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Microsoft word - tourette and farmacology.doc

J Child Adolesc Psychopharmacol. 2004 Summer;14(2):255-66. Related Articles, Links Olanzapine in the treatment of aggression and tics in children with Tourette's syndrome--a pilot study.
Stephens RJ, Bassel C, Sandor P.
Tourette's Syndrome Clinic, Department of Psychiatry, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada.
OBJECTIVE: The aim of this study was to examine the effects of olanzapine on aggressive behaviour and tic severity in children with
Tourette's Syndrome (TS). METHOD: Ten (10) subjects (aged 7-13 years) with a primary diagnosis of TS and a history of aggressive
behaviour were treated in a single-blind, 2-week placebo run-in, 8-week treatment phase trial. The starting dose of olanzapine was 1.25-2.5
mg/day and was titrated at biweekly intervals, as tolerated. The mean dosage at the end of the trial was 14.5 mg/day. RESULTS: All 10
subjects completed the study. Olanzapine produced clinically and statistically significant reductions of aggression and tic severity from
baseline to trial completion, as measured by the Achenbach Child Behavior Checklist (CBCL) and Yale Global Tic Severity Scale
(YGTSS). Weight gain during the treatment period was the most common adverse effect (range 2-20 lbs: group mean 12.0 lbs +/- 5.71).
No other significant adverse effects were observed during the 10-week trial. CONCLUSION: The results of this trial confirm clinical
observations that olanzapine may be an effective treatment for aggression and tics in children with Tourette's syndrome. Olanzapine was
generally well tolerated, although significant weight gain was observed throughout the trial.
Publication Types:
• Clinical Trial • Randomized Controlled Trial • Research Support, Non-U.S. Gov't PMID: 15319022 [PubMed - indexed for MEDLINE] 42: Clin Neuropharmacol. 2004 May-Jun;27(3):101-4.
Related Articles, Links Neuroleptic-induced Tardive Tourette treated with clonazepam: a case report and literature review.
Reid SD.
Psychiatry Unit, Department of Clinical Medical Sciences, Faculty of Medical Sciences, University of the West Indies, St. Augustine,
Trinidad, West Indies. [email protected]
Tardive Tourette syndrome has been reported as a rare complication of neuroleptic treatment. This report describes the first case of
neuroleptic-induced tardive Tourette syndrome in the Latin Americas and supports the successful treatment of this disorder with
clonazepam. The syndrome developed in a female schizophrenic patient who discontinued medication after 8 years of continuous
neuroleptic therapy. Symptoms were unresponsive to increased doses of typical antipsychotics and treatment with an atypical
antipsychotic. Significant, sustained improvement occurred with clonazepam. In this report all cases of adult-onset tardive Tourette are
Publication Types:
• Case Reports • Comparative Study PMID: 15190229 [PubMed - indexed for MEDLINE] 43: Eur Psychiatry. 2004 Apr;19(2):102-12.
Related Articles, Links
Clinical and attentional effects of acute nicotine treatment in Tourette's syndrome.
Howson AL, Batth S, Ilivitsky V, Boisjoli A, Jaworski M, Mahoney C, Knott VJ.
Adult Metabolic Disease Clinic, Vancouver General Hospital, Vancouver Coastal Health Authority, BC, Canada.
Evidence from pre-clinical infrahuman investigations, open-label clinical trials, and a single controlled trial found acute nicotine treatment
potentiated up to 4 weeks neuroleptic-induced reductions of dyskinetic symptoms characterizing Tourette's syndrome (TS). Given the
attentional disturbances associated with this syndrome, and the improvements in attentional processes reported with nicotine, this
randomized, double-blind, placebo-controlled trial examined the acute (4 h) and sustained (2 weeks) effects of a single dose of transdermal
nicotine on clinical (i.e., tics), attentional (continuous performance task, event-related potential, patient and parental reports) and
behavioral symptoms in 23 children and adolescents with TS receiving neuroleptic treatment. In the 14 evaluable patients with complete
primary efficacy data, nicotine (compared to placebo) failed to alter symptoms at 4 h but counteracted ERP-P300 signs of diminished attention seen 2 weeks following placebo treatment. Secondary efficacy measures, including patient self-reports and parental ratings, found nicotine to reduce complex tics and improve behaviors related to inattention. Additional work with intermittent dosing schedules is required to characterize optimal clinical and cognitive effects with nicotine treatment. Publication Types: • Clinical Trial • Randomized Controlled Trial • Research Support, Non-U.S. Gov't PMID: 15132126 [PubMed - indexed for MEDLINE] 44: Cell Mol Life Sci. 2004 Apr;61(7-8):886-98.
Related Articles, Links Neurobiology and neuroimmunology of Tourette's syndrome: an update.
Hoekstra PJ, Anderson GM, Limburg PC, Korf J, Kallenberg CG, Minderaa RB.
Child and Adolescent Psychiatry Center, Hanzeplein 1, 9713 GZ Groningen, The Netherlands. [email protected]
Tourette's syndrome is a childhood-onset neuropsychiatric disorder characterized by the presence of both multiple motor and vocal tics.
While the pathogenesis at a molecular and cellular level remains unknown, structural and functional neuroimaging studies point to the
involvement of the basal ganglia and related cortico-striato-thalamo-cortical circuits as the neuroanatomical site for Tourette's syndrome.
Moreover, Tourette's syndrome has a strong genetic component, and considerable progress has been made in understanding the mode of
transmission and in identifying potential genomic loci. Summaries of recent findings in these areas will be reviewed, followed by a critical
overview of findings both supporting and challenging the proposed autoimmune hypothesis of Tourette's syndrome. We conclude that
Tourette's syndrome is a heterogeneous disorder, and that immune factors may indeed be involved in some patients.
Publication Types:
PMID: 15095010 [PubMed - indexed for MEDLINE] 45: Brain Dev. 2003 Dec;25 Suppl 1:S37-42.
Related Articles, Links Neurology of Tourette's syndrome (TS) TS as a developmental dopamine disorder: a hypothesis.
Nomura Y, Segawa M.
Segawa Neurological Clinic for Children, Tokyo, Japan. [email protected]
The favorable effect of dopamine (DA) depletors or DA receptor blockers suggested the state of increased transmission of DA system as
the pathophysiology of Tourette's syndrome (TS). We have analysed the neurological signs of TS and evaluated the role of levodopa on
the symptoms of TS. The data were compared with age-matched patients with Hereditary Progressive Dystonia (HPD) with marked
diurnal fluctuation. Neurological examination of 81 drug naive TS patients revealed the clumsiness of rapid alternating pronation-
supination movements of the arms and induced rigidity in the contralateral arm, which responded to the oral levodopa, and suggested
hypofunction of the nigrostriatal (NS)-DA system. Postural asymmetry or scoliosis and abnormal tilting response suggested the
asymmetric involvement of DA. The rotation to the side of less affected DA neuron on stepping with closed eyes suggested DA receptor
supersensitivity. The favourable effects of a small dose of levodopa on these signs suggest the existence of DA receptor supersensitivity,
because a small dose of levodopa is considered to alleviate the supersensitized DA receptors.
Publication Types:
• Clinical Trial • Comparative Study PMID: 14980371 [PubMed - indexed for MEDLINE] 46: Psychiatry Res. 2004 Jan 15;130(1):85-95.
Related Articles, Links Dopamine transporter density of the basal ganglia assessed with [123I]IPT SPECT in drug-naive children with Tourette's

Cheon KA, Ryu YH, Namkoong K, Kim CH, Kim JJ, Lee JD.
Department of Psychiatry, Yonsei University, College of Medicine, Kangnamgu Dogokdong 146-92, Gangnam-Gu, Seoul, 135-720 South
Korea. [email protected]
There is evidence that abnormalities in the dopaminergic system involving the dopamine transporter (DAT) are involved in the
pathophysiology of Tourette's disorder (TD) from previous studies using [(123)I]2beta-carbomethoxy-3-(4-iodophenyl)tropane
([(123)I]beta-CIT) and single photon emission tomography (SPECT). However, because those studies were performed in medicated adult
patients with TD, we decided to compare DAT densities in nine drug-naive children with TD and eight normal children. The children with
TD did not suffer from associated psychiatric problems such as obsessive-compulsive symptoms, attention deficit hyperactivity disorder,
anxiety, depression and developmental difficulties. We performed brain SPECT 2 h after the intravenous administration of I-123N-(3-
iodopropen-2-yl)-2beta-carbomethoxy-3beta-(4-chlorophenyl)tropane ([(123)I]IPT) and carried out both quantitative and qualitative
analyses using the obtained SPECT data, which were reconstructed for the assessment of the specific/non-specific DAT binding ratio in
the basal ganglia. We then investigated the correlation between the severity of tics in children with TD assessed with the Yale Global Tic
Severity Scale (YGTSS) and the specific/non-specific DAT binding ratio of the basal ganglia. Drug-naive children with TD showed a
significantly increased specific/non-specific DAT binding ratio in the basal ganglia compared with normal children that did not correlate
significantly with the severity of tics. Our results with drug-naive children with TD between the ages of 6 and 12 may help to clarify
previous findings concerning DAT binding in adult patients with TD and suggest that DAT densities may be associated directly with the
pathophysiology of TD, regardless of disease progress or drug effect.
PMID: 14972371 [PubMed - indexed for MEDLINE]
47: Brain Dev. 2003 Dec;25 Suppl 1:S15-9.
Related Articles, Links Pathophysiology of Tourette's syndrome: striatal pathways revisited.
Saka E, Graybiel AM.
Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, 45 Carleton Street, E25-618, Cambridge, MA 02139,
Stereotypic behaviors and thoughts are manifested in a range of neuropsychiatric disorders including Tourette's syndrome. To understand
and to treat these pathologic stereotypies it is important to establish the molecular, pharmacological and systems-level alterations in brain
circuits that accompany such behaviors. We review here experiments performed in rodents and primates that focus on neural concomitants
of stereotypies induced by dopaminergic treatments. These studies emphasize the functional importance of the compartmental organization
of the striatum and raise the possibility that differential activation of striosomes is related to the severity of the expressed stereotypies and
sensitized responses.
Publication Types:
• Research Support, Non-U.S. Gov't • Research Support, U.S. Gov't, P.H.S. PMID: 14980366 [PubMed - indexed for MEDLINE] 48: Pharmacol Biochem Behav. 2003 Dec;76(3-4):409-15.
Related Articles, Links Effects of donepezil on DOI-induced head twitch response in mice: implications for Tourette syndrome.
Hayslett RL, Tizabi Y.
Department of Pharmacology, College of Medicine, Howard University, 520 W Street N.W., Washington, DC 20059, USA.
Tourette syndrome (TS) is a neurological disorder characterized by persistent motor and phonic tics. Administration of the selective 5-
HT(2A/2C) agonist 1-(2, 5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) induces head twitches in mice that have been proposed to
model tics seen in TS. Previous studies have demonstrated that nicotine markedly attenuates DOI-induced head twitch response (HTR).
This and the reports that nicotine may have clinical efficacy in reducing symptoms of TS suggest possible involvement of the nicotinic
cholinergic system in this disorder. Donepezil is an acetylcholinesterase inhibitor approved for use in mild to moderate Alzheimer's
disease. The purpose of this study was to investigate whether donepezil might also reduce DOI-induced HTR, and whether its combination
with nicotine might result in an additive or synergistic effect. Moreover, to elucidate the possible role of nicotinic receptors in this
paradigm, the effects of mecamylamine, a nicotinic antagonist, was also evaluated. Acute and chronic administration of donepezil (0.1
mg/kg) or nicotine (0.5 mg/kg base), significantly reduced DOI-induced HTR. No additive or synergistic effects of donepezil and nicotine
were observed. Acute mecamylamine administration (0.5-5.0 mg/kg) dose-dependently inhibited DOI-induced HTR. None of the mecamylamine doses blocked the inhibitory effects of donepezil or nicotine on DOI-induced HTR. These results suggest that donepezil may have therapeutic potential in treating motor tic symptoms of TS. Moreover, the action of donepezil and nicotine may be mediated through the same mechanism. Publication Types: • Research Support, Non-U.S. Gov't PMID: 14643839 [PubMed - indexed for MEDLINE] 49: J Child Adolesc Psychopharmacol. 2003 Fall;13(3):295-9.
