Protocol for a randomised controlled trial of ketamine versus ketamine and behavioural activation therapy for adults with treatment-resistant depression in the community

Abstract

Introduction

Although short-term benefits follow parenteral ketamine for treatment-resistant major depressive disorder (TR-MDD), there are challenges that prevent routine use of ketamine by clinicians. These include acute dissociative effects of parenteral ketamine, high relapse rates following ketamine dosing and the uncertain role of psychotherapy. This randomised controlled trial (RCT) seeks to establish the feasibility of evaluating repeated oral doses of ketamine and behavioural activation therapy (BAT), compared with ketamine treatment alone, for TR-MDD. We also aim to compare relapse rates between treatment arms to determine the effect size of adding BAT to oral ketamine.

Methods and analysis

This is a prospectively registered, two-centre, single-blind RCT. We aim to recruit 60 participants with TR-MDD aged between 18 and 65 years. Participants will be randomised to 8 weeks of oral ketamine and BAT, or 8 weeks of oral ketamine alone. Feasibility will be assessed by tracking attendance for ketamine and BAT, acceptability of treatment measures and retention to the study follow-up protocol. The primary efficacy outcome measure is the Montgomery-Asberg Depression Rating Scale (MADRS) measured weekly during treatment and fortnightly during 12 weeks of follow-up. Other outcome measures will assess the tolerability of ketamine and BAT, cognition and activity (using actigraphy). Participants will be categorised as non-responders, responders, remitters and relapsed during follow-up. MADRS scores will be analysed using a linear mixed model. For a definitive follow-up RCT study to be recommended, the recruitment expectations will be met and efficacy outcomes consistent with a >20% reduction in relapse rates favouring the BAT and ketamine arm will be achieved.

Ethics and dissemination

Ethics approval was granted by the New Zealand Central Health and Disability Ethics Committee (reference: 2023 FULL18176). Study findings will be reported to participants, stakeholder groups, conferences and peer-reviewed publications.

Trial registration number

UTN: U1111-1294-9310, ACTRN12623000817640p.

STRENGTHS AND LIMITATIONS OF THIS STUDY.

• All participants receive an 8-week course of oral ketamine.

• Participants are randomly allocated to receive a concurrent 8-week course of behavioural activation therapy or oral ketamine alone.

• Follow-up continues for 12 weeks following the treatment phase to compare relapse rates between treatment arms.

• We do not include a placebo medication arm.

Introduction

Major depressive disorder (MDD) is the most prevalent mental disorder in Aotearoa New Zealand (NZ).¹ It is associated with a high burden of illness for individuals and families globally.² MDD is also associated with high rates of physical comorbidity, substantial societal-level costs relating to reduced productivity and premature death by suicide.³ Established treatments for MDD are conventional antidepressant medications and psychotherapy.⁴ Each of these treatments and their combinations are limited by unsatisfactory response rates and substantial risk of relapse over time. There are, therefore, major individual and societal burdens as a result of treatment-resistant MDD (TR-MDD).⁵ There is a pressing need for effective innovative treatments for TR-MDD.

In recent years, attention has shifted to novel treatment strategies for MDD, including the N-methyl-D-aspartate receptor antagonist ketamine, and serotonergic psychedelic medications such as psilocybin and lysergic acid diethylamine.⁶ The evidence base for ketamine is larger and more robust than serotonergic psychedelic medications, despite much publicity about psychedelics in media forums.⁷ The short-term efficacy of ketamine for TR-MDD is well established.⁸ Ketamine can be delivered by intravenous infusion, intramuscular and subcutaneous injections, and intranasal and oral routes. The intravenous and intranasal routes are frequently used and result in a rapid improvement in depressive symptoms.⁸ Oral ketamine administration is better tolerated, with minimal dissociative symptoms at the time of ingestion.⁹ Oral ketamine is also associated with medium-large effect size improvements in depression severity after 2–6 weeks of treatment.⁹ However, several factors are impacting on the translation of ketamine use into mainstream clinical practice. A high percentage of patients who respond to single or repeated dosing of ketamine for MDD relapse in the weeks following treatment cessation.^{10 11} A previous reliance on parenteral dosing (with marked dissociative symptoms at the time of dosing) has restricted treatment to specialist centres. Concern about abuse potential is regarded as a barrier to routine care. However, dissociative symptoms and concerns about abuse are mitigated by oral dosing and there is little evidence that the abuse potential of ketamine is higher than other medications such as sedatives that are routinely prescribed by psychiatrists.¹² Ketamine-associated cystitis is reported in frequent, long-term, high-dose recreational ketamine users.^{13 13 14} However, a safety review of ketamine treatment for MDD reported that while lower tract urinary symptoms are increased with esketamine (the S enantiomer of ketamine) treatment, severe bladder pathology has not been reported for patients receiving ketamine treatment in standard doses, although longer term follow-up of this area is required.¹⁵

