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

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)

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.

This will be measured by the Timeline Follow Back and corroborated with Phosphatidylethanol (PEth) levels

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%

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.

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).

Measured by cumulative scores on the DASS-21 Depression Scale. This scale has a minimum score of 0 and maximum score of 21. A higher score indicates greater depression.

Measured by cumulative scores on the DASS-21 Anxiety Scale. This scale has a minimum score of 0 and maximum score of 21. A higher score indicates more anxiety.

Measured by cumulative scores on the DASS-21 Stress Scale. This scale has a minimum score of 0 and maximum score of 21. A higher score indicates more stress.

Measured by the Alcohol Dependence Scale. The minimum score is 0 and the maximum score is 47. A higher score indicates more severe dependence.

As measured by the PSQI (Pittsburgh Sleep Quality Index). This Index has a minimum score of 0 and a maximum score of 21. The higher the score indicates worse sleep quality.

To assess whether ketamine treatment improves executive functioning, specifically cognitive flexibility and task-switching ability, as measured by the Number-Letter Task (NLT). Key outcome measures include reaction time, accuracy, and switch cost (the performance difference between switch and repeat trials). Lower switch costs and faster, more accurate responses indicate improved executive control.

To assess whether ketamine treatment improves executive functioning and set-shifting, the Wisconsin Card Sorting Test (WCST) will be used.

Participants are required to match stimulus cards based on varying classification principles (e.g., color, shape, number), which change without warning. Key outcome measures include the number of categories completed, total errors, perseverative responses, and perseverative errors. Higher performance is indicated by more categories completed and fewer perseverative errors, reflecting improved cognitive flexibility and executive control.

To assess short term alcohol urge the Alcohol Urge Questionnaire (AUQ) will be used. This is a brief 8-item self-report questionnaire that evaluates acute alcohol craving as a single factor (unidimensional). Each item is rated on a Likert scale of 7 points, with higher scores indicating stronger urges to consume alcohol. Two of the questions are reversed scored.

As measured by the 7-item self-report Acceptance and Action Questionnaire, version 2 (AAQ-II). The items are rated on a 7-point Likert scale from 1 ("Never true") to 7 ("Always true"). Higher total scores are indicative of greater psychological inflexibility, while lower scores suggest more psychological flexibility. Scores between 24 and 28 are often used as a potential clinical cutoff indicating psychological distress.

Measured by The Brief Pain Inventory (BPI). Patients rate their current symptons, average experiences of pain and minimum and maximum intensities of symptoms on scales between 0 to 10. A total pain severity score can be found by averaging these individual items. Higher scores indicate greater severity and more interference. A score relating to impact on daily life can be calculated by averaging scores on each of the seven items, which also use scales from 0 to 10. Takes five minutes or less.

To determine changes in the severity of alcohol withdrawal symptoms the Revised Clinical Institute Withdrawal Assessment for Alcohol scale (CIWA-Ar) will be used. This 10-item scale evaluates common withdrawal symptoms including nausea/vomiting, tremor, paroxysmal sweats, anxiety, agitation, tactile disturbances, auditory disturbances, visual disturbances, headache and orientation. Each item is rated on a scale from 0 to 7 (except orientation, which is rated 0-4), with a total score ranging from 0 to 67. Higher scores indicate more severe withdrawal symptoms.

Daily texts will be sent out to participants querying the amount of alcohol they have consumed. Participant responses to this will be recorded. This will be managed through SEMA software.

To assess whether treatment can improve quality of life as measured by the World Health Organization Quality of Life (WHOQOL-BREF). This 26-item questionnaire evaluates four domains of quality of life: physical health, psychological health, social relationships, and environment. Each item is rated on a 5-point Likert scale, and domain scores are transformed to a 0-100 scale. Higher scores indicate a better quality of life.

This instrument measures clients satisfaction with treatment. Total scores range from 8 to 32, with the higher number indicating greater satisfaction.

To assess whether treatment enhances acute psychologically insightful experiences we will use the Psychological Insight Questionnaire (PIQ-23).

This 23-item self-report consists of two subscales: (a) Avoidance and Maladaptive Patterns Insights and (b) Goals and Adaptive Patterns Insights. The tool evaluates an individual's awareness and understanding of their own psychological processes, including recognition of patterns in thoughts, emotions, and behaviors. Each item is rated on a 5-point Likert scale, with higher scores indicating greater psychological insight.

As measured by the session rating scale (SRS). Following each CBT session, both the therapist and participant will complete a brief post-session rating. This scale measures; relationship, goals & topics, approach or method and overall psychotherapy session. Higher scores on each of these indicate a more positive experience.

As measured by the Penn Alcohol Craving Scale (PACS). 5-item self-report questionnaire that evaluates alcohol craving over the past week. Measures frequency, intensity, duration of craving, perceived control over drinking, and overall craving severity. Each item is rated on a 7-point Likert scale (0-6). Total scores range from 0 to 30, with higher scores indicating greater craving.

Assessed by the Stroop Task and Number-Letter Task at week 1 (baseline) and week 10.

To assess whether ketamine treatment influences instrumental contingency learning and sensitivity to punishment, this will be measured by the Planets and Pirates Task. Key outcome measures include instrumental responses (e.g., click rates on each planet) and Pavlovian responses (e.g., active avoidance or shield use). Improved performance is indicated by increased avoidance of punished choices and enhanced detection of action-outcome contingencies.

To assess whether ketamine treatment reduces acute alcohol craving across multiple dimensions, this will be measured by the Alcohol Craving Questionnaire Short Form-Revised (ACQ-SF-R). This 12-item questionnaire captures four factors: compulsivity, expectancy, purposefulness, and emotionality. Each item is rated on a Likert scale (strongly disagree - strongly agree), with higher scores indicating greater craving intensity. Takes less than 5 minutes to complete.

Global cognitive functioning assessed by the Montreal Cognitive Assessment (MoCA). The MoCA is a 30-point screening tool designed to detect mild cognitive impairment and assess multiple cognitive domains, including attention, concentration, executive functions, memory, language, visuospatial skills, conceptual thinking, calculations, and orientation. Higher scores indicate better cognitive performance, with a maximum score of 30.