What’s New About Attention Deficit/Hyperactivity Disorder? – Dale Mortimer, M.D.

Is Attention Deficit/Hyperactivity Disorder (also known as “ADD or “ADHD”) a fad, or a valid medical disorder? Don’t we all have some symptoms of attention–deficit/hyperactivity disorder? Isn’t attention–deficit/hyperactivity disorder just an excuse to escape culpability for blatantly rude or even criminal behavior? Just how effective are EEG neurobiofeedback, play therapy, gluten–free diets, various vitamins, caffeine, “energy drinks,” or herbs for the treatment of ADHD? Should those with ADHD receive effective treatment only during school days and school hours, or should these persons with impairing ADHD be treated throughout the waking day, 365 days a year? Why do some ADHD individuals do well with a very low dose of a certain medication, while others prescribed the same dose show no response – even if the ADHD individuals are of the same weight and age? What is the risk of addiction from taking prescribed stimulants? Should those with past substance abuse ever be prescribed stimulants? Is there a clinically absolute maximum daily stimulant dose?

In June, 2001, at the annual meeting of the Oregon State Pharmacists Association, Vancouver Child & Adolescent Psychiatrist Dale Mortimer, M.D., addressed these questions and more during his presentation on attention deficit/ hyperactivity disorder.  More than 80 pharmacists from Oregon, Washington and Idaho traveled to Oregon’s Sun River Resort to listen to Dr. Mortimer’s keynote presentation. Because of the enthusiastic response to his 2001 presentation and subsequent summary, Dr. Mortimer has recently provided the inquisitive reader with this update.^1,2

History OF ADHD. Back in 2001, Dr. Mortimer began his Sun River presentation by reciting a poem – which is known in English as Fidgety Phil. In one translation, the poem reads something like this:

“Phil, stop acting like a worm.

The table is not a place to squirm!”

Thus speaks the father to the son.

Severely speaking, not in fun.

Mother frowns

And looks around.

But Phillip will not heed the advice.

He’ll have his way at any price.

He turns and churns.

He wiggles and giggles.

“Phil these twists I cannot bear!”

Phillip then tips backward and out of his chair.

This poem was written in about 1848 by German physician Heinrich Hoffman who lived from 1809 to 1894. In this poem, Dr. Hoffman describes a boy with what would now be an example of the “hyperactive/impulsive subtype” of ADHD. A second poem by Dr. Hoffman, entitled [in English] Harry Stare at the Clouds, describes a boy with the inattentive type of ADHD. In English translation, the poem reads something like this:

  As he trudged along to school,

  It was always Harry’s rule

  To be looking at the sky

   And the clouds that floated by;

   But what just before him lay,

   In his way,

   Harry never thought about;

   So that every one cried out

   "Look at little Harry there,

   Little Harry Head-In-Air!"

   Running just in Harry’s way

   Came a little dog one day;

   Harry’s eyes were still astray

   Up on high,

   In the sky;

   And he never heard them cry

   "Harry, mind, the dog is nigh!"

   Bump!

   Dump!

   Down they fell, with such a thump,

   Dog and Harry in a lump!

Dr. Mortimer added: “From reading some descriptions about Dr. Hoffman’s own childhood, I suspect that Hoffman himself suffered from what would now be called untreated attention–deficit/hyperactivity disorder. For example, young Heinrich Hoffman was described as ‘lazy and easily distracted, gregarious, and struggling in school.’ Fortunately, Heinrich’s ‘stern father’ provided Heinrich with enough structure to permit young Heinrich to eventually complete his medical training.”

Dr. Mortimer then made several observations and conclusions: “The name of what is now known as Attention Deficit/Hyperactivity Disorder has gone through a change of name [and a slight change in diagnostic criteria] every decade or so. In 1902, Sir George Still named this condition Still’s Disease, of course. Then in the early 1900s, the condition was renamed Disorder of Moral Control. Later, in 1937, its name changed to Minimal Brain Damage. Since no gross³ brain pathology could be identified on autopsy, in 1960, the name was changed to Minimal Brain Dysfunction. Then in 1968, the name changed again to Hyperkinetic Reaction of Childhood. Then again, in 1980, the name changed again – this time with subtypes: Attention Deficit Disorder with or without Hyperactivity [i.e., “ADD with or without H”]. In retrospect, as Dr. Mortimer noted, this sub–classification was as useful as subtyping hypertension based on a patient’s eye color. In 1987, the name changed again slightly to Attention Deficit Hyperactivity Disorder – without the subtypes. Most recently, since 2013, the subtypes are now back in vogue, and there is now a vergule between “Deficit” and “Hyperactivity.” So we currently have ADHD [for stylistic purposes, I am omitting the vergule here] with five subtypes: (1) ADHD, predominately inattentive type; (2) ADHD, predominately hyperactive/impulsive subtype; (3) ADHD, combined subtype; (4) ADHD Not Otherwise Specified; and (5) ADHD, in partial remission. [For the current, “official” diagnostic criteria, please see The Diagnostic and Statistical Manual of Mental Disorders, fifth edition.]

Dr. Mortimer summarized: “My introduction above may sound pedantic, but here is my point: childhood–onset, chronic problems with attention, concentration, impulsivity and/or motivation is not a new condition. The name of this condition changes, but the ‘deck of cards” [each metaphorical card listing a single ADHD symptom] has remained still pretty much the same cards (or symptoms) for the past 160 years. Every ten or twenty years, the deck of cards is reshuffled, and, with each new edition of the Diagnostic and Statistical Manual of Mental Disorders, or “DSM” (since 2013, we have been currently using the fifth edition of the DSM), the name for the disorder is ‘tweaked.’”

Prevalence. Community prevalence of ADHD is the number of persons with attention–deficit/hyperactivity disorder in a representative population sample, according to pre–defined diagnostic criteria. Dr. Mortimer continued: “Please also note that what is now defined as ADHD was described in the medical and pediatric literature over 150 years ago – long before the invention of TV, computer games, fluorescent lights, and food additive.⁴ Furthermore, what is now called ADHD is not a disorder that is limited to the United States (– remember that Dr. Hoffman lived in what is now known as Germany). We also know from international epidemiological studies that ADHD is a common medical disorder with a world–wide distribution. More recent studies place the prevalence of ADHD at 8.9% of all children and 13.1% of all adults.^5,6 Previous and lower prevalence estimates of the diagnosis of ADHD in adolescence and in adults⁷ have been found to be misleading for several reasons. This underestimation happened because of the quirky statistical consequences of writing the diagnostic criteria in order to identify ADHD children. Now, in the vast amount of cases, children with ADHD don’t ‘outgrow it.’ Instead, their symptoms change over time as their brains [and, especially, their frontal lobes] mature.⁸ The ADHD adult (or the spouse) might focus his or her complains on inefficiencies at work, problems with completing projects, difficulty sitting through meetings, driving a car too quickly, or talking excessively, or making inappropriate comments. But it is the inattentiveness of ADHD that tends to continue in adulthood – which when ADHD is undiagnosed in adults, is much more difficult to identify by general adult psychiatrists, correctional psychiatrists, geriatric psychiatrists (– the majority of whom are not trained in child & adolescent psychiatry), or by the ADHD adults themselves.”

Orphan Adults. Where did all these “ADHD adults” suddenly come from? Is this just the latest fad? Dr. Mortimer explained that it wasn’t until 1995 before anyone saw a book on attention–deficit/hyperactivity disorder which had a chapter devoted to ADHD in adults.⁹ Until that time, ADHD in adults was an “orphan” medical condition, without any medical specialist “claiming” this group of patients as their bailiwick. Those physicians most familiar with the diagnosis and treatment of ADHD (i.e., pediatricians, child & adolescent psychiatrists, and pediatric neurologists) usually exclude adults from their patient population. Conversely, general adult psychiatrists and general adult neurologists are usually not trained to identify (or even think about the possibility of) ADHD in their adult patients.

A Fad? Being “thoroughly” familiar with the pediatric, genetic, neurological, and psychiatric literature on attention–deficit/hyperactivity disorder, Dr. Mortimer summarized: “ADHD is a valid medical disorder. It is one of the best–researched conditions in all of medicine. The overall data on its validity are far more compelling than is the case for most mental disorders – and even for many medical conditions.” While there is currently a lack of independent diagnostic tests for ADHD, “The evidence supporting the validity of the disorder in children, adolescents and adults includes: family, twin, and adoption studies; cross–national studies; long–term developmental course of ADHD over time; brain imaging studies; and segregation and molecular genetic analyses.^10,11 Those who claim that ADHD is just a fad, and that it is an invalid diagnosis have not done their homework – nor have they had the frustrating and sometimes ‘nightmarish’ experience of living with someone with untreated ADHD.”

A sampling of the evidence for ADHD being a legitimate medical disorder. First, there is the genetic evidence. A number of twin studies have established that attention–deficit/hyperactivity disorder is among the most heritable of neuropsychiatric disorders.¹² Second, there is the brain imaging evidence. Structural brain imaging studies have found that total gray matter volume in the brain is decreased by 2% to 3% in children with ADHD compared with typically developing children, with more pronounced decreases and atypical age–related changes in the brain’s frontal–striatal system. The striatum¹³ and its frontal lobe connections are rich in dopaminergic neurons, and ADHD symptoms are believed, at least in part, to stem from dopaminergic and noradrenergic imbalances. Functional connectivity analyses (conducted on data obtained during functional magnetic resonance imaging) have demonstrated decreased connectivity in the brain networks supporting sustained attention and working memory, spanning the prefrontal cortex, striatum, parietal cortex, and cerebellum, specifically identifying brain regions in the right thalamus, left occipital gyrus and cerebellum. A recent study by Li et al¹⁴ places the pulvinar nuclei of the thalamus at the center of dysfunctional attentional networks in those with ADHD. [The pulvinar nuclei are the largest group of nuclei within the thalamus, and act as an “umpire” adjudicating which items in a crowded visual environment win focused attention.]

Heritability and Genetics. Until very recently, medical insurance companies attempted to deny medical coverage for the medical treatment of attention–deficit/hyperactivity disorder by asserting that it is an educational or behavioral problem which does not belong in the physician’s domain of medically treatable problems. Dr. Mortimer responded: “There is, in fact, no controversy in the professional medical literature on this point: ADHD is one of the most strongly inherited neurological disorders in all of medicine. Those who claim otherwise are either not familiar with the voluminous research published over the past three or more decades – or they are simply liars.” While the specific genes causing ADHD remain elusive,^15,16 we know that twin, adoptive and family genetic studies have found the heritability of ADHD to be between 60% to 90%,¹⁷ meaning that somewhere between 60–90% [the most common number quoted in recent articles is 75%] of the variance in ADHD symptoms is accounted for by genetics. “In other words, in about 3 out of 4 cases of ADHD, there will be a genetic family history for ADHD. Thus, ADHD is one of the most strongly inherited medical conditions is all of medicine – the heritability of ADHD is as strong or even stronger than it is for ultimate adult height.”¹⁸

If a child meets criteria for attention–deficit/hyperactivity disorder, there is an approximately 25% likelihood that a sibling will also be found to meet diagnostic criteria for attention–deficit/hyperactivity disorder, and there is an 80% likelihood that one or both parents will also meet diagnostic criteria for ADHD. If a parent meets criteria for attention–deficit/hyperactivity disorder, there is a 50% likelihood that their child will also meet criteria for ADHD.

“Once I am convinced that a child meets criteria for attention–deficit/hyperactivity disorder, I next wonder which parent also meets ADHD criteria. Often, it makes more sense to treat the disorganized, inattentive, impulsive, or forgetful parent first before attempting to enlist the ADHD parent’s cooperation in administering and supervising the medications prescribed to treat the ADHD child or adolescent.”¹⁹

Environmental contribution. Environmental factors also influence our genes. Epigenetic²⁰ changes have been identified in a number of attention–deficit/hyperactivity disorder children with histories of exposure to such environmental stressors as prenatal nicotine and alcohol exposure, lead exposure, maternal malnutrition, prematurity,²¹ lower birth weight, stress violence, or severe psychosocial trauma.²²

Maturational delays and responsibility levels. Dr. Mortimer next referred to longitudinal neuroimaging studies of the brains of children with attention–deficit/hyperactivity disorder children compared to brains of normal controls. Some brain studies have shown a 2– to 3–year delay in maturation of prefrontal cortex and associated pathways in children with ADHD.²³ Other brain studies have demonstrated frontal lobe subcortical and cerebellar dysfunction with smaller striatal structures in particular. In MRI studies, difficulties have been found with the differential maturation of important neural circuits, along with the persistence of cortical thickening where it should be thinning over time. “The important thing to keep in mind is that children and adolescents are moving targets. Their brains continue to myelinate with time, allowing more “computer application programs” to go “on line” in their brains. You just have to be very, very patient, and realize that developmental disorders such as ADHD unfold in a nonlinear fashion over time. The life trajectory for those with untreated ADHD is curvy, not a straight line.”

Dr. Mortimer has found the following formula from psychologist Russell Barkley, Ph.D. to be very useful for parents’ decision–making: For a child or adolescent with untreated attention–deficit/hyperactivity disorder, multiply the youngster’s age (in years) by 70%. This will give the parent a “ball park” understanding of the youngster’s current level of emotional maturity and responsibility. Would you trust a normal 14 year–old to baby–sit your children? Yes, probably. OK, would you trust a 14 year–old with untreated ADHD to baby–sit your children? Well, 14 years old times 70% yields a level of emotional/maturity of a 9.8 year–old child. So no, you shouldn’t expect a 14 year–old with untreated ADHD to responsibly baby–sit your children. Would you trust an 18 year–old normal adolescent with a driver’s license to drive your car safely. Well…yes, I suppose. Consider next the situation of an 18 year–old with a driver’s license who takes ADHD medication but the benefits of the medication are typically gone by 6PM? Would you allow him or her to drive your car after supper? Well, let’s see: 18 years old times 70% results in an emotional/maturational level equivalent of 12.6 years old. So no; this ADHD adolescent must not be allowed to drive a car after 6PM without taking effective ADHD medication at an effective dose late enough in the day to allow him or her to drive responsibly and safely in the evening. Would you expect a normal 18 year old adolescent to be responsible and mature enough to live on his or her own? Yes, probably. How about an 18 year old with untreated ADHD? Well, 18 years times 70% results in an emotional/ maturational level equivalent to 12.6 years old, so no – the adolescent’s parents should expect to provide adult supervision for their young adult with untreated ADHD until sometime around age 26 (i.e., 26 years times 70% results in an emotional/maturational age of 18.2 years old). Good luck!

