Stephen V Faraone PhD AIA 2016 tatAj0

A recent CNN report, http://tinyurl.com/yannlfd6, highlighted a paper published in Pediatrics, which reported that pregnant women who use acetaminophen during pregnancy put their unborn child at two-fold increased risk for attention deficit hyperactivity disorder (ADHD).   In that study, acetaminophen use during pregnancy was common; nearly half of women surveyed used the painkiller during a pregnancy.   Other studies have reported similar associations of acetaminophen, also known as paracetamol with ADHD or with other problems in childhood (e.g., https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5300094/, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4177119/, https://www.ncbi.nlm.nih.gov/pubmed/24566677, https://www.ncbi.nlm.nih.gov/pubmed/24163279). Given these prior findings, it seems unlikely that the new report is a chance finding. But does it make any biological sense?   One answer to that question came from an epigenetic study. Such studies figure out if assaults from the environment change the genetic code. One epigenetic study found that prenatal exposure, changes the fetal genome via a process called methylation. Such genomic changes could increase risk for ADHD (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5540511/)/ . Because all of these studies are observational studies, one cannot assert with certainty that there is a causal link between acetaminophen use during pregnancy. The observed association could be due to some unmeasured third factor. Although the researchers did a respectable job ruling out some third factors, we must acknowledge some uncertainty in the finding. That said, what should pregnant women do if they need a acetaminophen.   I suggest you bring this information to your physician and ask if there is a suitable alternative.

Stephen_Faraone_PhD_ADHD_in_Adults
In the popular media, ADHD is sometimes portrayed as a minor condition or not a disorder at all.   In fact, it is easy to find web sites claiming that ADHD is an invention of the medical profession and that the symptoms used to diagnose the disorder are simply normal behaviors that have been “medicalized”.   These claims are wrong.  They miss the main point of any psychiatric diagnostic process which is to identify people who experience distress or disability due to a set of well-defined symptoms.  So, does ADHD cause serious distress and disability?   It is a serious psychiatric condition?  To illustrate the strong evidence base for the “Yes” answer to that question, my colleagues and I constructed this infographic for our “Primer” about ADHD,
http://rdcu.be/gYyV.   It describes the many ways in which the symptoms of ADHD impact and impair the lives of children, adolescents and adults with the disorder.  We divided these ‘impacts’ into four categories: other disorders (both psychiatric and medical), psychological dysfunction, academic and occupational failure, social disability and risky behaviors.  Let’s start with other health problems.  We know from many studies that have followed ADHD children into adolescence and adulthood that having the disorder puts patients at risk for several psychiatric disorders, addictions, criminality, learning disabilities and speech/language disorders. ADHD even increases the risk for non-psychiatric disease such as obesity, hypertension and diabetes.  Perhaps most worrisome is that people with ADHD have a small increased risk for premature death.  This increased risk is due in part to their having other psychiatric and medical conditions and also to their risky behaviors which, as research documents, lead to accidents and traumatic brain injuries.   In the category of ‘psychological dysfunction’ we highlighted emotional dysregulation, which makes ADHD people quick to anger or to fail to tame extreme emotions.  Other serious psychological issues are low self-esteem and increased thoughts of suicide, which lead to more suicide attempts than for people without ADHD.  This increased risk for suicide is small, but it is real.    A more prevalent impact of ADHD is the broad category of social disability, which includes marital discord, poor parenting, legal problems, arrests and incarceration.   This typical starts in youth with poor social adjustment and conflict with parents, siblings and friends.  Another common impact of ADHD is on academic and vocational pursuits.  ADHD youth are at risk for underachievement in school, repeating grades and dropping out.  As adults, they are more likely to unemployed or underemployed, which leads to them having lower incomes than expected for their level of achievement in school.   So, don’t believe anyone who claims that ADHD is not a disorder or is only a mild one.   To be sure, there is a wide range of impairment among people with ADHD but, in the absence of treatment, they are at risk for adverse outcomes.  Fortunately, the medications that treat ADHD have been documented to reduce this risk, which is why they are typically the first line treatment for most people with ADHD.

