Comorbidity of bipolar I disorder and conduct disorder: a familial risk analysis.

OBJECTIVE: To investigate the association between pediatric bipolar I (BP-I) disorder and conduct disorder (CD) using familial risk analysis. METHOD: We compared diagnoses in relatives of youth in four proband groups defined by the presence or absence of BP-I and CD: (1) probands with neither CD nor BP-I (probands: N = 550; relatives: N = 1656), (2) probands with CD and without BP-I (probands: N = 40; relatives: N = 127), (3) probands with BP-I and without CD (probands: N = 197; relatives: N = 579), and (4) probands with both CD and BP-I (probands: N = 176; relatives: N = 488). All subjects were evaluated with structured diagnostic interviews, and diagnoses of relatives were made blind to the diagnoses of probands. RESULTS: Relatives of probands with BP-I disorder had high rates of BP-I, and relatives of probands with CD had high rates of CD irrespective of the comorbidity with the other disorder. Relatives of probands with the combined condition of CD and BP-I had high rates of the combined condition. CONCLUSION: The finding of cosegregation between BP-I disorder and CD is consistent with the hypothesis that the combined condition represents a distinct subtype of either disorder.

Diagnostic utility of brain activity flow patterns analysis in attention deficit hyperactivity disorder.

BACKGROUND: A previous small study suggested that Brain Network Activation (BNA), a novel ERP-based brain network analysis, may have diagnostic utility in attention deficit hyperactivity disorder (ADHD). In this study we examined the diagnostic capability of a new advanced version of the BNA methodology on a larger population of adults with and without ADHD. METHOD: Subjects were unmedicated right-handed 18- to 55-year-old adults of both sexes with and without a DSM-IV diagnosis of ADHD. We collected EEG while the subjects were performing a response inhibition task (Go/NoGo) and then applied a spatio-temporal Brain Network Activation (BNA) analysis of the EEG data. This analysis produced a display of qualitative measures of brain states (BNA scores) providing information on cortical connectivity. This complex set of scores was then fed into a machine learning algorithm. RESULTS: The BNA analysis of the EEG data recorded during the Go/NoGo task demonstrated a high discriminative capacity between ADHD patients and controls (AUC = 0.92, specificity = 0.95, sensitivity = 0.86 for the Go condition; AUC = 0.84, specificity = 0.91, sensitivity = 0.76 for the NoGo condition). CONCLUSIONS: BNA methodology can help differentiate between ADHD and healthy controls based on functional brain connectivity. The data support the utility of the tool to augment clinical examinations by objective evaluation of electrophysiological changes associated with ADHD. Results also support a network-based approach to the study of ADHD.

Can subsyndromal manifestations of major depression be identified in children at risk?

OBJECTIVE: Children of parents with major depression are at significantly increased risk for developing major depression themselves; however, not all children at genetic risk will develop major depressive disorder (MDD). We investigated the utility of subsyndromal scores on the Child Behavior Checklist (CBCL) Anxiety/Depression scale in identifying children at the highest risk for pediatric MDD from among the pool of children of parents with MDD or bipolar disorder. METHOD: The sample was derived from two previously conducted longitudinal case-control family studies of psychiatrically and pediatrically referred youth and their families. For this study, probands were stratified based on the presence or absence of a parental mood disorder. RESULTS: Subsyndromal scores on the CBCL Anxiety/Depression scale significantly separated the children at high risk for pediatric MDD from those at low risk in a variety of functional areas, including social and academic functioning. Additionally, children at genetic risk without elevated CBCL Anxiety/Depression scale scores were largely indistinguishable from controls. CONCLUSION: These results suggest that the CBCL Anxiety/Depression scale can help identify children at highest risk for pediatric MDD. If implemented clinically, this scale would cost-effectively screen children and identify those most in need of early intervention resources to impede the progression of depression.

Functional effects of dopamine transporter gene genotypes on in vivo dopamine transporter functioning: a meta-analysis.

