THE POTENTIAL OF ESKETAMINE (SPRAVATO™) IN CHILDREN AND ADOLESCENTS

THE POTENTIAL OF ESKETAMINE (SPRAVATO™) IN CHILDREN AND ADOLESCENTS

Ketamine is a N-methyl-D-aspartate (NMDA) receptor antagonist that was approved by the FDA in 1970 as an anesthetic agent for diagnostic and surgical procedures that do not require skeletal muscle relaxation. Recently, we discussed a new formulation of the esketamine nasal product that was approved by FDA in March 2019 for the treatment of treatment-resistant depression.

The safety and effectiveness of ketamine in patients below the age of 16 has not been established.¹ Published evidence of ketamine use in the pediatric and adolescent population has been limited to its use as an anesthetic in the emergency room or pain management. Ketamine for anesthesia is often administered intravenously (IV) to children at a standard dose range from 1 mg/kg to 5 mg/kg.² In this range, additive effects of sedation were not observed in doses above 1.5 mg/kg; so lower doses may decrease rates of adverse events such as vomiting, apnea, and recovery agitation.

More recently, ketamine has been hypothesized to have beneficial effects on various psychiatric disorders. Perhaps the most notable non-anesthetic use of ketamine reported is for the potential treatment of major depressive disorder and treatment-resistant depression (TRD). 3,4 In a case study by Dwyer et. al, an adolescent patient with TRD who was deemed high risk for suicide was given 7 infusions of IV ketamine over an 8-week period, which lead to a successful decrease in symptoms of depression and suicide. Dwyer reported that the side effect profile was like that observed in adults,5 which included psychotomimetic effects and transient dissociative symptoms. Additionally, an open-label study by Cullen et. al observed adolescent patients with TRD who were given 6 infusions of IV ketamine over a two-week period.4 Although the drug was generally well tolerated, like the Dwyer study, the Cullen study observed hemodynamic effects in addition to transient dissociative symptoms. The most notable hemodynamic effect observed was a transient increase in mean blood pressure and heart rate at the 30 minute- and 45 minute- time points following the start of infusion. This occurrence is similar to what is seen in adults, where blood pressure increased 30 minutes after infusion.6 Thus, there may be some delayed effects taking place as ketamine is infused. Additional publications suggest that previous studies in adults, such as the effectiveness of IV ketamine for the treatment of posttraumatic stress disorder or intranasal ketamine for the treatment of autism, may be translatable to the pediatric and adolescent populations.7,8

Although data for the use of ketamine in children and adolescents is limited, previously published studies involving adults may serve as a precursor to areas where ketamine may be explored in younger populations. As stated above, minor side effects were experienced across the standard therapeutic ketamine dose range used to achieve anesthesia in the pediatric population; and recently explored areas of ketamine use for the treatment of psychiatric disorders used sub-therapeutic doses. Thus, the safety of ketamine may serve as a plausible starting platform when exploring new options to treat psychosomatic conditions in the pediatric and adolescent populations. However, for clinicians interested in exploring the use of ketamine in children, caution regarding abuse, addiction, and long-term effects should be considered. In addition, due to limited data on dosing intervals and adverse events in these patients, practitioners should be cognizant to identify any patient characteristics that deviate from baseline measures.

References

1KETALAR [Prescribing Information]. Chestnut Ridge, N.Y., Par Pharmaceutical.

2Green SM, Roback MG, Kennedy RM, et al. Clinical practice guideline for emergency department ketamine dissociative sedation: 2011 update. Ann Emerg Med 2011;57(5):449-61.

3Dwyer JB, Beyer C, Wilkinson ST, et al. Ketamine as a treatment for adolescent depression: a case report. J Am Acad Child Adolesc Psychiatry 2017;56(4):352-4.

4Cullen KR, Amayua P, Roback MG, et al. Intravenous ketamine for adolescents with treatment-resistant depression: an open-label study. J Child Adolesc Psychopharmacol 2018;28(7):437-44.

5Newport DJ, Carpenter LL, McDonald WM, et al. Ketamine and other NMDA antagonists: early clinical trials and possible mechanisms in depression. Am J Pshiatry 2015;172(10):950-66.

6Riva-Posse P, Reiff CM, Edwards JA, et al. Blood pressure safety of subanesthetic ketamine for depression: a report on 684 infusions. J Affect Disord 2018;236:291-7.

7Feder A, Parides MD, Murrough JW, et al. Efficacy of intravenous ketamine for treatment of chronic posttraumatic stress disorder: a randomized clinical trial. JAMA Psychiatry 2014;71(6):681-8.

8Wink LK, O’Melia AM, Shaffer RC, et al. Intranasal ketamine treatment in an adult with autism spectrum disorder. J Clin Psychiatry 2014;75(8):835-6.