Date of Award

January 2021

Document Type

Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Jennifer B. Dwyer

Abstract

Pediatric depression is a significant public health problem, and adolescents whose depression does not respond to first-line treatments have few evidence-based options. Interventional psychiatric services (IPS), including ketamine, esketamine, electroconvulsive therapy (ECT), and repetitive transcranial magnetic stimulation (rTMS) are promising approaches for adult depression, but data on efficacy and safety in the pediatric population are limited. The purpose of this thesis is two-fold: first, to better understand the current attitudes, level of access, and community practices surrounding the use of IPS in pediatric populations. Secondly, to build the IPS pediatric evidence base by assessing the intermediate-term safety and efficacy of intravenous (IV) ketamine in adolescent treatment-resistant depression (TRD). The first aim was accomplished through an online, anonymous survey of psychiatric healthcare providers who treat pediatric patients and providers of any discipline who advertise IPS. 898 healthcare providers were contacted, 330 of whom were sent the survey, with a response rate of 12.7%. Out of a total of 42 respondents, 4 providers treat pediatric patients with ketamine, 2 with rTMS, and 1 with ECT targeting diagnoses that include TRD, obsessive-compulsive disorder, post-traumatic stress disorder, Tourette’s syndrome, and schizophrenia/schizoaffective disorder. The second aim was accomplished through an interim analysis of an ongoing double-blind, midazolam-controlled clinical trial of a multiple-dose paradigm of IV ketamine to treat adolescent TRD. Of the three study participants, the one ketamine-randomized participant had a significant clinical response during the blinded phase, whereas the two midazolam-randomized participants did not have a response to midazolam. The midazolam-randomized subjects also did not respond to subsequent open ketamine treatment but did improve in the open phase of the trial from other treatments. Regarding safety, all infusion-related side effects were transient and resolved within 1.5 hours of infusion completion, and our intermediate-term safety outcome of cognitive function showed no significant decreases on composite scores of the Cogstate battery. In conclusion, here we demonstrate in a regional sample that IPS are being used off-label in the community to treat pediatric mental illness, despite having little data available for safety or efficacy in this population. We show preliminary data, however, that adolescent patients with TRD tolerate IV ketamine treatments, with variable efficacy in this small sample size, highlighting the need for continued study.

Comments

This thesis is restricted to Yale network users only. This thesis is permanently embargoed from public release.

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