Much psychiatric genetic research has focused on a 40-base pair variable number of tandem repeats (VNTR) polymorphism located in the 3'-untranslated region (3'UTR) of the dopamine active transporter (DAT) gene (SLC6A3). This variant produces two common alleles with 9- and 10-repeats (9R and 10R). Studies associating this variant with in vivo DAT activity in humans have had mixed results. We searched for studies using positron emission tomography (PET) or single-photon emission computed tomography (SPECT) to evaluate this association. Random effects meta-analyses assessed the association of the 3'UTR variant with DAT activity. We also evaluated heterogeneity among studies and evidence for publication bias. We found twelve studies comprising 511 subjects, 125 from PET studies and 386 from SPECT studies. The PET studies provided highly significant evidence that the 9R allele was associated with increased DAT activity in human adults. The SPECT studies were highly heterogeneous. As a group, they suggested no association between the 3'UTR polymorphism and DAT activity. When the analysis was limited to the most commonly used ligand, [123I]ß-CIT, stratification by affection status dramatically reduced heterogeneity and revealed a significant association of the 9R allele with increased DAT activity for healthy subjects. In humans, the 9R allele of the 3'UTR polymorphism of SLC6A3 regulates dopamine activity in the striatal brain regions independent of the presence of neuropsychiatric illness. Differences in study methodology account for the heterogeneous results across individual studies.

Examining the nature of the comorbidity between pediatric attention deficit/hyperactivity disorder and post-traumatic stress disorder.

OBJECTIVE: This study sought to address the link between attention deficit/hyperactivity disorder (ADHD) and post-traumatic stress disorder (PTSD) in youth by providing a comprehensive comparison of clinical correlates of ADHD subjects with and without PTSD across multiple non-overlapping domains of functioning and familial patterns of transmission. METHOD: Participants were 271 youths with ADHD and 230 controls without ADHD of both sexes along with their siblings. Participants completed a large battery of measures designed to assess psychiatric comorbidity, psychosocial, educational, and cognitive parameters. RESULTS: Post-traumatic stress disorder was significantly higher in ADHD probands vs. controls (5.2% vs. 1.7%, χ(2) (1) = 4.36, P = 0.04). Irrespective of the comorbidity with PTSD, ADHD subjects had similar ages at onset of ADHD, similar type and mean number of ADHD symptoms, and similar ADHD-associated impairments. PTSD in ADHD probands was significantly associated with a higher risk of psychiatric hospitalization, school impairment, poorer social functioning and higher prevalences of mood, conduct disorder, and anxiety disorders. The mean onset of PTSD (12.6 years) was significantly later than that of ADHD and comorbid disorders (all P < 0.05). Siblings of ADHD and ADHD + PTSD probands had higher prevalences of ADHD vs. siblings of controls (35% vs. 18%, z = 4.00, P < 0.001 and 67% vs. 18%, z = 4.02, P < 0.001 respectively) and siblings of ADHD+PTSD probands had a significantly higher prevalence of PTSD compared with the siblings of ADHD and control probands (20% vs. 3% and 3%, z = 2.99, P = 0.003 and z = 2.07, P = 0.04 respectively). CONCLUSION: Findings indicate that the comorbidity with PTSD in ADHD leads to greater clinical severity as regards psychiatric comorbidity and psychosocial dysfunction. ADHD is equally familial in the presence of PTSD in the proband indicating that their co-occurrence is not owing to diagnostic error.

Deficient emotional self-regulation and pediatric attention deficit hyperactivity disorder: a family risk analysis.

BACKGROUND: Although deficient emotional self-regulation (DESR) is associated with attention deficit hyperactivity disorder (ADHD), little research investigates this association and little is known about its etiology. Family studies provide a method of clarifying the co-occurrence of clinical features, but no family studies have yet addressed ADHD and DESR in children. METHOD: Subjects were 242 children with ADHD and 224 children without ADHD. DESR was operationalized using an aggregate score ≥180 and <210 in the anxious/depressed, attention and aggression scales (AAA profile) of the Child Behavior Checklist (CBCL), termed the CBCL-DESR profile. The CBCL-bipolar (CBCL-BP) profile was defined as ≥210 on the CBCL-AAA scale. We examined the familial transmission of ADHD and the CBCL-AAA scale in families selected through probands with and without these conditions. RESULTS: We found a linear increase in the prevalence of CBCL-DESR in siblings as indexed by the Control, ADHD, ADHD+CBCL-DESR and ADHD+CBCL-BP proband groups. While the ADHD siblings were at elevated risk for both the CBCL-DESR and CBCL-BP compared with non-ADHD siblings, a significantly higher rate of CBCL-BP in the siblings of ADHD+CBCL-BP probands was found compared with siblings of the Control probands. CONCLUSIONS: ADHD shows the same degree of familial transmission in the presence or absence of DESR. CBCL-DESR and CBCL-BP are familial, but further work is needed to determine if these definitions are distinctly familial or represent a continuum of the same psychopathology.