In NZ, esketamine is available for TR-MDD in combination with a conventional antidepressant and is delivered via nasal spray. Esketamine is not funded by the government funding agency Pharmac (and is therefore costly for consumers) and can only be administered in an appropriate clinic, making it an expensive treatment for health services in NZ. Royal Australian and New Zealand College of Psychiatry (RANZCP) clinical guidelines also report caveats that esketamine has not been compared directly with ketamine, the majority of esketamine data stem from industry-sponsored trials, and that longer term outcomes with this formulation are still a matter for debate.⁴

Standard ketamine does not have regulatory approval for the treatment of MDD in NZ. Despite this, limited off-label ketamine use occurs in clinical and research settings. Private psychiatric providers also offer ketamine treatment to paying consumers. However, the routine use of ketamine by clinicians does not occur because further research is needed to clarify the optimal circumstances for ketamine treatment of MDD. In particular, definitive recommendations about adjunctive psychotherapy and strategies to reduce relapse are required.

A key question in this area is whether psychotherapy delivered alongside ketamine enhances outcomes and delays relapse.¹⁶ To date, this area has only received a limited focus and there is substantial between-study heterogeneity with respect to diagnosis, psychotherapy type, ketamine protocols and outcome measurement.¹⁶ The only controlled study (n=42) evaluating ketamine and psychotherapy for TR-MDD reported preliminary data suggesting that the addition of cognitive–behavioural treatment (CBT) to ketamine treatment resulted in moderate to large effect size improvements in depressive symptoms.¹⁷ This study provided a 3-week course of intravenous ketamine followed by sequential treatment with either 14 weeks of CBT or treatment as usual (TAU). Issues with this study include the use of intravenous ketamine (difficult to translate to routine care) and the prolonged treatment protocol, with CBT being provided sequentially as opposed to concurrently.

Acute administration of ketamine is associated with impairment in cognition, particularly verbal learning and memory.¹⁸ Chronic recreational ketamine abuse has also been associated with verbal and visual memory impairment.¹⁹ However, a large systematic review of side effects associated with ketamine use in MDD suggested that research reporting on cognitive side effects has been short term, and that longer term risks associated with repeated use are unknown.²⁰ One randomised controlled trial (RCT) (n=62) reported that a single dose of ketamine treatment for TR-MDD was devoid of adverse cognitive effects 7 days post-treatment, although further research was recommended to define the cognitive profile of ketamine in clinical samples.²¹ It is therefore important for cognitive functioning to be measured and reported during ketamine and TR-MDD studies, particularly those involving repeated ketamine dosing. Further, measurement of cognitive functioning should occur outside of the acute ketamine administration period so that delayed effects can be quantified.

Psychomotor slowing is a core feature of severe/melancholic depression; a type of depression that is associated with poor functioning.²² A systematic review by our group reported that executive functioning deficits and slower psychomotor speed predict poorer treatment outcome in patients with MDD.²³ Ketamine treatment of MDD improves psychomotor speed,²⁴ and slow processing speed at baseline was predictive of greater improvement in depressive symptoms following ketamine treatment.²¹ To clarify the interplay between activity, cognition, depression and ketamine treatment, further research is required. Specific cognitive tasks can be administered to measure speed of response and processing. Actigraphy is the study of physical activity using a three-dimensional accelerometer usually worn on the wrist. Actigraphy may be an objective marker of mood and clinical response in MDD.²⁵ We have previously reported that in severely depressed inpatients, actigraphy was feasible to undertake and that improvements in activity correlated well with clinical measures and may predict earlier discharge from inpatient treatment.²⁶ We hypothesise that the measurement of objective psychomotor functioning using cognitive testing and actigraphy will inform predictors of response to ketamine and clinical improvement with behavioural activation therapy (BAT).²⁷

