F. (2009). Immunopathogenic mechanisms in Tourette syndrome: A critical review. Movement Disorders, 24, 1267–1279. McConville, B. J., Sanberg, P. R., Fogelson, M. H., King, J., Cirino, P., Parker, K. W., et al. (1992). The effects of nicotine plus haloperidol compared to nicotine only and placebo nicotine only in reducing tic severity and frequency in Tourette’s disorder. Biological Psychiatry, 31, 832–840. Mu¨ller-Vahl, K. R. (2013). Surgical treatment of Tourette syndrome. Neuroscience and Biobehavioral Reviews, 37(6), 1178–1185. http://dx.doi.org/10.1016/j.neubiorev.2012.09.012. Epub 2012 Oct 4. PubMed PMID: 23041074. Mu¨ller-Vahl, K. R., & Krueger, D. (2011). Does Tourette syndrome prevent tardive dyskinesia? Movement Disorders, 26, 2442–2443. Mu¨ller-Vahl, K. R., Prevedel, H., Theloe, K., Kolbe, H., Emrich, H. M., & Schneider, U. (2003). Treatment of Tourette syndrome with delta-9-tetrahydrocannabinol (delta 9-THC): No influence on neuropsychological performance. Neuropsychopharmacology, 28, 384–388. Mu¨ller-Vahl, K. R., Roessner, V., & European Society for the Study of Tourette Syndrome (2011). Treatment of tics in patients with Tourette syndrome: Recommendations according to the European Society for the Study of Tourette Syndrome. Movement Disorders, 26, 2447. Mu¨ller-Vahl, K. R., Schneider, U., Koblenz, A., Jo¨bges, M., Kolbe, H., Daldrup, T., et al. (2002). Treatment of Tourette’s syndrome with Delta 9-tetrahydrocannabinol (THC): A randomized crossover trial. Pharmacopsychiatry, 35, 57–61. Mu¨ller-Vahl, K. R., Schneider, U., Prevedel, H., Theloe, K., Kolbe, H., Daldrup, T., et al. (2003). Delta 9-tetrahydrocannabinol (THC) is effective in the treatment of tics in Tourette syndrome: A 6-week randomized trial. Journal of Clinical Psychiatry, 64, 459–465. Niederhofer, H. (2006). Donepezil also effective in the treatment of Tourette’s syndrome? Movement Disorders, 21, 2027. Ondo, W. G., Jong, D., & Davis, A. (2008). Comparison of weight gain in treatments for Tourette syndrome: Tetrabenazine versus neuroleptic drugs. Journal of Child Neurology, 23, 435–437.

