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Contents:
Tourette syndrome: prediction of phenotypic variation in monozygotic twins by caudate nucleus D2 receptor binding
Wolf SS, Jones DW, Knable MB, Gorey JG, Lee KS, Hyde TM, Coppola R, Weinberger DR: Science, August 30, 1996; 273:1225-1227wedo SE, Leonard HL, Kiessling LS: Pediatrics 1994; 93:323-326
Abstract: Tourette syndrome, a chronic tic disorder with autosomal dominant inheritance, exhibits considerable phenotypic variability even within monozygotic twin pairs. The origins of this variability remain unclear. Recent findings have implicated the caudate nucleus as a locus of pathology, and pharmacological evidence supports dopaminergic involvement. Within monozygotic twins discordant for Tourette syndrome severity, differences in D2 dopamine receptor binding in the head of the caudate nucleus predicted differences in phenotypic severity (r = 0.99); this relation was not observed in putamen. These data may link Tourette syndrome with a spectrum of neuropsychiatric disorders that involve associative striatal circuitry.
Malison RT, McDougle CJ, van Dyck CH, Scahill L, Baldwin RM, Seibyl JP, Price LH, Leckman JF, Innis RB: Am J Psychiatry 1995; 152:1359-1361
Abstract: Objective: The authors examined whether subjects with Tourette's disorder have greater than normal striatal dopamine transporter densities, as suggested by previous post-mortem findings. Method: Single photon emission computed tomography (SPECT) and [123-I]2beta-carbomethoxy-3b-(4-iodophenyl)tropane([123-I]beta-CIT) were used to assess dopamine transporter levels in five adult patients with Tourette's disorder and five age- and gender-matched healthy comparison subjects. Results: Striatal ([123--I]beta-CIT binding was a mean of 37% (range = 6%-79%) higher in the subjects with Tourette's disorder than in the comparison subjects, and each Tourette's disorder patient had a higher level than his or her paired comparison subject. Conclusions: These findings corroborate post-mortem results and support the hypothesis of a dysregulation in presynaptic dopamine function in Tourette's disorder.
Ever since the clinical observation that tics can be successfully suppressed by neuroleptic drugs such as haloperidol, dopaminergic systems have been presumed to play a central role in the pathogenesis of TS. Accumulated evidence suggests that tics are caused by failed inhibition in cortical-thalamic-striatal circuits. Recent structural imaging studies and a postmortem study implicate the basal ganglia as the likely anatomical site for this dysregulation.1,2,3 These two SPECT studies examined receptor binding in striatal dopamine pathways. Although the findings are not entirely consistent, both studies point to dysregulation in dopaminergic striatal circuits.
The study by Malison et al compared the level of dopamine transporter in the caudate and putamen of 5 adults with TS to that of 5 healthy controls. The finding of increased levels of dopamine transporter in the caudate suggests an abnormality in presynaptic dopamine function. By contrast, the study by Wolf et al examined postsynaptic receptor density in the striatum. The subjects were 5 pairs of monozygotic twins discordant for tic symptom severity. Postsynaptic dopamine receptor binding by iodobenzamide was greater in the five more severely affected twins. This finding was statistically significant in the caudate, but not in the putamen. In conclusion, though preliminary, both studies implicate the caudate nucleus in the pathophysiology of TS.
References: 1. Peterson SB, Riddle MA, Cohen DJ, et al: Reduced basal ganglia volumes in Tourette's syndrome, using 3-dimensional reconstruction techniques from MRIs. Neurology 1993; 43:941-949. 2. Singer HS, Reiss AL, Brown JE, et al: Volumetric MRI changes in basal ganglia of children with Tourette's syndrome. Neurology 1993; 43:950-956. 3. Singer HS, Hahn IH, Moran TH: Abnormal dopamine uptake sites in postmortem striatum from patients with Tourette's syndrome. Ann Neurol 1991; 30:558-562.
