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Objective To summarize the current state of the research literature on nonverbal learning disability (NVLD), including criteria used to define NVLD in research contexts and the quality of the extant research; and to determine what research can tell us about ways in which NVLD is distinct from DSM neurodevelopmental disorders and typical development. Method A systematic search of 7 databases was conducted to identify research on NVLD published through February 2019. Criteria used to define NVLD were extracted from identified studies and sorted by category. Each study was assessed for risk of bias and rated “good,” “fair,” or “poor;” findings from studies rated good or fair were summarized. Results A total of 61 articles (63 studies) met inclusion criteria. There was great heterogeneity in the criteria used to define NVLD. Deficits in visuospatial ability/intelligence was the most common criterion used, followed by discrepancy between verbal and nonverbal intelligence (VIQ>PIQ split of 10 or greater). All studies were cross-sectional and most included small, poorly described samples. Most studies focused on children and young adolescents. Eight studies were rated as good, 42 as fair, and 13 as poor. Review of results from the 50 good or fair studies suggest that there is sufficient evidence that youths with NVLD (as defined by significant deficits in visuospatial abilities) can be clearly differentiated from their typically developing peers, those with verbal learning disorders, and from other clinical groups (eg, individuals with high functioning autism). Conclusion A standard set of criteria for determining an NVLD diagnosis would greatly improve research studies and the possibility of inclusion in the DSM and ICD.

To evaluate the frequency of adverse events (AEs) across 4 treatment conditions in the Child/Adolescent Anxiety Multimodal Study (CAMS), and to compare the frequency of AEs between children and adolescents.Participants ages 7 to 17 years (mean = 10.7 years) meeting the DSM-IV criteria for 1 or more of the following disorders: separation anxiety disorder, generalized anxiety disorder, or social phobia were randomized (2:2:2:1) to cognitive-behavioral therapy (CBT, n = 139), sertraline (SRT, n = 133), a combination of both (COMB, n = 140), or pill placebo (PBO, n = 76). Data on AEs were collected via a standardized inquiry method plus a self-report Physical Symptom Checklist (PSC).There were no differences between the double-blinded conditions (SRT versus PBO) for total physical and psychiatric AEs or any individual physical or psychiatric AEs. The rates of total physical AEs were greater in the SRT-alone treatment condition when compared to CBT (p .01) and COMB (p .01). Moreover, those who received SRT alone reported higher rates of several physical AEs when compared to COMB and CBT. The rate of total psychiatric AEs was higher in children (≤12 years) across all arms (31.7% versus 23.1%, p .05). Total PSC scores decreased over time, with no significant differences between treatment groups.The results support the tolerability/safety of selective serotonin reuptake inhibitor (SSRI) treatment for anxiety disorders even after adjusting for the number of reporting opportunities, leading to no differences in overall rates of AEs. Few differences occurred on specific items. Additional monitoring of psychiatric AEs is recommended in children (≤12 years). Clinical trial registration information-Child and Adolescent Anxiety Disorders (CAMS); http://clinicaltrials.gov; NCT00052078.

Objective To describe the clinical course of attention-deficit/hyperactivity disorder (ADHD) symptom severity and diagnosis from ages 3 to 5 up to 9 to 12 years during a 6-year follow-up after the original Preschool ADHD Treatment Study (PATS). Method A total of 207 participants (75% male) from the original PATS, assessed at baseline (mean age, 4.4 years, when all met criteria for ADHD) and 3 months later (before medication treatment), were re-evaluated in three follow-up assessment visits (year 3, mean age 7.4 years; year 4, 8.3 years; and year 6, 10.4 years). Parents and teachers rated symptom severity, and clinicians established psychiatric diagnoses. Analyses examined longitudinal changes in symptom severity and ADHD diagnosis. Results Parent- and teacher-rated symptom severity decreased from baseline to year 3 but remained relatively stable and in the moderate-to-severe clinical range through year 6. Girls showed generally steeper decreases in symptom T-scores. At year 6, 89% (160/180) of remaining participants met ADHD symptom and impairment diagnostic criteria. Comorbidity of oppositional defiant disorder and/or conduct disorder was associated with a 30% higher risk of having an ADHD diagnosis at year 6 in the multiple logistic model. Medication status during follow-up, on versus off, did not predict symptom severity change from year 3 to year 6 after adjustment for other variables. Conclusions ADHD in preschoolers is a relatively stable diagnosis over a 6-year period. The course is generally chronic, with high symptom severity and impairment, in very young children with moderate-to-severe ADHD, despite treatment with medication. Development of more effective ADHD intervention strategies is needed for this age group.

