Biomedical subjects

Mark A Stein

Publications and source records attributed to Mark A Stein.

9 recordsLinked to original sources

PubMed2006

Plasma homovanillic acid correlates inversely with history of learning problems in healthy volunteer and personality disordered subjects.

Central dopaminergic activity is critical to the functioning of both motor and cognitive systems. Based on the therapeutic action of dopaminergic agents in treating attention deficit hyperactivity disorder (ADHD), ADHD symptoms may be related to a reduction in central dopaminergic activity. We tested the hypothesis that dopaminergic activity, as reflected by plasma homovanillic acid (pHVA), may be related to dimensional aspects of ADHD in adults. Subjects were 30 healthy volunteer and 39 personality disordered subjects, in whom morning basal pHVA concentration and a dimensional measure of childhood ADHD symptoms (Wender Utah Rating Scale: WURS) were obtained. A significant inverse correlation was found between WURS Total score and pHVA concentration in the total sample. Among WURS factor scores, a significant inverse relationship was noted between pHVA and history of "childhood learning problems". Consistent with the dopaminergic dysfunction hypothesis of ADHD and of cognitive function, pHVA concentrations were correlated with childhood history of ADHD symptoms in general and with history of "learning problems" in non-ADHD psychiatric patients and controls. Replication is needed in treated and untreated ADHD samples to confirm these initial results.

Adult↗

PubMed2006

Multisite controlled study of OROS methylphenidate in the treatment of adolescents with attention-deficit/hyperactivity disorder.

BACKGROUND: Despite the persistence of attention-deficit/hyperactivity disorder (ADHD) into adolescence, little is known about the efficacy and tolerability of stimulant medications in this age group. OBJECTIVE: To report the results of a multisite controlled study among adolescents with ADHD evaluating the efficacy and tolerability of osmotic-release oral system (OROS) methylphenidate. DESIGN: Adolescents (N = 220) having a confirmed Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition diagnosis of ADHD underwent dose titration to identify dosages of OROS methylphenidate that improved symptoms to predefined criteria. Subjects successfully completing the dose titration phase (n = 177) (ie, tolerated and responded to treatment and adhered to the protocol) were randomized to receive 2 weeks' treatment with their individualized dosage of OROS methylphenidate (18, 36, 54, or 72 mg once daily) or placebo. Treatment effectiveness was measured using investigator, parent, and adolescent assessments of ADHD. RESULTS: A significant reduction from baseline in the investigator-rated ADHD Rating Scale, the primary efficacy measure, was found with OROS methylphenidate treatment compared with placebo. Similar findings were noted with parent- and adolescent-report measures. Based on a Clinical Global Impression improvement subscale score of much or very much improved, 52% of subjects in the OROS methylphenidate group improved compared with 31% receiving placebo. Thirty-seven percent of subjects required the maximum dosage of 72 mg/d. The incidence of drug-related adverse events was similar between the 2 study groups. CONCLUSION: In adolescents, once-daily OROS methylphenidate significantly reduced ADHD symptoms and was well tolerated using dosages up to 72 mg/d.

Administration, Oral↗

PubMed2005

Sequence variation in the human dopamine transporter gene in children with attention deficit hyperactivity disorder.

The activity of the presynaptic dopamine (DA) transporter (DAT) is critical in mediating the magnitude and duration of dopaminergic signaling in the brain. Multiple genetic studies have found an association between attention deficit hyperactivity disorder (ADHD) and a variable number tandem repeat (VNTR) in the 3'-untranslated region (3'VNTR) of the hDAT gene (SLC6A3), however none of these studies examined the hDAT coding region for polymorphisms. Thus, we sought evidence of polymorphisms in hDAT, focusing on the coding region and splice junctions, utilizing genomic DNA from children diagnosed with ADHD. Two separate ADHD cohorts (N=70 and N=42) were screened and sampled for both status of the 3'VNTR and for common/novel genomic variants. We found evidence of increased DAT variation in African-American subjects as well as in predominantely hyperactive-impulsive probands. Cumulatively, multiple hDAT sequence variants were identified, including five novel variants, as well as one nonsynonymous single nucleotide polymorphism (SNP), converting Ala559 to Val (A559V). A559V was identified in two Caucasian male siblings with ADHD and both subjects were homozygous for the ADHD-associated, 10-repeat 3'VNTR allele. Interestingly, the A559V variant was previously identified in a subject with bipolar disorder [. Molecular Psychiatry 5, 275], a psychiatric disorder that has a significant number of overlapping symptoms with ADHD.

