Major Depressive Disorder
Conditions
Keywords
Treatment-resistant
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.
Interventions
DRUGKetamine
IV infusions of 0.5mg/kg of Ketamine hydrochloride over a 40-minute infusion period. Participants will receive a total of 6 doses over a 2-week period.
Sponsors
University of Minnesota
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
12 Years to 18 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Responders Measured by Clinical Global Impression (CGI) | 2 weeks | Responders will be defined as those with CGI ratings (given by the study clinician) of 1 or 2 (much or very much improved). Patients that are given a scores of 3-7 (minimally improved to very much worse) will be considered non-responders. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Montgomery-Åsberg Depression Rating Scale (MADRS) | 2 weeks | MADRS is a 10-item clinician-administered inventory measuring depression symptoms. Items are scored on a scare from 0 (none) to 6 (constant). Total scores are a sum of the 10 item scores, ranging from 0 to 60, with higher scores indicating greater symptom severity. |
| Beck Depression Inventory-II (BDI-II) | 2 weeks | BDI-II is a 21-item self-report multiple-choice inventory that assesses the severity of depressive symptoms over the prior week. Items are rated on a 4-point scale ranging from 0 to 3. Total scores are a sum of the 21 item scores ranging from 0 to 63. Higher scores indicate more severe depression symptoms. |
| Change in Clinician Administered Dissociative States Scale (CADSS) | baseline, 2 weeks | CADSS is a 27-item instrument measuring symptoms of dissociative stress, with 19 items completed by the patient and 8 items completed by the clinician. Items are rated on a scale of 0 (not at all) to 4 (extreme). Total scores are a sum of the 27 item scores and range from 0 to 108, with higher scores indicating greater symptom severity. |
| Children's Depression Rating Scale-Revised | 2 weeks | The CDRS-R measure is given in interview form to child and parent separately. A consensus is then created with best-estimate for 17 items (each with a range of 1-5 or 1-7) using both sources of information. The total score is the sum of 17 item scores, ranging from 17-113 with higher scores indicating greater depression symptoms. |
| Maximum Change in Diastolic Blood Pressure | baseline, 45 minutes post infusion | — |
| Maximum Change in Heart Rate | 4 hours | — |
| Maximum Decrease in Pulse Oximetry | 4 hours | — |
| Maximum Change in Systolic Blood Pressure | 2 hours and 40 minutes | Vital signs were measured every 15 minutes, starting from the beginning of the infusion and ending 2 hours after the infusion ended (2 hours, 40 minutes total). Maximum increase of blood pressure compared to baseline was calculated. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Ketamine Intravenous ketamine 0.5 mg/kg over 40 minutes will be given 6 times over 2 weeks.
Ketamine: IV infusions of 0.5mg/kg of Ketamine hydrochloride over a 40-minute infusion period. Participants will receive a total of 6 doses over a 2-week period. | 13 |
| Total | 13 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Ketamine |
|---|---|
| Age, Categorical <=18 years | 11 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants |
| Age, Continuous | 16.9 years STANDARD_DEVIATION 0.95 |
| Age of depression onset | 12.6 years STANDARD_DEVIATION 2.9 |
| Beck Depression Inventory-II | 29 units on a scale STANDARD_DEVIATION 10 |
| Body Mass Index | 30.7 kg/m^2 STANDARD_DEVIATION 6 |
| Children's Depression Rating Scale-Revised Score | 63.9 units on a scale STANDARD_DEVIATION 12 |
| Duration of current depressive episode | 3.8 years STANDARD_DEVIATION 1.6 |
| Estimated intelligence quotient | 114.1 IQ STANDARD_DEVIATION 56.96 |
| Montgomery-Asberg Depression Rating Scale (MADRS) | 30.15 units on a scale STANDARD_DEVIATION 5 |
| Number of Past Treatments | 5.7 Past treatments STANDARD_DEVIATION 3.1 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 13 Participants |
| Region of Enrollment United States | 13 participants |
| Sex: Female, Male Female | 5 Participants |
| Sex: Female, Male Male | 8 Participants |
| Socioeconomic Status (SES) | 56.96 units on a scale STANDARD_DEVIATION 7.45 |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 13 |
| other Total, other adverse events | 5 / 13 |
| serious Total, serious adverse events | 0 / 13 |
Outcome results
Primary
Number of Responders Measured by Clinical Global Impression (CGI)
Responders will be defined as those with CGI ratings (given by the study clinician) of 1 or 2 (much or very much improved). Patients that are given a scores of 3-7 (minimally improved to very much worse) will be considered non-responders.
