Atualização de agosto de 2010

1. The Shape of Things to Come in Attention Deficit Hyperactivity Disorder

Philip Shaw, M.D.,

Am J Psychiatry 167:363-365, April 2010

The search for a neuroanatomic signature of attention deficit hyperactivity disorder (ADHD) has already yielded important findings. At a lobar level, there is volume loss of around 3%–4% , and techniques that allow a finer level of spatial resolution—such as measures of gray matter density or thickness—demonstrate marked compromise of the prefrontal cortex and interconnected striatum. Such work is reliant on advances in analytic techniques, and as the study by Ivanov and colleagues in this issue elegantly demonstrates, a potentially powerful new tool lies in the delineation of shape anomalies in key brain structures.
The study focused on the thalamus, within which different nuclei interact richly and often reciprocally with both the striatum and the cortex, forming partially segregated loops that support cognitive processes as diverse as motor control and the allocation of attentional resources. The possibility that structural anomalies of the thalamus could disrupt these circuits and lead to the cardinal symptoms of ADHD has largely been unexplored. This reflects the difficulty in reliably defining the volume of different thalamic nuclei using conventional structural MRI scans, and thus in most studies the thalamus has been treated as a unitary structure, possibly missing localized compromise of one of its composite nuclei. The study by Ivanov and colleagues rectifies this neglect by first extracting the surface contours of the thalamus from structural MRI scans of 46 youths with ADHD and 59 typically developing comparison youths. Then the degree to which each thalamic surface had to be stretched or shrunk (warped) to fit a template of the thalamus was determined. This approach allows exquisite definition of local surface changes in the ADHD group that can then be related to a reference "cytoarchitectonic" map of the underlying nuclei (which uses cellular architecture to delineate the nuclei). Surface expansions are interpreted as reflecting volume increase in underlying nuclei and surface contractions as indicative of volume loss.
The study's most striking finding was marked volume loss in the region of the pulvinar nuclei bilaterally in the ADHD group. The pulvinar nuclei link action and vision, and the pulvinar's lateral portions, where the morphological anomalies were most prominent, support circuitry that detects salient somatosensory stimuli. The authors thus speculate that morphological disruption of the pulvinar could contribute to the inefficient allocation of attentional resources seen in ADHD. Somewhat distinct areas of the pulvinar were associated with symptom severity: increased volumes of the right pulvinar and medial-dorsal nuclei were correlated with the severity of inattention. By contrast, severity of hyperactivity was associated with decreased volumes in a distinct group of more lateral thalamic nuclei. Notably, these complex surface changes and associated underlying volumetric perturbations did not lead to a change in the overall volume of the thalamus in youths with ADHD relative to typically developing youths. Thus a traditional region-of-interest study examining the volume of the unitary thalamus would have missed these subtle but important diagnostic signals.
The study complements earlier work from the same group on shape anomalies of the amygdala, a limbic structure that is interconnected with the pulvinar. Given the amygdala's role in the processing of affectively charged stimuli, the authors speculate that the finding of conjoint shape anomalies in the pulvinar and amygdala could represent part of the neural substrate underpinning the emotional dysregulation frequently seen in ADHD. Disturbances in the shape of striatal components of the cortico-striatal-thalamic loops have also recently been found in ADHD with prominent surface compression in the head and body of the caudate and the anterior putamen. It would not be surprising if linked anomalies of cortical surface morphology in ADHD were soon reported.
Of possible interest to clinicians is that pulvinar reduction in the youths with ADHD in this study was largely driven by those who were not receiving treatment with psychostimulants at the time of the scan. The youths with ADHD who were medicated had thalamic surface morphology more closely resembling that of typically developing youths and thalamic volumes that tended to be larger than those of their unmedicated counterparts. This finding adds to other demonstrations that psychostimulant treatment in ADHD is associated with more normative brain dimensions—including white matter and key regions implicated in the pathogenesis of the disorder, such as the dorsolateral prefrontal cortex, the anterior cingulate cortex, and the cerebellar vermis. However, as the authors stress, these associations should not be overinterpreted. First, in this study, among the subgroup of 17 medicated patients for whom treatment duration could be determined, greater duration of treatment was associated with smaller volumes in regions of the right pulvinar that did not show the main effect of diagnosis—a finding running somewhat counter to the finding of pulvinar enlargement associated with psychostimulant treatment at the time of the scan. More generally, causality cannot be inferred from observational studies, and a definitive demonstration of any trophic effects of psychostimulants awaits a neuroimaging study conducted within the context of a randomized trial.
The study raises many important questions. The authors interpret the surface changes as indicative of volume loss in the underlying nuclei, which is very plausible. However, might surface changes also represent displacement of possibly volumetrically intact nuclei within the thalamus, or perhaps even result from anomalies of adjacent white matter and other structures? Second, what drives these changes? The complexity of answering this question is highlighted by the nature of the links between structural changes and symptom domains: whereas decreased local volumes accompanied hyperactivity, increased volumes accompanied inattention. Third, do these thalamic abnormalities reflect or drive structural changes in interconnected striatal, limbic, and cortical regions? Finally, how do these structural changes relate to abnormal cognitive and affective function—and which tasks are best suited to probe thalamic dysfunction?
The study exemplifies the increasing sophistication of morphological studies as they incorporate novel measures of local shape, complexity, volume, and thickness and align structural MRI with other imaging modalities, such as the delineation of white matter tracts by diffusion tensor imaging and maps of brain activation generated by functional MRI. In structural neuroanatomic studies of ADHD, things are indeed shaping up well.