Objective To report on the safety and tolerability of methylphenidate (MPH) 3- to 5-year-old children with attention-deficit/hyperactivity disorder (ADHD) during 1 year of treatment. Method Exactly 183 children (3-5 years old) entered a treatment study of MPH, consisting of a 1-week open-label lead-in (n = 183); a 5-week placebo-controlled, double-blind phase (n = 165); a 5-week double-blind, parallel phase (n = 114); and 10 months of open-label maintenance (n = 140 entered, 95 completed). Mean total daily MPH doses rose from the titration trial best dose, 14.1 (±8.1) mg/day, to 20.5 (±9.7) mg/day mean total daily dose at the end of maintenance. Pulse, blood pressure, and the presence of treatment emergent adverse events (AEs), parent and teacher AE ratings, and vital signs were recorded in each phase. Results Thirty percent of parents spontaneously reported moderate to severe AEs in all study phases after baseline. These included emotional outbursts, difficulty falling asleep, repetitive behaviors/thoughts, appetite decrease, and irritability. During titration, decreased appetite (X2 = 5.4, p < .03), trouble sleeping (X2 = 5.4, p < .03), and weight loss (X2 = 4.0, p < .05) occurred statistically more often on MPH than on placebo. During maintenance, trouble sleeping and appetite loss persisted and other MPH-related AEs decreased. There were transient, one-time pulse and blood pressure elevations in five children. Twenty-one children (11%) discontinued because of drug-attributed AEs. Conclusions Eleven percent of preschoolers discontinued treatment because of intolerable MPH AEs. Of the serious AEs reported, one occurred in baseline, two in lead-in, three in titration, one in parallel, and one in maintenance. Only one was possibly related to MPH.

Objective To investigate growth of children with attention-deficit/hyperactivity disorder (ADHD) in the Preschool ADHD Treatment Study (PATS) before and after initiation of treatment with methylphenidate at titrated doses (average, 14.2 mg/day) administered three times daily, 7 days/week for ≈1 year. Method The heights and weights of 140 children with ADHD were measured up to 29 times in the PATS protocol, starting at an average age of 4.4 years. The relationship between standard ( z ) scores and time on medication was examined using mixed-effect regression to estimate change in relative size (slope). Results Average relative size at baseline was significantly ( p z height (+0.45) and z weight (+0.78), indicating greater than expected height (by 2.04 cm) and weight (by 1.78 kg). During treatment, slopes were significantly ( p z height (−0.304/yr) and z weight (−0.530/yr), indicating reduction of growth rates. For 95 children who remained on medication, annual growth rates were 20.3% less than expected for height (5.41 cm/yr − 6.79 cm/yr = −1.38 cm/yr) and 55.2% for weight (1.07 kg/yr − 2.39 kg/yr = −1.32 kg/yr). Conclusions Risks of reduced growth rates should be balanced against expected benefits when preschool-age children are treated with stimulant medication.

