Aetna considers certain procedures and services medically necessary for assessment and treatment of Tourette's syndrome (TS) when all of the following selection criteria are met.

• Both multiple motor and 1 or more vocal tics have been present at some time during the illness, although not necessarily simultaneously; and
• The disturbance causes significant distress or marked impairment in social, occupational, or other important areas of functioning; and
• The disturbance is not due to direct physiological effects of a substance (e.g., stimulants) or a general medical condition (e.g., Huntington's disease or post-viral encephalitis); and
• The onset is before the age of 21 years; and
• The tics occur many times a day (usually in bouts) almost every day or periodically throughout a duration of more than 1 year, and during this period there was never a tic-free period of more than 3 consecutive months.

The following procedures and services are considered medically necessary for the assessment and treatment of TS when the selection criteria outlined above are met:

1. Assessment:

   1. Electroencephalography (EEG) or neurological consult (only in the presence of focal signs or clinical suggestions of seizure disorder or degenerative condition)
   2. Medical evaluation (complete medical history and physical examination)

2. Treatment:

   1. Pharmacotherapies*:

      1. Clonazepam (Klonopin and generics)
      2. Clonidine (Catapres and generics)
      3. Fluphenazine (Prolixin and generics)
      4. Haloperidol (Haldol and generics)
      5. Pimozide (Orap)
      6. Risperidone (Risperdal)
      7. Tricyclic anti-depressants (for TS members who also exhibit attention deficit hyperactivity disorder)

      * Note: Self-administered prescription medications are covered under the pharmacy benefit.  Formulary restrictions may apply.  Please check plan benefit description for details.

   2. Psychotherapy (if member also exhibits anxiety and/or depression).

Note: Psychotherapeutic interventions are covered under the member's behavioral health benefits.  Please check benefit plan descriptions.

The following procedures and services are considered experimental and investigational for the assessment and treatment of TS because of insufficient evidence of their effectiveness for this indication:

1. Assessment:
   
   
   1. Computerized EEG (brain mapping or neurometrics, please see CPB 0221 - Quantitative EEG (Brain Mapping))
   2. Genetic studies
   3. Neuroimaging (e.g., CT, MRI, PET, and SPECT)

2. Treatment:

   1. Aripiprazole
   2. Bilateral stereotactic lesions of the anterior cingulate gyrus
   3. Bilateral thalamic stimulation/deep brain stimulation (please see CPB 0208 - Deep Brain Stimulation)
   4. Botox injections (please see CPB 0113 - Botulinum Toxin)
   5. Cannabinoids
   6. EEG biofeedback (please see CPB 0132 - Biofeedback)
   7. Intravenous immunoglobulins (IVIG) (please seeCPB 0206 - Parenteral Immunoglobulins)
   8. Omega-3 fatty acids (also known as ω-3 fatty acids or n-3 fatty acids)
   9. Repetitive transcranial magnetic stimulation (please see CPB 0469 - Transcranial Magnetic Stimulation and Cranial Electrical Stimulation)
   10. Topiramate.

Note: Most Aetna medical plans exclude coverage of educational interventions.  Under these plans, educational and achievement testing as well as educational interventions (including classroom environmental manipulation, academic skills training, and parental training) are not covered.  Please check benefit plan descriptions for details.

Tourette's syndrome (TS) is a familial neurobehavioral disorder characterized by fluctuating motor and/or vocal tics.  Tics can also be classified as (i) simple or (ii) complex.  Simple motor tics include eye blinking, neck jerking, shoulder shrugging, and facial grimacing.  Complex motor tics include facial gestures, groaning behaviors, hitting or biting oneself, jumping, touching, stamping, and smelling.  Simple vocal tics entail coughing, throat clearing, grunting, sniffing, snoring, and barking.  Complex vocal tics entail repeating words or phrases out of context, coprolalia (use of obscenities), palilalia (increasingly rapid repetition of a phrase or word), and echolalia (repeating the words of other people).  The symptoms of TS generally appear before the patient is 21 years old.

