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ADHD Part 1: Current Status, Diagnosis, Etiology/Pathophysiology

  • Authors: Julie A Dopheide, PharmD, BCPP
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Target Audience and Goal Statement

This activity is intended for pharmacists.

By presenting the most current developments in the practice of pharmacy and pharmacotherapy, these conference summaries aim to enhance understanding of treatment of various disease states and reassess and modify current practice methods in order to enhance pharmaceutical care.

On completion of this continuing medical education offering, participants will be able to:

  1. Explain diagnostic criteria for ADHD.

  2. Review behavioral therapy techniques and pharmacologic therapies used for patients with ADHD and discuss their risks and benefits.

  3. Describe nonpharmacological and pharmacological strategies in the management of chronic pain.

  4. Discuss the appropriate use of opioids for patients with acute pain, cancer pain, and chronic pain.

  5. Describe the epidemiology, etiology, symptoms, and differential diagnosis of various dementias.

  6. Review nonpharmacologic approaches and pharmacologic options for the treatment of dementia.

  7. Recognize characteristic behavior patters of the chemically dependent practitioner.


  • Julie A Dopheide, PharmD, BCPP

    Psychiatric Pharmacist Specialist, Department of Pharmacy and Psychiatry, LAC and USC Inpatient Psychiatry, Rosemead, California; and Associate Professor of Clinical Pharmacy, Psychiatry and the Behavioral Sciences, USC Schools of Pharmacy and Medicine, Los Angeles, California

Accreditation Statements

    For Pharmacists

  • The American Pharmaceutical Association is approved by the American Council on Pharmaceutical Education (ACPE) as a provider of continuing pharmaceutical education. This activity has also been planned and implemented in accordance with the Quality Criteria of the American Council on Pharmaceutical Education (ACPE) through the sponsorship of The American Pharmaceutical Association.

    The American Pharmaceutical Association has assigned 3.0 contact hours (0.30 CEUs) of continuing pharmaceutical education credit . ACPE provider number: 202-999-01-155-H01

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ADHD Part 1: Current Status, Diagnosis, Etiology/Pathophysiology

Authors: Julie A Dopheide, PharmD, BCPPFaculty and Disclosures



Attention-deficit hyperactivity disorder (ADHD) is the most commonly diagnosed behavioral disorder in children, but it is often misunderstood as well as the subject of controversy. Confusion surrounding the disorder has led to both under- and overtreatment of children. This report, based on my presentation at APhA 2001,[1] will review the current status of ADHD in the United States, diagnostic recommendations, behavioral interventions, etiology, and pathophysiology.

Current Status of ADHD in the United States

In November 1998, the National Institutes of Health (NIH) gathered 44 experts in psychiatry, psychology, epidemiology, biostatistics, and pediatrics from across the United States to review the literature on ADHD and develop a consensus statement addressing key diagnostic and treatment issues.[2] Results confirmed that ADHD is a valid disorder with measurable and significant impairment in functioning caused by inattention, impulsivity, and hyperactivity. The experts reported a 3% to 5% incidence in school age children and acknowledged a need for improved assessment, treatment, and long-term follow-up. The need for better integration of parents, teachers, and healthcare providers for optimal assessment and treatment was emphasized. Stimulants were regarded as most effective in relieving symptoms according to research, although there was no consensus regarding the threshold of symptoms most appropriate for stimulant therapy.[2]

ADHD incidence rates are 5 to 10 times greater in the United States compared with other countries. There is significant regional variability in the diagnosis and treatment of ADHD across the United States as well. For example, 8% to 10% of 30,000 children in second to fifth grade were diagnosed with ADHD in 1 Virginia school system whereas the NIH reports a lower 3% to 5% incidence.[2,3] Cultural differences in prescribing stimulants were reported in the same study; by fifth grade, 18% to 20% of white boys were prescribed methylphenidate whereas rates were significantly lower in other ethnicities.[3] There is significant regional variability in the incidence of ADHD and drug therapy prescribing across the United States but there has been a general increase in both over the past 10 years. One epidemiologic study tracked 220,000 preschoolers from 1991-1995 (through Medicaid and HMO databases) and found that 1.2% were prescribed stimulants, 1.1% were prescribed antidepressants, and 0.32% were prescribed clonidine for behavioral control. This represents a 3-fold increase in stimulant prescribing, a 2-fold increase in antidepressant prescribing, and a 28-fold increase in clonidine prescribing between 1991 and 1995.[4] A greater acceptance of pharmacologic treatments for behavioral disorders in children was sited as 1 major reason for the increased prescribing in all age groups (2- to19-year-olds).[4]