Co–Occurring Medical Disorders (comorbidities). Not only is attention–deficit/hyperactivity disorder strongly genetic, ADHD is also a highly comorbid condition, with at least 50% of ADHD children, and 70% of ADHD adults having  at least one additional mental disorder, learning disorder or developmental disability –  e.g., major depression; bipolar disorder; obsessive compulsive disorder; a reading disorder [e.g., “dyslexia”]; a tic disorder (with Tourette’s disorder being the most severe form of a tic disorder); difficulties with sensory integration; problems with working memory; speech and language delay; and/or substance  [– the most prevalent substance of abuse in those with ADHD is nicotine dependence].^24,25

Dr. Mortimer explained: “Identifying whether or not a person meets diagnostic criteria for attention–deficit/hyperactivity disorder is often the easiest part of the physician’s task. It is often more difficult for the physician to sort out – for example – whether the ADHD person’s demoralization and worries are separate disorders, or whether these symptoms are the consequence of the ADHD person’s accurate assessment of his or her current, woefully inadequate difficulties with performance. Another diagnostically challenge is to sort out ADHD from bipolar disorder. ” This notion of comorbidity is important to keep in mind since the presence of additional, mental disorders (e.g., oppositional defiant disorder, a tic disorder, bipolar disorder) or the presence of non–ADHD general medical conditions (e.g., sleep apnea, an underactive thyroid, inadequate testosterone production in adolescents and adults, substance abuse, and/or other unidentified medical illness) can greatly interfere with reaching a satisfactory treatment outcome.

Sleep and ADHD. Studies are finding that as many as 77% of children with attention–deficit/hyperactivity disorder have sleep disturbances, irrespective of medication status.²⁶ Difficulty falling asleep (possibly a manifestation of a circadian sleep disorder with a circadian phase delay) is common in ADHD patients of all ages. Several studies have shown an association between ADHD and sleep–related motor disorders, with 44.% with restless legs syndrome (compared to 10% of the general population);²⁷ 40.4% with periodic leg movements associated with sleep [PLMS];²⁸ 21.8% with sleep–related rhythmic movement disorder; and 32.7% with bruxism.²⁹ Studies of ADHD adults have found 60–80% of ADHD adults have comorbid sleep disorders such as daytime sleepiness, insomnia, delayed sleep–phase syndrome, fractured sleep, restless legs syndrome, and sleep–disordered breathing [e.g., primary snoring;³⁰ upper airway resistance syndrome; obstructive hypoventilation; or obstructive sleep apnea].³¹  Actigraphy and polysomnography data have shown that ADHD patients have lower sleep efficiency and higher stage shifts per hour of sleep; increased nocturnal movements; decreased time spent in REM sleep, are more sleepier during the day; and have longer daytime reaction times.^32-34

Just to make it interesting for the clinician, untreated adults with a diagnosis of attention–deficit/hyperactivity disorder will frequently complain to a general adult psychiatrist about the “random noise in my head” of mostly negative and pessimistic self–talk, during which time³⁵ the untreated ADHD adult ruminates about what he or she said or didn’t say to others that day, or what the ADHD adult didn’t accomplish that day. Historically, the “noise in my head” is often misattributed as “racing thoughts” (– a diagnostic symptom of bipolar disorder), and – along with being easily distracted and often “on the go,” many general adult psychiatry–trained psychiatrists then misdiagnosed adults with ADHD with bipolar disorder. The good news is that now there is at least one adult psychiatry training program (at OHSU in Portland, Oregon) which trains its residents in identifying and treating adults with ADHD.

Although difficulty falling asleep is a chronic problem in most ADHD children, adolescents and adults, a common confusion arises when the ADHD patient (or the patient’s parent) forgets that the onset of sleep problems predated onset of ADHD treatment with stimulants. Consequently, stimulant medications commonly used to treat ADHD are often unjustly accused of causing sleep difficulties.

Longitudinal Course of Those with Untreated ADHD. In the 1960s, there was an unsubstantiated belief (which apparently became “gospel” after pediatrician Brian Laufer, M.D. publicly speculated about the longitudinal course of children with attention–deficit/hyperactivity disorder) that all individuals with ADHD “outgrew” their symptoms at the onset of puberty. We now know that this is not the case ( “…since when does anything improve with puberty?” asked Dr. Mortimer with a wry smile). Virtually all prospective studies of ADHD school-age children show persistence of symptoms through puberty and into adulthood. Since hyperactivity symptoms diminish with age, this may account for the long–held belief that children with ADHD outgrow the disorder during adolescence. However, the “core” ADHD symptom of inattention usually persists into adulthood. And it is often this profoundly impairing inattention which causes so many vocational, educational, medical, legal, and social problems. Dr. Mortimer explained: “For the vast majority of attention–deficit/hyperactivity disorder individuals, this is a life–long, inherited disorder. ADHD is ‘with’ the person 24 hours a day, 365 days a year. That is, ADHD is a chronic medical disorder, probably present in the majority of ADHD individuals since birth. Yet, despite this knowledge, many primary care physicians continue to prescribe medications that cover ADHD symptoms for only 4 hours a day, and only during school days. This prescribing strategy makes as much sense to me as trying to read in the afternoons or on weekends without my eyeglasses. Optimal treatment must cover as much of the waking day as possible every day of the year.”

Psychiatric Assessment of ADHD. Since attempts to demarcate attention–deficit/hyperactivity disorder vs non– attention–deficit/hyperactivity disorder along a continuum of behavioral inhibition and self–regulation causes problems similar to those of trying to precisely determine when day ends and night begins, and since everyone sometimes has ADHD–type impairments [just as everyone is occasionally sad, but not everyone meets diagnostic criteria for a major depressive episode], “...experienced clinical judgment is essential in distinguishing those who do and those who do not meet ADHD criteria.” A considerable amount of information must be collected in order to: accurately rule in or rule out a diagnosis of ADHD; identify other, co–existing mental disorders; and develop a safe, effective, and practical treatment plan. “A thorough evaluation may require three or more hours of face–to–face time with the family – in addition to reviewing as many medical and academic records as can be retrieved. Performing a thorough ADHD evaluation is not something that a physician can competently accomplish during a fifteen minute office visit.”

ADHD Checklists. Many physicians use symptom and behavior checklists, and some checklists are more accurate than others. Dr. Mortimer summarized: “For children with suspected attention–deficit/hyperactivity disorder, I prefer using the CAP [Child Attention Problems] checklist since it is short, normed, not copyrighted, and allows teachers to leave clinically rich, descriptive written comments. For about the past 25 years or more, I have been using the Brown Attention Activation Disorder Scale [BAADS] and Paul Wender’s Utah Rating Scale (WURS) [revised by Dr. Mortimer] to screen for ADHD in adults. Other clinicians frequently use the World Health Organization–supported Adult ADHD Self–Report Scale [ASRS]. However, I still cringe when I see pediatricians who are still using the Vanderbilt ADHD Parent Rating Scale to rule in or out a diagnosis of ADHD. Despite the Vanderbilt being insensitive and despite the Vanderbilt being incompatible with the current official diagnostic criteria for ADHD, the Vanderbilt is still widely used by pediatricians – probably because the Scale was devised by a pediatrician and also probably because the Scale isn’t copyrighted.” Dr. Mortimer summarized: “The Vanderbilt ADHD Parent Rating Scale checklist is not a sensitive ADHD screening instrument and, in my opinion, should be retired from use. The Vanderbilt especially misses too many children who have more subtle – but still disabling – forms of ADHD. I suspect that this is predominately why so many pediatricians miss making a correct diagnosis of ADHD in their children and teen patients.”

Elementary School Report Cards. “In addition to clinical interview, what is usually most useful for helping to identify attention–deficit/hyperactivity disorder in any age is a careful review of the patient’s elementary school reports cards – from kindergarten onward – even if the identified patient is seventy years old or older. For the purposes of assessing for ADHD, I care less about the actual academic letter grades, and look for a many–years pattern to teachers’ hand–written comments. Experienced teachers have a good “feel” for a child’s normal range of behavior for any specific age and sex. If teachers repeatedly comment over multiple school years throughout elementary school that the student is polite, but is: too social, not working up to his ability, needs to improve his time management skills, or needs to show more consistent effort, then the diagnosis of ADHD becomes much more likely than not.”

When the new patient is a child or an adolescent, the first office visit with Dr. Mortimer is for the parents alone. During this first meeting, among other things, Dr. Mortimer asks the parents about the patient’s biological relatives, the history of the child’s development,  – as well as the child’s academic, social, and family situation. “I want to hear about what could be better in the child’s life, and what interventions have been tried. But I also want to know what the child is doing well. We build on our strengths, not on our weaknesses.”

Diagnostic Criteria for ADHD. Dr. Mortimer reviewed the diagnostic criteria for attention–deficit/hyperactivity disorder as defined in the latest version of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition [DSM V],³⁶ and then discussed problems with the currently accepted diagnostic criteria. First, the good news. The latest edition of the DSM acknowledges that previous editions of the ADHD criteria more readily identify ADHD children, and often completely miss impairing ADHD in adolescents and adults. In addition, longitudinal studies of ADHD children followed into adulthood by Russell Barkley, Ph.D. and others have shown that ADHD adults had difficulty remembering symptoms dating back to early childhood, and therefore the DSM–V diagnostic criteria have been modified to reflect this.³⁷ Secondly, the latest DSM version also acknowledges that not only do the ADHD symptom manifestations change with age, but a lower number of symptoms should be considered indicative of the diagnosis of ADHD in both adolescents and adults.³⁸ Thirdly, “The diagnostic criterion in early version of the DSM asserted (without any research to support this claim) that ADHD symptoms must be present by the age of 7 years. This cut–off has since been found to be completely arbitrary. The committee members who selected this age limit for ADHD have been the first to admit this. While, in the latest edition of the DSM, the age–limit cut off for onset of at least some ADHD symptoms is now 12 years old – which was also selected by the committee without supportive research – this is a step in the right direction. Those with mild ADHD, and those with the predominately inattentive type plus high IQ may not show impairment until later adolescence when academic demands increase – yet they may still respond as robustly to the common ADHD treatments.”

ADHD, High IQ and/ or Learning Disorder. While – on average – the IQ of youth with attention–deficit/hyperactivity disorder is nine points lower than those of typically developing peers,³⁹ how many times has Dr. Mortimer heard the following? “My son [or daughter] doesn’t have ADHD – the teacher simply doesn’t know how to teach – and the classes are all boring!” Well, maybe. This is where a seasoned clinician’s judgment is especially important. In some cases, the parent is right, but sometimes, the child has ADHD – plus high IQ. “Thus, even though an undiagnosed and untreated ADHD student might be daydreaming in the classroom 80% of the time, if the student’s IQ is high enough, he or she can deduce what the teacher must have been discussing when the teacher attempts to ‘catch’ the daydreaming ADHD student through an unanticipated question. “In the high–IQ child whom you suspect also has ADHD, the clinician may have to examine the pervasiveness of the student’s boredom in different situations. The clinician may need to examine the school situation very carefully to sort out  ADHD vs legitimate classroom tedium.”

There is another potential problem in sorting out whether or not a student has high IQ, has high IQ plus attention–deficit/hyperactivity disorder, or has high IQ plus a learning disorder.  Because of normal variation, some students will have some academic weakness in relation to his or her IQ, and those weaknesses may seem to be more prominent, and more discrepant in those with higher IQ. So there is some controversy over whether that constitutes a true disability. Can you actually have a disability if you are doing better than 50% of the population? “Well…yes! – I see this all the time in my patients whose IQ is well above average. This is a situation when a psychologist can be very helpful in uncovering an unidentified learning disorder – such as what is now being called sluggish processing tempo.”

Undiagnosed ADHD in the Geriatric Population. While there is scant research focusing on attention–deficit/hyperactivity disorder in the geriatric population, the current consensus is that ADHD symptoms persist into adulthood in at least 67% of childhood ADHD cases. And a recent Dutch study⁴⁰ of non–institutionalized adults over the age of 60 years old estimated the prevalence of ADHD in this population at 2-4%. Dr. Mortimer summarized: “Older ADHD adults are especially prone to be misdiagnosed because they and their physicians are mostly likely more concerned about the possibility of a neurodegenerative disorder (e.g., dementia) instead of a life–long neurodevelopmental disorder such as ADHD. Thus, geriatric patients with ADHD will frequently not be correctly identified – or correctly treated.”

Teflon and Fog. “Having untreated attention–deficit/hyperactivity disorder is like  being covered with ‘psychic Teflon.’ Nothing sticks! If the person with untreated ADHD is praised, it doesn’t have any impact. If the untreated ADHD person is punished, the same maladaptive behaviors often continue unchanged. It’s as if the person with untreated ADHD doesn’t learn from experience.” Using another simile, Dr. Mortimer said: “Those with ADHD are like airplane pilots who are born in a fog, fly their airplanes in a fog, repeatedly crash their planes while flying in the fog, and remain bewildered by it all. What they do know is that their [non–ADHD] peers are learning more quickly, and performing better in flight school – and are often able to perform better with much less effort. They know something is wrong, but don’t have a clue about what exactly is the cause of their recurring difficulties with paying attention, anticipating, time–management, and impulse control.”

Solvents and Defoggers. Dr. Mortimer likened effective medications for the treatment of attention–deficit/hyperactivity disorder to solvents. Referring  to an earlier simile, effective ADHD medications taken at effective doses temporarily dissolve the Teflon so that those with ADHD can then learn from the consequences of their maladaptive behavior. In his second simile, the medications are likened to windshield defogging agents, allowing the ADHD “pilots” to see blue sky for the first time in their lives. “With effective medications, just about everything becomes infinitely easier. Of all medical disorders and diseases, ADHD is one of the most gratifying medical disorders to treat.”

Dr. Mortimer then hastened to add: “This is not to say that psychosocial treatment interventions – such as academic tutoring, social skills training, individual therapy, and family therapy – are not useful. However, without first initiating effective medication at effective doses which effectively manage symptoms throughout the entire day, these psychological interventions are largely a waste of time, precious resources, professional efforts, and money.”  

Prescription Medications are Essential for Effective ADHD Treatment. One common treatment goal for those with ADHD is to alter their catecholamine tone in their brain’s prefrontal cortex. This part of the brain has evolved to help guide our thinking toward distant goals and to metaphorically navigate us successfully through the world around us. The prefrontal cortex of the brain allows us to inhibit actions that are task–irrelevant or are not serving our long–term goals. The prefrontal cortex also enables us to regulate our emotions. When our prefrontal cortex is operating optimally, we have guided attention and our responses to the world are appropriate. We can listen, understand, make sense of the world and deviate or shift direction if something gets in the way of our goals. Our responses are flexible. We can say: ‘Since that didn’t work, I’ll try something else.’ The only treatment for ADHD that is effective in achieving this goal is prescription medication. Thus, prescription medications are the cornerstone of effective treatment of attention–deficit/hyperactivity disorder. The MTA longitudinal study⁴¹ has conclusively demonstrated this. ADHD medications are substantially much more effective than non–pharmacological treatments such as: dietary changes (e.g., restricted elimination diets; artificial food color exclusion; free fatty acid supplementation with omega–3 and /or omega–6 supplements); sunlight exposure; or psychological treatments (e.g., cognitive training; neurobiofeedback; or behavioral interventions such as parent training or teacher training).⁴²

Effective medical treatment can make a dramatic difference in an ADHD person’s life. Here are two cases typical of what I see in my office: Several years ago, when we first met, one of my eighth grade girls with attention–deficit/hyperactivity disorder had a GPA of 1.7. With an optimally dosed ADHD medication –  plus adding effective study strategies –  in less than six months, this girl’s semester GPA increased to 3.7! More recently, I had a high school student who presented to me with severe, untreated ADHD. His baseline cumulative GPA was zero. With effective ADHD treatment, his semester GPA improved to over 3.0!”

