Depression is a common condition, with serious negative effects on the health and quality of life of those affected. While there are currently various medications which attempt to treat depression, they often take a long time to begin to work and do not work at all for many people. There is therefore a need for new treatments which work quickly and effectively.

One such medication is called ketamine. Studies have shown that ketamine can treat symptoms of depression quickly. This quick action sets ketamine apart from many antidepressants that take weeks to show noticeable effects. One way that it may do this is by creating a transient sense or feeling of being separated from reality, such as seeing or hearing things that are not really there. Another way to create these same feelings is with virtual reality (VR), where a person can feel as though they are entering a 3-dimensional virtual computer-generated world by wearing a special headset or goggles with a computer inside.

In this study, all participants will receive standard ketamine treatments for depression. Half of the participants will also use a VR headset while receiving the ketamine treatments to see if ketamine and VR acting together provide a better treatment for symptoms of depression than ketamine alone.

This is a small pilot trial. The main purpose of this trial is to learn if it is possible to run a larger clinical trial comparing "ketamine and VR" with "ketamine alone", for adults with treatment-resistant depression. The researchers will study this by seeing how many participants take part in the study within 1-2 years, and how many complete the study treatments and tests. The researchers will also compare the two study groups to see if "ketamine and VR" provide a better treatment for symptoms of depression than "ketamine alone".

Depression is the single largest contributor to global disability, and afflicts individuals of all ages, races, genders, and classes. The significant morbidity is associated with depressive disorders relates to myriad direct and indirect financial costs to individuals and society. It also bears significant mortality, as one of the strongest risk factors for suicide.

Depression is also challenging to treat, with standard antidepressant therapy providing remission to only one third of patients, and incompletely improving the condition of another one third. Even when standard therapy is effective, it can take as long as six weeks for improvement of cognitive/emotional symptoms to become apparent. The final one third of patients often undergo a therapeutic odyssey in which various medications are attempted with no measurable benefit. Ultimately these patients receive a diagnosis of treatment-resistant depression (TRD).

Ketamine has emerged as a fast-acting intervention for the treatment of depressive disorders, which can reach maximum efficacy in only 24 hours and persist for 1-2 weeks. Ketamine is safe, well-tolerated, familiar to many providers and has become widely available as a treatment for depression.

Virtual reality (VR), a technology which immerses users in a controlled digital experience, has also recently been recognized for its potential in the treatment of mental health disorders and recent studies have identified similarities in proposed mechanisms for ketamine and VR in the treatment of depression (e.g. the creation of a non-ordinary and non-rigid experiences of consciousness, and the production of evocative or hallucinatory sensory experiences). However, this combination of interventions has not yet been studied.

Here, the investigators propose to study the combined effect of ketamine and VR in the vulnerable adult mental health population undergoing ketamine therapy for treatment-resistant depression (TRD).

In Phase I of the study, participants (N=3-5) will provide feedback to develop the VR software for this study population.

In Phase II, study participants (N=26) will be randomized to control (standard of care ketamine alone, Group I) or intervention (VR + ketamine concurrently (VR-K), Group II) groups to report on protocol feasibility and to inform the development of a definitive trial to assess VR-K treatment efficacy. All participants will receive a typical sub-anesthetic dose of ketamine (0.5mg/kg) infused intravenously (IV) over 45 minutes, and will be monitored by research staff for up to 90 minutes post-procedure. Each participant will receive a total of 4 ketamine treatments, 2 treatments per week for 2 weeks. All patients will continue their baseline antidepressant regimens while engaged in the study, consistent with standard ketamine therapy for TRD. Participants in the intervention group will wear a virtual reality headset at the onset of each standard ketamine therapy session, and will be immersed in a tailor-made virtual environment of positive outdoor scenes to provide relaxation and reprieve from negative thoughts.

Psychometric surveys will be used to assess the effects of both treatment arms on mood and psychiatric outcomes (depression and anxiety symptoms), side effects (sedation, dissociation, vitals), cognitive function, neural activity (EEG), and patient satisfaction with virtual reality.

Inclusion Criteria:

• Age ≥ 18, able to provide informed consent
• Patient diagnosed with treatment-resistant depression
• Outpatient recommended and approved by psychiatrist for ketamine treatment
• Patients who are on IV ketamine and requiring at least 4 treatments of IV ketamine per course (prescribed by their physiatrist)
• Cognitively alert, oriented, and able to watch immersive content and respond to questions
• Negative human chorionic gonadotropin test before treatment, for female participants of childbearing potential who are not practicing medically appropriate methods of birth control (e.g., hormonal contraceptives, implants, injectables, intrauterine devices, intrauterine systems, etc.)

Exclusion Criteria:

• History of psychosis/comorbid psychiatric disorders/psychotic depression/dissociative syndromes, significant personality disorder, as clinically assessed by psychiatrist
• Using non-prescribed substance (e.g., cannabis) or alcohol use within the preceding 48 hours of treatment
• History of substance misuse and/or dependence, including chronic alcohol abuse
• Previous ketamine use
• Acute dementia/delirium
• Acute risk of suicide at baseline, as determined by the study psychiatrist
• Pregnancy/breastfeeding
• Previous sensitivity to ketamine or related compounds
• Unstable medical condition which may require anesthesia consult
• History of elevated intracranial pressure or cerebrovascular accident
• Recent (within 6 weeks) major cardiovascular event (such as myocardial infarction)
• Significant motion sickness (i.e. occur during exposure to physical/visual and virtual motion, cybersickness, etc.) self-identified by patient
• Inability to communicate with the study team

De-identified participant-level data will be made available upon reasonable request to study PI following publication of full trial results.

This is a pilot trial and full inferential analysis will not be conducted until completion of the full trial. As such, data will be available following publication of the primary results of the subsequent full trial.

Data and supporting information will be made available following reasonable request directly to study PI.