Related Articles, Links Quetiapine treatment of children and adolescents with Tourette's disorder.
Mukaddes NM, Abali O.
Istanbul University, Child and Adolescent Psychiatry Department, Medical Faculty of Istanbul, Istanbul, Turkey. [email protected]
OBJECTIVE: The purpose of this study was to investigate the short-term safety and effectiveness of quetiapine in the treatment of
children and adolescents with Tourette's disorder. METHODS: This was an 8-week, open-label trial that included 12 subjects with a mean
age of 11.4 +/- 2.4 years. The subjects were seen every week throughout the study. RESULTS: Clinical responses, as measured by the
Turkish version of the Yale Global Tic Severity Scale, revealed a statistically significant reduction in tic scores ranging from 30-100%.
Mean dose of quetiapine at the end of the study was 72.9 +/- 22.5 mg/day. Three subjects complained of sedation in the first week of
treatment. CONCLUSIONS: The favorable results of this open-label study should be interpreted with caution due to the uncontrolled
nature of the study. Spontaneous waxing and waning of symptoms should also be considered. Further controlled studies are required.
Publication Types:
• Clinical Trial PMID: 14642017 [PubMed - indexed for MEDLINE] 50: Expert Opin Pharmacother. 2003 Oct;4(10):1717-25.
Related Articles, Links Cannabinoids reduce symptoms of Tourette's syndrome.
Müller-Vahl KR.
Department of Clinical Psychiatry and Psychotherapy, Medical School Hannover, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany.
[email protected]
Currently, the treatment of Tourette's syndrome (TS) is unsatisfactory. Therefore, there is expanding interest in new therapeutical
strategies. Anecdotal reports suggested that the use of cannabis might improve not only tics, but also behavioural problems in patients with
TS. A single-dose, cross-over study in 12 patients, as well as a 6-week, randomised trial in 24 patients, demonstrated that Delta9-
tetrahydrocannabinol (THC), the most psychoactive ingredient of cannabis, reduces tics in TS patients. No serious adverse effects occurred
and no impairment on neuropsychological performance was observed. If well-established drugs either fail to improve tics or cause
significant adverse effects, in adult patients, therapy with Delta9-THC should be tried. At present, it remains unclear whether herbal
cannabis, different natural or synthetic cannabinoid CB1-receptor agonists or agents that interfere with the inactivation of
endocannabinoids, may have the best adverse effect profile in TS.
Publication Types:
PMID: 14521482 [PubMed - indexed for MEDLINE] 51: Isr J Psychiatry Relat Sci. 2003;40(2):150-2.
Related Articles, Links
Quetiapine treatment in a patient with Tourette's syndrome, obsessive-compulsive disorder and drug-induced mania.
Matur Z, Uçok A.
University of Istanbul, Faculty of Medicine, Department of Neurology, Istanbul, Turkey.
A young man with a 13 year history of Tourette disorder and obsessive-compulsive disorder developed mania on clomipramine.
Quetiapine 600 mg, daily was followed by resolution of the mania and improvement of the symptoms of Tourette disorder and obsessive
compulsive disorder. It seems that quetiapine may be useful in treatment of Tourette disorder with or without comorbid disorders.
Publication Types:
• Case Reports PMID: 14509206 [PubMed - indexed for MEDLINE] 52: Curr Neurol Neurosci Rep. 2003 Jul;3(4):285-8.
Related Articles, Links
Tourette's syndrome: are stimulants safe?
Kurlan R.
Department of Neurology, University of Rochester School of Medicine, 601 Elmwood Avenue, Rochester, NY 14642-8673, USA.
[email protected]
Clinicians commonly encounter children with comorbid attention deficit hyperactivity disorder (ADHD) and the tic disorder Tourette's
syndrome. The pharmacologic treatment of children with this particular combination of conditions has been problematic because of long-
standing warnings against using psychostimulants due to concerns about worsening tics. The basis for these warnings was anecdotal
clinical observations. A recent group of placebo-controlled, double-blinded clinical trials have consistently shown that certain stimulants,
particularly methylphenidate and dextroamphetamine, are effective, well tolerated, and safe when administered to treat ADHD in children
with tics. Methylphenidate appears to be the best-tolerated stimulant compound, with tics often lessening during treatment.
Publication Types:
PMID: 12930697 [PubMed - indexed for MEDLINE] 53: Curr Drug Targets CNS Neurol Disord. 2002 Aug;1(4):433-42.
Related Articles, Links
The importance of nicotinic acetylcholine receptors in schizophrenia, bipolar disorder and Tourette's syndrome.
McEvoy JP, Allen TB.
Duke University Medical Center, Durham, NC, USA. [email protected]
As the prevalence of tobacco use has decreased, it has become clear that individuals with mental illness comprise a substantial portion of
the remaining smokers. Seventy to eighty percent of patients with schizophrenia smoke and their smoking is established before their first
psychotic episodes or the initiation of treatment. Many patients with schizophrenia, and approximately 50% of their first degree relatives
have abnormalities in auditory sensory gating and/or smooth pursuit eye movements. These abnormalities are corrected by nicotine, and
they appear to be transmitted as autosomal dominant traits. Evidence is accumulating that these abnormalities reflect genetic variations in
nicotine receptor number and function, that may increase susceptibility for schizophrenia. Recent studies suggest that bupropion, added to
treatment with an atypical antipsychotic, can enhance the likelihood of smoking cessation or reduction in patients with schizophrenia. The
prevalence of smoking is also substantially increased among patients with bipolar disorder, perhaps especially so among those with
psychotic features. Nicotine delivered by gum or transdermal patch can provide short term relief for exacerbations of Tourette's Syndrome,
but its use is limited by frequent toxicity, primarily nausea.
Publication Types:
PMID: 12769615 [PubMed - indexed for MEDLINE] 54: J Clin Psychiatry. 2002 Nov;63(11):1040-4.
Related Articles, Links Depression and dysphoria in adult and adolescent patients with Tourette's disorder treated with risperidone.
Margolese HC, Annable L, Dion Y.
Clinical Psychopharmacology Unit, Allan Memorial Institute, McGill University Health Centre, and the Department of Psychiatry, McGill
University, Montreal, Quebec, Canada. [email protected]
BACKGROUND: Depression is a common comorbid condition in patients with Tourette's disorder. While risperidone is not usually
known to induce dysphoria or depression in patients treated for other psychiatric disorders, previous short-term 4- to 12-week trials of
risperidone for Tourette's disorder have reported a 2.6% to 30.8% incidence of depression. METHOD: A retrospective study was carried
out in 58 adult and adolescent patients with Tourette's disorder (Tourette Syndrome Classification Study Group diagnosis) who received
risperidone between Jan. 1, 1993, and Dec. 31, 2000, at the Allan Memorial Institute, McGill University Health Centre, Montreal, Quebec,
Canada. Charts of all patients were examined for evidence of, and risk factors for, DSM-IV-defined major depressive disorder (MDD) or
dysphoria. RESULTS: Seventeen (29.3%) of 58 patients developed MDD, including 1 patient who later committed suicide and 13 patients
(22.4%) who became dysphoric while taking risperidone. Nine of the 17 patients who developed MDD were relapses, i.e., patients with a
history of depression prior to taking risperidone, while the remainder were new cases, i.e., patients with no previous history of depression.
A positive personal history of MDD was the only factor to significantly (p <.001) predict the development of depression while taking
risperidone. Seventy percent of those who developed MDD or dysphoria and discontinued risperidone did so specifically as a result of this
adverse event. CONCLUSION: MDD and dysphoria commonly occurred in this cohort of adult and adolescent Tourette's disorder patients
treated with risperidone, particularly in patients with a previous history of depression. Depression and dysphoria were frequent reasons for
risperidone discontinuation.
Publication Types:
• Evaluation Studies PMID: 12444819 [PubMed - indexed for MEDLINE] 55: Am J Psychiatry. 2002 Aug;159(8):1329-36.
Related Articles, Links Elevated intrasynaptic dopamine release in Tourette's syndrome measured by PET.
Singer HS, Szymanski S, Giuliano J, Yokoi F, Dogan AS, Brasic JR, Zhou Y, Grace AA, Wong DF.
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
OBJECTIVE: Dopaminergic abnormalities in frontal-subcortical circuits have been hypothesized as the underlying pathophysiologic
mechanism in Tourette's syndrome. The objective of this study was to test the hypothesis that presynaptic dopamine release from the
striatum is abnormal in adults with Tourette's syndrome. METHOD: Seven adults with Tourette's syndrome and five age-matched
comparison subjects each received two positron emission tomography (PET) scans with high specific activity [11C]raclopride. The first
scan followed an intravenous injection of saline; the second followed an intravenous injection of amphetamine. The relative dopamine
release was estimated as the percentage difference in binding potential between the postsaline and postamphetamine scans. RESULTS:
Binding potential determined after the initial [11C]raclopride scan did not significantly differ between Tourette's syndrome and
comparison subjects. After amphetamine challenge, the mean value of intrasynaptic dopamine in the putamen (as determined by true
equilibrium bolus estimation) increased by 21% in the subjects with Tourette's syndrome and did not change in the comparison subjects;
the mean values increased by 16.9% and decreased by 1.8%, respectively, when measured by the constrained method. Dopamine release in
the caudate region was not significantly different in the Tourette's syndrome and comparison subjects. CONCLUSIONS: Greater putamen
dopamine release was seen in adults with Tourette's syndrome than in comparison subjects after a pharmacologic challenge with
amphetamine. These results suggest that the underlying pathobiology in Tourette's syndrome is a phasic dysfunction of dopamine
Publication Types:
• Research Support, Non-U.S. Gov't • Research Support, U.S. Gov't, P.H.S. PMID: 12153825 [PubMed - indexed for MEDLINE] 56: Arch Pediatr Adolesc Med. 2002 Jul;156(7):696-701.
Related Articles, Links Decreased growth during therapy with selective serotonin reuptake inhibitors.
Weintrob N, Cohen D, Klipper-Aurbach Y, Zadik Z, Dickerman Z.
Institute for Endocrinology and Diabetes, Schneider Children's Medical Center of Israel, 14 Kaplan St, Petah Tikva 49202, Israel.
[email protected]
BACKGROUND: There is no information on the effects of selective serotonin reuptake inhibitors (SSRIs) on growth and puberty in
children. We examined growth and growth hormone secretion in 4 children treated with SSRIs for various psychiatric disorders. DESIGN:
Case study. PARTICIPANTS: Four children (3 boys) aged 11.6 to 13.7 years with obsessive-compulsive disorder or Tourette syndrome.
MAIN OUTCOME MEASURES: Growth, pubertal progression, and hypothalamic pituitary function. METHODS: The patients were
treated with SSRIs for 6 months to 5 years (dosage, 20-100 mg/d). All were regularly examined for changes in height and bone age and for
pubertal progression. They also underwent evaluation of somatotrophic axis and hypothalamic-pituitary axis function. RESULTS: All 4
patients had growth attenuation. Three of them exhibited growth retardation at a pubertal stage when a growth spurt was anticipated. Three
had a decreased growth hormone response to clonidine hydrochloride stimulation and 2 to both clonidine and glucagon stimulation, and 1
had decreased 24-hour secretion of growth hormone that normalized when therapy was stopped. The rest of the endocrine evaluations were
within reference ranges in all patients. At follow-up, 2 patients were being treated with somatropin while continuing SSRI therapy, and the
other 2 resumed normal growth after discontinuation of therapy. CONCLUSIONS: A decrease in growth rate, possibly secondary to
suppression of growth hormone secretion, may occur during SSRI therapy. As the use of this group of drugs is expected to increase in the
young age groups, larger studies are warranted to investigate their effect on growth and growth hormone secretion.
Publication Types:
• Case Reports PMID: 12090838 [PubMed - indexed for MEDLINE] 57: Am J Psychiatry. 2002 Apr;159(4):657-60.
Related Articles, Links An animal model of Tourette's syndrome.
