This pilot study will assess the safety and feasibility of intravenous (IV) ketamine in older adults with Treatment-Resistant Depression (TRD). In addition, this study will develop and utilize innovative methodological approaches to demonstrate the feasibility of precision medicine and mobile health approaches in depression treatment.

Participants in this study will receive ketamine infusions twice a week for 4 weeks (acute phase). Participants who respond or remit will continue with an additional 4 weeks of weekly ketamine infusions (continuation phase). Participants will be assessed at baseline, end of acute phase, and end of continuation phase for effectiveness, safety, and executive functioning. Participants will be asked to complete daily surveys of their depression symptoms during their participation.

Inclusion Criteria:

1. Community-living men and women age 65 years and older;
2. Treatment-resistant depression: defined as unipolar major depressive disorder, non-delusional (diagnosed by SCID-5) that persists despite ≥ 2 adequate antidepressant trials of different classes in the current episode; including at least one evidence-based second-line treatment in the current episode (including serotonin norepinephrine reuptake inhibitors, bupropion, tricyclics, monoamine oxidase inhibitors, or augmentation with an atypical antipsychotic, stimulant, bupropion, lithium, or triiodothyronine
3. Persistent moderate to severe depressive symptoms determined by Patient Health Questionnaire 9-item (PHQ-9)26 score ≥15 at baseline
4. Able to provide informed consent.

Exclusion Criteria:

1. Dementia per history, score < 24 on the Montreal Cognitive Assessment (MoCA), or determined by clinical interview with geriatric psychiatrist to have high likelihood of dementia;
2. Psychotic spectrum or bipolar disorder or severe personality disorder that at the PIs discretion would interfere with safe participation. Anxiety disorders are not an exclusion.
3. Unstable medical conditions such that IV ketamine is not safe or tolerated or that would interfere with participation in a long-term study (i.e., poorly controlled hypertension, life expectancy < 1 year because of terminal illness, unstable angina).
4. Baseline systolic BP > 165 systolic or 100 diastolic at evaluation.
5. Current alcohol or substance use disorder or lifetime recreational ketamine use or other dissociative agent (e.g., PCP).
6. Use of naltrexone, memantine, or any medication that could be considered contraindicated with ketamine.
7. Taking more than 2 adequately-dosed oral antidepressants.
8. High acute risk for suicide and unable to be managed safely in the clinical trial.

4-8 weeks: The first period (Acute Phase) lasted 4 weeks, those who went to the Continuation Phase continued for an additional 4 weeks to total 8 weeks

As far as adverse events (AE's) for this pilot study, all events were recorded during the Acute Phase. No AE's were reported in the Continuation Phase.