Neurogenetic interactions and aberrant behavioral co-morbidity of attention deficit hyperactivity disorder (ADHD): dispelling myths

Theoretical Biology and Medical Modelling Neurogenetic interactions and aberrant behavioral co-morbidity of attention deficit hyperactivity disorder (ADHD): dispelling myths David E Comings 2 Thomas JH Chen 1 Kenneth Blum 0 Julie F Mengucci 4 Seth H Blum 4 Brian Meshkin 3 0 Wake Forest University School Of Medicine, Department Physiology & Pharmacology, Medical Center Boulevard , Winston -Salem, North Carolina, Salugen , Inc. San Diego, California , USA 1 Changhua Christian Hospital , Taiwan, Republic Of China 2 Director, Carlsbad Science Foundation, Emeritus Professor City of Hope Medical Center , Duarte, California , USA 3 Salugen, Inc. , San Diego, California , USA 4 Synapatmine, Inc. , San Antonio, Texas , USA Background: Attention Deficit Hyperactivity Disorder, commonly referred to as ADHD, is a common, complex, predominately genetic but highly treatable disorder, which in its more severe form has such a profound effect on brain function that every aspect of the life of an affected individual may be permanently compromised. Despite the broad base of scientific investigation over the past 50 years supporting this statement, there are still many misconceptions about ADHD. These include believing the disorder does not exist, that all children have symptoms of ADHD, that if it does exist it is grossly over-diagnosed and over-treated, and that the treatment is dangerous and leads to a propensity to drug addiction. Since most misconceptions contain elements of truth, where does the reality lie? Results: We have reviewed the literature to evaluate some of the claims and counter-claims. The evidence suggests that ADHD is primarily a polygenic disorder involving at least 50 genes, including those encoding enzymes of neurotransmitter metabolism, neurotransmitter transporters and receptors. Because of its polygenic nature, ADHD is often accompanied by other behavioral abnormalities. It is present in adults as well as children, but in itself it does not necessarily impair function in adult life; associated disorders, however, may do so. A range of treatment options is reviewed and the mechanisms responsible for the efficacy of standard drug treatments are considered. Conclusion: The genes so far implicated in ADHD account for only part of the total picture. Identification of the remaining genes and characterization of their interactions is likely to establish ADHD firmly as a biological disorder and to lead to better methods of diagnosis and treatment. ADHDattentionhyperactivityinattentiongeneticsaberrant behavioral co-morbiditytreatmentgenomics - A. Either (1) or (2) (1) six (or more) of the following symptoms of inattention have persisted for at least 6 months to a degree that is maladaptive and inconsistent with developmental level: Inattention (a) often fails to give close attention to details or makes careless mistakes in schoolwork, work, or other activities (b) often has difficulty sustaining attention in tasks or play activities (c) often does not seem to listen when spoken to directly (d) often does not follow through on instructions and fails to finish schoolwork, chores, or duties in the workplace (not due to oppositional behavior or failure to understand instructions) (e) often has difficulty organizing tasks and activities (f) often avoids, dislikes, or is reluctant to engage in tasks that require sustained mental effort (such as schoolwork or homework) (g) often loses things necessary for tasks or activities (e.g., toys, school assignments, pencils, books, or tools) (h) is often easily distracted by extraneous stimuli (i) is often forgetful in daily activities (2) six (or more) of the following symptoms of hyperactivity-impulsivity have persisted for at least 6 months to a degree that is maladaptive and inconsistent with developmental level: Hyperactivity (a) often fidgets with hands or feet or squirms in seat (b) often leaves seat in classroom or in other situations in which remaining seated is expected (c) often runs about or climbs excessively in situations in which it is inappropriate (in adolescents or adults, may be limited to subjective feelings of restlessness) (d) often has difficulty playing or engaging in leisure activities quietly (e) is often "on the go" or often acts as if "driven by a motor" (f) often talks excessively Impulsivity (g) often blurts out answers before questions have been completed (h) often has difficulty awaiting turn (i) often interrupts or intrudes on others (e.g., butts into conversations or games) B. Some hyperactivity-impulsive or inattentive symptoms that caused impairment were present before age 7 years C. Some impairment from the symptoms is present in two or more settings (e.g., at school [or work] and at home) D. There must be clear evidence of clinically significant impairment in social, academic, or occupational functioning E. The symptoms do not occur exclusively during the course of a Pervasive Developmental Disorder, Schizophrenia, or other Psychotic Disorder and are not better accounted for by other mental disorder (e.g., Mood Disorder, Anxiety Disorder, Dissociative Disorder, or a Personality Disorder). Code based on type: 314.01 Attention-Deficit/Hyperactivity Disorder, Combined Type: if both Criteria A1 and A2 are met for the past 6 months 314.00 Attention-Deficit/Hyperactivity Disorder, Predominately Inattentive Type: if Criterion A1 is met but Criterion A2 is not met for the past 6 months 314.01 Attention-Deficit/Hyperactivity Disorder, Predominately Hyperactive-Impulsive Type: if Criterion A2 is met but Criterion A1 is not met for the past 6 months Prevalence ADHD is one of the most well-recognized childhood developmental problems. This condition is characterized by inattention, hyperactivity and impulsiveness. It is now known that these symptoms continue as problems into adulthood for 60% of children with ADHD. That translates into 4% of the US adult population, or 8 million adults. However, few ADHD adults are identified or treated. Adults with ADHD may have difficulty following directions, remembering information, concentrating, organizing tasks or completing work within time limits. If these difficulties are not managed appropriately, they can cause associated behavioral, emotional, social, vocational and academic problems. ADHD afflicts 3% to 7.5% of school-age children [1-4]. An estimated 30% to 70% of those will maintain the disorder into adulthood. Prevalence rates for ADHD in adults are not as well determined as rates for children, but fall in the 1% to 5% range. ADHD affects males at higher rate than females in childhood, but this ratio seems to even out by adulthood. Dispelling the myths How is ADHD diagnosed? The diagnosis of ADHD is based on criteria outlined by the Diagnostic and Statistical Manual of the American Psychiatric Association Version 4-TR [1]. This is referred to as the DSM-IV-TR. Table 1 illustrates these criteria. Several similar criteria were set out in earlier versi (...truncated)