Taylor JR, Morshed SA, Parveen S, Mercadante MT, Scahill L, Peterson BS, King RA, Leckman JF, Lombroso PJ.
Child Study Center, Children's Clinical Research Center, School of Nursing, Yale University School of Medicine, New Haven, CT 06520,
OBJECTIVE: An animal model was used to investigate an autoimmune etiology for some cases of Tourette's syndrome. METHOD: Sera
from 12 patients with Tourette's syndrome with high levels of antineural or antinuclear antibodies were infused bilaterally into the
ventrolateral striatum of rats. Sera from 12 additional Tourette's syndrome patients and 12 normal subjects (both groups with low levels of
autoantibodies) were infused for comparison. Rates of oral stereotypies were recorded by observers who were blind to the origin of the
infused sera. RESULTS: Oral stereotypies significantly increased in the rats infused with sera from the patients with high levels of
autoantibodies. CONCLUSIONS: The results are consistent with an autoimmune etiology in a subset of cases of Tourette's syndrome.
Publication Types:
• Research Support, Non-U.S. Gov't • Research Support, U.S. Gov't, P.H.S. PMID: 11925307 [PubMed - indexed for MEDLINE] 58: Curr Neurol Neurosci Rep. 2001 Mar;1(2):195-202.
Related Articles, Links
The treatment of tics.
Singer HS.
Departments of Neurology and Pediatrics, Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Harvey 811, Baltimore,
MD 21287-8811, USA. [email protected]
Tics are the essential component of a variety of disorders, notably Tourette syndrome. Because the mere presence of tics does not require
therapeutic intervention, criteria are essential for determining a functional disability. Suggested tic-suppressing treatments have been
extremely diverse, including hydrotherapy, behavioral treatments, pharmacotherapy, botulinum toxin, immunomodulatory therapy, and
surgery. This manuscript reviews each of these approaches with emphasis on more recent pharmacologic trials.
Publication Types:
PMID: 11898516 [PubMed - indexed for MEDLINE] 59: Med Hypotheses. 2002 Jan;58(1):47-60.
Related Articles, Links The central role of magnesium deficiency in Tourette's syndrome: causal relationships between magnesium deficiency, altered
biochemical pathways and symptoms relating to Tourette's syndrome and several reported comorbid conditions.

Grimaldi BL.
[email protected]
Prior studies have suggested a common etiology involved in Tourette's syndrome and several comorbid conditions and symptomatology.
Reportedly, current medications used in Tourette's syndrome have intolerable side-effects or are ineffective for many patients. After
thoroughly researching the literature, I hypothesize that magnesium deficiency may be the central precipitating event and common
pathway for the subsequent biochemical effects on substance P, kynurenine, NMDA receptors, and vitamin B6 that may result in the
symptomatology of Tourette's syndrome and several reported comorbid conditions. These comorbid conditions and symptomatology
include allergy, asthma, autism, attention deficit hyperactivity disorder, obsessive compulsive disorder, coprolalia, copropraxia, anxiety,
depression, restless leg syndrome, migraine, self-injurious behavior, autoimmunity, rage, bruxism, seizure, heart arrhythmia, heightened
sensitivity to sensory stimuli, and an exaggerated startle response. Common possible environmental and genetic factors are discussed, as
well as biochemical mechanisms. Clinical studies to determine the medical efficacy for a comprehensive magnesium treatment option for
Tourette's syndrome need to be conducted to make this relatively safe, low side-effect treatment option available to doctors and their
patients. Copyright 2002 Harcourt Publishers Ltd.
PMID: 11863398 [PubMed - indexed for MEDLINE]
60: Drugs. 2001;61(15):2207-20.
Related Articles, Links
Pharmacological options for the treatment of Tourette's disorder.
Jiménez-Jiménez FJ, García-Ruiz PJ.
Department of Medicine - Neurology, Hospital 'Príncipe de Asturias', Universidad de Alcalá, Alcalá de Henares (Madrid), and Neuro-
Magister S.L. Company, Madrid, Spain. [email protected]
Tourette's disorder is a neuropsychiatric disorder characterised clinically by motor and vocal tics, which may be associated to conductual
disorders such as obsessive-compulsive disorder (OCD) and attention-deficit hyperactivity disorder (ADHD). Although the
neurochemistry of Tourette's disorder is not well known, there are some effective therapies for tics, OCD and ADHD. However, these are
not devoid of adverse effects. Tics only require treatment when they interfere with the functioning of the patient. If therapy is needed,
monotherapy at the minimal effective dose is desirable, but some patients may require two or more drugs. The most frequently used drugs
for tics are antipsychotics (mainly pimozide and haloperidol) and clonidine. The potential usefulness of atypical antipsychotic drugs
(risperidone, olanzapine, clozapine, ziprasidone) and other dopaminergic drugs (fluphenazine, sulpiride, tiapride, metoclopramide,
piquindone, tetrabenazine), clonazepam, calcium channel antagonists, botulinum toxin, dopamine agonists, selegiline, and other drugs is
discussed. The drugs of choice for OCD in patients with Tourette's disorder are the selective serotonin reuptake inhibitors (SSRIs),
although the tricyclic antidepressant clomiplamine, which inhibits both serotonin and noradrenaline uptake, has also been found to be
useful. ADHD can be treated with some psychostimulants, mainly methylphenidate, although these drugs must be used with caution. Other
potentially useful drugs for the treatment of ADHD in patients with Tourette's disorder are clonidine, guanfacine, selegiline, some tricyclic
antidepressants, sertraline, pimozide and clonazepam. Finally, the potential value of some nonpharmacological therapies (hypnotherapy,
biofeedback, conductual therapies, electroconvulsive therapy, acupuncture and surgery) is briefly reviewed.
Publication Types:
PMID: 11772131 [PubMed - indexed for MEDLINE] 61: J Cardiovasc Pharmacol Ther. 2001 Jul;6(3):255-60.
Related Articles, Links

Pimozide (Orap) prolongs cardiac repolarization by blocking the rapid component of the delayed rectifier potassium current in
native cardiac myocytes.

Drolet B, Rousseau G, Daleau P, Cardinal R, Simard C, Turgeon J.
Institut de cardiologie de Québec, Hôpital Laval, Sainte-Foy, Québec, Canada.
BACKGROUND: Several cases of QT prolongation and ventricular tachyarrhythmia have been reported with pimozide, a potent
neuroleptic useful in the management of motor and phonic tics associated with Tourette syndrome. To further elucidate the mechanism
underlying these clinical observations, the effects of pimozide on monophasic action potential duration (MAPD(90)) and on potassium
currents involved in the repolarization of native isolated ventricular myocytes were examined. METHODS AND RESULTS: Studies were
undertaken in eight isolated guinea pig hearts that demonstrated reverse rate-dependent prolongation of cardiac repolarization by pimozide 100 nmol/L. Action potential duration increased 24% from baseline 115 +/- 2 to 142 +/- 4 msec with pimozide 100 nmol/L during pacing at 250 msec cycle length, while a 10% increase from 97 +/- 2 to 107 +/- 3 msec was seen with pacing at a cycle length of 150 msec. Experiments in native isolated ventricular myocytes (n = 20) demonstrated concentration-dependent block of the rapid component (I(Kr)) of the delayed rectifier potassium current: tail current was decreased by 50% at 15 nmol/L. CONCLUSIONS: Pimozide possesses cardiac electrophysiological effects similar to those of class III antiarrhythmic drugs. These effects are concentration-dependent and observed at recommended dosages of the drug. Since pimozide is strongly metabolized by CYP3A4, special care should be taken to avoid potential pharmacokinetic interactions leading to high plasma levels of pimozide and proarrhythmia. Publication Types: • Research Support, Non-U.S. Gov't PMID: 11584332 [PubMed - indexed for MEDLINE] 62: J Am Acad Child Adolesc Psychiatry. 2001 Sep;40(9):1103-10.
Related Articles, Links Multicenter, double-blind, placebo-controlled study of mecamylamine monotherapy for Tourette's disorder.
Silver AA, Shytle RD, Sheehan KH, Sheehan DV, Ramos A, Sanberg PR.
University of South Florida College of Medicine, Tampa 33613, USA.
OBJECTIVE: The safety and efficacy of mecamylamine as a monotherapy in children and adolescents with Tourette's disorder (TD) was
investigated in an 8-week multicenter, double-blind, placebo-controlled study. METHOD: Eligible subjects included subjects with TD
(DSM-IV), with a naturalistic mix of comorbid diagnoses, nonsmokers, aged 8 to 17 years, whose behavioral and emotional symptoms
(according to parents) were more disturbing than tics. After a washout period of all psychotropic medication, subjects were randomly
assigned to either mecamylamine (n = 29) or placebo (n = 32). Mecamylamine doses ranged from 2.5 to 7.5 mg/day. Primary efficacy
measures included the Tourette's Disorder Scale-Clinician Rated (TODS-CR) and 21-point Clinical Global Improvement scale; secondary
efficacy measures included the Yale Global Tic Severity Scale and a rage-attack scale (RAScal). RESULTS: Of the 61 subjects who were
randomized, 50 (82%) completed at least 3 weeks on medication and 38 (62%) completed the full 8-week trial. Study withdrawals
included 12/29 on mecamylamine and 11/32 on placebo. For the total sample, mecamylamine was no more effective than placebo on any
of the outcome measures. However, an item analysis of the TODS-CR suggested that mecamylamine may have reduced sudden mood
changes and depression in moderately to severely affected subjects. Except for a slight increase in heart rate during the 1st week in both
the mecamylamine and the placebo groups, there where no significant mecamylamine-related changes in vital signs, electrocardiogram,
complete blood cell count, or blood chemistry values. CONCLUSIONS: Mecamylamine, in doses up to 7.5 mg/day, is well tolerated in
children and adolescents, but as a monotherapy it does not appear to be an effective treatment for tics or for the total spectrum of
symptoms associated with TD. However, further studies should be conducted to investigate its possible therapeutic effects in subjects with
comorbid mood disorders and as an adjunct to neuroleptic medication.
Publication Types:
• Clinical Trial • Multicenter Study • Randomized Controlled Trial • Research Support, Non-U.S. Gov't PMID: 11556635 [PubMed - indexed for MEDLINE] 63: Prog Neuropsychopharmacol Biol Psychiatry. 2001 Oct;25(7):1445-57.
Related Articles, Links Nicotine attenuates DOI-induced head-twitch response in mice: implications for Tourette syndrome.
Tizabi Y, Russell LT, Johnson M, Darmani NA.
Department of Pharmacology, College of Medicine, Howard University, Washington, DC 20059, USA. [email protected]
Tourette syndrome (TS), a chronic neuropsychiatric disorder, is characterized by motor and vocal tics. Preliminary clinical studies indicate
possible therapeutic benefits of nicotine in the treatment of Tourette's syndrome (TS). It has been proposed that twitches of the head in
mice or twitches of head and shoulders in rats following administration of the selective 5HT(2A/C) agonist DOI (1-)2,5-dimethoxy-4-
iodophenyl-2-aminopropane, can serve as an animal model of tics in TS. In this study, the effects of acute and chronic administration of
nicotine on DOI-induced head twitch response (HTR) in male albino ICR mice were evaluated. Both acute and chronic nicotine (daily
injections for 10 days) reduced the DOI-induced HTR. Moreover, chronic administration of DOI (1 mg/kg/day for 10 days) resulted in
65% increase in [125I]alpha-bungarotoxin binding in cerebellum and 41% increase in striatal [3H]cytisine binding. However, the acute
inhibitory effects of nicotine were not blocked by pretreatment with the nicotinic antagonist, mecamylamine. Indeed, at higher doses, mecamylamine also reduced the DOI-induced HTR. The data suggest that both nicotine and mecamylamine may be of therapeutic potential in the treatment of some symptoms of TS. Publication Types: • Research Support, Non-U.S. Gov't • Research Support, U.S. Gov't, P.H.S. PMID: 11513358 [PubMed - indexed for MEDLINE] 64: J Child Adolesc Psychopharmacol. 2001 Summer;11(2):187-91.
Related Articles, Links • J Am Acad Child Adolesc Psychiatry. 2003 Jun;42(6):623-4.
