Ketamine for Combined Depression and Alcohol Use Disorder (KeDA)

• ClinicalTrials.gov Identifier: NCT06090422
• Recruitment Status: Not yet recruiting
• First Posted: October 19, 2023
• Last Update Posted: October 19, 2023
• Sponsor: University Hospital of North Norway
• Collaborator: University of Exeter
• Information provided by (Responsible Party): Andreas Wahl Blomkvist, University Hospital of North Norway

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Depression; Alcohol Use Disorder	Drug: Ketamine Hydrochloride; Drug: Midazolam Hydrochloride	Phase 1; Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 34 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Ketamine for Combined Depression and Alcohol Use Disorder: A Blinded Randomized Active Placebo-controlled Trial (the KeDA Trial)
• Estimated Study Start Date: January 1, 2024
• Estimated Primary Completion Date: July 1, 2027
• Estimated Study Completion Date: July 1, 2027

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

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

Secondary Outcome Measures :

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

Other Outcome Measures:

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

Eligibility Criteria

• Ages Eligible for Study: 15 Years to 65 Years (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Contacts

Contact: Andreas W Blomkvist, M.D.; 41694637 ext +47; andreas.wahl.blomkvist@unn.no

Contact: Ole K Grønli, Assoc Prof; 91713535 ext +47; ole.k.gronli@unn.no

Sponsors and Collaborators

University Hospital of North Norway

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

More Information

• Responsible Party: Andreas Wahl Blomkvist, Principal Investigator, University Hospital of North Norway
• ClinicalTrials.gov Identifier: NCT06090422
• Other Study ID Numbers: 2022/484848(REK); 2023-506052-24 ( EudraCT Number ); U1111-1293-2654 ( Other Identifier: WHO UTN )
• First Posted: October 19, 2023
• Last Update Posted: October 19, 2023
• Last Verified: October 2023

• 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

Keywords provided by Andreas Wahl Blomkvist, University Hospital of North Norway:

Depression; Alcohol use disorder; Ketamine; Addiction

Additional relevant MeSH terms:

Alcoholism; Depression; Depressive Disorder; Alcohol Drinking; Behavioral Symptoms; Mood Disorders; Mental Disorders; Drinking Behavior; Alcohol-Related Disorders; Substance-Related Disorders; Chemically-Induced Disorders; Midazolam; Ketamine; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Anesthetics, Dissociative; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Central Nervous System Depressants; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Adjuvants, Anesthesia; Hypnotics and Sedatives; Anti-Anxiety Agents; Tranquilizing Agents