6 Dosing Tips for Pediatric Patients With Mood Disorders

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Figure 1

Figure 2

RESEARCH UPDATE

Atypical antipsychotics play an important role in acute bipolar depression and mixed states. Among the atypicals, lurasidone is a good choice in children, for reasons I reviewed in an earlier column. Lurasidone’s pharmacokinetics have been well-researched in pediatric patients, and this article will discuss how to dose it in children with mood disorders.

1. Aim low in depression

Dopamine blockade is not the goal in depression, and it can be avoided by dosing in a lower range. For lurasidone, the daily FDA-approved ranges are:

• Depression: Pediatrics (aged 10 to 17 years) 20 mg to 80 mg, Adults 20 mg to 120 mg

• Schizophrenia and Psychosis: Pediatrics (aged 13 to 17 years) 40 mg to 80 mg, Adults 40 to mg to 160 mg

We cannot say for sure if lurasidone has a dose-dependent response because the adult and child studies used flexible dosing. In general, lower doses of atypicals are better for depression and higher doses only raise the side effect burden without additional benefits, according to a metaanalysis of 7 controlled trials in adults (including 1 for lurasidone).¹ That study favored a lower dose range of 20 mg to 60 mg/day (mean 31.8 mg) for lurasidone in adults, which is close to the mean dose of 32.5 mg/day arrived at in the pediatric trial (Figure 1).^1,2

2. Dosing is similar in children and adults, but watch for sedation in children

In connection with lurasidone, pharmacokinetics are similar in adults, adolescents, and children 10 and over. An adverse effect profile is also similar across the ages, but children are more prone to sedation, a finding consistent with other antipsychotics.³

3. Prepare for tolerability

For children, sedation, akathisia, and nausea are the main short-term tolerability issues of lurasidone. All of these are dose dependent, and most improve with time (akathisia may not). For nausea, some clinicians use ginger capsules or ondansetron (avoid promethazine and metoclopramide as their antipsychotic properties can aggravate akathisia). Akathisia is a serious adverse effect that has been linked to suicidality.⁴ Beta-blockers (propranolol, betaxolol) and benzodiazepines are the most common remedy, but high-dose vitamin B6 also has controlled trials for akathisia and compared well with propranolol in a recent study (and in my clinical experience).⁵

4. Take with food-but not with grapefruit

Patients who take lurasidone on an empty stomach only receive about half the intended dose. In adults and children, it needs to be taken within 30 minutes of eating a meal of at least 350 kcal (ie, a full meal).⁶ Larger meals do not increase the absorption further, but grapefruit juice can raise lurasidone levels through CYP3A4 inhibition (pomelos are fine, as are the new bioengineered grapefruits that lack drug interactions).^7,8

5. Drug interactions

Lurasidone is metabolized through one pathway, CYP3A4, which makes it vulnerable to a few significant interactions. Higher doses are needed with carbamazepine (160 mg with carbamazepine ≈ 30 mg without). Modafinil (Provigil) and St John’s wort lower lurasidone by about 50%, but arModafinil (Nuvigil) has a milder interaction. Two antidepressants-nefazodone and fluvoxamine-significantly raise lurasidone levels (Figure 2).⁷

6. Dosing in younger children

What about children under 10? Lurasidone is not FDA-approved in this group. They were excluded from the efficacy trial because an earlier pharmacokinetic study had found slightly higher serum levels and greater tolerability issues (mainly sedation) in younger children.³ Off-label use may be warranted in younger children with a severe episode of bipolar depression or mixed states, in which case aim for a lower dose.³

Dr Aiken is Instructor in Clinical Psychiatry at the Wake Forest University School of Medicine and the Director of the Mood Treatment Center in Winston-Salem, NC. He is Editor in Chief of The Carlat Psychiatry Report and Bipolar Disorder Section Co-Editor for Psychiatric Times.

Disclosures:

Dr Aiken does not accept honoraria from pharmaceutical companies but receives royalties from W.W. Norton & Co. for a book he co-authored with James Phelps, MD, Bipolar, Not So Much.

References:

1. Bartoli F, Dell'Osso B, Crocamo C, et al. Benefits and harms of low and high second-generation antipsychotics doses for bipolar depression: a meta-analysis.J Psychiatr Res. 2017;88:38-46.

2. DelBello MP, Goldman R, Phillips D, et al. Efficacy and safety of lurasidone in children and adolescents with bipolar I depression: a double-blind, placebo-controlled study.J Am Acad Child Adolesc Psychiatry. 2017;56:1015-1025.

3. Findling RL, Goldman R, Chiu YY, et al. Pharmacokinetics and tolerability of lurasidone in children and adolescents with psychiatric disorders.Clin Ther. 2015;37:2788-2797.

4. Seemüller F, Lewitzka U, Bauer M, et al. The relationship of akathisia with treatment emergent suicidality among patients with first-episode schizophrenia treated with haloperidol or risperidone. Pharmacopsychiatry. 2012;45:292-296.

5. Shams-Alizadeh N, Bakhshayesh H, Rezaei F, et al. Effect of vitamin B6 versus propranolol on antipsychotic-induced akathisia: a pilot comparative double-blind study.Iran J Pharm Res. 2018;17(Suppl):130-135.

6. Greenberg WM, Citrome L. Pharmacokinetics and pharmacodynamics of lurasidone hydrochloride, a second-generation antipsychotic: a systematic review of the published literature.Clin Pharmacokinet. 2017;56:493-503.

7. U.S. Food and Drug Administration. Drug development and drug interactions: table of substrates, inhibitors and inducers. November 14, 2017.

8. Bailey DG. Grapefruit-medication interactions.CMAJ. 2013;185:507-508.