Tourette syndrome associated with attention deficit hyperactivity disorder: The impact of tics and psychopharmacological treatment options.

Tourette syndrome (TS) is a neurodevelopmental disorder characterized by multiple chronic motor and vocal tics beginning in childhood. Several studies describe the association between TS and attention deficit hyperactivity disorder (ADHD). Fifty percent of children diagnosed with ADHD have comorbid tic disorder. ADHD related symptoms have been reported in 35% to 90% of children with TS. Since ADHD is the most prevalent comorbid condition with TS and those with concomitant TS and ADHD present with considerable psychosocial and behavioral impairments, it is essential for clinicians to be familiar with these diagnoses and their management. This paper highlights the association between treating ADHD with stimulants and the development of tic disorders. The two cases discussed underscore the fact that children with TS may present with ADHD symptomatology prior to the appearance of any TS related symptoms. Appropriate management of TS in a patient diagnosed with ADHD can lead to quality of life improvements and a reduction in psychosocial impairments.

Attention deficit hyperactivity disorder characteristics: II. Clinical correlates of irritable mood.

BACKGROUND: This study describes the relationship of irritable mood (IRR) with affective disorders in youths with attention deficit hyperactivity disorder (ADHD). METHODS: Five hundred ADHD subjects were assessed with the childhood version of the Schedule for Affective Disorder & Schizophrenia. Subjects were in a genetic ADHD protocol and limited to those of Caucasian/European descent. RESULTS: The most prevalent concurrent diagnoses were oppositional defiant disorder (ODD) (43.6%), minor depression/dysthymic disorder (MDDD) (18.8%), and generalized anxiety (13.2%)/overanxious disorder (12.4%). IRR subjects (21.0%) compared to the non-IRR (NIRR) group had higher rates of all affective disorders (76.2% vs. 9.6%) and ODD (83.8% vs. 32.9%) but lower rates of hyperactive ADHD (1.9% vs. 8.9%). Among those without comorbidities, 98.3% were NIRR. Logistic regression found IRR mood significantly associated with major depressive disorder (odds ratio [OR]: 33.4), MDDD (OR: 11.2), ODD (OR: 11.6), and combined ADHD (OR: 1.7) but not with anxiety disorders. Among symptoms, it associated IRR mood with a pattern of dysthymic and ODD symptoms but with fewer separation anxiety symptoms. Diagnostic and symptomatic parameters were unaffected by demographic variables. LIMITATIONS: Potential confounders influencing these results include patient recruitment from only one clinical service; a cohort specific sample effect because some presumed affective disorders and non-Caucasians were excluded; and the young mean age (10.2 years) limiting comorbid patterns. CONCLUSIONS: The prominence of an MDDD pattern suggests this IRR group is appropriate in the DSM V's proposed chronic depressive disorder, possibly with or without temper dysregulation. A new diagnosis of disruptive mood dysregulation disorder may be unwarranted.

What can ADHD without comorbidity teach us about comorbidity?

Neuropsychiatric comorbidity in ADHD is frequent, impairing and poorly understood. In this report, characteristics of comorbid and comorbid-free ADHD subjects are investigated in an attempt to identify differences that could potentially advance our understanding of risk factors. In a clinically-referred ADHD cohort of 449 youths (ages 6-18), age, gender, IQ, SES and ADHD symptoms were compared among ADHD comorbid free subjects and ADHD with internalizing and externalizing disorders. Logistic regression analyses were also carried out to investigate the relationship between comorbidity and parental psychiatric status. Age range was younger in the ADHD without comorbidity and older in ADHD+internalizing disorders. No significant difference in IQ or SES was found among ADHD comorbid and comorbid-free groups. ADHD with internalizing disorder has a significantly greater association with paternal psychiatric conditions. After matching by age, gender, IQ and SES, ADHD with externalizing disorders had significantly higher total ADHD, hyperactivity/impulsivity score and single item score of difficulty awaiting turn than ADHD without comorbidity and ADHD with internalizing disorders. Older age ranges, ADHD symptom severity and parental psychopathology may be risk factors for comorbidity.

Parental ADHD status and its association with proband ADHD subtype and severity.

