How do Stimulants Modulate the Brain to Improve ADHD Symptoms?

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 decade, relatively little is known about the mechanisms of action that lead to their therapeutic effect.    New data about 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 are 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 are 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.



Rubia, K., Alegria, A. A., Cubillo, A. I., Smith, A. B., Brammer, M. J. & Radua, J. (2014). Effects of stimulants on brain function in attention-deficit/hyperactivity disorder: a systematic review and meta-analysis. Biol Psychiatry 76, 616-28.


Is Cognitive Behavior Therapy Effective for Treating Adult ADHD?

By Stephen V. Faraone, PhD

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.


Young, Z., Moghaddam, N. & Tickle, A. (2016). The Efficacy of Cognitive Behavioral Therapy for Adults With ADHD: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. J Atten Disord.


Can ADHD be a Deadly Disorder?

Can ADHD be a Deadly Disorder?

By: Stephen V. Faraone, Ph.D.

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 include 1.92 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 in increase the risk for accidents and injuries.   For example, adults who are distracted while driving are clearly at risk for accidents.  In fact, 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 subsequent to the onset of symptoms.   The risk for early death increased with the age at diagnosis.  This suggests that failing to diagnoses 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.   Policy makers should allocate to 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 evidenced-based treatments for the disorder.


Dalsgaard, S., Ostergaard, S. D., Leckman, J. F., Mortensen, P. B. & Pedersen, M. G. (2015). Mortality in children, adolescents, and adults with attention deficit hyperactivity disorder: a nationwide cohort study. Lancet.

Vaa T. ADHD and relative risk of accidents in road traffic: a meta-analysis. Accident; analysis and prevention. 2014; 62: 415-25.

Adeyemo BO, Biederman J, Zafonte R, Kagan E, Spencer TJ, Uchida M, et al. Mild Traumatic Brain Injury and ADHD: A Systematic Review of the Literature and Meta-Analysis. J Atten Disord. 2014; 18(7): 576-84.

Cortese S, Faraone SV, Bernardi S, Wang S, Blanco C. Adult attention-deficit hyperactivity disorder and obesity: epidemiological study. Br J Psychiatry. 2013; 203: 24-34.

Spencer TS, Faraone SV, Tarko L, McDermott K, Biederman J. ADHD and Adverse Health Outcomes in Adults: Results from a Large Controlled Study. 2013.

Faraone SV. The scientific foundation for understanding attention-deficit/hyperactivity disorder as a valid psychiatric disorder. Eur Child Adolesc Psychiatry. 2005; 14: 1-10.

ADHD and the Risk for Suicide

Suicide is one of the most feared outcomes of any psychiatric condition.  Although its association with depression is well known, a small but growing research literature shows that ADHD is also a risk factor for suicidality.   Suicide is difficult to study. Because it is relatively rare, large samples of patients are needed to make definitive statements.  Studies of suicide and ADHD must also consider the possibility that medications might elevate that risk.  For example, the FDA placed a black box warning on atomoxetine because that ADHD medication had been shown to increase suicidal risk in youth.   A recent study of 37,936 patients with ADHD now provides much insight into these issues (Chen, Q., Sjolander, A., Runeson, B., D’Onofrio, B. M., Lichtenstein, P. & Larsson, H. (2014). Drug treatment for attention-deficit/hyperactivity disorder and suicidal behavior: register based study. BMJ 348, g3769.).    In Sweden, such large studies are possible because researchers have computerized medical registers that describe the disorders and treatments of all people in Sweden.  Among 37,936 patients with ADHD, 7019 suicide attempts or completed suicides occurred during 150,721 person years of follow-up.  This indicates that, in any given year, the risk for a suicidal event is about 5%.  For ADHD patients, the risk for a suicide event is about 30% greater than for non-ADHD patients.  Among the ADHD patients who attempted or completed suicide, the risk was increased for those who had also been diagnosed with a mood disorder, conduct disorder, substance abuse or borderline personality.  This is not surprising; the most serious and complicated cases of ADHD are those that have the greatest risk for suicidal events.  The effects of medication were less clear.   The risk for suicide events was greater for ADHD patients who had been treated with non-stimulant medication compared with those who had not been treated with non-stimulant medication.  A similar comparison showed no effect of stimulant medications.  This first analysis suffers from the fact that the probability of receiving medication increases with the severity of the disorder.  To address this problem, the researchers limited the analyses to ADHD patients who had had some medication treatment and then compared suicidal risk between periods of medication treatment and periods of no medication treatment.  This analysis found no increased risk for suicide from non-stimulant medications and, more importantly, found that for patients treated with stimulants, the risk for suicide was lower when they were taking stimulant medications.  This protective effect of stimulant medication provides further evidence of the long-term effects of stimulant medications which have also been shown to lower the risks for traffic accidents, criminality, smoking and other substance use disorders.

