Episode 6: Beyond Stimulants Understanding Atomoxetine, Guanfacine and Clonidine

Stimulant medicines like methylphenidate and Vyvanse often dominate conversations about ADHD, but they’re only part of the story.

In this episode of Prescribe or Pass: The PoP Pod, we take a deep dive into the three main non-stimulant medicines used to treat ADHD: atomoxetine, guanfacine and clonidine.

You’ll learn how these medicines work, why they’re prescribed, who they’re best suited for, and why they shouldn’t simply be thought of as “second-line” treatments. We explore the fascinating neuroscience behind alpha-2 adrenergic agonists, why atomoxetine takes weeks to reach its full effect, how guanfacine helps the brain’s executive networks function more efficiently, and why clonidine can improve ADHD symptoms while also causing drowsiness.

We also discuss:

• When non-stimulants may be preferred over stimulants
• Common side effects and counselling points
• Monitoring blood pressure, heart rate and mood
• Combination therapy with stimulant medicines
• Practical expectations for patients and families

As always, we finish with reflective CPD questions to help translate today’s learning into clinical practice.

Prescribe or Pass: The PoP Pod is an independent clinical education podcast designed for pharmacists, pharmacy students and other healthcare professionals. 

Transcript

SPEAKER_00 0:00

I'd like to acknowledge the traditional custodians of the land on which I'm recording today and pay my respects to elders past and present. I'm Kate. I'm an Australian pharmacist with more than 25 years of experience working across hospital pharmacy, community pharmacy, palliative care, aged care, and now voluntary assisted dying. Welcome to Pop Pod, the clinician edition of Prescribe All Pulls. Look for me on Instagram, TikTok, Facebook, and YouTube at Prescribe All Pons. Every episode explores one medicine, one condition, or one clinical concept, explaining not just what we do, but why we do it. Whether you're a pharmacy student, pharmacist, or any clinician who works with medicines, welcome to the Pop Pod. This is episode six in our ADHD Medicines series. Over the past five episodes, we've built a strong foundation. In episode one, we looked at what ADHD actually is, why it's much more than simply being distracted or hyperactive, and the different types of ADHD medicines available. Episode two explored why one person might receive Ritalin while another receives vivants, and how medication selection is based on far more than simply the severity of someone's ADHD. Episode three focused on methylphenidate itself, how it works, expected benefits, side effects, and counseling. Episode four compared the different methylphenidate formulations, including Ritalin immediate release, Ritalin LA and Concerta, along with the role of generic brands and when they can be interchanged. Then the last episode we shifted to the amphetamine medicines, looking at dexamphetamine and Lizdexamphetamine or Vivants, and why vivants lasts longer, how it's converted into active dexamphetamine inside red blood cells, and some of the common myths surrounding food, vitamin C, and duration of action. Today we're looking at the non-stimulant medicine treatment of ADHD. If you've worked in pharmacy for a while, you've probably dispensed far fewer prescriptions for atomoxetine, guanfacine, or clonidine than you have for methylphenidate or vivance. And because of that, many clinicians and many patients feel less confident explaining them. When someone says my doctor has started me on guanfacine instead of vivants, or I've been prescribed atomoxetine, it's common for people to ask, does that mean my ADHD isn't very severe? Or does that mean stimulants didn't work? The answer is no. These medicines aren't simply backup options, they're different medicines working in different ways for different people and different clinical situations. By the end of this episode, you should be able to describe the three main non-stimulant medicines used for ADHD, understand who they may be suitable for, explain why they often take longer to work than stimulants, recognize common adverse effects and monitoring requirements, and understand how they're sometimes used together with stimulant medicines. Why do non-stimulant medicines exist? When we think about ADHD medicines, it's easy to think that there are only two choices methylphenidate or amphetamines, dexamphetamine or vivants. After all, stimulants are generally considered first line treatment because they have the largest evidence base and tend to work quite quickly. Many people notice improvements within hours or days. So why would anyone choose something else? Well, there are actually many reasons. Some people simply don't tolerate stimulants well. They may develop troublesome insomnia, loss of appetite, weight loss, anxiety, palpitations, or significant increases in heart rate or blood pressure. Others may have medical conditions that make stimulants less suitable. Some people may have a history of stimulant misuse. Others have coexisting tick disorders where clinicians may decide a non-stimulant is more