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The stimulants methylphenidate and amphetamine are well known for their efficacy in treating symptoms of ADHD in both youth and adults.   Although these medications have been used for several decades, relatively little is known about the mechanisms of action that lead to their therapeutic effect.    

New data about the mechanism comes from a meta-analysis by Katya Rubia and colleagues. They analyzed 14 functional magnetic resonance imaging (fMRI) data sets comprising 212 youth with ADHD.  Each of these data sets assessed the short-term effects of stimulants on fMRI-assessed brain activations. In the fMRI paradigm, ADHD and control participants are asked to do a neurocognitive task while the activity of their brains is being measured. Dr. Rubia and colleagues analyzed data from fMRI assessments of time discrimination, inhibition, and working memory, each of which is known to be deficient in ADHD patients.    

The meta-analysis found that the most consistent brain activations were seen in a region comprising the right inferior frontal cortex(IFC) and insula, even when the analysis was limited to previously medication-naïve patients. The implicated region of the brain is known to mediate cognitive control, time estimation, and attention.  Dr.Rubia also notes that other studies show that the IFC/Insula is needed for updating information and allocating attention to relevant stimuli.  

Another region implicate by the meta-analysis was the right putamen, a region that is rich in dopamine transporters. This finding is consistent with the fact that the dopamine transporter is the main target of stimulant medications.    

What is the potential clinical implication of these findings?  As Dr. Rubia and colleagues note, it is possible that the fMRI anomalies they identified could be used as a biomarker for ADHD or a biomarker to select patients who should respond optimally to stimulant medication. Although fMRI cannot be used as a clinical tool at this time, research of this sort is opening up new horizons for how we understand the etiology of ADHD and the mechanisms whereby medications exert their effects.

Cognitive Behavioral Therapy (CBT) is a one-to-one therapy, for adolescents or adults, where a therapist teaches an ADHD patient how thoughts, feelings, and behaviors are all interrelated and how each of these elements affects the others.  CBT emphasizes cognition or thinking because a major goal of this therapy is to help patients identify thinking patterns that lead to problem behaviors.  For example, the therapist might discover that the patient frequently has negative automatic thoughts such as "I'm stupid" in challenging situations. We call the thought 'automatic' because it invades the patient's consciousness without any effort. Thinking "I'm stupid" can cause anxiety and depression, which leads to failure. Thus, stopping the automatic thought will modify this chain of events and, hopefully, improve the outcome from failure to success.

CBT also educates patients about their ADHD and how it affects them in important daily activities.

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For example, most ADHD patients need help with activity schedules, socializing, organizing their workspace, and controlling their distractibility. By teaching specific cognitive and behavioral skills, the therapist helps the patient deal with their ADHD symptoms productively. For example, some ADHD patients are very impulsive when conversing with others. They don't wait their turn during conversations and may blurt out irrelevant ideas. This can be annoying to others, especially in the context of school or business relationships. The CBT therapist helps the patient identify these behaviors and creates strategies for avoiding them.

So, does CBT work for ADHD? The evidence base is small, but when CBT has been used for adult ADHD, it has produced positive results in well-designed studies.   These studies typically compare patients taking ADHD medications with those taking ADHD medications and receiving CBT.  

So for now, it is best to consider CBT as an adjunct rather than a replacement for medication. There are even fewer studies of CBT for adolescents with ADHD.  These initial studies also suggest that CBT will be useful for adolescents with ADHD who are also taking ADHD medications.  Some data suggest that CBT can be successfully applied in the classroom, but the evidence base is very small.

How can this information be used by doctors and patients for treatment planning?  Current treatment guidelines suggest starting with an ADHD medication.  After a suitable medication and dose are found, the patient and doctor should determine if any problems remain.  If so, CBT should be considered an adjunct to ADHD medications.

The term "cognitive behavior therapy (CBT)" refers to a type of talk therapy that seeks to change the way patients think about themselves, their disorder, and the world around them in a manner that will help them overcome symptoms and achieve life goals.

Because CBT is typically administered by a psychologist or other mental health professionals, CBT services are not available in primary care. Nonetheless, it is useful for primary care practitioners to know about CBT so that they can refer appropriately as needed. So, what can we say about the efficacy of CBT for treating adults with ADHD?

Based on a meta-analysis by Young and colleagues, we know for certain that the number of published trials of CBT for adult ADHD is small; only nine trials are available. Five of these compared CBT with waiting list controls; three compared CBT with appropriate placebo control groups. In all of these studies, patients in the CBT and control groups were also being treated with ADHD medications.

