ABSTRACT
The National Institute of Mental Health (NIMH) proposed the Research Domain Criteria (RDoC) initiative as an alternate way to organize research of mental illnesses, by looking at dimensions of functioning rather than being tied to categorical diagnoses. This paper briefly discusses the motivation for and organization of RDoC, and then explores the NIMH portfolio and recent work to monitor the utility and progress that RDoC has afforded developmental research. To examine how RDoC has influenced the NIMH developmental research portfolio over the last decade, we employed a natural language processing algorithm to identify the number of developmental science grants classified as incorporating an RDoC approach. Additional portfolio analyses examine temporal trends in funded RDoC-relevant grants, publications and citations, and research training opportunities. Reflecting on how RDoC has influenced the focus of grant applications, we highlight examples from research on Attention-Deficit Hyperactivity Disorder (ADHD), childhood irritability, and Autism Spectrum Disorder (ASD). Lastly, we consider how the dimensional and transdiagnostic approaches emphasized in RDoC have facilitated research on personalized intervention for heterogeneous disorders and preventive/early interventions targeting emergent or subthreshold psychopathology.
Subject(s)
Attention Deficit Disorder with Hyperactivity , Autism Spectrum Disorder , Mental Disorders , Attention Deficit Disorder with Hyperactivity/therapy , Autism Spectrum Disorder/therapy , Child , Humans , Mental Disorders/diagnosis , Mental Disorders/therapy , National Institute of Mental Health (U.S.) , Psychopathology , United StatesABSTRACT
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.
Subject(s)
Attention Deficit Disorder with Hyperactivity/drug therapy , Attention Deficit Disorder with Hyperactivity/genetics , Central Nervous System Stimulants/therapeutic use , Membrane Glycoproteins/genetics , Membrane Transport Proteins/genetics , Methylphenidate/therapeutic use , Nerve Tissue Proteins/genetics , 3' Untranslated Regions/genetics , Adolescent , Attention Deficit Disorder with Hyperactivity/physiopathology , Child , Child, Preschool , Cross-Over Studies , Dopamine Plasma Membrane Transport Proteins , Dose-Response Relationship, Drug , Double-Blind Method , Female , Gene Frequency , Genotype , Humans , Male , Minisatellite Repeats/genetics , Neuropsychological Tests , Placebos , Reference Values , Sex Factors , Time Factors , Treatment OutcomeABSTRACT
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.
Subject(s)
Attention Deficit Disorder with Hyperactivity/drug therapy , Central Nervous System Stimulants/therapeutic use , Methylphenidate/therapeutic use , Adolescent , Central Nervous System Stimulants/administration & dosage , Central Nervous System Stimulants/adverse effects , Child , Child, Preschool , Cross-Over Studies , Delayed-Action Preparations , Dose-Response Relationship, Drug , Feeding and Eating Disorders/chemically induced , Female , Humans , Male , Methylphenidate/administration & dosage , Methylphenidate/adverse effects , Parents/psychology , Patient Compliance , Severity of Illness Index , Sleep Initiation and Maintenance Disorders/chemically induced , Teaching , Tics/chemically inducedABSTRACT
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.
