Anxiety Disorder, Major Depressive Disorder
Conditions
Keywords
Ketamine, Depression, Major Depressive Disorder, Anxiety, School refusal, Suicide, Generalized Anxiety, Suicidal Ideation
Brief summary
The purpose of this study is to determine the tolerability and short-term efficacy of a single ketamine infusion for the treatment of adolescents with 1) medication-refractory major depressive disorder (MDD) and/or 2) medication-refractory anxiety disorders (social anxiety disorder, panic disorder, generalized anxiety disorder and/or separation anxiety disorder).
Detailed description
We will conduct a crossover trial in which as many as 36 adolescents (18 with MDD and 18 with anxiety disorders) will be given a single infusion of ketamine (study drug) or midazolam (active control). MDD symptoms and anxiety symptoms will be monitored over a two-week period. If applicable, comorbid school refusal symptoms will also be monitored over a two-week period for both cohorts. A 2-week washout period will be required between infusion doses. Our primary outcomes will be 1) improvement in MDD symptoms (measured by Montgomery-Asberg Depression Rating Scale, revised (MADRS) score) 1 day after infusion, for the cohort of subjects enrolled in the MDD arm of this trial and 2) improvement in the anxiety symptoms (measured by the Multimodal Anxiety Scale for Children (MASC) acute physical symptoms subscale) for the cohort of subjects enrolled in the anxiety disorders arm of the trial.
Interventions
DRUGKetamine
A single dose of 0.5mg/kg of Ketamine will be administered Intravenously during 40 minutes in the Hospital Research Unit of YNHH. The subject will be monitored continuously during the procedure, and every hour for three hours after the infusion.
DRUGMidazolam
A single dose of 0.045mg/kg of Midazolam will be administered intravenously during 40 minutes in the Hospital Research Unit of YNHH. The subject will be monitored continuously during the procedure, and every hour for three hours after the infusion.
Sponsors
American Academy of Child Adolescent Psychiatry.
Yale University
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Midazolam was chosen as an active placebo in keeping with its similar pharmacokinetic profile and precedent as a reasonable comparator for nonspecific behavioral effects of ketamine
Intervention model description
Participants were randomly assigned the treatment order, with participants receiving a single infusion of either ketamine hydrochloride (0.5 mg/kg) or midazolam (0.045 mg/kg) on Day 1, and the alternate compound 2 weeks later.
Eligibility
Sex/Gender
ALL
Age
13 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
Inclusion: MDD Cohort: * Meet DSM-5 criteria for Major Depressive Disorder by structured interview (MINI-KID) * CDRS-R score \>40. * Failure to achieve remission with at least 1 adequate prior antidepressant trial (e.g. SSRI, SNRI, or TCA), meaning at least 8 weeks at therapeutic dosing, including at least 4 weeks of stable dosing. Anxiety Cohort: * Meet DSM-5 criteria for any of the following anxiety disorders: Social Anxiety Disorders, Generalized Anxiety Disorder, Separation Anxiety Disorder and/or Panic Disorder by structured interview (MINI-KID) * ADIS Clinical Severity Rating ≥4 (moderately severe) for any of the 4 included anxiety disorders * Failure to achieve remission with at least 1 adequate prior anxiolytic medication trial (e.g. SSRI, SNRI, or TCA), meaning at least 8 weeks at therapeutic dosing, including at least 4 weeks of stable dosing. * Failure to achieve remission with previous CBT or subject declines current CBT therapy Both cohorts: * Stable psychiatric medications and doses for the month prior to enrollment. Subjects may continue to engage in any ongoing psychotherapy. * Medically and neurologically healthy on the basis of physical examination and medical history. * Parents able to provide written informed consent and adolescents must additionally provide assent. Exclusion: * Current inpatient hospitalization or active suicidal ideation requiring referral for inpatient hospitalization for safety. * History of psychotic disorder or manic episode diagnosed by MINI-KID * History of substance dependence diagnosis by MINI-KID (excluding tobacco) or positive urine toxicology. * Pregnancy (urine pregnancy tests on the day of scans for menstruating girls). * Inability to provide written informed consent according to the Yale Human Investigation Committee (HIC) guidelines in English.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Montgomery-Asberg Depression Rating Scale Score 1 Day After Infusion | 1 day after the infusion | Depressive symptoms (measured by Montgomery-Asberg Depression Rating Scale, revised (MADRS) score) on 1 day after infusion, for the cohort of subjects enrolled in the MDD arm of this trial. Higher MADRS score indicates more severe depression, and each item yields a score of 0 to 6. The overall score ranges from 0 to 60. Usual cutoff points are: 0 to 6 - normal /symptom absent. 7 to 19 - mild depression. 20 to 34 - moderate depression. \>34 - severe depression. |
Countries
United States
Participant flow
Recruitment details
Adolescents (aged 13 to 17 years old) were recruited via (1) physician referral or (2) via direct inquiries from families via ClinicalTrials.gov listing. Subjects were enrolled at the Yale Child Study Center (New Haven, CT) between May 2016 and September 2018.
