Jefferson B. Prince

A large, double-blind, randomized clinical trial of methylphenidate in the treatment of adults with attention-deficit/hyperactivity disorder

BACKGROUND The few controlled studies of methylphenidate (MPH) in adults with attention deficit/hyperactivity disorder (ADHD) have reported equivocal results. A previous, pilot study by our group suggested that these results were due to inadequate dosing. METHOD We conducted a randomized, 6-week, placebo-controlled, parallel study of MPH in 146 adult patients with DSM-IV ADHD using standardized instruments for diagnosis, separate assessments of ADHD, depressive and anxiety symptoms, and a robust average oral daily dose of 1.1 mg/kg/day. RESULTS We found a marked therapeutic response for the MPH treatment of ADHD symptoms that exceeded the placebo response (76% vs. 19%). Treatment was safe and well tolerated. Response to MPH was independent of socioeconomic status, gender, and lifetime history of psychiatric comorbidity. CONCLUSIONS These results confirm that robust doses of MPH are effective in the treatment of adult ADHD.

Impact of low birth weight on attention-deficit hyperactivity disorder.

ABSTRACT. The objective of the study was to evaluate an association between low birth weight (LBW) and attention-deficit hyperactivity disorder (ADHD) attending to potential family-genetic and environmental confounders. We examined 252 ADHD cases (boys and girls) and 231 non-ADHD controls and their parents. All subjects were extensively assessed with structured diagnostic interviews, cognitive assessments, and structured interviews of prenatal, infancy, and delivery complications. ADHD cases were three times more likely to have been born LBW than were non-ADHD controls, after attending to potential confounders such as prenatal exposure to alcohol and cigarettes, parental ADHD, social class, and comorbid disruptive behavior disorders in parents and offspring. If this association was causal, 13.8% of all ADHD cases could be attributed to LBW. These results converge with prior studies documenting similar associations and indicate that LBW is an independent risk factor for ADHD. Children with LBW, however, make up a relatively small proportion of children with ADHD.

Clonidine for Sleep Disturbances Associated with Attention-Deficit Hyperactivity Disorder: A Systematic Chart Review of 62 Cases

OBJECTIVE Children and adolescents with attention-deficit hyperactivity disorder (ADHD), with or without psychostimulant treatment, frequently suffer from sleep disturbances. This report evaluates the use of clonidine in the treatment of sleep disturbances associated with ADHD. METHOD A systematic search of a computerized database in an outpatient pediatric psychopharmacology unit of patients treated with clonidine for ADHD-associated sleep disturbances (N = 62; 42 children and 20 adolescents) was performed. Patients were rated retrospectively about the type and severity of sleep disturbances at baseline and after treatment with clonidine. RESULTS A majority of patients (85%) treated with clonidine for ADHD-associated sleep disturbances were considered to be much to very much improved by the National Institute of Mental Health global assessment of improvement (sleep). Nighttime clonidine doses ranged from 50 to 800 micrograms (mean +/- SEM; 157 +/- 14 micrograms), and subjects received clonidine for 35.5 +/- 3.5 months. There was no association between response and age group, gender, comorbidity, or concurrent pharmacotherapy. Children and adolescents with ADHD with baseline, medicine-induced, or medicine-exacerbated sleep disturbances responded equally well to clonidine treatment. Mild adverse effects were reported in 19 subjects (31%). CONCLUSIONS These findings suggest that clonidine may be an effective agent for sleep disturbances associated with ADHD, or its treatment, and warrant further controlled investigations.

An open-label, dose-ranging study of atomoxetine in children with attention deficit hyperactivity disorder.

OBJECTIVE The goal of this study was to evaluate the tolerability and effectiveness of the experimental, noradrenergic specific reuptake inhibitor atomoxetine in the treatment of children with attention deficit hyperactivity disorder (ADHD). METHODS This was an open, prospective, dose-ranging study of atomoxetine monotherapy in the treatment of 30 children with ADHD between the ages of 7 and 14 years. Atomoxetine was started at 10-20 mg/day and titrated weekly up to 90 mg over 11 weeks, depending on response and adverse effects. Twenty-two children completed the full 11 weeks. We assessed efficacy with weekly clinician and parent ratings of ADHD and oppositional symptoms and monitored adverse effects, laboratory findings, and cardiovascular parameters. RESULTS Treatment with atomoxetine (mean final, total daily dose of 1.9 mg/kg/day) was very well tolerated without meaningful adverse effects. Atomoxetine significantly reduced core symptoms of ADHD (ADHD-Rating Scale-IV; 38.6% decrease vs. baseline, p < 0.001) with significant improvement (p < 0.05) in all but 1 of the 18 individual items in the ADHD-Rating Scale-IV. More than 75% of subjects who completed 10 weeks of treatment showed > 25% decrease in ADHD symptoms. CONCLUSIONS These findings extend to children the positive results previously reported in adults diagnosed with ADHD who were treated with atomoxetine. These results support additional controlled trials of atomoxetine in cases of pediatric ADHD.