There are no specific blood tests or other laboratory tests that definitively diagnose TS.  Diagnosis of this disorder is a clinical one, and is made by patient history, family history, family recounting of events and behaviors of the patient, as well as by direct observation of the patient.  A medical evaluation, including a complete history and physical is necessary for diagnosis.  According to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), both motor and vocal tics must be present for at least 1 year to establish a diagnosis of TS.  Brain mapping (computerized electroencephalography [EEG]) as well as neuroimaging studies, such as computed tomography, magnetic resonance imaging, positron emission tomography, and single photon emission computed tomography, usually do not aid in the diagnosis of TS.  Adams et al (2004) stated that the cause or causes of TS remain unknown.  Functional imaging studies have evaluated several implicated neurotransmitter systems and focused predominantly on the frequency or severity of tics.  The results have been inconclusive and frequently contradictory with little light shed on pathogenetic mechanisms.  Electroencephalography or neurological consultation is indicated only in the presence of focal signs or clinical suggestions of seizure disorder or degenerative condition.

A working group of the European Society for the Study of Tourette Syndrome (ESSTS) has developed the first European assessment guidelines of TS (Cath et al, 2011).  The available literature including national guidelines was thoroughly screened and extensively discussed in the expert group of ESSTS members.  Detailed clinical assessment guidelines of tic disorders and their co-morbidities in both children and adults were presented.  Screening methods that might be helpful and necessary for specialists' differential diagnosis process were suggested in order to further analyze cognitive abilities, emotional functions and motor skills.  Besides clinical interviews and physical examination, additional specific tools (e.g., questionnaires, checklists and neuropsychological tests) are recommended.

Tourette syndrome is a heterogeneous disorder with complex inheritance patterns and phenotypic manifestations.  O'Rourke et al (2009) assessed recent advances in the genetics of TS.  These investigators focused on (i) the genetic etiology of TS; (ii) common genetic components of TS, attention deficit hyperactivity disorder (ADHD), and obsessive compulsive disorder (OCD); (iii) recent linkage studies of TS; (iv) chromosomal translocations in TS; and (v) candidate gene studies.  Family, twin, and segregation studies provide strong evidence for the genetic nature of TS.  Family studies of TS and OCD indicate that an early-onset form of OCD is likely to share common genetic factors with TS.  While there apparently is an etiological relationship between TS and ADHD, it appears that the common form of ADHD does not share genetic factors with TS.  The largest genome wide linkage study to date observed evidence for linkage on chromosome 2p23.2 (P = 3.8x10(-5)).  No causative candidate genes have been identified, and recent studies suggest that the newly identified candidate gene SLITRK1 is not a significant risk gene for the majority of individuals with TS.  The authors concluded that the genetics of TS are complex and not well understood.  The Genome Wide Association Study (GWAS) design can hopefully overcome the limitations of linkage and candidate gene studies.  However, large-scale collaborations are needed to provide enough power to utilize the GWAS design for discovery of causative mutations.  Knowledge of susceptibility mutations and biological pathways involved should eventually lead to new treatment paradigms for TS.

Dehning et al (2010) stated that TS is a complex neuropsychiatric disorder probably originating from a disturbed interplay of several neurotransmitter systems in the prefrontal-limbic-basal ganglia loop.  Polygenetic multi-factorial inheritance has been postulated; nevertheless, no confirmed susceptible genes have been identified yet.  As neuroimaging studies allude to dopaminergic and serotonergic dysfunction in TS and serotonin as an important factor for dopamine release, genotyping of common polymorphisms in the serotonergic receptor (HTR1A: C-1019G; HTR2A: T102C, His452Tyr, A-1438G; HTR2C: C-759T, G-697C) and transporter genes (SLC6A4) was performed in 87 patients with TS, compared with 311 matched controls.  These investigators found a nominally significant association between both polymorphisms in the HTR2C and the GTS, which was more pronounced in male patients.  Analysis of the further serotonergic polymorphisms did not reveal any significant result.  A modified function of these promoter polymorphisms may contribute to the complex interplay of serotonin and dopamine and then to the manifestation of TS.

For most patients with TS, the clinical course is benign.  For patients whose symptoms interfere with daily functioning, pharmacotherapy may help in alleviating symptoms.  The most commonly used medications for the treatment of TS are haloperidol (Haldol), pimozide (Orap), fluphenazine (Prolixin), and clonidine (Catapres).  Clonazepam (Klonopin) and risperidone (Risperdal) have been shown to be beneficial in some patients.  Furthermore, tricyclic anti-depressants can be used for the treatment of TS patients who also exhibit attention deficit hyperactivity disorder.  Psychotherapy is appropriate for TS patients who experience anxiety or depression.

There is insufficient scientific evidence to support the use of Botox (botulinum toxin) injections, biofeedback, bilateral stereotactic lesions of the anterior cingulate gyrus, bilateral thalamic stimulation, intravenous immunoglobulins and repetitive transcranial magnetic stimulation for the treatment of TS.