appropriate. Some people need symptom control throughout the entire day and evening, including emotional regulation, without the peaks and troughs that can occur with stimulant medicines. Others simply prefer not to take a controlled medicine. So the important point is this. Non-stimulants aren't designed to replace stimulants, they're designed to expand the options available so treatment can be individualized. Remember what we discussed back in episode two. There isn't one best ADHD medicine. There is only the medicine that's most appropriate for this particular person. Let's start with atomoxetine. Atomoxetine was the first non-stimulant medicine approved specifically for ADHD. Unlike methylphenidate and amphetamines, atomoxetine is not a stimulant. It also isn't a controlled drug. Its mechanism of action is completely different. Rather than causing a relatively rapid increase in dopamine and noradrenaline signaling like the stimulant medicines do, atomoxetine selectively blocks the reuptake of noradrenaline. You might hear it described as a selective noradrenaline reuptake inhibitor. In fact, adomoxetine is chemically related to some antidepressants. Medicines like venlofaxine and geloxetine also affect noradrenaline, although they also increase serotonin. Despite that pharmacological similarity, adomoxetine isn't licensed or commonly used as an antidepressant because the evidence for depression simply isn't there. Remember back in episode one when we talked about noradrenaline being one of the brain's key chemical messengers involved in attention, planning, organization, and impulse control? Normally, once adrenaline has delivered its message between nerve cells, it's taken back up into the original nerve ending to be recycled. Atomoxetine slows that recycling process. As a result, more noradrenaline remains available between nerve cells for longer. Interestingly, in the prefrontal cortex, the area of the brain responsible for executive function, this also indirectly increases dopamine signaling because dopamine is handled a little differently in that part of the brain. The overall result is improved communication within the brain circuits responsible for attention, working memory, and self-regulation. But there's one word I want you to remember gradual. This is probably the single most important counseling point with atomoxetine. Unlike stimulant medicines, people won't notice a dramatic improvement on the first day or even the first week. Many people begin wondering whether it's working at all. In reality, some people start noticing improvements after two to four weeks, but for others it may take six to twelve weeks before the full effect is seen. And that's a huge difference compared with stimulant medicines. If patients aren't warned about this beforehand, they may stop taking it long before it's had a chance to work. So setting expectations is incredibly important. You might say, this medicine doesn't work like vivance, it gradually changes the way those attention pathways function over several weeks. Common side effects include nausea, reduced appetite, dry mouth, dizziness, and sometimes sleep disturbance. Interestingly, some people feel sleepy while others actually feel more awake. Taking the medicine consistently and sometimes with food if appropriate may help reduce nausea. Like several antidepressants, atomoxetine also carries a warning about possible increases in suicidal thoughts in children and adolescents, particularly during the early stages of treatment. That doesn't mean this occurs commonly, but it does mean clinicians and families should monitor for changes in mood, behavior, or emerging suicidal thinking. Blood pressure and heart rate should also be monitored because small increases can occur. Liver injury is extremely rare, but patients should be advised to seek medical review if they develop symptoms such as jaundice, dark urine, or unexplained abdominal pain. One final question that comes up is what happens when atomoxetine is stopped? Because it's chemically related to some antidepressants, people often assume it causes the same kind of withdrawal symptoms. Fortunately, that is generally not the case. Unlike many antidepressants, atomoxetine hasn't been shown to cause clinically significant discontinuation syndrome in most people. Instead, the main thing clinicians expect is the gradual return of ADHD symptoms as the medicine leaves the body. Although the medicine itself is cleared within a few days, the therapeutic benefits don't usually disappear overnight. Instead, symptoms generally tend to recur gradually over the following days to a couple of weeks. So unlike stimulant medicines, atomoxetine requires patience to start, but it also tends to fade away gradually rather than causing an abrupt crash. Now let's move on to guanfosine. Guanfosine often causes confusion because many people know it as a blood pressure medicine. Historically that's true. Immediate release guanfosine was originally developed as an antihypertensive, while the prolonged release formulation used in ADHD takes advantage of its effect within the prefrontal cortex. Guanfacine is a