Adolescent↗

PubMed2005

Dopamine transporter genotype and methylphenidate dose response in children with ADHD.

Stimulant medications, such as methylphenidate (MPH), are the most commonly used, effective treatment for ADHD. MPH acts primarily by inhibiting the dopamine transporter (DAT), a protein responsible for the reuptake of dopamine from the synapse into presynaptic terminals. We sought to evaluate the relationship between DAT1 3'-untranslated region (3'-UTR) variable number tandem repeats (VNTR) genotypes and dose response to MPH. Children with ADHD (n=47), ages 5-16 years (mean=9.02 years), underwent a 4-week, double-blinded, crossover trial with forced weekly dosage changes. Children were genotyped for the DAT1 VNTR and evaluated on placebo and three dosage levels of OROS MPH. Parents and clinicians who were blind to genotype and medication status rated ADHD symptoms, impairment, and stimulant side effects each week. Children who were homozygous for the less common, 9-repeat DAT1 3'-UTR genotype displayed a distinct dose-response curve from that of the other genotype groups, with an absence of typical linear improvement when the dose was increased from 18 mg to 36 and 54 mg. Further research is needed to determine the mechanisms related to poor response in patients with the 9/9-repeat genotype, and to determine if this group responds differentially to alternative treatments.

3' Untranslated Regions↗

PubMed2004

Innovations in attention-deficit/hyperactivity disorder pharmacotherapy: long-acting stimulant and nonstimulant treatments.

This article reviews innovations in attentiondeficit/hyperactivity disorder (ADHD) pharmacotherapy and describes research on the newer, long-acting stimulant and nonstimulant treatments for ADHD. Results from peer-reviewed articles comparing the efficacy and safety of longer-acting methylphenidate or amphetamine-based stimulants and the nonstimulant atomoxetine are described. Longer-acting stimulants and nonstimulants provide increased clinical utility compared with short-acting stimulants. Efficacy and safety are similar to 2- or 3-times-a-day treatment with short-acting stimulants. Longer-acting stimulants and nonstimulants provide increased convenience and flexibility for treating youth with ADHD and show considerable promise. Direct head-to-head studies are needed to better inform clinical decision making and to identify moderators and mediators of differential response.

Adolescent↗

PubMed2003

Thyroid function tests and neurocognitive functioning in children referred for attention deficit/hyperactivity disorder.

BACKGROUND: Thyroid abnormalities have been associated with attention deficit/hyperactivity disorder (ADHD) and with other childhood psychiatric disorders. The goal of this study was to determine the relationships between thyroid hormone concentrations, neurocognitive functioning, and psychiatric diagnosis in children. METHODS: Free thyroxine index (FT4I) and thyroid stimulating hormone (TSH) were obtained, along with diagnostic and descriptive information for 338 children referred to a clinic specializing in learning and behavior problems. RESULTS: Thyroid abnormalities were uncommon in children referred for ADHD. After excluding children with thyroid disease, there was a greater proportion with low concentrations of normal FT4I for ADHD-Predominantly Inattentive type (ratio=7.0), but not for ADHD-Combined Type. High concentrations of normal FT4I were associated with mood lability, preoccupations, and lower ratings of attention problems. Thyroxine concentrations within the normal range were differentially associated with ADHD-Combined Type compared to ADHD-Predominantly Inattentive, mood disorders, and pervasive developmental disorders. CONCLUSION: Thyroxine concentrations were associated with mood symptoms and unusual behaviors, and were less strongly related to attentional functioning. Thyroxine concentrations were not related to hyperactivity.

Adolescent↗

PubMed2003

A dose-response study of OROS methylphenidate in children with attention-deficit/hyperactivity disorder.

