Exploring psychotherapeutic issues and agents in clinical practice
With a new school year upon us, many children and adolescents will be referred for evaluation of suspected attention-deficit/hyperactivity disorder (ADHD). Although much has been published about pediatric ADHD, the current historical review offers new insights on the diagnosis and treatments of this old disorder (Figure A, available in the online version of this article).
Symptoms now attributed to ADHD were first described in 1775 by Melchior Adam Weikard, a German physician, in Der Philosophische Arzt (Barkley, Peters, & Weikard, 2012). By the end of the 19th century, Dr. Alexander Crichton noted the disabling features of ADHD, including restlessness, attentional difficulties, problems in school, and early onset (Palmer & Finger, 2001). By the turn of the 20th century, Sir George Still (1902) conducted the first study of 43 children who demonstrated problems with self-regulation and sustained attention contributing to the inability to learn. Still (1902) further discussed these symptoms as “an abnormal defect of moral control in children” (p. 1008). By the 1960s, a task force was developed to better understand this constellation of symptoms—then referred to as minimal brain dysfunction—which established the three core symptoms now associated with modern day ADHD: inattention, impulsivity, and hyperactivity (Clements, 1966).
With the advent of the Diagnostic and Statistical Manual of Mental Disorders (DSM; American Psychiatric Association [APA], 1952), minimal brain dysfunction was noted with a constellation of symptoms similar to those used today, although the disorder was thought to have its etiology in damage to the brain from illness or traumatic injury. The working diagnosis in the second edition of the DSM became hyperkinetic reaction of childhood/adolescence; the key factor was that the behaviors diminished by adolescence (APA, 1968). When the third edition (DSM-III) was published in February 1980, the world was first introduced to the diagnosis of attention-deficit disorder with or without hyperactivity, with onset before age 7 and symptom duration >6 months (APA, 1980). The next revision, the DSM-III-R (APA, 1987), changed the diagnosis to ADHD and noted that “the disorder is frequently not recognized until the child enters school” (p. 57). The DSMIII- R (APA, 1987) also noted that this disorder may persist into adulthood and that abnormalities of the central nervous system may be predisposing factors; prevalence at the time was indicated to be approximately 3% of children in the United States.
The fourth edition (DSM-IV; APA, 1994) changed the diagnosis to ADHD with three subtypes: predominantly hyperactive, predominantly inattentive, and combined. The DSM-IV noted that most individuals experience symptoms into late adolescence and adulthood, the disorder was common among first-degree relatives, and the prevalence was up to 5% in school-age children (APA, 1994). The text revision of the DSM-IV (APA, 2000), which remained in use until the current fifth edition (DSM-5; APA, 2013), offered no change to the diagnostic criteria. Today, clinicians must use diagnostic criteria set forth by the DSM-5 (APA, 2013). This latest edition moved ADHD from “Disorders Usually First Evident in Infancy, Childhood or Adolescence” to “Neurodevelopmental Disorders,” with an updated symptom onset of before age 12, allowing clinicians to more easily diagnose adults as it requires fewer symptoms to achieve diagnosis (APA, 2013). This change also allowed ADHD to be diagnosed as a comorbid condition with autism spectrum disorders for those who meet both sets of diagnostic criteria (APA, 2013).
ADHD is now considered a neurobehavioral disorder, affecting approximately 11% of school-age children (Visser et al., 2014), with approximately 75% persisting into adulthood (Brown, 2013). ADHD is characterized by symptoms of inattention, impulsivity, and hyperactivity, which are developmentally inappropriate and interfere with the individual's ability to function in home, academic, occupational, and social settings. Children with ADHD are at high risk for academic failure or delays, peer and family conflicts, risk-taking behaviors, substance abuse, motor vehicle accidents, and driving violations (Children and Adults with Attention-Deficit/Hyperactivity Disorder [CHADD], 2017a). Although family conflicts do not directly cause ADHD, they can change the way in which ADHD manifests and may result in additional psychiatric issues, such as antisocial and criminal behaviors (Langley et al., 2010).
