Anti-suicidal Effects of Buprenorphine In Depressed Individuals

Functional Brain Mechanisms Underlying the Anti-Suicidal Effects of Low-dose Buprenorphine in Major Depression

This study aims to examine the effect of low-dose buprenorphine as an add-on to treatment-as-usual for suicidal ideation in individuals with major depression, and investigate the functional brain activity related to its potential anti-suicidal effect.

Study Overview

• Status: Withdrawn
• Conditions: Suicidal Ideation; Major Depressive Disorder
• Intervention / Treatment: Drug: Belbuca Buccal Product; Other: Placebo

Detailed Description

Buprenorphine is an approved treatment for pain and opioid relapse prevention. Buprenorphine has recently shown promise in the treatment of depression and suicidal ideation relatively faster than currently available antidepressants, but its mechanisms in treating these conditions are unknown. Buprenorphine activates the mu opioid receptor in the brain and blocks the kappa opioid receptor. Activation of the mu receptors produces pleasant emotions while the kappa receptors are linked to dysphoria and other negative emotional states. By blocking kappa receptors, buprenorphine may reduce negative emotions and improve suicidal thoughts.

In this project, we will compare buprenorphine to placebo as adjunctive to usual treatments for patients who still have depression and suicidal thoughts despite being treated with adequate antidepressant medications for at least 4 weeks. We hypothesize that suicidal ideation will decrease after two weeks of treatment in the buprenorphine group relative to the placebo group.

Using functional magnetic resonance imaging, we will also examine the effects of buprenorphine on the activity of brain regions involved in the brain's response to negative emotions and test whether these effects are associated with the reduction in suicidal thoughts. This would provide some evidence that the antidepressant and anti-suicidal effects of buprenorphine are related to its kappa opioid receptor blockade.

The mechanism of action of buprenorphine is different from the currently available antidepressants. This study will help understand this mechanism which may help refine the use of buprenorphine in this context. Research in this area may also facilitate the development of new anti-suicidal treatments (i.e., other opioid-active compounds).

• Study Type: Interventional
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Mina M Rizk, MD; Phone Number: 929-305-5055; Email: mina.rizk@nyspi.columbia.edu
• Study Contact Backup: Name: Jeffrey M Miller, MD; Phone Number: 646-774-7613‬; Email: jeffrey.miller@nyspi.columbia.edu

Study Locations

• United States
  • New York
    • New York, New York, United States, 10032
      • New York State Psychiatric Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 63 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

In order to be eligible to participate in this study, an individual must meet all of the following criteria:

1. Provision of signed and dated informed consent form.
2. Stated willingness to comply with all study procedures and availability for the duration of the study.
3. Male or female.
4. Aged 18-65 years.
5. Ability to take oral medication and be willing to adhere to the treatment regimen.
6. Current major depressive episode.
7. Hamilton Depression Rating Scale (HDRS) Score > 16.
8. Active suicidal ideation (Columbia Suicide Severity Rating Scale (C-SSRS) of 3 or more).
9. Participants must have been on a medication regimen for depression that includes an adequate dose of antidepressant for at least the past 4 weeks.

Exclusion Criteria:

An individual who meets any of the following criteria will be excluded from participation in this study:

