Esketamine + Behavioural Activation Therapy for Depression

Overseen By Jeanne Talbot, MD PhD FRCP

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: The Royal's Institute of Mental Health Research

Must be taking: Antidepressants

Disqualifiers: Stroke, Cancer, Substance use, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of esketamine and behavioral activation therapy to determine its effectiveness for individuals unresponsive to other depression treatments. Esketamine can quickly elevate mood, while the therapy encourages patients to engage in new positive activities. The aim is for this combination to lead to a more lasting recovery from depression. Suitable candidates have major depressive disorder or bipolar disorder and have not found success with at least two different antidepressants. As an unphased trial, it provides a unique opportunity to explore innovative treatment options for those seeking alternatives.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. However, it does mention that participants must not be receiving psychotherapy treatment outside the clinical trial.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that esketamine is generally safe for long-term use. Studies have found no new safety issues when combined with standard antidepressants for up to 6.5 years. However, some individuals have reported serious side effects, including suicidal thoughts in about 1% of users and suicide attempts in 1.3%.

Behavioral activation therapy also has a good safety record. One study found that 3.7% of participants experienced increased suicidal thoughts, which is lower compared to another group that received enhanced usual care.

Both treatments have proven effective and are generally well-tolerated. However, awareness of potential risks, especially concerning mental health symptoms, is crucial. Participants should always consult healthcare providers to understand the benefits and risks before joining a trial. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Most treatments for depression, like SSRIs and SNRIs, work by altering neurotransmitter levels over several weeks. But esketamine works differently, targeting the NMDA receptors in the brain, which can potentially relieve symptoms much faster, sometimes within hours. Researchers are excited to combine esketamine with Behavioral Activation Therapy because this combination might enhance the benefits by not only rapidly improving mood but also encouraging positive behavioral changes. This dual approach could offer a more comprehensive treatment for depression, addressing both the chemical and behavioral aspects of the condition.

What evidence suggests that this trial's treatments could be effective for depression?

Research has shown that esketamine can help people with depression who haven't improved with other treatments, as it strongly lifts mood. In this trial, participants may receive esketamine alone or combined with Behavioural Activation Therapy, which encourages positive activities. Together, these treatments might extend the benefits. Previous studies using a similar method with ketamine and therapy showed good results in improving long-term recovery. This combination might aid recovery from depression by enhancing mood and promoting positive actions. ^{6 7 8 9 10}

Who Is on the Research Team?

Jeanne Talbot, MD PhD FRCP

Principal Investigator

The Royal's Institute of Mental Health Research

Are You a Good Fit for This Trial?

This trial is for English-speaking adults aged 18-65 with major depressive disorder or bipolar disorder, who haven't improved after trying at least two different antidepressants. It's not for those with a history of brain hemorrhage, severe medical illnesses causing depression, active psychosis, recent substance abuse (except caffeine/nicotine), cognitive impairment, ketamine intolerance, or those in other psychotherapy.

Inclusion Criteria

English speaking

I have been diagnosed with major depression or bipolar depression without psychosis.

I haven't improved after two different antidepressants for my current severe depression.

Exclusion Criteria

Active psychotic symptoms

I am not undergoing psychotherapy outside of this study.

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

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction

Participants receive esketamine treatment with or without concurrent behavioural activation therapy

4 weeks

Weekly visits (in-person or virtual)

Maintenance

Participants continue esketamine treatment; those in the esketamine alone group may start BA therapy

8 weeks

Bi-weekly visits (in-person or virtual)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Behavioural Activation Therapy
• Esketamine

Trial Overview The study tests if combining Behavioural Activation Therapy—a psychological treatment encouraging new behaviors—with Esketamine can help people whose depression hasn't improved with standard treatments. Participants are randomly assigned to receive both treatments and monitored for recovery from depression.

How Is the Trial Designed?

Group I: Esketamine + Behavioural Activation Therapy Experimental Treatment 2 Interventions

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).