Predictors of persistence in girls with attention deficit hyperactivity disorder: results from an 11-year controlled follow-up study.

OBJECTIVE: This study sought to examine the age-dependent persistence of attention deficit hyperactivity disorder (ADHD) and its predictors in a large sample of girls with and without ADHD followed prospectively for 11 years into young adulthood. METHOD: Participants were girls with (N=96) and without (N=91) ADHD and were 6-17 years old at the baseline assessment (mean age, 11 years) and 15-30 years old at the follow-up assessment (mean: 22 years). Participants were comprehensively and blindly assessed with structured diagnostic interviews and assessments of cognitive, social, school, and family functioning. RESULTS: At the 11-year follow-up, 33.3% met full criteria for ADHD, 29.2% showed partial persistence of the disorder, 10.4% had impaired functioning, and 4.2% were remitted but treated (77.1% of the sample). Predictors of persistence were psychiatric comorbidity, family history of psychopathology, and family and school functioning at baseline. CONCLUSION: These long-term, prospective, follow-up findings extend to girls findings that ADHD is persistent over the long term and can be predicted from psychosocial adversity and psychiatric comorbidity ascertained 11 years earlier.

A controlled family study of children with DSM-IV bipolar-I disorder and psychiatric co-morbidity.

BACKGROUND: To estimate the spectrum of familial risk for psychopathology in first-degree relatives of children with unabridged DSM-IV bipolar-I disorder (BP-I). METHOD: We conducted a blinded, controlled family study using structured diagnostic interviews of 157 children with BP-I probands (n=487 first-degree relatives), 162 attention deficit hyperactivity disorder (ADHD) (without BP-I) probands (n=511 first-degree relatives), and 136 healthy control (without ADHD or BP-I) probands (n=411 first-degree relatives). RESULTS: The morbid risk (MR) of BP-I disorder in relatives of BP-I probands (MR=0.18) was increased 4-fold [95% confidence interval (CI) 2.3-6.9, p<0.001] over the risk to relatives of control probands (MR=0.05) and 3.5-fold (95% CI 2.1-5.8, p<0.001) over the risk to relatives of ADHD probands (MR=0.06). In addition, relatives of children with BP-I disorder had high rates of psychosis, major depression, multiple anxiety disorders, substance use disorders, ADHD and antisocial disorders compared with relatives of control probands. Only the effect for antisocial disorders lost significance after accounted for by the corresponding diagnosis in the proband. Familial rates of ADHD did not differ between ADHD and BP-I probands. CONCLUSIONS: Our results document an increased familial risk for BP-I disorder in relatives of pediatric probands with DSM-IV BP-I. Relatives of probands with BP-I were also at increased risk for other psychiatric disorders frequently associated with pediatric BP-I. These results support the validity of the diagnosis of BP-I in children as defined by DSM-IV. More work is needed to better understand the nature of the association between these disorders in probands and relatives.

Executive functioning in high-IQ adults with ADHD.

BACKGROUND: To examine the association between psychological tests of executive functioning and functional outcomes among high-IQ adults with attention deficit hyperactivity disorder (ADHD). METHOD: Subjects were high-IQ adults with (n=64) and without ADHD (n=53). Subjects were administered a battery of neuropsychological tests assessing executive functioning. RESULTS: High-IQ adults with ADHD performed less well than those without ADHD on several psychological tests of executive functioning, including the Wisconsin Card Sorting Test (WCST), Stroop Color and Word Test, Rey-Osterrieth Complex Figure Test (ROCF), California Verbal Learning Test (CVLT) and an auditory continuous performance test (CPT). Test performance in the high-IQ adult ADHD group, however, was average. In the entire sample, performance on several tests of executive functioning including the ROCF and the CVLT were significant predictors of real-world functioning. CONCLUSIONS: High-IQ adults with ADHD perform less well on tests of executive functioning relative to high-IQ control participants. Performance on several tests of executive functioning was a significant predictor of functioning.