Thus, they speak to the efficacy of CBT when given as an adjunctive treatment. The meta-analysis examined the waiting list controlled studies and the placebo-controlled studies separately. For both types of study, the effect of CBT in reducing ADHD symptoms was statistically significant, with a standardized mean effect size of 0.4.

This effect size, albeit modest, is large enough to conclude that CBT will be useful for some patients being treated with ADHD medications. Given these results, a reasonable guideline would be to refer adults with ADHD to a CBT therapist if they are being maintained on an ADHD medication, but that medication is not leading to a complete remission of their symptoms and impairments. So listen to your patients. If, while on an appropriately titrated medication regime, they still complain about unresolved symptoms or impairments, you need to take action.  In some cases, changing their dose or shifting to another medication will be useful. If such approaches fail or are not feasible, you should consider referral to a CBT therapist.

In the world of research, it is unusual for a single study to be definitive. A possible exception is a recent report in the highly esteemed Lancet, which concluded that people diagnosed with ADHD were about two times more likely to die early than people without ADHD. The data came from the medical registers of Denmark that include1.92 a million people, of which 32,061 have ADHD. The registers included the times and causes of deaths spanning 32 years.

It is a remarkable resource. We know that people with very severe ADHD are at high risk for substance use disorders and antisocial behaviors. In the Danish study, these disorders also increased the risk for premature death, but the risk was even higher if people with those disorders also had ADHD. ADHD also increased the risk for early death among people without these extra problems. This latter finding points to an ADHD-specific pathway to premature death. What is it?  Well, we know that ADHD people are at risk for injuries, traffic accidents, and traumatic brain injury.  We don't know for certain why, but two symptom clusters of ADHD, inattention, and impulsivity, would be expected to increase the risk for accidents and injuries. For example, adults who are distracted while driving are clearly at risk for accidents. Accidents accounted for most of the early deaths in the Danish study. But the study also found an increase in natural causes of death due to having ADHD. This may be due to the well-replicated association between ADHD and obesity, or the possibility that ADHD symptoms lead to poor health habits.

In the Danish study, the mean age at diagnosis was 12.3, which means that many of the ADHD people in the study were not treated for many years after the onset of symptoms. The risk for early death increased with the age at diagnosis. This suggests that failing to diagnose and treat ADHD early makes the disorder worse and increases the risk for the types of behaviors that lead to premature death. Will these data change public policy or clinician behavior? I hope so. Perhaps the media will stop trivializing ADHD and accept it as a bona fide disorder in need of early identification and treatment.  Policymakers should allocate ADHD people their fair share of healthcare and research resources. For clinicians, early identification and treatment should become the rule rather than the exception.

Talk of premature death will worry parents and patients. That is understandable, but such worries can be alleviated by focusing on two facts: the absolute risk for premature death is low, and this risk can be greatly reduced by seeking and adhering to evidence-based treatments for the disorder.

I have too often seen on the Internet or media the statement that ADHD is a recent invention of psychiatrists and/or pharmaceutical companies. Such statements ignore the long history of ADHD that my colleague and I reviewed in our "Primer" about ADHD.  

ADHD has a long history. The first ADHD syndrome was described in a German medical textbook by Weikard in 1775. That's not a typo. The ADHD syndrome had been identified before the birth of the USA. Dr.Weikard did not use the term ADD or ADHD, yet he described a syndrome of hyperactivity and inattention that corresponds to what we call ADHD today.  

ADHD-like syndromes were described in Scotland in 1798 and in France in the late 19th century. The first description of an ADHD-like syndrome in a medical journal was by Dr. George Still in 1901 who described what he called a 'defect of moral control' in The Lancet. The discovery that stimulant drugs are effective in treating ADHD occurred in 1937 when Dr. Charles Bradley discovered that Benzedrine (an amphetamine compound) improved the behavior of children diagnosed with behavioral disorders. In subsequent years, several terms were used to describe children with ADHD symptoms. Examples are Kramer-Pollnow syndrome, minimal brain damage, minimal brain dysfunction, and hyperkinetic reaction.  