Ketamine and BAT; rationale for a combined approach

Guidelines explicitly state that the foundation of treatment for MDD should include psychological interventions.⁴ Pharmacotherapy and psychological intervention are described as complementary components of holistic treatment of MDD.⁴ BAT is one of the evidence-based psychotherapies recommended for acute depression by the RANZCP guidelines and National Institute for Health and Care Excellence guidelines.^{4 28} It uses activity scheduling to increase pleasant and mastery activities with a view to enabling the patient to re-engage with rewarding aspects of life.²⁷ BAT includes a functional assessment and formulation to address the social context of depression for the patient and reasons for existing coping behaviours.²⁷ It can also be delivered by junior mental health workers with less intensive and less costly training than CBT.²⁹ Major issues for the provision of psychotherapies in the community are their cost, training burden and availability to consumers. BAT therefore offers considerable advantages for translation into clinical practice and rapid roll-out. We believe combining BAT and ketamine could have synergistic effects for TR-MDD: ketamine treatment rapidly improves mood and psychomotor speed, which will enhance motivation and engagement in BAT goals for participants who otherwise may be slow and limited in their engagement with BAT tasks. BAT will then provide the behavioural change for therapeutic improvements to be longer lived.

Mental health service users provide new perspectives that complement and enhance the traditional researcher-led approach.³⁰ A service user perspective highlights the frustration that can occur with the usual slow response to treatment for depression (typically 2–4 weeks), which is in contrast with the very rapid (12 hours) response to ketamine. This perspective also highlights a desire for more than ‘quick fixes’ in the pathway to recovery and the need for full rather than abbreviated psychological interventions to provide meaning and connection in recovery. The combination of ketamine and psychotherapy is therefore an appealing balance between these two factors. Although importance of psychotherapy to recovery is well recognised, there is a need for therapy options that are easily implemented and can be provided at low cost. Our study team includes service user expertise to provide a lived experience perspective on study design, implementation and dissemination.

Our study

We propose an RCT comparing oral ketamine with oral ketamine plus BAT for TR-MDD to establish the feasibility of studying oral ketamine and BAT. We also aim to measure the clinical effect size of adding BAT to oral ketamine to guide a more definitive RCT evaluating this area.

• Feasibility will be determined by tracking recruitment, attendance to ketamine and BAT therapy, acceptability of treatment measures and retention to the study follow-up protocol.

• We hypothesise that adding psychotherapy (BAT) to ketamine treatment for TR-MDD will reduce relapse after the course of ketamine treatment ends.

• Our therapy choice is BAT to ensure that a positive outcome in a definitive RCT can be easily translated to routine practice in NZ. We will therefore compare the effects of ketamine plus an active therapy (BAT) with ketamine plus TAU. Given the paucity of published studies using ketamine and psychotherapy for TR-MDD, we believe this is appropriate; noting that response rates are likely to be high with ketamine treatment and the key issue to resolve is whether adding psychotherapy will maintain the positive clinical response. We will evaluate oral as opposed to parenteral ketamine to minimise side effects and ensure positive study results can be easily adapted to routine clinical care.

• We will include measures of objective cognitive functioning at baseline and 7 days following the end of ketamine treatment to clarify the impact of repeated ketamine treatment on cognition. Seven days following treatment ending is sufficient to ensure that any acute effects have worn off. We hypothesise that repeated treatment with ketamine in this controlled setting will not be associated with negative effects on cognitive function.

• We will also assess psychomotor function using cognitive tasks that have a strong psychomotor component as well as actigraphy. We hypothesise that a rapid increase in activity levels following ketamine treatment will be maintained by BAT and that impaired psychomotor function will predict a positive response to ketamine.

Methods and analysis

A Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) checklist³¹ details key elements of the study protocol (see the online supplemental SPIRIT checklist). Figure 1 outlines the key features of the study.

Figure 1.

Outline of the study. BAT, behavioural activation therapy; TAU, treatment as usual.

