Andrea G. Ludolph

European clinical guidelines for Tourette syndrome and other tic disorders. Part II: pharmacological treatment

To develop a European guideline on pharmacologic treatment of Tourette syndrome (TS) the available literature was thoroughly screened and extensively discussed by a working group of the European Society for the Study of Tourette syndrome (ESSTS). Although there are many more studies on pharmacotherapy of TS than on behavioral treatment options, only a limited number of studies meets rigorous quality criteria. Therefore, we have devised a two-stage approach. First, we present the highest level of evidence by reporting the findings of existing Cochrane reviews in this field. Subsequently, we provide the first comprehensive overview of all reports on pharmacological treatment options for TS through a MEDLINE, PubMed, and EMBASE search for all studies that document the effect of pharmacological treatment of TS and other tic disorders between 1970 and November 2010. We present a summary of the current consensus on pharmacological treatment options for TS in Europe to guide the clinician in daily practice. This summary is, however, rather a status quo of a clinically helpful but merely low evidence guideline, mainly driven by expert experience and opinion, since rigorous experimental studies are scarce.

European clinical guidelines for Tourette Syndrome and other tic disorders. Part I: assessment

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

Dopaminergic dysfunction in attention deficit hyperactivity disorder (ADHD), differences between pharmacologically treated and never treated young adults : a 3,4-dihdroxy-6-[18F]fluorophenyl-l-alanine PET study

The dopaminergic system plays a key role in attention-deficit/hyperactivity disorder (ADHD). Methylphenidate (MP), a dopamine (DA) reuptake inhibitor, is a drug of first choice for treating ADHD. This cross-over study investigated alterations in DA metabolism in young males with ADHD who had never been pharmacologically treated and MP-treated patients in comparison to healthy subjects. Dynamic 3,4-dihdroxy-6-[18F]fluorophenyl-L-alanine (FDOPA) PET scans were carried out on 20 male patients with ADHD and 18 healthy men. Eight ADHD patients had never been treated with psychostimulants, the rest had received MP. Based on the tissue-slope-intercept plot parametric images of FDOPA influx rate constant (Ki) were generated for each subject from dynamic 3D FDOPA datasets and transformed into standard stereotactic space. First a volume of interest analysis was performed on each single subject. In a second step data were introduced to a SPM2 analysis to detect significant changes in mean voxel Ki values between the normal control group and each patient group. In comparison to controls, ADHD patients as a group (irrespective of treatment status) showed a lower Ki in bilateral putamen, amygdala and dorsal midbrain. There was a lower Ki in the left putamen, right amygdala and right dorsal midbrain in untreated patients compared to controls together with a relative higher influx in the left amygdala and right anterior cingulate cortex. In contrast, methylphenidate treatment was associated with a significantly lower Ki in the striatum and amygdala bilaterally, and in the right dorsal midbrain. Untreated young adult ADHD patients showed a dopamine dysfunction that might be partly due to compensatory mechanisms. MP seems to down-regulate dopamine turnover. This effect might be one component in the mechanism of action of this drug in ADHD treatment.

Atomoxetine acts as an NMDA receptor blocker in clinically relevant concentrations

Background and purpose:  There is increasing evidence that not only the monoaminergic but also the glutamatergic system is involved in the pathophysiology of attention‐deficit hyperactivity disorder (ADHD). Hyperactivity of glutamate metabolism might be causally related to a hypoactive state in the dopaminergic system. Atomoxetine, a selective noradrenaline reuptake inhibitor, is the first non‐stimulant approved for the treatment of this disorder. Here we have evaluated the effects of atomoxetine on glutamate receptors in vitro.