Is adult attention deficit hyperactivity disorder a valid diagnosis in the presence of high IQ?

BACKGROUND: Because the diagnosis of attention deficit hyperactivity disorder (ADHD) in higher education settings is rapidly becoming a contentious issue, particularly among patients with high IQs, we sought to assess the validity of diagnosing ADHD in high-IQ adults and to further characterize the clinical features associated with their ADHD. METHOD: We operationalized high IQ as having a full-scale IQ120. We identified 53 adults with a high IQ who did not have ADHD and 64 adults with a high IQ who met diagnostic criteria for ADHD. Groups did not differ on IQ, socio-economic status or gender. RESULTS: High-IQ adults with ADHD reported a lower quality of life, had poorer familial and occupational functioning, and had more functional impairments, including more speeding tickets, accidents and arrests. Major depressive disorder, obsessive-compulsive disorder and generalized anxiety disorder diagnoses were higher in high-IQ adults with ADHD. All other psychiatric co-morbidities, including antisocial personality disorder and substance abuse, did not differ between the two high-IQ groups. ADHD was more prevalent in first-degree relatives of adults with ADHD relative to controls. CONCLUSIONS: Our data suggest that adults with ADHD and a high IQ display patterns of functional impairments, familiality and psychiatric co-morbidities that parallel those found in the average-IQ adult ADHD population.

Neurocognitive impairment in unaffected siblings of youth with bipolar disorder.

BACKGROUND: There is growing evidence for the familiality of pediatric bipolar disorder (BPD) and its association with impairments on measures of processing speed, verbal learning and 'executive' functions. The current study investigated whether these neurocognitive impairments index the familial risk underlying the diagnosis. METHOD: Subjects were 170 youth with BPD (mean age 12.3 years), their 118 non-mood-disordered siblings and 79 non-mood-disordered controls. Groups were compared on a battery of neuropsychological tests from the Wechsler Intelligence Scales, the Stroop Color Word Test, the Wisconsin Card Sorting Test (WCST), the Rey-Osterrieth Complex Figure (ROCF), an auditory working memory Continuous Performance Test (CPT) and the California Verbal Learning Test-Children's Version (CVLT-C). Measures were factor analyzed for data reduction purposes. All analyses controlled for age, sex and attention-deficit/hyperactivity disorder (ADHD). RESULTS: Principal components analyses with a promax rotation yielded three factors reflecting: (1) processing speed/verbal learning, (2) working memory/interference control and (3) abstract problem solving. The CPT working memory measure with interference filtering demands (WM INT) was only administered to subjects aged > or =12 years and was therefore analyzed separately. BPD youth showed impairments versus controls and unaffected relatives on all three factors and on the WM INT. Unaffected relatives exhibited impairments versus controls on the abstract problem-solving factor and the WM INT. They also showed a statistical trend (p=0.07) towards worse performance on the working memory/interference control factor. CONCLUSIONS: Neurocognitive impairments in executive functions may reflect the familial neurobiological risk mechanisms underlying pediatric BPD and may have utility as endophenotypes in molecular genetic studies of the condition.

Further evidence of association between two NET single-nucleotide polymorphisms with ADHD.

The norepinephrine transporter (NET) gene is an attractive candidate gene for attention-deficit hyperactivity disorder (ADHD). Noradrenergic systems are critical to higher brain functions such as attention and executive function, which are defective in ADHD. The clinical efficacy of medications that target NET also supports its role in the etiology of ADHD. Here, we have applied a dense mapping strategy to capture all genetic variations within the NET gene in a large number of ADHD families (474 trios). As a result, we found association of the same alleles from two single-nucleotide polymorphisms (rs3785143 and rs11568324) previously identified in another large-scale ADHD genetic study (International Multisite ADHD Geneproject). Furthermore, the effect sizes were consistent across both studies. This is the first time that identical alleles of NET from different studies were implicated, and thus our report provides further evidence that the NET gene is involved in the etiology of ADHD.

Long-term, open-label extension study of guanfacine extended release in children and adolescents with ADHD.