Design

Single-blind pilot RCT.

Inclusion criteria

Participants aged between 18 and 65 years with TR-MDD (Diagnostic and Statistical Manual of Mental Disorders-Fifth Edition, DSM-5) are eligible for entry into the study. Participants will be residing in the community. A standard definition for treatment resistance will be used: having trialled, and not responded to, at least two antidepressant medications at adequate doses for more than 6 weeks for the current depressive episode. We will also quantify the severity of treatment resistance using the Maudsley staging method.³² At screening, patients will have a Hamilton Depression Rating Scale-17 (HAMD)³³ score ≥17, reflecting depression of at least moderate severity. Screening is undertaken with the HAMD (as opposed to the main outcome measure Montgomery-Asberg Depression Rating Scale (MADRS)³⁴) to reduce the possibility that inflation of baseline measures will impact on outcome assessment. Participants will be required to be on stable medication treatment (or no treatment) for at least 1 month prior to screening for the study and commit to remaining on the same medication during active treatment to ensure treatment withdrawal or dose changes do not confound study effects. There are no known contraindications for the use of psychotropic medication and ketamine.

Exclusion criteria

Evidence of severe acute or chronic medical conditions (eg, diabetes, ischaemic heart disease, chronic obstructive airways disease, cerebrovascular disease, bladder disease); past or current diagnoses of schizophrenia, bipolar disorder or current psychotic symptoms; moderate-severe personality disorder; female patients who are pregnant or breast feeding; current or recent significant suicidal ideation; current or recent (past 6 months) substance use disorder; history of seizures; susceptibility to photosensitivity; or a history of allergic skin reactions; history of serious head injury or other neurological condition resulting in ongoing cognitive impairment; receiving active psychotherapy for MDD (supportive psychotherapy can be placed on hold during the study); having received a course of BAT in the last 12 months; previous non-response to BAT or ketamine treatment; Electro-Convulsive Therapy (ECT) in the last 6 months.

Centres

This study will be undertaken in the Clinical Research Units (CRU) of the Department of Psychological Medicine in Dunedin or Christchurch, NZ.

Recruitment

Recruitment commenced in February 2024 and is planned to finish in March 2026. We plan to recruit 60 participants over this period. 40 participants are sufficient to meet the feasibility, efficacy and qualitative goals. A further 20 participants ensure sufficient power to exclude deterioration in cognitive measures of effect sizes >0.5 (>80%, one-tailed α=0.05, assuming a maximum of 10 participants do not complete follow-up testing). We will accept self-referrals, referrals from primary care organisations and referrals from specialist mental health services if the inclusion and exclusion criteria are met. We plan to recruit at least 15 Māori participants, aided by existing relationships within Māori primary and secondary care services.

Following telephone screening, a face-to-face assessment with a study psychiatrist will be organised. At the assessment, further information will be provided and discussion will take place. Informed consent will be sought and, if given, further screening will occur, including physical observations (heart rate, blood pressure, arterial oxygen saturation), urine drug screen, urine pregnancy test (females), blood tests (full blood count, urea and electrolytes, liver function tests), baseline MADRS and a structured clinical interview (the Structured Clinical Interview for DSM-5 disorders). See the online supplemental appendix for the patient information sheet and consent form.

Setting

Ketamine treatment will be provided at the CRUs of Dunedin or Christchurch Department of Psychological Medicine. Each CRU is a warm, friendly clinical environment with welcoming staff. Participants will typically be allocated the same room for each ketamine dose to provide a consistent and familiar environment. BAT will be undertaken at the same setting or via the teleconferencing platform Zoom, depending on participant preference.

Randomisation and blinding

Randomisation to ketamine plus BAT or ketamine plus TAU will occur after assessment by computer-generated permuted block randomisation, stratified by centre (Christchurch, Dunedin). The data manager will hold the randomisation sequence and distribute the treatment arm allocation to the research team following enrolment. It is impossible to blind patients and therapists to the BAT intervention. However, the main outcome measures will be administered by the research assistant who will be blinded to treatment. At the start of each contact, the research assistant will explain to the participant the importance of not revealing which treatment they have received.