2. Morphological Abnormalities of the Thalamus in Youths with Attention Deficit Hyperactivity Disorder

Iliyan Ivanov, M.D., Ravi Bansal, Ph.D., Xuejun Hao, Ph.D., Hongtu Zhu, Ph.D., Cristoph Kellendonk, Ph.D., Loren Miller, M.S., Juan Sanchez-Pena, M.S., Ann M. Miller, M.D., Ph.D., M. Mallar Chakravarty, Ph.D., Kristin Klahr, M.S., Kathleen Durkin, M.S., Laurence L. Greenhill, M.D., and Bradley S. Peterson, M.D.

Am J Psychiatry 2010; 167:397-408

Objective: The role of the thalamus in the genesis of attention deficit hyperactivity disorder (ADHD) remains poorly understood. The authors used anatomical MRI to examine the morphology of the thalamus in youths with ADHD and healthy comparison youths.

Method: The authors examined 46 youths with ADHD and 59 comparison youths 8–18 years of age in a cross-sectional case-control study. Conventional volumes and measures of surface morphology of the thalamus served as the main outcome measures.

Results: A mixed-effects model comparing whole thalamic volumes revealed no significant differences between groups. Maps of the thalamic surface revealed significantly smaller regional volumes bilaterally in the pulvinar in youths with ADHD relative to comparison subjects. Post hoc analyses showed that ADHD patients who received stimulants (N=31) had larger conventional thalamic volumes than untreated youths with ADHD, and maps of the thalamic surface showed enlargement over the pulvinar in those receiving stimulants. Smaller regional volumes in the right lateral and left posterior thalamic surfaces were associated with more severe hyperactivity symptoms, whereas larger regional volumes in the right medial thalamic surfaces were associated with more severe symptoms of inattention.

Conclusion: These findings demonstrate reduced pulvinar volumes in youths with ADHD and indicate that this same area is relatively enlarged in patients treated with stimulants compared to those untreated. Associations of hyperactivity scores with smaller regional volumes on the lateral thalamic surface and inattention scores with larger regional volumes on the medial thalamic surface suggest the differential involvement of thalamic subcircuits in the pathogenesis of differing ADHD symptoms.

3. Adult Psychiatric Outcomes of Girls with Attention Deficit Hyperactivity Disorder: 11-Year Follow-Up in a Longitudinal Case-Control Study

Am J Psychiatry 2010; 167:409-417

Joseph Biederman, M.D., Carter R. Petty, M.A., Michael C. Monuteaux, Sc.D., Ronna Fried, Ed.D., Deirdre Byrne, B.S., Tara Mirto, B.A., Thomas Spencer, M.D., Timothy E. Wilens, M.D., and Stephen V. Faraone, Ph.D.

Objective: Few follow-up studies have been conducted of girls with ADHD, and none have followed girls into adulthood. The authors sought to estimate the prevalence of psychopathology in girls with and without ADHD followed into young adulthood.

Method: The authors conducted a longitudinal case-control study of 6- to 18-year-old girls with (N=140) and without (N=122) ADHD ascertained from psychiatric and pediatric sources. At the 11-year follow-up, 96 (69%) of the girls with ADHD and 91 (75%) of the comparison girls were reassessed (mean age=22 years). Participants were blindly assessed by structured diagnostic interviews.