Quetiapine treatment of children with Tourette's syndrome: report of two cases.
Párraga HC, Párraga MI, Woodward RL, Fenning PA.
Fourth Street Clinic, Springfield, Illinois 62703, USA. [email protected]
Two children with Tourette's syndrome and comorbid disorders were treated with quetiapine, an atypical antipsychotic successfully used
in patients with psychoses and schizophrenia with low incidence of extrapyramidal side effects. Clinical observations and standardized
rating scales suggested that this drug produced beneficial effects on tics and other symptoms. Adverse effects (at low doses) were minimal.
Because it was suggested that tic efficacy of the newer antipsychotics was related to higher D2 occupancy (with the exception of
quetiapine and clozapine, which have relatively low D2 activity), it is hypothesized that tic patients are D2 sensitive and need lower doses
of medications. These children were treated naturalistically and were reported retrospectively because of their encouraging outcomes.
However, these findings should be interpreted with caution, because no contrast groups, drug withdrawal, or placebo were utilized.
Controlled studies are needed to determine the efficacy of quetiapine in the treatment of Tourette's syndrome.
Publication Types:
• Case Reports PMID: 11436959 [PubMed - indexed for MEDLINE] Seishin Shinkeigaku Zasshi. 2006;108(5):459-65. Related Articles, Links
[Two cases of tardive Tourette syndrome]
[Article in Japanese]
Yamauchi K, Ohmori T.
Department of Psychiatry, Course of Integrated Brain Science, Medical Informatic, Institute of Health Biosciences, The University of
Tokushima Graduate School.
Tardive Tourette syndrome is an extrapyramidal symptom which appears after long-term neuroleptic use. We report two cases of this
syndrome and review case reports to introduce this extrapyramidal symptom. The first case is a 40-year-old male with schizophrenia. After
6 years of neuroleptic therapy, he began to have barking and grunting vocalizations and show neck and shoulderjerking. The second case is
a 53-year-old male with alcoholism. Sulpride was prescribed for three years to treat mood symptoms. Oral dyskinesia appeared after
sulpride was stopped. About five weeks after amantadine and trihexyphenidyl hydrochloride was started, he began to have grunting
vocalizations and show neck jerking. The involuntary movement disappeared quickly after intraveneous administration of haloperidol.
Including our two cases, there are 17 case reports of tardive Tourette syndrome. Twelve cases were schizophrenic patients. In addition to
typical movements, patients had coplolalia in 6 cases, and oral dyskinesia in 9 cases. In 8 cases, tardive Tourette syndrome appeared
during neuroleptic treatment, and in 9 cases the syndrome appeared after neuroleptics were stopped. Our two cases and previous case
reports showed that tardive Tourette syndrome appeared after long-term neuroleptic therapy, it was improved transiently by an increase of
neuroleptics and exacerbated by their decrease, it was exacerbated by dopaminergic and anticholinergic drugs, and tardive dyskinesia was
often seen concomitantly, indicating that tardive Tourette syndrome has a similar pathophysiology to tardive dyskinesia. Tardive Tourette
syndrome should not be misdiagnosed as an exacerbation of schizophrenic symptoms responsive to an increase of neuroleptics. This side
effect should be recognized widely and treated properly.
Publication Types:
• Case Reports • English Abstract PMID: 16869393 [PubMed - indexed for MEDLINE] 22: Semin Pediatr Neurol. 2005 Dec;12(4):217-21.
Related Articles, Links The relationship between tourette syndrome, attention deficit hyperactivity disorder, and stimulant medication: a critical review.
Erenberg G.
Department of Neurology, Section of Child Neurology, Cleveland Clinic Foundation, Cleveland, OH 44195, USA. [email protected]
The relationship between tic disorders and attention deficit hyperactivity disorder (ADHD) is of great clinical importance because both
disorders can lead to emotional, social, and academic difficulties. To further complicate this interrelationship is the concern that the use of
psychostimulant medication to treat ADHD will help the hyperactivity and attention problems but will lead to the onset of tics or will
worsen preexisting tics. The first part of this review investigates how often Tourette syndrome (TS) is associated with ADHD and finds
that ADHD has been reported in 35% to 90% of children with TS. The second part of the review looks at whether the ADHD seen in TS is
the same as in children who do not have tics. Recent studies lead to the conclusion that the ADHD seen in TS is the same, although the
attentional difficulties seen in TS are influenced also by the distraction of the tics themselves as well as by internal distractions such as is
seen in comorbid anxiety or obsessive-compulsive behavior. The final part of the review investigates the question of whether
psychostimulants worsen or cause tics. Twenty-two studies were found that investigated this possible relationship. Earlier studies were
confounded by the natural pattern seen in TS in which tics spontaneously wax and wane in occurrence, intensity, and frequency. More
recent double-blind, placebo-controlled studies have shown that psychostimulants are equally effective in improving ADHD symptoms
whether the disorder is associated with tics or not. When group data are analyzed, there is no significant increase in tics when
psychostimulants are used in patients with tics compared with controls. Individual patients, however, may experience an increase in tics.
This increase is not appreciated in analysis of group data. In conclusion, it is medically appropriate to provide treatment with
psychostimulant medication in persons with tics where the ADHD symptoms are significantly disturbing their quality of life.
Publication Types:
PMID: 16780292 [PubMed - indexed for MEDLINE] 23: Brain. 2006 Aug;129(Pt 8):2038-46. Epub 2006 Jun 7.
Related Articles, Links Dopamine transporter genotype influences the physiological response to medication in ADHD.
Gilbert DL, Wang Z, Sallee FR, Ridel KR, Merhar S, Zhang J, Lipps TD, White C, Badreldin N, Wassermann EM.
Division of Neurology Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229-3039, USA. [email protected]
Attention deficit hyperactivity disorder (ADHD) is a complex, multifactorial disorder characterized by physical hyperactivity and
behavioural disinhibition. Short interval cortical inhibition (SICI), measured in motor cortex with transcranial magnetic stimulation, is
reduced in ADHD and correlates with symptom severity. However, ADHD medication-induced changes in SICI vary widely among
normal individuals and have not been well studied in children with ADHD. Therefore, we undertook this study to measure and compare
effects of two ADHD medications, methylphenidate (MPH), a psychostimulant, and atomoxetine (ATX), a selective norepinephrine
reuptake inhibitor, on SICI in children with ADHD. In addition, we wished to determine whether a genetic variation in the dopamine
transporter (DAT1), a site of action of MPH, could influence the effects of MPH or ATX on SICI. We performed a randomized, double-
blind, single-dose, crossover study comparing 0.5 mg/kg MPH with 1.0 mg/kg ATX in 16 children with ADHD, aged 8-17. Seven were
homozygotes and 9 heterozygotes for the DAT1 variable number of tandem repeats 10-repeat allele. Medication and genotype effects on
SICI were estimated with repeated measures, mixed model regression. We found that MPH and ATX had similar effects on SICI.
However, medication effects differed significantly by DAT1 genotype [F(2,13) = 13.04, P = 0.0008]. Both MPH and ATX increased SICI
in heterozygotes but not in 10-repeat homozygotes. In conclusion, MPH and ATX have similar effects on SICI in children with ADHD. A
genetic variation in DAT1, previously linked to ADHD risk and MPH behavioural responses, influences the neurophysiological effects of
both MPH and ATX.
Publication Types:
• Randomized Controlled Trial • Research Support, N.I.H., Extramural • Research Support, Non-U.S. Gov't PMID: 16760197 [PubMed - indexed for MEDLINE] 24: Am J Psychiatry. 2006 Jun;163(6):1066-73.
Related Articles, Links Association between maternal smoking and increased symptom severity in Tourette's syndrome.
Mathews CA, Bimson B, Lowe TL, Herrera LD, Budman CL, Erenberg G, Naarden A, Bruun RD, Freimer NB, Reus VI.
Department of Psychiatry, University of California San Diego, La Jolla, CA, and the Department of Psychiatry, North-Shore University
Hospital/New York University School of Medicine, Manhasset, NY, USA. [email protected]
OBJECTIVE: Substantial evidence suggests that both environmental and genetic factors contribute to the development and clinical
expression of Tourette's syndrome. Although genetic studies of Tourette's syndrome are common, studies of environmental factors are
relatively few and have not identified consistent risk factors across studies. This study examines in a large cohort of subjects (N=180) the
relationship between prenatal/perinatal adverse events with Tourette's syndrome severity as determined by tic severity and rates of
commonly comorbid disorders such as obsessive-compulsive disorder (OCD), attention deficit hyperactivity disorder (ADHD), and self-
injurious behavior. METHOD: Tic severity, OCD, ADHD, self-injurious behavior, and exposure to a variety of prenatal/perinatal events
were systematically assessed in all subjects enrolled in three genetic studies of Tourette's syndrome. Using linear and logistic regression, a
best-fit model was determined for each outcome of interest. RESULTS: Prenatal maternal smoking was strongly correlated with increased
tic severity and with the presence of comorbid OCD in these Tourette's syndrome subjects. Other variables, such as paternal age and
subject's birth weight, were significantly but less strongly associated with increased symptom severity. The authors found no association
between symptom severity and hypoxia, forceps delivery, or hyperemesis during pregnancy, which have been previously identified as risk
factors. CONCLUSIONS: This study identifies prenatal maternal smoking as a strong risk factor for increased symptom severity in
Tourette's syndrome.
Publication Types:
• Comparative Study • Research Support, N.I.H., Extramural PMID: 16741208 [PubMed - indexed for MEDLINE] 25: J Am Acad Child Adolesc Psychiatry. 2006 Jun;45(6):720-8.
Related Articles, Links Single-dose pharmacokinetics and safety of ziprasidone in children and adolescents.
Sallee FR, Miceli JJ, Tensfeldt T, Robarge L, Wilner K, Patel NC.
Department of Psychiatry, College of Medicine, University of Cincinnati, OH, USA. [email protected]
OBJECTIVE: The purpose of this study was to provide single-dose pharmacokinetic, safety, and tolerability data for ziprasidone in youths
with tic disorder, for comparison to adult studies to discern whether ziprasidone pediatric dosing could be modeled from adult data.
METHOD: A single-dose, open-label study of ziprasidone was conducted in youths (ages 7-16 years) with Tourette's disorder or chronic
tic disorder. Dosing of ziprasidone oral suspension (40 mg/mL) was weight adjusted: >60 kg, 20 mg (group 1, n = 8); 31 to 60 kg, 10 mg
(group 2, n = 8); and 16 to 30 kg, 5 mg (group 3, n = 8). Patients were assessed for serum ziprasidone concentration, safety, tolerability,
and electrocardiogram pre- and postdose. RESULTS: Twenty-four patients were evaluated for safety and tolerability, and 23 were
evaluated for pharmacokinetics. Regression analysis of AUC(0-infinity) and Cmax values versus weight-normalized dose showed linear,
dose-related changes in ziprasidone exposure. Ziprasidone was well tolerated with frequent, although transient, somnolence. No clinically
significant change from baseline was observed in Bazett's or Fridericia's corrected QT(c) interval, and change in QT(c) interval was not
related to serum ziprasidone concentration. CONCLUSIONS: Oral ziprasidone exhibited linear pharmacokinetics and dose-related
exposure in youths with Tourette's disorder or chronic tic disorder, which are comparable to adult data. A single dose of ziprasidone was
well tolerated without clinically significant effects on electrocardiograms collected around the time of maximum serum concentration.
Publication Types:
• Clinical Trial • Research Support, N.I.H., Extramural • Research Support, Non-U.S. Gov't PMID: 16721322 [PubMed - indexed for MEDLINE] 26: Expert Rev Neurother. 2006 Apr;6(4):551-61.
Related Articles, Links Long-term outcomes of stimulant medication in attention-deficit hyperactivity disorder.
Poulton A.