OBJECTIVE: OROS methylphenidate HCL (MPH) is a recently developed long-acting stimulant medication used to treat attention-deficit/hyperactivity disorder (ADHD). This study was conducted to examine dosage effects on ADHD symptoms and stimulant side effects and to explore potential moderating effects of ADHD subtype. METHODS: Children with ADHD combined type (ADHD-CT) or predominantly inattentive type (ADHD-PI; n = 47), ages 5 to 16 years, underwent a placebo-controlled, crossover trial using forced titration with weekly switches at 3 dosage levels. Parent and teacher ratings of ADHD symptoms were used to evaluate efficacy. In addition, vital signs and standardized measures of stimulant side effects were obtained weekly. RESULTS: Parent ratings were more sensitive to treatment effects than teacher ratings. ADHD symptoms and Clinical Global Impressions Severity Index ratings at each dose condition differed significantly from placebo and baseline ratings, which did not differ from one another. For those with ADHD-CT, there was a clear linear dose-response relationship, with clinically significant reductions in ADHD Rating Scale-IV scores occurring in two thirds to three fourths of the subjects during either 36- or 54-mg dose conditions. Children with ADHD-PI, conversely, were more likely to respond optimally to lower doses and derived less benefit from higher doses, with 60% displaying significant improvement on the ADHD Rating Scale-IV at 36 mg or lower. Mild stimulant side effects were reported during placebo and at all dosage levels. With the exception of insomnia and decreased appetite, which were more common at higher doses, parent report of side effects was not related to dose. In addition, younger and smaller children were more likely to display sleep difficulties and decreased appetite at the higher dose levels Although pulse rate increased slightly with increasing dose, there were no dose effects on blood pressure. CONCLUSIONS: In children with ADHD-CT, the most common subtype of ADHD, increasing doses of stimulant medication were associated with increased improvement of inattention and hyperactivity symptoms. In children with ADHD-PI, symptom improvement occurred at lower doses and less benefit was derived from higher doses. In both ADHD subtypes, higher doses were associated with parent ratings of increased insomnia and decreased appetite.

Adolescent↗

PubMed2002

Can stimulant rebound mimic pediatric bipolar disorder?

The authors describe the case of a 7-year-old girl diagnosed with attention deficit hyperactivity disorder (ADHD) who, following an unsuccessful trial of stimulant medication and subsequent mood symptoms, was diagnosed with bipolar disorder. Following a comprehensive, multidisciplinary assessment, and withdrawal of her complex medication regimen, she was rediagnosed with ADHD. She displayed a positive response to behavioral parent training and pharmacological treatment with a long-acting stimulant. The case illustrates the benefits of a comprehensive, multidisciplinary evaluation and multimodal treatment. Her dramatic response to the long-acting stimulant suggests that many of her affective symptoms were due to stimulant "rebound" versus bipolar disorder. This case highlights the complexities of differentiating severe ADHD from bipolar disorder and suggests that stimulant rebound and other iatrogenic effects should be considered during the differential diagnostic process as potential mimics of bipolar disorder.

Age Factors↗

PubMed2002

Sex differences in young children who meet criteria for attention deficit hyperactivity disorder.

Examined sex differences in a mostly clinic-referred sample of 127 children (22 girls, 105 boys) who met Diagnostic and Statistical Manual of Mental Disorders (4th ed.; [DSM-IV], American Psychiatric Association, 1994) criteria for attention deficit hyperactivity disorder (ADHD) and 125 comparison children (24 girls, 101 boys) matched on age, sex, and race-ethnicity. Children in both groups ranged in age from 3 years, 10 months to 7 years, 0 months. Both girls and boys who met criteria for ADHD were more impaired than same-sex controls on a variety of measures when intelligence and other types of psychopathology were controlled. Teachers reported that boys with ADHD were more inattentive and more hyperactive/impulsive than girls with ADHD. These findings suggest that the diagnosis of ADHD is valid for both girls and boys in this young age range. Young girls and boys who meet DSM-IV criteria for ADHD are more similar than different, but boys tend to display more symptoms of ADHD, particularly in school.

Attention Deficit Disorder with Hyperactivity↗