Alpha-2 Agonists for Attention Deficit Hyperactivity Disorder: History
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Contributor:
Elisa E. Neuchat
,
Brooke E. Bocklud
,
Kali Kingsley
,
William T. Barham
,
Patrick M. Luther
,
Shahab Ahmadzadeh
,
Sahar Shekoohi
,
Elyse M. Cornett
,
Alan D. Kaye

Attention Deficit Hyperactivity Disorder (ADHD) is one of the most common neurodevelopmental disorders, characterized by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), which is marked by symptoms such as inappropriate levels of inattention, hyperactivity, and impulsivity that can affect academic, social, and personal functioning in children and adolescents.

  • Alpha-2 agonist
  • attention deficit hyperactivity disorder (ADHD)
  • neurodevelopmental disorder

1. Introduction

Attention deficit hyperactivity disorder (ADHD) is one of the most common mental diseases affecting children and adolescents. The main features of ADHD include difficulty with attention and concentration, impulsivity, and hyperactivity. These symptoms can significantly impact a child’s academic and social functioning [1]. ADHD is diagnosed in childhood and can persist into adulthood. The current standard of care for ADHD includes using stimulant medications, such as methylphenidate and amphetamines, and non-stimulant medications, such as atomoxetine [2]. These medications are effective in decreasing symptoms of ADHD, but they can also have significant side effects [3]. Alpha-2 agonists, such as guanfacine and clonidine, have been studied as a treatment option for ADHD in children. These medications selectively target the Alpha-2 adrenergic receptors in the brain, which can enhance attention and decrease impulsivity and hyperactivity symptoms in children with ADHD. The mechanism of action of Alpha-2 agonists is different from the traditional medications used for ADHD, and it is thought to be more specific and therefore has fewer side effects [3]. Research has shown that Alpha-2 agonists can be effective in decreasing symptoms of ADHD in children. Many studies assessed the efficacy and safety of these medications [4]. For example, a randomized, double-blind, placebo-controlled study conducted in 2013 found that guanfacine extended-release (XR) significantly improved symptoms of ADHD in children aged 6–12 years. Another study conducted in 2018 found that clonidine effectively reduced ADHD symptoms in children aged 6–12 years with comorbid tic disorders [5]. In addition to their efficacy, Alpha-2 agonists may also have advantages over traditional medications for ADHD in terms of their side effect profiles. Stimulant medications, such as methylphenidate and amphetamines, can cause side effects, including insomnia, decreased appetite, and weight loss. Non-stimulant medications like atomoxetine can cause side effects such as nausea, vomiting, and liver toxicity. In contrast, Alpha-2 agonists are generally well-tolerated and have been associated with fewer side effects [6].
Despite the potential benefits of Alpha-2 agonists, their use has some limitations. One of the major restrictions is that they may not be as functional as stimulant medications in treating the core symptoms of ADHD, particularly hyperactivity. Another limitation is that they may cause sedation, which can interfere with academic and social functioning. Also, Alpha-2 agonists may have cardiovascular side effects including reduced blood pressure and heart rate, which require monitoring [7].
Recent studies have explained that ADHD is not a homogeneous disorder, and there is considerable variability in treatment response among individuals [8]. Genetic variations, comorbidities, and environmental influences may play a role in treatment outcomes [9]. Therefore, identifying predictors of treatment response and individualizing treatment plans for each patient may improve treatment efficacy and reduce adverse effects. Additionally, the optimal dosing and duration of treatment with Alpha-2 agonists in children with ADHD remain unclear. Future studies should address these knowledge gaps to provide more personalized and effective treatment for children with ADHD. By investigating the efficacy and safety of Alpha-2 agonists and identifying factors that influence treatment response, we can advance our understanding of this complex disorder and provide better care for children and adolescents with ADHD.
Overall, Alpha-2 agonists have emerged as a promising treatment option for ADHD in children. They have a different action mechanism than traditional medications and may have fewer side effects. However, more research is required to investigate their long-term efficacy and safety, particularly in comparison to stimulant medications. Clinicians should consider each child’s needs and characteristics when making treatment decisions for ADHD, and Alpha-2 agonists may be a useful addition to the treatment arsenal for some children with ADHD.