Are amygdalar volume alterations in children with Tourette syndrome due to ADHD comorbidity

Recent studies have shown that changes in the basal ganglia circuitry and limbic loops may play an important role both in Tourette syndrome (TS) and attention‐deficit–hyperactivity disorder (ADHD). This study aimed to investigate in vivo possible morphological alterations of the amygdala as a key component of the limbic system. Amygdalar and total brain volumes were measured in three‐dimensional magnetic resonance imaging data sets of 17 male patients with TS (mean age 11y 8mo [SD 2y]; range 9–16y) and 17 age‐matched comparison children (mean age 12y 6mo (SD 2y 1mo); range 9–17y) by volume‐of‐interest‐based volumetry. Eight members of the TS group also fulfilled the diagnostic criteria for ADHD. A significant decrease in the left‐hemispheric amygdalar volumes and in the proportions of amygdalar to total brain volumes was observed in members of the TS group compared with the comparison group. Amygdalar volumes did not correlate with tic severity, but with behavioural impairment and especially with symptoms of ADHD. The amygdalar volume reduction might be the pathoanatomical correlate of an impaired input of the amygdala to the striatum and frontal cortex. Future studies should investigate if the involvement of the amygdala is due to TS or rather caused by the genetically‐linked most frequent comorbidity ADHD.

Prone to excitement: Adolescent females with non-suicidal self-injury (NSSI) show altered cortical pattern to emotional and NSS-related material

Emotion-regulation difficulties have been identified as one of the core components in Non-suicidal self-injury (NSSI), a behaviour often beginning in adolescence. This pilot study evaluated differences in emotion processing between 18 female adolescents with and without NSSI by using verbal responses and functional magnetic resonance imaging (fMRI). Responses to pictures taken from the International Affective Picture System and slides with reference to NSSI were recorded both by verbal rating of valence and arousal and by fMRI. The NSSI group rated pictures with self-injurious reference as significantly more arousing than controls. For emotional pictures, the NSSI group showed a significantly stronger brain response in the amygdala, hippocampus and anterior cingulate cortex bilaterally. Depression explained differences between groups in the limbic area. Furthermore, the NSSI group also showed increased activity in the middle orbitofrontal cortex, and inferior and middle frontal cortex when viewing NSSI picture material. Participants with NSSI showed decreased activity in correlation to arousal in the occipital cortex and to valence in inferior frontal cortex when watching emotional pictures. The fMRI data support the notion that individuals with NSSI show an altered neural pattern for emotional and NSSI pictures. Behavioural data highlight proneness to excitement regarding NSSI topics. This fMRI study provides evidence for emotion-regulation deficits in the developing brain of adolescents with NSSI.

‘‘Stop Cutting—Rock!’’: A Pilot Study of a Music Therapeutic Program for Self-Injuring Adolescents

Abstract Music and Medicine 2(1) 59-65 a The Author(s) 2010 Reprints and permission: http://www. sagepub.com/journalsPermissions.nav DOI: 10.1177/1943862109356928 http://mmd.sagepub.com Nonsuicidal self-injury (NSSI) is a common phenomenon in adolescence. This pilot study blended elements of dialectical behavior therapy for adolescents (DBT-A) with music therapy to reduce NSSI in a project for self-injuring female adolescents (N 1⁄4 5; mean age: 14 years 8 months; age range: 14-16 years). Four out of the 5 female adolescents had stopped self-injuring at the end of the program, and the depression score declined. The program proved to be a feasible alternative in an outpatient setting, although severe suicidal ideation presented as a problem. Blending different therapeutic approaches might be an interesting way to tailor effective treatments for specific patient groups. Keywords nonsuicidal self-injury (NSSI), self-harm, music therapy, dialectical behavior therapy for adolescents (DBT-A), adolescents

atomoxetine affects transcription/translation of the nMDa receptor and the norepinephrine transporter in the rat brain - an in vivo study