Biological and Neurochemical Bases for ADHD
In addition to the external (i.e., social) and environmental (i.e., clinical) symptom presentations leading to a diagnosis of ADHD, there are also internal or biological bases, which are often more difficult to detect. Such biological factors were compiled in a 2013 meta-analysis of the evidence-based genes associated with ADHD (Thapar, Cooper, Eyre, & Langley, 2013). Collingwood (2016) also compiled evidence of genes related to ADHD. Table 1 reviews these genes. Although genetics is only one component of the diagnostic conundrum, a meta-analysis of 1,800 genetic studies determined heritability of ADHD to be between 75% and 91%, and that multiple genes, as opposed to a single gene, were a likely factor (Zhang et al., 2012). As nurses, we examine external and internal factors—the biopsychosocial factors—when evaluating an individual for potential diagnosis and treatment. Thus, it is important to understand the entire context of how patients manifest their symptoms and explore the biological and genetic factors associated with a disorder, especially if pharmacotherapy is a potential treatment option.
Genes Associated with Attention-Deficit/Hyperactivity Disorder
The mechanism of action or neurochemistry of pharmacotherapeutic agents for the treatment of ADHD involves an understanding of the neuroscientific basis of the disorder. It has long been believed that the neurochemicals serotonin, dopamine, and norepinephrine are responsible for most symptoms attributed to psychiatric illness, and the neurochemistry of ADHD is no exception. The prefrontal cortex (PFC) or executive functioning portion of the brain is responsible for planning, organizing, reasoning, and control of impulses. Reduced levels of dopamine in the PFC impact memory and reinforcement, contributing to the symptoms of inattention and difficulty in memory formation (Conley et al., 2015). Inefficiency in the transport of norepinephrine in the PFC leads to impulsivity, inattention, and hyperactive behaviors (Conley et al., 2015). A decreased number of serotonin receptors, which aid in controlling impulses and improving the ability to think before acting, also leads to symptoms of hyperactivity and impulsivity seen in individuals with ADHD (Conley et al., 2015). As a class, psychostimulant medications act by blocking the transport of dopamine and norepinephrine, leading to increased concentrations in the synaptic cleft, which in turn leads to increased neurotransmission of these neurochemicals and, ultimately, the improvement of ADHD symptoms (Stahl, 2013).
Evolution of Pharmacotherapy for ADHD
Just as diagnostic criteria for ADHD have changed over time, so have pharmacological treatments. Most psychostimulant medications used in the treatment of ADHD increase dopamine and norepinephrine in the PFC. Although these drugs have existed for >80 years in the United States, their use did not become mainstream until the mid to late 1980s, when the diagnosis of ADHD was first published in the DSM-III and DSM-III-R. Table 2 provides a historical overview of the pharmaceutical agents used in the treatment of ADHD.
Historical Overview of Pharmaceutical Agents for the Treatment of Attention-Deficit/Hyperactivity Disorder
A Romanian chemist first synthesized the amphetamine compound in 1887, but it took until 1929 for a California biochemist to discover its physiological and psychoactive effects while seeking a cure for asthma (Hicks, 2012). The first psychostimulant/amphetamine tablet, Benzedrine® (racemic amphetamine), was introduced to the market in 1937 for the treatment of narcolepsy, postencephalitic Parkinsonism, and minor depression (American Medical Association Council on Pharmacy & Chemistry, 1937). The following year, Dr. Charles Bradley, a psychiatrist treating children with behavioral disorders in a therapeutic home setting, serendipitously discovered that when Benzedrine was given to children to alleviate headaches resulting from testing involving pneumonencephalograms, their behaviors, school performance, and social and emotional reactions all improved (Strohl, 2011). Bradley's studies continued and ultimately shaped the pharmacological treatment of ADHD, albeit >25 years later (Strohl, 2011). In 1943, Desoxyn® (methamphetamine) was introduced, but was not indicated for treatment of ADHD until decades later (Centers for Disease Control & Prevention [CDC], 2017).