Intervention

The duration of ketamine treatment will be 8 weeks. Dosing will follow an oral ketamine protocol currently underway in Christchurch and Dunedin (Ketamine therapy for neurotic disorders: is there a single mechanism? Australian NZ Clinical Trial Registry number 12619000311156). Oral ketamine will commence at 1 mg/kg mixed with 50 mL orange juice and sipped over 30–60 min. Initial dosing will be two times per week (with gaps of 3 and 4 days between doses). If tolerated, and if the Montgomery-Asberg Depression Rating Scale (MADRS) score is >6 on follow-up (indicating mild depression or greater), dose can be increased to 1.5 mg/kg and then 2 mg/kg. If the MADRS score is <6 on follow-up, dosing can be reduced to weekly intervals. Dosing will be individualised through discussion with nursing staff. All participants will receive nursing contact and oversight on ketamine dosing days and by telephone as needed over the study period.

TAU consists of nursing support as noted above and weekly attendance at the CRU for ketamine.

BAT consists of 12 sessions provided at twice-weekly intervals for 4 weeks, then weekly intervals for 4 weeks (8 weeks in total). Sessions will be timed to occur within 24 hours of ketamine treatments to take advantage of the improved mental state we anticipate will follow ketamine treatment and to maximise the opportunity for change. BAT will be based on the manual by Lejuez et al ³⁵ and adapted by JJ, KD and GM to work synergistically with the ketamine treatment. The therapy manual incorporates therapeutic strategies using He Puna Whakaata principles³⁶ for use with Māori participants. BAT will provide an individual formulation for the participant and be a holistic treatment package alongside ketamine therapy. BAT content includes a functional assessment, psychoeducation about depression and the BAT model, values, goal setting, scheduling pleasant and mastery activities, negotiating support from others, dealing with rumination and worry, skills training as needed (eg, problem solving, assertive communication) and managing early signs of relapse. BAT will include an initial focus on symptom reduction, followed by maintenance of improvements and behavioural change to prevent relapse. BAT will be provided by nurses, psychologists or psychiatrists. Supervision of BAT therapists and fidelity checks of BAT delivery will occur.

Training

The CRU in Christchurch has experience in delivering BAT in two clinical trials and will provide training and oversight of BAT delivery in Dunedin.

Primary outcome measures

Feasibility will be assessed by meeting the recruitment expectations, tracking weekly attendance with ketamine and BAT, acceptability of treatment measures and retention to the study follow-up protocol.

The primary efficacy outcome measure is the MADRS. The MADRS will be measured weekly during treatment and fortnightly during follow-up. Response will be defined as a ≥50% reduction in the MADRS and remission will be defined as MADRS score ≤10 for two consecutive measurements. Relapse will be defined as MADRS score ≥22 after previously responding or being in remission. Treatment non-response will be determined by never meeting response criteria during the active treatment phase of the study. Participants will be asked if they accessed externally prescribed ketamine during the follow-up phase of the study to ensure the impact of any additional treatment can be taken into account.

Secondary outcome measures

Cognitive functioning and psychomotor functioning will be assessed with a comprehensive battery of objective cognitive tests, many of which are part of the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery.³⁷ Tests will measure aspects of executive function, psychomotor function, attention, learning and memory, and emotion processing. The battery consists of the following tasks: Rey Auditory-Verbal Learning Task,³⁸ Brief Visuospatial Memory Test-Revised,³⁹ Digit Span Forward and Backward,⁴⁰ Trail Making Tests A and B,⁴¹ Delis-Kaplan Executive Function System-Fluency Battery,⁴¹ Digit Symbol Coding,⁴⁰ Continuous Performance Test and Facial Expression Recognition Test.⁴² The whole cognitive assessment will take about 1 hour to complete. This will be administered at baseline and 7 days following end of ketamine treatment. Tasks included in this battery are consistently found to be impaired in acute depression. Cognitive assessment will be conducted by a research assistant trained and supervised by a clinical psychologist with expertise in cognitive assessment (KD).

