Depressive Disorder, Treatment-ResistantNCT06431386
Behavioural Activation Therapy and Esketamine for Resistant Depression
A study testing Behavioural Activation (BA) Therapy and Esketamine in people with Depressive Disorder, Treatment-Resistant and Depressive Disorder, Major, run by The Royal's Institute of Mental Health Research at 1 site in Canada.
Trial summary
This is a randomized clinical trial to test the effectiveness of combining a proven psychological intervention called behavioural activation therapy alongside esketamine treatment for treatment resistant major depressive episodes in individuals with major depressive disorder or bipolar disorder. Read more about this study
- Who is it for?
- Ages 18 to 65 years
- Conditions the study is for
- Depressive Disorder, Treatment-Resistant, Depressive Disorder, Major, Bipolar Disorder
- What is being tested?
- Behavioural Activation (BA) Therapy and Esketamine
- Type of treatment
- Lifestyle or therapy programme
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 6 participants
- Where
- 1 siteCanada
- Study dates
- 11 Jun 2024to 17 Sep 2025
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- English speaking
- Ages 18-65
- Participants meeting criteria for major depressive disorder (MDD) or bipolar disorder, depressive episode without psychotic symptoms according to the Diagnostic and Statistical Manual for Mental Disorders (DSM-5).
- Participants who have not responded adequately to at least two separate courses of treatment with different antidepressants, each of adequate dose and duration, in the current moderate to severe depressive episode.
Who cannot join
- Depression secondary to a stroke, cancer, or other severe medical illnesses.
- Pregnant, lactating or of childbearing potential and unwilling to use an approved method of contraception during the study.
- A history of intracerebral hemorrhage, vascular disease.
- Active psychotic symptoms.
- Current and/or recent history (<12 months) of substance use/dependence (except for caffeine or nicotine) or problematic current alcohol use or dependence as defined by DSM-5 criteria.
- A diagnosis of major neurocognitive disorder or a Montreal Cognitive Assessment (MOCA) score <24.
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- Active suicidal intent with the absence of psychotic symptoms is not an exclusion criterion, as this is not atypical in individuals with treatment-resistant, and/or severe depression (safety monitoring will be carried out by research personnel/study psychiatrists).
- Known history of intolerance or hypersensitivity to ketamine.
- Any other condition that, in the opinion of the PI/study investigator(s), would adversely affect the participant's ability to complete the study or its measures.
- The participant must not be receiving psychotherapy treatment outside the clinical trial for the duration of the study.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Optimizing the Synergy Between Behavioural Activation Therapy and Esketamine for Resistant Depression
This is a randomized clinical trial to test the effectiveness of combining a proven psychological intervention called behavioural activation therapy alongside esketamine treatment for treatment resistant major depressive episodes in individuals with major depressive disorder or bipolar disorder. Encouraging participants to practice new behaviours while their mood is improved through esketamine treatment may lead to more lasting recovery from depression.
Read the detailed description
Depression is the leading cause of disability in the world and current treatments with medication are limited. Over one-third of individuals with major depressive disorder (MDD) and one quarter of individuals with bipolar disorder (BD) do not benefit from traditional pharmacotherapies, leading to treatment-resistant depressive episodes. Individuals with treatment-resistant depressive episodes (defined as a suboptimal response to two or more appropriate trials of antidepressant medication) have a higher burden of illness, higher healthcare utilization, poorer quality of life, worse occupational and social outcomes, and are at greater risk of death. Treatment-resistance may increase an individual's likelihood of engaging in suicidal behaviours and an estimated 30 percent of individuals with treatment-resistant depressive episodes will have a suicide attempt in their lifetime. To address these gaps in treatment, there has been growing interest in the use of intravenous (IV) ketamine as well as its newly marketed stereoisomer, esketamine, which is delivered intranasally.