Western Clinical School, Nepean Campus, University of Sydney, Australia. [email protected]
The rate of prescribing of stimulant medication for the treatment of attention-deficit hyperactivity disorder (ADHD) has been progressively
increasing in countries such as the USA and Australia. In the short term, stimulant medication is effective in reducing the symptoms of
ADHD and appears well tolerated with relatively minor side effects. In the long term, much of the benefit of stimulant medication
disappears after medication is ceased. Studies have demonstrated only marginal improvements in adult outcomes following a period of
treatment in childhood. This may be owing to the beneficial effects being masked by the variability of the condition, the developmental
changes in symptomatology that happen with maturation and the substantial influence of social and environmental factors. Stimulant
medication may give some protection against later substance abuse. Stimulant medication may slightly elevate the blood pressure and
possibly increase susceptibility to seizures and to tics and Tourette syndrome. Starting treatment with stimulant medication is usually
associated with weight loss and a transient slowing of the height velocity, although it is believed that most children catch up during
puberty. No studies were found that listed strokes or heart attacks as potential or actual complications, although one individual from a
group of normal controls died suddenly of cardiac arrest in adolescence. It would appear that the medical complications associated with
amphetamine addiction are not relevant to the therapeutic use of stimulant medication in the treatment of ADHD, although there is limited
information on extended periods of treatment lasting 10 years or more.
Publication Types:
PMID: 16623654 [PubMed - indexed for MEDLINE] 27: Psychopharmacology (Berl). 2006 Jun;186(2):246-54. Epub 2006 Apr 1.
Related Articles, Links Separable noradrenergic and dopaminergic regulation of prepulse inhibition in rats: implications for predictive validity and
Tourette Syndrome.

Swerdlow NR, Bongiovanni MJ, Tochen L, Shoemaker JM.
Department of Psychiatry, UCSD School of Medicine, La Jolla, CA 2093-0804, USA. [email protected]
INTRODUCTION: Startle inhibition by lead stimuli (prepulse inhibition, "PPI"), and the disruption of this process by dopamine agonists
and N-methyl-D: -aspartate (NMDA) antagonists, are used in predictive models for antipsychotic development. PPI is also disrupted by
the norepinephrine alpha-1 agonist, cirazoline, and the PPI-disruptive effects of the indirect dopamine agonist amphetamine are opposed
by the norepinephrine reuptake inhibitor, desipramine. The hypothesis that PPI may be regulated by norepinephrine, or by interactions
between dopamine and norepinephrine substrates, was tested in a series of experiments with the alpha-2 agonist, clonidine, which is used
clinically to treat Tourette Syndrome (TS). MATERIALS AND METHODS: PPI was measured in male Sprague-Dawley rats after
pretreatment with clonidine or the D2 antagonist haloperidol, and treatment with cirazoline, amphetamine, the D1/D2 agonist
apomorphine, or the NMDA antagonist, phencyclidine. RESULTS: PPI was disrupted by cirazoline; this effect was prevented by clonidine
but not haloperidol. PPI was disrupted by apomorphine; this effect was prevented by haloperidol but not clonidine. Clonidine also failed to
oppose the PPI-disruptive effects of amphetamine and augmented the PPI-disruptive effects of phencyclidine. Over a range of prepulse
intervals, clonidine enhanced PPI at short intervals and opposed the PPI-disruptive effects of cirazoline at long intervals.
CONCLUSIONS: PPI is regulated by both norepinephrine and dopamine substrates that are neurochemically separable. The PPI-
protective effects of clonidine suggest that the noradrenergic regulation of PPI may have utility for predicting therapeutic benefit in TS for
drugs other than antipsychotics. Clonidine's failure to prevent the PPI-disruptive effects of apomorphine or phencyclidine further support
the specificity of these PPI models for detecting drugs with antipsychotic properties.
Publication Types:
• Research Support, N.I.H., Extramural PMID: 16583235 [PubMed - indexed for MEDLINE] 28: Ann Pharmacother. 2006 Apr;40(4):775-7. Epub 2006 Mar 28.
Related Articles, Links Acute dystonia with low-dosage aripiprazole in Tourette's disorder.
Fountoulakis KN, Siamouli M, Kantartzis S, Panagiotidis P, Iacovides A, Kaprinis GS.
Laboratory of Psychophysiology, Third Department of Psychiatry, Aristotle University of Thessaloniki, Thessaloniki, Greece. [email protected] OBJECTIVE: To report a case of an acute dystonic episode in a patient with Tourette's disorder (TD) treated with the partial dopamine agonist aripiprazole. CASE SUMMARY: An 18-year-old male with TD was prescribed aripiprazole 10 mg orally daily, which produced a significant improvement in his symptoms. However, after 3 days of treatment, he experienced an acute episode of dystonia with facial muscle spasm, oculogyric crisis, and torticolis. All symptoms resolved after a single intramuscular injection of biperidine 5 mg. The Naranjo probability scale indicated that the adverse events were probably caused by aripiprazole. DISCUSSION: To our knowledge, as of this writing, this is the first report concerning an aripiprazole-induced dystonic episode in an adult, and it is especially notable because it occurred at low dosage. Aripiprazole is a dopamine partial agonist and a serotonin(2A) antagonist with a favorable adverse effect profile. Short-term clinical trials reported a very low incidence of extrapyramidal symptoms, with akathisia being the most common, although there have been reports of severe extrapyramidal symptoms in a 3-year-old child and in an adolescent with a previous history of such symptoms. CONCLUSIONS: Acute dystonic phenomena may be caused by aripiprazole, although the drug's suggested mode of action largely precludes them. Publication Types: • Case Reports • Research Support, Non-U.S. Gov't PMID: 16569800 [PubMed - indexed for MEDLINE] 29: Am J Psychiatry. 2006 Jan;163(1):159.
Related Articles, Links Tourette's symptoms provoked by lamotrigine in a bipolar patient.
Seemüller F, Dehning S, Grunze H, Müller N.
Publication Types:
• Case Reports PMID: 16390908 [PubMed - indexed for MEDLINE] 30: Neurology. 2005 Dec 27;65(12):1941-9.
Related Articles, Links Atomoxetine treatment in children and adolescents with ADHD and comorbid tic disorders.
Allen AJ, Kurlan RM, Gilbert DL, Coffey BJ, Linder SL, Lewis DW, Winner PK, Dunn DW, Dure LS, Sallee FR, Milton DR,
Mintz MI, Ricardi RK, Erenberg G, Layton LL, Feldman PD, Kelsey DK, Spencer TJ.
Lilly Research Laboratories, Indianapolis, IN 46285, USA. [email protected]
OBJECTIVE: To test the hypothesis that atomoxetine does not significantly worsen tic severity relative to placebo in children and
adolescents with attention deficit/hyperactivity disorder (ADHD) and comorbid tic disorders. METHODS: Study subjects were 7 to 17
years old, met Diagnostic and Statistical Manual of Mental Disorders-IV criteria for ADHD, and had concurrent Tourette syndrome or
chronic motor tic disorder. Patients were randomly assigned to double-blind treatment with placebo (n = 72) or atomoxetine (0.5 to 1.5
mg/kg/day, n = 76) for up to 18 weeks. RESULTS: Atomoxetine treatment was associated with greater reduction of tic severity at endpoint
relative to placebo, approaching significance on the Yale Global Tic Severity Scale total score (-5.5 +/- 6.9 vs -3.0 +/- 8.7, p = 0.063) and
Tic Symptom Self-Report total score (-4.7 +/- 6.5 vs -2.9 +/- 5.2, p = 0.095) and achieving significance on the Clinical Global Impressions
(CGI) tic/neurologic severity scale score (-0.7 +/- 1.2 vs -0.1 +/- 1.0, p = 0.002). Atomoxetine patients also showed greater improvement
on the ADHD Rating Scale total score (-10.9 +/- 10.9 vs -4.9 +/- 10.3, p < 0.001) and CGI severity of ADHD/psychiatric symptoms scale
score (-0.8 +/- 1.1 vs -0.3 +/- 1.0, p = 0.015). Discontinuation rates were not significantly different between treatment groups. Atomoxetine
patients had greater increases in heart rate and decreases of body weight, and rates of treatment-emergent decreased appetite and nausea
were higher. No other clinically relevant treatment differences were seen in any other vital sign, adverse event, or electrocardiographic or
laboratory measures. CONCLUSIONS: Atomoxetine did not exacerbate tic symptoms. Rather, there was some evidence of reduction in tic
severity with a significant reduction of attention deficit/hyperactivity disorder symptoms. Atomoxetine treatment appeared safe and well
Publication Types:
• Randomized Controlled Trial PMID: 16380617 [PubMed - indexed for MEDLINE] 31: Mov Disord. 2006 Feb;21(2):248-52.
Related Articles, Links Gilles de la Tourette syndrome: patient's knowledge and concern of adverse effects.
Kompoliti K, Goetz CG, Morrissey M, Leurgans S.
Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois 60612, USA. [email protected]
The objective of this study was to assess awareness and concern of neuroleptic (NL)-induced side effects in Gilles de la Tourette syndrome
(GTS) patients. Although NLs are effective tic suppressants, they can be associated with various side effects. Data on patient knowledge
and concern about side effects can guide educational efforts. One hundred consecutive GTS patients or parents in a tertiary referral
medical center responded to a standardized, in-person questionnaire. They were given a list of 15 side effects and asked which could be
ascribed to NLs (9) or not (6). Side effect concern was rated on a 0 (none) to 10 (extreme) scale. The mean age for the 100 patients was
19.4+/-14 years; 55 had a history of NL use, and 45 were NL-naive. Less than half the cohort met criteria for being well informed. Only
one third of the listed NL side effects were accurately identified by at least 75% of the respondents. Patients with past or current NL
treatment were more accurate in identifying NL side effects but less concerned about them than NL-naive patients. The side effects of
greatest concern were seizures, tardive dyskinesia, thinking and emotion disturbances, and cardiac irregularities. Overall, patient
awareness of NL side effects is insufficient, and although past exposure to NLs enhances knowledge, it decreases concern. Copyright (c)
2005 Movement Disorder Society.
PMID: 16161137 [PubMed - indexed for MEDLINE]
32: Neuropsychopharmacology. 2006 Apr;31(4):721-9.
Related Articles, Links Heritable differences in the dopaminergic regulation of behavior in rats: relationship to D2-like receptor G-protein function.
Swerdlow NR, Krupin AS, Bongiovanni MJ, Shoemaker JM, Goins JC, Hammer RP Jr.
Department of Psychiatry, University of California School of Medicine, San Diego, La Jolla, CA 92093, USA. [email protected]
We reported heritable differences between Sprague-Dawley (SD) and Long Evans (LE) rats in their sensitivity to the disruption of prepulse
inhibition of startle (PPI) by dopamine (DA) agonists, and in their basal levels and turnover of forebrain DA. In an effort to better
understand these differences, we assessed strain patterns in the efficacy of D2-like receptor-G-protein coupling using [35S]GTPgammaS
binding in brain regions that contribute to the dopaminergic regulation of PPI. Sensitivity to the PPI-disruptive effects of apomorphine
(APO) was examined in SD, LE, and F1 (SD x LE) rats. Basal and DA-stimulated [35S]GTPgammaS binding were then assessed in these
rats using conditions that preferentially exclude Gs proteins to favor visualization of D2-like receptors. To explore the behavioral
specificity of these strain differences, locomotor responses to APO and amphetamine (AMPH) were also assessed in SD, LE, and F1 rats.
Strain differences were evident in the PPI-disruptive effects of APO (SD>F1>LE), and in the locomotor responses to AMPH (LE>F1>SD)
and APO (SD exhibited motor suppression, LE exhibited motor activation). Compared to SD rats, LE rats exhibited greater DA-stimulated
[35S]GTPgammaS binding in nucleus accumbens and caudatoputamen, while F1 progeny had intermediate levels. In conclusion, SD and
LE rats exhibit heritable differences in D2-mediated behavioral and biochemical measures. Conceivably, genes that regulate heritable
differences in forebrain D2 function may contribute to heritable differences in PPI in patients with specific neuropsychiatric disorders,
including schizophrenia and Tourette Syndrome.
Publication Types:
• Comparative Study • Research Support, N.I.H., Extramural PMID: 16123742 [PubMed - indexed for MEDLINE] 33: Pharmacol Biochem Behav. 2005 Aug;81(4):879-86.
