Archive for the ‘AD/HD’ Category

The Treatment of ADHD: ADDenda

The Treatment of ADHD:  ADDenda

I can’t resist adding some extra ideas to Dr. Plyler’s review of Amy Arnsten’s article, Catecholamine Influences on Dorsolateral Prefrontal Networks 1.  As he indicated, ADHD is one of the conditions on which we focus in this practice.   Dr. Arnsten’s paper made several points that deserve special emphasis.

1. The neurochemical control of the DLPFC (that part of the frontal cortex mediating control of attention, response inhibition, and working memory – the neuropsychological capacities whose impairment generates the classic symptoms of ADHD) under normal conditions is exquisitely calibrated to environmental demands and internal reserves.  Put differently, the regulatory actions of our DLPFC are adjusted on an almost second to second basis, depending on the immediate cognitive tasks confronting us and our level of stress and fatigue.  This dynamic reality contrasts with the more popular but almost cartoonish view of certain brain regions monolithically carrying out set functions.

2. With this understanding of how the brain (the DLPFC in particular) operates under normal circumstances, a realization is inevitable:  our pharmacotherapeutic efforts at treating ADHD are laughably clumsy and primitive by comparison.  In contrast to the immediate neurochemical changes that cause fine-grained temporal adjustments in DLPFC functioning, our use of medication is bulky and nonspecific.  We do not have the capacity to alter our medications on a second to second basis, nor make quick adjustments in doses depending on the particular challenges facing the individual.  This realization should humble all of us engaged in the therapy of this challenging disorder.  We need a brain-based version of the insulin pump:  a delivery method that can more finely titrate dosing according to environmental demands.

3. This realization has a practical implication for the pharmacotherapy of ADHD:  Customize!  We should tailor our medication efforts to the specifics of each patient’s daily needs and the variability of their needs.   For those with regular daily schedules such as full-time businessmen, stay-at-home moms, or college students, using set doses of long acting stimulants may be the easiest and most effective treatment strategy.  For those with more erratic schedules though, such as part-time students, project-based workers, or parents whose demands ramp up in the morning and the evenings when their kids are home – these patients may benefit from more flexible dosing strategies of their stimulants.  They may also benefit from shorter-acting agents that allow greater therapeutic fine-tuning.  Whichever route is optimal, it should be carefully worked out together as part of the treatment process.

4. Last, ADHD is not only about dopamine.  Arnsten emphasizes the critical and overlooked role of norepinephrine in DLPFC function and impairment.  This leads to a second clinical implication:  Don’t forget about noradrenergic agents in treating ADHD.  Yes, stimulants will hit both dopamine and norepinephrine, but for those who cannot tolerate or those who fail to respond optimally to these agents, we must give more serious consideration to atomoxetine and guanfacine.  In our experience, these noradrenergic medications are under-utilized.


Arnsten, A. F. T. (2011). “Catecholamine influences on dorsolateral prefrontal cortical networks.” Biological Psychiatry 69(12): e89-99.

Fine-Tuning our Understanding of the ADHD Brain

The greater our understanding of an illness state, the better we are able to treat it.  As one of the core disorders in our practice, we constantly review and update our knowledge on ADHD. In the course of a recent review, I came across a wonderful compilation issue on ADHD in Biological Psychiatry (Biol Psychiatry June 15 2011, vol. 69).  The review issue covers a wide range of topics from psychostimulants as cognitive enhancers to the molecular genetics of ADHD.  The most relevant and clinically applicable article, however, was Amy Arnsten’s paper on “Catecholamine Influences on Dorsolateral Prefrontal Cortical Networks” (Biol Psychiatry. 2011 June 15;69(12):e89-99).  She does a masterful job of presenting complex material in a clear and elegant manner.  Dr. Arnsten is able to capture the fluidity and dynamics of cortical functions associated with ADHD while still giving the reader anchor points that are useful in everyday clinical practice.

Dr. Arnsten’s article focuses on the effects of dopamine (DA) and norepinephrine (NE) on the dorsolateral prefrontal cortex (PFC).  This area of the brain has long been associated with executive function and working memory – the two primary problem areas associated with ADHD.  Executive functions are the neuropsychological capacities involved in planning, prioritizing and organizing tasks.  Working memory is the mind’s ability to keep and utilize information in short term storage, like the random access memory on a computer.  Though dopamine was held to be the primary neurotransmitter involved with ADHD, recent evidence has demonstrated that norepinephrine plays a significant role as well.  Working backwards from the evidence that medications used to treat ADHD such as methylphenidate and atomoxetine affect catecholamine (NE and DA) transmission in the PFC, Arnsten honed in on the specific receptors affected by these medications.  In her investigation, she found that the α2A receptor and D1 receptor had particular relevance to ADHD.

