Ketamine for OUD and Comorbid Depression (OUDCD)

Increasing Retention in Methadone Maintenance Treatment: Feasibility and Preliminary Efficacy of Ketamine for the Treatment of Patients With OUD and Comorbid Depression (OUDCD)

Methadone is a first-line, evidence-based treatment for opioid use disorder (OUD). Unfortunately, retention and adherence in methadone treatment is a major challenge. OUD patients frequently present with co-morbid depression (OUDCD), a risk factor for poor OUD treatment outcomes, overdose, and suicide. The last two decades have seen an exciting and transformational development in the treatment of depression - ketamine. As a safe, rapid-acting anti-depressant deliverable within the context of methadone maintenance treatment, ketamine could feasibly change the landscape of treatment for OUD patients with comorbid depression. This proposal seeks to evaluate implementation outcomes (feasibility and patient acceptance) as well as preliminary efficacy of ketamine on methadone treatment outcomes for OUD patients (n=6) with comorbid depression and depressive symptoms presenting for methadone treatment.

Study Overview

• Status: Terminated
• Conditions: Depressive Disorder; Opioid Use Disorder
• Intervention / Treatment: Drug: Ketamine Hydrochloride

• Study Type: Interventional
• Enrollment (Actual): 5
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21223
      • University of Maryland Baltimore

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria

• From NHS prescreen (no contact, Study Day 0): Between the ages of 18 to 65 years old
• From NHS prescreen (no contact, Study Day 0): Daily use of illicit opioids
• From NHS prescreen (no contact, Study Day 0): Fulfillment of DSM-5/ICD-10 criteria for moderate-to-severe opioid or heroin use disorder
• From NHS prescreen (no contact, Study Day 0): Acceptance into methadone maintenance care for treatment of opioid or heroin use disorder
• From screening for study eligibility (Study Contact Day 1): A total of 10 or more points on the PHQ-9
• From screening for study eligibility (Study Contact Day 1): Have had no prior sustained experience/dependence on ketamine or PCP (i.e., must answer "no" to all four questions on the ketamine/PCP screen)

Exclusion Criteria

• From NHS prescreen (no contact, Study Day 0): Patients transferring from another program of opioid agonist treatment
• From NHS prescreen (no contact, Study Day 0): Electrocardiogram (ECG) findings of tachycardia, prior myocardial infarction, myocardial ischemia, or aberrant conduction
• From NHS prescreen (no contact, Study Day 0): Self-report of recent prescribed or illicit benzodiazepine use ("Xannies", or "bars")
• From NHS prescreen (no contact, Study Day 0): Urine screen positive for pregnancy
• From NHS prescreen (no contact, Study Day 0): Stage 2 hypertension, defined by a systolic blood pressure (SBP) > 140 mmHg or a diastolic blood pressure (DBP) > 90 mmHg
• From NHS prescreen (no contact, Study Day 0): Clinically significant abnormal laboratory values, physical exam findings or self-reported medical conditions for which a transient increase in blood pressure could be significantly detrimental (e.g., cardiovascular disease), as determined by the evaluating intake physician
• From NHS prescreen (no contact, Study Day 0): Any clinically significant abnormal findings from intake health and physical examination
• From NHS prescreen (no contact, Study Day 0): Any indication of serious mental illness or psychiatric disorder from the attending's evaluation notes
• From Liver Function Screen (Study Contact Day 2): Baseline alkaline phosphatase > 2.5 times the upper limit of normal
• From Liver Function Screen (Study Contact Day 2): Baseline aspartate aminotransferase > 3 times the upper limit of normal
• From Psychiatric Evaluation (Study Contact Day 2) Current or previous recreational use of ketamine or PCP
• From Psychiatric Evaluation (Study Contact Day 2): Subjects who meet DSM-5 criteria for current bipolar disorder
• From Psychiatric Evaluation (Study Contact Day 2): Past or current presence of psychotic symptoms, or diagnosis of a lifetime psychotic disorder including schizophrenia or schizoaffective disorder
• Subjects who meet DSM-5 criteria for current or history of psychotic spectrum disorders

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

Experimental: Ketamine

Drug: Ketamine Hydrochloride; Ketamine will be administered by a nurse in a 2-week treatment phase, during which participants will receive six IV infusions of 0.5 mg/kg (over 40-50 minutes) ketamine three times per week. Infusion days for patients will be on Mondays, Wednesdays, and Fridays, +/- 1 day. Ketamine infusions will take place at the UMB General Clinical Research Center (GCRC). The GCRC nurse will deliver ketamine within a private exam room. The infusions will last 40-50 min, and the participant will be observed by the GCRC clinical staff for 2 hours post-infusion. Vital signs will be monitored throughout the treatment; specifically, blood pressure, pulse ox and heart rate will be checked prior to treatment, q20 minutes during infusion, and q30-60 minutes after infusion for up to three hours.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Feasibility: Study Recruitment	Feasibility will be assessed via participant recruitment: 50% of eligible patients approached will consent to participation in the pilot.	One year
Feasibility: Study Retention	75% of participants will be retained throughout the duration of ketamine infusion procedures	One year
Patient Acceptability: Acceptability of the Intervention Measure (AIM)	Acceptance will be assessed via scores on the Acceptability of the Intervention Measure (AIM): Distribution summarized with mean and 95% C.I. Scale values range from 1 to 5 with higher mean values representing greater agreement and/or acceptability.	One month
Patient Acceptability: Engagement	Engagement will be assessed via dosing records of observed ketamine administration: distribution of percentage of completed infusions per patient.	One month