To improve the gathering of adverse events (AEs) in pediatric psychopharmacology by examining the value and acceptability of increasingly detailed elicitation methods.Trained clinicians administered the Safety Monitoring Uniform Report Form (SMURF) to 59 parents and outpatients (mean age +/- SD = 11.9 +/- 3.2 years) in treatment, with 36% on stimulants, 29% on selective serotonin reuptake inhibitor drugs, 10% on both, and 25% on other drug combinations. The SMURF included a brief general inquiry, a drug-specific inquiry, and a comprehensive body system review (BSR).SMURF administration took 24.6 +/- 13.9 minutes (median, 21). The BSR took 15.5 +/- 8.1 minutes (median, 14) longer (p.0001) than the general inquiry (4.3 +/- 5.4 minutes) and the drug-specific inquiry (4.2 +/- 2.9 minutes). The general inquiry elicited 48 AEs, the drug-specific inquiry elicited 16 additional AEs, and the BSR 129 additional AEs. Of all the clinically relevant AEs elicited by the SMURF (n = 36), 19 (53%) were elicited by the BSR. The BSR length and detail were acceptable to parents but not to clinicians.The BSR elicited additional clinically significant AEs that had been missed with less detailed methods. Parents, but not clinicians, rated satisfaction and acceptability of the BSR as good.

Objective To consider the relevance of prolonged QTc (QT interval corrected for rate) to pediatric psychopharmacology. Method The authors reviewed publications on QTc prolongation and publications on sudden death in Medline from 1968 to November 2002. Results The search yielded more than 20,000 publications. Review manuscripts with clinical recommendations outnumber the few pediatric studies of QTc duration during treatment. Most reviews have been published in the past 5 years, during a time when the Food and Drug Administration restricted five psychotropic medications because of QTc prolongation (sertindole: not approved; thioridazine, mesoridazine, and droperidol: black-box warning; and ziprasidone: bolded warning) and nine somatic medications because of QTc prolongation. Conclusions Pretreatment screening, careful selection of psychotropic and/or somatic medication combinations, and recognition of QTc prolongation in electrocardiographic tracings during treatment with medications that prolong QTc are important components of clinical practice.

Objective To identify approaches to improving methods for assessing tolerability and safety of psychotropic medications in children and adolescents. Method Strengths and limitations of current methodology were reviewed and possible alternatives examined. Results Research on the validity of safety evaluation has been extremely limited. No evidence-based “gold standard” exists. Clinical trials remain the best design to establish causality, but sample size limitations prevent the detection of infrequent, though serious, adverse events. Other designs, such as cohort and case-control studies, and approaches, such as mining of large databases, must be considered. Conclusions The current lack of methodological standardization across studies prevents generalizations and meta-analyses. Because the issues relevant to drug safety are diverse, a variety of methodological approaches and instruments are needed. It is, however, possible to adopt standard basic definitions of adverse events, degree of severity, ascertainment methods, and recording procedures, as a common “core,” to which more specific assessment instruments can be added. Systematic empirical testing and validation of safety methodology is needed.

To examine whether age, gender, ethnicity, type of anxiety disorder, severity of illness, comorbidity, intellectual level, family income, or parental education may function as moderators and whether treatment adherence, medication dose, adverse events, or blinded rater's guess of treatment assignment may function as mediators of pharmacological treatment effect in children and adolescents with anxiety disorders.The database of a recently reported double-blind placebo-controlled trial of fluvoxamine in 128 youths was analyzed. With a mixed-model random-effects regression analysis of the Pediatric Anxiety Rating Scale total score, moderators and mediators were searched by testing for a three-way interaction (strata by treatment by time). A two-way interaction (strata by time) identified predictors of treatment outcome.No significant moderators of efficacy were identified, except for lower baseline depression scores, based on parent's (but not child's) report, being associated with greater improvement (p.001). Patients with social phobia (p.05) and greater severity of illness (p.001) were less likely to improve, independently of treatment assignment. Blinded rater's guess of treatment assignment acted as a possible mediator (p.001), but improvement was attributed to fluvoxamine, regardless of actual treatment assignment. Treatment adherence tended to be associated (p = .05) with improvement.In this exploratory study, patient demographics, illness characteristics, family income, and parental education did not function as moderators of treatment effect. Social phobia and severity of illness predicted less favorable outcome. Attribution analyses indicated that study blindness remained intact. The presence of concomitant depressive symptoms deserves attention in future treatment studies of anxious children.

