Ndt-6371-levetiracetam-as-an-alternative-therapy-for-tourette-syndrom

Neuropsychiatric Disease and Treatment
open access to scientific and medical research This article was published in the following Dove Press journal: Neuropsychiatric Disease and Treatment3 May 2010Number of times this article has been viewed Abstract: Tourette syndrome is a common childhood-onset neuropsychiatric disorder
characterized by chronic tics and frequent comorbid conditions such as attention deficit disorder. Most currently used tic-suppressing drugs are frequently associated with serious adverse events. Thus, alternative therapeutic agents with more favorable side-effect profiles are being evaluated. New hypotheses and recent studies involving GABAergic system in the pathophysiology of Tourette syndrome suppose a reason for the evaluation of GABAergic drugs. Levetiracetam is a drug with an atypical GABAergic mechanism of action that might be expected to improve tics. Although trials performed to evaluate the efficacy of levetiracetam in the treatment of Tourette syndrome have provided conflicting results, it may be useful in some patients. The established safe profile of levetiracetam makes this drug an alternative for treatment if intolerance to currently used drugs appears, but additional evaluation with larger
and longer duration controlled studies are necessary to assess the real efficacy in patients
with Tourette syndrome.
Keywords: Tourette syndrome, levetiracetam, tics, children, adolescents, GABA
ette syndrome: Introduction
Tourette syndrome (TS) is a childhood-onset neuropsychiatric disorder characterized by multiple chronic motor and vocal tics with a waxing and waning, fluctuating course. Not fdisorder, with a prevalence of 1%–3% in school-age children and Inthe majority of patients with TS, tics are tion as attention deficit hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), learning difficulties, emotional problems, mood and anxiety symptoms, oppositional defiant disorder, and other disruptive behaviors. These comorbidities complicate the outcome of the condition, with negative effects on peer acceptance, self-esteem and academic performance.3,4 Pathogenesis of Tourette syndrome
The findings from the preceding studies support the notion that TS is a complex genetic disorder of synaptic neurotransmission that involves basal ganglia and frontocortical circuits. Anatomical and functional neuroimaging studies have shown abnormalities in prefrontal cortical, paralimbic and striatal regions of the brain. Abnormal activity in the cortico-striato-thalamo-cortical pathways are involved in TS and its accompanying submit your manuscript
Neuropsychiatric Disease and Treatment 2010:6 1–8 2010 Martínez-Granero et al, publisher and licensee Dove Medical Press Ltd. This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited.
Several neurotransmitters are involved in these pathways, They are a good alternative for patients with tics and ADHD, although it is widely believed that abnormalities of dopamine because both conditions may respond.20,21 neurotransmission play a primary role in the physiopathology The atypical neuroleptics risperidone22–24 and olanza- of TS. This hypothesis arises, in part, from evidence from pine25,26 showed efficacy in randomized, controlled trials. pharmacological trials of therapeutic response to blockade of Although associated with fewer side-effects than typical dopamine receptors, several functional imaging studies, and neuroleptics, these are still frequent,6,16 and children may post-mortem studies.9–11 However, in spite of the evidence be more vulnerable than adults.27 Attention must be paid to implicating dopaminergic dysfunction in TS, other neuro- sedation, weight gain, extrapyramidal reactions, electrocar- pathologic and functional imaging studies have demonstrated diographic alterations, and development of the metabolic syndrome (obesity, dyslipidemia, hypertension, and impaired Therefore, the precise neurobiologic abnormality remains undefined. Other different neurotransmitters within the Because of frequent side-effects, multiple non-neuroleptic cortico-striato-thalamo-cortical circuits may also be involved alternative medications and non-pharmacological treatments have been evaluated for the treatment of tics.6,9,12,30 Classical treatments in Tourette
syndrome