Maciunas et al (2007) performed a prospective double-blind cross-over trial of bilateral thalamic deep brain stimulation (DBS) in 5 adults with TS.  An independent programmer established optimal stimulator settings in a single session.  Subjective and objective results were assessed in a double-blind randomized manner for 4 weeks, with each week spent in 1 of 4 states of unilateral or bilateral stimulation.  Results were similarly assessed 3 months after unblinded bilateral stimulator activation while repeated open programming sessions were permitted.  In the randomized phase of the trial, a statistically significant (p < 0.03) reduction in the modified Rush Video-Based Rating Scale score (primary outcome measure) was identified in the bilateral on state.  Improvement was noted in motor and sonic tic counts as well as on the Yale Global Tic Severity Scale and TS Symptom List scores (secondary outcome measures).  Benefit was persistent after 3 months of open stimulator programming.  Quality of life indices were also improved; 3 of 5 patients had marked improvement according to all primary and secondary outcome measures.  The authors concluded that bilateral thalamic DBS appears to reduce tic frequency and severity in some patients with TS who have exhausted other available means of treatment.  The findings of this study need to be validated by longer studies with larger sample sizes.

Visser-Vandewalle (2007) noted that following the introduction of DBS of the thalamus as a new treatment for TS in 1999, several other brain loci (e.g., globus pallidus internus, anteromedial and ventroposterolateral part, and the nucleus accumbens) have been targeted in a small number of patients.  In published reports, a tic reduction rate of at least 66 % has been described.  The effects of DBS on associated behavioral disorders are more variable.  The number of treated patients is small and it is unclear if the effects of DBS are dependent on the target nucleus.  The author stated that a meticulous evaluation of the electrode position, and a blinded assessment of the clinical effects on tics and behavioral disorders, is absolutely mandatory in order to identify the best target of DBS for TS.

Habit reversal therapy (HRT), also known as cognitive behavior intervention for tics, is a behavioral ttreatment for TS.  It usually entails 4 main components: (i) awareness training, (ii) relaxation training, (iii) competing response training (contingent), and (iv) contingency management.  Habit reversal therapy usually involves making the patient aware of the tic or the urge to tic building up and training the patient to engage in a response that would be muscularly competing or incompatible with the tic.  Different investigators and clinicians may use slightly different variations in their protocols, but the competing response is a core feature of the technique (Black 2003).

Carr and Chong (2005) reviewed studies that used HRT to treat tics in terms of their methodological characteristics and rigor.  Guidelines developed by the Task Force on Promotion and Dissemination of Psychological Procedures were used to evaluate the state of the literature.  From an initial database that included 29 studies, 12 were included in the final analysis.  Results indicated that although research has been conducted in this area for almost 30 years, the majority of studies contain considerable methodological shortcomings.  Based on the Task Force guidelines, the existing literature on the use of HRT to treat tics can be classified as probably efficacious.  Furthermore, Bloch (2008) examined the evidence base for current treatments for TS; and indicated that emerging treatments for this disorder include DBS, HRT, and repetitive transcranial magnetic stimulation.

In a Cochrane review, Curtis and colleagues (2009) evaluated the safety and effectiveness of cannabinoids as compared to placebo or other drugs in treating tics, premonitory urges and obsessive compulsive symptoms (OCS), in patients with TS.  These investigators searched the Cochrane Central Register of Controlled Trials (CENTRAL) (in The Cochrane Library Issue 4 2008) , MEDLINE (January 1996 to date), EMBASE (January 1974 to date), PsycINFO (January 1887 to date), CINAHL (January 1982 to date), AMED (January 1985 to date), British Nursing Index (January 1994 to date) and DH DATA (January 1994 to date).  They also searched the reference lists of located trials and review articles for further information.  These researchers included randomized controlled trials (RCTs) comparing any cannabinoid preparation with placebo or other drugs used in the treatment of tics and OCS in patients with TS.  Two authors abstracted data independently and settled any differences by discussion.  Only 2 trials were found that met the inclusion criteria.  Both studies compared a cannabinoid, delta-9-tetrahydrocannabinol (Delta(9)THC), either as monotherapy or as adjuvant therapy, with placebo.  One was a double-blind, single-dose cross-over trial and the other was a double-blind, parallel-group study.  A total of 28 different patients were studied.  Although both trials reported a positive effect from Delta(9)THC, the improvements in tic frequency and severity were small and were only detected by some of the outcome measures.  The authors concluded that there is insufficient evidence to support the use of cannabinoids in treating tics and obsessive compulsive behavior in people with TS.

