Current pharmacotherapeutic approaches for the treatment of Tourette syndrome.

Tourette syndrome is a childhood onset neurodevelopmental disorder characterized by multiple motor and vocal tics. Although many youth experience attenuation or even remission of tics in adolescence and young adulthood, some individuals experience persistent tics which can be debilitating or disabling. The majority of patients also have one or more psychiatric comorbid disorders, such as attention deficit hyperactivity disorder and/or obsessive-compulsive disorder. Treatment is multimodal, including both pharmacotherapy and cognitive behavioral treatment, and requires disentanglement of tics and the comorbid symptoms. Although the only two formally approved medications in the United States are haloperidol and pimozide, these treatments are generally not used as first-line interventions due to their significant potential for adverse effects. The α-adrenoceptor agonists guanfacine and clonidine have an established evidence base for both efficacy and tolerability, and are usually recommended as initial pharmacotherapy. Atypical neuroleptics, such as aripiprazole or risperidone, are typically used if the α-adrenoceptor agonists are ineffective or intolerable. However, many other pharmacological agents reviewed in this manuscript have been studied as treatment alternatives.

Atomoxetine treatment in children and adolescents with ADHD and comorbid tic disorders.

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 tolerated.

Probing striato-thalamic function in obsessive-compulsive disorder and Tourette syndrome using neuroimaging methods.

In summary, contemporary pathophysiological models of OCD and related disorders implicate CSTC circuitry. In this chapter, we have reviewed relevant concepts related to implicit learning and more specifically, the use of an implicit sequence learning paradigm as a probe of striato-thalamic function. An initial PET investigation of patients with OCD confirmed a priori hypotheses of failure to recruit right striatum, despite the absence of a performance deficit (22). A modified version of the SRT was studied in conjunction with fMRI and yielded reliable right-lateralized striatal activation in a cohort of 10 male subjects, with clear spatial dissociation of caudate and putamen activation foci (119). Subsequent studies in our laboratory suggest that this paradigm also yields a reliable temporal window of thalamic deactivation, and hence a means for assessing thalamic gating in human subjects (120). Finally, as presented in this chapter, preliminary data from the fMRI-SRT in patients with OCD and TS as well as normal control subjects appear to replicate and extend the findings from our original PET-SRT study in OCD. Future investigations in our laboratory will seek to elaborate upon these preliminary results. In particular, we intend to study psychiatric comparison groups to establish the generalizability and/or specificity of these findings across disorders. Within OCD, we hope to explore the relationship between abnormal brain-activation patterns and symptom dimensions (34). Further, by studying subjects with remitted OCD who have been successfully treated, we hope to determine whether the observed brain-activation abnormalities represent state or trait markers. Finally, we have already begun to test a hypothesis of parallel processing deficiency in OCD by using a dual-task version of the SRT that makes simultaneous demands on implicit and explicit information processing systems (128). It is our hope that this program of research will yield new insights about OCD and related disorders, including TS. Most importantly, as other teams of investigators pursue complementary lines of inquiry, it is our wish that collective efforts in this field will lead to improved diagnosis and treatment, if not cure or prevention, for those who are afflicted with these illnesses.

Developmental aspects of obsessive compulsive disorder: findings in children, adolescents, and adults.

Although juvenile obsessive compulsive disorder (OCD) is increasingly recognized as a putative developmental subtype of the disorder, comparisons among children, adolescents, and adults with OCD have been lacking. We aimed to evaluate clinical correlates of OCD in three developmentally distinct groups. Subjects comprised children, adolescents, and adults meeting DSM-III-R and DSM-IV criteria for OCD referred to separate specialized OCD clinics. All subjects were systematically evaluated with structured diagnostic interviews and clinical assessments by OCD experts. Specific clinical correlates and symptom profiles were associated with the disorder in different age groups. These findings support a hypothesis of developmental discontinuity between juvenile and adult OCD and identify age specific correlates of the disorder across the life cycle. Further work is needed to validate whether juvenile-onset OCD represents a true developmental subtype of the disorder.

