ARTICLES ORIGINALLY WRITTEN IN ENGLISH

Genetic and environmental etiologies of ADHD, James M. Swanson, Ph.D.

I. Introduction. DSM-IV uses “phenomenological” rather than “etiological” subtypes of ADHD, but in DSM-V, an emphasis on etiology has been promised. Genetic and environmental etiologies have been proposed to account for the behavioral and neuropsychological characteristic of ADHD, but it is becoming increasingly clear that complex diseases such as ADHD result from the interplay of genetic and environmental risk factors.

II. Molecular Genetic Studies. The initial studies used the candidate gene approach based on the “dopamine hypothesis” of ADHD (Wender, 1971; Levy, 1991; Volkow, 1995).  Two candidate genes were targeted— the dopamine transporter (DAT) gene (Cook et al., 1995) with a 40-bp VNTR in the 3’ untranslated (non-coding) region that defined the primary alleles by 9 or 10 repeats (9R or 10R), and the DRD4 gene, with a 48-bp VNTR in a coding region (exon 3) that defined the primary alleles 2, 4, or 7 repeats (2R, 4R, or 7R).  In the initial studies of ADHD clinical samples, Cook et al (1995) reported that an increased prevalence (0.70 to 0.85) and transmission (0.50 to 0.60) of the most prevalent 10R-repeat DAT allele, and LaHoste et al  (1996) observed a higher than expected frequency (0.28 versus 0.12) of the DRD4 7R allele. In general, subsequent studies replicated the initial findings of association of ADHD with the DRD4 gene but not with the DAT gene (see Li et al, 2006). The DRD4 7R allele shows signs of recent (50,000 years ago) positive selection, which may be related to migration and the “Out of Africa” expansion of the human population (see Wang et al, 2005). Ethnic variations exist in population prevalence of the DRD4 allele, with lower prevalence in some ethnic groups in Asia (see Leung et al, 2005) and higher in South America (see Hutz et al., 2000). However, in general findings are similar in ADHD groups from South America and North America (Rohde et al, 2005), but in some South American clinical samples there are indications of interaction of the DRD4 and DAT genes (Roman et al, 2001; Carrasco et al, 2006). Recently, Brookes et al (2006) assessed 51 candidate genes in pathways related to dopamine, norepinephrine and serotonin, and confirmed association of ADHD with the DRD4 and DAT genes, and also provided suggestive evidence of association of ADHD with 16 other genes.

The functional significance of the DRD4 7R allele has been investigated by multiple groups (Swanson et al., 2000; Manor et al., 2002; Langley et al., 2003; Bellgrove et al., 2005), using neuropsychological tasks that required speeded response and comparing subgroups based on the 7-present and 7-absent genotype (i.e., those with and without a 7R allele) on measures of reaction time (RT) and RT variability.  In general, the 7-present subgroups had faster and less variable responses on choice RT tasks than the 7-absent subgroups. Based on performance on the Matching Familiar Figures test, Langley et al. (2003) suggested ADHD children with the 7-present genotype had an impulsive style of responding, and Kieling et al. (2006) provided similar evidence of impulsive responding on the Continuous Performance Test. These studies provided support for the speculation by Swanson et al (2000 and 2007) that the presence of the 7R allele identifies a genetic variant of ADHD characterized by a cognitive style that produces behavioral excesses without the usual cognitive deficits (slow and variable RT), while the absence of the 7R allele identifies an environmental variant of ADHD characterized by both behavioral excesses and cognitive deficits on speeded tasks (slow and variable RTs).

Genome scans (see Fisher et al., 2002 and Bakker et al., 2003) have also been used in attempts to discover additional genes involved in the etiology of ADHD.  Neither of these genome scans revealed a strong signal from a specific location on the human genome to direct the search for a specific gene, and the reported weak signals were different for these two genome scans (Fisher et al: 5p, 10q, 12q, and 16p; Bakker et al: 15q, 7p, and 9q). Ogdie et al (2003) provided a report on an expansion of the sample reported by Fisher et al (2002), and reported a signal for a gene in a region on 17p11 previously linked to autism. Arcos-Burgos et al. (2005) conducted a family study of a population isolate and identified linkage to loci at 4q13.2, 5q33.3, 11q22, and 17p11.

The lack of a strong signal from genome scans does not discount the existence of genes with high probability risk alleles, of multiple genes that combine to confer risk for ADHD, or of genes with effects that depend on interactions with environmental factors.

III. Environmental Studies. Taylor and Rogers (2005) review this area in detail. Linnett et al (2003) reviewed the literature on maternal lifestyle factors that exposed the developing fetus to nicotine, alcohol, caffeine, and stress, and only nicotine conferred risk for ADHD (see Millberger et al,  1996 and Thapar et al., 2003). Schmidt et al (2006) extended this finding and showed smoking during pregnancy was associated with ADHD-Inattentive Type. In a population sample, Braun et al (2006) reported 31.7% were exposed to prenatal tobacco exposure, which was associated with ADHD diagnosis (odds ratio = 2.5, with a population attributable fraction = 18.4%). Braun et al. (2006) also showed that exposure to very low levels of lead (in the range of 1-2 ug/dL) was common (7.9%) and was associated with ADHD (odds ratio = 4.1, with a population attributable fraction = 21.1%).

Barker et al (1989) proposed the hypothesis of developmental origins of health and disease (DOHaD), which was been elaborated by Gluckman and Hanson (2004). A similar hypothesis was proposed by Lou (1996), who revised the notion that a variety of types and degrees of stress during pregnancy produced specific minimal brain damage (Bax and McKeith, 1962) to striatal dopamine neurons and as a consequence, behavioral excesses and attentional deficits manifested as symptoms of ADHD. Recently, in a PET study of adolescents born premature, Neto et al (2002) documented low levels of extracellular dopamine in striatal regions, consistent with the prediction of Lou (1996).  In separate studies, similar abnormal (blunted) catecholamine response to stress was documented in children with a history of traumatic brain injury (Konrad et al, 2003) and ADHD (Wigal et al., 2003). Swanson et al (2007) review these and other studies and suggested that the etiology of an environmental variant of ADHD (associated with the 7-absent genotype) was related to subtle damage to striatal dopamine neurons during fetal development, while the etiology of a genetic variant (associated with the 7-present genotype) was related to the inheritance of a subsensitive dopamine receptor.

IV. Gene-Environment Interaction. Few molecular genetic studies of ADHD have addressed gene-environment interactions.  Kahn et al (2003) evaluated maternal smoking and the DAT gene and found for cases with maternal smoking during pregnancy, ADHD symptoms were more severe in individuals homozygous for the most frequent allele of the DAT gene (the 10R/10R genotype) but not if other alleles were present (e.g., the 9R/10 or the 9R/9R genotype).  Brookes et al (2006) evaluated the DAT gene and two environmental factors, maternal alcohol consumptions (any vs. none) and heavy smoking (at least 20 cigarettes/day), during pregnancy. They reported linkage disequilibrium (non-random association of alleles) was present only those cases where maternal alcohol consumption was reported, and that the interaction of DAT genotype with maternal smoking during pregnancy was not significant.

V. Conclusions and Next Steps. Much larger sample sizes will be required to go beyond these important first steps to evaluate gene by environment interactions related to ADHD. The National Children’s Study (NCS) (see www.nationalchildrensstudy.gov) planned for the USA will recruit a large birth cohort of 100,000 children and to obtain broad measures of exposure and outcome taken in 16 visits scheduled across stages of development. As outlined in Landrigan et al. (2006), the NCS assessments will occur before conception; 3 times during pregnancy; at birth; at 1, 6, 12, and 18 months of age in early childhood; at 3, 5, 7, 9, and 12 years of age in childhood; at 16 and 20 years of age in adolescence. This should provide a large sample of affected children (3,000 to 5,000 with diagnoses of ADHD, depending on diagnostic criteria) with careful documentation of genetic and environmental exposures that will allow for evaluation of critical issues about the genetic and environmental contributions to ADHD as well as other childhood disorders.

Swanson et al (2007) suggested the evaluation of subtypes of ADHD would be to consider two types of etiologic factors – genetic and environmental. The review presented here suggests the genetic factors should include at a minimum the DRD4 and DAT genotypes, and the environmental factors should include at a minimum some environmental toxicants (nicotine, alcohol, and lead) and some pregnancy factors (preterm birth and small size due to growth restriction).

____________________
James M. Swanson, Ph.D. Professor of Pediatrics; Director, Child Developmental Center, University of California, Irvine, USA.

Dr. Armando Filomeno thanks the distinguished psychologist and neuroscientist for this article which he translated into Spanish for APDA’s electronic newsletter nº 15, issued on March 25, 2007.

References.
Arcos-Burgos M, Castellanos FX, Pineda D, Lopera F, Palacio JD, Palacio LG, Rapoport JL, Berg K, Bailey-Wilson JE, Muenke M. (2004). Attention-Deficit/Hyperactivity Disorder in a Population Isolate: Linkage to Loci at 4q13.2, 5q33.3, 11g22, and 17p11. Am J Hum Genetics. 75: 998-1014.

Bakker SC, van der Meulen EM, Buitelaar JK, Sandkuijl LA, Pauls DL, Monsuur AJ et al. (2003). A whole-genome scan in 164 Dutch sib pairs with attention-deficit/hyperactivity disorder: suggestive evidence for linkage on chromosomes 7p and 15q. Am J Hum Genet. 72:1251-1260.

Barker DJO, Osmond C, Winter PD, Margetts B and Simmonds SJ. (1989). Weight in infancy and death from ischaemic heart disease. Lancet. 2:577-580.

Bax M and McKeith RM, eds. Minimal Cerebral Dysfunctions. Clinics in Developmental Medicine. Lavenham, Suffolk: The Lavenham Press LTD, 1962.

Bellgrove MA, Hawi Z, Lowe N, Kirley A, Robertson IH and H Gill. (2005). DRD4 gene variants and sustained attention in ADHD: effects of associated alleles at the VNTR and -521 SNP. Am J Med Genet B Neuropsychiatr Genet. 136:81-6.

