Ketamine in Adolescents With Treatment-Resistant Depression

Depression frequently emerges during adolescence and is associated with severe outcomes.
Current interventions do not lead to remission for many adolescents. Treatment-resistant
depression (TRD) in adolescence is an ominous prognostic indicator for a lifetime of
suffering and increased risk for suicide. Efforts should be directed toward novel
interventions that could alter this perilous course. Theoretically, restoration of healthy
development during this critical window would substantially improve outcomes over the
lifespan.

Ketamine is a noncompetitive, high-affinity antagonist of the N-methyl-D-aspartate type
glutamate receptor that has long been used for induction and maintenance of anesthesia in
children and adults, and recently has been investigated for its rapid antidepressant effects.
Randomized, double-blind, saline-controlled trials in adults with TRD have demonstrated that
a single, subanesthetic infusion of intravenous (IV) ketamine at 0.5 mg/kg over 40 minutes
can produce a rapid (within 2 hours) antidepressant response (Ibrahim et al., 2011; Zarate et
al., 2006). Recent evidence suggests that serial doses of ketamine may be even more effective
and may lead to more prolonged remission (aan het Rot et al., 2010; Murrough et al., 2012).
Our current research at using serial dosing of IV ketamine among adult veterans with TRD over
a 2-week period has shown promising results, with a response rate of 92% among the 12
participants to date.

No results from any studies examining effectiveness of either single-dose or serial-dose
ketamine have yet been published in adolescents with TRD. Because of the ongoing
neurodevelopment in adolescence, which is thought to confer enhanced neuroplasticity, it is
possible that adolescents with TRD could show greater responses and more sustained remission
than adults with TRD. The biological mechanisms of depression impacted by ketamine are only
now being uncovered in adults (Zarate et al., 2013). Characterization of the neural
mechanisms underlying ketamine response or non-response in adolescents with TRD will
represent a significant advance. The specific aims of this preliminary study are as follows:

Aim #1: To determine the efficacy of repeated-dose subanesthetic IV ketamine among adolescent
patients with TRD.

Hypothesis: Based on previous results in adults with TRD, we predict that response rates will
improve over the course of six treatments of ketamine.

Aim #2: To explore durability of antidepressant response to repeated dose of IV ketamine in a
4-week observational period.

Hypothesis: Based on the inherent neuroplasticity in adolescence due to ongoing
neurodevelopment, adolescents may show a more durable clinical response than has been seen in
adults.

Aim #3: To study the neurobiological mechanisms of response to ketamine. We will examine
relevant biological systems using several different brain imaging indices and measures of
intracellular functioning from peripheral blood.

Inclusion Criteria:

- Male and female adolescents aged 12 to 18 years.

- Presence of recurrent major depression without psychotic features confirmed by the
Kiddie-Schedule for Affective Disorders and Schizophrenia - Parent and Lifetime
Version (Kaufman et al., 1997).

- Current depression severity measured by the Children's Depression Rating Scale (CDRS)
(Poznanski, 1985) raw score greater than or equal to 36 at screening and the day
ketamine is due to be received for the first time.

- Current depressive episode resistant to treatment, defined as failure to achieve
remission (elimination of symptoms and restoration of pre-morbid psychosocial
functioning) from at least 2 antidepressant trials of different pharmacological
classes. Systematic evaluation of previous antidepressant trials will be assessed by
using the Antidepressant Treatment History Form (Sackeim, 2001).

- If present, current antidepressant medication treatment must be dose stable for at
least 2 months prior to beginning the study. (Patients will continue with current
antidepressant treatment throughout the study. Based on our experience in current
research at the VA Medical Center using serial ketamine for adult TRD, patients have
shown positive results while continuing their current antidepressant treatment.)

Exclusion Criteria:

- Inability to speak English

- Inability or unwillingness to provide written informed consent

- A history of Mental Retardation or any Pervasive Developmental Disorder

- Current or lifetime diagnosis of schizophrenia, schizoaffective disorder, or psychosis
Not Otherwise Specified.

- Family history with a first degree relative with schizophrenia, schizoaffective
disorder, or psychosis Not Otherwise Specified.

- Diagnosis of seizures or other neurological disorders.

- Comorbid diagnosis of substance abuse or dependence, current or past.

- Clinically unstable medical illness.

- Current use of the following medications: any barbiturates, any narcotics, any
non-benzodiazepine hypnotics at doses higher than zolpidem 10 mg qhs or equivalent for
insomnia.

- For women: pregnancy (confirmed by baseline lab test).

- The presence of any MRI contra-indications such as MRI-incompatible metals in the body
or claustrophobia.