Attention-deficit/hyperactivity disorder (ADHD) is the most frequently diagnosed neurodevelopmental disorder. The norepinephrine transporter (NET) inhibitor atomoxetine, the first nonstimulant drug licensed for ADHD treatment, also acts as an N-methyl-D-aspartate receptor (NMDAR) antagonist. The compound’s effects on gene expression and protein levels of NET and NMDAR subunits (1, 2A, and 2B) are unknown. Therefore, adolescent Sprague Dawley rats were treated with atomoxetine (3 mg/kg, intraperitoneal injection [ip]) or saline (0.9%, ip) for 21 consecutive days on postnatal days (PND) 21–41. In humans, atomoxetine’s earliest clinical therapeutic effects emerge after 2–3 weeks. Material from prefrontal cortex, striatum (STR), mesencephalon (MES), and hippocampus (HC) was analyzed either directly after treatment (PND 42) or 2 months after termination of treatment (PND 101) to assess the compound’s long-term effects. In rat brains analyzed immediately after treatment, protein analysis exhibited decreased levels of the NET in HC, and NMDAR subunit 2B in both STR and HC; the transcript levels were unaltered. In rat brains probed 2 months after final atomoxetine exposure, messenger RNA analysis also revealed significantly reduced levels of genes coding for NMDAR subunits in MES and STR. NMDAR protein levels were reduced in STR and HC. Furthermore, the levels of two SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) proteins, synaptophysin and synaptosomal-associated protein 25, were also significantly altered in both treatment groups. This in vivo study detected atomoxetine’s effects beyond NET inhibition. Taken together, these data reveal that atomoxetine seems to decrease glutamatergic transmission in a brain region-specific manner. Long-term data show that the compound’s impact is not due to an acute pharmacological effect but lasts or even amplifies after a drug-free period of 2 months, leading to altered development of synaptic composition. These alterations might contribute to atomoxetine’s clinical effects in the treatment of ADHD, a neurodevelopmental disorder in which synaptic processes and especially a dysregulated glutamatergic metabolism seem to be involved.

Methylphenidate exerts no neurotoxic, but neuroprotective effects in vitro

Summary.Methylphenidate (MPH) is the most common used drug in child and adolescent psychiatry. Despite of this fact, however, little is known about its exact pharmacological mechanisms.Here we investigated the toxic effects of MPH in vitro in human embryonic kidney (HEK-293) cells stably expressing the human dopamine transporter (HEK-hDAT cells) and in cultured rat embryonic (E14.5) mesencephalic cultures. MPH alone (up to 1 mM) affected neither the growth of HEK-hDAT cells nor the survival of dopaminergic (DA) neurons in primary cultures after treatment up to 72 h. No differences in neuronal arborisation or in the density of synapses were detected. 1-methyl-4-phenylpyridinium (MPP+) showed no toxic effect in HEK-293 cells, but had significant toxic effects in HEK-hDAT cells and DA neurons. MPH (1 µM – 1 mM) dose-dependently reduced this cytotoxicity in HEK-hDAT cells and primary mesencephalic DA neurons.The presented results show that application of MPH alone does not have any toxic effect on DA cells in vitro. The neurotoxic effects of MPP+ could be significantly reduced by co-application of MPH, an effect that is most likely explained by MPH blocking the DAT.

Tourette Syndrome and Other Tic Disorders in Childhood, Adolescence and Adulthood

BACKGROUND Tourette syndrome is a combined motor and vocal tic disorder that begins in childhood and takes a chronic course. It arises in about 1% of all children, with highly varying severity. Transient and usually mild tics are seen in as many as 15% of all children in elementary school. The diagnosis is often delayed by several years. METHODS We selectively reviewed the pertinent literature, including the guidelines of the European Society for the Study of Tourette Syndrome for the diagnosis and treatment of tic disorders. RESULTS Tic disorders usually take a benign course, with spontaneous improvement in adolescence in about 90% of patients. Psychoeducation is the basis of treatment in each case and almost always brings marked emotional relief. Specific treatment is needed only for more severe tics and those that cause evident psychosocial impairment. 80-90% of patients with Tourette syndrome have comorbidities (attention deficit-hyperactivity disorder, obsessive-compulsive disorder, depression, anxiety, emotional dysregulation, autoaggression), which often impair their quality of life more than the tics do and therefore become the main target of treatment. There is little evidence for the efficacy of treatment for tics. Small-scale controlled studies with a brief follow-up period have been carried out for some neuroleptic drugs. Behavior therapy should be tried before drug treatment. A further option for very severely affected adults is deep brain stimulation. CONCLUSION Because of the low level of the available evidence, no definitive recommendations can be made for the treatment of tics.