In a retrospective study, Kuo and Jimenez-Shahed (2010) examined the safety and effectiveness of topiramate in the treatment of TS.  Charts of subjects whose conditions were diagnosed as tic disorders seen at the authors' clinic from 2003 to 2007 were reviewed.  Patients who met diagnostic criteria for TS and were started on topiramate with at least 1 follow-up visit after beginning topiramate were included.  The efficacy of topiramate on a subjective scale, the global impression of response (0 = no response/worse, 1 = mild improvement, 2 = moderate improvement, 3 = marked improvement), and adverse effects were recorded for analysis.  Of 453 subjects, 367 met diagnostic criteria for TS and 41 (11.1 %; 34 males) were treated with topiramate for tics for 9.43 +/- 7.03 months (range of 1 to 27 months).  Mean age at onset of tics was 6.93 +/- 2.78 years (range of 2 to 14 years) and at start of topiramate treatment was 14.83 +/- 5.63 years (range of 9 to 27 years).  The average efficacy on tics was 2.15 +/- 1.11, and 75.6 % (n = 31) of subjects had moderate-to-marked improvement and adverse effects included cognitive/language problems (24.4 %, n = 10) and aggression or mood swings (9.8 %, n = 4).  The authors concluded that this retrospective chart review suggested that topiramate can be used for tics in TS with at least moderate efficacy and typical adverse effects.  They stated that RCTs are needed.

In a a randomized, double-blind, placebo-controlled, parallel-group study, Jankovic et al (2010) examined the effects of topiramate on TS.  To be included in the study, subjects required a DSM-IV diagnosis of TS, were 7 to 65 years of age, had moderate-to-severe symptoms (Yale Global Tic Severity Scale (YGTSS) greater than or equal to 19), were markedly impaired as determined by the Clinical Global Impression (CGI) scale severity score of greater than or equal to 4 and were taking no more than 1 drug each for tics or TS co-morbidities.  There were 29 patients (26 males), mean age of 16.5 (SD 9.89) years, randomized, and 20 (69 %) completed the double-blind phase of the study.  The primary endpoint was Total Tic Score, which improved by 14.29 (10.47) points from baseline to visit 5 (day 70) with topiramate (mean dose of 118 mg) compared with a 5.00 (9.88) point change in the placebo group (p = 0.0259).  There were statistically significant improvements also in the other components of the YGTSS as well as improvements in various secondary measures, including the CGI and premonitory urge CGI.  No differences were observed in the frequency of adverse events between the 2 treatment groups.  The authors concluded that this study provides evidence that topiramate may have utility in the treatment of moderately severe TS.  The drawbacks of this study were its small sample size, the relatively high drop-out rate (31 %), and the apparent lack of follow-up data.  These findings need to be validated by further investigation.

Pourfar et al (2011) studied metabolic brain networks that are associated with TS and co-morbid OCD.  These investigators utilized [(18)F]-fluorodeoxyglucose and PET imaging to examine brain metabolism in 12 unmedicated patients with TS and 12 age-matched controls.  They utilized a spatial co-variance analysis to identify 2 disease-related metabolic brain networks, one associated with TS in general (distinguishing TS subjects from controls), and another correlating with OCD severity (within the TS group alone).  Analysis of the combined group of patients with TS and healthy subjects revealed an abnormal spatial co-variance pattern that completely separated patients from controls (p < 0.0001).  This TS-related pattern (TSRP) was characterized by reduced resting metabolic activity of the striatum and orbito-frontal cortex associated with relative increases in pre-motor cortex and cerebellum.  Analysis of the TS cohort alone revealed the presence of a second metabolic pattern that correlated with OCD in these patients.  This OCD-related pattern (OCDRP) was characterized by reduced activity of the anterior cingulate and dorso-lateral pre-frontal cortical regions associated with relative increases in primary motor cortex and precuneus.  Subject expression of OCDRP correlated with the severity of this symptom (r = 0.79, p < 0.005).  The authors concluded that these findings suggested that the different clinical manifestations of TS are associated with the expression of 2 distinct abnormal metabolic brain networks.  These, and potentially other disease-related spatial co-variance patterns, may prove useful as biomarkers for assessing responses to new therapies for TS and related co-morbidities.  Furthermore, they noted that more studies are needed to evaluate the expression of TSRP and OCDRP patterns in larger patient and control cohorts, ideally including non-TS-associated OCD.  It is important to ascertain if existing or novel therapeutic interventions can suppress the activity of these and related functional brain networks.  If validated in independent populations, and found to be reproducible, these patterns may be useful as adjunctive outcome measures in clinical trials.  One of the drawbacks of this study was that subjects were all adults (mostly men) and the symptoms were "mild" as they did not require treatment with medication.