The discovery of the rapid antidepressant effects of low doses of ketamine has been hailed as a paradigm shift in psychiatry. However, a remaining challenge to address is the temporary nature of its effects. Ketamine induces neuroplasticity-enhancing effects more than conventional medications for depression. There may be the potential to harness this window of neuroplasticity to facilitate more lasting cognitive and/or behavioural changes through psychotherapy. To date, there are no randomized clinical trials of combined treatment with esketamine and psychotherapy for treatment-resistant depressive episodes. Studies to ensure that individuals can maximally benefit from this novel treatment are needed.
The overall goal of this project is to maximize and sustain the beneficial effects of esketamine through combined treatment with behavioural activation (BA) therapy. The central hypothesis is that combined esketamine and BA therapy will elicit larger and faster decrease in depressive symptoms and more improvement in functional recovery compared with esketamine treatment alone.
The specific aims of this research study are as follows:
Aim 1. To determine if there is a larger decrease in depressive symptoms in participants receiving BA concurrent with esketamine treatment compared to participants receiving esketamine alone.
Aim 2. To compare the speed of antidepressant response in participants receiving BA concurrent with esketamine treatment compared to participants receiving esketamine alone.
Aim 3. To assess if participants receiving BA concurrent with esketamine treatment perceive greater improvement in functioning (self-reported depressive symptoms, quality of life, anhedonia, hopelessness, and work and social functioning) compared to participants receiving esketamine alone.
This study is a single-site, parallel-arm, randomized clinical trial investigating the effects of augmenting esketamine treatment with BA therapy, an empirically supported treatment for depression.
Participants will be randomized to one of two groups: 1) concurrent esketamine and BA therapy started from treatment initiation, or 2) esketamine treatment alone.
Esketamine treatment will be offered as treatment as usual. All study participants will be offered a 12 session course of BA therapy, half will be randomized to receive BA concurrently with their esketamine treatment from initiation. Participants randomized to the esketamine treatment alone arm will be offered a full course of BA sessions after week 12 during the maintenance phase of treatment or at the time esketamine treatment ceases, whichever is earlier.
BA therapy will be delivered virtually or in person according to participant preference (mode of administration will be recorded and included in data analysis as appropriate). The aim of BA therapy is to help individuals learn to observe the relationship between what they did, felt, and thought and what was happening around them, and to identify conditions which maintained, increased, or weakened maladaptive behaviours. Functional behaviour analysis will be used in problem and behaviour evaluation and in planning and reviewing changes introduced by participants between sessions. Other techniques include self-observation and self-report, elaboration of activity hierarchies, behaviour programming, rehearsal and behavioural modelling, and contingency management. Between-session homework will develop relevant and rewarding day-to-day routines liable to offer reinforcement in each participant's environment. An independent expert will assess the quality and adherence to BA for the trial.
This will be the first clinical trial to test the concurrent use of esketamine and a behavioural intervention. The efficacy data for esketamine largely comes from randomized controlled trials and thus may not always reflect the clinical reality for individuals who present for treatment in hospital settings. Conducting research with esketamine in a naturalistic academic-hospital setting will inform clinical practice. The goal is to offer esketamine to individuals as part of a comprehensive treatment plan to help them achieve longer-term recovery as opposed to short-lived decrease in clinical symptoms.
- Being tested
- Behavioural Activation (BA) Therapy, Esketamine
- Keywords
- Major Depressive Disorder, Esketamine, Psychotherapy, Behavioural Activation, Bipolar Depression
- Medical subject headings
- Depressive Disorder, Treatment-Resistant, Depressive Disorder, Major, Bipolar Disorder
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Behavioural Activation (BA) TherapyBehavioural
Participants will receive weekly one-hour BA sessions on a day they are not receiving esketamine, delivered virtually or in person as per participant preference. The aim is for participants to learn to observe the relationship between what they did, felt, and thought and what was happening around them, and to identify conditions which maintained, increased, or weakened maladaptive behaviours. Functional behaviour analysis will be used in problem and behaviour evaluation and in planning and reviewing changes introduced by participants between sessions. Other techniques include self-observation and self-report, elaboration of activity hierarchies, behaviour programming, rehearsal and behavioural modelling, and contingency management. Between-session homework will develop relevant and rewarding routines to offer reinforcement in each participant's environment. Participants will be offered 12 BA sessions in total.