OBJECTIVE: To better understand the familial transmission of attention deficit hyperactivity disorder (ADHD), a highly heritable disorder, the effects of paternal and maternal ADHD status on probands' ADHD symptoms and subtypes were investigated. STUDY DESIGN: In 323 trios with ADHD, data from a structured interview and a self-report scale (score of >21) were used to determine ADHD probands' diagnostic status and parental ADHD status, respectively. Parental ADHD status on proband ADHD severity and subtypes was investigated. RESULTS: ADHD criteria were endorsed by 23% of fathers and 27% of mothers, and by at least one parent in 41% of the cases. ADHD severity was higher for children whose parents had ADHD versus those whose parents were without it. Paternal ADHD was associated with an increased likelihood of ADHD combined subtype (odds ratio = 3.56) and a decreased likelihood of the inattentive subtype (odds ratio = 0.34) in male children. CONCLUSIONS: Parental ADHD status appears to confer different risks for the severity of hyperactive-impulsive and inattentive symptoms depending on parental sex; however, parental ADHD self-report scale score has low to negligible correlation with proband's ADHD severity. Biparental ADHD does not appear to have an additive or synergistic effect on the proband's ADHD severity.

ADHD latent class clusters: DSM-IV subtypes and comorbidity.

ADHD (Attention Deficit Hyperactivity Disorder) has a complex, heterogeneous phenotype only partially captured by Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria. In this report, latent class analyses (LCA) are used to identify ADHD phenotypes using K-SADS-IVR (Schedule for Affective Disorders & Schizophrenia for School Age Children-IV-Revised) symptoms and symptom severity data from a clinical sample of 500 ADHD subjects, ages 6-18, participating in an ADHD genetic study. Results show that LCA identified six separate ADHD clusters, some corresponding to specific DSM-IV subtypes while others included several subtypes. DSM-IV comorbid anxiety and mood disorders were generally similar across all clusters, and subjects without comorbidity did not aggregate within any one cluster. Age and gender composition also varied. These results support findings from population-based LCA studies. The six clusters provide additional homogenous groups that can be used to define ADHD phenotypes in genetic association studies. The limited age ranges aggregating in the different clusters may prove to be a particular advantage in genetic studies where candidate gene expression may vary during developmental phases. DSM-IV comorbid mood and anxiety disorders also do not appear to increase cluster heterogeneity; however, longitudinal studies that cover period of risk are needed to support this finding.

Nocturnal enuresis: a suggestive endophenotype marker for a subgroup of inattentive attention-deficit/hyperactivity disorder.

OBJECTIVE: Attention-deficit/hyperactivity disorder (ADHD) and enuresis co-occur at a higher rate than expected; the cause for this is unclear. STUDY DESIGN: Diagnostic and demographic variables were compared in 344 children ages 6 to 12 years, with and without enuresis, recruited in an ADHD genetic study. Sleep variables were investigated in a subgroup of 44 enuretic children with age- and sex-matched nonenuretic controls. The association of enuresis with single nucleotide polymorphisms located in regions reported in linkage with enuresis was explored. RESULTS: The prevalence rate of nocturnal enuresis was 16.9% for the entire cohort. There were no differences in sex, age, socioeconomic status, intelligence quotient, medication treatment, or comorbidities. The enuresis group had a higher likelihood of inattentive symptoms than the nonenuretic group. Night wakings and ability of children to wake themselves in the morning were both significantly decreased in children with enuresis compared with control children in the Child Sleep Habits Questionnaire Night Wakings subscale. No significant association was found with chromosomal regions previously reported in linkage with enuresis. CONCLUSIONS: Deficits in arousal may contribute to both enuresis and inattentive ADHD. Nocturnal enuresis may be a useful clinical marker in identifying a subgroup of the inattentive phenotype in ADHD genetic studies.

Candidate gene analysis in an on-going genome-wide association study of attention-deficit hyperactivity disorder: suggestive association signals in ADRA1A.

OBJECTIVES: Attention-deficit hyperactivity disorder (ADHD) is a highly heritable, common developmental disorder. Although a few confirmed associations have emerged from candidate gene studies, these have shown the same limitations that have become evident in the study of other complex diseases, often with inconsistent and nonreplicated results across different studies. METHODS: In this report, 27 ADHD candidate genes were explored in greater depth using high-density tag single nucleotide polymorphism (SNP) genotyping. Association with 557 SNPs was tested using the transmission disequilibrium test in 270 nuclear pedigrees selected from an ongoing ADHD genetic study that includes all disease subtypes. RESULTS: SNPs in seven genes including SLC1A3, SLC6A3, HTR4, ADRA1A, HTR2A, SNAP25, and COMT showed a nominal level of association with ADHD (P values <0.05), but none remained significant after a stringent correction for the total number of tests performed. CONCLUSION: The strongest signal emerged from SNPs in the promoter region (rs3808585) and in an intron (rs17426222, rs4732682, rs573514) of ADRA1A, all located within the same haplotype block. Some of the SNPs in HTR2A and COMT have already been reported by others, whereas other SNPs will need confirmation in independent samples.