Braun J, Kahn RS, Froehlich T, Aulnger P and BP Lanphear. (2006). Exposures to Environmental Toxicants and Attention Deficit Hyperactivity Disorder in US Children. Environmental Health Perspectives. 114:1904-9.

Brookes K, Xu X, Chen W, Zhou K, Neale B, Lowe N, Aneey R, Franke B, Gill M, Ebstein R, Buitelaar J, Sham P, Campbell D, Knight J, Andreou P, Altink A, Amold R, Boer F, Buschgens et al.  (2006). The analysis of 51 genes in DSM-IV combined type attention deficit hyperactivity disorder: association signals in DRD4, DAT1 and 16 other genes.  Molecular Psychiatry.  11: 934-953.

Brookes KJ, Mill J, Guindalini C, Curran S, Xu, X, Knight J, Chen CK, Huang YS, Sethna V, Taylor E, Chen W, Breen G, Asherson P. (2006). A common haplotype of the dopamine transporter gene associated with attention-deficit/hyperactivity disorder and interacting with maternal use of alcohol during pregnancy.  Arch Gen Psychiatry. 63: 74-81.

Carrasco X, Rothhammer P, Moraga M, Henriquez H, Chakraborty R, Aboitiz F, Rothhammer F. (2006). Genotypic interaction between DRD4 and DAT1 loci is a high risk factor for ADHD in Chilean families.Am J Med Genet B Neuropsychiatr Genet. 141:51-4 .

Cook EH, Jr., Stein MA, Krasowski MD, Cox, NJ, Olkon DM, Kieffer JE, et al. (1995). Association of attention deficit disorder and the dopamine transporter gene. Am J Hum Genet. 56:993-998.

Crowe RR. (1993). Candidate genes in psychiatry: an epidemiological perspective. Am J Med Genet. 48:74-77.

Fisher SE, Francks C, McCracken JT, McGough JJ, Marlow AJ, MacPhie IL et al.(2002). A genome wide scan for loci involved in attention-deficit/hyperactivity disorder. Am J Hum Genet. 70:1183-1196.

Gillman M. (2005). Developmental Origins of Health and Disease. New England Journal of Medicine. 353:1848-50.

Gluckman PD and MA Hanson. (2004). Living with the Past: Evolution, Development, and Patterns of Disease. Science. 305: 1733-6.

Hutz MH, Almeida S, Coimbra CE Jr, Santos RV, Salzano FM. (2000). Haplotype and allele frequencies for three genes of the dopaminergic system in South American Indians. Am J Hum Biol. 12:638-645.

Kahn RS, Khoury J, Nichols WC, Lanphear BP. (2003). Role of dopamine transporter genotype and maternal prenatal smoking in childhood hyperactive-impulsive, inattentive, and oppositional behaviors.  J Pediatrics. 143: 104_110.

Kieling C, Roman T, Doyle AE, Hutz MH, Rohde LA. (2006). Association between DRD4 gene and performance of children with ADHD in a test of sustained attention. Biol Psychiatry. 10:1163-5.

Knopik VS, Health AC, Jacob T, Slutske WS, Bucholz KK, Madden PAF, Walron M, Martin NG.  (2006). Maternal alcohol use disorder and offspring ADHD: disentangling genetic and environmental effects using a children-of-twins design.  Psychological Medicine. 36: 1461-1471.

Konrad K, Gauggel S, Schurek J. (2003). Catecholamine functioning in children with traumatic brain injuries and children with attention-deficit/hyperactivity disorder. Brain Res Cogn Brain Res. 16:425-33.

LaHoste GJ, Swanson JM, Wigal SB, Glabe C, Wigal T, King N, Kennedy JL. (1996). Dopamine D4 receptor gene polymorphism is associated with attention deficit hyperactivity disorder. Molecular Psychiatry. 1:121-124.

Landrigan PJ, Trasande L, Thorpe LE, Gwynn C, Lioy PJ, D’Alton ME, Lipkind HS, Swanson J, Wadhwa PD, Clark EB, Rauh VA, Perera FP, Susser E.  (2006). The National Children’s Study: a 21-year prospective study of 100,000 American children. Pediatrics 118:2173-86.

Langley K, Marshall L, van den Bree M, Thomas H, Owen M, O’Donovan M et al. (2004). Association of the dopamine D4 receptor gene 7-repeat allele with neuropsychological test performance of children with ADHD. Am J Psych 161:133-138.

Leung PWL, Lee CC, Hung SF, Ho TP, Tang CP, Kwong SL, Leung SY, Yuen ST, Lieh-Mak F, Oosterlaan J, Grady D, Harxhi A, Ding YC, Chi HC, Flodman P, Shuck S, Spence MA, Moyzis R, Swanson JM. (2005). Dopamine receptor D4 (DRD4) gene in Han Chinese children with attention deficit/hyperactivity disorder (ADHD): Increased prevalence of the 2-repeat allele. Am J Med Genet B Neuropsychiatr Genet 133(1):54-6.

Levy F. (1991). The dopamine theory of attention deficit hyperactivity disorder (ADHD). Australian and New Zealand Journal of Psychiatry. 25:277-283.

Li D, Sham PC, Owen MJ, He L. (2006). Meta-analysis shows significant association between dopamine system genes and attention deficit hyperactivity disorder (ADHD). Hum Mol Genet. 15: 2276-84.

Linett K, Dalsgaard S, Obel C, Wisbord K, Henriksen TB, Rodriguez A, Kotimaa A, Moilanen I, Thomsen PH, Olsen J, Jarvelin M. (2005). Maternal Lifestyle Factors in Pregnancy Risk of Attention Deficit Hyperactivity Disorder and Associated Behaviors: Review of the Current Evidence. Am J Psychiatry. 160:1026-1040.

Linett KM, Wisborg K, Agerbo E, Sechor NJ, Thomsen PH, Henriksen TB. (2006). Gestational age, birth weight, and the risk of hyperkinetic disorder. Arch Dis Child. 91:655-60.

Lou HC. (1996). Etiology and pathogenesis of attention-deficit hyperactivity disorder (ADHD): significance of prematurity and perinatal hypoxis-haemodynamic encephalophy. Acta Paediatr. 85: 1266-1271.

Manor I, Tyano S, Eisenberg J, Bachner-Melman R, Kotler M, Ebstein RP. (2002). The short DRD4 repeats confer risk to attention deficit hyperactivity disorder in a family-based design and impair performance on a continuous performance test (TOVA). Mol Psychiatry. 7:790-794.

Millberger S, Biederman J, Faraone SV, Chen L, Jones L.  (1996). Is maternal smoking during pregnancy a risk factor for attention deficit hyperactivity disorder in children? Am J Psychiatry. 153: 1138-1142.

Mick E, Biederman J, Faraone SV, Sayer J, Kleinman S. (2002). Case-Control study of attention-deficit hyperactivity disorder and maternal smoking, alcohol use, and drug-use during pregnancy. J Am Acad Child Adolesc Psychiatry. 41:378-85.

Neto P, Lou H, Cumming P, Pryds O, Gjedde A. (2002). Methylphenidate-evoked potentiation of extracellular dopamine in the brain of adolescents with premature birth. Ann N Y Acad Sci. 965:434-439.

Ogdie M, Macphie IL, Minassian SL, Yang M, Fisher SE, Francis CF, Cantor RM, MacCracken JT, McGough JJ, Nelson SF, Monaco AP, Smalley SL. (2003). A genome wide scan for attention-deficit/hyperactivity disorder: suggestive linkage on 17p11.  Am J Hum Genet. 72:1268-1279.

Rohde LA, Szobot C, Polanczyk G, Schmitz M, Martins S, Tramontina S. (2005). Attention-deficit/hyperactivity disorder in a diverse culture: do research and clinical findings support the notion of a cultural construct for the disorder? Biol Psychiatry 57:1436-41.

Roman T, Schmitz M, Polanczyk G, Eizirik M, Rohde LA, Hutz MH. (2001). Attention-deficit hyperactivity disorder: a study of association with both the dopamine transporter gene and the dopamine D4 receptor gene. Am J Med Genet. 105:471-8.

Schmitz M, Denardin D, Laufer Silva T, Pianca T, Hutz MH, Faraone S, Rohde LA. (2006). Smoking during pregnancy and attention-deficit/hyperactivity disorder, predominantly inattentive type: a case-control study. J Am Acad Child Adolesc Psychiatry. 11:1338-45.

Swanson JM, Sunohara GA, Kennedy JL, Regino R, Fineberg E, Wigal T, Lerner M, Williams L, LaHoste GJ, Wigal S.  (1998). Association of the dopamine receptor D4 (DRD4) gene with a refined phenotype of attention deficit hyperactivity disorder (ADHD): a family-based approach.  Molecular Psychiatry, 3(1):38-41.

Swanson JM, Kinsbourne M, Nigg J, Lanphear B, Stefanatos G, Volkow N, Taylor E, Casey BJ, Castellanos FX, and Wadhwa. (2007). Etiologic Subtypes of ADHD: Brain Imaging, Molecular Genetic and Environmental Factors and the Dopamine Hypothesis. Neuropsychology Review 17: 39-59.

Taylor E and Rogers JW.  (2005). Practitioner review: early adversity and developmental disorders.  J Child Psychology and Psychiatry.  46: 451-467.

Volkow ND, Ding YS, Fowler JS, Wang GJ, Logan J, Gatley JS et al. Is methylphenidate like cocaine? Studies on their pharmacokinetics and distribution in human brain. (1995). Arch Gen Psychiatry; 52:456-463.

Wang E, Ding YC, Flodman P, Kidd JR, Kidd KK, Grady DL, Ryder OA, Spence MA, Swanson JM, Moyzis RK. (2004). The genetic architecture of selection at the human dopamine receptor D4 (DRD4) gene locus. Am J Hum Genet 74(5):931-944.