The Prescription Stimulant Options. In 1937, Rhode Island pediatrician Charles Bradley reported⁴³ an immediate and frequently dramatic improvement in the conduct and academic performance of a group of children with behavioral disturbances when they were treated with Benzedrine (i.e., racemic⁴⁴ amphetamine).⁴⁵ Since that time over eighty–five years ago, prescription stimulant medications have remained the cornerstone (i.e., the “first line” pharmacological treatment options^46,47 ) for the treatment of attention–deficit/hyperactivity disorder. The stimulants prescribed for ADHD have some of the highest effect sizes of any medical intervention.⁴⁸  And for most individuals with ADHD, the stimulants (e.g., dextroamphetamine, methamphetamine, methylphenidate, and dexmethylphenidate) are the treatments of first choice. However, patients’ response to specific medications is highly individual. An ADHD patient may respond well to a methylphenidate preparation but may fail to respond to – or may have significant adverse effects with – an amphetamine preparation. Some ADHD patients respond equally well to either class, while other ADHD patients have a preferential response to either a methylphenidate preparation or an amphetamine preparation. Or, as Dr. Mortimer often comments to his patients or their parents: “Some like fish; others like steak; and others like both.”

Dr. Mortimer then summarized: “There have been at least 3,000 studies in the past 80 or more years, plus over 180 controlled studies of at least 6,000 children, adolescents, and adults which have documented the efficacy of stimulants in the treatment of attention–deficit/hyperactivity disorder. With a history of over eighty or more years of clinical data, tens of millions of ADHD children, adolescents and adults have now been effectively and safely treated with the stimulants. Those with ADHD can be safely treated with stimulants even in the presence of co–existing depression, anxiety disorders, eating disorders, chemical dependence, or bipolar disorder – that is, if these clinically complex persons are treated by an experienced and knowledgeable physician.”

Prescription Stimulant Selection. “There is not yet any widely accepted algorithm that can be used to justify the selection of one prescription stimulant over another. As is the case with many medical disorders, but especially in the case of those with attention–deficit/hyperactivity disorder, a person’s treatment response to any one medication can be idiosyncratic. While I will often have a satisfactory result with either the first or the second prescription medication we try, studies have been unable to identify a reliable way to predict a  priori the best medication or the best dose of a prescription stimulant for a particular ADHD individual. The optimal stimulant dose for a particular ADHD patient is not correlated with age, sex, height, weight, body mass index, severity of symptoms, stressors, socioeconomic status, neurological soft signs, EEGs, auditory-evoked potentials, or neurochemical measures. Nothing!”

“Essentially, the prescription stimulants are all equally effective. However, their mode of action, likelihood of side effects, and effective duration of action will differ. And about one–third of those with attention–deficit/hyperactivity disorder will respond better to one medication than they will to another, similar prescription ADHD medication.”

Listed below are the current, first–line treatment options for attention–deficit/hyperactivity disorder. All the medications below are all classified as stimulants. And, not all of the stimulants are “amphetamines.” [And while it is a stimulant, do be aware that caffeine is completely ineffective in managing the core symptoms of ADHD.] In about 95% of Dr. Mortimer’s patients, the duration of each prescription stimulant  benefit to be as follows:

Dexedrine (dextroamphetamine) brand immediate release and Dextrostat (dextroamphetamine) generic tablets have a benefit for ADHD management which lasts no longer than 4 hours per dose.

Zenzedi is a newer, immediate–release dextroamphetamine which – in comparison to the old dextroamphetamine (Dextrostat) tablets – is lasting 5–6 hours in most of Dr. Mortimer’s ADHD patients.

Dexedrine Spansules (a very old, early attempt at making a time–release stimulant medication) provides a benefit for the management of ADHD symptoms which lasts no more than 5 hours per dose.

Vyvanse is a dextroamphetamine preparation in which its time–release properties are built into the molecule. It first became available for prescription in 2007. In about 90% of Dr. Mortimer’s ADHD patients, the Vyvanse benefit for ADHD management continues for the entire waking day (i.e., about 16 hours per dose). In the other 10% of Dr. Mortimer’s ADHD patients, the benefit lasts about 8 hours per dose.

Adderall IR⁴⁹ is a mixed amphetamine salt preparation which provides a benefit in the management of ADHD symptoms for 4 to 7 hours, depending on the individual patient’s genetics and kidney functioning.

Adderall XR is a double–beaded, time–release preparation of Adderall (“amphetamine mixed salts”) which provides a benefit for the management of ADHD symptoms for 8 to 10 hours per dose.

Adzenys XR ODT is an instant–dissolve–on–the–tongue preparation of Adderall XR which is designed to duplicate the benefit and duration of Adderall XR.

Mydayis first became available for prescription in the summer of 2017. It is a triple–beaded, longer–acting preparation of Adderall XR and provides a benefit for the management of ADHD symptoms of 14 or more hours, thus rivaling the duration of benefit of Vyvanse.

Evekeo is a racemic mixture of dextroamphetamine and levoamphetamine (this was known in the 1960s as Benzedrine) which provides a benefit for the management of ADHD symptoms for 4 hours per dose. It is chemically more or less very similar to Adderall.

Methamphetamine (Desoxyn) is now only available in immediate release tablets. Methamphetamine has been available as a prescription medication since at least the 1940s. Desoxyn (or methamphetamine) provides a duration of benefit for the management of ADHD symptoms of 7–8 hours per dose. Of all the stimulants, Desoxyn is probably the least likely to have any effect on blood pressure or pulse.

Methylphenidate (– the generic name for “Ritalin”) is available in a 4–hour immediate release preparation (also known as Ritalin immediate release and Methylin immediate release).

Ritalin SR is an early attempt to develop a time–release methylphenidate. This is, in effect, a 5–hour preparation of methylphenidate which, as Dr. Mortimer comments:  “…since you can’t cut the tablet, almost no–one prescribes this anymore.”

Metadate CD and Ritalin LA are competing methylphenidate time–release preparations which provide a benefit for the management of ADHD symptoms of 8–10 hours per dose.

Concerta is a 14–hour time–release capsule (plastic, uncuttable capsule) of methylphenidate. “However, be aware that the genetic tablet now available which is touted as equivalent to Concerta is crap.”

Focalin IR (or dexmethylphenidate tablets), the immediate release dextro–isomer⁵⁰ tablet of methylphenidate, provides a benefit for the management of ADHD symptoms of 5–6 hours per dose.

Focalin XR (dexmethylphenidate), the newer time–release form of Focalin, provides a benefit for the management of ADHD symptoms for 11–13 hours.

Daytrana is the time–release methylphenidate which is available as a patch. It provides a benefit for the management of ADHD symptoms from the time it is applied to the skin until the patch is removed – or until bedtime, whichever occurs first. So, Daytrana can potentially provide a benefit for the treatment of ADHD for up to 24 hours per dose. Because the patch can cause both skin irritation and skin de–pigmentation, Daytrana has fallen out of favor for the treatment of ADHD symptoms.

Quillivant is time–release methylphenidate in a liquid suspension. Its reported duration of benefit for the treatment of ADHD is 8–10 hours per dose.

Cotempla XR ODT tablets is a newer, instant –dissolve–on–your–tongue, time–released methylphenidate. Its reported duration of benefit for the treatment of ADHD symptoms is 12 or more hours per dose.
‍

If a particular stimulant for the treatment of attention–deficit/hyperactivity disorder decreases appetite or interferes with sleep, the problem can often be resolved by switching to another ADHD medication – or adding an antidote. “The most common and predictable stimulant side effects (decreased appetite and difficulty falling asleep) can usually be managed satisfactorily with adding one of my favorite antidotes: cyproheptadine (Periactin), mirtazapine (Remeron), hydroxyzine (Vistaril), clonidine (Catapres) or risperidone (Risperdal). Similarly, if other medication side effects occur, psychiatrists can usually find a way to manage the side effects while still being able to maintain the medication’s benefits. This is where the art of medicine comes in – similar to what a chef does in the kitchen (– or what a master chemist does in his lab). The master chef knows what he wants for a result, so he mixes and blends the available ingredients together in an artful way so that the end result for his customer [or patient] is both as elegant in its presentation and as enjoyable an experience [without, in the case of stimulants, causing euphoria, of course] as possible.”
Prescription medication dosing. Do keep in mind that just because the number of milligrams in two different prescription stimulant preparations are equivalent does not mean the responses will be identical. In over 90% of his clinical population, Dr. Mortimer has found the following dosing equivalences to be accurate: 10 mg of methylphenidate immediate release (e.g., Methylin, Metadate, or regular Ritalin) is equivalent in benefit – but not necessarily duration – to:

5 mg       Focalin immediate release (“IR”) tablet

5 mg       Dextroamphetamine (Dextrostat tablet or Dexedrine Spansule)

5 mg Evekeo tablet

5 mg Zenzedi tablet

5 mg       Methamphetamine (Desoxyn) tablet

5 mg       Adderall immediate release  (“IR”) tablet

6.3 mg    Adzenys XR ODT orally disintegrating tablet

       8.6 mg   Cotempla tablet

10 mg    Adderall extended release (XR) double–beaded capsule)        

10 mg     Metadate CD capsule

        10 mg    Focalin extended release (“XR”) capsule

        15 mg    Mydayis triple–beaded capsule

        20 mg    Ritalin sustained release (“SR”) capsule

36 mg    Concerta tablet (but Concerta is not really a tablet - the                       methylphenidate in Concerta is contained in an uncuttable                       plastic capsule)

Dr. Mortimer has not a reliable conversion algorithm for quickly switching from Vyvanse, Mydayis or Daytrana to each other to to any of the medications listed above or vice versa. Dr. Mortimer added: “…and at this point, having prescribed Vyvanse, Mydayis, and Daytrana to over 1,000 patients,⁵¹ so I doubt that a conversion algorithm will ever be identified and published. However, this has never been much of a problem for me. When switching to or from Vyvanse, Mydayis, or Daytrana to another stimulant (or vice versa), I can usually ‘ballpark estimate’ the optimal dose. We can then use a computer test [MedChek] which I have been using since about 1991 to quickly and accurately ‘nail down’ the optimal dose of any of these medications for any specific patient.”

“While certainly not always the case, sometimes in order to optimally control attention–deficit/hyperactivity disorder symptoms, specific doses may need to exceed FDA–approved⁵² manufacturers’ advertising daily dosage limits. One commonly used strategy that many physicians follow is to choose a stimulant, starting at the medication’s lowest dose size, and then increasing the dose to the optimal or maximum tolerated dose – whichever comes first. If the patient does not demonstrate a robust response, then the physician will switch to the next stimulant on his or her list of options. If all the stimulants are given a trial as first–line ⁵³ therapy for ADHD, then the overall treatment response rate should be greater than 95%.” True non–responders to stimulant therapy are rare but this possibility increases with the presence of additional mental disorders (e.g., those with an additional anxiety disorder such as obsessive compulsive disorder; those with a chronic tic disorder such as Tourette’s disorder; or in those who are experiencing the roller coaster ride of bipolar disorder.)

“The FDA-approved stimulant dosage guidelines were developed from the results of studies of attention–deficit/hyperactivity disorder patients without significant additional mental disorders. These dosage guidelines are, thus, largely inapplicable for the clinically complicated patient populations that medical specialists (e.g., general adult psychiatrists), or medical subspecialists (e.g., child and adolescent psychiatrists) are most likely to see.”

Finding the Optimal Dose. Suppose the first medication tried improves attention, motivation and impulse control. How does one determine if this is the optimal medication, and –  if it is –  how does one determine the optimal dose? “Since this is a disorder present from birth, the person with attention–deficit/hyperactivity disorder often doesn’t not know what is normal. Treatment with any of the stimulants usually results in profound improvements in attention, concentration, planning, impulse control and motivation. Here, though, is the challenge for the clinician: since the ADHD person has been in a fog all of his life, an effective ADHD medication may result in the best performance that the ADHD person has ever demonstrated – but there may still be much room for improvement. This is why it is so important to solicit observations from reliable, sober, non–ADHD significant others (e.g., teachers, parents, spouses, and siblings). Additionally, a computerized continuous performance task can be very helpful in objectively assessing treatment response. I can be as powerfully efficient as I am in determining optimal ADHD treatment because I use a sensitive continuous performance task computer program.”⁵⁴

Dose Sculpting. While Dr. Mortimer emphasized keeping medication treatment as simple as possible, “Sometimes a particular medication is profoundly effective, but side effects might sometimes turn out to be clinically significant for a particular patient – such as a stimulant causing appetite suppression throughout the day (which then leads to significant weight loss). If this is the case, I may take advantage of the different durations of action of different stimulant medications or time–release stimulant preparations to ‘sculpt’ the dosing schedule for a particular patient with attention–deficit/hyperactivity disorder. For instance, one ADHD patient might do well with a 4-hour duration Ritalin or 4–hour duration Dextrostat after breakfast. The medication’s effect on appetite suppression should then abate by lunch time. After eating a hearty lunch, this ADHD patient could then take a longer–acting prescription stimulant medication such as Adderall IR or Desoxyn to cover the afternoon, with its appetite–suppressing effects wearing off by supper time. Then, if a medication is needed to improve attention for evening events or for late–night studying,  a 4–hour duration stimulant medication could be taken after supper. For other ADHD patients, a  long–acting medication (e.g., Adderall XR, Concerta, Focalin XR, Ritalin LA, Vyvanse, or Mydayis) taken just in the morning might last long enough to achieve optimal symptom control throughout the waking day.”

