In our last article, we discussed ADHD and the mechanism of action of stimulants, the first-line medications for ADHD. In this, the second part of the ADHD discussion, we will be focusing on two more options for ADHD treatment: the group of medications known as “alpha-2 agonists” (specifically guanfacine and clonidine), as well as the medication atomoxetine (or Strattera). These are considered the second-line medications for ADHD primarily due to their lower average effectiveness compared to the stimulants (50-60% vs 80%).
First, a quick recap of the neurophysiological underpinnings of ADHD: As discussed in Part I, the current understanding is that ADHD symptoms are primarily due to an imbalance of two neurotransmitters, norepinephrine and dopamine, in an area called the prefrontal cortex (PFC). Unsurprisingly, alpha-2 agonists and atomoxetine also target neurotransmitter activity in the PFC, however unlike stimulants which work through alterations of both norepinephrine and dopamine, these medications work primarily through their actions on norepinephrine.
Alpha-2 Agonists:
The two “alpha-2 agonist” medications used for ADHD are clonidine and guanfacine. To start, it is important to define the term “agonist”. Simply, this means that the medication causes a similar action as a neurotransmitter or hormone when it binds/acts on a specific receptor. Clonidine and guanfacine exert this “agonist” activity at the alpha-2 family of receptors throughout the brain and body, with the alpha-2A subtype (plentiful in the PFC) being the most pertinent to their effects in ADHD. This activity leads to increases in norepinephrine, which (as discussed previously), helps to correct the imbalance of norepinephrine we see in ADHD and strengthen the networks responsible for attention, focus, and modulating behavior.
One significant difference between these two medications is that guanfacine is more selective and clonidine for the alpha-2A receptor subtype. This selectivity appears to be most impactful in their respective side effect profiles. While they have relatively the same list of side effects, guanfacine’s receptor selectivity leads to it carrying a moderately less risk of experiencing these unwanted effects including (most commonly) decreases in heart rate and blood pressure, dizziness and syncope drowsiness/fatigue, increased appetite, dry mouth, and stomach upset. It is worth noting that these effects are generally manageable and tend to diminish over time.
Atomoxetine:
Atomoxetine (or Strattera) is the last medication commonly prescribed for ADHD, and it also exerts its effects through its action on norepinephrine in the prefrontal cortex. Specifically, atomoxetine is a “selective norepinephrine reuptake inhibitor”. Atomoxetine works by binding to and blocking the pumps that “recycle” norepinephrine (and to a much lesser extent dopamine). This leads to increases in the amount of norepinephrine available in the PFC, resulting in downstream effects that help to correct the imbalance of norepinephrine (and dopamine) we see in ADHD. One important difference between atomoxetine and the other ADHD medications (stimulants, alpha-2 agonists) is that it often takes longer (weeks vs days) to experience the effect of the medication, similar to the SSRI class of medications used for depression and anxiety (which also act as “reuptake inhibitors”).
Similar to alpha-agonists, atomoxetine can also cause side effects through its alteration of norepinephrine in the prefrontal cortex, brain, and body. These include drowsiness/fatigue (worse in children), decreased appetite, increased HR and BP (limited clinical significance), dizziness, insomnia, increased anxiety, nausea, constipation, urinary hesitancy/retention, and dry mouth.
As always, please speak to your psychiatrist when considering any medication to assess if and how they could be part of your (or your loved one’s) mental health treatment. In the next installment of Psychopharm Made (More) Simple, we will begin a discussion of medications used to treat depression.