Related Articles, Links Effects of donepezil, nicotine and haloperidol on the central serotonergic system in mice: implications for Tourette's syndrome.
Hayslett RL, Tizabi Y.
Department of Pharmacology, Howard University College of Medicine, 520 W Street N.W., Washington, DC 20059, USA.
We have previously reported that acute and chronic donepezil and nicotine administration significantly attenuate DOI-induced head twitch response (HTR) in mice. This behavior, primarily mediated by stimulation of 5-HT2A receptors, has been proposed to model tic symptoms seen in Tourette's syndrome (TS). Haloperidol, a drug widely used to treat symptoms of TS, has also been reported to reduce DOI-induced head shakes in rodents when administered acutely. These findings suggest an inhibitory interaction of these drugs with 5-HT2A receptors. To test this hypothesis, we evaluated the effects of chronic donepezil, nicotine and haloperidol on expression levels of 5-HT2A mRNA and 5-HT2A receptor density in select brain regions. Initially, we established a dose-response relationship for the acute and chronic haloperidol and DOI-induced HTR. Male ICR mice were treated twice daily with donepezil (0.1 mg/kg), nicotine (0.5 mg/kg), and once daily with haloperidol (0.4 mg/kg) for 14 days and were sacrificed 16-18 h after the last injection. These drug regimens were chosen because of their significant effects on DOI-induced HTR. Donepezil significantly increased 5-HT2A mRNA level, but not the receptor density in the striatum. In the midbrain, donepezil significantly decreased the receptor density without affecting the 5-HT2A mRNA level. In the frontal cortex, only haloperidol significantly reduced the 5-HT2A receptor density. The cortex was the only area where donepezil, nicotine and haloperidol significantly reduced the 5-HT2A receptor density. The results suggest that the anti-tic properties of donepezil, nicotine and haloperidol in this paradigm might be due to antagonism of cortical 5-HT2A receptors. Thus, further investigation of involvement of cortical 5-HT2A receptors in TS as well as evaluation of selective 5-HT2A receptor antagonists in this disorder is warranted. Publication Types: • Comparative Study • Research Support, Non-U.S. Gov't PMID: 16045972 [PubMed - indexed for MEDLINE] 34: Mov Disord. 2005 Nov;20(11):1496-9.
Related Articles, Links Efficient internal pallidal stimulation in Gilles de la Tourette syndrome: a case report.
Diederich NJ, Kalteis K, Stamenkovic M, Pieri V, Alesch F.
Department of Neuroscience, Centre Hospitalier de Luxembourg, Luxembourg. [email protected]
The usefulness of deep brain stimulation (DBS) of thalamic nuclei in Gilles de la Tourette syndrome (GTS) has recently been advocated.
We report on a 14-month follow-up study of a patient with intractable GTS in whom bilateral DBS of the internal globus pallidus was
carried out. Tic frequency per minute decreased by 73% in the postoperative phase and in particular the vocal tics became less intense.
Pronation/ supination bradykinesia of the left extremities was a well-tolerated, permanent side effect. Pallidal DBS could become a
valuable rescue therapy for otherwise intractable GTS.
Publication Types:
• Case Reports PMID: 16037913 [PubMed - indexed for MEDLINE] 35: Neurosci Lett. 2005 Sep 9;385(2):120-5.
Related Articles, Links Serotonin transporter binding in Tourette Syndrome.
Müller-Vahl KR, Meyer GJ, Knapp WH, Emrich HM, Gielow P, Brücke T, Berding G.
Department of Clinical Psychiatry and Psychotherapy, Medical School Hannover, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany.
[email protected]
Recent studies provided evidence for an involvement of the dopaminergic system in the pathophysiology of Tourette Syndrome (TS).
However, little is known about possible impairment of other neurotransmitter systems. In obsessive-compulsive disorder (OCD), a
common comorbidity in TS, it is suggested that the serotonergic system plays a major role in the pathogenesis. We, therefore, used [I-
123]2[beta]-carbomethoxy-3[beta]-(4-iodophenyl)tropane ([123I]beta-CIT) and single photon emission computed tomography (SPECT) to
investigate serotonin transporter (SERT) binding capacity in 12 patients with TS with various degrees of associated obsessive compulsive
behaviour (OCB) and 16 age-matched healthy controls. Binding ratios in TS patients not receiving serotonin reuptake inhibitors (SSRI)
(n=8) were significantly reduced compared to age-adjusted ratios from normal controls (2.8 versus 3.2, p=0.003). Treatment with SSRI
resulted in a significant reduction of SERT availability. Performing linear regression analysis for this small group, SSRI-free patients
indicated trends for a negative correlation between [123I]beta-CIT binding on SERT and OCB (r=-0.78, p=0.023) as well as complex
motor tics (r=-0.68, p=0.064). In healthy controls, but not in the TS group, we found an age-related decline in SERT binding capacity
(0.28% decrease per year, p=0.038). Our data are in agreement with previous results suggesting an impairment of the serotonergic system
in TS. It can be speculated that the reduction in SERT binding capacity is associated with the degree of comorbid OCB.
PMID: 15936877 [PubMed - indexed for MEDLINE] 36: Brain. 2005 Jun;128(Pt 6):1292-300. Epub 2005 Mar 17.
Related Articles, Links Excitability of motor cortex inhibitory circuits in Tourette syndrome before and after single dose nicotine.
Orth M, Amann B, Robertson MM, Rothwell JC.
Sobell Department of Motor Neuroscience and Movement Disorders,The National Hospital for Neurology and Neurosurgery, Royal Free
and University College Medical School, Queen Square, London WC1N 3BG, UK. [email protected]
The pathophysiology underlying the involuntary tics of Gilles de la Tourette syndrome (GTS) remains unknown. Here we used
transcranial magnetic stimulation (TMS) to examine the excitability of two different inhibitory systems in the human motor cortex: short
interval intracortical inhibition (SICI) and short interval afferent inhibition (SAI) in 10 healthy non-smoking controls and eight untreated
non-smoking patients with GTS. Compared with the healthy control group, both SICI (measured at a range of conditioning intensities) and
SAI were reduced in patients. This is consistent with the suggestion that reduced excitability of cortical inhibition is one factor that
contributes to the difficulty that patients have in suppressing involuntary tics. In addition, the reduced SAI indicates that impaired
intracortical inhibition may not be limited to the motor cortex but also involves circuits linking sensory input and motor output. A single
dose of nicotine reduced tic severity as assessed by blind video scoring in the majority of patients. In addition, it abolished the difference
between patients and controls in SICI and SAI. There was no effect of nicotine, and no difference between controls and patients in
measures of motor or SICI threshold. This indicates that cholinergic input can modulate the efficiency of SICI and SAI differently in GTS
and healthy controls.
Publication Types:
• Clinical Trial PMID: 15774505 [PubMed - indexed for MEDLINE] 37: Am J Psychiatry. 2005 Mar;162(3):625.
Related Articles, Links Aripiprazole in a patient vulnerable to side effects.
Dehning S, Riedel M, Müller N.
Publication Types:
• Case Reports PMID: 15741488 [PubMed - indexed for MEDLINE] 38: J Child Adolesc Psychopharmacol. 2004 Winter;14(4):582-9.
Related Articles, Links Nutritional supplements and complementary/alternative medicine in Tourette syndrome.
Mantel BJ, Meyers A, Tran QY, Rogers S, Jacobson JS.
BJM Consulting, New York, New York.
OBJECTIVE: Tourette syndrome (TS) is a neuropsychiatric disorder associated with motor and vocal tics. Some people with TS have
reported using alternative or complementary medicine (CAM), including nutritional supplements to control their tics. In a recent national
survey, approximately 40% of people reported having used CAM in the prior year. We attempted to explore the use of supplements and
other CAM among TS patients. METHOD: We developed a survey instrument based on anecdotal accounts of CAM use and distributed it
to the mailing list of the New York Chapter of the Tourette Syndrome Association (n=500) and the subscription list of Latitudes, a
newsletter exploring CAM treatments for neurological conditions (n=750). Responses were entered in a database and analyzed using SPSS
version 10. RESULTS: Of 115 respondents, 87.8% reported using 1 or more of 29 nutritional supplements to control symptoms. Many
also reported using other CAM. Most supplement users reported an improvement in tics. CONCLUSIONS: Although these results are not
generalizable, they provide no evidence that use of supplements and other CAM is rarer among TS patients than in the general population.
Given that most of our respondents were also using conventional medication, further study of the use of supplements and other CAM
therapies by people with TS, the safety and efficacy of such therapies in this population, and possible interactions of such therapies with conventional treatment seems warranted. PMID: 15662150 [PubMed - indexed for MEDLINE] 39: J Clin Psychopharmacol. 2005 Feb;25(1):94-6.
Related Articles, Links Treatment of tics in tourette syndrome with aripiprazole.
Kastrup A, Schlotter W, Plewnia C, Bartels M.
Publication Types:
• Case Reports PMID: 15643108 [PubMed - indexed for MEDLINE] 40: Cogn Behav Neurol. 2004 Jun;17(2):109-17.
Related Articles, Links A pilot safety study of repetitive transcranial magnetic stimulation (rTMS) in Tourette's syndrome.
Chae JH, Nahas Z, Wassermann E, Li X, Sethuraman G, Gilbert D, Sallee FR, George MS.
Brain Stimulation Laboratory, Psychiatry Department, Medical University of South Carolina, Charleston, South Carolina, USA.
OBJECTIVE: We designed a randomized, blinded, crossover study to assess safety and test whether transcranial magnetic stimulation at
specific regions and frequencies might modify tics. We administered repetitive transcranial magnetic stimulation over prefrontal cortex or
motor cortex, with either fast or slow repetitive transcranial magnetic stimulation, to 8 Tourette's syndrome patients. METHODS: Over 5
days, we applied repetitive transcranial magnetic stimulation at 110% of the motor threshold over left motor cortex (twice) or left
prefrontal cortex (twice), using either 1 Hz or 15 Hz transcranial magnetic stimulation, or sham transcranial magnetic stimulation (once).
RESULTS: All 8 subjects completed the study with minimal side effects and no worsening of tics or other involuntary movements.
Ignoring site and frequency, tic symptoms improved significantly over the week of the study. The study design does not allow one to
address whether this was due to the presence or frequency of transcranial magnetic stimulation or to nonspecific factors involved in study
participation. CONCLUSIONS: Repetitive transcranial magnetic stimulation at these sites, doses, and use parameters appears to be safe in
adults with Tourette's syndrome. Further studies using repetitive transcranial magnetic stimulation in Tourette's syndrome are warranted,
using balanced parallel designs.
Publication Types:
• Clinical Trial • Randomized Controlled Trial • Research Support, Non-U.S. Gov't • Research Support, U.S. Gov't, P.H.S. PMID: 15453520 [PubMed - indexed for MEDLINE] Mol Pharmacol. 2008 Feb 26 [Epub ahead of print] Related Articles, Links Messing up with traffic: different effects of antipsychotics on glutamate receptor complexes in vivo (Relates to article by
Fumagalli, et al., Fast Forward 4 Feb 2008).

Del'guidice T, Beaulieu M.
Universite Laval/CRULRG.
Antipsychotics are major drugs for human neuropsychiatric conditions including schizophrenia, mood disorders, Tourette syndrome and
Alzheimer's disease. These drugs are divided in two groups--first-generation/typical and second-generation/atypical-- on the base of their
propensity to induce extra-pyramidal motor side effects. Furthermore, second-generation antipsychotics have been reported to be superior
in addressing cognitive deficits in schizophrenia. Understanding differences between the mechanism of action of first and second-
generation antipsychotics thus represents an interesting opportunity for the development of new compounds having better therapeutic
action and less side effects. In this issue of Molecular Pharmacology, Fumagalli et al. report that chronic treatment with the first-generation
drug haloperidol interferes with the trafficking of both AMPA and NMDA glutamate receptor complexes and associated molecules PSD95
and CaMKII in the rat frontal cortex. In contrast, the second-generation drug olanzapine did not affect glutamate receptor trafficking. The action of haloperidol on glutamate receptor trafficking in specific brain regions may contribute to the low efficacy of this drug on cognitive deficits and to the development of side effects. Overall, antipsychotics have been shown to act upon multiple signaling mechanisms (e.g.: cAMP-PKA, betaArrestin 2-Akt-GSK-3 and PLC-inositol-PKC pathways) mostly by blocking D2-class dopamine receptors (first-generation) or D2-class dopamine and 5-HT2 serotonin receptors (second generation). Identification of specific pathways by which haloperidol affects glutamate receptor trafficking may thus represent an important next step toward the development of better antipsychotic drugs. PMID: 18314495 [PubMed - as supplied by publisher] 2: J Child Neurol. 2008 Jan;23(1):108-11.