selective alpha-2A adrenergic receptor agonist. And this is one of my favorite areas of ADHD pharmacology because the mechanism is actually quite elegant. The important point is that guanphacine is not simply turning the whole brain down. Instead, it helps the prefrontal cortex work more efficiently. Think of the prefrontal cortex as the brain's CEO office. It helps us hold information in mind, resist distractions, control impulses, plan ahead, and stay within a task. The neurons responsible for these executive functions form networks that repeatedly communicate with each other, almost like colleagues passing information around a boardroom table. In ADHD, those networks may be less stable. Background signals can interrupt the conversation, and the CEO keeps losing their train of thought because people are constantly bursting through the office door. Guanfacine activates alpha-2A receptors located on neurons within these prefrontal networks. That activation triggers an intracellular signaling pathway that closes nearby channels called HCN channels or hyperpolarization activated cyclic nucleotide gated channels. You can think of those channels as open office doors. When they're open, irrelevant conversations and background noise keep drifting into the room. When guanphosine closes them, the neurons become less leaky and the important connections within the network become stronger. The CEO can finally finish the meeting. Working memory becomes more stable, attention is easier to sustain, and impulses may become easier to suppress. Importantly, guanphysine is not necessarily making those neurons fire more, it's helping them fire more reliably. And because of this, guanphosine may be particularly useful when hyperactivity, impulsivity, or emotional dysregulation are prominent. It may also be considered when stimulants are poorly tolerated, unsuitable, or not providing enough benefit on their own. Some people describe the effect as helping the brain feel calmer rather than faster. One important counseling point is sedation. Sleepiness is common when guanphine is first started, although this may improve over the following weeks as the body adjusts. Starting with a low dose and increasing it gradually can help reduce this effect. Guanfysine can also lower blood pressure and heart rate. That means some people may experience dizziness or lightheadedness, particularly when standing up. Patients should be advised to rise slowly and report persistent dizziness, fainting, or excessive tiredness. Blood pressure and heart rate should be monitored during treatment and following dose changes. And guanfosine should not usually be stopped suddenly. Abrupt discontinuation can cause rebound increases in blood pressure and heart rate, so the dose should be reduced gradually under medical supervision. The third medicine we'll discuss is clonidine. Like guanfosine, clonidine is an alpha-2 adrenergic receptor agonist. However, it is less selective than guanfacine, meaning it acts more broadly on alpha-2 receptors throughout the brain and body. This can sound confusing because in ADHD, we often talk about trying to improve noradrenaline and dopamine signaling. Clonidine does not simply increase noradrenaline throughout the brain. Instead, it directly activates alpha-2 receptors in the prefrontal cortex, helping the executive network involved in attention, working memory, and impulse control function more efficiently. At the same time, clonidine reduces firing from the locus corellius, the brain's main noradrenaline alert center. That lowers overall arousal, which is why clonidine can cause drowsiness. So even though less noradrenaline may be released more broadly, the receptors involved in executive function are still being activated directly by the medicine. In simple terms, stimulant medicines increase the amount of catecholamine signaling available while clonidine targets a particular receptor pathway. Because clonidine reduces overall arousal more strongly than guanphacine, it tends to be more sedating. That is not always a disadvantage. For a child with ADHD who struggles to settle or fall asleep, that sedating effect may sometimes be useful. Clonidine may also help reduce hyperactivity, impulsivity, and emotional or behavioral dysregulation. Clonidine and guanfysine may also be considered when ADHD occurs alongside a tick disorder. They are thought to improve the brain's ability to suppress unwanted motor impulses while also reducing the heightened noradrenergic effect that can make ticks worse during stress, excitement, or tiredness. As a result, some people may experience improvement in both their ADHD symptoms and their tics. Common side effects include drowsiness, dizziness, dry mouth, and constipation. Clonidine can also reduce blood pressure and heart rate, so these should be monitored during treatment and following dose changes. Patients and families should be advised to report fainting, persistent dizziness, or excessive sedation. Like guanphysine, clonidine should not usually be stopped suddenly. Abrupt discontinuation can cause rebound hypertension and an increase in sympathetic activity, so