Keep in Mind that Females are the Superior and the More Resilient Sex. Dr. Mortimer made the following observation: “Females are naturally more resilient than males. More boys than girls are stillborn; severe mental retardation is more prevalent in boys than in girls; autistic spectrum disorder (and what used to be considered Asperger’s syndrome) is more prevalent in boys than in girls;⁵⁶ and attention–deficit/hyperactivity disorder is four times more prevalent in boys than in girls.”⁵⁶  During her time as Dean of St. John’s College, Dr. Mortimer recalls Eva Brann, Ph.D. commenting to him that if an adolescent college male were to be “dumped” by an adolescent college female, he was often devastated and was likely to say to Dr. Brann: “My life is over.” However, if an adolescent college female were to be  “dumped” by an adolescent college male, she was more likely to shrug her shoulders and say to Dr. Brann: “Oh well…No big deal…There are plenty of other boys that I can still date.”⁵⁷

Thus, if a boy inherits a small number of attention–deficit/hyperactivity disorder genes from either ADHD parent, he will very likely show symptoms consistent with a diagnosis of ADHD. However, if a girl inherits the same “genetic load” from an ADHD parent as her brother, there is less likelihood that she will herself demonstrate any ADHD symptoms. This, then, is what Dr. Mortimer believes is the most likely reason for the four–to–one ratio in the prevalence of ADHD in boys versus girls. Conversely, if a girl shows ADHD symptoms, this means that – everything else being equal – she has inherited a very large number of all the twenty or more purported genes for ADHD, and the clinician (and parent) should not be surprised to learn that the girl requires a much higher stimulant dose to optimally control her ADHD symptoms than a boy with the same ADHD symptoms severity.

Several decades ago, Dr. Mortimer hypothesized that since females are more resilient than males, then: attention–deficit/hyperactivity disorder should be expected to be more prevalent in the relatives of females with a diagnosis of ADHD than in the relatives of males with a diagnosis of ADHD; the co–twins of females displaying an extreme degree of characteristic ADHD behaviors should display more such behaviors themselves than do the co–twins of males showing an extreme degree of ADHD traits; co–twins of females with particularly high ADHD trait scores should be more likely to display an extreme degree of ADHD behaviors than should the co–twins of males; relatives of females with ADHD are more likely to exhibit ADHD symptoms than relatives of males with ADHD; and females with ADHD are more likely to display more emotional difficulties than males with ADHD. More recently, Dr. Mortimer was pleased to see that his hypothesis has been confirmed.⁵⁸

Stimulant Safety. The popularity of the stimulant medications is, in part, due to their wide ratio of therapeutic dose to toxic dose, with a margin of safety of at least 100 to 1. For example, published studies have found the LD₅₀ (the dose which is lethal for 50% of a study population) of dextroamphetamine in rats to be 55 mg/kg of a rat’s body weight. The LD₅₀ for methylphenidate in other animals is 367 mg /kg of these other animals’ body weight.

“Curiously enough, however, stimulant toxicity findings in animals have not been replicated in humans. There simply aren’t any reputable studies showing that stimulants prescribed at therapeutic levels are associated with significant toxicity. In fact, studies using doses up to 4,000 mg of methylphenidate in human volunteers have been without clinically significant adverse effects.⁵⁹ And in Dr. Nora Volkow’s published PET scan study,⁶⁰ methamphetamine addicts were included in her study if their average methamphetamine use involved at least 500 mg methamphetamine administered intravenously at least five days per week for at least two years. Volkow found fifteen subjects who met her study’s criteria. I want to point out that these fifteen subjects had read her newspaper ad, answered her newspaper ad, drove to her laboratory out in rural Long Island without getting lost (this was before cell phones and GPS), and arrived on time for their appointments. Their average daily intravenous methamphetamine dose was 1,600 milligrams, with a range of 300 to 10,000 mg daily.⁶¹ These doses of methamphetamine are astronomical! The equivalent Ritalin (methylphenidate) dose of 1,600 mg of methamphetamine is 3,200 mg of methylphenidate. And yet these methamphetamine addicts kept their interview appointments with Dr. Volkow’s clinical staff. This is simply mind–boggling!”

Cardiovascular Risk? The effects of stimulants used in the treatment of attention–deficit/hyperactivity disorder on the cardiovascular system of healthy individuals are well established. In therapeutic doses, these stimulant medications increase blood pressure and heart rate, but such changes are not clinically meaningful.⁶² Furthermore, since 2009, there have been at least seven large–scale studies^63-69 looking into the association between stimulant use and sudden cardiac death. None of the studies found any statistical association between use of stimulants for the treatment of ADHD and sudden death. Healthy persons, in particular children and young adults, who do not have a diagnosed and significant cardiovascular illness (e.g., such as having had a previous stroke, or a previous myocardial infarction) do not require specific cardiac testing before starting treatment.

Risk of Addiction. Dr. Mortimer summarized: “Despite some in the chemical dependence treatment community arguing otherwise, there is no credible evidence that prescribing stimulants commonly used in the treatment of attention–deficit/hyperactivity disorder, major depression, narcolepsy, or chronic pain syndromes has ever caused euphoria or chemical dependence. There is no evidence that properly monitored prescribed stimulants results in drug abuse. Lastly, tolerance to a particular stimulant dose rarely if ever occurs in a clinical population.”

Dr. Mortimer then referred to a recently published review⁷⁰ of medications for the treatment of attention–deficit/hyperactivity disorder: “Despite the concern that ADHD may increase the risk of abuse in adolescents and young adults (or their associates), there are simply no scientific data confirming the abuse of prescribed stimulants by ADHD children who are receiving appropriate diagnosis and careful follow-up. Moreover, other studies⁷¹ have shown that the most commonly abused substances in untreated ADHD adolescents and adults are cigarettes, marijuana and alcohol –  not the stimulants.”

Lastly, Dr. Mortimer pointed out that rather than stimulants increasing the likelihood of future substance abuse, the contrary has been found. “There are now enough longitudinal studies of attention–deficit/hyperactivity disorder to demonstrate conclusively that treatment of ADHD with stimulants actually provides a protective effect in preventing future substance abuse.^72-75

Those ADHD Patients with a History of Past Substance Abuse. Regarding the question of prescribing stimulants to those with a prior history of substance abuse, Dr.  Mortimer referred to published works of four authorities on the treatment of ADHD. First, quoting from Paul Wender, M.D.: “The failure – or reluctance – to offer ADHD patients a trial of the amphetamines or methylphenidate often does not have a scientific basis but is related to the fact that these are Schedule  II drugs. Physicians are afraid to prescribe them not because of concern about toxicity or producing an iatrogenic addiction but because of the regulatory agencies. However, just as it is possible to employ methadone in a special administrative setting, it should be possible to work out a method of dispensing stimulants to ADHD adults that will relieve physicians of this extraneous concern. Comparably effective drugs would never be used so sparingly in internal medicine.”⁷⁶

Next, quoting from Dr. Josephine Elia’s study: “Stimulant–drug treatment as a specific risk factor for the ultimate use of or dependence on drugs, alcohol, or any other substance is unsupported by evidence from clinical studies.”⁷⁷ Lastly, Dr. Mortimer then modestly referred the interested listener to two^78-79 of his favorite articles on the effective, non–abusable ADHD medication options for use in special clinical populations and in special clinical circumstances.

ADHD and Fad Diets. Restriction diets and elimination diets have been studied for decades in the treatment of ADHD. “For probably the past sixty years, you can hear and see claims that special diets such as gluten–free or additive–free diets are effective for the treatment of attention–deficit/hyperactivity disorder. This claim has been repeatedly shown in controlled studies to be complete bullshit. Most recently, in 2015, Pliska and colleagues reported⁸⁰ that in their five week study with two groups of ADHD children, both groups treated with stimulants, those on a gluten–and additive–free diet who were then given a daily snack of a cookie (– which was inconsistent with the prescribed diet) still showed behavioral improvement to the same extent as those ADHD kids treated with stimulants who were on regular diets.” Dr. Mortimer summarized: “No one is going to assert that junk food, candy and highly processed foods are preferred over spinach, parsley, carrots, and salmon, but those who claim that diet restriction is an effective treatment for attention–deficit/hyperactivity disorder is simply psychotic nonsense. The cornerstone of ADHD treatment remains appropriately prescribed and monitored prescription stimulant medication.”

Overdiagnosed? Many pharmacists in the audience thought that more people were being treated for attention–deficit/hyperactivity disorder now than twenty years ago, and wondered if perhaps ADHD was being overdiagnosed.⁸¹ Dr. Mortimer responded that since the prevalence of ADHD in the United States general population⁸² is estimated at somewhere between 9% and 14%, “Prevalence studies have consistently found that at any one time, no more than 2.5% of the population is being treated for ADHD. Therefore, even taking an overly–conservative estimate of a five percent prevalence of ADHD, the majority of those with ADHD are never identified. From both reviewing the results of the MTA longitudinal study, and from what I have seen clinically over the past 35 years, here is what I think happens much too often: If those with ADHD are correctly identified, then they are usually not prescribed an effective medication at all – that is, too many times the child’s pediatrician outright dismisses the legitimate concerns of the child’s parents and child’s teachers. In the too–infrequent case where ADHD youngsters are prescribed a medication known to be effective for the management of ADHD symptoms, then the dose or duration of medication prescribed is too–often a homeopathic dose which is not anywhere close to that required for optimal symptom control. And if the ADHD youngster is lucky enough to be treated with and optimal medication and dose, then the ADHD youngster usually don’t continue taking the medication long enough to make a substantial improvement in his or her life trajectory. In fact, one recent study found that over half of prescriptions written for 30 days–worth of methylphenidate were not renewed a month later. ADHD is a woefully under–diagnosed and inadequately treated common medical condition – and, as I explain later – when untreated or inadequately treated, ADHD is a potentially lethal medical condition.”

To treat or not to treat. Rather than expatiate on this topic here, Dr. Mortimer simply referred to published comments from two acknowledged international ADHD experts. First, from J. McGough, M.D. (2004): “Successful management of ADHD in children includes a decrease in symptoms or an improvement in the quality of life. However, with the exception of antibiotics for viral colds, most parents do not want their child on medication, so there is a market for “natural” medication. Besides the fact that some of these [“natural”] treatments are dangerous, what is often missed is that having ADHD is dangerous. By not giving a medication that has been well tested and tried, you are increasing the time during which the child grows up having negative developmental experiences and not getting proper treatment. The child thereby becomes subjected more often to peer rejection; school failure; involvement with drugs, sex, and alcohol; and other serious consequences. Thus, failing to give medications that are known to be effective is really detrimental to the children. In fact, several authorities have stated that the evidence supporting the use of approved medicines for ADHD is so strong that a clinician who does not address this issues is probably being negligent.”⁸³

Dr. Mortimer then refers the interested reader to a summary statement from John Werry, M.D., Professor Emeritus of Child Psychiatry: “…in any other medical or psychiatric condition where the evidence for drug efficacy is this substantial and for drug side effects is this benign, the failure of a physician to consider medication treatment for the disorder would be considered tantamount to malpractice. Yet somehow many less–informed individuals have come to believe that it is the withholding of stimulant medication treatment for those with ADHD that is the more noble, ethical, and humane approach. Clearly, this can now be seen to be largely the result of naïveté or even a misunderstanding, unintentional or otherwise, of the extant scientific literature on ADHD and these medications.”⁸⁴‍

Treatment Duration. “Let’s say there’s a child who has failed each of his first five years of school. Eventually, he finds his way to an optometrist. A visual acuity problem is identified. The optometrist then prescribes corrective lenses, and with the glasses, the child is able to see clearly for the first time ever. With considerable effort, the student’s grades that year (i.e., sixth grade) improve to B’s. But at the end of the sixth grade, the boy’s parents then toss their son’s eyeglasses (so that the student doesn’t become “dependent” on their use). Is the experience of seeing clearly for one year in elementary school going to be sufficient to carry the student successfully through to high school graduation? I don’t think so. I’ve been wearing eyeglasses for over twenty–five years now, but whenever I remove them, printed words return to being as unreadable as they were before I first started wearing glasses. Short–term treatment interventions for a chronic disorder are profoundly unlikely to return the individual to a healthy, maximally productive and satisfying life trajectory. ADHD is a chronic medical condition. To make a difference, those who treat attention–deficit/hyperactivity disorder must adopt a longitudinal, multi–decade treatment perspective.”

In addition to looking for overall improvement in symptoms of attention–deficit/hyperactivity disorder with effective treatment, it is important to remember that the treatments must deliver symptomatic improvement at the times during the day where functional impairment is occurring. Alas, studies by Salee, Whalen, Mattingly and others have shown that physicians primarily focus on the consequences of untreated ADHD during school and work, while overlooking impairments that occur at the beginning and end of the day.^85-87 Salee found that 79% of caregivers of ADHD children have discussed early morning functional impairments, such as getting out of bed on time, getting dressed efficiently, self–hygiene, eating breakfast, packing their backpack, and being able to catch the bus on time, as being some of the most impairing issues for their ADHD children. Of these caregivers, 48% reported they had to wake up early in the morning themselves to personally administer their child’s ADHD medication before their child’s normal waking time because of the functional difficulties experienced in the home before their child’s medication had taken effect.

There is also the issue of transitioning from child & adolescent psychiatric services to adult psychiatric services. Children and teens who might have their attention–deficit/hyperactivity disorder under optimal symptom control can fall apart when they transition from adolescence to adulthood and are no longer treated by the most experienced group of ADHD specialists: pediatricians, pediatric neurologists and child & adolescent psychiatrists. Many adult mental health practitioners (e.g., general adult psychiatrists) have little experience and training in the management of ADHD, and many have negative and skeptical attitudes towards ADHD as a condition that warrants intervention. The transition from adolescent to adult psychiatric services poses particular challenges because of differences in training, symptom severity thresholds needing to be reached before treatment is offered, and focus between child and adult psychiatric services, and leaving a proportion of young adults with ADHD without a clear treatment pathway. Young adults in general often face multiple other transitions around that time that adolescent medical services are withdrawn, and given the nature of ADHD, many young adults with ADHD struggle to organize themselves adequately in order to arrive on time for follow–up appointments and continue ADHD treatment.‍

FDA Dosing Guidelines. Some pharmacists in the audience expressed concerns about the relatively high–dose stimulant prescriptions they were occasionally asked to fill. Dr. Mortimer acknowledged this as a legitimate concern. “We should always keep in mind the potential for diversion of medications, but this has not been a significant problem either locally or nationally.” Dr. Mortimer then added: “However, I am more concerned with the number of ADHD individuals I see receiving ineffective treatments – or potentially effective ADHD treatments at clearly ineffective, sub–therapeutic doses. While some ADHD individuals might do best on 5 milligrams of a particular medication, others might not find their ADHD symptoms under optimal control until they reach a much higher dose.⁸⁸ In addition to needing sufficient clinical experience to make an accurate diagnosis  and identifying an optimal treatment response, using a sensitive continuous performance task (CPT) program can, again, be very helpful both clinically, legally, and forensically.”

