Mechanism of action moment
Why does adrenergic alpha-2 receptor agonism treat ADHD symptoms?
Stimulating presynaptic alpha-2 receptors in the LC, with the use of approved antihypertensive medications within this pharmacological family of medicines (e.g., guanfacine [Tenex] and clonidine [Catapres]), dampens adrenergic tone by reducing NE release, and thus causes a lowering of blood pressure
Dampening of peripheral sympathetic, noradrenergic tone makes sense from an anxiolytic point of view in that palpitations, diaphoresis, tremulousness are driven by the sympathetic nervous system and diminished by certain antihypertensives
– However, this mechanism may not explain how these drugs treat ADHD, where good cortical noradrenergic tone is actually needed to treat ADHD symptoms
The slow-release preparations of these medications are now approved for childhood ADHD (e.g., guanfacine-ER [Intuniv] and clonidine-ER [Kapvay])
– When prescribed for ADHD, they hypothetically stimulate postsynaptic alpha-2 receptors on cortical glutamate pyramidal neurons, instead of those located presynaptically in brainstem regulatory centers that control blood pressure
– Centrally in the DLPFC, these noradrenergic agonist drugs hypothetically affect postsynaptic cortical heteroreceptors in that they bind to alpha-2 NE heteroreceptors located upon glutamate neurons
Alpha-2 adrenergic receptors
– Are present throughout the CNS, including the prefrontal cortex, but do not have high concentrations in the nucleus accumbens
– In particular, are believed to mediate the inattentive, hyperactive, and impulsive symptoms of ADHD, while other alpha-2 adrenergic receptors may have other functions
Clonidine is an alpha-2 adrenergic receptor agonist that is non-selective, and binds to alpha-2a, -2b, and -2c receptors
– It also binds to imidazoline receptors, which contribute to its more sedating and hypotensive effects as well
– Although clonidine’s actions at alpha-2a receptors make it a therapeutic option for ADHD, its actions at other receptors may increase side effects
– The slower-release preparation of clonidine (Kapvay) is approved for ADHD, keeping drug plasma levels lower and helping mitigate these side effects
Guanfacine-ER (Intuniv) is a more selective alpha-2a receptor agonist, and thus has therapeutic efficacy with a reduced side-effect profile as it does not stimulate the alpha-2b and -2c receptors as much as clonidine products do
In Figure 21.2A, a DLPFC glutamate pyramidal neuron is depicted
Situated on this neuron’s spine is an alpha-2a adrenergic heteroreceptor and a D1 dopaminergic receptor
These are both connected via cAMP to cation channels called HCN channels
If DA and NE act in concert and are in balance, binding their respective receptors, then the HCN channels are opened to the appropriate size allowing the pyramidal glutamate neuron to fire efficiently – not too much and not too little
If millions of these cortical neurons fire efficiently and in synchrony, adequate attention and concentration theoretically occur
In ADHD, patients may have an imbalance in this cortical system, which allows inefficient processing with subsequent inattention
In situations such as those with inattention due to ADHD, or even anxiety, these HCN channels may be out of balance
In Figure 21.2B, endogenous NE may bind to an alpha-2a heteroreceptor and this will in turn close down its associated HCN channel
– This allows the glutamate pyramidal neuron to retain some of its internal electrical signal (it maintains or improves its signal to noise ratio) and to become focused on its own firing
– If this occurs, in millions of these neurons, the DLPFC may become more efficient and allow for better focus and concentration symptomatically
It is at these alpha-2a receptor sites where ADHD medications such as clonidine-ER and guanfacine-ER may exert their anti-ADHD mechanism of action
Figure 21.1. Mechanism of action of alpha-2a agonists guanfacine and clonidine.
Figure 21.2. The pyradimal glutamate neuron: structure and mechanism of action of receptors.
Two-minute tutorial
Using antihypertensives in psychiatric practice
Clinicians have to be aware and competent in their use
– This may be achieved by reading each drug’s approved package insert or by reviewing relative prescribing textbooks
All antihypertensives are antihypertensive; therefore, a key therapeutic effect in patients with elevated blood pressure includes a lowering of the problematic blood pressure
– However, in psychiatric care, many of our patients treated with antihypertensives are actually normotensive, so that lowering their blood pressure may not be desired
A standard of care likely should involve routine blood pressure monitoring in the office setting of the psychopharmacologist because
– Many of our antidepressant medications that elevate NE may increase blood pressure
– Many of our medications that increase weight gain may increase blood pressure
– Many of our medications that antagonize alpha-2a or alpha-1 receptors may lower blood pressure
These three things likely encompass most prescribing practices, and therefore, should drive better use of blood pressure monitoring
Clinical pearls should include
In those patients who are normotensive, provide adequate informed consent and start at low doses of the antihypertensive drug being used
Warn of common side effects: lightheadedness, dizziness, orthostasis, and syncope
Suggest patients start treatment on a day where they can afford to lie down and not drive, if they need to combat fatigue or hypotensive side effects
Initially suggest patients also increase fluids and salts if these side effects occur
Start at a lower than normal dose when compared to patients suffering from essential HTN, and titrate more slowly to avoid side effects
Consider teaching the patient to self-monitor at home with a commercially available automated blood pressure cuff/system
A win–win scenario may occur if the patient is hypertensive from an idiopathic or iatrogenic point of view
– For example, if the patient becomes hypertensive on an SNRI (iatrogenic) or comes to your practice with essential HTN (idiopathic), then use of an antihypertensive becomes warranted for the HTN and for their ADHD, insomnia, or anxiety
– Clinicians, in these cases, may treat HTN and psychiatric symptoms simultaneously
Posttest self-assessment question and answer
How does an alpha-2a receptor agonist really improve attention?
A. It lowers NE output similar to its antihypertensive effects
B. It promotes DA activity in the DLPFC secondarily
C. It lowers GABA activity, which allows greater glutamate activity in the thalamus
D. It allows fine tuning of cortical pyramidal glutamate neurons to improve signal to noise ratios in cortical information processing
Answer: D
As depicted in the figures in this case, specifically for inattention symptoms, these antihypertensive, alpha-2 noradrenergic receptor agonists act upon heteroreceptors. They modulate glutamate pyramidal neurons originating in the frontal cortex. In synchrony with other pyramidal neurons, alpha-2 receptor agonists improve signal to noise ratios and may fine tune neuronal firing, thus improving attention and concentration. Lowering NE tone for HTN reasons would not help attention. This is a separate mechanism of action. Alpha-2 agonists do not promote DA activity; rather they act in concert with endogenous DA activity, which occurs at the D1 receptor also situated on glutamate neurons. The alpha-2 agonists do not manipulate GABA in order to modulate glutamate neurons.
References
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2.Jensen PS, Hinshaw SP, Kraemer HC, et al. Bottom of form ADHD comorbidity findings from the MTA study: comparing comorbid subgroups. J Am Acad Child Adolesc Psychiatry 2001; 40:147–58.
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Patient file
The Case:
This one’s too hot, this one’s too cold…this one is just right
The Question:
What to do when patients cannot tolerate low-dose atypical antipsychotics
The Dilemma:
Activation or sedation, not sure what you are going to get when taking the atypical antipsychotics
Pretest self-assessment question (answer at the end of the case)
In which of the following clinical situations is ECT felt to be robustly effective?
A. MDD with psychotic features
B. MDD
C. OCD
D. Schizophrenia
E. A and B
F. A, B, and C
G. All of the above
H. None of the above