,It was not until the 1980s that the term Attention Deficit Disorder (ADD) came into widespread use with the publication of the American Psychiatric Association's Diagnostic and Statistical Manual (DSM).   During the ensuing decades, several changes were made to the diagnostic criteria and the term ADD was replaced with ADHD so as not to overemphasize either inattention or hyperactivity when diagnosing the disorder. And, as the graphic below describes, these new and better diagnostic criteria led to many breakthroughs in our understanding of the nature of the disorder and the efficacy of treatments. So, if you think that ADHD is an invention of contemporary society, think again. It has been with us for quite some time.

The diagnosis of ADHD should only be done by a licensed clinician, and that clinician should have one goal in mind: to plan a safe and effective course of evidence-based treatment. The infographic gives a summary of this diagnostic approach which my colleagues and I prepared for our "Primer" about ADHD,http://rdcu.be/gYyV.  A key point that parents of ADHD youth and adults with ADHD should keep in mind is that there is only one way to diagnose ADHD.An expert clinician must document the criteria for the disorder as specified by either the Diagnostic and Statistical Manual of the American Psychiatric Association, which is now in its fifth edition (DSM-5), or the World Health Organization's International Classification of Diseases (ICD-10). The two sets of criteria are nearly identical. These criteria are most commonly applied by a clinician asking questions of the parent (for children) and/or patient (for adolescents and adults).For children, information from the teacher can be useful. Some clinicians get this information by having the parent ask the teacher to fill out a rating scale. This information can be very useful if it is available.  When diagnosing adults, it is also useful to collect information from a significant other, which can be a parent for young adults or a spouse for older adults. But when such informants are not available, diagnosing ADHD based on the patient's self-report is valid. As the infographic indicates, any diagnosis of ADHD should also assess for comorbid psychiatric disorders, as these have implications for which ADHD medications will be safe and effective. And because a prior history of cardiovascular disease or seizures frequently contraindicate stimulants. These must also be assessed.

There is a growing interest (and controversy) in 'adult-onset ADHD. No current diagnostic system allows for the diagnosis of ADHD in adulthood, yet clinicians sometimes face adults who meet all criteria for ADHD, except for age at onset. Although many of these clinically referred adult-onset cases may reflect poor recall, several recent longitudinal population studies have claimed to detect cases of adult-onset ADHD that showed no signs of ADHD as a youth (Agnew-Blais, Polanczyk et al. 2016, Caye, Rocha, et al. 2016). They conclude, not only that ADHD can onset in adulthood, but that childhood-onset and adult-onset ADHD may be distinct syndromes(Moffitt, Houts, et al. 2015)

In each study, the prevalence of adult-onset ADHD was much larger than the prevalence of childhood-onset adult ADHD). These estimates should be viewed with caution.  The adults in two of the studies were 18-19 years old.  That is too small a slice of adulthood to draw firm conclusions. As discussed elsewhere (Faraone and Biederman 2016), the claims for adult-onset ADHD are all based on population as opposed to clinical studies.
Population studies are plagued by the "false positive paradox", which states that, even when false positive rates are low, many or even most diagnoses in a population study can be false.  

Another problem is that the false positive rate is sensitive to the method of diagnosis. The child diagnoses in the studies claiming the existence of adult-onset ADHDused reports from parents and/or teachers but the adult diagnoses were based on self-report. Self-reports of ADHD in adults are less reliable than informant reports, which raises concerns about measurement error.   Another longitudinal study found that current symptoms of ADHD were under-reported by adults who had had ADHD in childhood and over-reported by adults who did not have ADHD in childhood(Sibley, Pelham, et al. 2012).   These issues strongly suggest that the studies claiming the existence of adult-onset ADHD underestimated the prevalence of persistent ADHD and overestimated the prevalence of adult-onset ADHD.  Thus, we cannot yet accept the conclusion that most adults referred to clinicians with ADHD symptoms will not have a history of ADHD in youth.

The new papers conclude that child and adult ADHD are "distinct syndromes", "that adult ADHD is more complex than a straightforward continuation of the childhood disorder" and that adult ADHD is "not a neurodevelopmental disorder". These conclusions are provocative, suggesting a paradigm shift in how we view adulthood and childhood ADHD.   Yet they seem premature.  In these studies, people were categorized as adult-onset ADHD if full-threshold add had not been diagnosed in childhood.  Yet, in all of these population studies, there was substantial evidence that the adult-onset cases were not neurotypical in adulthood (Faraone and Biederman 2016).  Notably, in a study of referred cases, one-third of late adolescent and adult-onset cases had childhood histories of ODD, CD, and school failure(Chandra, Biederman, et al. 2016).   Thus, many of the "adult onsets" of ADHD appear to have had neurodevelopmental roots. 