Dr. Mortimer believes that molecular genetics studies of proteins involved in dopamine transmission⁸⁹ provides a compelling model for why there is such inter–individual variation in dosing in those with attention–deficit/hyperactivity disorder, and why some patients might need a relatively higher stimulant dose to optimally control their symptoms. “As seasoned physicians know, dogmatism about doses is generally incompatible with good medical practice. There is tremendous inter–individual variability in determining doses of many psychiatric medications – not just the stimulants. For example, while most tricyclic antidepressants are generally recommended in a daily dose of 150 to 200 mg/day, some patients require a doubling of this dose, while others respond favorably and even have therapeutic serum concentrations with daily doses of only 10 mg. Hypogonadal women may only need 5 mg of testosterone daily (topically applied) for optimal symptom control, whereas hypogonadal men often require 200 mg of testosterone daily (topically applied) for optimal symptom control. Some ADHD patients do best with low stimulant doses, others do best with doses above the FDA–approved single or daily dose limits. But do remember that FDA dosing limits are for the purpose of regulating pharmaceutical companies’ claims about their medications, not what physicians can safely and responsibly prescribe.”

Dr. Mortimer added: “The Food and Drug Administration itself is clear on this issue, with its own publication⁹⁰ stating: ‘Under the Federal Food, Drug, and Cosmetic Act, a drug approved for marketing may be labeled, promoted, and advertised by the manufacturer only for those uses for which the drug’s safety and effectiveness have been established and which the FDA has approved. The Act does not limit the manner in which a physician may use an approved drug. Once a product has been approved for marketing, a physician may prescribe it for uses or in treatment regimens or patient populations that are not included in approved labeling. Accepted medical practice often includes drug use that is not reflected in approved drug labeling.’ ” ‍

Neurotransmitters. There is  a substantial body of evidence from molecular genetics that points to catecholamine neurotransmitter dysfunction in those with attention–deficit/hyperactivity disorder. That is, abnormalities in the brain have been identified in both dopamine and norepinephrine neurotransmitter systems. More specifically, ADHD studies have found genetic and structural variations in both the dopamine transporter protein (SLC6A3, commonly known as DAT₁)⁹¹ and at least one dopamine receptor protein (DRD₄).⁹² The dopamine transporter gene (DAT, or SLC6A3) produces a protein that transfers dopamine from the neuronal synapse back into the presynaptic dopaminergic neuron. The dopamine receptor protein (i.e., DRD₄) on the post–synaptic side of the synaptic cleft and is analogous to the back side of the “lock” into which the dopamine “key” inserts when a dopaminergic signal is sent down a neuronal pathway in the neuron’s cytoplasm.‍

Locks and Keys. First to be found was an association between a variant of the dopamine receptor protein DRD₄ and attention–deficit/hyperactivity disorder.⁹³ Normally, when the post–synaptic DRD₄ receptor is stimulated by dopamine neurotransmitter, the cytoplasmic loop component of the receptor efficiently binds to a guanine nucleotide regulatory protein. In turn, this “G protein” inhibits cyclic–AMP synthesis, which then causes changes in protein kinase enzyme activity, which then might change the rate of the flow of calcium or potassium through neuronal membrane ion channels, or alter neuron cell nucleus gene activation. Dr.  Mortimer used the following metaphor. “The dopamine transmitter serves as a key which inserts into a post–synaptic neuronal receptor lock. When activated, the internal portion of the lock apparatus triggers a series of cascading intracellular events that transmits the dopamine signal along neurons from one part of the brain to another – just as a twist of the key in the lock causes a cascade of levers to move to their ‘open’ position inside the door.” A particular segment of the third cytoplasmic protein loop of the DRD₄ dopamine receptor is normally repeated four times, but in some ADHD individuals, it is repeated seven times. “This 7–repeat leads to a ten–fold blunted intracellular dopamine response. This is an important finding, and offers us a way to make sense of the observed differences in the individual responses that ADHD persons have to medication dosing.”  

Dr. Mortimer likened the genetic polymorphisms and resulting excess protein receptor loop material to the presence of bubble gum in a door locking mechanism. “Because of the extra loops in the internal side of the receptor lock, then those with attention–deficit/hyperactivity disorder need a stronger dopamine signal to engage the brain’s frontal lobe’s motivation and planning programs. ADHD medications accomplish this by providing more torque to turn the dopamine keys in the sticky door locking mechanism of the post–synaptic neuronal cellular mechanism.”‍

Bungy Cords. Researchers specializing in attention–deficit/hyperactivity disorder have also found a second polymorphism (i.e., another variation in the genetic code for the structure of a dopamine–related protein) in the presynaptic dopamine transporter gene DAT₁. This transporter protein is responsible for terminating the action of dopamine released into the inter–neuronal synapse. It does this by recycling the dopamine back into the presynaptic neuronal membrane. “That is, when you’ve completed the task of opening the door, you then pull the key out of the lock.” In at least some persons with ADHD, this DAT₁ protein has been linked to increased dopamine reuptake, so that in those with this DAT₁ polymorphism, binding between dopamine and its transporter is too efficient. “It’s as if there is a bungy cord attached to the dopamine. In those with ADHD, the DAT₁ dopamine transporter protein yanks the dopamine out of the receptor before the locking mechanism has been fully activated.” This structural variation of the DAT₁ protein decreases the efficiency with which dopamine signals are sent through the brain to the motivation, inhibition, and executive planning areas of the brain. “Finding an effective medication at the optimal dose then maximizes the person’s ability to route instructions to various processing areas of the brain. And, again, finding the best medication and the best dose are determined empirically.”‍

Noisy Norepinephrine. Studies are also finding an overactive norepinephrine system in the brains of some with attention–deficit/hyperactivity disorder. Due to a lack of inhibition of certain neurons originating in the locus coeruleus (i.e., the brain’s “panic center”) in the brainstem, there is excess norepinephrine transmission. This increases the “noise” in the dopaminergic neurotransmission lines as well, thus decreasing the “signal–to–noise” ratio of dopamine to norepinephrine. In addition to enhancing dopamine neurotransmission, the stimulants used in ADHD treatment act via alpha₂-adrenergic receptors on the locus coeruleus to reduce spontaneous firing. Clonidine and guanfacine are non–stimulant ADHD medication options which act on these alpha₂ receptors to decrease the “noisy norepinephrine” that interferes with the dopamine signals. “Some with ADHD have tremendous difficulty with impulse control. Medications can often make a tremendous difference. Or, as internationally published child & adolescent psychiatrist Robert Hunt, M.D. describes it, if you have a hyperactive ADHD locomotive engine, the stimulants apply the brakes harder, while clonidine and guanfacine decrease the heat in the engine.”⁹⁴‍

Executive Functions and Executive Control. Some of the more intriguing recent thinking about attention–deficit/hyperactivity disorder involves the functions of the brain’s frontal lobes – particularly executive functions (i.e., those parts of the brain that are responsible for: engaging motivation; planning; organizing; and weighing options – including philosophizing). Some authorities⁹⁵ are now describing ADHD as being primarily a disorder of motivation and planning, rather than one of distractibility, impulsivity, or fidgetiness.Referring to a recent book authored by Russell Barkley, Ph.D.,⁹⁶ executive function can be defined as “the use of self–directed actions so as to choose goals, and to select, enact, and sustain actions across time toward those goals, usually in the context of others, often relying on social and cultural means for the maximization of one’s longer–term welfare as the person defines that to be.”  There are believed to be at least five of these executive functions that appear to be involved in self–regulation. Research suggests that most of the five executive functions – and probably all of these five executive functions – are implicated in attention–deficit/hyperactivity disorder. The first of these five Executive Functions is the ability to inhibit our behavior – to stop what we are doing in order to allow the other executive functions to be able to take over and  guide our behavior toward the future.The second of these five Executive Functions is the ability to use visual imagery. This is often called non–verbal working memory. Humans have the ability to hold images in mind about what they are proposing to do. We use those images as mental maps to guide our behavior toward the intended target. We also use those images to remember the sequence of steps that is necessary to accomplish that goal or that task. Out of this executive ability also comes our sense of hindsight, foresight, and overall our subjective sense of time. We would expect all of these executive functions to be impaired in those with ADHD, and so this seems to be the case. The third executive ability is the ability to talk to ourselves in our minds as a form of self–guidance.Throughout the day, all of our waking moments include a voice in our head that we use not just to converse with ourselves, but also to give ourselves instructions – and even to question ourselves when we face a novel situation or a problem. This mind’s voice is often called verbal working memory and it is another form of self–control that humans use to guide behavior over time to accomplish goals. The fourth executive ability is the ability to control our own emotions and with it, our motivations. It is out of this fourth executive function that we get emotional self–control – the ability to inhibit strong emotion that is being elicited by things around us, and the ability to moderate those emotions so that they are more in keeping with our long term welfare and our long term goals.Then finally there is the ability to plan and problem solve. This executive function involves mental play. This executive function provides us with the ability to manipulate information in mind in order to discover novel combinations that might serve to overcome obstacles toward our goals and allow us to accomplish our tasks and goals as we aim our behavior toward the future. These five executive functions by adulthood serve as a set of mind tools – as Russell Barkley, Ph.D. describes it, they are a veritable Swiss Army Knife of mental faculties that allow people to regulate their own behavior over time for their own long–term welfare.

“The vast majority of those with attention–deficit/hyperactivity disorder don’t need another class or book on time management. They know what they have to do. The problem is that they just don’t – or can’t – do it. This isn’t to say that those with untreated ADHD should be excused from the consequences of execrable behaviors. All of us have some tasks that are harder for us to do than others. What I am presenting here is a way of understanding ADHD, not excusing it.”

While the brain’s motivation programs are intact in those with attention–deficit/hyperactivity disorder, these ADHD individuals often have difficulty “booting up” these programs without the help of adrenalin – or effective ADHD treatment. “I see many unidentified and untreated ADHD adults who gravitate to careers and environments where they can use novelty (their tasks or work locations are different every day) or terror (bosses, teachers, and others screaming about completing projects by their deadlines) to help them compensate for their motivation problems. However, relying exclusively on one’s environment to activate one’s motivation and executive planning programs may be clever, but it is not always the most efficient strategy to use in managing one’s otherwise untreated ADHD.” ‍

Dopamine. For some with untreated or sub–optimally treated attention–deficit/hyperactivity disorder, the difficulty in “booting up” the brain’s executive functions programs located in the brain’s frontal lobes leads to chronic problems with: motivation, poor time management, impulsiveness, and paying adequate attention to intrinsically boring but important task details. Dopamine is believed to be the primary neurotransmitter involved in ADHD, motivation and behavioral reinforcement; the frontal lobes are rich in dopamine neurons; and the stimulants can boost dopamine signals. However, there are also dopamine–enhancing, non–stimulant medications which can be effective in treating individuals with ADHD. These medication options include amantadine (Symmetrel), atomoxetine (Strattera), bupropion (Wellbutrin IR, SR and XL; and Forfivo XL), clonidine (Catapres tablets and patch; Kapvay); and guanfacine (Tenex; Intuniv).‍

RAM Chips. “In 1990, when I first started using a computer in psychiatric practice, I often found myself wanting to keep both the Word and FileMaker applications open at the same time. However, since my little Apple computer didn’t have enough RAM to have both applications open at the same time, the computer would almost always freeze. I would then have an emotional reaction when confronted by this frustration. The RAM chip is analogous to our brain’s working memory, and a similar thing happens when those with untreated attention–deficit/hyperactivity disorder try to manage the complexity of the demands which one typically encounters in everyday life. That is, many with ADHD appear to have “thin skins:” they are exquisitely sensitive to rejection, criticism and teasing. They often react to daily stressors with paralyzing anxiety, panic attacks, or explosive rages.”          

Acetylcholine. Some of the newer medications being used off–label⁹⁷ for the treatment of attention–deficit/hyperactivity disorder” were first developed to enhance the efficacy of acetylcholine –  which is believed to be the brain’s main memory neurotransmitter. These “working memory–enhancing” medications include donepezil (Aricept), rivastigmine (Exelon), galantamine (Reminyl) and memantine (Namenda). “When medications improve ADHD symptoms in certain individuals, they appear to me, in effect,  to be increasing the size of the brain’s RAM chip – at least temporarily while the medication is active – so that those with ADHD can more adaptively respond to the multifarious demands on their attention throughout their day without their human biocomputer freezing.” Indirectly, these medications may manage ADHD symptoms by indirectly improving the “signal to noise ratio” of dopamine relative to norepinephrine.”‍

Lack of Consensus.  Despite over 80 years of research on attention–deficit/hyperactivity disorder, a consensus on ADHD treatment or ADHD prevention does not yet exist.⁹⁸ In one survey, only 19% of general and child and adolescent psychiatrists followed published practice parameters for the assessment and treatment of ADHD. Dr. Mortimer then quoted from Larry Greenhill, M.D.: “There is no empirically proven threshold of ADHD symptoms that can be used to initiate stimulant treatment. There are no universally recognized dosage guidelines, nor are there blood tests to confirm that a patient’s dose is in the therapeutic range. There are no systematically gathered data on whether practitioners follow the FDA guidelines or use lower or higher stimulant doses in practice. Research based weight–adjusted guidelines, which suggest that doses of 0.3 mg per kg [of body weight] show optimal effects, have not been supported by studies of dose response curves for children with ADHD. Most published randomized control trial data showing stimulant efficacy are group–based and do not help the clinician select the best dose for the individual patient. Important issues facing the practitioner are not found in most practice parameters articles.”⁹⁹‍

Mere Clinical Response, or Optimal Treatment? Studies with all three classes of medications (i.e., methylphenidates, amphetamines and non–stimulants) have highlighted that is is all too easy for physicians to settle for a partial improvement in symptom control of attention–deficit/hyperactivity disorder, while still leaving ADHD patients with ongoing, clinically compromising symptoms and impaired quality of life. Clinical response in Phase III clinical drug trials is often defined as a 25–30% improvement in symptoms from baseline, but this still leaves patients with ongoing and significant symptomatic and functional impairment. Long–term trials with sustained–release stimulants have shown that 90–95% of ADHD patients will achieve a 30% improvement in symptoms in the clinical trials. However, the problems is that physicians then interpret the 30% symptom improvement as “much” or even “very much improved” on global clinical outcome measures.^100-103

Patients and physicians may be tempted to be satisfied with a 30% improvement in attention–deficit/hyperactivity disorder symptoms, even though the evidence is clear that such minimal improvement in ADHD symptom management almost inevitably means continued functional impairment. For almost all ADHD patients, further improvement in functioning and quality of life is still possible. Long–term trials have demonstrated that if the patient and physician is willing to pursue optimal symptom control, then 75–80% of ADHD patients can achieve at least a 50% reduction in symptom impairment (as measured by such ADHD research scales as the ADHD Rating Scale) to reach symptomatic remission.^104-105‍