ADHD characteristics: I. Concurrent co-morbidity patterns in children & adolescents.

OBJECTIVE: 342 Caucasian subjects with attention deficit/hyperactivity disorder (ADHD) were recruited from pediatric and behavioral health clinics for a genetic study. Concurrent comorbidity was assessed to characterize the clinical profile of this cohort. METHODS: Subjects 6 to 18 years were diagnosed with the Schedule for Affective Disorders & Schizophrenia for School aged Children (K-SADS-P IVR). RESULTS: The most prevalent diagnoses co-occurring with ADHD were Oppositional Defiant Disorder (ODD) (40.6%), Minor Depression/Dysthymia (MDDD) (21.6%), and Generalized Anxiety Disorder (GAD) (15.2%). In Inattentive ADHD (n = 106), 20.8% had MDDD, 20.8% ODD, and 18.6% GAD; in Hyperactive ADHD (n = 31) 41.9% had ODD, 22.2% GAD, and 19.4% MDDD. In Combined ADHD, (n = 203), 50.7% had ODD, 22.7% MDDD and 12.4% GAD. MDDD and GAD were equally prevalent in the ADHD subtypes but, ODD was significantly more common among Combined and Hyperactive ADHD compared to Inattentive ADHD. The data suggested a subsample of Irritable prepubertal children exhibiting a diagnostic triad of ODD, Combined ADHD, and MDDD may account for the over diagnosing of Bipolar Disorder. CONCLUSION: Almost 2/3rd of ADHD children have impairing comorbid diagnoses; Hyperactive ADHD represents less than 10% of an ADHD sample; ODD is primarily associated with Hyperactive and Combined ADHD; and, MDDD may be a significant morbidity for ADHD youths from clinical samples.

Cardiovascular effects of mixed amphetamine salts extended release in the treatment of school-aged children with attention-deficit/hyperactivity disorder.

BACKGROUND: The cardiovascular safety of mixed amphetamine salts extended release (MAS XR) was evaluated in 2968 children 6-12 years of age with attention-deficit/hyperactivity disorder (ADHD). METHODS: In this prospective, open-label, noncomparative, community-based study, subjects whose symptoms of ADHD were well controlled with stimulant medication maintained their established treatment regimens for 2 weeks before enrollment into the current study. Subjects' regimens were then converted to an approximately equivalent once-daily dose of MAS XR 10, 20, or 30 mg/d according to a medication-conversion algorithm, which could be adjusted to 40 mg/d for optimal efficacy and tolerability. Systolic blood pressure (SBP), diastolic BP (DBP), and pulse were measured at each study visit. Twelve-lead electrocardiography was performed at screening and at the end of the extension phase or early termination. RESULTS: No clinically significant changes in BP or pulse were observed. Although one subject experienced a QT-prolongation interval > 25%, no clinically significant prolongation in the mean QT interval was seen. Approximately 2.5% of subjects demonstrated two consecutive SBP or DBP values > 95th percentile for age, sex, and height, and 3.6% of subjects' pulse increased by > or = 25 to > or = 110 beats per minute. No serious cardiovascular adverse events or deaths occurred. CONCLUSIONS: In addition to demonstrated efficacy and safety, the cardiovascular profile of MAS XR showed generally small divergences from age-specific population norms that pose very limited risk in this patient population.

Sertraline in children and adolescents with major depressive disorder.

OBJECTIVE: To explore time to first response and time to first persistent response of sertraline versus placebo and compare these parameters between children (6-11 years old, n = 177) and adolescents (12-17 years old, n = 199) with major depressive disorder. METHOD: A 10-week placebo-controlled treatment was followed by a 24-week open-label sertraline treatment. The double-blind studies were not powered to detect efficacy differences between age groups. A post hoc analysis explored time to first response and first persistent response using the Children's Depression Rating Scale-Revised and Clinical Global Impressions-Improvement predefined criteria. RESULTS: There were no statistically significant differences in time to first response or first persistent response between sertraline and placebo in children, except for time to first response on Clinical Global Impressions-Improvement. Sertraline had a significantly faster time to first persistent response in adolescents compared to placebo. Within treatment groups, children had a significantly faster time to first response than adolescents, whether treated with placebo or sertraline, but not on time to first persistent response. Both age groups showed similar improvement over 34 weeks of treatment. CONCLUSION: In the double-blind studies, children and adolescents had different patterns of response with sertraline vs. placebo.

