# NIMH Ketamine Mechanism of Action Study

The study was completed at the National Institute of Mental Health (NIMH) Intramural Research Program (IRP)  (ID: 04-M-0222) within the Experimental Therapeutics and Pathophysiology Branch.  It is a double-blind placebo cross-over trial of a single infusion of ketamine or saline placebo which included both patients and healthy volunteers. Patients with major depressive disorder (MDD) were medication-free for at least 2 weeks prior to the start of the study. Recruitment for the bipolar (BP) group was ended early on, but is included here for completeness. Some measurements (tasks/scans/scales) were added part-way into the study and have fewer completed measurements.

Nominally, there are five Magnetic Resonance Imaging (MRI) scans per subject at 3 Tesla with the details listed below. Note that not all planned scans were completed: some participants dropped out of the trial, some people did not want to have an MRI (infrequent), and sometimes there were technical issues.

## MRI Data Description

Scans are normally performed at baseline (`ses-b0`) (about 2 days before) and then 2-3 (`ses-d2`/`ses-p2`) and 10-11 (`ses-d10`/`ses-p10`) days after blinded infusion on a 3 Tesla GE Signa HDx scanner with an 8-channel head coil unless otherwise specified.

- Subjects: total N = 58
  - n, Group 1 (MDD) = 33
  - n, Group 2 (BP) = 3
  - n, Group 3 (HC) = 22
- Sessions per subject: total = 5
  - Baseline (`ses-b0`)
  - Post-infusion 1 (ketamine: `ses-d2` or placebo: `ses-p2`)
  - Interim 1 (ketamine: d10, or placebo: p10)
  - Post-infusion 2 (opposite, ketamine: `ses-d2` or placebo: `ses-p2`)
  - Interim 2 (ketamine: `ses-d10`, or placebo: `ses-p10`)
- Session identifiers are documented in the `phenotype/phenotype.json` file
- Anatomical runs per session:
  - T1-weighted: 1 run (often 1 or 2 additional T1-weighted runs in the baseline session)
  - T2-weighted: 3 runs (baseline session only)
- Diffusion-Weighted Imaging (DWI): 2 runs (baseline session only)
  - 30 directions, bval: 1100 s/mm^2, acquired "multi-part" in two groups (g1/g2)

- Functional runs per session:
  - Resting state: 1 run, 8 min, eyes closed, cardiac and respiratory physiological data was collected during this run only
  - [Dot probe task](https://www.sciencedirect.com/science/article/pii/S2213158218302183): 2 runs, 8.75 min each
  - [Emotional faces evaluation task](https://www.sciencedirect.com/science/article/pii/S0165032720328512): 2 runs, 4.8 min each
  - [N-back task](https://doi.org/10.1007/s00213-006-0334-2): 1-3 runs, 4-6 min each

- Magnetic Resonance Spectroscopy (MRS)
  - Nominally all sessions for participants after `sub-MOA115`/`sub-MOA306`
  - 7 Tesla Siemens, 32-channel head coil
  - 2 cm isotropic voxel centered on the perigenual ACC, TE-optimized J-suppression PRESS sequence at 7 Tesla optimized to measure glutamate

### Exceptions

1. The anatomical data of `sub-MOA133/ses-b0` came from an excluded scan two weeks earlier in order to have anatomical data to go along with the functional data.
1. Not every functional run has an events file of timings of stimuli presented during the run.
1. Not every session has a resting state scan. 5 sessions are missing a resting state scan.
1. Not every resting state scan has physiological data. 22 sessions are missing physiological data.

## Tabular Phenotypic Data Description

The Montgomery-Asberg Depression Rating Scale (MADRS), the abbreviated Hamilton Rating Scale for Depression (HAMD-6), and the Hamilton Depression Rating Scale (HAMD-17) surveys participants filled out at the MRI sessions are collected in the `phenotype/` folder with the data dictionary in the `phenotype.json` file and the data itself in the `phenotype.tsv` file.

## Inclusion/Exclusion Criteria

Please see [https://clinicaltrials.gov/study/NCT00088699](https://clinicaltrials.gov/study/NCT00088699) for a detailed list, also included below.

