Ketamine for Severe Adolescent Depression: Intermediate-term Safety and Efficacy

Ketamine for Severe Adolescent Depression: Intermediate-term Safety and Efficacy

The purpose of this study is to evaluate the intermediate-term efficacy and tolerability of a multiple-dosing ketamine infusion paradigm for the treatment of medication-refractory major depressive disorder (MDD). We are using a two-phase design. The first phase is a 3-week double blind parallel design clinical trial comparing 6 infusions of ketamine compared to 6 infusions of midazolam in 24 adolescents with treatment resistant depression. The primary outcome of this phase will be Children's Depression Rating Scale (CDRS) score at Day 18. The second phase is a 6-month open phase in which patients who received midazolam and remain depressed with be offered open ketamine treatment (6 infusions over 3 weeks). All participants will be followed weekly for 6 months and tracked for time to relapse.

The purpose of this study is to evaluate the intermediate-term efficacy and tolerability of a multiple-dosing ketamine infusion paradigm for the treatment of medication-refractory major depressive disorder (MDD). The specific aims of the study are: To evaluate the efficacy and tolerability of a multiple-dosing ketamine infusion paradigm (2 infusions per week for 3 weeks) compared to midazolam in adolescents with treatment resistant depression (TRD), . To test these aims we have designed a two-phase trial. The first phase is a 3-week double blind parallel design clinical trial comparing 6 infusions of ketamine compared to 6 infusions of midazolam in 24 adolescents with TRD. The primary outcome of this phase will be Children's Depression Rating Scale (CDRS) score at Day 18. The second phase is a 6-month open phase in which patients who received midazolam and remain depressed with be offered open ketamine treatment (6 infusions over 3 weeks). All participants will be followed weekly for 6 months and tracked for time to relapse. In those who initially responded to ketamine, symptom triggered maintenance infusions will be offered during this 6-month time period. All participants will receive standard of care treatment in addition to experimental procedures, and will be tracked monthly with extensive neurocognitive assessments.

Inclusion Criteria:

1. Male or female ages 13-17 years
2. Meet DSM-5 (Diagnostic and Statistical Manual 5 ) criteria for Major Depressive Disorder by structured interview (MINI-KID)
3. Children's Depression Rating Scale, Revised CDRS score ≥40 at screening
4. Failure to achieve remission with at least 2 antidepressant trials (e.g. SSRI, SNRI or TCA), meaning at least 6 weeks at therapeutic dosing, including at least 4 weeks of stable dosing
5. Stable psychiatric medications and doses for the month prior to enrollment. Subjects may continue to engage in any ongoing psychotherapy.
6. Medically and neurologically healthy on the basis of physical examination and medical history.
7. Parents able to provide written informed consent and adolescents must additionally provide assent.

Exclusion Criteria:

1. History of psychotic disorder, manic episode, autism spectrum disorder diagnosed by MINI-KID
2. History of substance dependence diagnosis by MINI-KID (excluding tobacco) or positive urine toxicology.
3. Intellectual disability (IQ<70) per medical history
4. Pregnancy (urine pregnancy tests on the day of infusions for menstruating girls) or lactation
5. Prior treatment with ketamine for depression or prior recreational use of ketamine.
6. Inability to provide written informed consent according to the Yale Human Investigation Committee (HIC) guidelines in English.