Wender P. (1971). Minimal brain dysfunction in children. New York: Wiley-Liss.

Wigal SB, Nemet D, Swanson JM, Regino R, Trampush J, Ziegler MG, Cooper DM. (2003).  Catecholamine response to exercise in children with attention deficit hyperactivity disorder. Pediatr Res, 53(5):756-761.

Coaching children and teens with ADHD – It works!, Jodi Sleeper-Triplett, MCC

For many children and teens with AD/HD, coaching helps them learn techniques to be more focused, stay on task, and improve time management and organizational skills.  These skills are the building blocks for success in the future. By initiating the coaching process with school-aged children, we are able to keep students motivated and help them to build self-confidence and self-awareness during the formative years.

Coaching can be successful with children who have the cognitive ability to understand rewards and consequences.  The level of understanding varies by age and by the individual child. If the child can understand that completing a task, such as brushing teeth, will result in a sticker or token, a positive reward, it is possible to institute a coaching program. Many times the coaching is most successful when the parents, families and/or school personnel are actively involved in the process.

Together the coach and child collaborate with the “team” to design an appropriate coaching program. This process requires the coach helping the child to explore and identify motivators, in particular external ones that will be appealing to the child.

Readiness for the coaching process is critical to results/success in children. Chronological age is not always the best indicator for children with AD/HD. They may mature more slowly than their peers.  It is important to be sure that the child is ready to work independently with an “outsider”.  It is recommended that with young children, ranging in age from 5 to 8, that the coaching is done directly with the parents. In turn, the parents will implement the coaching plan and set the structures at home and at school.  Choose a coach who has had positive experiences working with the age group in which your child falls. When the child is slightly older, it may be helpful to arrange for coaching sessions with both the parents and the child, separately and as a team.

Teens are drawn to coaching once they understand that a coach is a non-judgmental, supportive partner. Most teens are interested in improving academic achievement and social skills; and in learning new organizational and time management strategies. Coaching can be very beneficial for teenagers. However, it requires involvement from the parents as well. Teens are not going to seek out a coach; the parents usually request services. Therefore, it is important to have them involved from the beginning.  As a part of the coaching agreement, the coach, the teen and the parents can agree to terms that will work for everyone involved. Creating and posting a written coaching contract, which includes clear expectations and rewards, is helpful for both parents and teens.

One of the more sensitive areas when working with teens is trust. It can become a problem if not addressed at the initial meeting. There must be a clear understanding of the issues that are to be held confidential between client and coach, and what information is shared with the parents. One solution to this potential problem is a weekly or bi-weekly update with the parents and teen. These updates provide information for the parents to discuss with their teen. Include a review of the goals, which have been previously agreed upon by the parents and the teen.

Suggestions for effective behavioral coaching for younger children are as follows:

– Target a behavior you wish to increase or improve.
– To increase the frequency of the behavior, select a reinforcement that is rewarding/appealing to the child, such as:
Attention and praise – use these as often as possible
Extra free time or special playtime  (this may include TV and video game time)
Tokens or stickers to be tallied up for weekly tangible rewards
Special one-on-one time with mom or dad
– Reward behaviors immediately and continuously.
– If the child does not demonstrate the target behavior, reward those behaviors that are very close to the
target behavior.
– Use of positive reinforcement should ALWAYS outnumber the use of any negative consequences. Use
negative consequences only after the positive reinforcement program has had ample time to be effective.
– The child should always be told what to do to avoid the negative consequences and the negatives should
be  clearly explained.
– Negative consequences should be delivered in a firm way, without emotion, lectures or long explanations.
– Ignoring inappropriate behavior can be used instead of delivering specific negative consequences, but only
if the behavior can be completely ignored and does not continue to escalate, cause harm or disruption.

Suggestions for effective goal setting for teens:

– Develop a contract. List the goals you wish to increase or improve. Sit down with your teen and work
out this list together. Be reasonable and set goals that are attainable and clear.
– Include a list of rewards and consequences. Be clear about the limits and set weekly or bi-weekly review time to assess progress. Be sure YOU stick to the plan to help your teen stick with the target goals.
– Be sure all parties sign the contract – parents and teen. Post it prominently.
– Use of positive reinforcement should ALWAYS outnumber the use of any negative consequences. Give the positive reinforcement program ample time to be effective.
– The teen should always be told what to do to avoid the negative consequences and the negatives should be clearly explained.
– Negative consequences should be delivered in a firm way, without emotion,lectures or long explanations.  The rules are set in the contract.
– To increase the frequency of success, select a reward/motivator that is appealing to the teen. Examples include:
Extra free time                                   Computer time
Time with friend                                 Reduction of work/chores
Dinner out                                          Money for a CD or video
Cash for gas                                       “Chips” toward a large purchase
– Reward progress frequently. Goals are reached in steps/stages. Each step deserves positive recognition. A  positive attitude is the key to success. It builds skills, self-confidence and self-esteem.
– If the teen does not demonstrate effort toward the target goals, review the goals. Are they too “lofty”, too difficult? Might it help to restate the goals or provide a new motivational tool? Work it out together, calmly.

Coaching is a beneficial tool for many children and teens. Choosing a coach who has experience working with children and teens, understands the intricacies of the AD/HD brain, medications and co-existing conditions is of the utmost importance. It is essential to work with a coach who has a good rapport with the child or teen. Be sure that the young client, especially teens, interview the coach before the process begins. The connection between coach and client, of any age, is essential for coaching to be a success.

____________________
Jodi Sleeper-Triplett is a master certified coach. She is an active member of CHADD, ADDA and of the American Coaching Association.
E-mail: Jstcoach@aol.com

Beatriz Duda, who attended Jodi Sleeper-Triplett’s coaching courses and workshops at CHADD International Conferences in Dallas (2005) and Chicago (2006), thanks her for this article which was published in Spanish in APDA’s electronic newsletter nº 14, issued on December 22, 2006.

ADHD and its comorbid disorders, Steven R. Pliszka, M.D.

ADHD is the most common behavioral disorder of childhood. Uncomplicated ADHD is a fairly straightforward disorder to diagnose and treat, but significant numbers of children and adolescents with ADHD have comorbid disorders. In these situations, the differential diagnosis is much more difficult and treatment can be quite complex. Over the last several decades, considerable research has been done to determine the prevalence of various comorbid diagnoses in children with ADHD. The most common comorbid diagnosis is that of oppositional defiant disorder, which can affect up to 60% of both boys and girls with ADHD. A smaller percentage of around 20% children with ADHD may develop conduct disorder. The prevalence rates for mood and anxiety disorders are somewhat more variable and less well defined, but at least a third of children with ADHD may develop an anxiety disorder. The rate of major depressive disorder (MDD) among children with ADHD has been estimated to range from 10 to 30%. Figures for the prevalence of mania on children with ADHD are somewhat more difficult to come by. Biederman and his colleagues found that up to 16% of their sample of ADHD children met criteria for mania.  In contrast, U.S. National Institute of Mental Health Multimodal Treatment Study of Children with  ADHD (MTA) did not find it necessary to exclude any children. Nonetheless, the MTA study did find a subgroup of ADHD children who showed very high levels of mood lability, aggression and hyperactivity. There is often disagreement among clinicians as to how many of these types of children truly have bipolar disorder.

Oppositional defiant disorder (ODD) is a pattern of negativistic, hostile and defiant behavior.  Children with ODD lose their tempers easily, argue with and frequently defy adults, and show irritating behavior toward peers. They tend to remain angry and resentful for long periods of time and are often spiteful or vindictive. ODD varies greatly in its severity. It is important to note that both ODD and conduct disorder are descriptive diagnosis that do not imply any particular etiology. This is in contrast to the diagnosis of ADHD which is a primarily neuro-biological condition. ODD may be secondary to ADHD —a child with ADHD may be so impulsive that he reacts with anger and poor judgment to any adult request or to any stressor. Therefore it is important that when the child meets criteria for both ADHD and ODD, the clinician should consider the ADHD to be primary. A number of studies have now shown that oppositional behaviors improved with treatment of the ADHD. This is true for all of effective treatments for ADHD, including both stimulants and atomoxetine.

Conduct disorder is a much more severe disorder, because it involves aggression and antisocial behavior. Children with ADHD and conduct disorder can be differentiated from those with ADHD alone by a number of factors. ADHD children with comorbid ODD/CD are also more likely to have learning disorders, particularly in the area of language. They are more likely to have a family history of antisocial behavior and are at greater risk for developing delinquent behavior during adolescence. Children with ADHD alone have a higher risk of developing substance-abuse disorders as adults, but children with ADHD and comorbid ODD/CD often began experimentation with illegal substances during early adolescence.

It is important to bear in mind that children with ADHD and comorbid ODD/CD respond as well to stimulants as children with ADHD alone. There is no evidence that stimulants or other medications used to treat ADHD increase aggression at appropriate doses except in very rare circumstances. There has also been considerable research on whether treatment with stimulants itself is a risk factor for substance abuse. Timothy Wilens and his colleagues reviewed a number of studies examining the rate of substance-abuse disorders in children with ADHD as a function of their stimulant treatment history. In fact, children with ADHD who never received treatment with medication had a higher rate of substance abuse than those who received treatment. This suggests that effective treatment of the ADHD may actually prevent the development of later substance-abuse disorders.

If oppositional and aggressive behaviors persist after the ADHD has been adequately treated, then several approaches should be considered. The clinician should consider adding a behavior management program. This usually consists of identifying key oppositional behaviors that need to be targeted —for instance a child needs to improve on behaviors such as not hitting a sibling, doing things first-time asked and doing his homework promptly. Each day he receives points from the parent based on how well he has performed these tasks. His weekly allowance is then based on how many points he earns during the week. If he earns a particularly high level of points, then some special privilege is awarded. In contrast, if the number of points earned is extremely low, then some restriction from weekend activities is called for. Alpha agonists such as clonidine or guanfacine have been combined with stimulant medication to treat temper outbursts and aggression. Adverse events such as dizziness and low blood pressure may occur however, and parents should be warned about these risks. In severe situations, where the aggressive behavior is dangerous to the patient or to others, then mood stabilizing or atypical antipsychotic medication may be appropriate. I will return to this topic after our discussion of ADHD and bipolar disorder.