### INCLUSION CRITERIA

#### General patient inclusion criteria

- Male or female subjects, 18 to 65 years of age.
- Each subject must have a level of understanding sufficient to agree to all required tests and examinations and sign an informed consent document.
- Subjects must fulfill DSM-IV criteria for Major Depressive Disorder (MDD) without psychotic features, based on clinical assessment and confirmed by a structured diagnostic interview, SCID-P.
- Subjects must have an initial score of at least 20 on the MADRS at screen and at baseline of study phase I.
- Subjects must have failed to respond in the past to an adequate dose and duration of at least one antidepressant (SSRI, bupropion, or venlafaxine) during a depressive episode
- Current depressive episode of at least 4 weeks duration.
- Additional inclusion criteria for substudy 4 (patients with MDD):
  - Age of onset less than 40 years of age.
  - Subjects with MDD must fulfill DSM-IV criteria for Major Depression single episode or recurrent without psychotic features based on clinical assessment and confirmed by a structured diagnostic interview (SCID-P).
  - A failed adequate trial of ECT would count as an adequate antidepressant trial.
  - In women of childbearing age, a negative pregnancy test within 24 hours of MRI.
- Inclusion criteria for healthy control subjects (Substudy 4 only)
  - Age 18-65 years.
  - Written informed consent completed.

### EXCLUSION CRITERIA

#### General patient exclusion criteria

- Current or past diagnosis of Schizophrenia or any other psychotic disorder as defined in the DSM-IV.
- Subjects with a history of DSM-IV drug or alcohol dependency or abuse (except for nicotine or caffeine) within the preceding 3 months.
- Female subjects who are either pregnant or nursing.
- Serious, unstable illnesses including hepatic, renal, gastroenterologic, respiratory, cardiovascular (including ischemic heart disease), endocrinologic, neurologic, immunologic, or hematologic disease.
- Subjects with uncorrected hypothyroidism or hyperthyroidism.
- Subjects with one or more seizures without a clear and resolved etiology.
- Treatment with a reversible MAOI within 4 weeks prior to study phase I.
- Treatment with fluoxetine within 5 weeks prior to study phase I.
- Treatment with any other concomitant medication not allowed (Appendix A for Substudy 2; Appendix G for Substudy 4) 14 days prior to study phase I.
- No structured psychotherapy will be permitted during the study.
- Current NIMH employee/staff or their immediate family member.
- Additional Exclusion Criteria for substudy 2 (patients with MDD)
  - Previous treatment with ketamine or hypersensitivity to amantadine.
- Additional Exclusion Criteria for Substudy 4 (patients with MDD)
  - Subjects who currently are using drugs (except for caffeine or nicotine), must not have used illicit substances in the 2 weeks prior to screen and must have a negative alcohol and drug urine test (except for prescribed benzodiazepines) urine test at screening.
  - Presence of any medical illness likely to alter brain morphology and/or physiology (e.g., hypertension, diabetes) even if controlled by medications.
  - Clinically significant abnormal laboratory tests.
  - For imaging procedures, Presence of metallic (ferromagnetic) implants (e.g, heart pacemaker, aneurysm clip).
  - Subjects who, in the investigator's judgment, pose a current serious suicidal or homicidal risk, or who have a MADRS item 10 score of greater than 4.
- Exclusion Criteria for healthy control subjects (Substudy 4 only)
  - Current or past Axis I diagnosis
  - Presence of metallic (ferromagnetic) implants (e.g., heart pacemaker, aneurysm clips).
  - Presence of medical illness likely to alter brain morphology and/or physiology (e.g., hypertension, diabetes) even if controlled by medications.
  - Treatment with any of the exclusionary medications detailed in Appendix G 14 days prior to Phase 1 of the Substudy 4.
  - Current or past alcohol or substance abuse or dependence diagnosis (except for nicotine or caffeine).
  - Presence of psychiatric disorders in first-degree relatives.
  - Female subjects who are either pregnant or nursing.
  - Current NIMH employee/staff or their immediate family member.

## Questions or feedback

For dataset curation questions, feedback, or requests please email the NIMH Data Science & Sharing Team at [nimhdsst@mail.nih.gov](mailto:nimhdsst@mail.nih.gov) or comment here. For questions about the study design or any other available data, please email Jen Evans at [jennifer.evans@nih.gov](mailto:jennifer.evans@nih.gov).