Related Articles, Links The successful use of ondansetron in a boy with both leukemia and Tourette syndrome.
Rizzo R, Marino S, Gulisano M, Robertson MM.
Section of Child Neuropsychiatry, Department of Pediatrics University of Catania, Azienda Policlinico, Catania, Italy. [email protected]
This article reports an 8-year-old boy with both acute lymphoblastic leukemia and Gilles de la Tourette syndrome. Initially, for his
leukemia, he was treated with chemotherapy, which resulted in severe nausea and vomiting for which he was given ondansetron. This not
only relieved the target symptoms, but also those of his Gilles de la Tourette syndrome. Following a reduction of the ondansetron dosage,
his Gilles de la Tourette syndrome symptoms reemerged.
Publication Types:
• Case Reports PMID: 18184945 [PubMed - indexed for MEDLINE] 3: J ECT. 2007 Dec;23(4):278-80.
Related Articles, Links Neurobiological substrates of electroconvulsive therapy for Tourette syndrome: a Serial SISCOM study.
Morais SL, Derenusson GN, Pinto JP, Hounie AG, Dursun SM, Wichert-Ana L, Kato M, de Oliveira LF, de Azevedo-Marques
, Sakamoto AC, Hallak JE.
Department of Neurology, Psychiatry, and Clinical Psychology, São Paulo, Brazil.
We report the case of an adult male patient with Tourette syndrome, self-injurious behavior and depression, refractory to conventional
treatment, and whose symptoms remitted after electroconvulsive therapy. Serial Technetium 99m-Ethyl-Cysteinate-Dimer single photon
emission tomographies were applied, before, during, and after electroconvulsive therapy. The neural substrates of this treatment process
were further analyzed by woxel-wise subtracted single photon emission tomography images.
Publication Types:
• Case Reports PMID: 18090703 [PubMed - indexed for MEDLINE] 4: Stereotact Funct Neurosurg. 2008;86(2):87-91. Epub 2007 Dec 12.
Related Articles, Links Microelectrode-guided deep brain stimulation for Tourette syndrome: within-subject comparison of different stimulation sites.
Shields DC, Cheng ML, Flaherty AW, Gale JT, Eskandar EN.
Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, Mass., USA.
BACKGROUND: As medical therapy for Tourette syndrome (TS) is ineffective in a small subset of patients, surgical interventions,
including deep brain stimulation at various sites, have been developed in recent years. CASE DESCRIPTION: We present the case of a
40-year-old woman with TS whose severe tics had caused unilateral blindness. Despite trials of more than 40 medications, her symptoms
improved significantly only after placement of bilateral deep brain stimulators in the anterior inferior internal capsule. However,
symptomatic improvement was not complete, and her electrode connections eventually became permanently damaged by the remaining
retrocollic jerks. She underwent removal of the internal capsule electrodes and placement of centromedian nucleus thalamic stimulators with significantly improved tic control. CONCLUSION: Whereas the anterior internal capsule site had also produced psychiatric side effects such as altered mood and impulse control, the thalamic site has not done so to date. Thus, distinct surgical targets for TS may be appropriate for patients with specific comorbidities. (c) 2007 S. Karger AG, Basel Publication Types: • Case Reports • Comparative Study PMID: 18073521 [PubMed - indexed for MEDLINE] 5: Nursing. 2007 Oct;37(10):17.
Related Articles, Links Shedding light on Tourette's syndrome.
Thomure A.
Neuroscience Intensive Care Unit at Duke University Medical Center in Durham, NC, USA.
PMID: 17906520 [PubMed - indexed for MEDLINE]
6: Dialogues Clin Neurosci. 2007;9(2):161-71.
Related Articles, Links
Tourette's syndrome: clinical features, pathophysiology, and therapeutic approaches.
Müller N.
Hospital for Psychiatry and Psychotherapy, Ludwig-Maximilians-Universität, Munich, Germany. [email protected]
Tourette's syndrome (TS) is a disorder characterized by simple and complex motor tics, vocal tics, and frequently obsessive-compulsive
symptoms. Its onset occurs before the age of 21. Typically, TS shows a waxing and waning course, but a chronification of the tics, even
during later life, is often observed. TS mainly occurs in boys, and shows genetic heritability with differing penetrance. The pathological
mechanism is still unclear Neuroanatomical and neuroimaging studies, as well as effective treatment using antipsychotics, suggest that a
disturbance of the dopaminergic system in the basal ganglia plays an important role in the pathogenesis of TS. Several possibly causative
mechanisms of the disturbed dopaminergic neurotransmission are discussed, with the main emphasis on the-infection-triggered-
inflammatory immune process. Extrapyramidal movement disorders are known to occur as a symptom of poststreptococcal disease, such
as in Sydenham's chorea. Cases of childhood TS are proposed to be caused by such a poststreptococcal mechanism, being part of a
spectrum of childhood neurobehavioral disorders termed pediatric autoimmune neuropsychiatric disorder associated with streptococcal
infection (PANDAS). The overlap between TS and PANDAS is discussed, and a critical view of the PANDAS concept is presented. The
therapeutic implications of the different pathological mechanisms are described, taking into consideration not only the acute or chronic
natures of different infections, but also an autoimmune process. Moreover, therapeutic strategies using typical and atypical antipsychotics,
and also experimental therapies such as repetitive transcranial magnetic stimulation and deep brain stimulation, are critically discussed.
Publication Types:
PMID: 17726915 [PubMed - indexed for MEDLINE] 7: Mov Disord. 2007 Nov 15;22(15):2256-62.
Related Articles, Links Abnormal brain tryptophan metabolism and clinical correlates in Tourette syndrome.
Behen M, Chugani HT, Juhász C, Helder E, Ho A, Maqbool M, Rothermel RD, Perry J, Muzik O.
Carman and Ann Adams Department of Pediatrics, Children's Hospital of Michigan, Wayne State University School of Medicine, Detroit,
Michigan 48201, USA.
Symptoms in Tourette syndrome (TS) are likely related to abnormalities involving multiple neurotransmitter systems in striatal-thalamo-
cortical circuitry. Although prior studies have found abnormal levels of tryptophan, serotonin, and their metabolites in blood, cerebrospinal
fluid and brain tissue of TS patients, understanding of focal brain disturbances and their relationship to clinical phenotype remains poor.
We used alpha-[(11)C]methyl-L-tryptophan (AMT) positron emission tomography (PET) to assess global and focal brain abnormalities of
tryptophan metabolism and their relationship to behavioral phenotype in 26 children with TS and nine controls. Group comparisons on regional cortical and subcortical AMT uptake revealed decreased AMT uptake in bilateral dorsolateral prefrontal cortical and bilaterally increased uptake in the thalamus (P = 0.001) in TS children. The ratio of AMT uptake in subcortical structures to dorsolateral prefrontal cortex was significantly increased bilaterally (P < 0.01) in TS patients also. Behaviorally defined subgroups within the TS sample revealed differences in the pattern of AMT uptake in the fronto-striatal-thalamic circuit. This study demonstrates cortical and subcortical abnormalities of tryptophan metabolism in TS and provides neuroimaging evidence for a role of serotonergic mechanisms in the pathophysiology of TS. (c) 2007 Movement Disorder Society. Publication Types: • Research Support, Non-U.S. Gov't PMID: 17708557 [PubMed - indexed for MEDLINE] 8: J Clin Psychiatry. 2007 Jul;68(7):1148-50.
Related Articles, Links Quetiapine in patients with Tourette's disorder: an open-label, flexible-dose study.
de Jonge JL, Cath DC, van Balkom AJ.
Publication Types:
• Clinical Trial PMID: 17685760 [PubMed - indexed for MEDLINE] 9: Clin Neurophysiol. 2007 Aug;118(8):1835-41. Epub 2007 Jun 27.
Related Articles, Links Atomoxetine treatment of ADHD in Tourette syndrome: reduction in motor cortex inhibition correlates with clinical

Gilbert DL, Zhang J, Lipps TD, Natarajan N, Brandyberry J, Wang Z, Sallee FR, Wassermann EM.
Division of Neurology, Cincinnati Children's Hospital Medical Center, and The University of Cincinnati, Department of Neurology,
School of Medicine, OH 45229-3039, USA. [email protected]
OBJECTIVE: In children with attention deficit hyperactivity disorder (ADHD), clinical responses to the selective norepinephrine reuptake
inhibitor atomoxetine (ATX) vary. We sought to determine in children with Tourette Syndrome (TS) whether clinical responses correlate
with changes in short interval cortical inhibition (SICI). METHODS: Fourteen children, ages 8-16, with ADHD and TS were treated open-
label with ATX for one month. ADHD rating scale scores and SICI, measured with paired-pulse transcranial magnetic stimulation
(pTMS), were assessed blindly and independently at treatment onset and one month later. RESULTS: Eleven children, mean ADHD rating
scale scores 31.8 (SD 8.2) at onset, completed the study. After one month, ADHDRS changes ranged from an increase of 4 points to a
decrease (improvement) of 24 points (mean change -9.6, SD 9.1). The changes in ADHDRS scores correlated with reduction in SICI
(r=.74, p=.010). CONCLUSIONS: In children with TS, one month of atomoxetine treatment appears to induce correlated improvements in
ADHD and, paradoxically, further reductions in cortical inhibition. SIGNIFICANCE: PTMS-evoked SICI in ADHD with TS may be a
biomarker of both deficiency and compensatory changes within cortical interneuronal systems. Effective atomoxetine treatment may
augment compensatory processes and thereby reduce SICI.
Publication Types:
• Research Support, N.I.H., Extramural • Research Support, Non-U.S. Gov't PMID: 17588810 [PubMed - indexed for MEDLINE] 10: Prog Neuropsychopharmacol Biol Psychiatry. 2007 Aug 15;31(6):1339-40. Epub 2007 Apr 29.
Related Articles, Links Co-occurence of blepharospasm, tourettism and obsessive-compulsive symptoms during lamotrigine treatment.
Alkin T, Onur E, Ozerdem A.
Publication Types:
• Case Reports PMID: 17537560 [PubMed - indexed for MEDLINE] 11: Eur Neuropsychopharmacol. 2007 Jul;17(8):523-6. Epub 2007 Mar 6.
Related Articles, Links Reduced platelet vesicular monoamine transporter density in Tourette's syndrome pediatric male patients.
Ben-Dor DH, Zimmerman S, Sever J, Roz N, Apter A, Rehavi M, Weizman A.
Geha Mental Health Center, Petah Tiqva, Israel.
The vesicular monoamine transporter (VMAT2) plays a major role in the synaptic accumulation and quantal release of monoamines. In
this study, we assessed high affinity [(3)H]dihydrotetrabenazine binding to platelet VMAT2, in a group of untreated male Tourette's
syndrome (TS) patients (age: 8-17.5 years, n=9) and in a group of age- and sex-matched healthy controls (age: 9-16 years, n=16).
Significantly decreased platelet VMAT2 density (B(max)) (-23%, p=0.016) was observed in the TS patients. The affinity (K(d)) of the
ligand to platelet VMAT2 was similar in both groups. If the lower platelet VMAT2 density also occurred in the brain, it may have serve as
an adaptive mechanism geared to decrease dopamine storage in the presynaptic neurons and thereby to attenuate the dopaminergic
overactivity and ameliorate the movement disorder.
PMID: 17344033 [PubMed - indexed for MEDLINE]
12: Clin Drug Investig. 2007;27(2):123-30.
Related Articles, Links
Clinical effectiveness of quetiapine in children and adolescents with Tourette's syndrome : a retrospective case-note survey.
