Ketamine for Combined Depression and Alcohol Use Disorder (KeDA)

Ketamine for Combined Depression and Alcohol Use Disorder: A Blinded Randomized Active Placebo-controlled Trial (the KeDA Trial)

The goal of this clinical trial is to investigate the effects of ketamine, in combination with standard inpatient addiction therapy, for adults with depression and alcohol use disorder. After screening and enrollment, participants will undergo baseline assessments of depression, measures of alcohol use and craving, as well as neurocognitive function. Participants will then be randomized to either ketamine (intervention) or midazolam (control). All participants will be admitted for standard inpatient addiction therapy while receiving ketamine or midazolam. Measures on safety, depression and alcohol use disorder will be repeatedly assessed during and after treatment. Final follow-up assessment is scheduled 6 months after baseline assessment.

Study Overview

• Status: Not yet recruiting
• Conditions: Depression; Alcohol Use Disorder
• Intervention / Treatment: Drug: Ketamine Hydrochloride; Drug: Midazolam Hydrochloride

Detailed Description

Depression and alcohol use disorder (AUD) often coexist and can create significant challenges for individuals seeking effective treatment. Traditional treatment approaches have shown limited success in addressing both conditions simultaneously. Ketamine has shown to have promising rapid antidepressant effects and a possible role in the treatment of substance use disorders. By targeting both depression and AUD simultaneously, ketamine has the potential to offer dual benefits, improving depressive symptoms while addressing alcohol cravings or consumption. Furthermore, rapid relief from depressive symptoms may enhance motivation for recovery, reduce the risk of relapse, and improve overall treatment engagement and outcomes. Although ketamine is generally considered safe when administered under medical supervision, the safety profile in individuals with comorbid depression and AUD needs further investigation. The overall objective of this study is to examine the safety and efficacy of ketamine on adults with depression and AUD that are admitted for standard inpatient addiction therapy.

The study will only include adults with at least moderate depression and alcohol use disorder as their primary substance use disorder that are admitted for inpatient addiction therapy. Participants that are unable to give informed consent or have contraindication(s) for ketamine will be excluded.

After screening and enrollment, participants will undergo baseline assessments with measures on depression (using Montgomery-Åsberg Depression Rating Scale (MADRS) and Beck Depression Inventory-II (BDI-II)), alcohol use (using Timeline Follow-Back method (TLFB)), alcohol craving (using Short version of Alcohol Craving Questionnaire (ACQ-Short) and Penn Alcohol Craving Scale (PACS)) and neurocognitive function (using Cambridge Neuropsychological Test Automated Battery (CANTAB)). Participants will then be randomized to intervention group or control group. The intervention group will receive ketamine as four single doses, given biweekly for two weeks. The control group will receive midazolam as active placebo. Participants will undergo several follow-up assessments after treatment (1-2 day(s), 1 week, 2 weeks and 4 weeks after treatment). Final follow-up assessment will be 6 months after baseline.

By using open questions and specific instruments for assessing adverse effects associated with ketamine (using modified version of Ketamine Side Effect Tool (mKSET)), the trial will assess the frequency, severity and duration of any adverse events and severe adverse events. All adverse events will be evaluated with regards to its causal relationship to ketamine. In addition, physician-assessed and patient-assessed tolerability will be registered. Changes in neurocognitive function from baseline will be assessed after treatment.

Changes in depression will be measured several times using rater-blinded MADRS-assessment and self-report instrument (BDI-II). Measures of alcohol use (TLFB), alcohol craving (ACQ-short and PACS), relapse risk and time until relapse will used as measures on alcohol use disorder following treatment. Several exploratory objectives will be examined, including changes in alcohol dependence severity (using Severity of Alcohol Dependence Questionnaire (SADQ)), changes in quality of life (using World Health Organizations brief quality of life questionnaire (WHOQOL-BREF)), changes in self-reported treatment effectiveness (using Treatment Effectiveness Assessment (TEA)) and changes in anxiety (using Generalized Anxiety Disorder scale (GAD-7)). Finally, data on the subjective experience of the treatment (using Ego Dissolution Inventory (EDI), Emotional Breakthrough Inventory (EBI) and Mystical Experience Questionnaire (MEQ30)) will be collected and used in a regression model with baseline measures to assess predictors of treatment response on measures of depression and AUD .

• Study Type: Interventional
• Enrollment (Estimated): 34
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Andreas W Blomkvist, M.D.; Phone Number: +47 41694637; Email: andreas.wahl.blomkvist@unn.no
• Study Contact Backup: Name: Ole K Grønli, Assoc Prof; Phone Number: +47 91713535; Email: ole.k.gronli@unn.no

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Please contact the project team for a full and detailed list of inclusion/exclusion criteria

Inclusion Criteria:

• Currently abstinent from alcohol
• At least moderate depression without psychotic features
• Minimum Montgomery-Åsberg Depression Rating Scale (MADRS) of 20
• Alcohol dependence
• Admitted for inpatient addiction therapy at University Hospital of North Norway

Exclusion Criteria:

