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).

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.

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.

1 hour after after infusion.

The small sample size and the smaller number of subjects who were randomized to receive ketamine prior to midazolam.

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