Studies examining the prevalence of depressive disorders in children and adolescents with ADHD have yielded variable results. Roughly 11% of the patient’s in the MTA of ADHD study met criteria for major depressive disorder. In most studies of children with depression the rate of ADHD is approximately 30%. When a child presents with both ADHD and MDD the clinician faces the dilemma as to which condition to treat the first. The Texas Children’s Medication Algorithm Project (CMAP) recommends that the clinician assess each disorder and determine which is the most severe; this disorder should be the focus of initial psychopharmacologic management.   After the ADHD has been successfully treated, the clinician should assess whether the depressive symptoms remain problematic. If so, the clinician should begin treatment of the depression, usually with a serotonin reuptake inhibitor or institute a psychosocial intervention. In contrast, if the major depressive episode is quite severe (with a high level of the neurovegetative signs and/or suicidal ideation), then an antidepressant treatment should be the initial intervention. If the ADHD symptoms persist after the depression has remitted, then a stimulant may be added to the antidepressant regimen.

Up to one third of children with ADHD may also have a comorbid anxiety disorder. Quite often, these anxiety symptoms are mild in severity, and are related to the high level of stress that the child feels due to the dysfunction in his life. If the child’s worries are confined to the consequences of his ADHD behaviors, then the clinician can be reasonably optimistic that these anxiety symptoms will remit once the ADHD is under control. In other cases, however, the child will suffer from intense anxiety including phobias, obsessive-compulsive symptoms, or high levels of generalized anxiety associated with physiological symptoms such as racing heart, muscle tension or trouble sleeping. The Texas Children’s Algorithm Project (CMAP) recommended two different approaches for dealing with this situation. Atomoxetine has been shown to be effective for the treatment of both anxiety and ADHD, so it may be considered an initial treatment in this situation. Alternatively, the child may be treated with a stimulant, but if the anxiety symptoms do not remit after treatment of the ADHD, then a serotonin reuptake inhibitor can be added to the stimulant in the treatment of both anxiety and depressive disorders. One should not lose track of the fact that psychotherapy, particularly cognitive behavioral psychotherapy, is a very effective treatment for these disorders. Thus it is equally acceptable to combine pharmacologic treatment of the ADHD with a psychosocial intervention for the anxiety.

The treatment of the comorbidity of ADHD and bipolar disorder is perhaps one of the most difficult problems in child and adolescent psychiatry. For the purposes of this paper, we will include in the bipolar spectrum those patients with severe mood lability and aggression who may not have all of the classic DSM-IV symptoms of bipolar disorder. If a patient with ADHD is floridly manic, then mood stabilization is the priority and treatment of the ADHD should be deferred until this has occurred. In childhood and adolescence, lithium and valproate have been studied in controlled trials. Considerable open trial data suggests the efficacy of atypical antipsychotics.  Atypical antipsychotics have the advantage that they have a rapid onset of action and very flexible dosing. They generally require less laboratory monitoring than lithium or valproate.  Nonetheless they are associated with weight gain, a risk of diabetes, metabolic syndrome and elevated cholesterol. Children on atypical antipsychotics require monitoring of weight, and serum lipids at least twice a year.  When mood stabilization has been achieved then treatment of the ADHD can progress. In situations in which the diagnosis of the mania is less clear or in doubt, then the initial treatment should address the ADHD. If the putative mania symptoms resolve with successful treatment of the ADHD then it is unlikely that the child was in fact suffering from a bipolar disorder. In contrast, if the child’s inattentive impulsive and mood symptoms do not resolve with treatment of the ADHD or if the child worsens, then the clinician may move to treatment with anti-manic agents.

The final issue to address is the comorbidity of tics and ADHD. At one time, it was believed that tics were an absolute contraindication to stimulant treatment. Recent evidence has shown, however, that there is no statistically significant difference between placebo and stimulants in terms of their propensity to cause tics in children with comorbid ADHD and tic disorders.  However, most clinicians will encounter patients with comorbid ADHD and tics who have an increase in tics when they are started on a stimulant medication. In this situation, the clinician should try an alternative medication for the ADHD in an effort to control the ADHD symptoms without exacerbating the tics. In some situations however, the patient only responds to a stimulant in terms of the ADHD, but the stimulant worsens the number or severity of the tics.  If this occurs the clinician should consider adding an alpha-agonist to the stimulant medication.  Only in the most severe situations, should the clinician consider adding an atypical antipsychotic.

In summary ADHD can be comorbid with a wide range of disorders. Fortunately there is an equally diverse array of treatment approaches that the clinician can apply to these situations. As a result, we can substantially help these difficult patients.

____________________
Steven R. Pliszka M.D.,Professor and Vice Chair; Chief, Division of Child & Adolescent Psychiatry, Dept. of Psychiatry, University of Texas Health Science Center at San Antonio , San Antonio, Texas, USA.

Dr. Armando Filomeno, who met Dr. Pliszka at CHADD’s 17th Annual International Conference in Dallas, USA, October 2005, thanks the distinguished professional for this excellent article which he translated into Spanish for APDA’s electronic newsletter nº 12, issued on June 28, 2006.

CHADD: a voice for individuals with AD/HD and their families, Anne Teeter Ellison, Ed.D.

“CHADD (Children and Adults with Attention-Deficit/Hyperactivity Disorder) is the nation’s leading non-profit organization serving individuals with AD/HD and their families.”

Initially founded in 1987 by Dr. Harvey Parker, parents and professionals joined together to advocate for research on the nature and treatment of AD/HD, to disseminate the science of AD/HD to the public, and to advocate for the educational and legal rights of individuals with AD/HD. Today, we enjoy many accomplishments as a result of our collaboration with leading scientists, clinical/medical professionals, legal experts and educators around the globe.

Over the past nineteen years advances in the science of AD/HD has been remarkable. We now have a solid foundation for understanding the biogenetic, neurobiological, and neurochemical mechanisms of AD/HD. Research indicates that problems in behavioral inhibition or self-control are a result of dysfunction in frontal-striatal networks, while other brain regions (basal ganglia including the caudate nucleus and cerebellum) are also implicated. The evidence of genetic transmission of AD/HD, primarily involving the dopamine systems that innervate frontal-striatal regions is well established. Studies estimate that 70-95% of deficits in behavioral inhibition and inattention are genetically transmitted. Investigation of the interaction between environmental factors, subtle brain anomalies and genetic mutations is ongoing. Although not causal, we know traumatic life events, the presence of co-morbid disorders, and other psychosocial stressors (i.e., poverty, family dysfunction) complicate AD/HD. In the future it will be important for us to further clarify these interactions in an effort to create home, school and work environments that are AD/HD friendly and prevent the development of co-existing disorders that are so common in AD/HD. Researchers are beginning to address prevention strategies and these efforts will no doubt lead to more productive, fulfilling lives for persons with AD/HD.

CHADD has been fortunate to have strong relationships with the leading scientists and clinicians investigating and treating AD/HD across the national and international community. These individuals serve on our Professional Advisory Board (PAB), and provide invaluable advice by interpreting and communicating the science of AD/HD. Education is one of our major goals at CHADD, so it is important that we have accurate and up-to-date information which we publish in our fact sheets and other printed materials. Members of he PAB also serve on the editorial board of ATTENTION!â Magazine, contribute articles for the magazine and interpret controversies regarding assessment and treatment of AD/HD. I believe that these ongoing relationships and strong affiliations with the science of AD/HD help us communicate a message that the public can have confidence.

Over the past 15 years, there have been significant changes in federal laws regulating educational services for children and youths with AD/HD. In 1991, the U.S. Department of Education issued a Policy Memorandum with new regulations implementing the Individuals with Disabilities Education Act (IDEA) Amendments and for the first time explicitly incorporated AD/HD within the definition of “Other Health Impaired.” This memorandum provided access to special education services for children with significant impairment as a result of their attention-hyperactivity deficits. Two other federal laws — the Rehabilitation Act of 1973 (RA) and the Americans with Disabilities Act of 1990 (ADA) — prohibit discrimination against individuals with disabilities in higher education and the workplace. Adults with AD/HD may be eligible for protection and accommodations in higher education and the workplace. While protecting access to services and accommodations, we are routinely reminded that implementation of these laws often lags behind their enactment.  Through our public policy work, CHADD continues to monitor changes in federal laws in an effort to maintain these legal rights including the Re-Authorization of IDEA (2004).

Working together, persons with AD/HD and their families have a powerful, compelling story to tell. These life stories describe the daily challenges of living with AD/HD. E. Clarke Ross, the CEO of CHADD has emphasized the need for us “to build a social movement, CHADD continues to educate public policy makers emphasizing the lived experience of persons with AD/HD and their families.” Dr. Ross asserts that “CHADD will continue to advocate that consumer and family lived experience becomes an important part of health care decision making. For this reason, my April 2003 and February 2006 ATTENTION!® CEO columns focused on enhancing quality of treatment, including respect of the consumer and family lived experience.” In our effort to advocate for consumer and family driven care, we are bolstered by a number of significant national movements that are summarized in these messages.

Although we have made great strides since 1987, today we face continued attacks from anti-psychiatry groups who perpetuate the false notion that AD/HD is not a real disorder, that there is no science behind AD/HD, and we are needlessly drugging our kids. Persons with other mental health disorders face similar public attacks and misinformation. These attacks stigmatize mental illnesses, and discourage individuals and their families from seeking needed treatment. In an effort to counter these unfounded attacks with science and education, CHADD is working with other advocacy groups (Child and Adolescent Bipolar Foundation, CABF; National Alliance on Mental Illness, NAMI; Federation of Families; National Mental Health Association, NMHA) and professional organizations (American Academy of Child and Adolescent Psychiatry, AACAP; American Academy of Pediatrics, AAP; American Psychiatric Association, APA).