INTRODUCTION: Guanfacine is a noradrenergic agonist that is believed to improve symptoms of attention-deficit/hyperactivity disorder (ADHD) through selective actions at alpha2A-adrenoceptors in the prefrontal cortex. A recent double-blind, multicenter trial supports the efficacy and safety of guanfacine extended release (GXR) for pediatric ADHD. This long-term, open-label extension was conducted to study the safety profile and effectiveness of GXR for up to 2 years. METHODS: Subjects were 240 children 6-17 years of age with a diagnosis of ADHD who participated in the preceding randomized trial. GXR was initiated at 2 mg/day and titrated as needed in 1-mg increments to a maximum of 4 mg/day to achieve optimal clinical response. RESULTS: The most common adverse events were somnolence (30.4%), headache (26.3%), fatigue (14.2%), and sedation (13.3%). Somnolence, sedation, and fatigue were usually transient. Cardiovascular-related adverse events were uncommon, although small reductions in mean blood pressure and pulse rate were evident at monthly visits. ADHD Rating Scale, Version IV, total and subscale scores improved significantly from baseline to endpoint for all dose groups (P<.001 for all comparisons, intent-to-treat population). CONCLUSION: Long-term treatment with GXR was generally safe for up to 24 months of treatment, and effectiveness was maintained over this treatment period.

On fitting the k-C* first order model to batch loaded sub-surface treatment wetlands.

The k-C* first order model was fit to time-series COD data collected from batch-loaded model wetlands. Four replicates of four plant species treatments; Carex utriculata (sedge), Schoenoplectus acutus (bulrush), Typha latifolia (cattail) and unplanted controls were compared. Temperature was varied by 4 degrees C from 24 degrees C to 4 degrees C to 24 degrees C over a year-long period. One mathematical fit was made for each wetland replicate at each temperature setting (192 fits). Temperature effects on both parameters were subsequently estimated by fitting the Arrhenius relationship to the estimated coefficients. Inherent interactions between k and C* make values dependent on sample timing and statistical technique for either time series (batch load) or distance profile (plug flow) data. Coefficients calibrated using the Levenberg-Marquardt method are compared to values previously reported using a nonlinear mixed effect regression technique. Overall conclusions are similar across approaches: (a) the magnitude of the coefficients varies strongly by species; (b) the rate constant k decreases with increasing temperature; and (c) temperature and species variation in the residual concentration C* is greater than the variation in k, such that variation in k alone is a poor predictor of performance. However, the magnitudes of the coefficients, especially the rate parameter k, vary between the statistical techniques, highlighting the need to better document the statistical routines used to calibrate the k-C* model.

Combination of lithium carbonate and haloperidol in schizo-affective disorder: a controlled study.

Lithium carbonate alone has been shown to be inferior to neuroleptics alone in the treatment of excited schizo-affective illness. However, in clinical practice, lithium carbonate and neuroleptics are often combined in this disorder. We report a double-blind five-week controlled trial of lithium carbonate plus haloperidol vs placebo plus haloperidol in the treatment of excited schizo-affective patients. Eighteen patients were studied in each treatment group. Modest but statistically significant differences in favor of lithium carbonate plus haloperidol were found by week 5, using the Brief Psychiatric Rating Scale. Lithium carbonate plus haloperidol was favored both for affective schizo-affectives and for schizophrenic schizo-affectives. Lithium carbonate benefit did not seem to be restricted to affective symptoms only. In the clinical treatment of acute schizo-affective illness, the modest benefits of added lithium carbonate must be weighed against the risks of the drug's toxicity.

Evidence of familial association between attention deficit disorder and major affective disorders.

With the use of family study methods and assessments by "blinded" raters, we tested hypotheses about patterns of familial association between DSM-III attention deficit disorder (ADD) and affective disorders (AFFs) among first-degree relatives of clinically referred children and adolescents with ADD (73 probands, 264 relatives) and normal controls (26 probands, 92 relatives). Among the 73 ADD probands, 24 (33%) met criteria for AFFs (major depression, n = 15 [21%]; bipolar disorder, n = 8 [11%]; and dysthymia, n = 1 [1%]). After stratification of the ADD sample into those with AFFs (ADD + AFF) and those without AFF (ADD), familial risk analyses revealed the following: (1) the relatives of each ADD proband subgroup were at significantly greater risk for ADD than were relatives of normal controls; (2) the age-corrected morbidity risk for ADD was not significantly different between relatives of ADD and ADD + AFF (27% vs 22%); however, these two risks were significantly greater than the risk to relatives of normal controls (5%); (3) the risk for any AFF (bipolar disorder, major depressive disorder, or dysthymia) was not significantly different between relatives of ADD probands and ADD + AFF probands (28% and 25%), but these two risks were significantly greater than the risk to relatives of normal controls (4%); (4) ADD and AFFs did not cosegregate within families; and (5) there was no evidence for nonrandom mating. These findings are consistent with the hypothesis that ADD and AFFs may share common familial vulnerabilities.