Ackermans et al (2011) stated that DBS of the thalamus has been proposed as a therapeutic option in patients with TS who are refractory to pharmacological and psychotherapeutic treatment.  Patients with intractable TS were invited to take part in a  randomized, double-blind, cross-over study evaluating the safety and effectiveness of stimulation of the centromedian nucleus-substantia periventricularis-nucleus ventro-oralis internus cross-point in the thalamus.  After surgery, the patients were randomly assigned to 3 months stimulation followed by 3 months OFF stimulation (group A) or vice versa (group B).  The cross-over period was followed by 6 months ON stimulation.  Assessments were performed prior to surgery and at 3, 6 months and 1 year after surgery.  The primary outcome was a change in tic severity as measured by the Yale Global Tic Severity Scale and the secondary outcome was a change in associated behavioral disorders and mood.  Possible cognitive side effects were studied during stimulation ON at 1 year post-operatively.  Interim analysis was performed on a sample of 6 male patients with only 1 patient randomized to group B.  Tic severity during ON stimulation was significantly lower than during OFF stimulation, with substantial improvement (37 %) on the Yale Global Tic Severity Scale (mean 41.1 +/- 5.4 versus 25.6 +/- 12.8, p = 0.046).  The effect of stimulation 1 year after surgery was sustained with significant improvement (49 %) on the Yale Global Tic Severity Scale (mean 42.2 +/- 3.1 versus 21.5 +/- 11.1, p = 0.028) when compared with pre-operative assessments.  Secondary outcome measures did not show any effect at a group level, either between ON and OFF stimulation or between pre-operative assessment and that at 1 year post-operatively.  Cognitive re-assessment at 1 year after surgery showed that patients needed more time to complete the Stroop Colour Word Card test.  This test measures selective attention and response inhibition.  Serious adverse events included 1 small hemorrhage ventral to the tip of the electrode, 1 infection of the pulse generator, subjective gaze disturbances and reduction of energy levels in all patients.  The authors concluded that these preliminary findings suggest that stimulation of the centromedian nucleus-substantia periventricularis-nucleus ventro-oralis internus cross-point may reduce tic severity in refractory TS, but there is the risk of adverse effects related to oculo-motor function and energy levels.  They stated that further RCTs on other targets are urgently needed since the search for the optimal one is still ongoing.

The European clinical guideline for "Tourette syndrome and other tic disorders. Part IV: Deep brain stimulation" (Muller-Vahl et al, 2011) stated that "[a]t present time, DBS in TS is still in its infancy.  Due to both different legality and practical facilities in different European countries these guidelines, therefore, have to be understood as recommendations of experts.  However, among the ESSTS working group on DBS in TS there is general agreement that, at present time, DBS should only be used in adult, treatment resistant, and severely affected patients.  It is highly recommended to perform DBS in the context of controlled trials".

Piedad et al (2012) noted that over the past decade, DBS has been increasingly advocated as a reversible and controllable procedure for selected cases of TS.  These researchers set out to answer 2 clinically relevant questions: (i) what patients with TS should be treated with DBS, and (ii) what is the best target?  They conducted a systematic literature review of the published studies of DBS in TS and critically evaluated the current evidence for both patient and target selection.  Since 1999, up to 99 cases of DBS in TS have been reported in the scientific literature, with varying selection criteria, stimulation targets, and assessment protocols.  The vast majority of studies published to date are case reports or case series reporting successful outcomes in terms of both tic severity improvement and tolerability.  The reviewed studies suggested that the best candidates are patients with significant functional impairment related to the tic symptoms, who did not respond to conventional pharmacological and behavioral interventions.  The globus pallidus internus and thalamus appear to be the safest and most effective targets, especially for patients with "pure" TS and patients with co-morbid obsessive-compulsive symptoms, anxiety, and depression.  The authors concluded that DBS is a promising treatment option for severe cases of GTS.  They stated that there is a need to reach consensus on the definition of "treatment-refractoriness" and to conduct larger double-blind RCTs on the most promising targets.