REFERENCE

Faraone, S. V. et al. (2015) Attention-deficit/hyperactivity disorder Nat. Rev. Dis. Primers doi:10.1038/nrdp.2015.20 ;  http://rdcu.be/gYyV

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Stephen_Faraone_PhD_ADHD_in_Adults

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 rule of thumb 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 prior to 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 of 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 provide 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 taken 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 for here the main point is to find an evidenced-based treatment.  For children the biggest evidence base is for behavioral family therapy.  For adults, cognitive behavior therapy (CBT) is the best choice.   With the exception of 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.  

REFERENCE
Faraone, S. V. et al. (2015) Attention-deficit/hyperactivity disorder Nat. Rev. Dis. Primers doi:10.1038/nrdp.2015.20 ;  http://rdcu.be/gYyV

Stephen_Faraone_PhD_ADHD_in_Adults

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 rule of thumb 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 prior to 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 of 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 provide 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 taken 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 for here the main point is to find an evidenced-based treatment.  For children the biggest evidence base is for behavioral family therapy.  For adults, cognitive behavior therapy (CBT) is the best choice.   With the exception of 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.  

REFERENCE

Faraone, S. V. et al. (2015) Attention-deficit/hyperactivity disorder Nat. Rev. Dis. Primers doi:10.1038/nrdp.2015.20 ;  http://rdcu.be/gYyV

Stephen V. Faraone, PhD - ADHD in Adults


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 evidenced-based treatment.  The infographic below gives a summary of this diagnostic approach over time, which my colleagues and I prepared for our “Primer” about ADHD, referenced below.

.   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 Organizations 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.

REFERENCE

Faraone, S. V. et al. (2015) Attention-deficit/hyperactivity disorder Nat. Rev. Dis. Primers doi:10.1038/nrdp.2015.20 ;  http://rdcu.be/gYyV

 

Stephen_Faraone_PhD_ADHD_in_Adults
Although ADHD was conceived as a childhood disorder, we now know that many cases persist into adulthood.  My colleagues and I charted the progression of ADHD through childhood, adolescence and adulthood in our “Primer” about ADHD,
http://rdcu.be/gYyV.   Although the lifetime course of ADHD varies among adults with the disorder, there are many consistent themes, which we described in the accompanying infographic.   Most cases of ADHD start in utero, before the child is born.  As a fetus, the future ADHD person carries versions of genes that increase risk for the disorder.  At the same time they are exposed to toxic environments.  These genetic and environmental risks change the developing brain, setting the foundation for the future emergence of ADHD.  In preschool early signs of ADHD are seen in emotional lability, hyperactivity, disinhibited behavior and speech, language and coordination problems.  The full blown ADHD syndrome typically occurs in early childhood but can be delayed until adolescence.   In some cases, the future ADHD person is temporarily protected from the emergence of ADHD due to factors such as high intelligences or especially supportive family and/or school environments.  But as the challenges of life increase, this social, emotional and intellectual scaffolding is no longer sufficient to control the emergence of disabling ADHD symptoms.  Throughout childhood and adolescence the emergence and persistence of the disorder is regulated by additional environmental risk factors such as family chaos along with the age dependent expression of risk genes that exert different effects at different stages of development.  During adolescence, most cases of ADHD persist and by the teenage years, many youth with ADHD have onset with a mood, anxiety or substance use disorder.   Indeed, it is essential for parents and clinicians to monitor ADHD youth for early signs of these disorders.  Prompt treatment can prevent years of distress and disability.  By adulthood, the number of comorbid conditions has increased, including obesity, which likely has effects of future medical outcomes.   The ADHD adult tends to be very inattentive by shows fewer symptoms of hyperactivity and impulsivity.  They remain at risk for substance abuse, low self-esteem, occupational failure and social disability, especially if they are not treated for the disorder.   Fortunately, there are several classes of medicine available to treat ADHD that have been shown to be safe and effective.  And the effects of these medications are enhanced by cognitive behavior therapy as I’ve written about in prior blogs.