• Intoxicated or in significant withdrawal from alcohol or drug use
• Not able to give adequate informed consent
• Current or past history of schizophrenia, schizophreniform disorder, paranoid delusional disorder, schizoaffective disorder
• Current or historical diagnosis of schizophrenia in a first degree relative
• Cardiovascular conditions: recent stroke (< 1 year from informed consent), recent myocardial infarction (< 1 year from informed consent), uncontrolled hypertension (>150/100 mm Hg) or recent arrhythmia (< 1 year from informed consent; clinically significant arrhythmia requiring treatment at hospital)
• Liver (Child-Pughs Class C) or kidney (Creatinin clearance < 30 mL/min) failure
• Heart failure (the New York Heart Association Functional Classification (NYHA) class III or IV)
• Chronic respiratory failure (requiring long-term oxygen therapy (LTOT) and/or Global Initiative for Chronic Obstructive Lung Disease system (GOLD) stage 3 or higher)
• Previous anaphylactic reaction to ketamine or midazolam
• Illegal use of ketamine the last 6 months
• Pregnancy or breastfeeding
• Current or suspected increased intracranial pressure

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Intervention group; Ketamine, 0,8 mg/kg body weight, given as four single doses (biweekly for two weeks)	Drug: Ketamine Hydrochloride; Four single-doses, given two times per week for two weeks Dose: 0,8 mg/kg body weight Route of administration: intravenous infusions over 40 minutes
Active Comparator: Control group; Midazolam, 0,8 mg/kg body weight, given as four single doses (biweekly for two weeks)	Drug: Midazolam Hydrochloride; Four single-doses, given two times per week for two weeks Dose: 0,02 mg/kg body weight Route of administration: intravenous infusions over 40 minutes

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Depression	Change from baseline using rater-blinded Montgomery-Åsberg Depression Rating Scale (MADRS) (range 0-60; higher score indicate worse outcome)	Within 3 days after final treatment session
Adverse reaction severity	Number of severe, moderate and severe adverse reactions	Up to 6 months
Adverse reaction frequency	Frequency of adverse reactions	Up to 6 months
Cambridge Neuropsychological Test Automated Battery (CANTAB)	Assess within- and between-group changes in neurocognitive function from baseline to within three days from the final treatment session	Within 3 days after final treatment session
Tolerability using the ketamine side effect tool (KSET)	Physician- and self-reported tolerability of each treatment session (good, moderate and poor)	Up to 1 month

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Alcohol craving tonic	Penn Alcohol Craving Scale (PACS) (range 0-30; higher score indicate worse outcome)	Repeated measurements from baseline and 1 day, 1 week, 2 weeks and 4 weeks after final treatment session
Alcohol craving phasic	Alcohol Craving Questionnaire - Short version (ACQ-short) (range 12-84; higher score indicate worse outcome)	Repeated measurements from baseline and 1 day, 1 week, 2 weeks and 4 weeks after final treatment session
Depression response/remission	Rates of response (50% or more reduction in MADRS from baseline) and remission (9 points or less in MADRS)	Repeated measurements from baseline and 1 day, 1 week and 2 weeks after final treatment session

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Relapse risk	Incidence of relapse in each group (defined as two or more consecutive heavy drinking days)	From baseline until 6 months after baseline
Time until relapse	Average time from final treatment session until relapse	From baseline until 6 months after baseline
Duration of antidepressant effect (blinded-rater assessed)	Change in Montgomery-Åsberg Depression Rating Scale (MADRS) (range 0-60; higher score indicate worse outcome)	From baseline until 6 months after baseline
Duration of antidepressant effect (self-report)	Change in the Beck Depression Inventory-II (BDI-II) (Range 0-63; higher score indicate worse outcome)	From baseline until 6 months after baseline

Collaborators and Investigators

• Sponsor: University Hospital of North Norway
• Collaborators: University of Exeter
• Investigators: Study Director: Ole K Grønli, Assoc Prof, University Hospital of North Norway; Principal Investigator: Andreas W Blomkvist, M.D., University Hospital of North Norway

Study record dates

Study Major Dates

• Study Start (Estimated): January 1, 2024
• Primary Completion (Estimated): July 1, 2027
• Study Completion (Estimated): July 1, 2027

Study Registration Dates

• First Submitted: July 1, 2023
• First Submitted That Met QC Criteria: October 16, 2023
• First Posted (Actual): October 19, 2023

Study Record Updates

• Last Update Posted (Actual): October 19, 2023
• Last Update Submitted That Met QC Criteria: October 16, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: Depression; Ketamine; Addiction; Alcohol use disorder
• Additional Relevant MeSH Terms: Behavioral Symptoms; Mental Disorders; Chemically-Induced Disorders; Drinking Behavior; Alcohol-Related Disorders; Substance-Related Disorders; Mood Disorders; Alcohol Drinking; Alcoholism; Depression; Depressive Disorder; 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; Tranquilizing Agents; Psychotropic Drugs; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Ketamine; Midazolam
• Other Study ID Numbers: 2022/484848(REK); 2023-506052-24 (EudraCT Number); U1111-1293-2654 (Other Identifier: WHO UTN)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No