Underdiagnosis and suboptimal treatment of children with ADHD is also a well-documented public health issue. One study of treatment services for ADHD nationwide found that only 50% of children with identified ADHD in real-world practice settings receive care that corresponds to guidelines of the American Academy of Child and Adolescent Psychiatry. Barriers to appropriate service provision include a lack of pediatric specialists, insurance obstacles, and long waiting lists to appropriate services. Between 1989 and 1996, related services, such as health counseling, for children with ADHD increased 10-fold, and diagnostic services increased 3-fold. Provision of psychotherapy, however, decreased from 40% of pediatric visits to only 25% in the same time frame. Follow-up care also decreased from more than 90% of visits to only 75%.[5] Other barriers to appropriate diagnosis and treatment include a fear of stigma, fear of substance abuse, and unknown long-term effects of treatment.[2,4,5]

Behavioral Interventions

The effectiveness of behavioral interventions was compared with methylphenidate therapy in the Multimodal Treatment Study of Children With Attention-Deficit/Hyperactivity Disorder (MTA).[6] This landmark study included 579 children aged 7-10 years with DSM-IV ADHD combined type. There were 3 active treatments (methylphenidate, behavioral treatment, and combination methylphenidate and behavioral treatment), which were compared with community care or "naturalistic" treatment. This controlled multicenter study was continued for 14 months. All active treatments received ongoing monitoring and coordination with parents, teachers, and clinicians. Community care included stimulant therapy in two thirds of cases, but there was no systematic coordination of care. Parent training was an integral part of behavioral interventions. Parent training included education on ADHD, counseling for parents, training in contingency management techniques, and development of realistic expectations of treatment.

Results of the MTA study showed that methylphenidate with or without behavioral therapy was superior to behavioral therapy alone.[6] All active treatments were superior to community care. Behavioral interventions were regarded as valuable and effective treatments by parents and teachers. Researchers concluded that clinician support, parent training, and teacher involvement were essential for optimal treatment outcome in ADHD.[2,6]

The most effective behavioral interventions include parent training and contingency management. Contingency management involves rewards for good behavior, positive verbal feedback, and consistent limit setting. Encouragement of focused exercises (such as assembling jigsaw puzzles) and attention to the environment (avoiding excessive or understimulation) can also be therapeutic.

Biofeedback, audiovisual stimulation, and dietary changes have all been studied as behavioral interventions for ADHD. Biofeedback involves monitoring brainwaves with electroencephalogram (EEG) and providing positive reinforcement for "attentive" beta brain waves and negative consequences for "distractible" theta brain waves. Special sets of glasses which provide lights and sounds to promote attentive brain waves through "entrainment" has been proposed as an effective audiovisual stimulation treatment. These types of behavioral interventions including dietary manipulation and nutritional supplements require further study before their place in therapy is determined.[7]

Confirming the Diagnosis Across the Life Span

A clinician with specialized expertise in child and adolescent neurodevelopment and behavior is best able to generate a reliable diagnosis of ADHD. Because children are highly reactive to their environment, it is crucial to enlist multiple informants (parents, teachers, siblings, child, caregivers) and rate symptoms in multiple settings. A child or teen must exhibit at least 6 of 9 symptoms of inattention or hyperactivity-impulsivity, or both, that are maladaptive and inconsistent with his or her developmental level. The symptoms must present in multiple settings over a period of 6 months and have an onset by age 7 before a diagnosis is confirmed.[8] Several validated rating scales exist which are designed for optimal diagnostic assessment.[9] Adolescents with ADHD tend to exhibit less hyperactivity but continue inattention and impulsivity. Approximately one third of individuals with ADHD continue to experience significant symptoms into adulthood. Common comorbid conditions include oppositional-defiant disorder, major depression, anxiety disorders, learning disability, and Tourette's disorder. The presence of comorbid conditions can increase the likelihood of ADHD chronicity.[10-13]


Both genetic and environmental factors contribute to ADHD, "nature and nurture." Twin studies confirm a genetic link as monozygotic twins show a 55% to 90% concordance rate for ADHD. Recent studies describe ADHD as a polygenic disorder that involves multiple genes that determine the severity of symptoms. ADHD may be best viewed as the extreme of a behavior that varies genetically throughout the entire population on a continuum.[14-16] There is no brain scan or blood test which confirms ADHD, however, the right prefrontal cortex, caudate nucleus, and globus pallidus are typically smaller, which suggests lack of connectivity of key brain regions that modulate attention, stimulus processing, and impulsivity.[17]

The neurotransmitters dopamine (DA) and norepinephrine (NE) are implicated in the pathophysiology of ADHD. Dopamine is a neurotransmitter involved in reward, risk taking, impulsivity, and mood. Norepinephrine modulates attention, arousal and mood. Brain studies on individuals with ADHD suggest a defect in the dopamine receptor D4 (DRD4) receptor gene and overexpression of dopamine transporter-1 (DAT1). The DRD4 receptor uses DA and NE to modulate attention to and responses to one's environment. The DAT1 or dopamine transporter protein takes DA/NE into the presynaptic nerve terminal so it may not have sufficient interaction with the postsynaptic receptor. The implications of these limited receptor findings require further study, however, it seems clear that dopamine and norepinephrine are involved in the pathophysiology of ADHD.

