Ketamine-Enhanced Therapy for Individuals With Alcohol Use Disorder and Depression: A Pilot Study (KET-DUAL)

Official title

An Open-label Pilot Evaluation of Ketamine-Enhanced Psychotherapy in Individuals With Alcohol Use Disorder (AUD) and Co-morbid Major Depressive Disorder (MDD)

Overview

To assess the safety, feasibility and preliminary efficacy of ketamine-enhanced therapy (KET) for alcohol use disorder (AUD) and comorbid major depressive disorder (MDD) in an open-label, single arm, pilot clinical trial.

Detailed description

New strategies for the treatment of alcohol use disorder (AUD) and co-morbid major depressive disorder (MDD) are urgently required. This population represents a high-risk group that has largely been excluded from addiction-focused trials despite its clinical complexity and poor response to standard interventions.

Recent early phase studies have shown that ketamine-enhanced psychotherapy (KET) can reduce alcohol consumption, enhance motivation and alleviate depressive symptoms. Effects have been shown to be particularly pronounced among participants who also received motivational enhancement therapy, suggesting a synergistic effect between ketamine and psychotherapy.

Emerging evidence suggests that KET may be of promise for AUD, and has demonstrated a good safety profile and potential efficacy in alcohol dependence. However, no trials to date have specifically targeted AUD and co-morbid MDD.

This project will assess the clinical safety, feasibility and preliminary efficacy of KET in individuals with AUD and co-morbid MDD. The investigators hypothesise that KET will be safe and feasible to deliver in this population, and expect to observe preliminary improvements in alcohol consumption, depressive symptoms, and treatment engagement. The KET intervention is also anticipated to be well tolerated with high levels of session attendance and acceptable rates of adverse events.

The trial will utilise an open-label, single-arm, pilot clinical trial design. A sample of 20 individuals will receive 6 weeks of treatment including 6 manualized cognitive-behavioural therapy sessions and 3 dosing sessions with Ketamine administered at 2 week intervals (0.7mg/kg initially up).

Interventions

• Drug Ketamine
  Subcutaneous administration of of Ketamine across 3 dosing sessions (at week 2, 4 and 6). Dosing adjustments are permitted based on tolerability, with a minimum dose of 0.7mg/kg and a potential maximum of 1.2 mg/kg, at the discretion of the principal investigator (previous studies have found efficacy at 0.8mg/kg for AUD).
• Behavioral Cognitive Behavioural Therapy
  This study uses a manualized CBT program adapted for ketamine-assisted context. It integrates evidence-based CBT for substance use and depression with principles of psychedelic-assisted therapy, including "set and setting." considerations central to psychedelic-assisted therapy. The therapist manual includes guidance on psychological preparation, intention-setting, integration, and therapeutic framing of ketamine experiences. Participants receive six 90-minute sessions over six weeks, delivered

Primary outcome measures

• Feasibility will be assessed through recruitment rates, retention to follow-up, session attendance, and treatment adherence. [Time frame: 22 weeks]
• Safety will be assessed through the frequency, severity, and relatedness of adverse events (AEs), including dissociation, affective destabilisation, and vital sign abnormalities. [Time frame: 22 weeks]

Secondary outcome measures (4)

• Number of Heavy Drinking Days per week (HDDs) (>5 standard drinks/day for men; >4 for women) and total alcohol consumption. [Time frame: 22 weeks]
• Change in depressive symptoms measured by MADRS and DASS-21. [Time frame: 22 weeks]
• Changes in suicidal ideation (weekly monitoring) using the Columbia Suicide Severity Rating Scale (C-SSRS). [Time frame: 22 weeks]
• Changes in Positive and Negative Mood States [Time frame: Week 2 (integration session 1), Week 4 (integration session 2), Week 6 (optional - at ketamine dose 3), Week 6 (integration session 3 and end of treatment)]

Eligibility criteria

Inclusion criteria

• Moderate to severe AUD according to the Diagnostic and Statistical Manual of Mental Disorders 5th Edition (DSM-V) criteria
• Presence of current Major Depressive Disorder (MDD), according to the Diagnostic and Statistical Manual of Mental Disorders 5th Edition (DSM-V) criteria
• Expressed motivation to reduce or cease alcohol consumption.
• Consumed at least 21 standard drinks per week or 2 HDD per week (≥5 standard drinks/day for men; ≥4 for women) in the month prior to screening
• Age 18-70
• Adequate cognition and English language skills to give valid consent and complete research interviews
• Stable housing
• Willingness to give written informed consent.
• Willingness to comply with study procedures and attend scheduled visits.

Exclusion criteria

• DSM-5 diagnosis of current or past psychotic disorder, bipolar I disorder, or substance-induced psychosis.
• Current acute suicidality, defined as high risk by the Columbia Suicide Severity Rating Scale (C-SSRS) or clinical judgment or attempts in the past 6 months.
• DSM-5 diagnosis of current or past moderate-to-severe ketamine or other dissociative drug use disorder.
• Use of ketamine (prescribed or non-prescribed) in the previous 4 weeks.
• Enrolment in another interventional clinical trial that may interfere with safety, data quality, or trial participation.
• Pregnant or breastfeeding, or planning to become pregnant during the course of the study.
• Significant uncontrolled medical conditions, including but not limited to:

• Severe or poorly controlled hypertension (>160/100 mmHg)
• Severe cardiovascular disease (e.g., heart failure, recent myocardial infarction, dysrhythmia)
• History of stroke, cerebral trauma, or intracranial mass/haemorrhage
• Severe hepatic impairment (e.g., MELD ≥10) or end-stage liver disease, bladder or kidney disease
• Clinically significant alcohol withdrawal at screening (e.g., CIWA-Ar ≥10, history of delirium tremens).
• History of heightened intracranial pressure, seizures, or diagnosed seizure disorder (except childhood febrile seizures).
• Known hypersensitivity to ketamine or any excipients.
• Concurrent use of psychotropic medications (other than stable-dose antidepressants ≥4 weeks).
• Active substance use disorder (moderate or severe) other than nicotine or caffeine; stable opioid use disorder permitted if on maintenance therapy (with strict stability criteria).
• Inability or unwillingness to comply with study procedures, judged by the principal investigator.
• Any clinically significant medical or psychiatric condition that, in the judgment of the Principal Investigator, poses a safety risk or could confound study results or hinder protocol adherence.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

Australia · 1 center

• Drug Health Services, Royal Prince Alfred Hospital — Sydney

Identifiers

NCT: NCT07247370 · X25-0138

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