Maximum Stimulant Dose? Is there a maximum stimulant dose beyond which one should never prescribe? Dr. Mortimer responded: “There are no credible, published clinical studies indicating that there is an absolute maximum single or daily stimulant dose for the treatment of attention–deficit/hyperactivity disorder in children, adolescents, or adults. I think that the reason that the reason that national ADHD experts will not address this issue publicly is for political reasons. However, privately, all of the ADHD experts with whom I have consulted over the past thirty–five years have acknowledged this lack of an absolute stimulant dose maximum.” And more recently, there are now three published studies looking at whether or not prescription stimulant use increases the risk of sudden death. The result: there was nothing to suggest that this was the case. Dr. Mortimer adds: “In fact, there was statistical evidence in one of the epidemiological studies to support the idea that stimulants actually have a protective effect on cardiac health. That is, compared with those with a diagnosis of ADHD who don’t take medications, those persons with a diagnosis of ADHD who take their medications consistently are less likely when driving an automobile to run through an intersection when the traffic light is red – which then increases the likelihood of a sudden, adverse cardiac event (i.e., sudden cardiac death from a motor vehicle accident).”‍

Possible Outcomes without Effective ADHD Treatment? In addressing the topic of outcomes of those with ADHD who do not receive appropriate treatment, Dr. Mortimer reminds his audience of the most quoted sentence in Thomas Hobbes’ political philosophical treatise, The Leviathan (published in 1651):  “…the life of man, solitary, poor, nasty, brutish and short.”¹⁰⁶  Dr. Mortimer then summarized: “Attention–deficit/hyperactivity disorder is not a trivial condition. Compared with normal controls, those with untreated ADHD are at a much greater risk for:^107-108 lower educational attainment (by 2.5 less years of education);¹⁰⁹ academic failure (i.e., higher high school and college drop–out rates); risky sexual behavior (e.g. younger initiation of sexual activity, more casual sex, more sexual partners, and no use of condoms);¹¹⁰ unplanned pregnancies (i.e., untreated ADHD youngsters are more sexually impulsive and less likely to carry condoms;¹¹¹ and the ADHD girls are both more impulsive, and less likely to either use condoms or remember to consistently take oral birth control pills);¹¹² more children (on average, untreated ADHD men have more than three children; and untreated ADHD women have more than four children);¹¹³ criminal behavior/ antisocial personality disorder (– what Dr. Mortimer calls “Future Felons of America” now grown up);¹¹⁴ substance use disorders (including over twice the rate of nicotine dependence compared to the general population); psychiatric hospitalizations; head injuries (from more fights and more motor vehicle accidents in those with untreated ADHD compared to the general population); more frequent divorce; more frequent job changes; lower occupational achievement; decreased lifetime earnings;¹¹⁵ increased difficulties with financial management (e.g., paying bills on time); lower socioeconomic status; lower social functioning/increased difficulties in interpersonal relationships;¹¹⁶ increased likelihood of receiving state benefits;¹¹⁷ increased likelihood of homelessness;¹¹⁸ more incarcerations (in one prison study, the prevalence of ADHD in male prison inmates was found to be 25.5%); more social isolation (from dramatically increased difficulties maintaining ongoing friendships and romantic relationships); development of additional mental disorders (e.g., pessimistic explanatory style, major depression, bipolar disorder, tic disorders, various anxiety disorders; nicotine dependence; other substance abuse disorders); more frequent and more expensive motor vehicle accidents (47% increased risk of untreated ADHD men having a traffic crash 45% increased risk of untreated ADHD women being involved in a traffic crash).¹¹⁹ This all leads, naturally, to finding significantly lower evaluations of self–esteem and self–worth in those adults with untreated ADHD. Studies are also finding that – compared with the general population – those with untreated ADHD have higher rates of premature death from homicide, suicide;^120-121 and general medical disorders – with double the rate of death from motor vehicle accidents.^122-123

Attention–deficit/hyperactivity disorder is thus a chronic medical condition¹²⁴ which – if untreated or undertreated –  can lead to a prematurely fatal outcome. For example, utilizing the Danish birth registry, Dalsgaard found that on a nationwide basis, untreated ADHD persons had dramatically increased death rates compared to the general population: pre–school children with a diagnosis of ADHD had an 86% increased mortality rate; school–aged students had a 58% increased mortality rate; and adults with untreated ADHD had a 325% increased mortality rate relative to non–ADHD individuals within the same population, with accidents being the most common cause of death.^125,126 The good news is that with effective ADHD treatment, there was an overall decrease in accidental injury and medical utilization due to accidents and trauma. On a national–wide basis, Dalsgaard et al. found a 25–37% decrease in emergency room utilization among ADHD persons receiving treatment versus those not receiving treatment.”

“There are still too many well–intentioned but misinformed individuals – including physicians – who actively discourage parents and other family members from pursuing competent medical assessment of and treatment for attention–deficit/hyperactivity disorder. This irresponsible behavior of unenlightened others leads those with untreated ADHD on to an increasingly dysfunctional life trajectory. Unfortunately, without ever receiving effective treatment for their ADHD symptoms, the lives of some of these ADHD individuals will result in a solitary, poor, nasty, brutish, short, violent, and premature Hobbesian death.

“With what we now know from longitudinal studies, there is now another item that physicians can add to their increasingly long list of potential legal pitfalls: physicians who refuse to treat a patient with a diagnosis of ADHD and refuse to refer their patient to a physician competent in assessment and treatment of ADHD now run the risk  of a medical malpractice lawsuit, disciplinary action by the state’s medical licensing board – or both.”‍

Summary.  Attention–deficit/hyperactivity disorder is a highly genetic, prevalent neuropsychiatric condition, and it affects numerous cortical and subcortical pathways that coordinate information processing, impulsivity, emotional modulation, and neurochemical pathways which modulate communication between these cortical regions. The result of this medical and often genetically–determined condition is too–frequent compromised quality of life for both the patient and those around him or her. Both the data on the validity of the diagnosis of ADHD, and the evidence of the efficacy and safety of using stimulants in the treatment of ADHD is overwhelming. If stimulants are not an option in a particular clinical situation, there are a variety of safe, effective non–stimulant treatment choices available. Effective medical treatment can result in a profound improvement in the quality of life for not only the individual with ADHD, but also for the ADHD patient’s families, friends, teacher, employers – and the general public.

Dr. Mortimer concludes with this riddle for the discerning, liberally–educated reader's consideration: “If my understanding of attention–deficit/hyperactivity disorder is accurate, then those with ADHD who have thus far not been treated with effective medication at an effective dose will not be able to sit still long enough to either read or understand many of the implications of the information contained in these thirty–one pages. So, recalling Aristotle’s introduction to his Nicomachean Ethics, you might ask who, then, is my audience? – Well, I would submit, it is mostly those without ADHD.”

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About Dale Mortimer, M.D. After successfully and publicly defending his Senior Essay (– a commentary on Darwin’s Origin of Species), Dr. Mortimer received his undergraduate degree (Bachelor of Arts) in Liberal Arts from St. John’s College in Annapolis, Maryland. Subsequently earning his medical degree from Oregon Health Sciences University in 1985, Dr. Mortimer continued at OHSU to complete general adult psychiatry training, and then a two–year child & adolescent psychiatry fellowship training program. Dr. Mortimer is, thus, not only a fully trained general adult psychiatrist, but Dr. Mortimer is also a fully–trained child & adolescent psychiatrist. The value of having such broad, developmental psychiatric training first became readily apparent when Dr. Mortimer served as the principle psychiatrist for the Oregon Department of Corrections from 1990 to 1997. During this time, Dr. Mortimer evaluated 1,304 adult male and female inmates (ages 16 to 80 years old). Using his extensive medical and psychiatric training to make clinical sense of these inmates’ developmental trajectories “from play pen to state pen,” Dr. Mortimer was then able to provide – sadly, often for the first time in these inmate’s lives – safe and effective psychiatric treatment for many psychiatric and some medical conditions the symptoms of which had been present (but too–often ignored or dismissed by teachers, pediatricians, parents and others) since their early years in elementary or middle school.

Among Dr. Mortimer’s professional medical accomplishments, Dr. Mortimer is a diplomate of (– that is, he has a diploma in general adult psychiatry from) the American Board of Psychiatry and Neurology (i.e., Dr. Mortimer is “Board Certified in Psychiatry”). Dr. Mortimer has also been on the clinical teaching faculty for Oregon Health Science University’s Department of Psychiatry, and for the Family Practice Training Program at Eastmoreland Osteopathic Hospital in Milwaukie, Oregon. Dr. Mortimer has served as both a principle investigator and as a clinical investigator for phase III clinical drug trials, several of which investigated stimulants in the treatment of ADHD; in other clinical drug trials, other medications were investigated for their efficacy in such psychiatric disorders as social anxiety disorder, and in post–traumatic stress disorder. Over the past 35 years, Dr. Mortimer has enjoyed seeing some of his many clinical writings published in peer–reviewed international medical journals.

Following Euripides’ example in 408 B.C. (at which time, at the invitation from the King of Macedonia, Euripides left poorly–governed, politically psychotic Athens for Macedonia – where, in his new, more politically stable home, he wrote The Bacchae as a graphic warning to others of what misfortune may likely befall them should they remain in Athens), Dr. Mortimer has said a fond farewell to his former home in Portland, Oregon. Dr. Mortimer is currently licensed to practice medicine in the State of Washington, maintaining a full–time, solo private practice in child, adolescent, and general adult psychiatry in the non–incorporated Hazel Dell neighborhood of Vancouver, Washington. Also of perhaps some interest to the reader: Dr. Mortimer currently enjoys the distinction of having the longest–surviving, private practice in child and adolescent psychiatry in the county.

For more information about Dr. Mortimer’s academic and professional credentials, and his significant clinical and research experience, please see both his LinkedIn page and his website (www.mortimermd.com). His office phone number is: 360-882–9058

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END NOTES

1. As geneticist and educator Greg Fowler, Ph.D. once said to Dr. Mortimer: “If you want the mass media to present scientific or medical information accurately, write it yourself, then send your article to your favorite reporter for publication under the reporter's byline.”

2. "I often quote myself. It adds spice to an otherwise vapid conversation.” George Bernard Shaw (paraphrased)

3. gross: i.e., no obvious physical, anatomical, or histological evidence of anything gone awry

4. History trivia: The first food additive was vitamin–A enriched margarine – which was introduced in 1926.

5. McKeown RE, Holbrook JR, Danielson ML, Cuffe SP, Wolraich ML, Visser SN, “The impact of case definition on attention–deficit/hyperactivity disorder prevalence estimates in community–based samples of school–aged children.” Journal of the American Academy of Child and Adolescent Psychiatry.2015;54(1):53-61

6.  “Another 5% or more of children have substantial difficulties with these behaviours that are just under the threshold to meet full diagnostic criteria.” See: Sayal K, Prasad V, Daley D, Ford T, Coghill D. “ADHD in children and young people: prevalence, care pathways, and service provision.” Lancet Psychiatry.2018;5:175-186.

7. “Too many journal articles and “authorities” cite one terribly done study asserting that the prevalence of ADHD in adults is 4.4%, but this underestimate for the prevalence of adults with ADHD is simply flapdoodle.” – Dale Mortimer, M.D.

8. Szekely E, Sudre GP, Sharp W, Leibenluft E, Shaw P. “Defining the neural substrate of the adult outcome of childhood ADHD: a multimodal neuroimaging study of response inhibition. American Journal of Psychiatry. 2017 (June)

9. Attention Deficit Hyperactivity Disorder in Adults – Paul Wender, M.D. 1995. Oxford University Press,  New York

10. Faraone et al (2015): “In most cases, ADHD arises from several genetic and environmental risk factors that each have a small individual effect and act together to increase susceptibility. The multifactorial causation of ADHD is consistent with the heterogeneity of the disorder, which is shown by its extensive psychiatric co–morbidity, its multiple domains of neurocognitive impairment and the wide range of structural and functional brain anomalies associated with it. The diagnosis of ADHD is reliable and valid when evaluated with standard criteria for psychiatric disorders. Rating scales, and clinical interviews facilitate diagnosis and aid screening. The expression of symptoms varies as a function of patient developmental stage and social and academic contexts.”

11. As published in Nature Genetics (November 26, 2018), combing through the DNA sequences of 20,183 people with ADHD and 35,191 people without ADHD from study populations in China, Europe, and North America, Demontis et al. identified genetic variants at 12 regions strongly associated with ADHD risk. Additional analysis revealed that people with a greater number of ADHD risk variants were more likely to have had children at a younger age and have more children. Smoking and obesity were also associated with having more ADHD risk variants. “Shared genetic risk with health risk behaviors may…reflect an impaired ability to self–regulate and inhibit impulsive behavior.” Demontis D, Walters RK, Martin J, et al. “Discovery of the first genome–wide significant risk loci for attention-deficit/hyperactivity disorder. Nat Genet. Nov 26, 2018

12. For example, see: Larsson H, Anckarsater H, Rastam M, Chang Z, Lichtenstein P. “Childhood attention–deficit hyperactivity disorder as an extreme of a continuous trait: a quantitative genetic study of 8,500 twin pairs.” J Child Psychol Psychiatry. 2012;53:73-80

13. The striatum is composed of the caudate and putamen together which sit next to one another in the core of the brain, deep in the center; the stratum is part of what is considered the brain’s basal ganglia. The striatum takes in messages from very complicated parts of the brain - those that control body movement, physical feelings, and the thinking and planning that involve those movements and feelings. The messages function in unison like an automatic transmission, assuring the smooth transition from one behavior to another.

14. Li X, Sroubek A, Kelly M, et al. “Atypical pulvinar–cortical pathways during sustained attention performance in children with attention–deficit/hyperactivity disorder.” Journal of the American Academy of Child and Adolescent Psychiatry. 2012;51:1197-1207

15. Dr. Mortimer underscores that ADHD, similar to other psychiatric disorders, is not determined by a single gene. In fact, in 2006, the International Multicenter ADHD Genetics (IMAGE) group defined a high–priority set of 51 ADHD candidate risk genes, then focused on associations with ADHD for single nucleotide polymorphisms (SNPs) in 18 of the analyzed genes. These genes are predominantly involved in dopamine, norepinephrine and serotonin neurotransmission and circadian rhythm. In 2010, Neal et al. included CDH13 in their analysis of the gene set. Thus far, approximately 10 genes from these candidate gene sets have been found as statistically significant. However, these genes account for only a small fraction of the total ADHD heritability. Other approaches (e.g., genome–wide association studies, or GWAS) looking for single–nucleotide polymorphisms across the entire genome; and approaches focused on rare copy number variants of DNA has only contributed 0.2% to ADHD heritability. Therefore, although ADHD is highly heritable, the total contribution of the genes identified thus far is very small. Researchers refer to this as the “missing heritability problem.” Thus, comments Dr. Mortimer, “ Those who claim that genetic testing can give useful information about the genetic risk for inheriting ADHD are complete charlatans.” Stay tuned! For more information, see: Brookes K, Xu X, Chen W, et al. “The analysis of 51 genes in DSM–IV combined type attention deficit hyperactivity disorder: association signals in DRD4, DAT1 and 15 other genes.” Mol Psychiatry. 2006;11:934-953. And see: Neale BM, Medland SE, Ripke S, et al. “Meta–analysis of genome–wide association studies of attention–deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry.2010;49:884-897. And see also: Hawi Z, Cummins TD, Tong J, et al. “The molecular genetic architecture of attention deficit hyperactivity disorder.” Mol Psychiatry. 2015;20:289-297

16. As mentioned above: as published in Nature Genetics (November 26, 2018), combing through the DNA sequences of 20,183 people with ADHD and 35,191 people without ADHD from study populations in China, Europe, and North America, Demontis et al identified genetic variants at 12 regions strongly associated with ADHD risk. Additional analysis revealed that people with a greater number of ADHD risk variants were more likely to have had children at a younger age and have more children. Smoking and obesity were also associated with having more ADHD risk variants. “Shared genetic risk with health risk behaviors may…reflect an impaired ability to self–regulate and inhibit impulsive behavior.” Demontis D, Walters RK, Martin J, et al. “Discovery of the first genome–wide significant risk loci for attention-deficit/hyperactivity disorder. Nat Genet. Nov 26, 2018

17. See: Faraone SV, Asherson P, Banaschewski T, et al. “Attention–deficit/hyperactivity disorder.” Nat Rev Dis Primers.2015;1:15020, and: Lichtenstein P, Carlstrom E, Rastam M, Gillberg C, Anckarsater H. “The genetics of autism spectrum disorders and related neuropsychiatric disorders in childhood.” Am J Psychiatry.2010;167:1357-1363. And: Faraone SV, Asherson P, Banaschewski T, et al. “Attention–deficit/hyperactivity disorder.” Nat Rev Dis Primers. 2015;1:15020

18. Just for reference: the heritability for height is about 80%. The twin concordance rates for autism spectrum disorder range from 77% to 95%.