Although tics tend to fluctuate within short periods of time, The pathophysiology of TS is not fully understood, but basal and improve or resolve over time, especially after puberty, ganglia dysfunction involving GABAergic neurons is one tics can impair the quality of life of children and adolescents by interfering with social interactions, school performance, Aberrant development of GABAergic circuits has been implicated in TS. In one study, marked alteration in the For patients with mild symptoms, educational and distribution of GABAergic neurons was found through psychological interventions may be sufficient. Drug therapy neuropathological examination of basal ganglia tissue from should be considered for patients whose symptoms interfere TS patients. A decreased number and density of GABAergic interneurons in the striatum and external segment globus pal- Treatment of tics in TS is symptomatic. The goals of lidus, as well as an increase in the number and proportion of treatment should be to reduce the severity, frequency, and dis- GABAergic projection neurons of the internal segment of the ruptive impact of symptoms, to manage associated psychiatric globus pallidus were found. The authors speculated that these and learning problems, and to improve social functioning.13 alterations would be consistent with a developmental defect The presence of comorbidities can complicate the treat- in tangential migration of some GABAergic neurons.31 ment of patients with TS. Therapy must be individualized, Many inhibitory GABAergic interneurons of the cerebral and the most troublesome symptoms should be targeted first. cortex migrate tangentially from the same embryogenic Treatment of comorbid behavioral symptoms usually exerts a regions in the ganglionic eminence that also give rise significant beneficial effect on tics. In other patients, a reduc- to the GABAergic projecting neurons of the striatum.32 tion in tics might improve self-esteem, which in turn results One hypothesis is that an adverse event at a specific devel- in improved behavior and school performance.
opmental point could impair the appropriate migration and There is no ideal anti-tic pharmacotherapy. Drugs have maturation of these cells and their assembly into inhibitory highly variable results and, unfortunately, are often associated with side-effects.6,13–16 The most widely used treatments have It is not completely understood how alterations in consisted of neuroleptics and alpha-2 adrenergic agents.
GABAergic interneurons and globus pallidus projection neu- Dopamine receptor-blocking drugs (neuroleptics) are rons could lead to a tic disorder. It has been hypothesized that considered the most effective tic-suppresing agents. Classical in TS, a decrease in striatal GABAergic projections would or typical neuroleptics have shown great efficacy in con- cause insufficient inhibition of excitatory thalamocortical trolled clinical trials,17,18 but frequent side-effects often limit neurons, with the ultimate result being increased glutamater- gic cortical excitation and the appearance of tics.6 Alpha-2 adrenergic agents (clonidine and guanfacine) are Most TS patients over the age of ten years report better tolerated but may be not as effective as neuroleptics. premonitory sensations preceding motor or vocal tics, submit your manuscript |
Neuropsychiatric Disease and Treatment 2010:6 Levetiracetam as an alternative therapy for Tourette syndrome and an irresistible urge to perform the tic.33 This probably binding was observed in peripheral tissues. More recently, reflects a failure in motor inhibition because of diminished this binding site has been identified as the SV2A protein, a ability to appropriately manage sensory inputs.34 Comorbid protein ubiquitously distributed in the central nervous system behavioral conditions such as OCD, ADHD, impulse control as a component of synaptic vesicles.44 The binding of LEV is disorder, and intermittent explosive disorder are also related reversible, saturable, and highly selective to this protein.
to impaired inhibition of inappropriate behaviours. Studies SV2A is required for normal neurotransmission. In with transcranial magnetic stimulation have shown that the absence of this protein, action potential-dependent the cortical silent period (period of decreased excitability GABAergic neurotransmission is reduced. The exact role following stimulation) is significantly shortened, and the of the SV2A protein is not fully understood, but it is thought intracortical inhibition is defective in TS patients compared to be involved in the regulation of vesicle exocytosis.45 to controls.35 This intracortical excitability is also seen fre- The most frequently reported adverse events with LEV quently in children with ADHD comorbid with a tic disorder. include somnolence, irritability, asthenia, headache, dizziness, Because motor cortex lesions are unlikely in TS patients, and flu syndrome and are usually mild. In clinical trials, the abnormal intracortical inhibition must be the consequence incidence of adverse effects leading to dosage reduction or of a dysfunction of the subcortical input.
