Psychotropic Management of Pediatric Anxiety

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Featured Guest: Megan O’Connell, PharmD, BCPP

Objectives

• Review the use of SSRIs for management of various anxiety disorders in pediatric patients.
• Review the use of SNRIs for the management of various anxiety disorders in pediatric patients.
• Apply the use of benzodiazepines for the acute management of anxiety.
• Apply the use of other non-benzodiazepine as needed medications for anxiety including hydroxyzine.

Resources

• Practical Psychopharmacology Translating Findings From Evidence-Based Trials into Real-World Clinical Practice. (Cambridge University Press)
• Stahl’s Essential Psychopharmacology Neuroscientific Basis and Practical Applications. (4th edition) (Cambridge University Press)
• Stahl’s Essential Psychopharmacology Prescriber’s Guide. (5th ed.). (Cambridge University Press)
• Stahl’s Essential Psychopharmacology Prescriber's Guide Children and Adolescents. (1st edition) Cambridge University Press.

CME

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Transcript

Dr. Heidi Burns:

Hello, and welcome to our podcast, Breaking Down Mental Health, with myself, child and adolescent psychiatrist, Dr. Heidi Burns, social worker Syma Khan, and nurse practitioner, Dr. Christina Cwynar. We are joined today by Dr. Megan O'Connell to discuss psychotropic management of pediatric anxiety. Dr. O'Connell is a clinical pharmacy specialist in psychiatry and neurology at the University of Michigan. She works with adult inpatient psychiatry and general neurology services and collaborates with both the adult and pediatric psychiatry consult liaison teams and psychiatry emergency services at Michigan Medicine. Thank you for joining us today.

Dr. O'Connell:

It's great to be here, thanks for having me.

Dr. Heidi Burns:

None of our speakers today have any disclosures or any conflicts of interest.

Syma Khan:

Thanks so much for joining us today, Dr. O'Connell. So to review, in season two, we did discuss SSRIs and SNRIs as indicated for depression, but let's take a closer look at how these two classes of medications work for anxiety. Dr. O'Connell, can you tell us a little bit about how SSRIs work for individuals with anxiety?

Dr. O'Connell:

Sure. Well, to be honest, we don't really know how medications work in anxiety, because we don't really know what causes anxiety. So we know how medications work in the brain, we know how SSRIs interact with neurotransmitters in the body, but we don't exactly know how that translates into an improvement in anxiety, so I just wanted to preface with that. The mechanism of SSRI medications is to inhibit the reuptake or prevent, essentially, the cleanup of serotonin in the synapse in our brains, so the end result is an increase in the neurotransmitter, serotonin.

This likely doesn't directly translate into an improvement in anxiety, it's most likely a complex downstream effect of this change in neurotransmission of serotonin. And we know this because it takes some time for SSRI medications to start working, both in depression and anxiety, but for most people, when they start an SSRI medication, they will notice improvement two to four weeks, maybe, or even up to six weeks. So we know that SSRIs quickly increase serotonin in the brains, that happens much faster than the improvement in symptoms for most patients. So it's likely complex downstream effects of the changes in serotonin neurotransmission that lead to an improvement in anxiety.

Dr. Christina Cwynar:

Thank you, Dr. O'Connell, it's really helpful to understand that SSRIs and some of the medications that we use for anxiety don't have those immediate effects, and there are reasons for that, and we don't completely understand that. Oftentimes in practice, we do trial SSRIs first, and then, when a patient hasn't gotten adequate relief, then we move to a class of medications called selective norepinephrine reuptake inhibitors, or SNRIs. Can you tell us a little bit about how these medications work for anxiety and why we might consider them over an SSRI?

Dr. O'Connell:

Yeah, so SNRIs, like you said, inhibit, again, the reuptake of serotonin, similar to SSRIs, but they also inhibit the reuptake of norepinephrine. At this point, we don't really know what role norepinephrine plays in anxiety, because in clinical trials, meta-analyses, there really aren't major differences between the effectiveness of SSRIs versus SNRIs. So at this point, SSRIs are recommended first line, as you said, and in pediatric anxiety, oftentimes, it's recommended to move to another SSRI before moving on, then, if neither of those medications work, to an SNRI. SNRIs in meta-analyses have shown to be a little bit more tolerable than SSRIs in pediatric patients, specifically for anxiety. In most situations, I would start with an SSRI. If that was ineffective, move to another SSRI, unless the patient had significant intolerable adverse effects to the first SSRI. In that case, I would consider an SNRI as second choice therapy. If the patient just didn't find the first SSRI effective, I would move to a second SSRI, and then to an SNRI if the second SSRI was also ineffective.