The power of persons with AD/HD and their families working together with researchers, clinical and medical professionals, and other advocacy groups can be formidable. Together we can dispel the myths, misinformation and stigma associated with AD/HD. We look forward to working with our international friends in your efforts to address similar challenges to the AD/HD community.

____________________
Phyllis Anne Teeter Ellison, Ed.D., Professor, Department of Educational Psychology; Director of Training, School Psychology Program. University of Wisconsin-Milwaukee, USA. CHADD President (2006).

Dr. Armando Filomeno, who met Dr. Anne Teeter Ellison at CHADD’s 17th Annual International Conference in Dallas, USA, October 2005, thanks CHADD President for this article which he translated into Spanish for APDA’s electronic newsletter nº 11, issued on March 15, 2006.

Girls with ADHD, Martha B. Denckla, M.D.

Whatever is distinctive about girls with ADHD must be viewed against the background facts concerning how girls in general differ from boys in general; the rate and consequent quality of development differs in well-known ways.  Girls talk earlier and are more easily brought into compliance with social demands like toilet training and sitting still for a meal.  Girls are more natural “people-pleasers” and less natural “environment-explorers” than are boys.  It is likely that adult positive reinforcement of verbal and social skills throws a bias into girls’ choices and then experience/nurture further imbalances girls’ cognitive styles.  In pre-school, only 20% of the little girls will seek out the block corner when free play choices are made available.  The play-time choices are further crowded by girls’ earlier ease acquiring reading and writing skills, heavily positively praised and reinforced.  The mix of nature, nurture, experience, and reinforcement starts so early that studies of gender differences must be interpreted with caution.

There is a biological/natural basis for observed developmental differences.  From mid-gestation, the traditional “quickening” point of pregnancy right on up to puberty (which arrives, on average, earlier in girls than in boys) the brains of girls are more mature in all the stages of cellular migration, proliferation, connectivity, pruning, and myelination.  The left side of the brain, so dominant in language and academic skills, gets such a “headstart” in girls that it may excessively dominate the right side, leading to the observed phenomena of girls excelling up to puberty in the language arts (emphasized in the skill set of elementary school) while boys are the “late bloomers” who emerge in the adolescence as the mathematics/science or even creative leaders. (Sometimes the male high-achievers in high school or college still cannot spell or write legibly!)  A particularly useful piece of my research on normal coordination, the PANESS,1 shows that the timed motor skills curve for kindergarten girls fits perfectly over the one for first grade boys, and this pattern persists through fifth grade!  It is because we have the “folk wisdom” of generations of observations of such developmental differences that we smile and shake our heads as we say, “Boys will be boys” but cannot come up with an analogous saying for a mischievous or messy little girl.

Consider then the plight of the little girl with ADHD, widely acknowledged and publicized mainly in the persons of little boys.  Traditional diagnostic schemes capture four times as many boys as girls under the ADHD heading; but recently it has been suggested that estimated ADHD prevalence figures of 3-5% of the school-age population are under-estimates, due to under-diagnosis of many girls with ADHD.  With the DSM-IV subtype of “predominantly inattentive” ADHD legitimized, some surveys redress the total diagnostic imbalance to the extent of three boys to every one girl with AD(H)D.

Still, it remains the case that girls with AD(H)D (the parenthetical H standing for the “predominantly inattentive” subtype) continue to be under-represented even as candidates for diagnosis because the girls are less disruptive, less likely to be oppositional, less blatantly or obviously off-task than the boys.  Girls, with or without AD(H)D, following their “people-pleaser” tendencies, may appear outwardly attentive to a teacher or go docilely to a bedroom to “do” homework while in actuality day-dreaming, doodling, writing notes to classmates in school, or “instant messaging” on the homework-intended home computer!  Girls with ADHD may appear “passive-aggressive” (and may eventually become so) by saying “yes” to requests to do chores and then forgetting to do them. Even when resembling boys in their ADHD-related physical restlessness or boisterousness, girls with ADHD are rarely as extreme in “physicality”.  Many clinicians, however, are eager to introduce into ADHD diagnostic schemata the physical “hyperactivity and impulsivity” domain of the mouth; girls with ADHD talk more, blurt more, boss more, and even eat more than other girls or their age!  Many clinicians see one subgroup of the current obesity-prone generation as girls with ADHD.  Thus, a genuine physical health risk attaches to girls with ADHD, just as accident-proneness attaches to boys with ADHD.

Girls with ADHD may be more troublesome at home than at school, more impaired socially among peers than academically (at least in elementary school).  They may control themselves in the structured school environment but “let down their hair” and irritate or agitate their families.  Their messiness, sloppy eating habits or even neglect of personal hygiene may be far more alarming to parents than would similar characteristics in a boy.  Psychological interpretations (often only partially relevant) other than possible ADHD may rise to greater prominence than warranted in a messy, sloppy, unkempt girl with ADHD.  Add obesity and a whole chain of social rejection events may complicate the girl’s development.  By middle school, social rejection can loom so large that emotional problems may overshadow the underlying ADHD; adding to the organizational deficits that ADHD (of even the mildest type) usually entail, the unhappy girl does not have the energizing and reinforcing social rewards of school life.  The clinician asked to search for ADHD (any subtype) in a girl of 11 to 14 years is doing a kind of neuropsychiatric “archaeology,” attempting by careful history-taking and neurological/neuropsychological examination to piece together the neurodevelopmental diagnosis underlying an emotional collapse.  Had the girl been referred earlier, the diagnosis of ADHD (not to speak of comorbid learning disabilities experienced by a third of those with ADHD) would have been more evident, less covered over by psychiatric complications and psychotropic drug effects.

What about treatment for girls with ADHD?  As with boys, ADHD requires a customized multimodal treatment program (home/parental management training, school program of accommodations, facilitating achievement, individual psychotherapy or tutoring or both, and adjunctive use of a stimulant medication). Notice the “final position” of medication, which is “neither curse nor cure” and must be customized for each patient at each age level and task demand/supply ratio, titrated very individually towards short-term target improvements and re-addressed frequently!  In this regard, the special needs of girls are simply that each set be described in terms of specific target signs or symptoms, acknowledging that in development all targets are “moving targets.”  The home, school, and individual therapeutic programs for girls with ADHD are even more important than the appropriate adjunctive medications, because the social-emotional complications of ADHD so insidiously overtake the girls before medication may even seem worthy of consideration.

In summary, girls with ADHD present with less-obvious, later-recognized, more “internal” forms of the disorder that Russell Barkley has so succinctly educated us to understand as revealing the nature of all kinds of “self-control.” The price paid by girls with ADHD for their less-obvious, later-recognized course is that emotional complications have more time to gain a foot-hold as comorbid depression or anxiety or “passive-aggressive personality” before correct multi-modal therapeutic programming can be implemented for the ADHD syndrome itself.  There is thus an urgent need to look at little girls with more sensitivity towards manifestations of ADHD, even of the non-disruptive, predominantly inattentive type, lest social rejection and “creeping” academic underachievement combine to make a much more seriously troubled adolescent girl who is, by the way, highly vulnerable to substance abuse.

____________________
Martha Bridge Denckla, M.D., Batza Family Endowed Chair; Director, Developmental Cognitive Neurology, Kennedy Krieger Institute;  Professor, Neurology, Pediatrics, Psychiatry, Johns Hopkins University School of Medicine.

Dr. Armando Filomeno —who was at the Johns Hopkins Hospital as a fellow when the KKI’s name was John F. Kennedy Institute for Habilitation of the Mentally and Physically Handicapped Child— thanks Dr. Denckla for this interesting article, which he translated into Spanish for APDA’s electronic newsletter nº 9, issued on September 15, 2005.

(1) Physical and Neurological Examination for Soft Signs (editor’s note).

What is neuropsychiatry?, Prof. G. E. Berrios

The word and its referents
Names help or hinder in all walks of life, particularly when they behave as drifting signifiers. For example, since it first appeared in fin de siècle France as a double-barrelled word (‘neuro-psychiatrie’), the meaning of ‘neuropsychiatry’ has repeatedly changed. By the interbellum period, and now converted in ‘neuropsychiatrie’, it referred to the clinical doings of medics trained both in neurology and psychiatry. By 1918, the word appeared in the Anglo-Saxon to name a form of: “Psychiatry which relates mental or emotional disturbance to disordered brain function”. My own definition is narrower: “discipline that deals with the psychiatric complications of neurological disease”. On the other hand, American usage is broader and tantamount to “biological psychiatry”.

Currently, and first and foremost “neuropsychiatry” refers to overlapping clinical disciplines sharing the belief that mental symptoms are produced at disordered brain sites. It is also used to make a professional claim vis-à-vis rival views of mental disorder such as psychoanalysis. Lastly, it creates a social and economic space wherein like-minded researchers safely congregate to usufruct their fashionable ideas.

The context
Whether there is ‘neuropsychiatry’ in a particular country, and whether it has a broad or narrow meaning will depend, to a large extent, upon the structure of its health services and on the quality of the relationship between neurology and psychiatry.

This is interesting and ironical as both specialisms are new. Alienism (the original name for psychiatry) and neurology developed by the 1830s and 1860s respectively as the direct result of the fragmentation of the old grand Cullean category of ‘Neurosis’, and of the broadening of the notion of ‘lesion’ which by the end of the century indistinctly referred to failures and solutions of continuity in putative ‘structural’, ‘physiological’ or ‘psychological’ domains. In Germany and France, the formation of alienists included neurological training and this facilitated the use of the term ‘neuropsychiatrist’. In Great Britain, on the other hand, and due to important socio-economic reasons (which there is no space to discuss), neurology and psychiatry had fully diverged by the 1880s. This means that for more than 90 years there was little communication between the two and that during the 1970s ‘neuropsychiatry’ had to be reinvented. It is not altogether surprising that those of us who were involved in such re-creation had both neurological and psychiatric training. This also explains why to this day we do not have in the UK a unified definition of neuropsychiatry. The American definition has become popular and this has encouraged psychiatrists holding a biological orientation au outrance to call themselves ‘neuropsychiatrists’. Others (like myself) continue defining neuropsychiatry in a narrow way. The former can be found in all venues of psychiatric care, the latter work in general hospitals and do a great deal of ‘neuro-liaison’ work (I introduced this term in a lecture given in Wellington, New Zealand some years ago).