Gabbay et al (2012) noted that clinical observations have suggested therapeutic effects for omega-3 fatty acids (O3FA), also known as ω−3 fatty acids or n−3 fatty acids, in Tourette's disorder (TD), but no RCTs have been reported.  In a placebo-controlled trial, these researchers examined the effectiveness of O3FA in children and adolescents with TD.  A total of 33 children and adolescents (ages of 6 to 18 years) with TD were randomly assigned to O3FA or placebo for 20 weeks.  Omega-3 fatty acids consisted of combined eicosapentaenoic acid and docosahexaenoic acid.  Placebo was olive oil.  Groups were compared by using (i) intent-to-treat design, with the last-observation-carried-forward controlling for baseline measures and ADHD via (a) logistic regression, comparing percentage of responders on the primary Yale Global Tic Severity Scale (YGTSS)-Tic and secondary (YGTSS-Global and YGTSS-Impairment) outcome measures and (b) analysis of covariance; and (ii) longitudinal mixed-effects models.  At end point, subjects treated with O3FA did not have significantly higher response rates or lower mean scores on the YGTSS-Tic (53 % versus 38 %; 15.6 +/- 1.6 versus 17.1 +/- 1.6, p > 0.1).  However, significantly more subjects on O3FA were considered responders on the YGTSS-Global measure (53 % versus 31 %, p = 0.05) and YGTSS-Impairment measure (59 % versus 25 %, p < 0.05), and mean YGTSS-Global scores were significantly lower in the O3FA-treated group than in the placebo group (31.7 +/- 2.9 versus 40.9 +/- 3.0, p = 0.04).  Obsessive-compulsive, anxiety, and depressive symptoms were not significantly affected by O3FA.  Longitudinal analysis did not yield group differences on any of the measures.  The authors concluded that O3FA did not reduce tic scores, but it may be beneficial in reduction of tic-related impairment for some children and adolescents with TD.  Drawbacks of this study included small sample size and the possible therapeutic effects of olive oil.

Wenzel et al (2012) stated that aripiprazole is an atypical neuroleptic with agonistic and antagonistic dopaminergic and serotonergic effects.  Because preliminary data obtained from uncontrolled studies suggested that aripiprazole may be effective in the treatment of tics, these investigators performed a retrospective study with a large group of patients with TS.  A total of 100 patients (78 men and 22 women; mean +/- SD age, 27.1 years (+/- 11.5) years) who had been treated with daily doses of 5 to 45 mg (mean, 17.0 +/- 9.6 mg) aripiprazole at the authors’ specialized TS outpatient clinic were included; 95 patients with insufficient pre-treatment (1 or more neuroleptics) were switched to aripiprazole.  Eighty-two patients exhibited a considerable reduction in tic severity.  In 48 patients, effective treatment lasted for more than 12 months.  Five patients reported additional beneficial effects on behavioral co-morbidities such as depression, anxiety, and auto-aggression.  Altogether, 31 patients (31 %) dropped out of the treatment owing to inefficacy (n = 7), adverse effects (n = 15: drowsiness, agitation, weight gain, and sleep disturbances), both (n = 4) or other reasons (n = 5).  The authors concluded that this study was the largest case series on the treatment of tics with aripiprazole so far.  Overall, these findings corroborated previous data suggesting that aripiprazole is safe and effective in most patients.  In particular, these data confirmed effectiveness in adult patients and clarified that beneficial effects sustain.  However, in contrast to previous data, in 1 of 3 of the highly selected patients, aripiprazole was ineffective or not well-tolerated.  Optimal dose seems to be individually different and may range from 5 to 45 mg.

Waldon et al (2013) the pharmacological treatment of TS focuses on the modulation of monoaminergic pathways within the cortico-striato-thalamo-cortical circuitry.  These investigators evaluated the safety and effectiveness of pharmacological agents used in the treatment of tics in patients with TS, in order to provide clinicians with an evidence-based rationale for the pharmacological treatment in TS.  In order to ascertain the best level of evidence, these researchers conducted a systematic literature review to identify double-blind RCTs of medications in TS populations.  They identified a large number of pharmacological agents as potentially effective in improving tic symptoms.  The alpha-2 agonist clonidine is among the agents with the most favorable efficacy-versus-adverse events ratio, especially in patients with co-morbid ADHD, although effect sizes vary evidence-based studies.  The authors concluded that these findings are in line with the findings of uncontrolled open-label studies.  However, most trials have low statistical power due to the small sample sizes, and newer agents, such as aripiprazole, have not been formally tested in double-blind RCTs.  They stated that further research should focus on better outcome measures, including Quality of Life instruments.