Pre-assignment details
Participants were to remain on stable dosing of their current medication regimen for the four weeks prior to the first infusion, and during the four-week trial itself. All participants underwent a physical examination, laboratory screening, and electrocardiography.
Participants by arm
| Arm | Count |
|---|---|
| Received Ketamine in the First Infusion Participants that were randomly assigned to receive a dose of 0.5 mg/kg of Ketamine to be administered Intravenously during 40 minutes in the Hospital Research Unit of YNHH. Participants were monitored continuously during the procedure, and every hour for three hours after the infusion. | 6 |
| Received Midazolam in the First Infusion Participants that were assigned to receive a dose of 0.045mg/kg of Midazolam, administered Intravenously during 40 minutes in the Hospital Research Unit of YNHH. Participants were monitored continuously during the procedure, and every hour for three hours after the infusion | 11 |
| Total | 17 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Received Ketamine in the First Infusion | Received Midazolam in the First Infusion | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 6 Participants | 11 Participants | 17 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Continuous | 15.3 years | 15.6 years | 15.4 years |
| Baseline Score for the Montgomery-Asberg Depression Rating Scale sc ore | 35.6 units on a scale STANDARD_DEVIATION 7.1 | 31.8 units on a scale STANDARD_DEVIATION 10.2 | 32.9 units on a scale STANDARD_DEVIATION 9.1 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 5 Participants | 9 Participants | 14 Participants |
| Sex: Female, Male Female | 5 Participants | 8 Participants | 13 Participants |
| Sex: Female, Male Male | 1 Participants | 3 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 17 | 0 / 16 |
| other Total, other adverse events | 15 / 17 | 13 / 16 |
| serious Total, serious adverse events | 0 / 17 | 0 / 16 |
Outcome results
Primary
Montgomery-Asberg Depression Rating Scale Score 1 Day After Infusion
Depressive symptoms (measured by Montgomery-Asberg Depression Rating Scale, revised (MADRS) score) on 1 day after infusion, for the cohort of subjects enrolled in the MDD arm of this trial. Higher MADRS score indicates more severe depression, and each item yields a score of 0 to 6. The overall score ranges from 0 to 60. Usual cutoff points are: 0 to 6 - normal /symptom absent. 7 to 19 - mild depression. 20 to 34 - moderate depression. \>34 - severe depression.
Time frame: 1 day after the infusion
Population: A total of 17 patients were randomized to receive either Ketamine or Midazolam in the first infusion, one participant in withdrew from the trail after the first infusion because of improvement in her depressive symptoms and did not receive the second infusion.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Ketamine | Montgomery-Asberg Depression Rating Scale Score 1 Day After Infusion | 15.44 units on a scale |
| Midazolam | Montgomery-Asberg Depression Rating Scale Score 1 Day After Infusion | 24.13 units on a scale |