Ritalin® (methylphenidate), arguably the “game changer” for the treatment of ADHD, was first synthesized in 1944 and first approved in 1955 for the treatment of chronic fatigue, narcolepsy, and depression in adults and geriatric patients (Center for Substance Abuse Research, 2013). By 1963, the effectiveness of Ritalin as a treatment for emotionally disturbed children was being researched and published by C. Keith Conners, who went on to develop the many times revised and widely used Conners Comprehensive Behavior Rating Scales for parents and teachers in 1969 (Iannelli, 2017). By 1975, the American Academy of Pediatrics' Council on Child Health published their first official statement, “Medication for Hyperkinetic Children,” regarding use of psychostimulant drugs in children (Kugel et al., 1975). Although amphetamine and mixed amphetamine drugs were discovered and synthesized since the late 19th century, Ritalin remained relatively unchallenged in the pharmaceutical marketplace until the mid-1970s when Cylert® (pemoline), DextroStat®, and Dexedrine® (both dextroamphetamine agents) were introduced. Ritalin remained the gold standard until Adderall® (mixed amphetamine/dextroamphetamine salt agent) was introduced in 1996 (after approved to be marketed in 1960) (CDC, 2017).
From 1997–2006, the diagnosis and subsequent pharmacological treatment of ADHD began a rapid period of growth in the United States, with a quadrupling of sales of psychostimulant medications (Pal, 2008). Various new delivery systems for psychostimulant medications have been developed, some providing longer lasting beneficial effects on the symptoms of ADHD than others. Despite being labeled as sustained release, many of the longer-acting psychostimulant agents did not provide coverage long enough to abate symptoms for an entire school day. In 2000, when Concerta® (methylphenidate-OROS™) received marketing and sales approval from the U.S. Food and Drug Administration (FDA) (CDC, 2017), the pharmacological treatment of ADHD was again revolutionized. Concerta became the first ADHD medication whose effects and abatement of ADHD symptoms lasted throughout the day on a single morning dose. This new delivery system technology helped increase adherence and decrease visits to the nurse for a late morning or lunchtime dose of medication, which also reduced stigma associated with being a child medicated for ADHD (Coghill, 2002).
Since Concerta was introduced, many new delivery system technologies have been developed to offer personalized psychopharmacotherapy to individuals with ADHD. Although no new compounds or active ingredients have been synthesized over the past 17 years, methylphenidate, amphetamine agents, and mixed amphetamine salts have been produced in tablets, capsules, liquid, oral solutions, chewable tablets, transdermal patches, and orally disintegrating extended release tablets. Table 2 shows the active ingredients and dosage forms of FDA-approved treatments for ADHD.
Psychostimulant drugs are not the only pharmacological agents approved by the FDA for the treatment of ADHD. Various non-stimulant medications with varied delivery systems, as well as a prescription medical food, have been approved since 2002. With the inception of Strattera® (atomoxetine), a specific norepinephrine reuptake inhibitor (CDC, 2017), parents who were concerned about having their child prescribed and medicated with a controlled dangerous substance (CDS) now had alternatives. All currently available psychostimulant drugs are classified as CDS Schedule II medications due to the high potential for abuse and dependency (FDA, 2017). Strattera's action of blocking the reuptake of norepinephrine allows for increased neurotransmission of norepinephrine and dopamine in the PFC (Bymaster et al., 2002), thus improving sustained attention and recall. In 2009, Intuniv® (guanfacine) and Kapvay® (clonidine), both selective alpha-2 adrenergic antihypertensives in extended release delivery formulations, were introduced as non-stimulant alternatives (CDC, 2017). Intuniv and Kapvay improve the hyperactive and impulsive symptoms of ADHD by indirectly affecting dopamine by their initial action on norepinephrine in the PFC (CHADD, 2017b).
In addition to the three FDA-approved, non-stimulant medications available to treat ADHD, in 2013, Vayarin®, a prescription medical food, offered another alternative to those individuals wanting a more natural treatment (FDA, 2017). Vayarin is said to reduce hyperactivity and improve attention by managing the lipid deficiency associated with ADHD through a unique compound of phosphatidylserine and omega-3 fatty acids. This medical food increases the bioavailability of lipid nutrients across the blood–brain barrier, which cannot occur simply through dietary modification (VAYA Pharma, 2016).
Since 1937, there have been 35 brand name drugs used in the treatment of ADHD. Only two—Biphetamine® (mixed amphetamine/dextroamphetamine resin) and Cylert® (pemoline)—have been discontinued in the U.S. marketplace. Although many of these drugs now have generic formulations available, pharmaceutical companies continue to manufacture brand name versions of the primary psychostimulant compounds (i.e., methylphenidate and various amphetamines), but with delivery systems offering unique features to allow for ease of portability and swallowing, improve adherence, and allow for patient preferences regarding taste and texture. In addition, the varied delivery systems offer differing onset of immediate versus delayed action and overall duration of action depending on the formulation. Prescribing clinicians can now offer a truly personalized treatment regimen to patients with ADHD. For more information on drug delivery systems, refer to the May issue of the Journal of Psychosocial Nursing and Mental Health Services and the article, “From Immediate Release to Long Acting Drug Delivery Systems: What Do They Mean and Why Do They Matter?” (Leahy, 2017).
