BHIPP Bulletin

Volume 9, Issue 6

December 2023

This month's BHIPP Bulletin is a contribution from

Rheanna Platt, MD, Assistant Professor in the Department of Psychiatry and Behavioral Sciences at Johns Hopkins School of Medicine and BHIPP Consultant.

There are over 100 psychotropic medications available for prescribing worldwide – a number that can be overwhelming even for experienced specialists. When selecting medications, there are several considerations, including efficacy, safety, side effect profile, FDA approval, convenience, and cost. In this newsletter, we will discuss considerations related to safety, side effects, and strategies for managing common side effects. We will focus on common medications with indications for ADHD, depressive, and anxiety disorders. As an overarching framework for discussing medications with patients and families, it is important to weigh the risks of medication side-effects with the risks of non-treatment or under-treatment of symptoms. 

Stimulants

For ADHD, stimulant medications (including methylphenidate and amphetamine preparations) are first-line due to their superior efficacy and effect size on both inattention and hyperactivity symptoms. One of the most common stimulant side effects is appetite suppression, which may lead to weight loss. Strategies to manage appetite suppression include eating nutrient-dense, high-calorie foods before medication administration and having patients drink after they finish eating during meals and snacks. With respect to weight loss, this typically happens early in treatment but improves over time; the effect of ‘drug holidays’ on weight trajectories is unclear. Another common side effect is insomnia, though of note, insomnia is also a common clinical feature of ADHD itself. Strategies to manage insomnia include changing medication administration to earlier in the day, using shorter-acting formulations, adding an alpha agonist (if there are residual ADHD symptoms) or melatonin, and reviewing other aspects of sleep hygiene (e.g., no electronics 1 hour before bedtime, blue light-blocking apps on electronic devices). 

Stimulants may also increase heart rate (typically <10 beats per minute) and blood pressure (typically <5 mmHg), which in most cases is not clinically significant. While stimulant medications have not been shown to increase the risk of sudden death, and universal baseline EKGs are not recommended prior to stimulant treatment, in the event that there is a personal or family history of sudden death, cardiomyopathy, or arrythmia, further evaluation is recommended. A less common side effect that is more common among younger (e.g., preschool) patients is dysphoric mood. Some patients experience rebound irritability when stimulants wear off, which can sometimes be managed by adding a short-acting stimulant in the afternoon or switching to a stimulant with a more gradual drop in level (e.g., Concerta). Long-term, there may be an impact (with a small effect size) of consistent stimulant treatment on ultimate adult height, a risk that should be weighed in the context of other factors that may impact height as well as treatment benefits. Growth should be regularly monitored amongst patients receiving stimulants; if growth decrement occurs and is of clinical concern, it may be reversible if the stimulant is stopped within one year of growth decrement. Finally, there have been concerns about stimulant medications precipitating or worsening tics; however, a 2015 meta-analysis did not support this association (Cohen et al., 2015). In terms of differences between methylphenidate and amphetamine preparations, while there have been few head-to-head studies, amphetamine has a higher potency than methylphenidate and therefore may have higher rates of the aforementioned side effects. 

Alpha-2 Adrenergic Agonists

Second-line medications for ADHD include alpha-agonists such as guanfacine and clonidine and norepinephrine reuptake inhibitors such as atomoxetine. Common alpha-agonist side effects include sedation, dizziness, and hypotension, as well as rebound hypertension if alpha-agonists are stopped (with these effects being more marked with clonidine compared to guanfacine). Typically, these effects decrease over time, and one strategy for their management is to adjust the timing of medication administration so the side effects may work to the patient’s advantage (e.g., administration of medication at night when sedation may be an advantage; for example, taking guanfacine ER at bedtime may lessen daytime somnolence compared to taking it in the morning). More rarely, alpha-agonists may also worsen sinus node function or AV block. Common side effects of atomoxetine (Strattera) include GI upset, appetite suppression (typically to a lesser degree than stimulant medication), and sedation. Some of these effects can be decreased by slowing titration. Of note, atomoxetine also carries a black box warning related to the small risk of suicidal ideation, which should be monitored particularly early in treatment. An additional rare side effect of atomoxetine is liver dysfunction. While this side effect does not occur frequently enough to warrant monitoring of Liver Function Tests (LFTs) for all patients, it should be clinically monitored. Viloxazine (Qelbree) is a recently approved (in 2021) SNRI with a similar mechanism of action and side effects to atomoxetine but does not carry a warning about liver dysfunction. 