Dr. Heidi Burns:

So you talked a little bit about both SSRIs and SNRIs, and discussed how oftentimes, we will start with an SSRI as a provider and move on to another SSRI trial, and then, potentially an SNRI trial. What would be an adequate trial for those medications?

Dr. O'Connell:

Yeah, so an adequate trial means that the patient has been taking the medication for three months duration at an adequate dose in order to treat anxiety. So in anxiety, we often find that higher doses are needed than in depression to treat the condition well. So for example, a patient taking fluoxetine for depression may only need 40 to 60 milligrams, whereas a patient taking fluoxetine for anxiety may need up to 80 milligrams or more to treat that anxiety adequately.

Dr. Christina Cwynar:

I think that's a really good point to make, because oftentimes, on our consult team, we get this question a lot, or we see these patients a lot, where they're struggling with anxiety or even depression, but their provider just started citrulline at 25 milligrams, and yeah, that's why it's not hitting your anxiety, because we need to get up closer to that 150 or 200. And that does take time, but also, it's not an adequate trial if we haven't even reached those doses.

Dr. O'Connell:

Yeah, and I think sometimes, too, side effects of medications like antidepressants show up more quickly than benefits. Patients will occasionally notice worsened anxiety, potentially, or stomach upset or headache within a couple days or weeks of starting an antidepressant or increasing the dose of an antidepressant. The improvements in anxiety tend to take weeks to months to show up.

Syma Khan:

I appreciate you sharing that, Dr. O'Connell, because I think so often, patients, and even providers are pretty anxious about ... They themselves are anxious about the potential side effects, or that things aren't effective, and really, we do need that time, and time at an adequate dose to really see the effect. And so, that's just something to reflect onto, is that there is not really an easy solution to managing anxiety, though I know that it can be really hard for individuals that are struggling with anxiety, because it can be so impairing, but staying the course and continuing to take the medication, those side effects will also improve over time.

Dr. Christina Cwynar:

And I think we always hear, start low and go slow, but sometimes providers mistaken that slow as uber slow, and really, we can be increasing at a steady pace. So let's say, citrulline for a child, a starting dose is 25 milligrams, if they're tolerating, you can increase that to 50 in a week or two, and building them up to an adequate dose for that symptom relief.

Dr. Heidi Burns:

So clearly, there are a lot of things to consider when a provider is trying to choose the right course for a patient, which medications, SSRIs versus SNRIs, and the next steps if you do end up not responding well or having significant side effects to one of these agents. What are some of the other considerations that providers make when they are choosing between different agents?

Dr. O'Connell:

Yeah, so there are a lot of things providers can consider when they're choosing an individual medication. Patient-specific factors, like how adherent a patient normally is with their medications, can steer you one way or another. For example, some antidepressants have longer half-lives than others, some have very short half-lives, so a medication like fluoxetine is better for a patient who has a hard time remembering to take their medications every day. Has a very long half-life, so will stick around for several weeks even if the patient misses a dose here or there, so it's a good medication for someone who has a hard time remembering to take them every day. Some medications, mostly the SNRIs, like duloxetine and venlafaxine, have shorter half-lives, so they're more likely to cause withdrawal symptoms if a patient misses a dose.

So that's something to consider if someone has difficulty remembering to take their medications every day. If they forget to take a duloxetine, they're much more likely to experience side effects like malaise or irritability, or sometimes some nausea associated with the withdrawal of an antidepressant medication than someone taking fluoxetine who misses a dose. Other things to consider in pediatrics could be whether the patient is good at swallowing tablets or not. There are some antidepressants that come in liquid formulations. Most of the SSRIs, other than fluvoxamine, all come in liquid formulation, duloxetine and venlafaxine and fluvoxamine do not. However, venlafaxine and duloxetine are extended release capsules that can be opened and sprinkled on applesauce if needed for patients who have a hard time swallowing capsules or tablets.