1. Current active psychosis or mania.
2. Current or past alcohol use disorder or substance use disorder involving any prescribed or any illicit drug (opioid, benzodiazepine, or other drug use) including mild severity.
3. Family history of alcohol or substance use disorder in a first-degree relative.
4. Current or past history of prescription or non-prescription opioid use.
5. History of other risk factors for the development of opioid misuse and opioid use disorder other than comorbid depression (e.g., homelessness, criminal record, aggressive or violent behavior that resulted in injury to another person).
6. Current acute or chronic pain.
7. Neurological disorders (e.g., epilepsy, brain tumors or patients with increased intracranial pressure due to other reasons).
8. A history of prior head trauma with evidence of cognitive impairment. Participants who endorse a history of prior head trauma will be administered the Trail-making A and B test. Those who score 1.5 standard deviations below the mean on the Trail-making A or B will be excluded from study participation.
9. Active significant medical illness that would make study participation hazardous to the participant or compromise study findings or would prevent the participant from completing the study (e.g., oral mucositis, orthostatic hypotension, history of hypotensive disorders, hypokalemia, hypomagnesemia, or clinically unstable cardiac disease, including unstable atrial fibrillation, symptomatic bradycardia, unstable congestive heart failure, or active myocardial ischemia, history of Long QT syndrome or immediate family member with this condition, moderate to severe hepatic impairment or hepatitis, liver cirrhosis , severe chronic pulmonary diseases, significant respiratory depression, acute or severe bronchial asthma, known or suspected gastrointestinal obstruction, including paralytic ileus).
10. Participants taking medications that prolong the QT interval (e.g., Class IA antiarrhythmic medications (e.g., quinidine, procainamide, disopyramide) or Class III antiarrhythmic medications (e.g., sotalol, amiodarone, dofetilide)).
11. Participants taking medications with potentially clinically-significant drug interactions with BELBUCA , including benzodiazepines, central nervous system (CNS) depressants (e.g., alcohol, anxiolytics, general anaesthetics, hypnotics, neuroleptics, phenothiazines, sedatives, tranquilizers), other opioid analgesics, muscle relaxants, diuretics, anticholinergic drugs, non-nucleoside reverse transcriptase inhibitors (e.g., efavirenz, nevirapine, etravirine, delavirdine), protease inhibitors (e.g., atazanavir, ritonavir). Additionally, patients must discontinue CYP3A4 strong inhibitors (e.g., clarithromycin, telithromycin, nefazodone, itraconazole, ketoconazole) 2 weeks before initiation of the study.
12. Known allergy or sensitivity to buprenorphine.
13. If female, pregnancy, abortion or miscarriage in the previous two months, current breastfeeding or plans to conceive during the course of study participation. Patients who are not on contraceptives will be asked to at least use barrier methods during sexual intercourse. All patients must commit to not attempting to become pregnant during participation in the study.
14. Inability to read and speak English fluently.
15. Metal implants or paramagnetic objects contained within the body (including heart pacemaker, shrapnel, or surgical prostheses) which may present a risk to the subject or interfere with the MR scan, according to the guidelines set forth in the following reference book commonly used by neuroradiologists: "Guide to MR procedures and metallic objects", F. G. Shellock, Lippincott Williams and Wilkins NY 2001. Additionally, transdermal patches will be removed during the MRI.
16. Claustrophobia significant enough to interfere with MRI scanning.
17. Weight over 350 lbs or inability to fit into MRI scanner.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Buprenorphine; Buccal Films	Drug: Belbuca Buccal Product; Buprenorphine Buccal Films
Placebo Comparator: Placebo; Buccal Films	Other: Placebo; Placebo Buccal Films

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in Beck Scale for Suicidal Ideation (SSI) scores from pre- to Week 2 post-treatment.	Clinician-based questionnaire measuring level of suicidal ideas over the last 7 days; 21 items scored 0 to 2; total score ranges from 0 to 38 (last 2 items not counted), higher scores mean more intense suicidal ideas.	2 Weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in functional magnetic resonance imaging (fMRI) blood oxygen- level dependent (BOLD) signal in the amygdala in response to negative vs. neutral pictures from pre- to Week 2 post-treatment	fMRI negative picture task administered at baseline and week 2 post-treatment	2 Weeks

Collaborators and Investigators

• Sponsor: New York State Psychiatric Institute
• Investigators: Principal Investigator: Mina M Rizk, MD, New York State Psychiatric Institute; Principal Investigator: Jeffrey M Miller, MD, New York State Psychiatric Institute

Study record dates

Study Major Dates

• Study Start (Actual): October 10, 2022
• Primary Completion (Estimated): January 14, 2024
• Study Completion (Estimated): January 14, 2024

Study Registration Dates

• First Submitted: June 16, 2022
• First Submitted That Met QC Criteria: June 16, 2022
• First Posted (Actual): June 22, 2022

Study Record Updates

• Last Update Posted (Actual): November 14, 2023
• Last Update Submitted That Met QC Criteria: November 10, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Behavioral Symptoms; Mental Disorders; Mood Disorders; Self-Injurious Behavior; Suicide; Depressive Disorder; Suicidal Ideation; Depressive Disorder, Major; Physiological Effects of Drugs; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Opioid; Narcotics; Narcotic Antagonists; Buprenorphine
• Other Study ID Numbers: IRB #8086

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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