EsketamineDrug
Participants will receive intranasal esketamine twice weekly during the induction phase (first 4 weeks of treatment). Maintenance treatments are administered once per week or once every two weeks at the discretion of the treating physician for 8 additional weeks, totaling 12 weeks of esketamine treatment. Dosing for esketamine usually starts at 56mg on Day 1, followed by 56 or 84mg doses for subsequent treatments.
| Study group | Role | What they receive |
|---|---|---|
| Esketamine + Behavioural Activation Therapy | Experimental | Participants randomized to this arm will be administered esketamine treatment as per standard clinical care in conjunction with behavioural activation (BA) therapy. Both treatments will be initiated in Week 1 of the induction phase (first 4 weeks of esketamine treatment). Receives: Behavioral: Behavioural Activation (BA) Therapy; Drug: Esketamine |
| Esketamine Alone | Active comparator | Participants randomized to this arm will be administered esketamine treatment as per standard clinical care and will be offered a course of BA therapy (12 one hour sessions) after their completion of the trial. Receives: Drug: Esketamine |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in depressive symptoms
Change in Montgomery-Åsberg Depression Rating Scale (MADRS) score
Measured: Baseline to the end of the induction phase (week 4); additional efficacy assessment time points will include end of weeks 2, 8 and 12
Secondary outcomes (2)
Speed of therapeutic effects
Time required to first meet response criteria (≥50% improvement in MADRS scores)
Measured: Induction phase (weeks 1-4)
Change in participant perceived functioning
Change in self-reported depressive symptoms, quality of life, anhedonia, hopelessness, and physical, emotional and social functioning
Measured: Baseline to end of induction phase (week 4), and the end of weeks 8 and 12
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted28 May 2024
- Study start11 Jun 2024
- Primary completion17 Sep 2025
- Study completion17 Sep 2025
Why it stopped: The study was terminated prematurely due to significant recruitment challenges.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Depressive Disorder, Treatment-ResistantStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- This pilot study is a single-site, parallel-arm, randomized clinical trial.
- Masking
- Single blind
- Who is masked
- Outcomes assessor
- Enrolment
- 6 participants (actual)
Sponsor and investigators
- Lead sponsor
- The Royal's Institute of Mental Health Research
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Dr. Jeanne Talbot, The Royal's Institute of Mental Health Research
- Investigators
- Jeanne Talbot, MD PhD FRCP, Principal investigator, The Royal's Institute of Mental Health Research
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06431386
- Sponsor's protocol ID
- REB 2024002
- Status last verified
- Sep 2025
- First submitted
- 22 May 2024
- Last updated
- 1 Oct 2025
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 1 Oct 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Optimizing the Synergy Between Behavioural Activation Therapy and Esketamine for Resistant Depression
- ClinicalTrials.gov ID
- NCT06431386
- Acronym / sponsor ID
- REB 2024002
- Keywords
- Major Depressive Disorder, Esketamine, Psychotherapy, Behavioural Activation, Bipolar Depression
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: The study was terminated prematurely due to significant recruitment challenges.
- Enrolment
- 6 participants (actual)
- Lead sponsor
- The Royal's Institute of Mental Health ResearchUniversity, hospital or other
- Study start
- 11 Jun 2024 (actual)
- Primary completion
- 17 Sep 2025 (actual)
- Study completion
- 17 Sep 2025 (actual)
- First posted
- 28 May 2024 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This is a randomized clinical trial to test the effectiveness of combining a proven psychological intervention called behavioural activation therapy alongside esketamine treatment for treatment resistant major depressive episodes in individuals with major depressive disorder or bipolar disorder. Encouraging participants to practice new behaviours while their mood is improved through esketamine treatment may lead to more lasting recovery from depression.