Disentangling chronological age from age of onset in children and adolescents with obsessive--compulsive disorder.

Although paediatric obsessive--compulsive disorder (OCD) is increasingly recognized as a putative developmental subtype of the disorder, it remains uncertain as to whether additional subtyping by age at onset in childhood or adolescence is warranted. Subjects included children and adolescents meeting DSM-III-R and DSM-IV criteria for OCD referred to a specialized OCD clinic. All youth were systematically evaluated with structured diagnostic interviews and clinical assessment by an OCD expert. Irrespective of current age, an earlier age at onset predicted increased risk for attention deficit hyperactivity disorder, simple phobia, agoraphobia and multiple anxiety disorders. In contrast, mood and psychotic disorders were associated with chronological age and were more prevalent in older subjects. Tourette's disorder showed associations with both chronological age and age at onset. Chronological age and age at onset predicted different patterns of comorbidity and dysfunction in children and adolescents with OCD. Considering the heterogeneity of OCD, age at onset may help identify meaningful developmental subtypes of the disorder beyond chronological age.

Stability of atmospheric CO2 levels across the Triassic/Jurassic boundary.

The Triassic/Jurassic boundary, 208 million years ago, is associated with widespread extinctions in both the marine and terrestrial biota. The cause of these extinctions has been widely attributed to the eruption of flood basalts of the Central Atlantic Magmatic Province. This volcanic event is thought to have released significant amounts of CO2 into the atmosphere, which could have led to catastrophic greenhouse warming, but the evidence for CO2-induced extinction remains equivocal. Here we present the carbon isotope compositions of pedogenic calcite from palaeosol formations, spanning a 20-Myr period across the Triassic/Jurassic boundary. Using a standard diffusion model, we interpret these isotopic data to represent a rise in atmospheric CO2 concentrations of about 250 p.p.m. across the boundary, as compared with previous estimates of a 2,000-4,000 p.p.m. increase. The relative stability of atmospheric CO2 across this boundary suggests that environmental degradation and extinctions during the Early Jurassic were not caused by volcanic outgassing of CO2. Other volcanic effects-such as the release of atmospheric aerosols or tectonically driven sea-level change-may have been responsible for this event.

Impact of tic disorders on ADHD outcome across the life cycle: findings from a large group of adults with and without ADHD.

OBJECTIVE: The impact of tic disorders on the outcome of attention deficit hyperactivity disorder (ADHD) remains a subject of high scientific and clinical interest. To evaluate the impact of comorbid ADHD and tic disorders from a lifespan perspective, the authors systematically examined data from adults with and without ADHD. METHOD: They comprehensively evaluated 312 consecutively referred adults with ADHD and 252 comparison subjects without ADHD. Tic disorders were characterized along with a wide range of neuropsychiatric correlates, including other comorbid disorders as well as indexes of function in the domains of school, cognition, and interpersonal functioning. RESULTS: A significantly greater proportion of adults with ADHD (12%) than those without ADHD (4%) had tic disorders. Tic disorders followed a mostly remitting course and had little impact on functional capacities. In addition, tic disorders were not associated with stimulant use. CONCLUSIONS: These findings in adults with ADHD confirm and extend previous findings in young subjects with ADHD, documenting that although individuals with ADHD are at greater risk for tic disorders, the presence of tic disorders has a limited impact on ADHD outcome.

The course of Tourette's disorder: a literature review.

With the goal of evaluating the available literature on the course of Tourette's disorder, we conducted a systematic literature search through electronic databases for pertinent scientific articles in English with a minimum of 20 subjects. We also examined bibliographies of papers identified in this manner for additional sources. We found only 16 articles; most consisted of retrospective reports on treated samples. Overall, the available literature suggests that Tourette's disorder follows a remitting course in a sizeable number of individuals. Little has been published regarding predictors of remission or persistence. More work is needed using longitudinal prospective studies to better define the course and outcome of Tourette's disorder.

Informativeness of structured diagnostic interviews in the identification of Tourette's disorder in referred youth.