Neuropsychiatry in Cambridge, UK
In keeping with the above, my own ‘neuropsychiatric’ clinical service is organize on the narrow view that neuropsychiatry is a branch of psychiatry that deals with the mental complications of neurological disease. I do not believe that such practice should in any way be interpreted as a statement about the nature of mental disorders in general. Even within the confines of my narrow definition, it seems clear that neurological patients who develop delusions, hallucinations, obsessions, sadness, anxiety, etc., etc. do so on account of a variety of mechanisms. On the one hand, there are the causal aetiologies. As my work on musical hallucinations and irritability states in Huntington’s disease patients showed years ago, a direct link can be demonstrated between symptom and brain site or CAG repeat, respectively. On the other hand, neurological patients have reasons for their symptoms, that is, neurological diseases happen to real people and hence have semantic contexts. This adds an entire new layer of meaning, hermeneutics and therapeutic response. Patients may show behavioural copies of mental symptoms and these do not have the same brain representation as the conventional symptoms.

Neuropsychiatric clinical work generates clinical templates which can be translated into research paradigms. There is nothing new in this and each university will use a different rhetoric to sell what they do. Some sell themselves as top-to-bottom research institutions (i.e. grand ideas governing action), others, are bottom-up ones (piecemeal, low level research converging upwards). This is the case of the Cambridge University Neuroscience Campus (the largest in the UK) which includes research institutes and a neuroimaging suite with inter alia 12 MRI magnets. My Neuropsychiatry Service (6 clinics) is linked with most of the research centres in the campus. For example, the PD Clinic provides patients for the large projects on receptor expression, fMRI, pharmacology, and neurosurgery. The HD Clinic is held in the ‘Brain Repair Centre’ where about 12 patients who have already received fetal cell implants in their caudate nuclei are followed up at 3 months intervals. The Traumatic Brain Damage clinic takes place in the ‘Oliver Zangwill Centre’, the leading cognitive neuropsychological rehabilitation clinic in Europe. The Sleep Disorders Clinic works closely with the ‘Respiratory Unit’ at Papworth hospital which includes the more advanced polysomnographic set up in the UK. The Memory Complaints Clinic services the large complex of memory research at the ‘Cognitive and Brain sciences Unit’, a ‘Medical Research Council’ facility where concepts such as executive functions and working memory were first developed; and my General Neuropsychiatry Clinic is linked up with the ‘Epilepsy Neurosurgical Unit’, the ‘Tinnitus Clinic’, etc. All these clinical- basic-sciences associations create ideal opportunities for translational research which has traditionally been the British way of developing new ideas.

The findings
Whatever the clinical context, neurological disorders are often accompanied by psychiatric appurtenances. The psychiatric component of some, like Parkinson’s disease, Multiple Sclerosis, Huntington’s disease, Wilson’s disease, Binswanger’s disease, etc., etc. has been known for a long time, and in some cases the severity and management of that component is more important for social re-entry than any motor or sensory disorder. In other cases, however, such as the taupathies, mitochondriopathies, CADASIL, X-Linked Adrenoleukodystrophy, etc. etc., not enough research has yet been carried out to identify the psychiatric component. In all situations, an intelligent practice provides the neuropsychiatrist with conundra whose resolution has direct relevance to psychiatry in general; two of such will be briefly discussed below.

The implications
Diagnostic conundrum
The neuropsychiatrist often finds that there is a lack of fit between the clinical phenomena met with in neuro-liaison work and the conventional psychiatric categories of ICD-10 and DSM IV. Neurological patients exhibit a variety of mental symptoms but these are often isolated and/or fleeting and rarely achieve critical mass to qualify for a ‘psychiatric diagnosis’. This raises theoretical and practical issues. The former have to do with their nature and formation mechanisms, the latter with their management / therapy. In the UK psychiatric therapies are currently tightly governed by guidelines which themselves are based on meta-analytic exercises and health economy evaluations. Likewise, psychiatric drugs are licensed for specific disorders and share with the guidelines the same sets of random clinical trials. Before the time guidelines started to be issued, psychiatric treatments were based on a combination of psychopharmacological knowledge, therapeutic imagination and specific negotiations between doctor and patient. This no longer obtains and unless a patient qualifies for a clear diagnosis he will not be offered medication as this might expose the clinician to legal action. In neuropsychiatry, this is particularly acute as neurological patients have mostly mental symptoms and only rarely mental disorders. Furthermore, the expression of such symptoms may be distorted by the presence of cognitive, expressional or emotional deficits directly related to the neuropathological lesions.

Behavioural copies and the problem of symptom-formation
In view of the above, the neuropsychiatrist often wonders whether the mental symptoms (and occasional mental disorders) that he/she comes across in the context of his specialized practice are, in fact, the same clinical phenomena as those seen in general psychiatry. For example, are the visual hallucinations of Parkinson’s disease or Lewy body dementia the same phenomena as those seen by a melancholic elderly with Cotard’s syndrome? Is the affective disorder associated with frontal lobe strokes the same as the common garden depressive illness? Is the mania triggered by steroid treatment the same as the mania of a bipolar disorder?

These comparisons go directly to the core of psychopathology and call into question the epistemic capacity of the language of psychiatry, that is, its discriminating value. Over the years, these questions have been responded in different ways. There was a time when the answer was that so-called organic hallucinations were different phenomena from psychiatric hallucinations. Currently, the predictable view is that they are, that they must be the same phenomena. Biological psychiatry is ruthless in its reductionism and efforts to impose its causal mechanism. Many neuropsychiatrists with long clinical experience in their trade, however, are no longer that cocksure. They often wonder about multiple aetiologies and about the existence of mechanisms that generate behavioural copies of the organic symptoms; or they postulate the hypothesis that the expressional systems in the human may have a narrow repertoire and act as final common pathways to a variety of triggers, some organic, some semantic.

Such psychopathological hypotheses generate fresh approaches to the analysis of mental symptoms which can only be undertaken by trained psychiatrists. They offer a natural and privileged space for psychiatric research. Unfortunately, it is one space that it is being abandoned by psychiatrists who want to become mini-neurologists, -radiologists or -geneticists. Descriptive psychopathology remains the fons et origo of all others ancillary disciplines in psychiatry, and hence such diaspora must be deeply regretted.

____________________
Prof. G.E. Berrios
BA (Oxford); DPhilSci (Oxford); MD; FRCPsych; FBPsS; FMedSci
Dr. Med. honoris causa [Heidelberg; San Marcos]
Consultant Neuropsychiatrist, Head Neuropsychiatry Service;
Reader in the Epistemology of Psychiatry, University of Cambridge
Addenbrooke’s Hospital (Box 189) Hills Road, Cambridge, UK, CB2 2QQ
Voice: 44 (0)1223-336965; Fax 44 (0)1223 336968; email: geb11@cam.ac.uk

Dr. Armando Filomeno —who translated this article into Spanish for its publication in the newsletter nº 8 issued by the Asociación Peruana de Déficit de Atención (APDA), on June 15.2005— thanks Dr. German Berríos, a distinguished peruvian physician and former classmate of his during their early years of medical studies at San Marcos University, for writing this excellent essay.

This article has been reproduced by: Revista Colombiana de Psiquiatría, vol.36 suppl.1, p.9-14,Oct. 2007. Link. 

Adult ADHD in the everyday neurological practice, Michael Finkel M.D.

Dr. Armando Filomeno met Dr. Michael Finkel (who also did his neurology residency at the Strong Memorial Hospital of the University of Rochester) at the Nashville CHADD Conference in October 2004. At his request, Dr. Finkel —who does an important job in the field of international relations in the above mentioned institution— sent this article, written as a letter, about a subject in which he is an expert.

February 21, 2005

Dear Armando,

I am grateful for the opportunity to discuss the issue of AD/HD in adults with you, with our colleagues, and with our patients and families in Peru. As a means of introduction, let me say that I am a parent and spouse of individuals with AD/HD, as well as a neurologist who has worked with children and adults with this disorder for 15 years.

DEFINING THE CONDITION. It is now widely recognized that AD/HD is a disorder that often extends beyond childhood, and rarely occurs by itself. comorbid conditions are medical syndromes which occur at a frequency greater than what would be expected by chance alone. These comorbid conditions can be subcategorized as follows. Neurological comorbities include migraine headaches, restless leg syndrome and periodic limb movement disorder of sleep, epilepsy, tic disorders, Tourette syndrome, stutter, and enuresis. Psychiatric comorbities include depression, bipolar disorder, anxiety disorders, obsessive compulsive disorder, oppositional defiant disorder, conduct disorder, antisocial behavior, and substance abuse/chemical dependency.

Migraine headaches can occur before puberty in males, with the peak occurrence during the second decade of life.  For females, the migraines can begin with menarche and continue through the reproductive years, to diminish with menopause. Restless legs and periodic limb movement disorder of sleep usually do not become a problem until the third decade, although parents will frequently note that the child has excessive limb movements during sleep. Epilepsy tends to be in the teen age years, and is not a common comorbidity.  It is usually absence seizures, consisting of staring spells and eye blinking. Tic disorders can begin around 9-10 years of age, more often in males, and consist of two types. Motor tics involve simple and/or complex movements of the head, eyes, face, and limbs. Verbal tics involve simple noises or throat clearing, or complicated ones whereby the person blurts out things that are offensive to those who are around them.  Fortunately, both types tend to peak around age 15.  However, if both types occur in the same person who has AD/HD, often with obsessive compulsive disorder, the diagnosis broadens to be called Tourette syndrome. Stutter can be a lifelong problem. Enuresis ends by age 15.