Other things to consider would be things like drug interactions. Some antidepressants inhibit the metabolism of other medications, so patients who are taking ADHD medication, such as atomoxetine or amphetamine, dextroamphetamine, may have increased side effects to a medication that inhibits their metabolism. The antidepressants that commonly do this are fluoxetine, duloxetine, and paroxetine. Some antidepressants that are good from a drug-drug interaction standpoint would be escitalopram and citalopram and sertraline.

Fluvoxamine is another antidepressant that has a lot of drug-drug interactions due to significant CYP metabolism inhibition. It's not necessarily recommended to do genetic testing prior to starting an antidepressant, but if a provider has access to previous genetic testing for CYP metabolism, this information can be used to guide medication choice, as well. Escitalopram and citalopram have recommendations in the CPIC guidelines to avoid if the patient is an ultra-rapid or poor metabolizer of CYP2C19, and if the patient is a 2D6 poor metabolizer, the CPIC guidelines also have recommendations regarding paroxetine dosing.

Syma Khan:

Thanks so much for sharing those, Dr. Connell, and I think it's important for providers to know that there are resources to guide them in terms of thinking through what medication may be indicated at a time, or what steps to take. And especially that genetic testing is not necessary, I think a lot of this is on patient rapport and working through a collaborative process around determining what's the best medication, that the genetic testing can be helpful, but really not necessary to help guide us in our clinical decision-making. Shifting a little bit, thinking about pediatric populations, we're often careful about medications in general, and in particular medications that may have different side effects or have potential for negative complications. So we wanted to talk specifically about some non-benzodiazepine medications that can be used to help with anxiety, such as hydroxyzine.

Dr. O'Connell:

Yeah, so hydroxyzine is sometimes used in place of a benzodiazepine for short relief from acute anxiety. It's rarely prescribed as a scheduled medication for long-term anxiety outside of, or as monotherapy. Hydroxyzine is a histamine antagonist, so similar to something like diphenhydramine, can help the patient feel a little calmer without necessarily binding to the GABA receptors that confer some of the risk with benzodiazepine medications. Another medication that's sometimes used as needed for anxiety when trying to avoid benzodiazepines can be clonidine, which is an Alpha-2 agonist originally developed for hypertension, we've found also helps calm patients down during acute anxiety episodes.

Dr. Christina Cwynar:

I really like using some of the non-benzodiazepines with patients, particularly in the hospital setting that we work in. Patients who are nervous about getting the IV start or something like that can be really helpful without over-sedating them. And the way I like to explain it to the kids is, it dampens that fight-or-flight response, it helps it so you don't want to just run out of this room when something scary comes in, but it doesn't impede your ability to participate in whatever's going on at that moment, as well.

Dr. Heidi Burns:

So like Syma suggested, when it comes to a pediatric population, we're often trying a non-medication option first. And so, typically, like we've talked about before in previous seasons, we will opt for trying more therapeutic interventions, and then kind of go on to these non-benzodiazepine medications, to see if those can help us with the short-term bursts of anxiety or panic attacks, things like that. Because those SSRIs and SNRIs are really kind of going for the root of the problem, but sometimes while we're waiting for those to take effect, and we know that takes a long time, we do need those periodic short-acting medications that help people through panic attacks or through significant periods of anxiety.

Benzodiazepines are something that we still do use with kids. Even though there's some controversy, lots of people have big opinions about whether or not to use them, there's lots of things that patients might see in the news about benzodiazepines, or have personal experiences with things like Xanax or Ativan, Klonopin, things like that. There is some risk of benzodiazepines causing some disinhibition in children, and that's something that we see clinically. Oftentimes, it's the first time they've been exposed to something like that. They may go in for a surgery and be given a little bit of Versed, something like that, and they act pretty silly, and so, that's something that we're often watching out for. But there are situations where people are either so anxious or agitated that we do use benzodiazepines occasionally. Can we talk a little bit more, Dr. O'Connell, about how benzodiazepines work and when we actually would use those?

Dr. O'Connell:

Yeah, so benzodiazepines bind to the GABA receptor, GABAA receptor specifically, and allow for enhanced activity of GABA. This leads to influx of chloride, ions, hyperpolarization, and relaxation, or an inhibitory effect. These medications work quickly and are often a good bridge to an antidepressant medication beginning to take effect. The issue with them can be, in addition to what Dr. Burns said about paradoxical reactions, such as disinhibition, other issues can be tolerance or dependence when a benzodiazepine medication is used regularly and consistently for a long period of time, withdrawal if a patient is taken off of a benzodiazepine without a prolonged taper, if they've been on the medication for a long time. We can also sometimes see cognitive issues in patients who are on benzodiazepines, higher doses of benzodiazepines, and in patients who are old enough to drive or walk, you can see risk of increased falls, increased motor vehicle accidents, those kinds of issues, when a patient is chronically taking a medication like a benzodiazepine.