Looking through a more parsimonious lens, Faraone and Biederman(2016)proposed that the putative cases of adult-onset ADHD reflect the existence of subthreshold childhood ADHD that emerges with full threshold diagnostic criteria in adulthood.   Other work shows that subthreshold ADHD in childhood predicts onsets of full-threshold ADHD in adolescence(Lecendreux, Konofal, et al. 2015).   Why is onset delayed in subthreshold cases? One possibility is that intellectual and social supports help subthreshold ADHD youth compensate in early life, with decompensation occurring when supports are removed in adulthood or the challenges of life increase.  A related possibility is that the subthreshold cases are at the lower end of a dimensional liability spectrum that indexes risk for onset of ADHD symptoms and impairments.  This is consistent with the idea that ADHD is an extreme form of a dimensional trait, which is supported by twin and molecular genetic studies(Larsson, Anckarsater, et al. 2012, Lee, Ripke, et al. 2013).  These data suggest that disorders emerge when risk factors accumulate over time to exceed a threshold.  Those with lower levels of risk at birth will take longer to accumulate sufficient risk factors and longer to onset.

In conclusion, it is premature to accept the idea that there exists an adult-onset form of ADHD that does not have its roots in neurodevelopment and is not expressed in childhood.   It is, however, the right time to carefully study apparent cases of adult-onset ADHD to test the idea that they are late manifestations of a subthreshold childhood condition.

Although there has been much research documenting that ADHD adults are at risk for other psychiatric and substance use disorders, relatively little is known about whether ADHD puts adults at risk specifically for somatic medical disorders.  

Given that people with ADHD tend toward being disorganized and inattentive, and that they tend to favor short-term over long-term rewards, it seems logical that they should be at higher risk for adverse medical outcomes.  But what does the data say?

In a systematic review of the literature, Instances and colleagues have provided a thorough overview of this issue.  Although they found 126 studies, most were small and were of "modest quality".   Thus, their results must be considered to be suggestive, not definitive for most of the somatic conditions they studied.  

Also, they excluded articles about traumatic injuries because the association between ADHD and such injuries is well established. Using qualitative review methods, they classified associations as being a) well-established; b) tentative, or c) lacking sufficient data.

Only three conditions met their criteria for being a well-established association: asthma, sleep disorders, and obesity.  

They found tentative evidence implicating ADHD as a risk factor for three conditions: migraine headaches, celiac disease, and diseases of the circulatory system.  

These data are intriguing, but cannot tell us why ADHD people are at increased risk for somatic conditions. One possibility is that suffering from ADHD symptoms can lead to an unhealthy lifestyle, which leads to increased medical risk. Another possibility is that the biological systems that are dysregulated in ADHD are also dysregulated in some medical disorders.  For example, we know that there is some overlap between the genes that increase the risk for ADHD and those that increase the risk for obesity. We also know that the dopamine system has been implicated in both disorders.

Instances and colleagues also point out that some medical conditions might lead to symptoms that mimic ADHD. They give sleep-disordered breathing as an example of a condition that can lead to the symptom of inattention.    

But this seems to be the exception, not the rule. Other medical conditions co-occurring with ADHD seem to be true comorbidities, rather than the case of one disorder causing the other. Thus, primary care clinicians should be alert to the fact that many of their patients with obesity, asthma, or sleep disorders might also have ADHD.  

By screening such patients for ADHD and treating that disorder, you may improve their medical outcomes indirectly via increased compliance with your treatment regime and an improvement in health behaviors. We don't yet have data to confirm these latter ideas, as the relevant studies have not yet been done.

If you've ever wondered how experts make treatment recommendations for patients with ADHD, take a look at this ADHD treatment decision tree that my colleagues and I constructed for our "Primer" about ADHD,http://rdcu.be/gYyV.  

Although a picture is worth a thousand words, keep in mind that this infographic only gives the bare bones of a complex process. That said, it is telling that one of the first questions an expert asks is if the patient has a comorbid condition that is more severe than ADHD. The general rule is to treat the more severe disorder first and after that condition has been stabilized plan a treatment approach for the other condition. Stimulants are typically the first-line treatment due to their greater efficacy compared with non-stimulants.