ADHD and Emotional Dysregulation

ADHD and Emotional Dysregulation

By Stephen V. Faraone, PhD

One of the many great contributions of Dr. Russell Barkley was his conceptualization of ADHD as a disorder of self-regulation.   ADHD people have difficulties regulating their behavior, which lead to the classic diagnostic criteria of hyperactivity and impulsivity and they have problem regulating cognitive processes which leads to the well-known inattentive diagnostic criteria for the disorder.    In a 2010 paper, Dr. Barkley argued persuasively that deficient emotional self-regulation should also be considered a core component of ADHD alongside deficient behavioral and cognitive self-regulation.  Although the DSM 5 did not add any emotional symptoms to the revised criteria for ADHD a new paper by Graziano and Garcia supports Dr. Barkley’s position.   They conducted a meta-analysis of 77 studies of emotional dysregulation that comprised a total of 32,044 participants.  They defined emotional dysregulation as the failure to modify emotional states in a manner that promotes adaptive behavior and leads to the success of goal directed activities.  They identified three types of emotional dysregulation: emotion recognition and understanding (ERU), emotional reactivity/negativity/lability (ERNL) and empathy/callous-unemotional traits (ECUT).   ERU refers to the ability to perceive, process and infer one’s own emotions and the emotions of others.  ERNL refers to the intensity and valence of the emotional response.  Reactivity refers to the rapidity of the emotional response (e.g., is a person quick tempered rather than reflective); negativity refers to the valence of the emotion.  Is it extreme or appropriate to the situation; and lability refers to how quickly emotional states shift or cycle over time.  The ECUT dimension has two poles.  At one extreme is the empathic person whose reactions are guided by a clear understanding of the emotional states of others.  At the other pole is the psychopath who shows little or no emotion to stimuli that evoke strong emotional reactions in the average person.    When the data from the 77 studies was sorted into these three categories, the authors found that ADHD people had impairments in all three domains.   The magnitude of impairment was a bit greater for ERNL than it was for ECUT and ERU, but not dramatically so.  The association between ADHD and these domains of emotional dysregulation increased with increasing age.  It is for this reason that some ADHD experts think that emotional dysregulation should be included in the diagnostic criteria for adult ADHD.  Because behavioral hyperactivity diminishes with age, these criteria are less sensitive for adult ADHD than they are for child ADHD.  Substituting emotional dysregulation items for hyperactivity items could, potentially, improve diagnoses of adult ADHD.  Future work will address this issue.  In the meanwhile, those who screen and diagnose adult ADHD should be aware that symptoms of emotional dysregulation might be the most prominent for some adults with the disorder.


Barkley, R. A. (2010). Deficient Emotional Self-Regulation: A Core Component of Attention-Deficit/Hyperactivity Disorder. Journal of ADHD and Related Disorders 1, 5-37.


Graziano, P. A. & Garcia, A. (2016). Attention-deficit hyperactivity disorder and children’s emotion dysregulation: A meta-analysis. Clin Psychol Rev 46, 106-23.