Depression can occur before puberty, and is not necessarily caused because the child is having difficulties in school.  Puberty will exacerbate it in both sexes, and menstrual irregularities can provoke or intensify episodes of this condition.  For many adults in their fourth and fifth decades, the mood disorder is more disabling than the AD/HD. Bipolar disorder has different types, with variable presentations and ages of onset.  A manic or hypomanic episode can be mistaken for the first onset of AD/HD or an exacerbation, and a psychiatrist has to separate the two conditions to treat them. Anxiety disorder can manifest as separation anxiety in children, and generalized anxiety, with or without panic disorders, from the second decade onward. Obsessive compulsive disorder is part of Tourette syndrome, although it can occur as an independent comorbidity.  It may begin in the first or second decades, and becomes more problematic with age. Oppositional defiant disorder involves disrespect for adult authority.  When property damage, criminal behavior and physical threats occur before age 18, it is called conduct disorder.  After 18, the name changes to antisocial behavior, as the individual has reached the arbitrary and statutory definition of adulthood. Substance abuse/chemical dependency involves use of tobacco by minors, tobacco as adults, and drug/alcohol abuse as a minor and/or an adult.

Frequently, the AD/HD is the presenting problem during the first decade of life. However, the comorbid conditions can occur later, in a sequence and at an age that can be predicted.   By being aware of the different types of AD/HD, one can be prepared to recognize when a patient might develop a comorbid condition later in life, plan a strategy, and prevent or lessen the impact of the condition, and even cause remission. The patients, families, and doctors need to visualize AD/HD as if it is the tip of the clinical iceberg, warning us of future danger below the surface.

TREATMENT STRATEGIES. First, we establish that the patient has AD/HD, and decide how to treat it.  Many adults have learned to cope with the problem at work by taking jobs that are not sedentary and boring, or which allow the individual to learn a repetitious sequence of events from which there is little deviation, or by becoming self employed, with no one else to make the rules.  However, requirements at home may require behavioral modifications as well a medications.  The medical treatments are primarily stimulants (dextroamphetamine or methylphenidate based medications), atomoxetine, tricyclic antidepressants, and new antidepressants like venlefaxine and buproprion. However, one has to use stimulants cautiously in hypertensive individuals, and men in the fifth decade and above may experience erectile dysfunction, loss of libido, and problems emptying the bladder with atomoxetine. Therefore, one needs to be thorough in evaluation before starting them.

Second, we establish which comorbidities are present, and how to treat them. The neurological and psychiatric conditions have several additional medications that can treat them, as well as behavioral strategies. Sometimes the comorbid condition is more serious at the moment than the AD/HD, so we treat the most significant problem first.

We try to use the fewest number of medications, but we often need more than one type of medication.  Therefore, many patients need two or more medications, depending on the type and severity of the problems, and whether or not a medicine can treat more than one condition.  For example, some anticonvulsants and antidepressants will reduce the frequency of migraines.

Third, we have to modify the plan as conditions change. Sometimes migraines and depressions may need only 6-12 months of intensive treatment, while AD/HD medications might be needed for long periods of time.

I hope that this clinical discussion will help our colleagues, patients, and families understand how we physicians approach treatment plans in adults.

Yours sincerely,

Michael F. Finkel MD, FAAN
Cleveland Clinic Florida in Naples

____________________
A Spanish translation of this article appeared in the newsletter nº 7 issued by the Asociación Peruana de Déficit de Atención (APDA), on March 14, 2005.

Does neurofeedback help kids with AD/HD?, D. Rabiner, Ph.D., O. Palsson, Psy.D., and P. Freer, M.S.Ed.

What is neurofeedback?
Due to increasing coverage in major publications like Discover, Time and Newsweek, neurofeedback has become a popular, albeit controversial, intervention used for the treatment of AD/HD. Scientists have known for many years that the brain emits various brain waves that are indicatives of the electrical activity of the brain. Different types of brain waves are emitted depending on whether the person is in a focused and attentive state or a drowsy/daydream state. Neurofeedback allows a person to view these brain waves on a computer screen as they occur. By teaching a person to produce the brain waves patterns associated with a relaxed, alert and focused state, and then practicing this skill for many hours, neurofeedback practitioners believe that individuals with AD/HD can learn to maintain this state. As a result, many symptoms of AD/HD will diminish. However, many scientists do not believe that such claims have been sufficiently documented.

How is neurofeedback training conducted?
A typical clinical session of neurofeedback training for a child with Ad/HD involves pasting electrodes (sensors that pick up the electrical activity of the brain) to the head with a conductive gel. This is a completely painless process. Wires from this electrodes are connected to a device that amplifies the small signal from the electrodes. The child sits in a comfortable chair and watches a computer monitor. The monitor displays a picture, such as a moving graph, that indicates the degree to which the child is producing the desired pattern of brainwave activity. The goal is for the child to learn to produce the type of brain wave activity associated with a focused and attentive state.

Over the course of numerous training sessions, it may gradually become easier for the child to achieve and maintain this state for longer periods of time. Supporters of  neurofeedback often describe this training as an exercise program for the brain. The training continues until the child is able to consistently achieve and maintain a pattern that shows a relaxed and attentive state. This training typically requires 40 to 60 sessions, with sessions ranging from $40 to $120. By the conclusion of treatment, neurofeedback advocates believe that increases in attention and reductions in impulsivity evident during training will transfer to important areas of the child’s life (e.g., home and school). There are several published studies discussed in this article that are consistent with this position. Critics of neurofeedback however, do not believe there is credible evidence to indicate that such a transfer occurs.

A Brief History of Neurofeedback
As early as the 1970s, neurofeedback was used as an experimental treatment for neurological conditions such as epilepsy. When clients were taught to relax and produce site-specific brain wave activity, they reduced the frequency of the seizures (Sterman et al., 1974). In subsequent research, scientists reported that neurofeedback could help reduce the symptoms associated with AD/HD (Lubar & Shouse, 1976). Later, the National Aeronautics and Space Administration (NASA) began to investigate whether attention training using neurofeedback could help to prevent accidents among astronauts and pilots during flight. This led NASA scientist to develop a new application of neurofeedback training technology where children’s ability to maintain a desired EEG state was linked to their ability to control video games. This approach to neurofeedback treatment has gradually become more widespread.

As promising reports of neurofeedback treatment emerged, it moved from an experimental technique with preliminary research support to a treatment provided to a growing number of children. Many scientists who research AD/HD expressed concern that neurofeedback was an expensive and unproven treatment that could dissuade parents from selecting other treatments that are supported by greater empirical support evidence (i.e., stimulant medication and behavior therapy). These scientists argued that the efficacy of neurofeedback had not been conclusively demonstrated through carefully controlled clinical trials, and that parents should be extremely cautions about selecting this treatment.

The Current State of the Evidence for Neurofeedback Treatment
The debate about the value of neurofeedback treatment for AD/HD has continued for the past several decades. Advocates point to a number of published studies that support numerous anecdotal reports from parents and clinicians about the utility of this approach. Critics argue that all these studies have significant limitations that prohibit making any firm conclusion about the effectiveness of neurofeedback treatment. A review of two recently published studies may help clarify why these strongly opposing views continue to be held with such conviction.

In the first study (Monastra et al., 2001), 101 children and adolescents with AD/HD received multimodal treatment that included stimulation medication, behavioral therapy and school consultation services. Fifty-one of these participants also received neurofeedback because their parents decided to include it in their children’s overall treatment plan. Participants in each group (multimodal treatment vs. multimodal treatment plus neurofeedback) did not differ in the severity of symptoms before treatment began, and the treatment provided differed only by whether it included neurofeedback. Twelve months later, according to parent and teacher behavior ratings, participants whose treatment included neurofeedback showed greater improvement and no longer demonstrated the brain wave patterns that were substantially different from children without AD/HD. These gains remained evident a week after medication was discontinued and suggested that adding neurofeedback to a multimodal treatment program was associated with important incremental benefits.

In a second study (Fuchs et al., 2003), parents of 34 children with AD/HD between the ages of 8 and 12, chose either stimulant medication or neurofeedback treatment for their children. The majority —the parents of 22 children— opted for neurofeedback treatment. After three months, children in both groups showed significant and comparable reductions in AD/HD symptoms according to parents and teachers. Laboratory tests of attention also showed equivalent improvement.

What conclusions can be drawn from these recent reports? Clearly, in both studies, children who received neurofeedback appeared to benefit from this treatment. These benefits were evident in reports from parents and teachers, as well as on laboratory measures of attention. Given the compelling nature of these results, which are consistent with results from other studies, why do many scientists continue to regard neurofeedback as an unproven and highly experimental treatment for AD/HD?

The reason of this skepticism is that although children in these studies appeared to improve, limitations in the researches’ methods made it impossible to know what was responsible for the improvement. An important limitation o both studies is that parents decided whether to use neurofeedback with their child, rather than this being determined by chance (i.e., random assignment). The absence of random assignment makes it impossible to rule out other factors the groups may have differed on besides whether they received neurofeedback as an explanation for the results obtained. This limitation is found in virtually all studies of neurofeedback.

Another limitation is the failure to control for the substantial extra attention the therapist provided to children who received neurofeedback treatment. It is possible that this extra attention —and not neurofeedback training— accounted for the children’s improvement. Although this may be unlikely given the intractability of AD/HD symptoms to adult attention and support alone, it cannot be conclusively ruled out as an explanation.

It is also important to note that neither study permitted any conclusion about whether providing children with “feedback” on their brain wave activity was a necessary treatment component. Perhaps focusing on various computer tasks several times each week over an extended period would help children develop their attention skills regardless of whether such feedback is provided. The experimental controls that would be necessary to determine this were not included in either study.

Finally, because children in these studies were not followed for any sustained time period after treatment ended, it is not known whether improvements associated with neurofeedback persisted beyond the end of training. Some neurofeedback proponents have claimed that unlike medication treatment, where benefits are typically not sustained after medication is stopped, improvements are sustained because the child has learned a new skill (e.g., the ability to produce and maintain a focused, attentive state). We are unaware, however, of studies in which this claim has been documented.