the dose should be reduced gradually under medical supervision. Clonidine begins acting in the body within hours, so sleepiness may occur from the first dose. However, the full benefit for ADHD symptoms is not immediate. Some people may feel calmer within the first week, but a more meaningful improvement in hyperactivity, impulsivity, and attention usually develops over around two to four weeks as the dose is gradually adjusted. Combination therapy. Non-stimulants aren't always used instead of stimulants, sometimes they're used together. For example, someone might obtain good improvement in concentration with methylphenidate, but continue to experience significant emotional dysregulation in the evenings. Or perhaps stimulant doses are limited by side effects. Adding guanfacine may allow better overall symptom control without continually increasing stimulant doses. Similarly, clonidine may sometimes be used alongside stimulant therapy when sleep difficulties become problematic. Combination therapy isn't appropriate for everyone, it requires careful monitoring. But it's another reminder that ADHD management is rarely about finding one perfect medicine. It's about building a treatment plan that best matches that person's symptoms, goals, and tolerability. Expectations. One of the biggest differences between stimulants and non-stimulants is expectations. When someone starts vivants, they may notice changes on the very first day. With atomoxetine, they likely won't. With guanfacine, improvements develop gradually, and that means adherence is especially important. Missing occasional doses, stopping early because it isn't working, or changing doses without medical advice can significantly affect outcomes. It's also important to explain that benefits may be more subtle. Patients might say, I don't really feel anything, but then their teacher notices they're completing work, or their partner notices fewer arguments, or their workplace notices they're more organized. Sometimes it's the people around them who notice the changes first. And finally, let's talk about monitoring. Regardless of which ADHD medicine someone receives, monitoring remains an important part of safe prescribing. Blood pressure, heart rate, weight, growth in children, sleep, appetite, mood, side effects, and most importantly, whether the medicine is actually helping the person achieve the goals that matter to them. Remember, the goal isn't simply to improve a questionnaire score. It's to improve real life. Can they study more effectively? Can they finish conversations? Can they manage work? Can they drive more safely? Can they regulate their emotions more consistently? Can they function in the way they want to? That's the outcome we're really looking for. Key take-home messages. Let's summarize today's episode. Non-stimulants are an important part of ADHD treatment, not because stimulants are bad, but because different people have different needs. Atomoxetine works by increasing noradrenaline signaling and usually takes several weeks to achieve its full effect. Guanfacine and clonidine work by improving the function of the brain's executive control networks, often helping with impulsivity, hyperactivity, and emotional dysregulation. Unlike stimulants, these medicines usually require more patience. Setting realistic expectations before treatment begins is one of the most important parts of counseling. Monitoring remains essential, particularly blood pressure, heart rate, growth in children, sleep, appetite, and mood. And remember that these medicines may sometimes be used alongside stimulants as part of an individualized treatment plan. Some reflective questions for your CPD. As always, if you're listening as part of your continuing professional development, here are a few questions to reflect on before the next episode. How confident do I currently feel explaining the difference between stimulant and non-stimulant ADHD medicines to a patient or parent? If someone collecting atomoxetine tells me it's been two weeks and I don't think it's working, how would I explain the expected time course while encouraging appropriate follow-up? Do I routinely remember to counsel patients about monitoring blood pressure, heart rate, sleep, appetite, and mood when dispensing non-stimulant ADHD medicines? Have I considered that combination therapy may sometimes be an intentional and evidence-based treatment strategy rather than assuming one medicine has failed? Is there anything I've learnt today that has changed the way I think about non-stimulant ADHD medicines? And are there any areas where I'd like to read the Australian therapeutic guidelines or product information in more detail? Thank you for joining me for episode six of Prescribe or Pass the Pop Pod. In our next episode, we'll move beyond individual medicines and look at one of the most practical parts of ADHD management. What to do when treatment isn't quite right. We'll discuss switching between ADHD medicines, dose titration, managing common adverse effects, and the real world counseling tips that help patients get the best possible outcomes for their treatment. I'll see you then.