2. Current Understanding of the Use of Alpha-2 Agonists as a Treatment Option for ADHD in Children

Alpha-2 agonists stimulate alpha-2 receptors, most predominantly in the prefrontal cortex. The most used agents for ADHD are clonidine and guanfacine. Clonidine stimulates Alpha-2A, Alpha-2B, and Alpha2C, whereas guanfacine stimulates the Alpha-2A receptors in the prefrontal cortex. These actions on both the pre-and post-synaptic membrane alter arousal and cognitive processes that are implicated in ADHD. The most prominent side effect of both drugs is sedation and orthostatic hypotension. Sudden discontinuation of these drugs could also result in rebound hypertension. However, it has milder side effects than clonidine due to the longer duration of action of guanfacine’s longer duration of action [10].
Alpha-2 agonists are second-line agents to stimulants. They were originally administered simultaneously to extend the duration of action of stimulants. Some data showed that doing this allowed for equal efficacy while using a smaller dose of stimulant. Also, patients with ADHD are prone to sleep disorders that can be worsened with use of stimulants. Due to the sedative side effects of Alpha-2 agonists, especially clonidine, they can be advantageous in patients experiencing insomnia. Now that there are long-action formulations of stimulants, this is no longer indicated unless additional therapy is required for complex ADHD. Examples are when a patient suffers from comorbid conditions such as Tourette syndrome, oppositional defiant disorder, or aggressive/impulsive behavior [11]. These comorbid conditions often respond poorly to stimulants alone. In addition, research has shown that patients can have worsening core symptoms of autism when treating their ADHD with stimulants [10].
Monotherapy of Alpha-2agonists for ADHD is currently being researched. It is currently thought that they are effective in treating the hyperactivity and impulsivity of ADHD but not in improving inattention. Also, current formulations do not maintain adequate plasma concentrations without causing significant side effects. There are currently phase 3 trials underway on sustained-release formulations of clonidine, but Alpha-2 agonist monotherapy for ADHD is considered off-label [11].
Recent studies have also investigated the potential use of Alpha-2 agonists as a monotherapy for ADHD in children [12][13]. However, studies in this field are still in their early steps, and more studies are needed to completely understand the effectiveness of these medications when used alone. It is believed that Alpha-2 agonists may be effective in treating hyperactivity and impulsivity symptoms but may not be as effective in improving inattention symptoms compared to stimulant medications. Additionally, current formulations of Alpha-2 agonists may not maintain adequate plasma concentrations without causing significant side effects, making it challenging to achieve optimal treatment outcomes [12]. Nevertheless, sustained-release formulations of clonidine are currently in phase 3 trials, which may provide a more viable option for monotherapy in the future [12]. Despite the current limitations, the potential benefits of Alpha-2 agonists, such as fewer side effects and potential effectiveness in treating specific symptoms, make them an interesting area of study for treating ADHD in children. Continued research and exploration of these medications as a monotherapy may provide additional treatment options for children with ADHD.

3. Safety and Effectiveness of Alpha-2 Agonist drugs

Guanabenz, guanfacine, clonidine, tizanidine, medetomidine, and dexmedetomidine are all α-2 agonists that vary in their potency and affinities for the various α-2 receptor subtypes. Clonidine, tizanidine, and dexmedetomidine are metabolized in the liver have received the greatest clinical use [14]. Clonidine and guanfacine are drugs used to treat attention deficit/hyperactivity disorder in children and adolescents. These drugs work via agonism of the α2 receptors which decrease the firing rate of presynaptic neurons and release norepinephrine into the prefrontal cortex. In turn, this opens potassium channels and decreases cyclic adenosine monophosphatase levels. Clonidine is believed to primarly improve impulsivity and hyperactivity in ADHD through this mechanism [15]. Clonidine has both central and peripheral actions. In the central nervous system, stimulation of the α2-adrenergic receptors increase vagal tone leading to a reflex increase in parasympathetic activity and inhibition of sympathetic outflow. This inhibition of the efferent sympathetic pathway results in a decrease in the vascular tone of the heart, kidneys and peripheral vasculature and a reduction in peripheral resistance, which is the primary mechanism by which clonidine regulates blood pressure [15].
Clinical trials have demonstrated that guanfacine, a preferential α2A-adrenoceptor agonist, is an effective treatment for ADHD treatment in children and adolescents. These trials primarily focused on the combined ADHD subgroup, which includes both hyperactive/impulsive and inattentive symptoms [16]. Nevertheless, it has been observed that guanfacine is not as effective in treating the inattentive subtype of ADHD compared to other subtypes. In children receiving guanfacine treatment, response rates of 50–60% have been reported, which is comparable to other non-stimulant drugs in terms of efficacy [16]. Adverse events associated with guanfacine include hypotension, bradycardia, and in some cases, syncope, drowsiness, fatigue, sedation, upper abdominal pain, dry mouth, nausea, and dizziness, as reported by studies [17]. Unlike other ADHD medications, guanfacine has been found to cause moderate weight gain. A study was conducted to investigate the long-term safety and effectiveness of guanfacine extended-release (GXR) in treating adults with ADHD [18]. The study revealed no significant safety concerns associated with the long-term use of GXR to ADHD adults. The most frequently reported treatment-emergent adverse events (TEAEs), occurring in 10% of patients, were drowsiness, thirst, nasopharyngitis, decreased blood pressure, bradycardia, malaise, constipation, and postural dizziness. Patients treated with GXR showed significant improvements in ADHD symptoms, executive functioning and quality of life after long term treatment, compared to baseline [18].
Over 13 weeks, a randomized, placebo-controlled trial was performed to determine the safety and efficacy of guanfacine extended release (GXR) in adolescents with ADHD. Most participants received optimal doses of 3, 4, 5, or 6 mg, with 46.5% receiving optimal dose in excess of the currently permitted maximum of 4 mg. Most treatment-emergent adverse events were mild to moderate in severity, with sedation-related events being the most frequently reported [19].