Objectives To review extant data on the efficacy and safety of anxiolytic medications (benzodiazepines, buspirone, and other serotonin 1A agonists), adrenergic agents (β-blockers and α 2 -adrenergic agonists clonidine and guanfacine), and the opiate antagonist naltrexone that have been used to treat various psychopathologies in children and adolescents. To identify critical gaps in our current knowledge about these agents and needs for further research. Method All available controlled trials of these medications in children and adolescents published in English through 1997 were reviewed. In addition, selected uncontrolled studies are included. Results The major finding, that there are virtually no controlled data that support the efficacy of most of these drugs for the treatment of psychiatric disorders in children and adolescents, is both surprising and unfortunate. For some drugs, e.g., buspirone and guanfacine, this is because no controlled studies have been carried out in children and/or adolescents. For other drugs, e.g., clonidine and naltrexone, most of the placebo-controlled studies have failed to demonstrate efficacy. Conclusions The strongest recommendations for controlled studies of safety and efficacy in children and adolescents can be given for the following drugs: benzodiazepines for acute anxiety; buspirone (and newer serotonin 1A agonists as they become available) for anxiety and depression; β-blockers for aggressive dyscontrol; guanfacine for attention-deficit/hyperactivity disorder; and naltrexone for hyperactivity, inattention, and aggression in autistic disorder.

The four open and uncontrolled pharmacological trials published in this issue of the Journal are timely and of interest to the psychiatrist who treats children and adolescents. These articles include important informa­ tion on dosage, tolerability, and usefulness of four dif­ ferent medication treatments used in children and adolescents. Each of these clinical trials is unmasked, i.e., unblinded (Meinert, 1986), and none of the studies uses a concurrent control group, i.e., a placebo or com­ parison treatment group. The subjects in each trial were given the medication, and the treating physician, the rater of symptoms, the subject, and family were all aware that the patient was taking active medication. The problem with unmasked and uncontrolled trials is the potential for introducing bias that can influence the results of the study. Of most concern is bias that results in inflated estimates of efficacy and unrealistic reporting of adverse events. We do not suggest that authors of open trials intend to bias the outcome of a study. Rather, in uncontrolled trials, nonspecific treat­ ment effects and the natural course of illness can often account for the observed clinical improvement and be falsely attributed to the active treatment. In addition, the publication of unmasked and uncontrolled trials can create the impression that a medication is effective or lead uniformed readers to conclude that because the trial was published, the results must be "true." The authors must therefore be very clear about the limitation of interpreting the results, and the reader must be skeptical of claims made on the basis of unmasked and uncontrolled trials (Meinert, 1986). Why are these studies published, if there is some chance that bias affected the outcome of the study? The

The sudden death of three children receiving the tricyclic antidepressant medication desipramine for behavioral disorders was reported in 1990. We now provide new information about these children and describe a fourth case. Because desipramine is a useful medication for many children, these deaths pose clinical dilemmas for physicians and families. The cardiac long QT syndrome has been proposed as a mechanism for these sudden deaths. Considerable uncertainty remains about the basis of the apparent association between the use of desipramine and the sudden deaths.

Rigorously designed clinical trials have demonstrated the efficacy and safety of fluoxetine in adults with major depressive disorder and obsessive-compulsive disorder (OCD) but not in patients below 18 years old. This report describes a randomized, double-blind, placebo-controlled, fixed-dose (20 mg qd) trial of fluoxetine in 14 children and adolescents with OCD, ages 8 to 15 years old; the study was 20 weeks long with crossover at 8 weeks. Obsessive-compulsive symptom severity was measured on the Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS) and the Clinician's Global Impression-Obsessive Compulsive Disorder scale (CGI-OCD). The CY-BOCS total score decreased 44% ( N = 7, p = .003) after the initial 8 weeks of fluoxetine treatment, compared with a 27% decrease ( N = 6, p = .13) after placebo. During the initial 8 weeks, the magnitude of improvement for the fluoxetine group significantly exceeded that for the placebo group as measured by the CGI-OCD ( p = .01) but not by the CY-BOCS ( p = .17). The most common drug side effects were generally well tolerated. The results suggest that fluoxetine is a generally safe and effective short-term treatment for children with OCD.

