Long-Term Maintenance With Ketamine and Esketamine for Reduction of Suicide in High-Risk Patients With Depression

The study will consist of a 24-week-long trial examining outcomes in patients with Major Depressive Disorder and suicidal ideation who will receive intravenous (IV) ketamine and intranasal (IN) esketamine, compared to a large sample of matched historical controls. Patients will be recruited from an inpatient psychiatric unit. Eligible patients who provided informed consent will be enrolled in the study that will include a eight IV ketamine treatments, 13 esketamine treatment visits, seven long assessment visits, five short assessment visits, and daily surveys. The study will examine the feasibility, tolerability, and efficacy of repeated IV ketamine followed by esketamine, as well as predictors of treatment response.

Study Overview

• Status: Recruiting
• Conditions: Major Depressive Disorder
• Intervention / Treatment: Drug: Ketamine; Drug: Esketamine

• Study Type: Interventional
• Enrollment (Estimated): 100
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Cristina Cusin, MD; Phone Number: 617-724-5510; Email: mghketamindstudy@partners.org
• Study Contact Backup: Name: Catherine Schuessler, BS; Phone Number: 617-643-7690; Email: mghketamindstudy@partners.org

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Recruiting
      • Massachusetts General Hospital
      • Principal Investigator: Cristina Cusin, MD
      • Contact: Catherine Schuessler, BS; Phone Number: 617-643-7690; Email: mghketamindstudy@partners.org
      • Contact: Catherine Schuessler, BS; Email: mghketamindstudy@partners.org

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Inpatient at a psychiatric unit (or MGH medical unit, awaiting transfer to psychiatry).
2. Male and female, 18-70 years of age, inclusive, at screening.
3. Diagnosis of MDD, single or recurrent, and currently experiencing a major depressive episode (MDE) at least eight weeks in duration, prior to screening, according to the criteria defined in the Diagnosis and Statistical manual of Mental Disorders, Fifth Edition (DSM-5). The diagnosis of MDD will be made by a site psychiatrist and supported by the Mini-International Neuropsychiatric Interview (MINI).
4. Suicidal ideation determined by a minimum score of 1 on item 12 of the QIDS-C assessment and based on admission to the inpatient unit for suicidal thoughts or behaviors.
5. In good general health, as ascertained by medical history. If needed to verify health status, the investigator may order/conduct physical examination (PE) (including measurement of supine and standing vital signs), clinical laboratory evaluations, or ECG.
6. A status of non-childbearing potential or use of an acceptable form of birth control per the following specific criteria:

1. Non-childbearing potential (e.g., physiologically incapable of becoming pregnant, i.e., permanently sterilized (status post hysterectomy, bilateral tubal ligation), or is post-menopausal with her last menses at least one year prior to screening); or 2. Childbearing potential, and meets the following criteria:

1. Childbearing potential, including women using any form of hormonal birth control, on hormone replacement therapy started prior to 12 months of amenorrhea, using an intrauterine device (IUD), having a monogamous relationship with a partner who has had a vasectomy, or is sexually abstinent.
2. Negative urinary pregnancy test at screening, confirmed by a negative urinary pregnancy test prior to receiving study treatment.
3. Willing and able to continuously use a method of birth control during the course of the study (implants, injectable or patch hormonal contraception, oral contraceptives, IUD, double-barrier contraception, sexual abstinence). The form of birth control will be documented at screening.

7. Access to a mobile phone or computer with internet connection. 8. Ability to read, understand and provide written and dated informed consent prior to screening.

9. Must have a provider to manage psychiatric medication, such as a psychiatrist, nurse practitioner, primary care physician, etc., either prior to admission or at discharge from the inpatient unit.

Exclusion Criteria:

1. Any history of previous treatment with IV ketamine.
2. Pregnant or breastfeeding.
3. Subject of childbearing potential who is not willing to use birth control during the study.
4. Unstable medical illness, i.e., severe liver or kidney disease, uncontrolled hypertension, uncontrolled hyperthyroidism
5. Current diagnosis of a moderate to severe substance use disorder (excluding mild or moderate alcohol or cannabis use disorder which will be permitted), within the last six months prior to screening based on DSM-5 criteria.
6. History of bipolar disorder, or any psychotic symptoms in the current or previous depressive episodes.
7. An Axis I or Axis II Disorder, which at screening is clinically predominant to their MDD or has been predominant to their MDD at any time within six months prior to screening (i.e., eating disorder, OCD, PTSD).
8. Currently receiving ECT treatment.
9. Currently receiving frequent or high dose benzodiazepines, opiates, barbiturates, or other CNS depressant medications, based on an increased risk of sedation in combination with ketamine.
10. Has dementia, delirium, amnestic, or any other primary cognitive disorder.
11. Has a clinically significant abnormality on the screening physical examination that might affect safety, study participation, or confound interpretation of study results according to a licensed physician on the study staff.
12. Inability to consent to or comply with the study procedures.