Although specialized programs have greatly advanced the treatment of youth with Tourette's disorder (TD), not all children with TD reach such programs, raising questions as to whether TD is adequately identified outside specialized settings. There is thus a need for evidence that cases identified in the nonspecialty setting are "true cases." Because structured diagnostic interview methodology can reduce errors of omission, this approach can facilitate the identification of TD in referred youth outside specialized programs. Similarities between cases ascertained in specialty and nonspecialty settings would suggest that those identified in the nonspecialty setting were indeed "true cases." Comparisons were made between youth with TD ascertained through a specialized TD program who had both a structured diagnostic interview-derived diagnosis of TD plus an expert evaluation of TD (N = 103), with youth ascertained through a non-TD specialized pediatric psychopharmacology program who had a structured diagnostic interview-derived diagnosis of TD (N = 92). Irrespective of ascertainment source, children with structured interview-derived diagnosis of TD shared similar correlates in terms of tic severity, mean age of onset and duration of tics, as well as patterns of comorbidity well known to be associated with TD in clinical samples. Children meeting diagnostic criteria for TD on structured diagnostic interviews share similarities and patterns of clinical correlates, irrespective of ascertainment through a specialized TD or non-TD specialized clinic. These findings support the usefulness of structured diagnostic interview methodology as a diagnostic aid for the identification of TD in non-TD specialized settings and facilitate delineation of patterns of comorbidity.

Clinical correlates of obsessive compulsive disorder in children and adolescents referred to specialized and non-specialized clinical settings.

The objective of this study was to assess the extent of referral bias by comparing children and adolescents with Obsessive Compulsive Disorder (OCD) ascertained through a specialized pediatric OCD and a general child psychiatry clinic. Subjects were juveniles meeting DSM-III-R and DSM IV criteria for OCD referred to a general pediatric psychopharmacology clinic and to a specialized OCD clinic within the same academic medical center. Subjects were evaluated clinically and with structured diagnostic interviews using the Kiddie SADS-E. OCD was identified in 8.6% of the general psychiatry clinic subjects. The only differences between ascertainment sources in clinical or sociodemographic characteristics of OCD subjects were higher rates of social phobia and ADHD in the non-specialized clinic, while specialty clinic subjects had a greater lifetime severity of OCD and were more likely to have received treatment of their OCD. Because we found limited evidence for referral biases, our results suggest that findings from studies using either of these sources may generalize to the other. It also suggests that pooling subjects from the two sources is justified. Nevertheless, because some group differences did emerge, researchers should acknowledge referral bias as a potential limitation of their work.

Distinguishing illness severity from tic severity in children and adolescents with Tourette's disorder.

OBJECTIVE: To examine whether tic severity, comorbid disorders, or both are associated with illness morbidity in youths with Tourette's disorder (TD). METHOD: Subjects were 156 consecutively referred youths (aged 5-20 years) who met DSM-III-R criteria for Tourette's disorder at a major academic medical center. All subjects were evaluated with a clinical interview by a child and adolescent psychiatrist and an assessment battery that included the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Epidemiologic version. Statistical analysis used chi 2 and multivariate logistic regression. RESULTS: Nineteen (12%) of the 156 youths with TD required psychiatric hospitalization. Current age, TD severity, TD duration, obsessive-compulsive disorder, psychosis, major depression, bipolar disorder, panic disorder, and overanxious disorder were significant univariate predictors of psychiatric hospitalization (p < .01). While tic severity was marginally significant as a predictor of psychiatric hospitalization (p < .05), major depression (p < .016) and bipolar disorder (p < .001) were robust predictors of psychiatric hospitalization, even after statistical adjustment for collinearity and correction for all other variables assessed. CONCLUSION: The findings indicate that comorbid mood disorders are strongly associated with illness morbidity in youths with TD, highlighting the importance of attention to comorbidity in patients with TD.

Anxiety disorders and tic severity in juveniles with Tourette's disorder.