Copur M, Arpaci B, Demir T, Narin H.
Bakirkoy Dr Mazhar Osman Psychiatric and Neurological Diseases Research and Education Hospital, Paediatric Psychiatry Clinic,
Istanbul, Turkey. [email protected]
BACKGROUND AND OBJECTIVE: Tourette's syndrome is a relatively common biological genetic disorder with a broad spectrum of
neurobehavioural manifestations. Unfortunately, treatment of the condition is often unsatisfactory and all available drugs are associated
with potential adverse effects. We therefore aimed to investigate the efficacy of quetiapine, a newer atypical antipsychotic, in the treatment
of children and adolescents with Tourette's syndrome. METHODS: This was a retrospective study carried out in outpatient clinics. Twelve
patients aged 8-18 years with Tourette's syndrome (diagnosed according to Diagnostic and Statistical Manual IV criteria) who were
receiving quetiapine therapy and had no diagnosis of epilepsy, major depression or psychotic disorder, were included in the study. The
main outcome measure was the Yale Global Tic Severity Scale (YGTSS) score. RESULTS: The initial dose of quetiapine was 25 mg/day,
but the mean dose was increased to 114.6 +/- 51.6 mg/day and 175.0 +/- 116.8 mg/day at the fourth and eighth weeks of treatment,
respectively. The YGTSS score, which was 21.6 +/- 4.0 at baseline, showed significant decreases at 4 and 8 weeks (reducing to 7.5 +/- 7.4
and 5.6 +/- 8.1, respectively; p < 0.003). Routine laboratory parameters and serum prolactin level were all normal and did not change
throughout treatment. Mild but significant increases in both bodyweight and body mass index at 4 and 8 weeks compared with baseline
were observed. CONCLUSION: Other than causing mild weight gain, quetiapine appears to be an effective, safe and well tolerated drug in
children and adolescents with Tourette's syndrome.
PMID: 17217317 [PubMed - indexed for MEDLINE]
13: Eur Neurol. 2007;57(2):116-7. Epub 2006 Dec 18.
Related Articles, Links New-onset Tourette syndrome following human growth hormone therapy.
Doneray H, Tan H, Orbak Z.
Publication Types:
• Case Reports PMID: 17179718 [PubMed - indexed for MEDLINE] 14: Psychopharmacology (Berl). 2007 Feb;190(2):221-31. Epub 2006 Nov 11.
Related Articles, Links Role of atypical opiates in OCD. Experimental approach through the study of 5-HT(2A/C) receptor-mediated behavior.
Rojas-Corrales MO, Gibert-Rahola J, Mico JA.
Group of Research and Development in Neuropsychopharmacology, Department of Neuroscience, Faculty of Medicine, University of
Cádiz, Plz Falla 9, 11003, Cádiz, Spain.
RATIONALE: The selective serotonin (5-HT) reuptake inhibitors (SSRIs) represent the first-line pharmacotherapy for obsessive-
compulsive disorder (OCD), and atypical antipsychotic drugs, which block 5-HT2A receptors, are used in augmentation strategies. Opiate
drugs are also effective in treatment-refractory OCD and Tourette syndrome. The 5-HT2A-related behavior (i.e., head twitch) has been
related with tics, stereotypes, and compulsive symptoms observed in Tourette syndrome and OCD. OBJECTIVES: The aim of this study
was to explore whether 5-HT2A-related behavior is affected by atypical opiate drugs. MATERIALS AND METHODS: Head-twitch
response was induced in mice by administration of either 5-hydroxytryptophan (5-HTP) or the 5-HT2A/C agonist (+/-)-1-(2,5-dimethoxy-
4-iodophenyl)-2-aminopropane (DOI). Dose-effect curves of atypical opiate drugs [(+/-)-tramadol, (-)-methadone and levorphanol],
morphine, and other psychoactive drugs (fluvoxamine, desipramine, nefazodone, and clozapine) were performed. Opioid mechanisms
were investigated by administration of naloxone. RESULTS: All the opiates tested reduced both 5-HTP and DOI-induced behavior in a
naloxone-reversible fashion, atypical opiates being more effective. The effects of the other drugs depended on the protocol, clozapine
being the most effective. CONCLUSIONS: Combined 5-HT and opioid properties result in a greater efficacy in antagonizing 5-HT2A-
related behavior. These results provide behavioral evidence to support convergent effects of the 5-HT and opioid systems in discrete brain
areas, offering the potential for therapeutic advances in the management of refractory stereotypes and compulsive behaviors.
Publication Types:
• Comparative Study • Research Support, Non-U.S. Gov't PMID: 17102981 [PubMed - indexed for MEDLINE] 15: Neurology. 2006 Nov 14;67(9):1695-7.
Related Articles, Links Altered mesolimbocortical and thalamic dopamine in Tourette syndrome.
Gilbert DL, Christian BT, Gelfand MJ, Shi B, Mantil J, Sallee FR.
Movement Disorder Clinic, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229-3039, USA. [email protected]
We used [F-18]fallypride PET in six adults with Tourette syndrome and age-matched controls to assess extrastriatal dopamine 2 (D2)
receptors. D2 receptor availability was significantly lower in the orbitofrontal cortex, primary motor cortex, anterior cingulate gyrus,
mediodorsal nucleus of thalamus, and hippocampus, areas important for motivation and reward, sensory gating, movement, and attention.
Altered dopaminergic function in mesolimbocortical systems and thalamus may contribute to increased motivational salience of tics.
Publication Types:
• Research Support, N.I.H., Extramural • Research Support, Non-U.S. Gov't PMID: 17101911 [PubMed - indexed for MEDLINE] 16: J Child Neurol. 2006 Aug;21(8):704-14.
Related Articles, Links
Obsessive-compulsive disorder in Tourette syndrome.
Goodman WK, Storch EA, Geffken GR, Murphy TK.
Department of Psychiatry, University of Florida, Gainesville, FL 32610, USA. [email protected]
Several lines of evidence suggest a meaningful association between obsessive-compulsive disorder and Tourette syndrome, including
comorbidity, phenomenologic overlap, evidence from family and genetic studies, and the possible role of basal ganglia circuitry in both conditions. Obsessive-compulsive behaviors occur frequently in patients who have Tourette syndrome and tend to have a later onset than tics. Despite commonalities, the approaches to treating tics and obsessive-compulsive symptoms are actually quite distinct. A specialized form of cognitive behavior therapy and pharmacotherapy with a potent serotonin reuptake inhibitor are the two established first-line therapies for obsessive-compulsive disorder. An adequate trial of a serotonin reuptake inhibitor is 10 to 12 weeks in duration at doses near the upper end of the recommended range for age and weight. Cases of obsessive-compulsive disorder that do not sufficiently improve with serotonin reuptake inhibitors might benefit from adjunctive low-dose antipsychotic (eg, risperidone) medication whether or not tics are present. Warnings about an increased risk of suicidality among children and adolescents taking antidepressants for pediatric depression extend to those taking the medications for obsessive-compulsive disorder, but the risk-to-benefit ratio is more favorable in this latter population because several serotonin reuptake inhibitors have been shown to be efficacious in obsessive-compulsive disorder. Publication Types: • Research Support, N.I.H., Extramural • Research Support, Non-U.S. Gov't PMID: 16970872 [PubMed - indexed for MEDLINE] 17: J Child Adolesc Psychopharmacol. 2006 Aug;16(4):505-6.
Related Articles, Links A pilot study of aripiprazole in children and adolescents with Tourette's disorder.
Yoo HK, Kim JY, Kim CY.
Publication Types:
PMID: 16958578 [PubMed - indexed for MEDLINE] 18: Int J Neuropsychopharmacol. 2007 Apr;10(2):245-52. Epub 2006 Feb 28.
Related Articles, Links Cerebral 5-HT2A receptor binding is increased in patients with Tourette's syndrome.
Haugbøl S, Pinborg LH, Regeur L, Hansen ES, Bolwig TG, Nielsen FA, Svarer C, Skovgaard LT, Knudsen GM.
Neurobiology Research Unit, Copenhagen University Hospital, Denmark. [email protected]
Experimental and clinical data have suggested that abnormalities in the serotonergic neurotransmissions in frontal-subcortical circuits are
involved in Tourette's syndrome. To test the hypothesis that the brain's 5-HT2A receptor binding is increased in patients with Tourette's
syndrome, PET imaging was performed. Twenty adults with Tourette's syndrome and 20 healthy control subjects were investigated with
PET-[18F]altanserin using a bolus-infusion protocol. Regions of interest were delineated automatically on co-registered MRI images, and
partial volume-corrected binding parameters were extracted from the PET images. Comparison between control subjects and Tourette's
syndrome patients showed increased specific [18F]altanserin binding, not only in the a-priori selected brain regions hypothesized to be
involved in Tourette's syndrome, but also post-hoc analysis showed a global up-regulation when testing for a overall difference with a
randomization test (p<0.03). Increased 5-HT2A receptor binding was found not only in regions closely related to subcortical regions in
patients with Tourette's syndrome, but also in most other brain regions. Our data suggest that the serotonergic transmitter system is
pathophysiologically involved in Tourette's syndrome and that a clinical trial with 5-HT2A receptor antagonists may be justified.
Publication Types:
• Research Support, Non-U.S. Gov't PMID: 16945163 [PubMed - indexed for MEDLINE] 19: Nervenarzt. 2007 Mar;78(3):264, 266-8, 270-1.
Related Articles, Links [The benzamides tiapride, sulpiride, and amisulpride in treatment for Tourette's syndrome]
[Article in German]
Müller-Vahl KR.
Abteilung für Klinische Psychiatrie und Psychotherapie, Medizinische Hochschule Hannover, Carl-Neuberg-Stasse 1, 30625 Hannover.
[email protected]
The treatment of Tourette's syndrome is a challenge. Dopamine receptor antagonists are the drugs of first choice for the treatment of tics.
Because large controlled trials are lacking, there is no consensus about which of the different neuroleptic drugs should be preferred. In
Germany, tiapride seems to be used most often for the treatment of tics in children - although only one small controlled trial has been
performed on it till now. In adults, other dopamine receptor antagonists such as risperidone, pimozide, and sulpiride seem to be more
effective than tiapride. Today it is unknown whether new atypical neuroleptic drugs including the benzamide amisulpride are more
effective than the older benzamides tiapride and sulpiride.
Publication Types:
• English Abstract PMID: 16924461 [PubMed - indexed for MEDLINE] 20: J Child Neurol. 2006 Apr;21(4):358.
Related Articles, Links • J Child Neurol. 2005 Jul;20(7):603-10.
Aripiprazole in childhood and adolescence for Tourette syndrome.
Duane DD.
Publication Types:
• Research Support, Non-U.S. Gov't PMID: 16900939 [PubMed - indexed for MEDLINE



Il nostro scheletro Contrariamente alle apparenze, anche il nostro scheletro, con le sue 203 ossa fra grandi e piccole, è una parte "viva" del nostro corpo. Basta osservare i cambiamenti che esso subisce nel corso della vita. Dalla nascita fino ai vent'anni circa lo scheletro cresce e si sviluppa. Le ossa aumentano di peso e di volume mentre assumono la loro forma adulta

Npgrj_nbt_1481 1.8

A small molecule enhances RNA interference andpromotes microRNA processing Ge Shan1,6, Yujing Li1,6, Junliang Zhang2, Wendi Li1, Keith E Szulwach1, Ranhui Duan1,Mohammad A Faghihi3, Ahmad M Khalil3, Lianghua Lu2, Zain Paroo4, Anthony W S Chan1,Zhangjie Shi5, Qinghua Liu4, Claes Wahlestedt3, Chuan He2 & Peng Jin1 Small interfering RNAs (siRNAs) and microRNAs (miRNAs) are sequence-specific post-transcriptional regulators of geneexpression. Although major components of the RNA interference (RNAi) pathway have been identified, regulatory mechanismsfor this pathway remain largely unknown. Here we demonstrate that the RNAi pathway can be modulated intracellularly by smallmolecules. We have developed a cell-based assay to monitor the activity of the RNAi pathway and find that the small-molecule