Detailed description
Depression is the leading cause of disability in the world and current treatments with medication are limited. Over one-third of individuals with major depressive disorder (MDD) and one quarter of individuals with bipolar disorder (BD) do not benefit from traditional pharmacotherapies, leading to treatment-resistant depressive episodes. Individuals with treatment-resistant depressive episodes (defined as a suboptimal response to two or more appropriate trials of antidepressant medication) have a higher burden of illness, higher healthcare utilization, poorer quality of life, worse occupational and social outcomes, and are at greater risk of death. Treatment-resistance may increase an individual's likelihood of engaging in suicidal behaviours and an estimated 30 percent of individuals with treatment-resistant depressive episodes will have a suicide attempt in their lifetime. To address these gaps in treatment, there has been growing interest in the use of intravenous (IV) ketamine as well as its newly marketed stereoisomer, esketamine, which is delivered intranasally.
The discovery of the rapid antidepressant effects of low doses of ketamine has been hailed as a paradigm shift in psychiatry. However, a remaining challenge to address is the temporary nature of its effects. Ketamine induces neuroplasticity-enhancing effects more than conventional medications for depression. There may be the potential to harness this window of neuroplasticity to facilitate more lasting cognitive and/or behavioural changes through psychotherapy. To date, there are no randomized clinical trials of combined treatment with esketamine and psychotherapy for treatment-resistant depressive episodes. Studies to ensure that individuals can maximally benefit from this novel treatment are needed.
The overall goal of this project is to maximize and sustain the beneficial effects of esketamine through combined treatment with behavioural activation (BA) therapy. The central hypothesis is that combined esketamine and BA therapy will elicit larger and faster decrease in depressive symptoms and more improvement in functional recovery compared with esketamine treatment alone.
The specific aims of this research study are as follows:
Aim 1. To determine if there is a larger decrease in depressive symptoms in participants receiving BA concurrent with esketamine treatment compared to participants receiving esketamine alone.
Aim 2. To compare the speed of antidepressant response in participants receiving BA concurrent with esketamine treatment compared to participants receiving esketamine alone.
Aim 3. To assess if participants receiving BA concurrent with esketamine treatment perceive greater improvement in functioning (self-reported depressive symptoms, quality of life, anhedonia, hopelessness, and work and social functioning) compared to participants receiving esketamine alone.
This study is a single-site, parallel-arm, randomized clinical trial investigating the effects of augmenting esketamine treatment with BA therapy, an empirically supported treatment for depression.
Participants will be randomized to one of two groups: 1) concurrent esketamine and BA therapy started from treatment initiation, or 2) esketamine treatment alone.
Esketamine treatment will be offered as treatment as usual. All study participants will be offered a 12 session course of BA therapy, half will be randomized to receive BA concurrently with their esketamine treatment from initiation. Participants randomized to the esketamine treatment alone arm will be offered a full course of BA sessions after week 12 during the maintenance phase of treatment or at the time esketamine treatment ceases, whichever is earlier.
BA therapy will be delivered virtually or in person according to participant preference (mode of administration will be recorded and included in data analysis as appropriate). The aim of BA therapy is to help individuals learn to observe the relationship between what they did, felt, and thought and what was happening around them, and to identify conditions which maintained, increased, or weakened maladaptive behaviours. Functional behaviour analysis will be used in problem and behaviour evaluation and in planning and reviewing changes introduced by participants between sessions. Other techniques include self-observation and self-report, elaboration of activity hierarchies, behaviour programming, rehearsal and behavioural modelling, and contingency management. Between-session homework will develop relevant and rewarding day-to-day routines liable to offer reinforcement in each participant's environment. An independent expert will assess the quality and adherence to BA for the trial.