OBJECTIVE: It was hypothesized that comorbidity with anxiety disorders would predict tic severity in youths with Tourette's disorder (TD). METHOD: Subjects were 190 youths meeting DSM-III-R diagnostic criteria for TD who were consecutively referred to a pediatric psychopharmacology program between 1994 and 1997. Subjects were initially evaluated with a clinical interview and the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Epidemiologic version. Statistical analysis used t tests, chi 2 tests, and logistic regression analysis. RESULTS: One hundred thirty-four subjects were classified as mild/moderate and 56 as severe TD cases. No meaningful differences were found in socioeconomic status, gender distribution, or age at onset of TD between the 2 groups. The 2 groups could not be differentiated by the presence of comorbid mood or disruptive behavior disorders including attention-deficit hyperactivity disorder. Although obsessive-compulsive disorder (OCD) was overrepresented among the severe TD cases, the difference failed to reach statistical significance. Excluding social and simple phobias, all other anxiety disorders were more clearly overrepresented among subjects with severe TD; separation anxiety disorder most robustly predicted tic severity, irrespective of the presence of OCD or other anxiety disorders. CONCLUSION: Findings suggest that non-OCD anxiety disorders in general and separation anxiety disorder in particular may be significantly associated with tic severity in referred TD patients.

Sensory phenomena in obsessive-compulsive disorder and Tourette's disorder.

BACKGROUND: Recent studies have suggested that obsessive-compulsive disorder (OCD) is a heterogeneous disorder with some forms related to tics and Tourette's disorder. The present study was undertaken to investigate the sensory phenomena in patients with OCD and/or Tourette's disorder to determine if these phenotypic features represent valid clinical indices for differentiating tic-related OCD from non-tic-related OCD. METHOD: We evaluated 20 adult outpatients with OCD, 20 with OCD plus Tourette's disorder, and 21 with Tourette's disorder, using a semistructured interview designed to assess several definitions of sensory phenomena reported in the literature. DSM-III-R criteria were used for the OCD and Tourette's disorder diagnoses. RESULTS: Sensory phenomena including bodily sensations, mental urges, and a sense of inner tension were significantly more frequent in the 2 Tourette's disorder groups when compared with the OCD alone group. Feelings of incompleteness and a need for things to be "just right" were reported more frequently in the OCD plus Tourette's disorder group compared with the other 2 groups. CONCLUSION: Sensory phenomena may be an important phenotypic measure for grouping patients along the OCD-Tourette's disorder spectrum. Sensory phenomena include bodily and mental sensations. Bodily sensations include focal or generalized body sensations (usually tactile, muscular-skeletal/visceral, or both) occurring either before or during the patient's performance of the repetitive behaviors. These sensations are more frequently found in patients with OCD plus Tourette's disorder than in patients with OCD alone. Mental sensations include urge only, energy release (mental energy that builds up and needs to be discharged), incompleteness, and just-right perceptions. They are all more frequently found in patients with OCD plus Tourette's disorder than in patients with OCD alone.

Comparisons of eye movements before and after a speed-reading course.

BACKGROUND: The techniques of speed reading are widely used and generally accepted, but few studies have investigated whether- and how-speed reading actually improves reading ability in the typical reader. METHODS: Using the Ober2, an infrared monitoring device that accurately tracks eye movements, we measured the eye movements of 59 students. The Ober2 calculates reading speed, number of fixations per 100 words, number of words seen in each fixation, number of regressions per 100 words, and duration of fixation. Comprehension was assessed with ten detailed true or false questions. RESULTS: One group of the students (n = 25) participated in a speed reading class; the other group (n = 34) did not. After completion of the course, all 59 were re-measured on the Ober2. The speed-reading group improved significantly in five of the six aspects tested. Comprehension for the speed reading group showed an insignificant decrease. CONCLUSIONS: We conclude that measurable changes in reading eye movements accompany successful completion of a speed-reading course.

Hospital executives and ethics committees: an effective collaboration.

Should hospital and healthcare executives participate on their organization's ethics committee? This question becomes more relevant in the current healthcare environment as nurses and physicians assume more managerial responsibilities. This article reviews functions of the ethics committee and discusses moral, conceptual, and practical issues surrounding managerial participation on these committees. The authors conclude that executive management's participation on ethics committees is both appropriate and necessary in the current healthcare environment.