Dr. Christina Cwynar:

And I think it's great to remember that these medications come with risk, but we also do find them as helpful tools in those acute situations where somebody's anxiety may just be impeding their life or their ability to function or get necessary cares. So another tool in our toolbox, but not necessarily the first one we jump to, like we've been talking about. So sometimes patients, they get some relief from an SSRI or an SNRI, but it might not be enough. Sometimes we consider adjunctive medications like BuSpar, can you tell us a little bit about that, Dr. O'Connell, when we may consider that?

Dr. O'Connell:

Yeah, so BuSpar is another medication that deals with serotonin, it's a partial serotonin receptor agonist, 1A receptor agonist. And again, the net result of using a medication like BuSpar is to try and increase serotonin just by different mechanism from an SSRI, so they make sense to use as an adjunct to SSRI medication when, for example, a patient isn't experiencing severe adverse effects, has found some benefit, maybe, from an SSRI, but is looking for additional improvement, or symptoms have not improved to the point that the patient and the provider are satisfied. BuSpar is generally pretty well-tolerated by most patients, the most common adverse effect is usually some lightheadedness or maybe some stomach upset that generally passes within the first couple of days.

Syma Khan:

We spent a lot of time talking about different classes of medications today, as well as medications that we can add if we're not seeing full benefit or full relief for our patients that we're working with in managing their anxiety. Are there other questions around the table around the medication management aspect of anxiety?

Dr. Christina Cwynar:

One reflection that I always discuss with families and children is that anxiety is a normal experience. We all have anxiety. If we didn't have anxiety, that would be worrisome, it's like a survival emotion. But it's when that anxiety starts impeding somebody's life that we start having these discussions about medications, and we have another episode coming up that talks about some of the therapies for anxiety, and oftentimes, the combination of those two is truly what's indicated to help this person thrive in their life.

Syma Khan:

That's definitely something to reflect on, because I think so often, when it comes to mental health and things like depression or anxiety, adults and youth often think, I need to push through this, and it's really having that discussion of like, how is this impacting my life? Is it keeping me from going places? Is it keeping me from talking to people? And things like that can be really important to reflect on, to say, I maybe need to see someone, and I maybe need some more specialized treatment to help me with this. Because there is this neurochemical aspect of it, too, beyond just the therapeutic skills that you learn in therapy to help manage anxiety, that there are aspects of our brain that play a role in having anxiety, too.

Dr. Heidi Burns:

And I think one of the things that we often see in the clinical space is parents particularly really grappling with this question about whether to move on to medications and using medications. And I think we hope there's a bit of normalization that can happen about the fact that most of these medications have been around for decades, many of them used in pediatric populations for just as long. There is data out there, and there's indications for this, and there's reasons that you may want to help counsel your parents that their kids are ready for that, especially if you're seeing things like Syma said, this real impact that their disorder is having on their lives. We want kids to be able to thrive and live happy lives, and sometimes that means therapy and medications to help them get there.

Dr. Christina Cwynar: 

And I think it's important to remember that medications aren't necessarily lifetime. We go through, we get to a therapeutic dose, we allow them to work in therapy and be stable for a while in a good comfortable spot, and then we can have conversations about coming off. And sometimes people trial and come off very successfully, never need a medication again, where others need it throughout their life or through periods of their life. It just depends on the person and their brain chemistry and their life.

Dr. Heidi Burns:

And I think as we've sort of mentioned before, it surprises people sometimes to know that from ages around 8 to 11, that's often when anxiety disorders emerge in the pediatric population. So I think it's surprising that at such a young age, this process actually ends up being one of the most common psychiatric disorders that happens not only at that age, but generally, so it is something that is among us very commonly.

Dr. Christina Cwynar:

Well, thank you, Dr. O'Connell, for joining us today, we truly appreciate your time and your expertise. Thank you to everybody who tuned in this week. Nurses, social workers, and physicians can claim CMEs and CEs at uofmhealth.org/breakingdownmentalhealth. You are able to do this anytime within three years of the initial air date. We hope that you will join us next time.