Clinical Pharmacology of Nondopaminergic Drugs

371

Perlmutter, S. J., Leitman, S. F., Garvey, M. A., Hamburger, S., Feldman, E., Leonard, H. L., et al. (1999). Therapeutic plasma exchange and intravenous immunoglobulin for obsessive-compulsive disorder and tic disorders in childhood. Lancet, 354, 1153–1158. Porta, M., Maggioni, G., Ottaviani, F., & Schindler, A. (2004). Treatment of phonic tics in patients with Tourette’s syndrome using botulinum toxin type A. Neurological Sciences, 24, 420–423. Porta, M., Sassi, M., Cavallazzi, M., Fornari, M., Brambilla, A., & Servello, D. (2008). Tourette’s syndrome and role of tetrabenazine: Review and personal experience. Clinical Drug Investigation, 28, 443–459. Pringsheim, T., Doja, A., Gorman, D., McKinlay, D., Day, L., Billinghurst, L., et al. (2012). Canadian guidelines for the evidence-based treatment of tic disorders: Pharmacotherapy. Canadian Journal of Psychiatry, 57, 133–143. Pringsheim, T., & Pearce, M. (2010). Complications of antipsychotic therapy in children with Tourette syndrome. Pediatric Neurology, 43, 17–20. Rath, J. J., Tavy, D. L., Wertenbroek, A. A., van Woerkom, T. C., & de Bruijn, S. F. (2010). Botulinum toxin type A in simple motor tics: Short-term and long-term treatmenteffects. Parkinsonism & Related Disorders, 16, 478–481. Rickards, H., Cavanna, A. E., & Worrall, R. (2012). Treatment practices in Tourette syndrome: The European perspective. European Journal of Paediatric Neurology, 16, 361–364. Roessner, V., Plessen, K. J., Rothenberger, A., Ludolph, A. G., Rizzo, R., Skov, L., et al. (2011). European clinical guidelines for Tourette syndrome and other tic disorders. Part II: Pharmacological treatment. European Child & Adolescent Psychiatry, 20, 173–196. Sanberg, P. R., McConville, B. J., Fogelson, H. M., Manderscheid, P. Z., Parker, K. W., Blythe, M. M., et al. (1989). Nicotine potentiates the effects of haloperidol in animals and in patients with Tourette syndrome. Biomedicine & Pharmacotherapy, 43, 19–23. Sandor, P. (2003). Pharmacological management of tics in patients with TS. Journal of Psychosomatic Research, 55(1), 41–48. Review. PubMed PMID: 12842230. Scahill, L., Aman, M. G., McDougle, C. J., McCracken, J. T., Tierney, E., Dziura, J., et al. (2006). A prospective open trial of guanfacine in children with pervasive developmental disorders. Journal of Child and Adolescent Psychopharmacology, 16(5), 589–598. PubMed PMID: 17069547. Scahill, L., Chappell, P. B., Kim, Y. S., Schultz, R. T., Katsovich, L., Shepherd, E., et al. (2001). A placebo-controlled study of guanfacine in the treatment of children with tic disorders and attention deficit hyperactivity disorder. American Journal of Psychiatry, 158, 1067–1074. Scott, B. L., Jankovic, J., & Donovan, D. T. (1996). Botulinum toxin injection into vocal cord in the treatment of malignant coprolalia associated with Tourette’s syndrome. Movement Disorders, 11, 431–433. Shapiro, A. K., Shapiro, E., & Eisenkraft, G. J. (1983). Treatment of Gilles de la Tourette’s syndrome with clonidine and neuroleptics. Archives of General Psychiatry, 40, 1235–1240. Silver, A. A., Shytle, R. D., Philipp, M. K., Wilkinson, B. J., McConville, B., & Sanberg, P. R. (2001). Transdermal nicotine and haloperidol in Tourette’s disorder: A double-blind placebo-controlled study. Journal of Clinical Psychiatry, 62, 707–714. Singer, H. S., Morris, C., & Grados, M. (2010). Glutamatergic modulatory therapy for Tourette syndrome. Medical Hypotheses, 74, 862–867. Singer, H. S., Wendlandt, J., Krieger, M., & Giuliano, J. (2001). Baclofen treatment in Tourette syndrome: A double-blind, placebo-controlled, crossover trial. Neurology, 56, 599–604. Singh, S. K., & Jankovic, J. (1988). Tardive dystonia in patients with Tourette’s syndrome. Movement Disorders, 3, 274–280.

372

Andreas Hartmann

Skerritt, J. H., & Johnston, G. A. (1983). Enhancement of GABA binding by benzodiazepines and related anxiolytics. European Journal of Pharmacology, 89, 193–198. Stahl, S. M., & Berger, P. A. (1981). Physostigmine in Tourette syndrome: Evidence for cholinergic underactivity. American Journal of Psychiatry, 138, 240–242. Steingard, R. J., Goldberg, M., Lee, D., & DeMaso, D. R. (1994). Adjunctive clonazepam treatment of tic symptoms in children with comorbid tic disorders and ADHD. Journal of the American Academy of Child and Adolescent Psychiatry, 33, 394–399. Sulzer, D., Joyce, M. P., Lin, L., Geldwert, D., Haber, S. N., Hattori, T., et al. (1998). Dopamine neurons make glutamatergic synapses in vitro. Journal of Neuroscience, 18, 4588–4602. Swedo, S. E., Leonard, H. L., Garvey, M., Mittleman, B., Allen, A. J., Perlmutter, S., et al. (1998). Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections: Clinical description of the first 50 cases. American Journal of Psychiatry, 155, 264–271. Tanner, C. M., Goetz, C. G., & Klawans, H. L. (1982). Cholinergic mechanisms in Tourette syndrome. Neurology, 32, 1315–1317. Tourette’s Syndrome Study Group (2002). Treatment of ADHD in children with tics: A randomized controlled trial. Neurology, 58, 527–536. Trimble, M. R., Whurr, R., Brookes, G., & Robertson, M. M. (1998). Vocal tics in Gilles de la Tourette syndrome treated with botulinum toxin injections. Movement Disorders, 13(3), 617–619. PubMed PMID: 9613771. van de Griendt, J. M., Verdellen, C. W., van Dijk, M. K., & Verbraak, M. J. (2013). Behavioural treatment of tics: Habit reversal and exposure with response prevention. Neuroscience and Biobehavioral Reviews, 37(6), 1172–1177. http://dx.doi.org/10.1016/j. neubiorev.2012.10.007. Epub 2012 Oct 23. PubMed PMID: 23089154. Weisman, H., Qureshi, I. A., Leckman, J. F., Scahill, L., & Bloch, M. H. (2012). Systematic review: Pharmacological treatment of tic disorders—Efficacy of antipsychotic and alpha-2 adrenergic agonist agents. Neuroscience and Biobehavioral Reviews, 37, 1162–1171. http://dx.doi.org/10.1016/j.neubiorev.2012.09.008, pii: S0149-7634(12) 00161-3.