19. Parental ADHD strongly influences treatment outcomes: children with untreated ADHD who have parents with high levels of untreated ADHD symptoms have poorer outcomes. See: Jans T, Jacob C, Warnke, A, et al. “Does intensive multimodal treatment for maternal ADHD improve the efficacy of parent training for children with ADHD? A randomized controlled multicenter trial.” J Child Psychol Psychiatry. 2015;56:1298–1313

20. Epigenetics [“upon or over the genome”] refers to biochemical mechanisms whereby environmental factors induce changes in gene expression that are independent of the primary DNA sequence. See: Bhat V, Joober R, Sengupta S. “How environmental factors can get under the skin: epigenetics in attention–deficit/hyperactivity disorder. Journal of the American Academy of Child and Adolescent Psychiatry.2017;56(4):278-279

21.  In the developed world, 8.6% of individuals are born preterm (i.e., before 37 completed weeks of gestation). See: Peterson E, Sjolander A, Almqvist C, et al. “Birth weight as an independent predictor of ADHD symptoms: a within–twin pair analysis.” J Child Psychol Psychiatry. 2015;56:453-459. And: Rommel A, James S, McLoughlin G, Brandeis D, Banaschewski T, Asherson P, Kuntsi J. “Association of preterm birth with attention–deficit/hyperactivity disorder–like and wider–ranging neurophysiological impairments of attention and inhibition.” Journal of the American Academy of Child and Adolescent Psychiatry.2017;56(1):40-45

22. See: Banerjee TD, Middleton F, Faraone SV. “Environmental risk factors for attention–deficit hyperactivity disorder.” Acta Paediatr.2007;96(9):1269-1274. And: Zhu J, Lee KP, Spencer TJ, Biederman J, Bhide PG. “Transgenerational transmission of hyperactivity in a mouse model of ADHD.” J Neurosci. 2014;34(8):2768-2773. And: Schuch V, Utsumi DA, Costa TV, Kulikowski LD, Muszkat M. “Attention deficit hyperactivity disorder in the light of the epigenetic paradigm.” Front Psychiatry. 2015;6:126

23. See: Shaw P, Eckstrand K, Sharp W, et al. “Attention–deficit/hyperactivity disorder is characterized by a delay in cortical maturation.” Proc Natl Acad Sci U S A.2007;104(49(:19649-19654

24. In children, about 50% diagnosed with autism spectrum disorder will also have a comorbid diagnosis of ADHD – however, since autism spectrum disorder is much less prevalent than ADHD, the reverse is not the case.

25. The National Comorbidity Survey Replication Study found that 47% of adults with ADHD had a comorbid anxiety disorder; 30% met diagnostic criteria for social anxiety disorder; 15–20% met a lifetime diagnostic criteria for bipolar disorder; 15–20 % met diagnostic criteria for comorbid major depressive disorder; 12% met diagnostic criteria for chronic dysthymia; and 5–10% met diagnostic criteria for generalized anxiety disorder, panic disorder and post–traumatic stress disorder.

26. Ganelin–Cohen E, Ashkenasi A. “Disordered sleep in pediatric patients with attention deficit hyperactivity disorder: an overview.” Isr Med Assoc J. 2013;15(11):705-709

27. Iron deficiency is correlated with both ADHD and restless legs syndrome. Iron is a coenzyme essential in dopamine synthesis, suggesting altered dopamine central nervous system functioning as the etiology. Serum ferritin levels less than 20 ng/mL has been found to be correlated with more severe ADHD symptoms and cognitive impairment.

28. Periodic limb movements associated with sleep is present in up to 80% of those with restless legs syndrome. PLMS involves involuntary limb movements in which there is flexion of the hips, knees, and ankles, and patients are not generally aware of the restlessness of their sleep. Sleep is generally described as non–restorative, with frequent awakenings, and daytime fatigue or sleepiness.
29. Silvestri R, Gagliano A, Arico I, et al. “Sleep disorders in children with attention–deficit/hyperactivity disorder (ADHD) recorded overnight by video–polysomnography.” Sleep Med. 2009;10:1132-1138
30. In the general population, 7-12% of children snore habitually, and have a high risk for sleep disordered breathing.
31. Yoon SYR, Jain U, Shapiro C. “Sleep in attention–deficit/hyperactivity disorder in children and adults: past, present and future.” Sleep Med Rev. 2012;16:371-388
32. Ganelin–Cohen E, Ashkenasi A. “Disordered sleep in pediatric patients with attention deficit hyperactivity disorder: an overview.” Isr Med Assoc J. 2013;15(11):705-709.
33. Lecendreux M, Konofal E. “Sleep and alertness in children with ADHD.” J Child Psychol Psychiatry.2000;41(6):803-812
34. Owens J, Sangal RB, Sutton VK, Bakken R, Alen AJ, Kelsey D. “Subjective and objective measures of sleep in children with attention–deficit/hyperactivity disorder.” Sleep Med. 2009;10(4):446-456
35. Most frequently, these non–productive, ruminative, “racing thoughts” in those with untreated ADHD occur at bedtime.
36. See the Diagnostic and Statistical Manual of Mental Disorders, fifth edition
37. Barkley RA, Murphy KR, Fischer M. ADHD in Adults: What the Science Says. New York, NY: Guilford Press; 2010
38. From internationally–acknowledged ADHD expert and psychologist Russell Barkley, Ph.D., we learn that for 1.5 standard deviations above the mean (of the general population), adolescents need only four  symptoms of inattention for the diagnosis of ADHD; and for adults age 50 or older need only three symptoms of inattention for the diagnosis of ADHD.
39. Ahuja A, Martin J, Langley K, Thapar A. “Intellectual disability in children with attention deficit hyperactivity disorder.” J Pediatr. 2013;163:890-895
40. Michielsen M, Semeijn E, Comijs HC, van d Ven P, Beekman AT, Deeg DJ, Kooij JJ, “Prevalence of attention-deficit hyperactivity disorder in older adults in The Netherlands.” British Journal of Psychiatry. 2012 (Oct);201(4):298-305
41. MTA: “The Multimodal Treatment of children with ADHD.” For a sampling of study results, see: MTA Cooperative Group. “A 14–month randomized clinical trial of treatment strategies for attention–deficit/ hyperactivity disorder,” Archive of General Psychiatry, 1999;56:1073-1086
42. “Meta-analyses suggest that when the analyses focus on outcomes with some degree of blinding to the intervention received, behavioral treatments appear to improve parenting and conduct problems but are fairly ineffective at reducing ADHD symptoms. By contrast with these analyses, even the most conservative approaches to assessing the effectiveness of pharmacological treatments for children and adolescents with ADHD suggest moderate to large effect sizes with respect to symptoms.” For more discussion of this topic, see: Sayal K, Prasad V, Daley D, Ford T, Coghill D. “ADHD in children and young people: prevalence, care pathways, and service provision.” Lancet Psychiatry.2018;5:175-186.
43. Bradley C, “The behavior of children receiving benzedrine,” American Journal of Psychiatry, 1937;94(3):577-85
44. In chemistry, a mixture of “half and half” of each of two asymmetrical molecules which are mirror images of each other – like a pair of gloves.
45. The story goes that at least some children who had survived the encephalitis epidemic caused by the Spanish flu of 1918 (sometimes called von Economo’s disease or encephalitis) had persistent behavioral, academic and neurological compromise. This particular encephalitis caused lesions in the ascending inhibitory portion of the reticular substance of the pons and medulla of the brainstem. Lesions in this part of the brain led to the hyperactivity and distractibility (i.e., it looked like what we would now call ADHD) seen in some of Bradley’s young patients.
46. Briars L, Todd T. “A review of the pharmacological management of attention–deficit/hyperactivity disorder.” J Pediatr Pharmacol Ther. 2016;21(3):192-206
47. Childress A, Tran C, “Current investigational drugs for the treatment of attention–deficit/hyperactivity disorder.” Expert Opin Investig Drugs. 2016;25(4):463-474
48. Faraone SV, Glatt SJ. “A comparison of the efficacy of medications for adult attention–deficit/hyperactivity disorder using meta–analysis of effect sizes.” Journal of Clinical Psychiatry. 2010;71(6):754-763
49. Immediate release, or “IR”
50. Analogously, a pair of hands is a racemic mixture of hands. One hand is an isomer of the pair. There are rules for naming each of two molecules which are mirror images of the other. One is designated “dextro” (using “the right hand rule” of chemical nomenclature), and the other form is designated “levo” (using “the left hand rule” of chemical nomenclature).
51. As of May 7, 2023, Dr. Mortimer has prescribed Vyvanse to at least 126 patients; Daytrana to at least 155 patients; and Mydayis to at least 726 patients.
52. FDA: The Federal Food and Drug Administration. “FDA approved” is a complicated legal term. Briefly, the FDA supervises the claims that manufacturers can make about their medications. Thus, if the manufacturer of Vyvanse submitted clinical evidence that Vyvanse was safe and effective in its clinical trials in doses up to 70 mg daily, then the FDA “approves” the manufacturer’s advertising that Vyvanse is safe and effective in doses up to 70 mg daily. However, the FDA has jurisdiction neither over what a responsible physician can prescribe nor what dose is prescribed.
53. “First line” treatment options are those treatments most likely to produce the desired result safely and effectively for any group of patients with a particular diagnosis. The “first line” treatment for ADHD are the stimulants. The “second line” ADHD treatments include: desipramine and nortriptyline. The “third line” ADHD treatments include bupropion (Wellbutrin), viloxazine (Qelbree), and atomoxetine (Strattera). “Fourth line” ADHD treatments include: clonidine (Catapres; Kapvay) and guanfacine (Tenex; Intuniv). “Fifth line” ADHD treatments might possibly include: neurobiofeedback; play therapy; vitamins; gluten–free diets; caffeine; “energy drinks;” herbs; hypnosis; meditation; prayer; and good luck.
54. While no longer commercially available, MedChek was a neurodevelopmentally–based, sophisticated software tool used in the neuropsychiatric assessment of higher cerebral functioning. It was developed by Oregon Medical Software, LLC, as an objective way to monitor the effectiveness of medications used in the treatment of various neuropsychiatric and cognitive disorders – such as attention deficit hyperactivity disorder (“ADHD”) – both inattentive and hyperactive impulsive types. Those persons older than age 12 without  ADHD or a cognitive dysfunction are expected to achieve a perfect or near–perfect score (0–2 total errors) on this test, with an average reaction time of no greater than 400 milliseconds. Starting in 1991, Dr. Mortimer was the principal beta tester for this program, and found the program not only helpful in quickly identifying the optimal stimulant dose for a particular patient, but found the program sensitive enough to identify cognitive compromise from otherwise unidentified hypothyroidism, hypogonadism, and/or substance abuse.
55. See, for example: Robinson EB, Lichtenstein P, Anckarsater H, Happe F, Ronald A. “Examining and interpreting the female protective effect against autistic behavior.” Proc Natl Acad Sci U.S. A. 2013;110:5258-5262
56. Willcutt EG. “The prevalence of DSM–IV attention–deficit/hyperactivity disorder: a meta–analytic review.” Neurotherapeutics. 2012;9:490-499
57. Personal communication with Eva Brann, Ph.D. while we strolled around Ashland, Oregon one sunny day in October 1997
58. Taylor MJ, Lichtenstein P, Larsson H, Anckarsater H, Greven CU, Ronald A, “Is there a female protective effect against attention–deficit/hyperactivity disorder: Evidence from two representative twin samples.” Journal of the American Academy of Child and Adolescent Psychiatry. 2016;55(6):504-212
59. Diener R, “Toxicology of methylphenidate.” In: Osman B, Greenhill LL (eds): Ritalin: Theory and Patient Management. NY, Mary Ann Liebert Press, 1991;435-455.
60. Nora Volkow, M.D., personal communication on 10/25/2001, at the annual meeting of the American Academy of Child & Adolescent Psychiatry, Hawaii
61. Volkow N, Wang G, Fowler J et al., “Dopamine transporter occupancies in the human brain induced by therapeutic doses of oral methylphenidate,” American Journal of Psychiatry, 1998;155:1325-1331
62. Kaplan G, Newcorn JH, “Pharmacotherapy for child and adolescent attention–deficit hyperactivity disorder. Pediatric Clinics of North America. 2011;58:99-120
63. Gould MS, Walsh BT, Munfakh JL, et al, “Sudden death and use of stimulant medications in youths. American Journal of Psychiatry. 2009; 166:992-1002
64. Hammerness PG, Perrin JM, Shelley–Abrahamson R, Wilens TE, “Cardiovascular risk of stimulant treatment in pediatric attention–deficit/hyperactivity disorder: update and clinical recommendations. Journal of the American Academy of Child Adolescent Psychiatry. 2011;50:978-990
65. Schelleman H, Bilker WB, Stron BL, et al, “Cardiovascular events and death in children exposed and unexposed to ADHD agents. Pediatrics. 2011;127:1102-1110
66. Habel LA, cooper WO, Sox CM, et al, “ADHD medications and risk of serious cardiovascular events in young and middle–aged adults. Journal of the American Medical Association. 2011;306:2673-2683
67. Cooper WO, Habel LA, Sox CM, et al, “ADHD drugs and serious cardiovascular events in children and young adults. New England Journal of Medicine. 2011;365:1896-1904
68. Olfson M, Huang C, Gerhard T, et al. “Stimulants and cardiovascular events in youth with attention–deficit/hyperactivity disorder. Journal of the American Academy of Child Adolescent Psychiatry. 2012;51:147-156
69. Vitiello B, Elliott GR, Swanson JM, et al, “Blood pressure and heart rate over 10 years in the multimodal treatment study of children with ADHD. American Journal of Psychiatry. 2012:169:167-177
70. Wilens TE, Adler LA, Adams J, et al, “Misuse and diversion of stimulants prescribed for ADHD: a systematic review of the literature,” Journal of the American Academy of Child Adolescent Psychiatry 2008;47:21-31.
71. See, for example: Wilens T, Faraone S, Biederman J, Gunawardene S, “Does the pharmacotherapy of ADHD beget later substance abuse? A meta–analytic review of the literature,” Pediatrics, 2003
72. Barkley RA, “Major life activity and health outcomes associated with attention–deficit/ hyperactivity disorder,” Journal of Clinical Psychiatry.2002;63 [suppl 12]10-15
73. Wilens T, Faraone S, Biederman J, Gunawardene S, “Does the pharmacotherapy of ADHD beget later substance abuse? A meta–analytic review of the literature,” Pediatrics, 2003
74. Biederman J, “Practical considerations in stimulant drug selection for the attention–deficit/hyperactivity disorder patient – efficacy, potency and titration,” Today’s Therapeutic Trends, 2002;20(4):311-328
75. Quinn PD, Chang Z, Hur K, et al. “ADHD medications and substance–related problems.” American Journal of Psychiatry. 2017 (June)
76. Wender PH, Attention Deficit Hyperactivity Disorder in Adults, 1995, Oxford University Press, New York
77. Elia J, Ambrosini PJ, Rapaport JL, “Treatment of attention deficit/ hyperactivity disorder: review article,” New England Journal of Medicine, 1999;340:780-788
78. Mortimer DB, George RA, “Identification and treatment of adult male attention deficit disorder,” Corrective and Social Psychiatry, 1997;43(1): 6-20
79. George RA, Mortimer DB, “Identification and medical treatment of ADHD in the juvenile justice setting,” The ADHD Report, 1998:6(6);1-9
80. Pliska, S and Castellanos FX, “Neuroimaging of Diet and Medication in the Treatment of ADHD.” 2015
81. Polanczyk et al (2014): “There is no evidence, worldwide, of an increase in the real prevalence of ADHD over the past three decades.”
82. In 2007, a meta–analysis by Polanczyk et al of more than 100 studies estimated the world–wide prevalence of ADHD in children and adolescents to be 5.29% and that the prevalence of ADHD does not significantly differ between countries in Europe, Asia, Africa and the Americas, as well as in Australia. But, subsequent published studies have led Dr. Mortimer to conclude that while the prevalence may be the same throughout the world, the 5.3% prevalence rate in children and adolescents “…is simply wrong; the estimate is much too low.”
83. McGough J, “Pediatric ADHD: clinical criteria fro diagnosis and management.” Medical Crossfire Monograph Supplement. 2004 (Feb)
84. ADHD and the Nature of Self–Control – Russell Barkley, Ph.D. (1997), pages 340-341)
85. Sallee FR. “Early morning functioning in stimulant–treated children and adolescents with attention–deficit/hyperactivity disorder, and its impact on caregivers.” Journal of Child and Adolescent Psychopharmacology. 2015;25(7):558-565
86. Whalen CR, Henker B, Jamner LD, et al. “Toward mapping daily challenges of living with ADHD: maternal and child perspectives using electronic diaries.” J Abnorm Child Psychol. 2006;34(1):115-130
87. Mattingly G, Surman CB, Mao AR, Eagan CA, Onofrey M, Lerner M. “Improving communication in ADHD care: results from in–office linguistic research.” CNS Spectrums. 2011;16(4):85-94
88. McGough J, McCracken J, Swanson J, Riddle M, Kollins S, Greenhill L, et al, “Pharmacogenetics of methylphenidate response in preschoolers with ADHD.” Journal of the American Academy of Child & Adolescent Psychiatry. 2006;45(11):1314-1322): Preschool subjects with ADHD who had a 7–repeat VNTR in the third exon of the DRD₄ receptor gene required higher doses of methylphenidate to achieve a comparable symptom response.
89. Dr. Mortimer is particularly suspicious that a mutation of the DRD₄ 7R allele  (i.e., one of the mutations for the gene which codes for the dopamine receptor subtype D₄ ) is one of the biologically–based causes of ADHD. Dopamine D₄ receptors are located predominately in the prefrontal cortex of the brain. The gene for DRD₄ is located on the short arm of chromosome 11. The variable number tandem repeats (VNTR) for DR D₄ (i.e., HincII) is located in exon 3 and is defined by the number of 16 amino acid repeated sequences present. The amino acids coded by these repeated sequences of 48 nucleotides are located in the third–cytoplasmic loop of the D₄ receptor.The polymorphisms created by these multiple repeats produce proteins that contain polypeptides in the cytoplasmic loop. The cytoplasmic loop of the DRD₄ receptor is thought to bind G–proteins that link receptor activation to the creation of intracellular second messengers. The 7–repeat allele of the 48–base pair variable–number tandem repeat (VNTR) has been referred to as the “long allele” and has been reported to be less responsive to dopamine stimulation than some of the shorter versions of this allele. The 7–repeat allele of this 48–base pair VNTR has also been associated with novelty seeking. In a Northern American samples composed of only individuals of European ancestry, normal control subjects had a 7–repeat allele frequency of 26%.
90. Department of Health and Human Services, United States Government. “Use of approved drugs for unlabeled indications.” Food and Drug Administration Drug Bulletin. 1982; 12:3-4
91. Specifically, the 3’–untranslated region (3’UTR) of the gene encoding the dopamine transporter (SLC6A3 or DAT₁), which is located in exon 15, on the short arm of chromosome 5, contains a variable number of tandem repeat (VNTR) polymorphisms influencing presynaptic dopamine transporter density, especially in the striatum, where gene expression is high. The 9– and 10–repeat alleles are most frequently encountered in the population. In children and adolescents, the 10–repeat allele has been associated with increased risk of ADHD, smaller striatal volumes, and distinct striatal activity patterns. Recent studies on a haplotype of the 3’UTR VNTR and a second NTR of the DAT₁ gene located in intron 8 has found that  the 10–6 haplotype (10–repeat allele in the 3’UTR VNTR and 6–repeat allele in the intron 8 VNTR) has been identified as the risk haplotype for ADHD in children and adolescents; the 9–6 haplotype has been associated with adults with continued ADHD symptoms.
92. Specifically, the DRD₄ 7R allele (that is, the 7–repeat allele of a variable number of tandem repeat [VNTR] in exon 3)
93. For example, see the discussion in: Froehlich TE, Epstein JN, et al. “Pharmacogenetic predictors of methylphenidate dose–response in attention–deficit/hyperactivity disorder.” Journal of the American Academy of Child and Adolescent Psychiatry.2011;50(11):1129-1139
94. Personal communication with Robert Hunt, M.D., 9/14/2004, at Ruth’s Chris Steak House in Portland, Oregon.
95. One of the best explanations I’ve found for this can be found in Russell Barkley’s most excellent 2012 book, Executive Functions: What they Are, How They Work, and Why They Evolved.
96. Executive Skills: What They Are, How They Work, and Why They Evolved – Russell Barkley, Ph.D. (2012)
97. “Off–label: relating to the prescription of a medication for a condition other than that for which it has been officially approved by the Federal Food and Drug Administration (– The FDA decides what advertising claims the manufacturers can make about their medications – not what physicians can prescribe).
98. “Many published guidelines lack the detail and organizational structure required to make them readily implementable in day–to–day practice.” For more, see: See: Sayal K, Prasad V, Daley D, Ford T, Coghill D. “ADHD in children and young people: prevalence, care pathways, and service provision.” Lancet Psychiatry.2018;5:175-186.
99. Greenhill LL, Halperin JM, Abikoff H, “Stimulant medications,” Journal of the American Academy of Child and Adolescent Psychiatry, 1999;38(5):503-512