When considering any medication treatment for ADHD safety is the first concern, which is why medical contraindications to stimulants, such as cardiovascular issues or concerns about substance abuse, must be considered. For very young children (preschoolers) family behavior therapy is typically used before medication. Clinicians also must deal with personal preferences.  Some parents and some adolescents and adults with ADHD simply don't want to take stimulant medications for the disorder. When that happens, clinicians should do their best to educate them about the costs and benefits of stimulant treatment.

If, as is the case for most patients, the doctor takes the stimulant arm of the decision tree, he or she must next decide if methylphenidate or amphetamine is more appropriate. Here there is very little guidance for doctors. Amphetamine compounds are a bit more effective, but can lead to greater side effects.  Genetic studies suggest that a person's genetic background provides some information about who will respond well to methylphenidate, but we are not yet able to make very accurate predictions. After choosing the type of stimulant, the doctor must next consider what duration of action is appropriate for each patient.

There is no simple rule here; the choice will depend upon the specific needs of each patient. Many children benefit from longer-acting medications to get them through school, homework, and late afternoon/evening social activities. Likewise for adults. But many patients prefer shorter-acting medications, especially as these can be used to target specific times of day and can also lower the burden of side effects.  

For patients taking down the non-stimulant arm of the decision tree, duration is not an issue but the patient and doctor must choose from among two classes of medications norepinephrine reuptake inhibitors or alpha-2-agonists. There are not a lot of good data to guide this decision but, again, genetics can be useful in some cases. Regardless of whether the first treatment is a stimulant or a non-stimulant, the patient's response must be closely monitored as there is no guarantee that the first choice of medication will work out well. In some cases, efficacy is low, or adverse events are high. Sometimes this can be fixed by changing the dose, and sometimes a trial of a new medication is indicated.

If you are a parent of a child with ADHD or an adult with ADHD, this trial-and-error approach can be frustrating. But don't lose hope. In the end, most ADHD patients find a dose and a medication that works for them. Last but not least, when medication leads to a partial response, even after adjusting doses and trying different medication types, doctors should consider referring the patient for a non-pharmacologic ADHD treatment.

You can read details about these in my other blogs, but here the main point is to find an evidence-based treatment. For children, the biggest evidence base is for behavioral family therapy. For adults, cognitive behavior therapy (CBT) is the best choice.  Except for preschoolers, the experts I worked with on this infographic did not recommend these therapies before medication treatment. The reason is that the medications are much more effective, and many non-pharmacologic treatments (such as CBT) have no data indicating they work well in the absence of medication.

We know from many studies that ADHD is associated with a slightly lower intelligence quotient (IQ) and with problems in thinking known as executive function deficits. If that's the case, you might think that people with a high IQ cannot have ADHD.  You would be wrong. Data on groups sometimes mislead us about individuals. Although on average, ADHD people have IQ scores that are about 9 points lower than others, there is a wide spread of IQs in both ADHD and non-ADHD people. So many people with ADHD have higher IQs than those without ADHD and vice-versa. Moreover, studies of people with high IQs support the idea that ADHD can be validly diagnosed among very intelligent individuals.

A series of studies using Antshel and colleagues showed that the clinical profile of high IQ ADHD was very similar to what has been observed for ADHD in general. For example, like their less intelligent counterparts, high IQ ADHD children have an increased risk for mood, anxiety, and disruptive behavior disorders. Children with a high IQ and ADHD showed a pattern of familial transmission as well as cognitive, psychiatric, and behavioral impairments consistent with the diagnosis of ADHD. The degree to which ADHD persisted into adulthood was also similar between the two groups.

In studies of adults with ADHD, the same group concluded that "adults with ADHD and a high IQ display patterns of functional impairments, familiarity and psychiatric co-morbidities that parallel those found in the average-IQ adult ADHD population." Of particular interest, despite their high intelligence, High-IQ adults with ADHD show impaired executive functioning, and their performance on tests of executive functioning predicted life impairments.

Why are these data important? Milioni and colleagues argue that among higher IQ adults with ADHD, a higher degree of intellectual efficiency may compensate for deficits in executive functions. This ability to compensate allows them to succeed in many tasks, which otherwise might have been impaired by their ADHD symptoms. But, in many cases, such compensation is not sufficient or is too burdensome. When compensation fails, ADHD symptoms and other impairments emerge. When this occurs later in life, some clinicians are reluctant to diagnose ADHD. Caution is warranted, but clinicians need to know that the diagnosis of ADHD among high IQ is valid.