4. Optimal Dosing and Duration of Treatment for These Medications

Clonidine and guanfacine are Alpha-2 agonist drugs, that can be administered through oral, transdermal, intravenous, or epidural routes [14]. Clonidine’s oral administration is rapidly absorbed within 3 to 5 h, while the extended-release formula has a slower absorption rate, with peak absorption occurring within 4 to 7 h. The transdermal form of clonidine is absorbed at a constant rate for 7 days, with an initial Tmax of 2 to 3 days [15]. The immediate-release formulation of clonidine starts showing effects within 30 to 60 min, with peak effects observed within 2 to 4 h. The effectiveness can last up to 8 h after administration, and similarly, the transdermal form may last for 8 h after discontinuation [15].
For clonidine’s oral dosage form (extended-release tablets), the initial dosing for teenagers and children aged six years and older is 0.1 milligram (mg) once a day, given at bedtime [20].
For guanfacine’s oral dosage form (extended-release tablets), the initial dosing for adults and children aged six years and older is 1 mg once a day, either in the morning or evening, at the same time each day. The doctor may adjust the dose using increasing increments (not exceeding 1 mg/wk). The recommended target dose range, based on clinical response and tolerability, is 0.05–0.12 mg/kg/day PO initially. For children aged 6–12 years, doses >4 mg/day have not been evaluated, while for those aged 13–17 years, doses >7 mg/day have not been evaluated [21]. In a randomized placebo-controlled study of adolescents, a total of 314 participants were randomized, with most participants receiving optimal doses of 3, 4, 5, or 6 mg (30 [22.9%], 26 [19.8%], 27 [20.6%], or 24 [18.3%] participants, respectively). However, 46.5% of participants received an optimal dose above the currently approved maximum dose limit of 4 mg [19].
Optimal dosing and duration of treatment for Alpha-2 agonists, such as clonidine and guanfacine, must be individualized to the patient’s needs and response. While there are general dosing guidelines for these medications, the optimal dose may vary depending on the patient’s age, weight, and comorbidities. For example, renal or hepatic impairment patients may require lower doses of these medications to avoid potential toxicity [16]. Additionally, the duration of treatment may vary depending on the patient’s reaction to therapy and the severity of their symptoms. Some patients may require long-term treatment, while others may only need short-term treatment to manage acute symptoms. Hence, it is essential for healthcare providers to regularly monitor patients receiving Alpha-2 agonists to assess treatment response and evaluate any adverse effects. Moreover, dose titration is necessary to achieve the desired therapeutic effect while minimizing adverse effects. Patients should start at the lowest possible dose and increase gradually, under medical supervision, until the optimal dose is reached. The optimal dose is the lowest effective dose that provides clinical benefit without causing significant adverse effects. When discontinuing treatment, patients should be gradually tapered off the medication to avoid rebound hypertension or other adverse effects [17]. Additionally, treatment duration and dosage must be evaluated on a case-by-case basis, and patients must receive close medical follow-ups to ensure that they receive the best possible care for their ADHD symptoms.
Patients may require different dosages and treatment durations to attain the desired therapeutic effect. In addition, these medications can cause adverse effects, so patients should be closely monitored to make sure that the profits of treatment outweigh the risks.

This entry is adapted from the peer-reviewed paper 10.3390/neurolint15020043

References

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