Long-term sertraline treatment of children and adolescents with major depressive disorder.

OBJECTIVE: The aim of this study was to assess the long-term safety, tolerability, and efficacy of sertraline 50-200 mg once-daily in children (6-11 year olds) and adolescents (12-18 year olds) with a Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) diagnosis of major depressive disorder (MDD). METHODS: This study consisted of a 24-week open-label observational study of children and adolescents who had completed either of two 10-week double-blind, placebo-controlled trials. The Children's Depression Rating Scale-Revised (CDRS-R) was the primary measure of efficacy. RESULTS: Two hundred ninety nine (299) patients completed the acute studies and were eligible for the extension study. Of these, 226 enrolled, but 5 did not receive treatment. Of 221 patients (107 children and 114 adolescents), 62.4% completed the study. The endpoint mean daily dose was 109.9 mg/day. The mean decrease in CDRS-R score from double-blind baseline was 34.8 points (p < 0.001), with patients showing continued improvement in CDRS-R scores regardless of which treatment they received in the double-blind studies. At endpoint, 86% of patients met CDRS-R responder and 58% CDRS-R remitter criteria. CONCLUSIONS: Sertraline appears to be well tolerated and safe over 24 weeks of treatment in children and adolescents with MDD. Children and adolescents treated with sertraline appear to have increased improvement over that seen in the first 10 weeks of treatment. These findings need confirmation in placebo-controlled studies.

A community assessment, open-label study of the safety, tolerability, and effectiveness of mixed amphetamine salts extended release in school-age children with ADHD.

OBJECTIVE: To assess the safety, tolerability, and effectiveness of mixed amphetamine salts extended release (MAS XR) in school-age children with attention-deficit/hyperactivity disorder (ADHD) treated in a community practice setting. METHODS: Children aged 6-12 years (N = 2968) with DSM-IV-defined ADHD entered a 9-week prospective, open-label, non-comparative study of MAS XR at 386 sites. For at least 2 weeks before enrollment, subjects with well-controlled ADHD received their consistent dose of previously prescribed psychostimulant. Subsequently, this regimen was converted to an equivalent once-daily dose of 10-, 20-, or 30-mg MAS XR, according to a conversion algorithm. Tolerability and safety were assessed based on reported treatment-emergent adverse events and observed changes in vital signs and body weight. Effectiveness was assessed using a parent-completed Conners' Global Index Scale (CGIS-P) measured 8 and 12 h postdose and a clinician-scored Clinical Global Impressions-Improvement (CGI-I) scale after 1, 3, and 7 weeks of treatment. The dose of study medication could be adjusted at weeks 1 and 3 to a maximum of 40 mg/day. Outcome analyses used an intent-to-treat methodology, with last observations carried forward. RESULTS: Statistically significant improvement in ADHD behavior 8 and 12 h postdose occurred during the first week of treatment and was maintained through study endpoint (p < 0.0001). Results of the investigator-rated CGI-I at weeks 1, 3, and 7 were consistent with the parent-rated CGIS-P results, indicating that MAS XR treatment significantly improved symptoms compared with the baseline stimulant regimen (p < 0.0001). The incidence of treatment-related adverse events was low, and most AEs were mild in intensity. CONCLUSION: MAS XR 10-40 mg is a safe and effective once-daily medication for treatment of children with ADHD in a community practice setting. ADHD symptoms may be further reduced by converting from current pharmacotherapy to an optimally titrated dose of MAS XR.

Gender differences in adolescent depression: do symptoms differ for boys and girls?

BACKGROUND: Limited prior research suggests that depressed women are more likely to experience certain symptoms of depression than are depressed men. The purpose of this study was to examine whether such gender differences in depressive symptoms are present during adolescence. METHODS: The Childhood Version of the Schedule for Affective Disorders and Schizophrenia and the Beck Depression Inventory were administered to adolescents presenting for evaluation at an outpatient clinic (n=383; ages 11.9 to 20.0). RESULTS: Depressed girls and boys had similar symptom prevalence and severity ratings for most depressive symptoms. However, depressed girls had more guilt, body image dissatisfaction, self-blame, self-disappointment, feelings of failure, concentration problems, difficulty working, sadness/depressed mood, sleep problems, fatigue, and health worries than depressed boys on some comparisons. In contrast, depressed boys had higher clinician ratings of anhedonia, depressed morning mood, and morning fatigue. LIMITATIONS: Longitudinal research is needed to test whether such relatively gender-specific symptoms play different roles in the onset, maintenance, or remittance of depression for boys and girls. CONCLUSIONS: These findings indicate that, in general, the experience of depression is highly similar for adolescent girls and boys. However, some gender differences previously found among depressed adults appear to be present by adolescence, possibly suggesting somewhat distinct etiologies for depression among males and females.