Psychomotor impacts of ketamine (with vs without BAT) will be measured via actigraphy. Patients will wear GENEActiv actigraphs (a small wrist-worn device) on the non-dominant wrist. GENEActiv actigraphs are recommended by the US National Institute of Mental Health mMARCH working group that coordinates international actigraphy research in mood disorders.⁴³ Actigraphs will be worn for 6 weeks in total: (a) 1 week prior to and for 2 weeks after first ketamine treatment to test the acute impacts of ketamine, (b) 1 week prior to and 1 week after completion of ketamine treatment to test the impact of ketamine withdrawal and (c) for week 20 to investigate maintenance of psychomotor benefits. The primary actigraphic outcome measure will be total waking activity counts per waking day (averaged across 7 days of data collection).

Exploratory outcome measures

These include the Depression Anxiety and Stress Scale (DASS-21)⁴⁴ and the Work and Social Adjustment Scale (WSAS).⁴⁵

Urinary tract symptoms will be measured using the Bladder Pain Interstitial Cystitis⁴⁶ questionnaire.

Participant adherence to BAT will be measured by the self-report Behavioral Activation for Depression Scale-Short Form.⁴⁷

Therapy quality (adherence and competence) will be monitored in real time by regular rating of audio recordings by the BAT supervisor using the Quality of Behavioral Activation Scale-Short Form.⁴⁸ All therapy sessions will be recorded and a random selection of two sessions/participant across all therapists will be selected for review. Therapists will complete a checklist to ensure all relevant therapy elements have been delivered at each session.

Beyond total activity, actigraphy has been widely used to investigate circadian, sleep and non-linear aspects of activation in mood disorders: these variables will be explored in hypothesis-generating analyses.

Qualitative evaluation

Qualitative evaluation will be conducted to provide depth to the quantitative findings and determine participant views on the acceptability and experience of the intervention being trialled. Embedding qualitative evaluation in RCTs is increasingly common, with identified benefits for facilitating interpretation of trial findings by providing a more nuanced understanding of the context and underlying mechanisms of outcomes. Given this is a feasibility study, qualitative assessment will contribute to future trial design by identifying potential challenges and solutions to participating, as well as understanding the overall impact of the trial on participants.

Sampling

A subsample will be invited to participate in in-depth qualitative interviews. Purposeful sampling will be used based on distribution for intervention arm, age, gender and ethnicity. Sample size is difficult to determine prior to data collection but smaller sample sizes are generally sufficient to reach saturation in qualitative studies.⁴⁹ An approximate subsample of 10–15 participants is expected. There is a need to assess the NZ context of the intervention and, in particular, how the intervention is received by Māori. A specific attempt to sample Māori participants for the qualitative interviews will be made to assess acceptability of the treatment for this population. To assist in this process, participants will be offered to review their transcripts and provide feedback to ensure their perspectives are represented accurately. Qualitative participants will be given a $50 reimbursement to compensate for the additional expenses associated with participating in the interviews.

Data collection and analysis

Qualitative interviews will be conducted at treatment end and at the 3-month follow-up period. Semistructured interviews will be used as the means of data collection. Interview topics covered at treatment end will include: participants’ preferences related to the intervention; the impact of the trial on participants, including enablers and challenges associated with participating; experience of ketamine intervention; and experience and acceptability of combined BAT and ketamine intervention (for those receiving it) including perceived synergy. Interviews at the 3-month follow-up period will focus on the longer term experience and impact of the intervention received. The data will be analysed using an inductive thematic approach as described by Braun and Clarke.⁵⁰ Table 1 shows the timing of the outcome measures.

Table 1.

Timing of outcome measures

Screening	Baseline (week 0) to end of treatment (week 8)	Follow-up period (weeks 10–20)	Final follow-up (week 20)
HAMD	MADRS weekly	MADRS (phone) at fortnightly intervals	MADRS (phone)
	Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery at baseline and 7 days following final ketamine dose
	Actigraphy: for 1 week pretreatment and 2 weeks post-treatment	Actigraphy weeks 8 and 9, and week 20
	DASS-21, WSAS, BADS-SF at baseline and end of treatment		DASS-21, WSAS, BADS-SF (phone)
	BPIC weekly		BPIC (phone)
	Quality of Behavioral Activation Scale-Short Form: random sample ensuring participant and therapist representation
	Qualitative evaluation (subgroup) at treatment end		Qualitative evaluation (subgroup)

BADS-SF, Behavioral Activation for Depression Scale-Short Form; BPIC, Bladder Pain Interstitial Cystitis; DASS-21, Depression Anxiety and Stress Scale; HAMD, Hamilton Depression Rating Scale; MADRS, Montgomery-Asberg Depression Rating Scale; WSAS, Work and Social Adjustment Scale.