13. Other medical issues:

    1. Hypertension, (SBP ≥160 mmHg or DBP ≥100 mHg) at Screening - untreated
    2. Recent myocardial infarction (within one year)
    3. Lifetime history of surgical procedures involving the brain or meninges, encephalitis, meningitis, degenerative central nervous system (CNS) disorder (e.g., Alzheimer's or Parkinson's Disease), epilepsy, mental retardation, or any other disease/procedure/accident/intervention which, according to the screening done by a licensed physician, is deemed associated with significant injury to or malfunction of the CNS, or history of significant head trauma within the past 2 years
    4. Thyroid stimulating hormone (TSH) outside of the normal limits and clinically significant as determined by the Investigator.
    5. Any other clinically significant abnormal laboratory result (determined as such by the Investigator and/or medical monitor) at the time of the screening.
    6. Patients with diabetes mellitus fulfilling any of the following criteria:

1. Unstable diabetes mellitus defined as glycosylated hemoglobin (HbA1c) >8.5% at screening.

2. Admitted to hospital for treatment of diabetes mellitus or diabetes mellitus- related illness in the past 12 weeks.

g. Patients with a history of narrow angle glaucoma - untreated 14. Inability to comply with ketamine clinic safety procedures, including having reliable escorts to and from visits.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Other: Ketamine and Esketamine Treatment; All study subjects will receive intravenous (IV) ketamine and intranasal (IN) esketamine treatment.

Drug: Ketamine; Study participants will start treatment including two ketamine infusion visits per week during the acute phase, for up to eight ketamine infusion visits. Participants will then be transitioned to maintenance with intranasal esketamine.; Drug: Esketamine; After one month from the eighth ketamine infusion visit, participants will initiate weekly esketamine for 12 weeks, for a total of 13 esketamine treatments. The esketamine visits will happen as per standard of care at the clinic and as instructed by the SPRAVATO Risk Evaluation and Mitigation Strategy.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Feasibility - Retention	For examining the feasibility of treatment with ketamine and esketamine, descriptive analyses will be conducted to assess participants' retention across study visits.	24 weeks
Feasibility - Drop-out Rates	For examining the feasibility of treatment with ketamine and esketamine, descriptive analyses will be conducted to assess participants' drop-out rates across participation in the study.	24 weeks
Tolerability - Cognitive Function and Side Effects	In regard to tolerability, the investigators will closely monitor cognitive functions and side effects during the administration of ketamine and esketamine.	Weeks 0, 1, 2, 3, 4, 8, and 12-24
Tolerability - Dosage of Treatment	In regard to tolerability, the investigators will record the Necessary Clinical Adjustments (NCAs) for dosage of ketamine and esketamine treatments.	Change between weeks 0, 4, 6, 8, 10, 12, 14, 16, 20, 22, and 24
Tolerability - Frequency of Treatment	In regard to tolerability, the investigators will record the Necessary Clinical Adjustments (NCAs) for the frequency of ketamine and esketamine administration.	Change between weeks 0, 4, 6, 8, 10, 12, 14, 16, 20, 22, and 24

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Efficacy - Treatment Response	Descriptive analyses will be performed for percentage of responders (defined as 35% improvement on the QIDS-16) at the end of the IV ketamine acute phase, after the eighth ketamine infusion, and across the esketamine maintenance phase.	Weeks 4, 8, and 12-24
Efficacy - Trajectory of Suicidal Ideation	The change in participants' suicidal ideation will be examined over time and compared to historical controls.	24 weeks
Efficacy - Trajectory of Depression	The change in participants' depression will be examined over time and compared to historical controls.	24 weeks
Efficacy - Hospital Readmission Rates	The change in participants' hospital readmission rates will be examined over time and compared to historical controls.	24 weeks
Efficacy - Prevalence of Suicidal Behavior	The occurrence of suicidal behavior (gestures, attempts, and completed suicide) among participants will be examined over time and compared to historical controls.	24 weeks
Efficacy - Healthcare Utilization	The change in participants' healthcare utilization rates will be examined over time and compared to historical controls.	24 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Exploratory Aim - Predictors of Treatment Response	Exploratory aims will be examined, including predictors of treatment response (defined as 35% improvement in QIDS score) at the end of the acute and maintenance phases.	24 weeks
Exploratory Aim - Predictors of Suicidal Ideation Relapse	Exploratory aims will be examined, including predictors of suicidal ideation relapse (defined as SSI5>1) during time intervals between intravenous ketamine visits and during the esketamine maintenance phase.	24 weeks

Collaborators and Investigators

• Sponsor: Massachusetts General Hospital
• Collaborators: American Foundation for Suicide Prevention

Study record dates

Study Major Dates

• Study Start (Actual): October 13, 2022
• Primary Completion (Estimated): June 1, 2026
• Study Completion (Estimated): June 1, 2026

Study Registration Dates

• First Submitted: June 16, 2022
• First Submitted That Met QC Criteria: July 5, 2022
• First Posted (Actual): July 8, 2022

Study Record Updates

• Last Update Posted (Actual): December 12, 2025
• Last Update Submitted That Met QC Criteria: December 5, 2025
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Keywords: depression; suicidal ideation
• Additional Relevant MeSH Terms: Mental Disorders; Behavioral Symptoms; Self-Injurious Behavior; Mood Disorders; Suicide; Depressive Disorder; Behavior; Suicidal Ideation; Depression; Depressive Disorder, Major; Organic Chemicals; Hydrocarbons; Cyclohexanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Esketamine; Ketamine
• Other Study ID Numbers: 2022P000972

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: The investigators do not plan to share IPD.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No