discontinuation was similar to placebo (15% vs 11.6%).39,40 If these alterations in GABAergic system play a role in In a systematic review of adults receiving LEV in long-term the pathophysiology of TS, then GABAergic drugs might be clinical trials, LEV had a relatively low incidence (13%–16%) expected to improve tics. Thus, GABAergic drugs such as of adverse psychiatric and behavioral events; apathy, emotional clonazepam, baclofen, and topiramate have been evaluated lability, agitation, anxiety, depression, anger, hostility, personal- in treatment of tics, with varying results.
ity changes, and suicidal ideation are reported events.46 Revers- Only a modest tic-suppressing effect has been reported ible psychosis associated with LEV therapy was observed in with clonazepam in the published case series.14 children and adolescents.47 These adverse behavioral symptoms The GABA-B agonist baclofen has been effective in are more common in patients with epilepsy or a previous history improving tics in one open-label trial, without baseline of behavioral or psychiatric problems, and can be the primary or follow-up scores.36 In a small, double-blind, placebo- reason for discontinuation of the medication.39,40,47 Adverse controlled, crossover study, baclofen had benefit over behavioral events did not appear to be dose-related. Most of placebo, although the beneficial response was associated the behavioral problems associated with LEV therapy resolved with improvement in impairment scores rather than with a within days after discontinuation of medication, and were not associated with any long-term disability.
In a randomized, double-blind, placebo-controlled trial, The metabolism of levetiracetam is independent of the topiramate produced a statistically significant improvement cytochrome P450 system. The absence of hepatic metabolism in TS patients with moderate to severe symptoms.38 is associated with a very low potential for drug interac-tions and levetiracetam has no known clinically significant Levetiracetam
Levetiracetam (LEV) is a broad-spectrum antiepileptic agent that has been used effectively for a variety of seizure types in adults and children, and for different psychiatric Due to its GABAergic mechanism of action, LEV could LEV does not have a direct effect on GABA receptor- produce a beneficial effect in patients with TS. Several mediated responses. In vitro findings reveal that LEV behaves studies, discussed below, were conducted to investigate the as a modulator of GABA type A and of the glycine receptors, effectiveness of LEV for the treatment of tics in children and suppressing the inhibitory effect of other negative modulators (beta-carbolines and zinc). LEV inhibits the ability of zinc The most widely-used instruments for measuring tic and beta-carbolines to interrupt chloride influx, an effect that severity in therapeutic trials are the Yale Global Tic Sever- enhances chloride ion influx at the GABA type A receptor ity Scale (YGTSS) and Clinical Global Impression (CGI) A brain-specific binding site for LEV was demonstrated The YGTSS consists of a rating of severity for motor for the first time in the brain tissue of rats.43 No specific and vocal tics separately, with a scale of 0 to 5 for each tic’s Neuropsychiatric Disease and Treatment 2010:6 submit your manuscript
Table 1 Studies with Levetiracetam in Tourette syndrome patients
Ref
Study type
Subjects
Intervention
Outcomes
Remarks and limitations
because exacerbation of previous behavioral or ADHD symptoms.
max 50 mg/K/d) Lev in tics, ADHD or OCD.
or clonidine (0.15–0.3 mg/d) in randomized sequence, 6 weeks each Abbreviations: Ref, reference list item number; LEV, levetiracetam; ADHD, attention deficit hyperactivity disorder; OCD, obsessive-compulsive disorder.
number, frequency, intensity, complexity, and interference Behavior Scales. The effects on measures of behavior and with daily life. Summation of these scores result in a total tic school performance were also assessed. All patients showed score (TTS). The tic impairment score (TIS) is based on the significant clinical improvements in their vocal and motor impact of the tic disorder on self-esteem, family life, social tics. Also, 43 of the 60 patients showed improvement in their acceptance, and school performance. TIS is added to TTS behavior and school performance. Three patients discontin- to obtain the total or global YGTSS score.48 ued the treatment because of exacerbation of preexisting The CGI scale is a seven-point, ordinal scale that uses all available information to determine the impact of tics on the In a 4-year follow-up of this prospective, open-label subject’s quality of life: 1 (healthy), 2 (borderline), 3 (mild), study, data was included from 10 additional patients, LEV 4 (moderate), 5 (marked), 6 (severe), and 7 (extreme).
