Attention-deficit-hyperactivity disorder and reward deficiency syndrome

REVIEW Attention-deficit-hyperactivity disorder and reward deficiency syndrome Kenneth Blum 1,6,7,8,9,10 Amanda Lih-Chuan Chen 2 Eric R Braverman 3,9 David E Comings 4 Thomas JH Chen 5 Vanessa Arcuri 9 Seth H Blum 6 Bernard W Downs 7,8 Roger L Waite 7 Alison Notaro 9 Joel Lubar 10 Lonna Williams 7 Thomas J Prihoda 11 Tomas Palomo 12 Marlene Oscar-Berman 13 Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, NC; 2Department of Engineering and Management of Advanced Technology, Chang Jung University, Tainan, Taiwan, Republic of China; 3Department of Neurosurgery, Weill College of Medicine, New York, NY; 4Department of Medical Genetics, City of Hope Medical Center, Duarte, CA; 5Department of Occupational Safety and Health, Chang Jung University, Tainan, Taiwan, Republic of China; 6Department of Psychoneurogenetics, Synapatamine, Inc., San Antonio, TX; 7LifeGen, Inc., La Jolla, CA; 8Allied Nutraceutical Research, Lederach, PA; 9PATH Research Foundation, New York, NY; 10Department of Physiology, University of Tennessee, Knoxville, TN; 11Department of Pathology, University of Texas Health Science Center, San Antonio, TX; 12 Hospital Universitario 12 de Octubre, Madrid, Spain; 13Boston University School of Medicine, and Boston VA Healthcare System, Boston, MA 1 Parts of this manuscript have been published in Theor Biol Med Model (Comings et al 2005), which is an open access journal Correspondence: Marlene Oscar Berman Boston University School of Medicine and VA Healthcare System, 715 Albany Street, L-815, Boston, MA 02118, USA Email Reprint requests: Kenneth Blum, Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, North Carolina Email Abstract: Molecular genetic studies have identified several genes that may mediate susceptibility to attention deficit hyperactivity disorder (ADHD). A consensus of the literature suggests that when there is a dysfunction in the “brain reward cascade,” especially in the dopamine system, causing a low or hypo-dopaminergic trait, the brain may require dopamine for individuals to avoid unpleasant feelings. This high-risk genetic trait leads to multiple drugseeking behaviors, because the drugs activate release of dopamine, which can diminish abnormal cravings. Moreover, this genetic trait is due in part to a form of a gene (DRD2 A1 allele) that prevents the expression of the normal laying down of dopamine receptors in brain reward sites. This gene, and others involved in neurophysiological processing of specific neurotransmitters, have been associated with deficient functions and predispose individuals to have a high risk for addictive, impulsive, and compulsive behavioral propensities. It has been proposed that genetic variants of dopaminergic genes and other “reward genes” are important common determinants of reward deficiency syndrome (RDS), which we hypothesize includes ADHD as a behavioral subtype. We further hypothesize that early diagnosis through genetic polymorphic identification in combination with DNA-based customized nutraceutical administration to young children may attenuate behavioral symptoms associated with ADHD. Moreover, it is concluded that dopamine and serotonin releasers might be useful therapeutic adjuncts for the treatment of other RDS behavioral subtypes, including addictions. Keywords: attention deficit hyperactivity disorder (ADHD), genes, reward dependence, reward deficiency syndrome, treatment, neuropsychological deficits Characteristics of attention deficit hyperactivity disorder (ADHD) Attention deficit hyperactivity disorder (ADHD) is a complex disorder having multiple causes including genetics as impacted by one’s environment. The condition is usually diagnosed in childhood, when difficulties arise during play and school, and it is marked by lack of concentration, short attention span, and physical restlessness (APA 1994; APA 2000). ADHD often is blamed on bad parenting, or a “bad” attitude. However, brain-imaging studies have shown that children with this disorder have an underlying neurological dysfunction, which likely accounts for their behavior (Zametkin et al 1990; Lou et al 1998). In the simplest terms, the brains of these children have yet to come fully “on-line.” It is conjectured that while certain important brain pathways are working normally, cortical regions involved in attention, impulse control, and stimulus integration abilities, have yet to become fully active. ADHD is a widespread affliction that we are just beginning to understand. People with ADHD suffer from overload (Miller and Blum 2008). That is, they have heightened awareness of incoming stimuli, particularly sight, sound, and touch. They are so bombarded by the normal stimuli in their environment that they cannot filter out the background noise, and they have trouble focusing or concentrating on a problem or a task. Because of their inability to focus, those with ADHD have trouble completing what they start. They have difficulties Neuropsychiatric Disease and Treatment 2008:4(5) 893–917 © 2008 Blum et al, publisher and licensee Dove Medical Press Ltd. This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited. 893 Blum et al with making plans and even more difficulty in carrying out plans in an orderly fashion. People with ADHD tend to be disorganized. Children have messy rooms; adults have cluttered desks; daily activities tend to be chaotic. Attics and basements are likely to be filled with partly completed sewing projects, woodworking projects, repairs, and notebooks; desk drawers are likely to be cluttered with unfinished letters, outlines, and project plans. Many people with the disorder are highly intelligent, but they tend to be underachievers because they cannot concentrate or sustain interest. As a result, family, friends, teachers, and coworkers become impatient and expect them to fail. People with ADHD also have trouble adapting to change. Their life is so full of tumult that even a minor additional change in their routine can be upsetting or can even create a crisis, eg, a parent goes away on a trip, a new teacher takes over a class, the family moves to a new city, or a pet dies. ADHD afflicted people live under stress so severe they cannot tolerate frustration, and when they are frustrated, they are likely to become angry. The anger tends to come suddenly and explosively, accompanied by slamming doors, harsh words, tantrums, and leaving important meetings in a frenzy. Children get into fights; adults lose jobs and alienate friends. Afterwards, they may be sorry, but the damage is done. With their high level of frustration, people with ADHD are impatient. They hate to wait in line, and delays of any kind can make them frantic. Whatever is going on – a trip, a movie, a class, a discussion – they want it to go quickly and be finished. Their impatience makes people with ADHD impul (...truncated)