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Hi! David Rosenberg here for the Psychopharmacology Institute. In this CAP—or Child and Adolescent Psychiatry—Smart Take, we will closely examine the current state of best practice treatment algorithms for pediatric bipolar disorder for both manic/mixed and depressive episodes. This is timely given clinicians’ continued challenges in treating pediatric bipolar disorder. This illness takes an enormous toll on patients and their families. And for many, effective treatment still remains elusive. Side effects and monitoring can create additional challenges.
In this article, Hobbs and colleagues provide a thoughtful and comprehensive update to the American Academy of Child and Adolescent Psychiatry’s 2005 algorithm for manic/mixed episodes of pediatric bipolar disorder. In 2005, lithium was the only FDA-approved treatment for manic or mixed episodes in the pediatric population. As you know, a lot has changed since then, although significant challenges remain.
Nowadays, there are several approved treatments for pediatric bipolar manic or mixed episodes and 2 medications, lurasidone and olanzapine–fluoxetine combination, which are FDA approved for treating pediatric bipolar disorder depressive episodes. Interestingly, divalproex sodium, a go-to medication for many clinicians for many years treating pediatric bipolar disorder, failed to separate from placebo in randomized clinical trials (RCTs) of pediatric bipolar disorder. That is interesting because we know, particularly in female patients, that divalproex sodium can be associated with polycystic ovarian syndrome, and yet, at least in pediatric populations in the reports reviewed, there was no separation from placebo. Oxcarbazepine also failed to separate from placebo in RCTs of pediatric bipolar disorder.
For pediatric bipolar disorder depressive episodes, lurasidone is the first-line treatment. Furthermore, although lurasidone and olanzapine–fluoxetine combination have comparable efficacy for pediatric bipolar disorder depressive episodes, lurasidone has a significantly lower metabolic side-effect risk than olanzapine–fluoxetine.
If lurasidone is partially but not sufficiently effective, augmentation with lamotrigine is warranted. Remember, though, especially in youth 15 and under, to monitor very closely for Stevens-Johnson syndrome, which can be potentially lethal or permanently disfiguring. If you are using lamotrigine, start low, go slow, and discuss this potential side effect with the patient and family while monitoring very closely. Even in older adolescents, close monitoring is essential, although the risk is lower.
If depressive symptoms remain problematic after augmentation with lamotrigine, the addition of an FDA-approved SSRI for pediatric population is recommended: Fluoxetine or escitalopram. All things being equal, I recommend trying escitalopram first because it is the SSRI with the fewest drug–drug interactions, with fluoxetine having the most risk for drug–drug interactions. Now, if lurasidone treatment is deemed to have failed, that is, no response, cross-tapering to olanzapine–fluoxetine combination is recommended. It was noted that olanzapine–fluoxetine combination in pediatric bipolar disorder is frankly underused despite being effective and FDA approved for pediatric bipolar depression. There is also evidence that weight gain and metabolic changes associated with olanzapine–fluoxetine combination can be significantly mitigated by either using topiramate or diet, exercise, or lifestyle changes. So, whenever I use olanzapine with or without fluoxetine, I always discuss exercise and diet planning proactively ahead of time. As you know, exercise can also have antidepressant and antianxiety effects, so it is a no-brainer, a win-win. Moreover, if there is a partial or insufficient response to olanzapine–fluoxetine combination for pediatric bipolar disorder, lamotrigine can be added. If the FDA-approved treatments fail, non-FDA–approved treatments like quetiapine, aripiprazole, asenapine, risperidone, other SSRIs, and lithium can be tried. Remember only to use SSRIs in combination with a mood-stabilizing agent to prevent a switch to mania. Where possible, nonmedication options, such as CBT, are indicated to eliminate or even reduce antidepressant doses. For patients with pediatric bipolar disorder depressive episodes failing more than 2 SGAs, ECT can be considered.
For treating manic/mixed episodes of pediatric bipolar disorder, there are more suitable options. The first-line treatment is still an SGA that is FDA-approved for pediatric bipolar disorder mixed or manic episodes, including aripiprazole, asenapine, olanzapine, quetiapine, or risperidone. If there is no response to the initial SGA, one of the other FDA-approved SGAs is indicated as monotherapy. If there is a partial but still insufficient response to the FDA-approved SGA, augmentation with lithium is recommended.
The advantages of lithium use include its neuroprotective and antisuicidal properties, and there are intriguing data that lithium can help decrease substance use and abuse in pediatric patients with bipolar disorder—it lessens the risk in those high-risk patients for developing a substance use disorder. Another advantage of using lithium combined with SGAs is that when the acute episode is resolved, the SGA can be tapered to minimize the risk of metabolic side effects. That being said, lithium is not considered a first-line monotherapy for pediatric bipolar disorder for acute manic or mixed episodes because of its lower efficacy compared with SGAs. Furthermore, do not forget that lithium and SGAS have significant side-effect burdens, but the increased efficacy of the SGAs in pediatric bipolar disorder makes them the first-line recommendation. The bottom line is this is an excellent, clinically relevant article that provides real-world algorithms for treating pediatric bipolar disorder manic/mixed and depressive episodes.
There are obvious limitations. Treatment remains a substantial challenge for many patients. There are many gaps. For example, the neurodevelopmental implications are vast and likely require more scrutiny. For example, lamotrigine may be more effective in adolescents with bipolar disorder, whereas oxcarbazepine may be more effective in younger children with pediatric bipolar disorder. Exciting times are ahead, particularly with the possibility of combining these RCTs with studies to identify objective markers of psychiatric illness with neuroimaging and pharmacogenetic strategies.
Abstract
Psychopharmacological Treatment Algorithms of Manic/Mixed and Depressed Episodes in Pediatric Bipolar Disorder
Elizabeth Hobbs, Rachel Reed, Boris Lorberg, Adelaide S Robb, Julia Dorfman
Introduction: Pediatric bipolar disorder (PBD) is a severe psychiatric illness diagnosed before the age of 18, which is associated with extreme shifts in mood characterized by manic and depressive episodes. In 2005, AACAP published algorithms to guide pharmacological treatment of manic/mixed episodes associated with PBD. At that time, lithium was the only Food and Drug Administration (FDA)-approved treatment for pediatric bipolar manic/mixed episodes. The goal of this article is to review evidence that has emerged since the AACAP algorithm in 2005. Methods: Literature searches were conducted through PubMed and limited to studies published between 2005 and 2021, using keywords that focused on randomized controlled trials (RCTs) for available psychopharmacological medications. In addition, the authors conducted in-depth searches for articles providing evidence for agents included in the 2005 AACAP algorithm. Results: Since the publication of the AACAP algorithm in 2005, multiple RCTs have been conducted in PBD, leading to FDA approval of five medications (aripiprazole, asenapine, olanzapine, quetiapine, and risperidone) for the treatment of manic/mixed episodes and two medications (lurasidone and olanzapine-fluoxetine combination) for the treatment of depressed episodes. Divalproex sodium and oxcarbazepine were studied in pediatric RCTs and failed to separate from placebo. Conclusions: We offer an update to the 2005 AACAP algorithms for the treatment of pediatric bipolar mixed/manic episodes and added an evidence-based algorithm for the treatment of depression in PBD. In addition to treatment algorithms, we review current evidence for efficacy of agents proposed in the AACAP algorithm and provide tables summarizing medication side effects and efficacy.
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Reference
Hobbs, E., Reed, R., Lorberg, B., Robb, A. S., & Dorfman, J. (2022).
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Journal of Child and Adolescent Psychopharmacology, 32
(10), 507-521.