A double-blind, crossover comparison of methylphenidate and placebo in adults with childhood-onset attention-deficit hyperactivity disorder.

BACKGROUND: There are few controlled studies of methylphenidate hydrochloride in adults with attention-deficit hyperactivity disorder (ADHD), and their results have been equivocal. The discrepancies among these studies may be related to low doses, diagnostic uncertainties, and lack of attention to comorbid disorders. METHODS: We conducted a randomized, 7-week, placebo-controlled, crossover study of methylphenidate in 23 adult patients with DSM-III-R ADHD using standardized instruments for diagnosis, separate assessments of ADHD and depressive and anxiety symptoms, and a robust daily dose of methylphenidate hydrochloride, 1.0 mg/kg per day. RESULTS: We found a marked therapeutic response for methylphenidate treatment of ADHD symptoms that exceeded the placebo response (78% vs 4%, P < .0001). Response to methylphenidate was independent of gender, psychiatric comorbidity with anxiety or moderate depression, or family history of psychiatric disorders. CONCLUSION: Robust doses of methylphenidate are effective in the treatment of adult ADHD.

Behavioral inhibition in children of parents with panic disorder and agoraphobia. A controlled study.

To investigate the role of "behavioral inhibition to the unfamiliar" as an early temperamental characteristic of children at risk for adult panic disorder and agoraphobia (PDAG), we compared children of parents with PDAG with those from psychiatric comparison groups. Fifty-six children aged 2 to 7 years, matched for age, socioeconomic status, ethnic background, and ordinal position, were blindly evaluated at the Harvard Infant Study laboratory, Cambridge, Mass. The rates of behavioral inhibition in children of probands with PDAG, with or without comorbid major depressive disorder (MDD), were significantly higher than for our comparison group without PDAG. Further, the data suggest a progression of increasing rates of inhibition from the comparison group without MDD (15.4%), to MDD (50.0%), and to comorbid PDAG and MDD (70%) and PDAG (84.6%). In contrast, the rate of behavioral inhibition in children of probands with MDD did not meaningfully differ from the comparison group without MDD. Behavioral inhibition to the unfamiliar, as defined and measured in the previous work of the Harvard Infant Study program, is highly prevalent in the offspring of adults in treatment for PDAG. These children appear to be at risk for distress and disability in childhood and also perhaps for development of psychiatric disorder in later childhood and aulthood.

Family-environment risk factors for attention-deficit hyperactivity disorder. A test of Rutter's indicators of adversity.

BACKGROUND: This study investigated whether family-environment risk factors are associated with attention-deficit hyperactivity disorder (ADHD). Compelling work by Rutter and coworkers revealed that it was the aggregate of adversity factors (severe marital discord, low social class, large family size, paternal criminality, maternal mental disorder, and foster care placement) rather than the presence of any single factor that led to impaired development. Based on the work of Rutter, we hypothesized a positive association between indicators of adversity and the diagnosis of ADHD and ADHD-associated impairments. METHODS: We studied 140 ADHD and 120 normal control probands. Subjects were non-Hispanic white boys between the ages of 6 and 17 years. Rutter's indicators of adversity were used to predict ADHD-related psychopathology as well as impaired cognitive and psychosocial functioning. RESULTS: The odds ratio for the diagnosis of ADHD increased as the number of Rutter's adversity index predicted ADHD-related psychopathology (depression, anxiety, and conduct disorder), learning disabilities, cognitive impairment, and psychosocial dysfunction. CONCLUSIONS: A positive association appears to exist between adversity indicators and the risk for ADHD as well as for its associated psychiatric, cognitive, and psychosocial impairments. These findings support the work of Rutter and stress the importance of adverse family-environment variables as risk factors for children with ADHD.