Time frame: 2 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ketamine | Number of Responders Measured by Clinical Global Impression (CGI) | 5 Participants |
Secondary
Beck Depression Inventory-II (BDI-II)
BDI-II is a 21-item self-report multiple-choice inventory that assesses the severity of depressive symptoms over the prior week. Items are rated on a 4-point scale ranging from 0 to 3. Total scores are a sum of the 21 item scores ranging from 0 to 63. Higher scores indicate more severe depression symptoms.
Time frame: 2 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ketamine | Beck Depression Inventory-II (BDI-II) | 17.8 score on a scale | Standard Deviation 15.7 |
Secondary
Change in Clinician Administered Dissociative States Scale (CADSS)
CADSS is a 27-item instrument measuring symptoms of dissociative stress, with 19 items completed by the patient and 8 items completed by the clinician. Items are rated on a scale of 0 (not at all) to 4 (extreme). Total scores are a sum of the 27 item scores and range from 0 to 108, with higher scores indicating greater symptom severity.
Time frame: baseline, 2 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ketamine | Change in Clinician Administered Dissociative States Scale (CADSS) | -19.8 score on a scale | Standard Deviation 14.8 |
Secondary
Children's Depression Rating Scale-Revised
The CDRS-R measure is given in interview form to child and parent separately. A consensus is then created with best-estimate for 17 items (each with a range of 1-5 or 1-7) using both sources of information. The total score is the sum of 17 item scores, ranging from 17-113 with higher scores indicating greater depression symptoms.
Time frame: 2 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ketamine | Children's Depression Rating Scale-Revised | 44.1 score on a scale | Standard Deviation 16.3 |
Secondary
Maximum Change in Diastolic Blood Pressure
Time frame: baseline, 45 minutes post infusion
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ketamine | Maximum Change in Diastolic Blood Pressure | 13.6 mmHg | Standard Deviation 11.7 |
Secondary
Maximum Change in Heart Rate
Time frame: 4 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ketamine | Maximum Change in Heart Rate | 8.9 beats per minute | Standard Deviation 8.8 |
Secondary
Maximum Change in Systolic Blood Pressure
Vital signs were measured every 15 minutes, starting from the beginning of the infusion and ending 2 hours after the infusion ended (2 hours, 40 minutes total). Maximum increase of blood pressure compared to baseline was calculated.
Time frame: 2 hours and 40 minutes
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ketamine | Maximum Change in Systolic Blood Pressure | 13.9 mmHg | Standard Deviation 9.4 |
Secondary
Maximum Decrease in Pulse Oximetry
Time frame: 4 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ketamine | Maximum Decrease in Pulse Oximetry | -2.5 percent | Standard Deviation 9.4 |
Secondary
Montgomery-Åsberg Depression Rating Scale (MADRS)
MADRS is a 10-item clinician-administered inventory measuring depression symptoms. Items are scored on a scare from 0 (none) to 6 (constant). Total scores are a sum of the 10 item scores, ranging from 0 to 60, with higher scores indicating greater symptom severity.
Time frame: 2 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ketamine | Montgomery-Åsberg Depression Rating Scale (MADRS) | 18.5 score on a scale | Standard Deviation 11.2 |