Catecholamine dysfunction in attention-deficit/hyperactivity disorder: an update.

Attention-deficit/hyperactivity disorder (ADHD) is a heterogeneous disease that affects children, adolescents, and adults. Genetic research has confirmed that there is a large hereditary component to this condition and has helped identify some of the genes associated with it. Among these are several genes associated with the catecholaminergic system including the dopamine receptor genes (DRD4 and DRD5), the dopamine transporter gene, and the gene for dopamine &bgr;-hydroxylase, which catalyzes conversion of dopamine to norepinephrine. Attention-deficit/hyperactivity disorder is believed to be a result of abnormalities in the frontal regions of the brain, particularly the prefrontal cortex and associated subcortical structures and circuits. Underpinning these abnormalities are disturbances of catecholamine neurotransmission. Studies have demonstrated that patients with ADHD have depleted levels of dopamine and norepinephrine thought to be largely the result of dysfunction of their respective transporter systems. The efficacy of stimulant agents confirms that the neurotransmitter abnormalities seen in ADHD are primarily catecholaminergic in origin. This article focuses on the catecholaminergic networks of higher cognitive functions such as attention and focus and of motor functions that may be associated with such networks, reviewing both the physiology of such functions and the pathophysiology of ADHD. Researchers are currently investigating whether other neurotransmitter systems may be partially involved and are investigating whether agents that affect these other systems will prove complementary to currently used treatments.

Pharmacotherapy of adult attention deficit/hyperactivity disorder: a review.

Adult attention deficit/hyperactivity disorder (ADHD) is an increasingly recognized disorder with associated psychiatric comorbidity and impairment. Although pharmacotherapy serves an important role in treating ADHD and other concurrent psychiatric disorders in children and adolescents, the use of pharmacotherapeutics for adults with ADHD remains less established. In this report, the effectiveness and dosing parameters of the various agents investigated for adult ADHD are reviewed. A systematic review of the available literature identified 7 studies (N = 193 subjects) of psychostimulants and 10 studies of nonstimulant medications (N = 167 subjects) including antidepressants, antihypertensives, and amino acids for the treatment of ADHD in adults. The majority of double-blind investigations were with the psychostimulants, with the nonstimulant agents, generally antidepressants, studied under open conditions. There was considerable variability in diagnostic criteria, dosing parameters, and response rates between the various studies. Under controlled conditions, the aggregate literature shows that the stimulants had a clinically and statistically significant effect on reducing ADHD symptoms. Open studies on the nonserotonergic antidepressants (tricyclics, bupropion, and monoamine oxidase inhibitors) also show a moderate anti-ADHD effect. The literature appears to support the use of robust doses of both stimulants and antidepressants for ADHD in adults. Further controlled studies applying stringent diagnostic criteria and outcome methodology are necessary to define the range of pharmacotherapeutic options for adults with ADHD.

Improving Access to Mental Health Care for Children: The Massachusetts Child Psychiatry Access Project

BACKGROUND: Inadequate access to care for mentally ill children and their families is a persistent problem in the United States. Although promotion of pediatric primary care clinicians (PCCs) in detection, management, and coordination of child mental health care is a strategy for improving access, limitations in training, time, and specialist availability represent substantial barriers. The Massachusetts Child Psychiatry Access Project (MCPAP), publicly funded with 6 regional consultation teams, provides Massachusetts PCCs with rapid access to child psychiatry expertise, education, and referral assistance. METHODS: Data collected from MCPAP teams measured participation and utilization over 3.5 years from July 1, 2005, to December 31, 2008. Data were analyzed for 35 335 encounters. PCC surveys assessed satisfaction and impact on access to care. RESULTS: The MCPAP enrolled 1341 PCCs in 353 practices covering 95% of the youth in Massachusetts. The MCPAP served 10 114 children. Practices varied in their utilization of the MCPAP, with a mean of 12 encounters per practice per quarter (range: 0–245). PCCs contacted the MCPAP for diagnostic questions (34%), identifying community resources (27%), and consultation regarding medication (27%). Provider surveys revealed improvement in ratings of access to child psychiatry. The rate of PCCs who reported that they are usually able to meet the needs of psychiatric patients increased from 8% to 63%. Consultations were reported to be helpful by 91% of PCCs. CONCLUSIONS: PCCs have used and value a statewide system that provides access to teams of psychiatric consultants. Access to child mental health care may be substantially improved through public health interventions that promote collaboration between PCCs and child mental health specialists.