Results: Lifetime and 1-year risks for all composite categories of psychopathology were significantly greater in girls with ADHD grown up relative to comparison girls; lifetime hazard ratios were 7.2 (95% CI=4.0–12.7) for antisocial disorders, 6.8 (95% CI=3.7–12.6) for mood disorders, 2.1 (95% CI=1.6–2.9) for anxiety disorders, 3.2 (95% CI=2.0–5.3) for developmental disorders, 2.7 (95% CI=1.6–4.3) for addictive disorders, and 3.5 (95% CI=1.6–7.3) for eating disorders. For lifetime psychopathology, all six composite categories remained statistically significant after controlling for other baseline psychopathology. Except for addictive disorders, significant 1-year findings remained significant after controlling for baseline psychopathology. The 1-year prevalences of composite disorders were not associated with lifetime or 1-year use of ADHD medication.

Conclusion: By young adulthood, girls with ADHD were at high risk for antisocial, addictive, mood, anxiety, and eating disorders. These prospective findings, previously documented in boys with ADHD, provide further evidence for the high morbidity associated with ADHD across the life cycle.

4. Pharmacological treatment patterns among patients with attention-deficit/hyperactivity disorder: retrospective claims-based analysis of a managed care population

Christensen L, Sasané R, Hodgkins P, Harley C, Tetali S;

Current Medical Research and Opinion (Feb 2010)

Objective: To develop a descriptive profile of attention-deficit/hyperactivity disorder (ADHD) pharmacological treatment patterns in terms of persistence, adherence, augmentation, switching, and dosing changes; and to assess differences in treatment patterns with regard to ADHD medication type, class, and duration of action.

Methods: This retrospective claims database analysis used medical data, pharmacy data, and enrollment information to examine treatment patterns among patients with at least one claim with a diagnosis code for ADHD and a filled prescription for ADHD medication (index therapy) during the period 01 January 2004 through 30 September 2006. Treatment persistence and adherence (days supplied/days persistent) were calculated. Dose changes, medication switching, and augmentation were analyzed at three levels of comparison: class (stimulant vs nonstimulant [atomoxetine]), drug type (amphetamine vs methylphenidate), and duration of action (short, intermediate, long). Statistical comparisons were made using the chi-square test for proportions and Student's t-test or the F-test from one-way ANOVA for means.

Results: Of 60,010 patients meeting eligibility criteria, 58.4% were younger than age 18. Most (78.4%) were prescribed a stimulant as their index therapy. Persistence and adherence were greater for patients on stimulants (vs the nonstimulant), for patients on amphetamines (vs methylphenidates), and for patients on long-acting medications (vs short- and intermediate-acting medications; all p<0.0001). Index drug dose changes were least likely among individuals taking the nonstimulant (vs stimulants), methylphenidates (vs amphetamines), or intermediate-acting drugs (vs short- and long-acting drugs; all p<0.0001), and medication switches were more frequent among those on nonstimulants, methylphenidates, or short-acting drugs (all p<0.0001). Subjects taking long-acting medication were less likely to augment with a drug with a different duration of action than those taking intermediate- or short-acting medication (p<0.0001). This claims-based study is limited by possible discrepancies between claims and patient behaviors (i.e., a claim for a prescription does not necessarily indicate that the medication was taken as prescribed).

Conclusions: Patients were more stable on treatment compared with their respective comparator groups if their index therapy was a stimulant, long-acting drug, or amphetamine.

5. Effects of lisdexamfetamine dimesylate treatment for ADHD on growth.

Faraone SV, Spencer TJ, Kollins SH, Glatt SJ.
State University of New York Upstate Medical University, Syracuse, NY 13210, USA.

J Am Acad Child Adolesc Psychiatry. 2010 Jan;49(1):24-32.

OBJECTIVE: To complete an exploratory uncontrolled study of the effects of lisdexamfetamine dimesylate (LDX) on growth of children treated for attention-deficit/hyperactivity disorder (ADHD).

METHOD: Height, weight, and body mass index (BMI) from 281 children ages 6 to 13 years from longitudinal assessments up to 15 months were compared to norms from the Centers for Disease Control.

RESULTS: At study entry, children were taller and heavier than average. Growth delays were largest for weight and BMI, and there was a 13 percentile point decrease in height. Children continued to grow in terms of height while treated with LDX; we found no increase in raw weight or BMI during the study period. LDX treatment was significantly associated with diminished gains in height, weight, and BMI compared to levels that would be expected based on age-appropriate standards from the Centers for Disease Control. Growth delays were greatest for the heaviest and tallest children, for those who had not previously received stimulant therapy, and for those with a greater cumulative exposure to LDX. More work is needed to determine effects on ultimate adult height.

CONCLUSIONS: Consistent with prior studies of stimulants, treatment with LDX leads to statistically significant reductions in expected height, weight, and BMI. Growth of patients with ADHD treated with LDX should be closely monitored and corrective action taken should growth delays be observed.