Psychotropic prescription practices in child psychiatric inpatients 9 years old and younger.

OBJECTIVE: We set out to examine psychotropic prescribing patterns among inner city children on public assistance admitted to a university-based inpatient service. METHODS: A chart review of children 9 years old and younger admitted between 1998 and 2001 recorded demographic variables, diagnoses, and admission and discharge medications. RESULTS: The sample (N = 301) was 78% male, 66% African American, and averaged 7.2 years of age. Of this sample, 85% had a behavior disorder on admission and discharge; 51.8% of the patients were medicated on admission, 78.7% on discharge. Approximately 25% received polypharmacy on either admission or discharge. Stimulants were the most widely used psychotropic (38.2% on admission, 60.5% on discharge). Other medications prescribed at admission versus discharge were alpha-2 agonists (9.3% vs. 9%), atypical antipsychotics (9% vs. 12%), antidepressants (8.3% vs. 15.9%), and mood stabilizers (5.6% vs. 2.3%). CONCLUSIONS: Among inner city children, pharmacotherapy is more prevalent in an inpatient unit compared with the community standard. Community physicians prescribed more mood stabilizers; the academic faculty used more stimulants, atypical antipsychotics, and antidepressants. Predictors of pharmacotherapy in the community such as age, sex, race, and a behavior disorder shifted at discharge to include only length of stay and a behavior disorder diagnosis. Further research is needed to clarify whether nonadherence, treatment failure, and social factors account for lower medication utilization in the community.

Efficacy of sertraline in the treatment of children and adolescents with major depressive disorder: two randomized controlled trials.

CONTEXT: The efficacy, safety, and tolerability of selective serotonin reuptake inhibitors (SSRIs) in the treatment of adults with major depressive disorder (MDD) are well established. Comparatively few data are available on the effects of SSRIs in depressed children and adolescents. OBJECTIVE: To evaluate the efficacy and safety of sertraline compared with placebo in treatment of pediatric patients with MDD. DESIGN AND SETTING: Two multicenter randomized, double-blind, placebo-controlled trials were conducted at 53 hospital, general practice, and academic centers in the United States, India, Canada, Costa Rica, and Mexico between December 1999 and May 2001 and were pooled a priori. PARTICIPANTS: Three hundred seventy-six children and adolescents aged 6 to 17 years with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition-defined MDD of at least moderate severity. INTERVENTION: Patients were randomly assigned to receive a flexible dosage (50-200 mg/d) of sertraline (n = 189) or matching placebo tablets (n = 187) for 10 weeks. MAIN OUTCOME MEASURES: Change from baseline in the Children's Depression Rating Scale-Revised (CDRS-R) Best Description of Child total score and reported adverse events. RESULTS: Sertraline-treated patients experienced statistically significantly greater improvement than placebo patients on the CDRS-R total score (mean change at week 10, -30.24 vs -25.83, respectively; P =.001; overall mean change, -22.84 vs -20.19, respectively; P =.007). Based on a 40% decrease in the adjusted CDRS-R total score at study end point, 69% of sertraline-treated patients compared with 59% of placebo patients were considered responders (P =.05). Sertraline treatment was generally well tolerated. Seventeen sertraline-treated patients (9%) and 5 placebo patients (3%) prematurely discontinued the study because of adverse events. Adverse events that occurred in at least 5% of sertraline-treated patients and with an incidence of at least twice that in placebo patients included diarrhea, vomiting, anorexia, and agitation. CONCLUSION: The results of this pooled analysis demonstrate that sertraline is an effective and well-tolerated short-term treatment for children and adolescents with MDD.

Taxonicity of adolescent melancholia: a categorical or dimensional construct?

A taxometric analysis was conducted to test the hypothesis that the latent structure of melancholia in adolescents is categorical. Two taxometric procedures were used: Mean Above Minus Below a Cut (MAMBAC) and Maximum Covariance (MAXCOV) analyses. Participants were 378 adolescents presenting for a depression evaluation. Indicators of melancholia were constructed using items from the Schedule for Affective Disorders and Schizophrenia for School Aged Children (K-SADS) and the Beck Depression Inventory (BDI). The indicators of melancholia were consistent with a categorical latent variable. The findings suggest that the latent structure of melancholia in adolescents is similar to its previously identified categorical structure in adults. Implications for clinical research are discussed.