Although not a primary cause, family environment adversity factors (eg. high degree of psychosocial stress, maternal mental disorder, paternal criminality, low socioeconomic status, foster care) have been linked to increased rates of ADHD as well.[18] Dietary causes are unlikely, although an overall healthy diet which includes whole grains, 5 or more servings of fruits and/or vegetables, and protein with minimal processed sugars, as recommended by the American Dietetic Association, can eliminate diet as a contributing factor.


ADHD is a valid diagnosis that affects 3% to 5% of school age children and may persist into adulthood. Evaluation by an experienced clinician who uses objective ratings from multiple informants in different settings is important for a reliable diagnosis. Once a diagnosis of ADHD is confirmed, a treatment plan can be developed which considers comorbid conditions. For symptoms of ADHD, stimulants are the most effective treatment probably due to dopaminergic and noradrenergic modulation. Behavioral interventions, such as contingency management and parent training, are important adjuncts to a multimodal treatment plan that should include regular follow-up, psychoeducation, and coordination with teachers.


  1. Dopheide J. ADHD. Platform presentation of the American Pharmaceutical Association 148th Annual Meeting; March 16-20, 2001; San Francisco, California.
  2. National Institutes of Health (NIH) Consensus Statement on the Diagnosis and Treatment of ADHD. NIH Consensus Statement. 1998;16:1-37.
  3. Le Fever GB, Dawson KV, Morrow AL. The extent of drug therapy for attention deficit-hyperactivity disorder among children in public schools. Am J Public Health. 1999;89:1359-1364.
  4. Zito JM, Safer DJ, dos Reis S, et al. Trends in the prescribing of psychotropic medications to preschoolers. JAMA. 2000;283:1025-1030.
  5. Hoagwood K, Kelleher KJ, Feil M, et al. Treatment services for children with ADHD: a national perspective. J Am Acad Child Adolesc Psychiatry. 2000;39:198-206.
  6. MTA Group. Moderators and mediators of treatment response for children with ADHD: the multimodal treatment study of children with attention-deficit/hyperactivity disorder. Arch Gen Psychiatry. 1999;56:1088-1096.
  7. Amen DG. Change Your Brain, Change Your Life. New York, NY: Three Rivers Press; 1998.
  8. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994.
  9. Conners CK. Rating scales in ADHD: use in assessment and treatment monitoring. J Clin Psychiatry. 1998;59(suppl 7):S24-S30.
  10. Pliszka SR. Comorbidity of attention-deficit hyperactivity disorder with psychiatry disorder: an overview. J Clin Psychiatry. 1998;59(suppl 7):S50-S58.
  11. Clinical Practice Guideline: diagnosis and evaluation of the child with attention-deficit/hyperactivity disorder. Pediatrics. 2000;105:1158-1170.
  12. Goldman LS, Genel M, Bezman RJ, et al. Diagnosis and treatment of attention-deficit/hyperactivity disorder in children and adolescents. Council on Scientific Affairs, American Medical Association. JAMA. 1998;279: 1100-1107.
  13. Spencer T, Biederman J, Wilens TE, et al. Adults with attention-deficit/hyperactivity disorder: a controversial diagnosis. J Clin Psychiatry. 1998;59 (suppl 7):59-68.
  14. State MW, Lombroso PJ, Pauls DL, et al. The genetics of childhood psychiatric disorders: a decade of progress. J Am Acad Child Adolesc Psychiatry. 2000;39:946-962.
  15. Barkley RA. Attention-deficit hyperactivity disorder. Sci Am. 1998;279:66-71.
  16. Levy F, Hay DA, McStephen M, et al. Attention-deficit hyperactivity disorder: a category or a continuum? Genetic analysis of a large-scale twin study. J Am Acad Child Adolesc Psychiatry. 1997;36:737-744.
  17. Zametkin AJ, Liotta W The neurobiology of attention-deficit/hyperactivity disorder. J Clin Psychiatry. 1998;59 (suppl 7): S17-S23.
  18. Dopheide JA, Theesen KA. Disorders of childhood. In: Dipiro JT, Talbert RL, Yee GC, et al, eds. Pharmacotherapy: A Pathophysiological Approach. 4th ed. New York, NY: McGraw-Hill Professional Publishing; 1999.