Selective Serotonin Reuptake Inhibitors (SSRIs)

For anxiety and depression, SSRIs are first-line when pharmacotherapy is indicated. It is worth noting that in the Treatment of Resistant Depression in Adolescents (TORDIA) study, similar remission rates were found with SSRIs as compared to venlafaxine (an SNRI), but participants taking venlafaxine had greater side effects in particular an increase in diastolic blood pressure and skin problems. The most common side effects in youth treated with SSRIs and SNRIs include nausea and headaches, which tend to occur early and are usually transient or self-resolving. Other side effects that tend to occur early in the course of treatment with SSRIs include insomnia or fatigue and activation. Insomnia or fatigue can be managed by changing medication administration to bedtime (Strawn et al., 2023). Activation is characterized by agitation, impulsivity, and insomnia and is more likely to occur in younger patients and with rapid dose titration and/or higher starting doses (one factor behind the mantra of starting low and going slow with respect to SSRI dose titration) (Luft et al., 2018). Symptoms of activation typically resolve when the dose is decreased and/or discontinued. Activation is much more common and less severe than mania, which is characterized by a markedly decreased need for sleep, marked irritability, or an expansive mood. A family history of bipolar disorder (which would potentially signify an increased risk of antidepressant-induced mania) should be ascertained prior to starting antidepressants. Side effects that may occur later in the course of SSRI treatment include weight gain (more common with paroxetine and citalopram), dry mouth, and sexual dysfunction (which is a common cause of SSRI discontinuation in adolescents and may respond to lowering the dose or switching to a non-serotonergic agent (e.g., bupropion)) (Deshmukh & Franco, 2003; Levine & McGlinchey, 2015; Montejo et al., 2019). 

Some SSRI side effects are specific to certain medications and/or most frequently occur in the context of using combinations of medications. For example, citalopram is associated with QT prolongation, which prompted an FDA notification in 2011 advising providers not to increase the dose beyond 40 mg/day (beyond which the cardiac effects are increased, and no clear clinical benefit is noted). As a potent inhibitor of CYP2D6, the prescription of fluoxetine should take into consideration the potential for drug-drug interactions. An important drug-drug interaction to consider with all SSRIs (and SNRIs) is serotonin syndrome, which can occur when SSRIs are co-administered with other serotonergic agents including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John’s Wort. The use of SSRIs with medications that affect coagulation may increase the risk of bleeding. When discontinuing SSRIs, it is important to taper medications (other than fluoxetine, due to its long half-life) to avoid SSRI discontinuation syndrome, which can include flu-like symptoms, dizziness, sleep disruption, and irritability. 

One of the most concerning potential side effects for families is suicidality which was first issued in 2004 as a black box warning by the FDA. The initial warning was based on drug industry trials showing a small (~1-2%) increase in risk for suicidal ideation in medication as compared to placebo groups (with no difference in completed suicides). Subsequent studies have found either a lower risk (0.7% difference) than the initial evaluation or no significant increase in risk. When discussing the warning with families, it can be helpful to frame the discussion around the risk of under-treated depression, which itself carries a risk for suicidal ideation and behavior; as there is evidence that following the issued black box warning, there was a decline in SSRI prescriptions and an increase in suicide rates. While causality in this case is unclear, the warning does alert providers to monitor for suicidal ideation and behavior, particularly early in the course of treatment. Use BHIPP's Quick Tips for Providers: Assessing and Responding to Youth Suicidal Ideation as a resource when monitoring for suicidal ideation and behavior.

Related Resources:

1. BHIPP Resilience Break focusing on Managing Side Effects of Psychiatric Medications in Pediatric Primary Care: Practical Tips and Clinical Pearls

2. Harvard Health Publishing resource on Children, Teens, and the Safety of Psychotropic Medicines

3. Healthy Place Guide to Psychiatric Medication for Children and Adolescents

4. Pediatric Psychopharmacology for Primary Care (3rd Edition)

5. Ways to Increase the Calories in your Child's Diet

As always, if you have questions about the behavioral health needs of your patients, we encourage you to call the BHIPP consultation line at 

855-MD-BHIPP (632-4477), open 9am-5pm Monday-Friday, for resource/referral networking or consultation support.

We will keep you informed about all our services and training events through our website (www.mdbhipp.org) and monthly e-newsletters. Additionally, BHIPP is on LinkedIn, Twitter, and Facebook. We invite you to follow us there to stay up-to-date on upcoming training events, pediatric mental health research, and resources for providers, families and children.

BHIPP Announcements

Join the BHIPP ECHO Core Foundations Series Learning Collaborative!

Register for the BHIPP ECHO Core Foundations series! The third session will be held on January 3rd from 8:00-9:00am. Join our multidisciplinary team of child behavioral health experts on the first Wednesday of every month between November 2023 and June 2024 for virtual case-based learning and didactic presentations. This series is great for providers who want to improve their knowledge of child mental health and develop foundational skills. Free CME and CEU credit is available for participation.

Sign up for the BHIPP ECHO Beyond the Basics Series!

Register for the BHIPP ECHO Beyond the Basics series! The next session will be held on January 11th from 12:00-1:00pm. Join our multidisciplinary team of child behavioral health experts every month for virtual case-based learning and didactic presentations. This series is great for providers who have already participated in BHIPP ECHO, or who feel like they are experienced in treating behavioral health in their practice and are looking to explore advanced topics. This series is held on the second Thursday of the month from 12:00-1:00pm between October 2023 and May 2024. Free CME and CEU credit is available for participation.

Save the date for the upcoming BHIPP & MACS Training!

Save the date for a BHIPP and Maryland Addiction Consultation Service (MACS) training on January 18th from 12:00-1:00pm focusing on Trends in Adolescent Substance Use: Identification, Screening, and Treatment Planning. This training will be presented by MACS consultant, Marc Fishman, MD. Free CME and CEU credit is available for participation.