ADHD has undergone many revisions and changes in its diagnostic label and pharmaceutical treatments over the past 80 years. Symptoms have been recognized for centuries, but have only been acknowledged as a viable disorder in children since 1980 and adults since 2013. ADHD is known to have a complex etiology rooted in social and environmental spheres, as well as genetic and biological spheres. As holistic practitioners, nurses incorporate the biological, psychological, and social elements when evaluating patients. Nurses are in a prime role to identify and treat individuals across the lifespan who present with the symptoms of ADHD.
Just as the diagnostic label for ADHD has changed, so have the treatment options. Given the extensive role social and environmental factors play in the symptoms of ADHD, it is important to incorporate psychosocial therapies, behavior modification, and environmental manipulations in treatment plans for individuals with ADHD. Psychopharmacology is simply another tool that can be incorporated in the treatment plan to address the biological and physiological underpinnings of this disorder, which impact functioning in the family, as well as in school/occupational and social settings. As stigma remains regarding psychiatric disorders and specifically ADHD, the current historical overview and available pharmacological treatments can serve as a guide when clinicians are providing individuals and their loved ones with information regarding this highly treatable, old disorder.
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Genes Associated with Attention-Deficit/Hyperactivity Disordera
|Dopaminergic||Dopamine D4 Receptor||DRD4|
|Dopamine D5 Receptor||DRD5|
|Dopamine Active Transporter 1||DAT1/SLC6A3|
|Dopamine Beta Hydroxylase||DBH|
|Serotonergic||Serotonin Transporter 2||5HTT/SLC6A4|
|Serotonin 1B Receptor||HTR1B|
|Serotonin 2A Receptor||HTR2A|
|Tryptophan Hydroxylase 2||TPH2|
|Noradrenergic||Neuroepithelial Cell Transforming Gene 1||NET1/SLC6A2|
|Alpha-2A Adrenergic Receptor||ADRA2A|
|Alpha-2C Adrenergic Receptor||ADRA2C|
|Other||Synaptosome Associated Protein 25||SNAP-25|
|Brain-Derived Neurotrophic Factor||BDNF|
|Cholinergic Receptor Nicotinic Alpha 4||CHRNA4|
Historical Overview of Pharmaceutical Agents for the Treatment of Attention-Deficit/Hyperactivity Disordera
|Approval Date||Brand Name||Active Ingredient(s)/Generic Name||Dosage Form|
|1955–1983b||Biphetamine®||Mixed amphetamine/dextroamphetamine resin||Tablet|
|1960||Adderall®||Mixed amphetamine salts||Tablet|
|1975–2003b||Cylert®||Pemoline||Tablet, chewable tablet|
|2001||Adderall XR®||Mixed amphetamine salts||Capsule|
|2002||Methylin®||Methylphenidate||Oral solution, chewable tablet|
|2006||Daytrana®||Methylphenidate||Transdermal film patch|
|2007||Vyvanse®||Lisdexamfetamine dimesylate (prodrug of dextroamphetamine)||Capsule|
|2012||Quillivant XR®||Methylphenidate||Liquid suspension|
|2013||Vayarin®||Phosphatidylserine-elcosapentaenoic acid-docosahexaenoic acid compound||Capsule (Rx medical food)|
|2015||Quillichew ER®||Methylphenidate||Chewable tablet|
|2015||Dyanavel XR®||Amphetamine||Liquid suspension|
|2016||Adzenys XR-ODT®||Amphetamine||Orally disintegrating tablet|
|2017||Vyvanse®||Lisdexamfetamine dimesylate (prodrug of dextroamphetamine)||Chewable tablet|
|2017||Mydayis®||Mixed salts of single-entity amphetamine||Capsule|
|2017||Cotempla XR-ODT®||Methylphenidate||Orally disintegrating tablet|