Hunt RD, Arnsten AFT Asbell MD: J Am Acad Child Adolesc Psychiatry 1995; 34:50-54
Abstract: Objective: Medications such as clonidine have been shown to facilitate calming, to enhance frustration tolerance, and to reduce aggression in hyperactive children. The use of guanfacine (Tenex), an Alpha2 noradrenergic agonist similar to clonidine, was studied as an alternative because of its longer excretion half-life, decreased sedative side effects, and more selective binding profile. Method: Thirteen psychiatric outpatients diagnosed with ADHD were rated at baseline and while taking guanfacine to determine its efficacy as a treatment for ADHD. Comparisons of Conners parent ratings within subject were used to measure behavioral changes in the subjects. Results: During guanfacine treatment, patients' mean scores improved significantly overall (1.27 off, 0.85 on, t = 2.55, p < .015) and in Conners Hyperactivity (1.63 off, 0.94 on, t = 3.69, p < .01), Inattention (1.92 off, 1.21 on, t = 3.32, p < .01), and Immaturity (1.81 off, 0.92 on, t = 3.77, p < .01) factors. Conclusions: This preliminary study indicates that guanfacine is a beneficial and useful treatment of ADHD, reducing hyperactive behaviors and enabling greater attentional ability with minimal side effects. We are currently collecting data in a double-blind study measuring guanfacine's efficacy with and in comparison to methylphenidate.
Bruun RD, Budman CL: J Clin Psychiatry 1996; 57:29-31
Abstract: Background: An open-label trial was performed to assess the efficacy and safety of risperidone, a benzisoxazole derivative with potent D2 and 5-HT2 antagonism, for treatment of Tourette's syndrome. Method: Thirty-eight patients with Tourette's syndrome volunteered to take risperidone for treatment of their tics. All patients had failed to respond adequately to conventional treatments (with neuroleptics such as haloperidol and/or with the a2-adrenergic agonist clonidine) or had suffered from intolerable side effects from such treatments. Patients were rated for tic severity by the Yale Global Tic Severity Scale (YGTSS) before treatment and after 1 month of treatment with risperidone. Patients were monitored carefully for side effects and clinical response. Results: Of the 38 patients, 8 discontinued risperidone treatment before the end of the trial because of intolerable side effects. At the end of the 4-week trial, 22 patients (58%) were improved, 7 patients (18%) had no appreciable change in their symptoms, and 1 patient (3%) had a documented worsening of tics. Doses of risperidone at the end of the trial ranged from 0.5 mg to 9 mg/day (mean = 2.7 mg/day). Conclusion: This open clinical trial suggests that risperidone may be a promising alternative to conventional medications used for treating the symptoms of Tourette's syndrome. Risperidone is one of a new class of neuroleptics that also includes clozapine and two newer compounds such as ziprasidone(1) and olanzapine.(2) These drugs can be distinguished from standard neuroleptics because they contain both serotonin and dopamine blocking properties. Within this group of new neuroleptics, there are differences in the ratio of serotonin and dopamine antagonism. For example, ziprasidone has a greater serotonin to dopamine receptor affinity ratio than risperidone. The importance of these differences with respect to efficacy in the treatment of schizophrenia or TS is unclear at the present time.
Collectively, these open-label studies with risperidone have treated 50 to 60 patients with TS. Although preliminary, they provide promising results for the treatment of tics with minimal side effects. Adverse effects reported in these studies include weight gain, transient sedation, akathisia and, occasionally, dystonic reactions.
References: 1. Seeger TF, Seymour PA, Schmidt AW, et al: Ziprasidone (CP-88,059): A new antipsychotic with combined dopamine and serotonin receptor antagonist activity. J Pharm Exper Therapuetics 1995; 275:101-113. 2. Borison RL: Clinical efficacy of serotonin-dopamine antagonists relative to classic neuroleptics. J Clin Psychopharm 1995; 15(S1):24S-29S.
March JS: J Am Acad Child Adolesc Psychiatry 1995; 34:7-18
Abstract: Objective: To critically review the published literature on cognitive-behavioral psychotherapy for obsessive- compulsive disorder (OCD) in children and adolescents. Method: The psychiatric and psychological literature was systematically searched for "studies" applying cognitive-behavioral principles to children and adolescents with OCD. Results: Thirty-two investigations, most of them single case reports, were identified. Despite manifold differences in terminology and theoretical framework, all but one showed some benefit for cognitive-behavioral interventions. Graded exposure and response prevention form the core of treatment; anxiety management training and OCD-specific family interventions may play an adjunctive role. Poor compliance, inadequately documented and inconsistently applied treatment, and lack of exportability were recurrent problems. Conclusions: Abundant clinical and emerging empirical evidence suggest that cognitive-behavioral psychotherapy, alone or in combination with pharmacotherapy, is an effective treatment for OCD in children and adolescents. Future research in this area will need to focus on comparisons of cognitive-behavioral psychotherapy to other treatments, on component analyses, and on the application of exportable protocol-driven treatments to divergent patient populations. This is a comprehensive review of available case reports and the case series using cognitive-behavioral therapy in children and adolescents. As with adult studies, successful behavioral therapy relies on exposure and response prevention. The author notes the difficulties in applying these techniques to children and adolescents.
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