It is important to emphasize that the limitations discussed previously were unavoidable because these studies were conducted in regular treatment settings where parents paid for the services provided. In this context, assigning children to different treatments at random is not possible. Providing equivalent attention from a therapist to children whose parents did not choose neurofeedback —or the type of control necessary to establish that direct feedback on brain wave activity— is also impractical. The fact that these limitations could not be avoided, however, does not eliminate the problems created for interpreting the study results. Thus we believe that neurofeedback critics are correct to stress that the efficacy of this treatment has yet to be conclusively demonstrated according to accepted scientific standards.

On the other hand, it is also important to recognize that these studies reflect the context in which parents actually make treatment decisions for their child. That is, parents are aware of and are presented with different treatment options and must decide which to pursue. From this perspective, the promising results from these studies can be interpreted to suggest that when parents select neurofeedback treatment for their child, either alone or in combination with more conventional approaches, there is a reasonable chance they will find it to be helpful.

What next?
In many ways, the debate about neurofeedback that is evident today is no different from that was taking place 10 to 15 years ago. On the one hand, there is evidence that children with AD/HD who receive neurofeedback treatment obtain some benefits from the experience. On the other hand, for the reasons previously discussed, the efficacy of neurofeedback has not been conclusively demonstrated according to widely accepted scientific standards. As one critic recently pointed out, the evidence to date world not meet FDA standards for classifying neurofeedback as a medical intervention for AD/HD (Barkley, 2003). Uncertainty about the efficacy of neurofeedback will continue until large scale studies that include the necessary experimental controls are conducted.

Until such research becomes available, parents considering neurofeedback treatment for their children should be aware that despite the promising results reported, there are other interventions (e.g., medication treatment, behavior therapy and their combination) whose efficacy has been clearly demonstrated in a number of carefully controlled studies. For this reason, these are the interventions that are recommended in treatment guidelines recently published by the American Academy of Child and Adolescent Psychiatry (1997) and the American Academy of Pediatrics (2001).

One hopes that the research necessary to provide more definitive answers to important questions about neurofeedback treatment will soon be forthcoming so that parents can make informed decisions about this treatment. The issues about neurofeedback that are unresolved today may remain so far many years unless scientists begin to initiate the necessary studies.

____________________
David Rabiner, Ph.D., is a senior research scientist in the Center for Child and Family Policy at Duke University and a former member of CHADD’s Professional Advisory Board. He writes a free e-mail newsletter called “Attention Research Update” that is available at www.helpforadd.com

Olafur Palsson, Psy.D., is a clinical psychologist: He is an associate professor in the department of medicine at the University of North Carolina at Chapel Hill. Dr Palson conducts research on the relationship between mental activity and physical health. He has worked with scientists at NASA’s Langley Research Center for several years to develop new ways to train brain functioning to treat AD/HD and enhance the mental performance of pilots in the cockpit.

Peter Freer, M.S. ED., is the founder and CEO of Unique Logic + Technology, Inc., a leader in feedback-based attention training. Mr. Freer is a veteran teacher with extensive training in computer science and educational psychology. He is currently developing a hybrid feedback system combining NASA-based technology with the aforementioned patents.

Originally published in Attention! December 2003, 30-35, CHADD.
Reproduced thanks to Patricia Grady from the National Resource Center on AD/HD and to Petrina Chong-Hollingsworth, both from CHADD.

A Spanish translation of this article appeared in the newsletter nº 6 issued by the Asociación Peruana de Déficit de Atención (APDA), on December 11, 2004.

References.
American Academy of Child and Adolescent Psychiatry (1997) «Practice parameters for the assessment and treatment of children, adolescents and adults with attention-deficit hyperactivity disorder». Journal of the American Academy of Child and Adolescent Psychiatry, 36, pp. 85S-121S.

American Academy of Pediatrics (2001) «Clinical practice guidelines. Treatment of the school- aged child with attention-deficit/hyperactivity disorder». Pediatrics, 108, pp. 1033-1044.

Barkley, R. A. (2003)  «Editorial commentary on EEG and neurofeedback findings in AD/HD». The AD/HD Report, 11, pp. 7-9.

Fuchs, T.,  Birbaumer N.,  Lutzenberger W.,  Gruzelier J. H. y  Kaiser J. (2003) «Neurofeedback treatment for AD/HD in children: A comparison with methylphenidate». Applied Psychophysiology and Biofeedback, 28, pp. 1-12.

Lubar, J. F. y  Shouse M. N. (1976) «EEG and behavioral changes in a hyperactive child concurrent with training of the sensorimotor rhythm (SMR). A preliminary report». Biofeedback and Self-Regulation, 1, pp. 293-306.

Monastra V. J., Monastra D. M.  y  George S. (2001) «The effects of stimulant therapy, EEG biofeedback and parenting style on the primary symptoms of attention-deficit/hyperactivity disorder». Applied Psychophysiology and Biofeedback, 27, pp.231-249.

Monastra V. J.,  Lubar J. F. y  Linden M. (2001) «The development of a quantitative electroencephalographic scanning process for attention-deficit/hyperactivity disorder: Reliability and validity studies». Neuropsychology, 15, pp. 136-144.

Sterman, M. B.,  Macdonald L. R. y  Stone R. K. (1974) «Biofeedback training of the sensorimotor electroencephalogram rhythm in man: Effects on epilepsy». Epilepsia, 15, pp. 395-416.

Additional Resource
Loo, S. K. (2003) «EEG and neurofeedback findings in AD/HD». The AD/HD Report.

My experience with atomoxetine, Gerald Erenberg, M.D.

Dr. Armando Filomeno —who had talked with Dr. Gerald Erenberg about atomoxetine in November 2002, at the biennial Tourette Syndrome Association meeting in the US—  recently asked the distinguished pediatric neurologist for an article about his personal experience with atomoxetine almost a year and a half after its introduction in his country. This is Dr. Erenberg’s article written as a letter.

June 20, 2004

Dear Armando,

The following is my experience with atomoxetine for ADHD:

Atomoxetine represents a departure from the traditional treatment of ADHD. Such treatment has traditionally been with the psychostimulant class of drugs, and the major effect is thought due to an increase in dopamine activity. Use of psychostimulants dates back to the 1930’s when benzedrine was first used. Amphetamines were already available in the 1940’s, and methylphenidate has been in use since 1954. Psychostimulants have been extensively studied, and their usefulness has been well established. Concerns about psychostimulants include their addictive potential (hence they are controlled substances in the United States), appetite suppression, sleep difficulties, possible effect on growth, and possible causing or worsening of tics.

Atomoxetine is a norepinephrine reuptake inhibitor, and its effect on dopamine is unclear. It has been suggested that dopamine may be increased in the frontal lobes because of the effect on tracts connecting the deeper structures and the frontal lobes. How norepinephrine helps the symptoms of ADHD is not understood, but the drug clearly showed efficacy when tested in phase 3 studies. Separate studies showed that there was no danger of the medication increasing tics. Safety was good including a lack of cardiovascular side-effects. This was important to show since desipramine, a tricyclic antidepressant with effect on norepinephrine, was linked to sudden death due to its effect on the cardiac conduction system.

Atomoxetine came into wide use in the United States early in 2003. The public as well as many physicians were intrigued with the idea of a non-stimulant medication with no addictive potential and no risk of tics. Within 6 months of introduction, atomoxetine represented over 16% of new prescriptions for the treatment of ADHD. The phase 3 testing had shown side-effects such as sedation, gastrointestinal distress, dizziness, dry mouth, and decreased appetite, but in relatively small percentages of patients administered the drug.

Instructions for beginning treatment suggested that the initial dose be 0.5 mg/kg/day taken as a once a day dose in the morning. The full dose of 1.2 mg/kg/day could be started as soon as 3 days after introduction of the medication. The manufacturer’s studies had shown no advantage to a dose above 1.2 mg/kg/day. Some effect would be seen quite early, but full effect might take 4-6 weeks, similar to the pattern seen when starting the SSRI medications.

In my practice, our initial experience with atomoxetine was when we began switching patients from their stimulant medication to this new drug. Thus, our first group of patients had actually been treated with psychostimulants or atomoxetine at different times. Subsequently, we began starting our newly diagnosed ADHD patients with atomoxetine, representing a group who had never received psychostimulants. This was especially attractive when the patient being treated either already had tics or had a first degree relative with tics.

By now, we have treated over 200 patients with atomoxetine. Unfortunately, the results have been disappointing. The incidence of side-effects has been higher than in the patients treated with psychostimulants. This has led to our reducing the highest dose to not more than 1.0 mg/kg/day. Sedation and GI distress were so common that we now instruct patients to take their medication at night rather than in the morning, and to never take the medication on an empty stomach. When atomoxetine is found helpful, the time of administration should not be important since the effect lasts for over 24 hours, another advantage over the psychostimulants. When families compared the improvement seen with psychostimulants to that seen with the switch to atomoxetine, almost every one of them requested that their children be placed back on a psychostimulant. And in those patients started initially on atomoxetine, reports from parents and teachers generally showed only minor improvement in the ADHD symptoms. The results were rarely as robust as are the results when treating with psychostimulants.

Based on these results, we are again starting most newly diagnosed patients on a 12 hour psychostimulant preparation. The exceptions are those who have previously failed treatment with a psychostimulants, those who had severe side-effects on psychostimulants, or those patients who have ADHD and active tics. I would hope that further refinements will lead to better medications for the treatment of ADHD, but for now, psychostimulants remain the drugs of choice in treating ADHD.

Gerald Erenberg, MD
Senior Pediatric Neurologist
Cleveland Clinic Foundation
Cleveland, OH
USA

Immediate past Chairman, Tourette Syndrome Medical Advisory Board

____________________
A Spanish translation of this article appeared in the newsletter nº 4 issued by the Asociación Peruana de Déficit de Atención (APDA), on July 14, 2004.