Ketamine-Assisted Psychotherapy for Treatment-Resistant Depression

The goal of this clinical trial is to understand the effect of ketamine on the brain in people with treatment-resistant depression (TRD). TRD occurs in around a third of people with depression and leads to higher suicide rates compared to those with major depressive disorder. A desperate need for a rapid acting antidepressant drug (RAAD) is needed to help improve quality of life for people with TRD. Ketamine has been shown to be a RAAD, and esketamine (a form of ketamine) was approved by the FDA to treat TRD. Ketamine has been known to cause dissociative experiences, that can lead to an increase in the "Openness to Experience" personality trait and psychological flexibility that occurs at "peak experience". This has been shown to improve mental health conditions and lower suicide risk. This study aims to further understand if there is a connection between this new change of mind and changes in brain activity. Ketamine has been shown to improve brain plasticity as well, specifically in the frontolimbic region of the brain, an area associated with depression. The investigators are analyzing the brain using functional magnetic resonance imaging (fMRI), a method used to measure brain activity. The frontolimbic region is also associated with cognitive flexibility and emotional processing, an important hurdle in treating TRD. Due to this, the investigators are pairing the ketamine treatment with psychotherapy sessions, to guide the processing experience, which can lead to higher emotional flexibility. The main questions this study aims to answer are: * Are frontolimibic plasticity circuitry changes associated with openness to experience and peak experience? * Is it feasible to recruit and retain people through a two-month KAP study? * Is the structure of the study effective for treating TRD? Participants will: * Visit the facilities 6-8 times * Complete 2 MRI brain scans * Complete 3-4 psychotherapy sessions * Receive 1-2 doses of ketamine * Complete online surveys between 3-4 visits

The proposed study is a single center study investigating the effect of ketamine modulation on the brain signature of treatment resistant depression (TRD). The patients will undergo 2 scanning visits (baseline and follow-up). They will also receive 1-2 treatments of ketamine IM injection and 3-4 psychotherapy sessions. Patients with TRD will be asked to come to the PI's lab for 2 visits, and 6 in the Department of Psychiatry. On visit 1, after consenting and doing the drug screen, the subjects will be asked questions on their depression experience. Subjects will then fill out demographic and clinical questionnaire to assess mood, anxiety, pain, history of early trauma, and stress. Patients will be asked to rate their depression and pain level using a visual analogue scale (VAS). During visit 1, Drs. Geha and Swogger will interview the patients to inquire about any prior drug allergies including allergies to medications that could be possibly used in this study (ketamine/ondansetron/lorazepam/clonidine). Possible side effects will be explained to the patients. They will then undergo 60 minutes of functional and structural brain scanning, which will serve as a baseline scan. Visits 2 and 3 will be psychotherapy sessions with Dr. Swogger to prepare for the ketamine session and focus on their difficulties and goals for the medicine session. Strategies for working with ketamine will be reviewed. Visits 4 and 6 will be the ketamine IM injection sessions. Visit 4 they will receive 0.5 mg/kg but will not exceed 60 mg regardless of weight. Visit 6 may be a higher dose, but will not exceed 60 mg. The dose will be determined by Drs. Geha and Swogger based on the patients' experience and response in visit 4. Ondansetron will be available for nausea, lorazepam for uncontrolled agitation, and clonidine for uncontrolled hypertension. Throughout the visits members of the study team will be present to ensure patient comfort and offer reassurance, redirection, etc. They will also take notes for later processing in psychotherapy visits. When the patient emerges from non-ordinary state of consciousness, they will complete the MEQ, and the study team will complete CADSS-6 and record any other pertinent information about the experience. Once it is deemed safe, the patient may leave via someone driving them home after the visit and will be instructed on safety measures for the rest of the day. Visits 5 and 7 will be follow up psychotherapy visits the day after the ketamine treatment. They will discuss and process the experience. If the patient wishes not to receive another dosage, then visit 7 will not occur and they will proceed with visit 8 after visit 5. Visit 8 is conducted in the PI's lab about 4 weeks after visit 5 (one dose) or 7 (two doses). This will include answering similar questionnaires from the baseline visit to assess depression, pain, anxiety, mood, trauma, and personality. The patient will discuss the accessibility and feasibility of the study wi trial.show_full_description

Inclusion Criteria The following inclusion criteria must be met for all subjects to be considered eligible to participate: 1. 18 years old or older 2. Able to speak, read, and understand English 3. In generally stable health 4. Must have treatment resistant depression, as defined as scoring in the moderate or above range on the HDRS and having failed two adequate trials of antidepressants in the last two years. Exclusion Criteria General exclusion criteria for all subjects include: 1. Uncontrolled hypertension 2. Impaired cardiac status a. Abnormal ECG report in the last month prior to screening 3. Chronic Obstructive Pulmonary Disease 4. Congenital Long QT Syndrome 5. ≥265lbs or 120kg 6. Severe obesity (BMI ≥40) 7. Increased intracranial or cerebrospinal pressure 8. Pregnancy or breastfeeding 9. Hyperthyroidism 10. Prior adverse response to ketamine, including allergic reaction 11. Symptoms of psychosis or prodromal phase 12. Severe personality disorder 13. Autistic Spectrum Disorders 14. Bipolar disorder 15. History of substance abuse, defined as a score of three or more on Drug Abuse scale (prior use of psychedelics allowed) 16. Past-year suicide attempt or ongoing ideation with intent to act 17. All exclusion criteria for magnetic resonance imaging safety: any metallic implants, brain or skull abnormalities, tattoos on large body parts, and claustrophobia. 18. Taking medications that could interact with ketamine. Examples include but are not limited to: any types of stimulants, aripiprazole, diphenhydramine, hydromorphone, escitalopram, fluoxetine, alprazolam, and sertraline. Each subject's current medications will be evaluated for interactions with ketamine before admission into the trial.