100. Guy W. “Clinical global impression.” In: ECDEU Assessment Manual for Psychopharmacology. Revised edition. Rockville, MD: U.S. Department of Health, Education, and Welfare; Public Health Service, Alcohol, Drug Abuse and Mental Health Administration, NIMH Psychopharmacology Research Branch;1976:218-222

101. Goodman D, Faraone SV, Adler LA, Dirks B, Hamdani M, Weisler R. “Interpreting ADHD rating scale scores: linking ADHD rating scale scores and CGI levels in two randomized controlled trials of lisdexamfetamine dimesylate in ADHD.” Primary Psychiatry. 2010;17(3):44-52

102. Steele M, Jensen PS, Quinn DMP. “Remission versus response as the goal of therapy in ADHD: a new standard for the field?” Clin Ther. 2006;28(11):1892-1908

103. Mattingly G, Culpepper L, Babcock T, Arnold V. “Aiming for remission in adults with attention deficit/hyperactivity treatment: the primary care goal.” Postgrad Med. 2015;127(3):323-329

104. Mattingly GW, Weisler RH, Young J, et al. “Clinical response and symptomatic remission in short and long term trials of lisdexamfetamine dimesylate.” BMC Psychiatry. 2013;13:39

105. Mattingly G, Childress A, Nordbrock E, Adej A, Kupper RJ, Weiss M. “Clinical response and symptomatic remission with Aptensio XR (methylphenidate extended release) in children and adolescents with ADHD. Post. Presented at: American Psychiatry Association Meeting; May 14-18, 2016; Atlanta, GA

106. Hobbes, T, Leviathan, Chapter 13, paragraph 9

107. Klein RG, Mannuzza S, Olazagasti MA, et al. “Clinical and functional outcome of childhood attention-deficit/hyperactivity disorder 33 years later.” Archives of General Psychiatry. 2012;69;1295-1303

108. Crump C, Sundquist K, Winkleby MA, Sundquist J, “Mental disorders and risk of accidental death.” British Journal of Psychiatry. 2013 (Oct);203(4):297-302

109. The percentage of US adolescents not completing high school is 5%, whereas it is about 35% for ADHD adolescents. See: Barkley RA. “Major life activity and health outcomes associated with attention–deficit/hyperactivity disorder.” J Clin Psychiatry.2002;63(Suppl 12):10-15. And: Loe IM, Feldman HM. “Academic and educational outcomes of children with ADHD.” J Pediatr Psychol. 2007;32:643-654

110. Sarver DE, McCart MR, Sheidow AJ, Letourneau EJ. “ADHD and risky sexual behavior in adolescents: conduct problems and substance use as mediators of risk.” J Child Psychol Psychiatry. 2014;55:1345-1353

111. Huggins SP, Rooney ME, Chronis–Tuscano A. “Risky sexual behavior among college students with ADHD: is the mother–child relationship protective?” J Atten Disord. 2015;19:240-250

112. Ostergaard et al (2017) found the relative risk of parenthood in ages 12 to 16 years old to be increased by: 3.62 times in ADHD girls and 2.30 times more likely for ADHD boys ages 12 to 16; and 1.94 times in ADHD girls and 2.27 times in ADHD boys ages 17 to 19 years old compared to the non–ADHD adolescent control group.

113. Ostergaard SD, Dalsgaard S, Faraone SV, Munk–Olsen T, Laursen T.  “Teenage parenthood and birth rates for individuals with and without attention–deficit/hyperactivity disorder: a nationwide cohort study.” Journal of the American Academy of Child and Adolescent Psychiatry. 2017;56(7):578-584

114. Dalsgaard S, Mortensen PB, Frydenberg M, Thomsen PH. “Long–term criminal outcome of children with attention deficit hyperactivity disorder.” Crim Behav Ment Health. 2013;23:86-98

115. Kotsopoulos N, Connolly MP, Sobanski E, Postma MJ. “The fiscal consequences of ADHD in Germany: a quantitative analysis based on differences in educational attainment and lifetime earnings.” J Ment Health Poly Econ. 2013;16:27-33

116. Gardner DM, Gerdes AC. “A review of peer relationships and friendships in youth with ADHD.” J Atten Disord. 2015;19:844-948

117. Riglin L, Todd A, Blakey R, et al, “Young–adult social outcomes of attention–deficit/hyperactivity disorder.” Journal of Clinical Psychiatry.2023;84(2):6–12

118. Riglin et al. found that in their longitudinal study of outcomes of men and women who continued to meet diagnostic criteria for ADHD at 25 years of age, approximately 20% of those with NEET status (not in education, employment or training) receiving state benefits, and who were homeless had a diagnosis of ADHD.

119. Chang Z, Lichtenstein P, D’Onofrio BM, Sjolander A, Larsson H. “Serious transport accidents in adults with attention–deficit/hyperactivity disorder and the effect of medication: a population–based study.” JAMA Psychiatry.2014;71:319-325

120. As reported in Lancet Psychiatry (May, 2018, page 393), Huang et al studied Taiwanese youth aged 12 to 29 years old and found  that, compared to healthy controls and adjusting for psychiatric comorbidities and ADHD medications, a diagnosis of ADHD was associated with increased risk for suicide compared with controls (hazard ratio for any suicide attempt was 3.84; hazard ratio for repeated attempts was 6.52).121.

121. See also: Balaza J and Kereszteny A. “Attention–deficit/hyperactivity disorder and suicide: A systematic review.” World Journal of Psychiatry.2017;7:44

122. Barkley RA, “Accidents and attention–deficit hyperactivity disorder,” TEN.2001; 3(4):64-68

123. Dalsgaard S, Ostergaard SD, Leckman JF, Mortensen PB, Pedersen MG “Mortality in children, adolescents, and adults with attention deficit hyperactivity disorder: a nationwide cohort study.” Lancet. 2015; Feb 26

124. Although there are not yet any curative treatments for ADHD, evidence–based treatments can markedly reduce its symptoms and associated impairments.

125. Dalsgaard S, Leckman JF, Mortensen PB, Nielsen HS, Simonsen M. “Effect of drugs on the risk of injuries in children with attention deficit hyperactivity disorder: a prospective cohort study.” Lancet Psychiatry. 2015;2(8):702-709. Specifically, there was a 220% increase in mortality in persons with ADHD at all ages. The mortality rate ration was 1.86 for ADHD before age 6; 1.58 for ADHD between ages 6 to 17; and the mortality rate ratio was 4.25 for those with ADHD greater than 18 years old.

126. Dalsgaard S, Ostergaard SD, Leckman JF, Mortensen PB, Pedersen MG. “Mortality in children, adolescents, and adults with attention deficit hyperactivity disorder: a nationwide cohort study. Lancet. 2015;385(9983):2190-2196

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