REFERENCE

Faraone, S. V. et al. (2015) Attention-deficit/hyperactivity disorder Nat. Rev. Dis. Primers doi:10.1038/nrdp.2015.20 ;  http://rdcu.be/gYyV

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The Journal of Attention Disorders has published two papers about a new formulation of mixed amphetamine salts that uses a triple bead technology (MAS-TB). This technology allows for a delayed release of the medication and enables a duration of effect up to sixteen hours.

This 16-hour effect is significantly higher than existing stimulant medications which on average last for 8-10 hours. This new formulation is based on patient desire to experience beneficial medication effects from morning through evening.

Previously, Spencer et al. (https://www.ncbi.nlm.nih.gov/pubmed/19012813) reported a 7-week, randomized, double-blind, multicenter, placebo-controlled, parallel-group, dose-optimization study of 272 adults with ADHD.   They found that MAS-TB significantly reduced ADHD symptoms, behavioral measures of executive dysfunction and increased quality of life ratings. (Other studies have confirmed the benefit of select medications not only for ADHD symptoms, but for executive dysfunctions as well, although no ADHD medications treat executive dysfunction as well as they treat ADHD.)

An assessment of ADHD symptoms 13 to 16 hours post-dose confirmed the duration of action. The first new paper by Frick et al. (https://www.ncbi.nlm.nih.gov/pubmed/28413925) reported a 6 week, randomized controlled study comparing MAS-TB with placebo.   As with the prior study, MAS-TB significantly reduced ADHD symptoms. Mean ± SD pulse and systolic blood pressure increases at end of study were 3.5 ± 10.33 bpm and 0.3 ± 10.48 mmHg, which are medically non-consequential.  

In the second new study, Adler et al. (https://www.ncbi.nlm.nih.gov/pubmed/28412886) reported a long-term, open-label, safety study of MAS-TB in adults with ADHD. Of 505 enrolled participants, 266 completed the study.   Study discontinuation was more likely for patients taking higher (37.5-75 mg) vs. lower doses (12.5 and 25 mg). Blood pressure and pulse increases were observed at end-of-study. ADHD symptoms decreased modestly during the follow-up period.

The most frequently reported treatment emergent adverse events in both studies were insomnia, decreased appetite, and dry mouth. These observed side effects are similar to those seen for other stimulant medications, and are typically well managed by physicians when they occur by adjusting the dose or changing medications.

Stephen_Faraone_PhD_ADHD_in_Adults

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, http://rdcu.be/gYyV.   As you can see from The Figure, 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.  As you can see from the Figure, 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 of 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.

REFERENCE

Faraone, S. V. et al. (2015) Attention-deficit/hyperactivity disorder Nat. Rev. Dis. Primers doi:10.1038/nrdp.2015.20 ;  http://rdcu.be/gYyV

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Stephen_Faraone_PhD_ADHD_in_Adults

Eight Pictures Describe Brain Mechanisms in ADHD

When my colleagues and I wrote our “Primer” about ADHD, http://rdcu.be/gYyV, the topic of brain mechanisms was a top priority.   Because so much has been written about the ADHD brain, it is difficult to summarize.   Yet we did it with the eight pictures reproduce here in one Figure.   A quick overview of this Figure shows you the complexity of ADHD’s pathophysiology.  There is no single brain region or neural circuit that is affected.   Figures (a) and (b) show you the main regions implicated by structural and functional neuroimaging studies.  As (c) shows, these regions are united by neural networks rich in noradrenalin (aka, norepinephrine) and dopamine, two neurotransmitters whose activity is regulated by medications that treat ADHD.  Figure (d) describes two functional networks.   The Executive Control network is, perhaps, the best described network in ADHD.  This network regulates behavior by linking dorsal striatum with the dorsolateral prefrontal cortex.  This network is essential for inhibitory control, self-regulation, working memory and attention.  The Corticocerebellar network is a well-known regulator of complex motor skills.  Data also suggest it play a role in the regulation of cognitive functions.   Figure (d) describes the Reward Networks of the brain that link ventral striatum with prefrontal cortex.   This network regulates how we experience and value rewards and punishments.   In addition to its involvement in ADHD, this network has also been implicated in substance use disorders, for which ADHD persons are at high risk. Figures (f) (g) and (h) complete the puzzle with additional regions implicated in ADHD whose role is less well understood.  One role for these regions is in the regulation of the Default Mode Network, which controls what the brain does when it is not focused on any specific task (e.g., daydreaming, mind wandering).  People differ in the degree to which they shift between the default mode network and networks like Reward or Executive Control, which are active when we engage the world.  Recent data suggest that the brains of ADHD people may be in ‘default mode’ when they ought to be engaged in the world.    