Self-injurious ideation or behavior appeared de novo or intensified during fluoxetine treatment of obsessive-compulsive disorder in six patients, age 10 to 17 years old, who were among 42 young patients receiving fluoxetine for obsessive-compulsive disorder at a university clinical research center. These symptoms required the hospitalization of four patients. Before receiving fluoxetine, four patients had major risk factors for self-destructive behavior including depression or prior suicidal ideation or self-injury. Three hypotheses concerning the apparent association between fluoxetine and these self-injurious phenomena are discussed: (1) coincidence; (2) disorganization of vulnerable individuals secondary to drug-induced activation; and (3) a specific serotonergic-mediated effect on the regulation of aggression.

New technology has played a catalytic role in advancing understanding of etiology, diagnosis, and treatment in virtually all fields of medicine. Child psychiatry, a relatively new medical specialty, has begun to employ such advanced technology in diagnosis and treatment monitoring. This current study demonstrates that, in an inpatient child psychiatric setting, such advanced technology has a positive diagnostic yield of 5% for new medical diagnoses and a cost of about 0.5% of the hospital bed cost. Other tests, such as psychotropic blood level monitoring and psychometric evaluation of cognitive functioning, have a much higher yield. J. Am. Acad. Child Adolesc. Psychiatry , 1990, 29, 6:905–908.

Phenomenology and family history in 21 clinically referred children and adolescents with obsessive compulsive disorder are described. Each child and family participated in a standard clinical psychiatric assessment. The most frequently reported symptoms were repeating rituals, washing, ordering and arranging, checking, and contamination concerns. Controlling behaviors involving other family members were seen in 57% of the patients. Associated psychopathology was common: 38% received an anxiety disorder diagnosis; 29% received a mood disorder diagnosis; tics were observed in 24%. Fifteen (71%) of the children had a parent with either obsessive compulsive disorder ( N = 4) or obsessive-compulsive symptoms ( N = 11). The clinical and research implications of these findings are discussed. J. Am. Acad. Child Adolesc. Psychiatry, 1990, 29, 5:766–772.

Considerable data have been reported concerning comorbidity of various individual psychiatric disorders in children within the diagnostic supradomains of affect/anxiety disorders and behavior disorders as well as between these supradomains. To further examine such comorbidity, 35 psychiatrically hospitalized children were studied in terms of the prevalence of comorbidity, demographic and cognitive characteristics, adaptive functioning and maladaptive behaviors. The prevalence of comorbid behavior + affect/anxiety disorders exceeded 50% of the samples. Children with such comorbidity were similar to children with Behavior only diagnoses in terms of demographic and cognitive characteristics but differed in terms of adaptive functioning and maladaptive behaviors.

About 50% of children referred for clinical evaluation of Tourette's syndrome (TS) also meet criteria for attention-deficit hyperactivity disorder (ADHD). Standard treatment of ADHD with CNS stimulants results in an exacerbation of the tic symptoms in 20 to 50% of these patients. Symptoms of ADHD were treated with desipramine (DMI) in seven boys with chronic tic disorders, aged 7 to 11 years. Five patients (71%) had a moderate or marked reduction in their ADHD symptoms on a clinician's global improvement rating and on parent and teacher rating scales. There was no change in the severity of tic symptoms during DMI treatment in six patients. An intermittent eyeblink became persistent during DMI treatment in one patient. Mild tachycardia was the most common side effect. DMI appears to be safe and effective for children with ADHD and tics or a family history of TS.