The 4-year course of tic disorders in boys with attention-deficit/hyperactivity disorder.

BACKGROUND: Despite long-standing clinical concerns, relatively little is known about the comorbidity between attention-deficit/hyperactivity disorder (ADHD) and tic disorders. Therefore, we examined tic disorders in an ongoing prospective follow-up study of male subjects with ADHD, a sample unselected for any comorbid disorder. METHODS: One hundred twenty-eight male children and adolescents with ADHD and 110 male controls were comprehensively evaluated at baseline and 4 years later. We characterized tic disorders along with a wide range of neuropsychiatric correlates, including other comorbid disorders and indices of psychosocial function in multiple domains (school, cognitive, social, and family). RESULTS: Compared with controls, subjects with ADHD showed more tic disorders at baseline and more new onsets were reported at follow-up. Attention-deficit/hyperactivity disorder and tic disorders appeared to be independent in course: in contrast to low rates of ADHD remission, tic disorders mostly remitted. The age-adjusted rate of ADHD remission was 20% and that of tic remission, 65%. Tic disorders had little effect on the psychosocial functioning of subjects with ADHD. CONCLUSIONS: These findings suggest that comorbidity with a tic disorder has a limited effect on ADHD outcome. However, because of the relatively small sample of subjects with tic disorders, our conclusions should be considered preliminary until confirmed in larger studies of medicated and unmedicated children with ADHD with and without tic disorders.

Disentangling the overlap between Tourette's disorder and ADHD.

OBJECTIVE: To identify similarities and differences in neuropsychiatric correlates in children with Tourette's syndrome (TS) and those with ADHD. METHOD: The sample consisted of children with Tourette's syndrome with ADHD (N = 79), children with Tourette's syndrome without ADHD (N = 18), children with ADHD (N = 563), psychiatrically referred children (N = 212), and healthy controls (N = 140). RESULTS: Disorders specifically associated with Tourette's syndrome were obsessive compulsive disorder (OCD) and simple phobias. Rates of other disorders, including other disruptive behavioral, mood, and anxiety disorders, neuropsychologic correlates, and social and school functioning were indistinguishable in children with Tourette's and ADHD. However, children with Tourette's syndrome plus ADHD had more additional comorbid disorders overall and lower psychosocial function than children with ADHD. CONCLUSIONS: These findings confirm previously noted associations between Tourette's syndrome and OCD but suggest that disruptive behavioral, mood, and anxiety disorders as well as cognitive dysfunctions may be accounted for by comorbidity with ADHD. However, Tourette's syndrome plus ADHD appears to be a more severe condition than ADHD alone.

Tourette's disorder with and without obsessive-compulsive disorder in adults: are they different?

Clinical research has documented a bidirectional overlap between Tourette's disorder (TD) and obsessive-compulsive disorder (OCD) from familial-genetic, phenomenological, comorbidity, and natural history perspectives. Patients with Tourette's disorder plus obsessive-compulsive disorder (TD + OCD), a putative subtype, share features of both. The purpose of this exploratory study was to evaluate correlates of patients with TD, OCD, and TD + OCD to determine whether TD + OCD is a subtype of TD, OCD, or an additive form of both. Sixty-one subjects with TD, OCD, or TD + OCD were evaluated with the Structured Clinical Interview for DSM-III-R supplemented with additional modules. The three groups differed in the rates of bipolar disorder (p < .04), social phobia (p < .02), body dysmorphic disorder (p < .002), attention deficit hyperactivity disorder (p < .03), and substance use disorders (p < .04). These findings were accounted for by the elevated rates of the disorders in the TD + OCD group compared with the TD and OCD groups. These finding are most consistent with the hypothesis that TD + OCD is a more severe disorder than TD and OCD and may be more etiologically linked to TD than to OCD. These findings highlight the importance of assessment of the full spectrum of psychiatric comorbidity in patients with TD and OCD.