REFERENCE

Faraone, S. V. et al. (2015) Attention-deficit/hyperactivity disorder Nat. Rev. Dis. Primers doi:10.1038/nrdp.2015.20 ;  http://rdcu.be/gYyV

Faraone 8 Brain Images

http://medicalwritingtraining.com/With the growth of the Internet, we are flooded with information about attention deficit hyperactivity disorder from many sources, most of which aim to provide useful and compelling “facts” about the disorder. But, for the cautious reader, separating fact from opinion can be difficult when writers have not spelled out how they have come to decide that the information they present is factual.

My blogs several guidelines to reassure readers that the information they read about ADHD is up-to-date and dependable. They are as follows:
Nearly all the information presented is based on peer-reviewed publications in the scientific literature about ADHD. “Peer-reviewed” means that other scientists read the article and made suggestions for changes and approved that it was of sufficient quality for publication. I say “nearly all” because in some cases I’ve used books or other information published by colleagues who have a reputation for high quality science.

When expressing certainty about putative facts, I am guided by the principles of evidenced based medicine, which recognizes that the degree to which we can be certain about the truth of scientific statements depends on several features of the scientific papers used to justify the statements such as the number of studies available and the quality of the individual studies. For example, compare these two types of studies. One study gives drug X to 10 ADHD patients and reports that 7 improved. Another gave drug Y to 100 patients and a placebo to 100 other patients and used statistics to show that the rate of improvement was significantly greater in the drug treated group. The second study is much better and much larger, so we should be more confident in its conclusions. The rules of evidence are fairly complex and can be viewed at the Oxford Center for Evidenced Based Medicine (OCEBM; http://www.cebm.net/).

The evidenced-based approach incorporates two types of information: a) the quality of the evidence and b) the magnitude of the treatment effect. The OCEBM levels of evidence quality are defined as follows (higher numbers are better:

  1. Mechanism based reasoning.   For example, some data suggest that oxidative stress leads to ADHD and we know that omega-3 fatty acids reduce oxidative stress.  So there is a reasonable mechanism whereby omega-3 therapy might help ADHD people.
  2. Studies of one or a few people without a control group or studies that compare treated patients to those that were not treated in the past.
  3. Non-randomized, controlled studies.    In these studies the treatment group is compared to a group that receives a placebo treatment, which is a fake treatment not expected to work.   Non-randomized means that the comparison might be confounded by having placed different types of patients in the treatment and control groups.
  4. Single randomized trial.   This type of study is not confounded.
  5. Systematic review and meta-analysis of randomized trials.  This means that many randomized trials have been completed and someone has combined them to reach a more accurate conclusion.

It is possible to have high quality evidence proving that a treatment ‘works’ but the treatment might not work very well.  So it is important to consider the magnitude of the treatment effect, also called the “effect size” by statisticians.  For ADHD, it is easiest to think about ranking treatments on a ten point scale.   The stimulant medications have a quality rating of 5 and also have the strongest magnitude of effect, about 9 or 10.  Omega-3 fatty acid supplementation ‘works’ with a quality rating of 5, but the score for magnitude of effect is only 2 so it doesn’t work very well.  We have to take into account patient or parent preferences, comorbid conditions, prior response to treatment and other issues when choosing a treatment for a specific patient, but we can only use an evidenced-based approach when deciding which treatments are well supported as helpful for a disorder.