This will be the first clinical trial to test the concurrent use of esketamine and a behavioural intervention. The efficacy data for esketamine largely comes from randomized controlled trials and thus may not always reflect the clinical reality for individuals who present for treatment in hospital settings. Conducting research with esketamine in a naturalistic academic-hospital setting will inform clinical practice. The goal is to offer esketamine to individuals as part of a comprehensive treatment plan to help them achieve longer-term recovery as opposed to short-lived decrease in clinical symptoms.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind (outcomes assessor)
- Number of arms
- 2
- Model description
- This pilot study is a single-site, parallel-arm, randomized clinical trial.
| Arm | Type | Receives |
|---|---|---|
| Esketamine + Behavioural Activation Therapy | Experimental | Behavioral: Behavioural Activation (BA) Therapy, Drug: EsketamineParticipants randomized to this arm will be administered esketamine treatment as per standard clinical care in conjunction with behavioural activation (BA) therapy. Both treatments will be initiated in Week 1 of the induction phase (first 4 weeks of esketamine treatment). |
| Esketamine Alone | Active comparator | Drug: EsketamineParticipants randomized to this arm will be administered esketamine treatment as per standard clinical care and will be offered a course of BA therapy (12 one hour sessions) after their completion of the trial. |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (4 listed)
- English speaking
- Ages 18-65
- Participants meeting criteria for major depressive disorder (MDD) or bipolar disorder, depressive episode without psychotic symptoms according to the Diagnostic and Statistical Manual for Mental Disorders (DSM-5).
- Participants who have not responded adequately to at least two separate courses of treatment with different antidepressants, each of adequate dose and duration, in the current moderate to severe depressive episode.
Key exclusion criteria (10 listed)
- Depression secondary to a stroke, cancer, or other severe medical illnesses.
- Pregnant, lactating or of childbearing potential and unwilling to use an approved method of contraception during the study.
- A history of intracerebral hemorrhage, vascular disease.
- Active psychotic symptoms.
- Current and/or recent history (<12 months) of substance use/dependence (except for caffeine or nicotine) or problematic current alcohol use or dependence as defined by DSM-5 criteria.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Behavioural Activation (BA) TherapyParticipants will receive weekly one-hour BA sessions on a day they are not receiving esketamine, delivered virtually or in person as per participant preference. The aim is for participants to learn to observe the relationship between what they did, felt, and thought and what was happening around them, and to identify conditions which maintained, increased, or weakened maladaptive behaviours. Functional behaviour analysis will be used in problem and behaviour evaluation and in planning and reviewing changes introduced by participants between sessions. Other techniques include self-observation and self-report, elaboration of activity hierarchies, behaviour programming, rehearsal and behavioural modelling, and contingency management. Between-session homework will develop relevant and rewarding routines to offer reinforcement in each participant's environment. Participants will be offered 12 BA sessions in total. | Behavioural | Esketamine + Behavioural Activation Therapy |
| EsketamineParticipants will receive intranasal esketamine twice weekly during the induction phase (first 4 weeks of treatment). Maintenance treatments are administered once per week or once every two weeks at the discretion of the treating physician for 8 additional weeks, totaling 12 weeks of esketamine treatment. Dosing for esketamine usually starts at 56mg on Day 1, followed by 56 or 84mg doses for subsequent treatments. | Drug | Esketamine + Behavioural Activation Therapy, Esketamine Alone |
Primary outcome
Change in depressive symptoms
Time frame: Baseline to the end of the induction phase (week 4); additional efficacy assessment time points will include end of weeks 2, 8 and 12
Change in Montgomery-Åsberg Depression Rating Scale (MADRS) score
2 secondary outcomes
Speed of therapeutic effects
Time frame: Induction phase (weeks 1-4)
Change in participant perceived functioning
Time frame: Baseline to end of induction phase (week 4), and the end of weeks 8 and 12
Results and safety
The study was stopped early (reason given: The study was terminated prematurely due to significant recruitment challenges.). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 1 Oct 2025.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Jeanne Talbot, MD PhD FRCP principal investigator
The Royal's Institute of Mental Health Research
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Behavioural Activation (BA) Therapy and Esketamine in people with Depressive Disorder, Treatment-Resistant and Depressive Disorder, Major, run by The Royal's Institute of Mental Health Research at 1 site in Canada.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 10 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 1 Oct 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Canada. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study was stopped early (reason given: The study was terminated prematurely due to significant recruitment challenges.). Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in depressive symptoms (time frame: Baseline to the end of the induction phase (week 4); additional efficacy assessment time points will include end of weeks 2, 8 and 12). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 1 Oct 2025.