Ketamine for Combined Depression and Alcohol Use Disorder

Study Overview
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Brief Summary
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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.

Detailed Description
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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 .

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

Conditions
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Depression, Alcohol Use Disorder

Intervention / Treatment
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* Drug: Ketamine Hydrochloride
* Drug: Midazolam Hydrochloride


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 15 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intervention group<br>Ketamine, 0,8 mg/kg body weight, given as four single doses (biweekly for two weeks) | Drug: Ketamine Hydrochloride<br>* 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<br>|
| Active Comparator: Control group<br>Midazolam, 0,8 mg/kg body weight, given as four single doses (biweekly for two weeks) | Drug: Midazolam Hydrochloride<br>* 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<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Depression, Alcohol use disorder, Ketamine, Addiction