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Patient Treatment Retention	One-month (30-day) methadone treatment retention as a binomial (yes/no) variable outcome.	Three months
Changes in Psychiatric Diagnosis of Depression	Assessment of changes in depression (MADRS score) will be made at baseline and on the final study day based on a Minimal Clinically Important Difference (MCID) defined change of 1.9 points	One month
Changes in Depressive Symptoms	Assessment of changes in symptoms of depression, measured with the Patient Health Questionnaire (PHQ-9) will be made at baseline and on the final study day.	One month

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Self-report of illicit substance use	Assessment of changes in number of days of substance use from baseline to the last study contact. Drug use is assessed via self-report of past-two-week use of four common substances: opioids (including heroin, fentanyl, and nonprescribed opioids), cocaine, benzodiazepines, and alcohol; "other" is a fifth category. Total days used (out of a possible 14) is recorded.	One month
Subjective Opioid Withdrawal Scale (SOWS)	Assessment of changes in scores on the SOWS from baseline to the last study contact day. SOWS is a 16-item patient self-report instrument to assess common subjective symptoms of craving and withdrawal.	One monrh
Objective Opioid Withdrawal Scale (OOWS)	Assessment of changes in scores on the OOWS from baseline to the last study contact day. The OOWS is a 13-item clinical assessment of observable physiological signs of withdrawal.	One month
Craving Assessment	Assessment of changes in scores on the Craving Assessment from baseline to the last study contact day. This assessment is an adapted one-item visual-analog scale of self-report of craving for drugs.	One month
Pittsburgh Sleep Quality Index (PSQI)	Assessment of changes in scores on the PSQI from baseline to the last study contact day. The PSQI is a self-rated 19-item questionnaire that assesses sleep quality and disturbances over a one-month time interval. Seven component scores are generated: subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medication, and daytime dysfunction. The sum of scores for the 7 components yields one global score. Assessment of changes will be based on the global score.	One month
The Short Inventory of Problems-Revised (SIP-R)	Assessment of changes in scores on the SIP-R from baseline to the last study contact day. The SIP-R is a 15-item self-report assessment of the adverse consequences of substance use.	One month
Generalized Anxiety Disorder 7-item scale (GAD-7)	Assessment of changes in scores on the GAD-7 from baseline to the last study contact day. The GAD-7 is a 7-item screen designed to identify individuals with probable anxiety. Each item is scored with a score between 0 and 3 (Not at all sure= 0; Several days= 1; Over half the days= 2; Nearly every day= 3), yielding a total between 0 and 21.	One month
Acceptability of the Intervention (AIM)	Assessment of changes in scores on the AIM from baseline to the last study contact day. An established implementation instrument used widely in clinical research, the AIM is a 4-item Likert-type measure of acceptability of an intervention.	One month
Clinician Administered Dissociative Symptom Scale (CADSS-6)	Assessment of changes in scores on the CADSS-6 across ketamine infusion days. The CADSS-6 is a 6-item clinician-administered assessment of treatment-emergent dissociation, an adverse event associated with I.V. ketamine; administered 5-10 minutes following cessation of the ketamine infusion on all infusion days	Two weeks
Drug Effects Questionnaire-5 (DEQ-5)	Assessment of changes in scores on the CADSS-6 across ketamine infusion days. The DEQ is a five-point self-report visual analogue scale-based assessment of two key aspects of an individual's acute, subjective response to the experience of drug consumption: (i) the strength of substance effects and (ii) desirability of substance effects; administered immediately following CADSS-6 administration.	Two weeks
Modified Aldrete	This assessment determines safe discharge from the hospital following each day of ketamine infusion, and will be administered just prior to release. This 5-point clinical assessment is used as a post-operative tool to determine safe discharge following anesthesia. Scores of 0 to 2 are assigned to each of five domains, which include Activity, Respiration, Circulation, Consciousness and Oxygen Saturation.	Two weeks

Collaborators and Investigators

• Sponsor: University of Maryland, Baltimore
• Investigators: Principal Investigator: Annabelle Belcher, PhD, University of Maryland, Baltimore

Study record dates

Study Major Dates

• Study Start (Actual): April 4, 2022
• Primary Completion (Actual): November 17, 2023
• Study Completion (Actual): November 30, 2023

Study Registration Dates

• First Submitted: September 10, 2021
• First Submitted That Met QC Criteria: September 10, 2021
• First Posted (Actual): September 21, 2021

Study Record Updates

• Last Update Posted (Actual): March 7, 2024
• Last Update Submitted That Met QC Criteria: March 5, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Chemically-Induced Disorders; Substance-Related Disorders; Mood Disorders; Narcotic-Related Disorders; Depressive Disorder; Opioid-Related Disorders; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anesthetics, Dissociative; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Ketamine
• Other Study ID Numbers: HP-00096377

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
• product manufactured in and exported from the U.S.: No