Recent studies found that norepinephrine strengthens PFC signaling through post- synaptic stimulation of α2A receptors on PFC neurons.   Conversely, dopamine acts at D1 receptors to decrease the signal to noise ratio by inhibiting stimulation from non-relevant external cues.  They also found that there is a “sweet spot” in the amount of norepinephrine and dopamine being released in the system, i.e. too much or too little markedly impairs PFC function. To break it down to a clinical level – medications such as methylphenidate or atomoxetine affect both norepinephrine and dopamine levels.  Appropriately increased levels of these neurochemicals then cause two actions to treat the symptoms of ADHD.  First, the norepinephrine ramps up signal strength for relevant stimuli through effects on α2A receptors, and second, the dopamine reduces the signal strength of non-relevant stimuli.

How do these ideas translate into the clinical realm?  Let’s imagine a person with ADHD working on a report on the computer.  Suddenly, an email pops up or the phone rings.  Untreated, his/her attention is immediately diverted to the new stimuli and a cascade of distractions ensues.  The report is left half -finished and the person doesn’t get back to it for hours.  Treated with methylphenidate, the non-relevant stimuli of an email pop up or phone call is now recognized but the dopamine working on the D1 receptor keeps that signal strength low, and the norepinephrine targeting the α2A receptor keeps the signal strength high for the report in front of him/her that needs to be finished.  This is referred to as “sculpting” or “spatial tuning” as the signal to noise ratio is kept appropriately calibrated to the task in front of the person that needs to be completed. This flow of dynamic signaling management is one of the hallmarks of executive function that can be so affected by ADHD.

Returning to the theme that greater understanding leads to better treatment, appreciation of the two component nature of attentional “sculpting” or “spatial tuning” enhances our ability to fine tune the treatment of our patient’s ADHD.   Clarifying whether our patient is having trouble with target signal emphasis and/or reducing distractor stimuli enables us to customize and more precisely adjust our medication interventions.  This insight is also useful for patients to better understand their specific challenges with this disorder.

We will continue to stay on top of advances like these in our practice areas of specialization so that we can better educate ourselves and you.


Vyvanse – The New Kid on the Adhd Block.

ADHD is an increasingly recognized disorder and pharmaceutical companies are regularly developing new drugs and new formulations of older drugs in an attempt to gain an increasing share of this lucrative market. Whether the new pharmaceuticals bring actual therapeutic advantage or simply represent new ‘brands’ with similar effectiveness is an ongoing question. Vyvanse (Lisdexamfetamine dimesylate) is the newest arrival on this competitive turf. It was shown to be effective compared to placebo in two clinical trials of children ages 6-12 and in one trial in adults.

Vyvanse is a prodrug formulation of dextroamphetamine. A prodrug is a pharmacological substance (drug) that is administered in an inactive (or significantly less active) form. Once administered, the prodrug is metabolized into an active metabolite. In the case of Vyvanse, this process takes place in the gastrointestinal tract, thus releasing active dextroamphetamine. The active metabolite dextroamphetamine then mediates the therapeutic effect in a fashion similar to other stimulants. Though the mode of therapeutic action in Attention-Deficit/Hyperactivity Disorder (ADHD) is not known, the amphetamines are thought to block the reuptake of norepinephrine and dopamine into the presynaptic neuron and increase the release of these substances in the brain.

Lisdexamfetamine does not produce high dextroamphetamine levels when injected or snorted, and thus may have lower abuse potential compared to conventional stimulants. Vyvanse was developed specifically in this prodrug formulation with the goal of providing an extended duration of effect that is consistent throughout the day, with a reduced potential for abuse, overdose toxicity, and drug tampering. Side effects were consistent with other psychostimulants, and long term monitoring demonstrated no significant changes in blood pressure or electrocardiographic parameters. There have been no comparative studies between Vyvanse and other stimulants, and it’s duration of effectiveness is similar to other long acting stimulant formulations (8-10 hours). The only circumstances that Vyvanse seems to be more useful in treatment over other stimulants are those in which there is a significant abuse potential. With the possibility of this rather slender exception, our verdict on Vyvanse is that it is more of the same: another long-acting stimulant in a field that is growing in size but not diversity. We look forward to different drug development strategies, perhaps those which derive from a more precise molecular genetic understanding of the neurobiology of ADHD, that will one day generate truly novel and improved therapeutic agents for this disorder.