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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
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8.11 Chlor-Alkali The chlor-alkali electrolysis process is used in the manufacture of chlorine, hydrogen, andsodium hydroxide (caustic) solution. Of these 3, the primary product is chlorine. Chlorine is 1 of the more abundant chemicals produced by industry and has a wide variety ofindustrial uses. Chlorine was first used to produce bleaching agents for the textile and paper industriesand for
Inspired Journeys http://www.old.inspiredjourneys.co.za About our Workshops 2008-02-22 06:39:17 by admin About Hallucinogenic Plants For the Explorers of Inner Space Introduction There are a variety of tools available to anyone interested in exploring altered states of consciousness. Such toolsinclude meditation, out-of-body experiences, brain and biofeedback instruments, occult