remained 100% effective for tic suppression. Improvements Awaad et al49 suggested in 2005 that levetiracetam may were observed within the first six weeks of treatment, which be a useful treatment for tics. They conducted a prospective, persisted over time. Also, 70% of patients showed improve- open-label, clinical trial with sixty children and adolescents ment in behavior and school performance.50 with tics and previously-untreated TS. Patients were treated A randomized, placebo-controlled, double-blind, cross- with LEV in doses of 1000–2000 mg/day, and no concomitant over trial51 was performed to determine whether LEV could medications were used. Outcomes were assessed at 1 year significantly reduce tics in children and adolescents with TS. with the YGTSS and CGI scales and the Revised Conners This study enrolled twenty-two children aged 8–16 years submit your manuscript |
Neuropsychiatric Disease and Treatment 2010:6 Levetiracetam as an alternative therapy for Tourette syndrome old with TS, with moderate to moderately severe tics. In a and at 12 weeks. Twenty-seven patients completed the study. randomized drug sequence, patients received four weeks of Tics improved in 59% patients (markedly, in half of them), LEV with a maximum dosage of 30 mg/kg/day, or placebo, 26% did not reveal significant changes, and tics worsened with a two-week intervening wash-out period between cycles. in 15% of cases. In the statistical analysis, a significant The primary outcome measures included the total score from improvement was observed in TTS and the global score from the YGTSS and the TTS from the subscale. Measurements YGTSS and the CGI scale. When the results of two separate were taken at the baseline (before randomization), on day 28 groups (patients with and without associated ADHD) were (end of phase I), on day 42 (end of wash-out period and base- analyzed, only patients with ADHD-associated diagnosis line for phase II), and on day 70 (end of phase II). In both revealed a significant improvement in TTS and CGI. Most placebo and treatment groups, there was a slight reduction of these patients (63%) were treated simultaneously with in tics compared with baseline measures, but no significant methylphenidate. Ten cases (37%) presented adverse effects difference was found between groups. The results were not (most frequently, irritability and drowsiness), which caused affected by the sequence of treatment. Neither was there discontinuation of treatment in 3 patients (11%).
found any difference in secondary outcome measures for A recent prospective, double-blinded, randomized, pla- tics (tic impairment score from subscale of YGTSS and CGI cebo controlled study54 included twenty-four children aged scale) nor any effect on attentional symptoms or obsessive- 6–18 years old with TS and associated diagnoses of epilepsy (14 patients) or headache (10 patients). Children were given A randomized, double-blind, flexible-dose, crossover LEV (500 to 1250 mg/day) or placebo in a randomized study52 compared LEV and clonidine for the treatment of sequence. Twelve patients received LEV: nine of them tics in TS patients: twelve subjects with moderate to mod- showed improvement in tics, two were lost to follow-up, and erately severe tics were enrolled. Patients received placebo one patient with comorbid ADHD and OCD discontinued during week 1 to screen for high placebo responders. Sub- LEV because of aggressiveness. One patient in the placebo sequently, in a randomized drug sequence, patients received group showed a great placebo effect with improvement in six weeks of LEV with a maximum dosage of 50 mg/kg/day tics, two were lost to follow-up, and the remaining nine or 2500 mg/day, or clonidine with a two-week wash-out showed no improvement. Patients receiving LEV showed a period between both cycles. Ten patients aged 8–27 years significant decrease in frequency, interference, and impair- completed the study. Two were withdrawn before the ment of motor and vocal tics in YGTSS. Seven patients filled medication phase (one because of important improvement the Conners Parent Rating scale before and after treatment. during the placebo run-in phase, and the other as a paren- The four patients who improved were in the LEV group.
