Clinical trial NCT02078817: Ketamine in Adolescents With Treatment-Resistant Depression
Official title: Open-Label Intravenous Subanesthetic Ketamine for Adolescents With Treatment-Resistant Depression
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Major Depressive Disorder
Keywords: Treatment-resistant
Lead sponsor: University of Minnesota
Sponsor class: OTHER
First posted: 2014-03-05
Enrollment: 14
Sex: ALL
Minimum age (years): 12
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This study will test the use of ketamine for treatment of depression in adolescents that have not responded to other treatments. We will also examine neurobiological mechanisms of treatment.

Detailed description: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Number of Responders Measured by Clinical Global Impression (CGI)
timeFrame: 2 weeks
Secondary outcomes:
measure: Children's Depression Rating Scale-Revised
timeFrame: 2 weeks
measure: Montgomery-Åsberg Depression Rating Scale (MADRS)
timeFrame: 2 weeks
measure: Beck Depression Inventory-II (BDI-II)
timeFrame: 2 weeks
measure: Change in Clinician Administered Dissociative States Scale (CADSS)
timeFrame: baseline, 2 weeks
measure: Maximum Change in Systolic Blood Pressure
timeFrame: 2 hours and 40 minutes
measure: Maximum Change in Diastolic Blood Pressure
timeFrame: baseline, 45 minutes post infusion
measure: Maximum Change in Heart Rate
timeFrame: 4 hours
measure: Maximum Decrease in Pulse Oximetry
timeFrame: 4 hours
Other outcomes:
Locations:
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
Study officials:
References:
citation: Roy AV, Thai M, Klimes-Dougan B, Westlund Schreiner M, Mueller BA, Albott CS, Lim KO, Fiecas M, Tye SJ, Cullen KR. Brain entropy and neurotrophic molecular markers accompanying clinical improvement after ketamine: Preliminary evidence in adolescents with treatment-resistant depression. J Psychopharmacol. 2021 Feb;35(2):168-177. doi: 10.1177/0269881120928203. Epub 2020 Jul 9.