Use of citalopram in pervasive developmental disorders.

ABSTRACT. This study assessed the effectiveness and tolerability of the selective serotonin reuptake inhibitor citalopram in the treatment of patients with pervasive developmental disorders (PDDs). The medical charts of 15 children and adolescents (aged 6–16 yr) with Asperger syndrome, autism, or PDD not otherwise specified treated with citalopram were retrospectively reviewed. The final dose of citalopram was 16.9 ± 12.1 mg/day with a treatment duration of 218.8 ± 167.2 days. Independent ratings of the Clinical Global Impression (CGI) Severity and Improvement scales allowed comparison between baseline and PDD symptoms at the last visit. Eleven adolescents (73%) exhibited significant improvement in PDD, anxiety, or mood CGI score (z = 2.95;p = .003). Anxiety symptoms associated with PDDs improved significantly in 66% of patients (z = 2.83, p = .005), and mood symptoms improved significantly in 47% of patients (z = 2.78, p = .005). Mild side effects were reported by five patients (33%). These data suggest citalopram may be effective, safe, and well tolerated as part of the treatment of PDDs.

Patterns of psychopathology and dysfunction in clinically referred preschoolers.

ABSTRACT. Despite the growing interest in the use of psychotropic medications in preschoolers, little is known about the clinical presentation of young children referred for psychiatric services. We describe the clinical characteristics, psychiatric disorders, and functioning of preschoolers referred for pediatric psychiatry evaluation. Structured psychiatric interviews assessing lifetime psychopathology by DSM-III-R criteria were completed on clinically referred youth. Family, social, and overall functioning were assessed at intake. From the pool of 1658 consecutive referrals, we identified 200 children less than or equal to (≤) 6 years of age (12%). The most common psychopathology identified was attention deficit hyperactivity disorder (ADHD) (86%), followed by other disruptive behavioral (61%), mood (43%), and anxiety disorders (28%). Co-occurring psychiatric disorders were common with preschoolers manifesting a mean of two major psychiatric disorders per child. Despite their young age, the onset of psychopathology preceded evaluation by a mean (±SD) of 2.2 ± 1.3 years. Preschoolers referred for psychiatric services had high rates of psychopathology with prominent comorbidity and associated dysfunction. These preschoolers are likely to require aggressive interventions including psychopharmacology.

A Controlled Study of Nortriptyline in Children and Adolescents with Attention Deficit Hyperactivity Disorder

OBJECTIVES To study the efficacy and tolerability of nortriptyline (NT) in the treatment of pediatric attention deficit hyperactivity disorder (ADHD). METHODOLOGY Subjects were outpatient children and adolescents with ADHD ascertained from clinical referrals. Subjects were enrolled in a 6-week open study in which NT was titrated to 2 mg/kg/day as tolerated over 2 weeks. Using either a 30 % reduction in the ADHD rating scale or a score of 1 or 2 on the Clinical Global Impression (CGI) scale for ADHD improvement, responders to treatment were then randomized into a 3-week, controlled discontinuation phase. During this phase, subjects either continued on their current dose of NT or were tapered to placebo under double-blind conditions. Subjects were monitored for symptoms of ADHD, oppositionality, anxiety, and depression. RESULTS Of the 35 subjects enrolled in the study, 32 completed the open phase and 23 completed the discontinuation phase. The mean dose of NT was 80 mg (1.8 mg/kg/day), resulting in a serum level of 81 ng/ml. At the conclusion of the open 6-week study, NT was related to a significant reduction in ADHD (p < 0.001) and oppositional symptoms (p < 0.001). At the conclusion of the discontinuation phase, the 12 subjects randomized to NT had significantly lower scores on the DSM-IV ADHD symptom checklist than those 11 subjects randomized to placebo (31 versus 21; t = 2.2; p < 0.04). No significant adverse events were observed, and children were noted to have weight gain during the trial. CONCLUSIONS These data suggest that NT is effective in reducing symptoms not only of ADHD but also of oppositionality. This group of children and adolescents tolerated robust dosing of NT well, with few clinical or cardiovascular adverse events.