tal decision). The primary outcome measure was the TTS Other publications are limited to isolated case reports: component of the YGTSS. Secondary outcome measures • A 23 year old female with refractory TS whose symptoms included the global score of the YGTSS, the CGI scale, improved significantly, when treated with LEV, and and other scales for obsessive-compulsive, attention deficit hyperactivity, depression, and anxiety symptoms. In this • A 25 year old male with severe and refractory TS, who study, a small but statistically significant improvement in presented an ischemic stroke in association with antiphos- TTS was fround with clonidine (13% from baseline). There pholipid syndrome and secondarily epilepsy, was treated was no improvement in any tic scores with LEV. Evaluating with LEV, with improvement in both tic disorder and comorbidities, no significant change in secondary behavioral measures was demonstrated with clonidine or LEV. The most commonly reported side-effect with LEV was irritability, in Discussion
New hypotheses and recent studies involving GABAergic sys- A prospective, open-label study53 included 29 patients tem in the pathophysiology of Tourette syndrome propose the with TS aged 6–17 years. Patients received LEV with a starting point for therapeutical trials with GABAergic drugs.
dosage of approximately 30–40 mg/kg/day (maximum First, trials with the GABAergic drug clonazepam 2000 mg/day). Concomitant treatment with neuroleptics, show only a modest effect. Baclofen did not prove to have clonidine, or methylphenidate was present in more than a clear benefit in suppressing tics in a randomized trial. half of the cases. The authors evaluated the scores from the More recently, topiramate showed a beneficial effect in a YGTSS and modified CGI scale at the beginning of the study Neuropsychiatric Disease and Treatment 2010:6 submit your manuscript
LEV, with an atypical enhancing activity at GABA-A serious events requiring withdrawal of treatment were receptors, could be of interest in treatment of tics. Although unusual (generally exacerbation of previous behavioral promising results were found in open-label studies,49,50,53 and disorders such as aggressiveness or impulse behavior in one randomized study54, other controlled trials could not Several important factors must be taken into account when Conclusions
interpreting the results of therapeutic trials in TS patients, LEV is a drug with potential benefits in alleviating tics which may explain the contradictory results with LEV.
and neuropsychiatric disorders. Although, at this moment, First, tics have a natural waxing and waning pattern, with trials performed to evaluate the efficacy of LEV in the treat- marked fluctuations in severity and frequency, and usually ment of TS have provided conflicting results, it seems to improve over time. Even without intervention, a period of be useful in some patients. Children and adolescents with severe tics will be followed by one of spontaneous waning. associated ADHD may be better candidates for treatment This fluctuating course and variability of symptoms in TS must be considered when interpreting results of clinical The established safe profile of LEV makes this drug a better-tolerated alternative for treatment if intolerance to On the other hand, there is evidence that GABA plays currently-used drugs appears. The low risk of drug interac- a key role in the pathophysiology of anxiety and stress dis- tions with LEV might be another consideration for patients orders, and for that reason, LEV has a potential efficacy for who require the concurrent use of other medications for the treatment of anxiety.57,58 Other studies have suggested a positive effect of LEV on cognitive functioning. In a study The results of some studies, and its safety profile, make with adult patients with partial epilepsy, patients receiv- LEV an alternative candidate for the treatment of TS. ing LEV as an add-on therapy had a significant cognitive However, additional evaluation with larger, and longer- improvement in attention and oral fluency not related to the duration, controlled studies are necessary to assess the real seizure frequency, probably due to the effects of LEV itself.59 As tics can be exacerbated by factors such as stress, anxiety, and learning difficulties, LEV may indirectly improve tics References
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Neuropsychiatric Disease and Treatment
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Neuropsychiatric Disease and Treatment is an international, peer- journal of The International Neuropsychiatric Association (INA). The reviewed journal of clinical therapeutics and pharmacology focusing on manuscript management system is completely online and includes a concise rapid reporting of clinical or pre-clinical studies on a range of very quick and fair peer-review system, which is all easy to use. Visit neuropsychiatric and neurological disorders. This journal is indexed on http://www.dovepress.com/testimonials.php to read real quotes from PubMed Central, the ‘PsycINFO’ database and CAS, and is the official Submit your manuscript here:
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Neuropsychiatric Disease and Treatment 2010:6

Source: http://www.pacomontanes.es/levetiracetam-as-an-alternative-therapy-for-tourette-syndrom%20030510-NDT-6371-.pdf