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.
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).
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
20
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).
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 by trained health professionals (e.g., psychologists, mental health nurses, social workers) with specific training in the adapted CBT protocol and psychedelic-assisted therapy. Sessions include: Preparation (Week 1): Review of alcohol use, treatment goals, and ketamine orientation. Integration (Weeks 2, 4, 6): Post-dose processing and linking experience to recovery goals occurring 24-48 hours post dose. Continued CBT (Weeks 3, 5): Coping strategies, goal setting, and relapse prevention.
Drug Health Services, Royal Prince Alfred Hospital
Sydney, New South Wales, Australia
Feasibility will be assessed through recruitment rates, retention to follow-up, session attendance, and treatment adherence.
Feasibility outcomes will be assessed by the traffic light framework may be applied to guide progression decisions for future trials for each of the following variables: (i) time taken to recruit the sample; (ii) proportion of ineligible participants at (a) pre tele-screening and (b) onsite screening; (iii) number of participants who receive (a) at least two doses of ketamine and (b) at least four CBT sessions; (iv) retention rate over the trial. As this is the first study of its kind in this population and pilot studies are not generalisable to other contexts, these will be assessed and reported descriptively. Results will be synthesised in consideration of the feasibility to progress to larger studies, taking into account the measures described above. Specifically, based on our prior trials of CBT, pharmaco-assisted therapy and complex S9 trials, the following would be an estimation of failure to progress to full trial for each variable and when taken together: (i) \> 24 months; (ii)
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.
Safety outcomes including adverse events (AEs), serious adverse events (SAEs), and vital sign abnormalities, will be summarised descriptively across the study period. Feasibility outcomes (e.g., recruitment and retention rates, session attendance) will be analysed using proportions with corresponding 95% confidence intervals.
Time frame: 22 weeks
Number of Heavy Drinking Days per week (HDDs) (>5 standard drinks/day for men; >4 for women) and total alcohol consumption.
This will be measured by the Timeline Follow Back and corroborated with Phosphatidylethanol (PEth) levels
Time frame: 22 weeks
Change in depressive symptoms measured by MADRS and DASS-21.
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MADRS is a clinician-administered rating scale designed to assess the severity of depressive episodes in patients with mood disorders. It is widely used in clinical trials and psychiatric evaluations due to its sensitivity to treatment-related changes. The MADRS will be administered by trained health care professionals. The MADRS total score is calculated by summing the scores of 10 individual items, each rated on a scale from 0 to 6, yielding a total score range of 0 to 60. Higher scores indicate greater severity of depressive symptoms. The 10 items assessed in the MADRS include: Apparent sadness Reported sadness Inner tension Reduced sleep Reduced appetite Concentration difficulties Lassitude/Sluggishness Inability to feel (emotional capacity) Pessimistic thoughts Suicidal thoughts Each item is rated based on clinical judgment following a semi-structured interview, focusing on the past week. Clinically meaningful changes will be reported descriptively, including rates of ≥50%
Time frame: 22 weeks
Changes in suicidal ideation (weekly monitoring) using the Columbia Suicide Severity Rating Scale (C-SSRS).
The C-SSRS is a structured clinician-administered instrument with strong predictive validity for suicidal behavior, used in clinical and research settings to assess the presence, severity, and intensity of suicidal ideation and behavior. The C-SSRS is administered by trained clinicians. C-SSRS scoring includes four subscales: ideation severity (items 1-5, scored by the most severe type endorsed); intensity of ideation (sum of five items including frequency, duration, controllability, deterrents, and reasons for ideation; range 2-25; higher number indicates more intense ideation); suicidal behavior (presence or absence of actual, interrupted, aborted, or preparatory behavior recorded separately); and potential lethality (medical damage rated 0-5, potential lethality rated 0-2). At baseline, this is measured by the baseline version. At each visit following this, this will be recorded on the since last visit. Higher scores indicate more severe suicidality.
Time frame: 22 weeks
Changes in Positive and Negative Mood States
Mood states before/after ketamine sessions assessed by PANAS (Positive and Negative Affect Schedule). This will be measured at integration session 1 (week 2), 2 (week 4) and 3 (week 6). Used to measure an individual's emotional state, assessing two dimensions: Positive Affect (PA; captures feelings like enthusiasm and alertness), and Negative Affect (NA; measures distress and negative emotions like anger and anxiety).
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)