Safety

Although clinical trials suggest that ketamine reduces suicidal ideation in the short term, suicidal ideation and any clinical deterioration will be monitored by tracking responses to the MADRS suicide item, additional therapy or support nurse contacts and any crisis contacts or return to specialist mental health services. Scores ≥4 on the MADRS suicide item will prompt specific clinical input from study nurses and clinical input from mental health services according to need (including withdrawing from the study protocol if required).

Data

Clinical data will be stored in locked filing cabinets and clinical databases. Research data will be collected in coded form and stored in locked filing cabinets before entry by the data manager into password-protected secure databases. An independent Data and Safety Monitoring Committee (DSMC) consisting of two researchers and a biostatistician is appointed to review the study initially and the data at regular recruitment intervals. They will review safety and efficacy data and make recommendations about study conduct and continuation if serious adverse events arise. The DSMC charter is available on request. All investigators will have access to the full dataset for research purposes. Deidentified individual participant data underlying published results will be shared to researchers who provide sound proposals and for meta-analysis.

Statistical analysis

A full flow chart will be generated showing the numbers of patients screened, recruited, randomised, attendance at treatment visits and attendance at follow-up. This will allow description of the degree to which the final sample is a subset of those referred or responding to advertisement. The details of any non-compliance with the treatment protocol will be recorded and reported. Standard descriptive statistics will be used to describe the presenting demographic and clinical features of the randomised sample. These will include means, medians, SDs and ranges for continuous measures and frequencies and percentages for categorical data.

The primary efficacy outcome, MADRS, will be measured weekly during active treatment, then fortnightly during follow-up. It will be used to categorise patients as treatment non-response (never meeting response criteria during the active treatment phase (0–8 weeks)), responders (≥50% reduction in the MADRS during treatment), remitters (MADRS score ≤10 on two consecutive measurements during treatment) and relapsed (MADRS score ≥22 after previously responding or being in remission during follow-up (8–20 weeks)). These outcomes are not mutually exclusive so each will be analysed and compared between randomised groups using binary logistic regressions, with the effect sizes summarised as ORs with 95% CIs. Additionally, the MADRS scores from baseline to follow-up will be further analysed using a linear mixed model, which will include patient as a random effect, baseline levels as a covariate and time and treatment as fixed factors. The estimated means at each time for each treatment group will be summarised and presented with 95% CIs. For a definitive follow-up RCT study to be recommended, the recruitment expectations will be met (60 participants over 3 years) and efficacy outcomes consistent with a >20% reduction in relapse rates favouring the BAT arm will be achieved. The secondary and exploratory outcomes including the cognitive functioning, psychomotor functioning, activity count (actigraphy), DASS and WSAS scales and measures will be compared between randomised groups using a linear mixed model, which will include patient as a random effect and time and treatment as fixed factors. These models will include specific comparisons of the changes from baseline to end of treatment and end of follow-up as appropriate to the measurement timing of each outcome.

Ethics and dissemination

The NZ Central Health and Disability Ethics Committee granted ethical approval for this study (reference: 2023 FULL18176). All participants will give informed consent to enter the study and will be free to leave the study at any stage. Although clinical trials suggest that ketamine reduces suicidal ideation in the short term, suicidal ideation and any clinical deterioration will be monitored by tracking responses to the MADRS suicide item, additional therapy or support nurse contacts, and any crisis contacts or return to specialist mental health services. Scores ≥4 on the MADRS suicide item will prompt specific clinical input from study nurses and clinical input from mental health services according to need. Any serious adverse events will be discussed with the DSMC. If the DSMC recommends significant changes to the study protocol, this will prompt further correspondence with the ethics committee and updating of the trial registry. Following study completion and analysis we will publicise the study results to participants and key community stakeholders. We also plan to publish the findings in peer-reviewed publications and present the findings in conferences.

Patient and public involvement

The research team includes service user expertise that contributed to study design and protocol development.

Ethics statements

Patient consent for publication

Not applicable.