Group II: Esketamine Alone Active Control 1 Intervention

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.

Who Is Running the Clinical Trial?

The Royal's Institute of Mental Health Research

Lead Sponsor

Trials

8

Recruited

1,300+

Published Research Related to This Trial

Esketamine offers a new treatment option for patients with major depressive disorder (MDD) who have not responded adequately to two or more antidepressant therapies, addressing a significant gap in care for those with moderate to severe depression.

An expert panel of 11 professionals has developed practical recommendations for establishing esketamine clinics in Australia, focusing on patient selection, administration, adverse event management, and long-term follow-up to ensure effective treatment delivery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Establishing an esketamine clinic in Australia: Practical recommendations and clinical guidance from an expert panel. Thornton, NLR., Black, W., Bognar, A., et al.[2023]

Ketamine and esketamine demonstrate rapid antidepressant effects, with improvements in clinical response observed within 40 minutes to 1 week for ketamine and 2 hours to 4 weeks for esketamine, along with reductions in depression scores and suicidality.

Despite their effectiveness, the long-term safety and efficacy of ketamine and esketamine remain uncertain, and the overall quality of the studies reviewed was critically low, highlighting the need for more rigorous research in this area.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of ketamine and esketamine for depression: an overview of systematic reviews with meta-analyses. Lima, TM., Visacri, MB., Aguiar, PM.[2022]

In a study involving 518 patients with treatment-resistant depression, those treated with esketamine nasal spray plus an oral antidepressant showed a significantly higher response rate at day 28 compared to those receiving an oral antidepressant plus placebo (58.7% vs 45.2%).

Even patients who did not respond within the first week of treatment (day 2 nonresponders) benefited from continuing esketamine treatment, with 54.9% achieving a response by day 28, indicating that a full 4-week course can still be effective.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment Response With Esketamine Nasal Spray Plus an Oral Antidepressant in Patients With Treatment-Resistant Depression Without Evidence of Early Response: A Pooled Post Hoc Analysis of the TRANSFORM Studies. Turkoz, I., Daly, E., Singh, J., et al.[2021]

Esketamine (ESK) nasal spray combined with standard care significantly reduced the time to remission in adults with major depressive disorder (MDD) and acute suicidal ideation, with median times of 15 days for ESK compared to 23 days for placebo.

Patients receiving ESK also had a higher proportion achieving remission by Day 25 (65.2% vs. 55.5%) and spent more days in remission (27.1% vs. 8.3%), highlighting its efficacy in treating severe depression with suicidality.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Esketamine versus placebo on time to remission in major depressive disorder with acute suicidality. Fu, DJ., Zhang, Q., Shi, L., et al.[2023]

In a phase 3 study involving 705 adults with treatment-resistant depression (TRD), continuing esketamine nasal spray alongside an oral antidepressant significantly reduced the risk of relapse in patients who had achieved stable remission or response, with a 51% and 70% reduction in relapse rates, respectively.

The most common side effects of esketamine included transient dysgeusia, vertigo, and dizziness, but these were reported in fewer patients compared to those receiving placebo, indicating a manageable safety profile for long-term use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression: A Randomized Clinical Trial. Daly, EJ., Trivedi, MH., Janik, A., et al.[2021]

Esketamine has shown significant efficacy and safety in treating treatment-resistant depression (TRD) and major depressive disorder (MDD) with acute suicidal ideation, but there are concerns about its potential for addiction.

In a clinical case study, a 34-year-old woman exhibited drug-seeking behaviors while on esketamine, highlighting the need for careful monitoring and management of craving symptoms, which was effectively addressed by combining esketamine with bupropion.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Craving and addictive potential of esketamine as side effects? Orsolini, L., Salvi, V., Volpe, U.[2022]

Intranasal esketamine is an effective treatment for patients with treatment-resistant depression (TRD), showing faster reduction in depressive symptoms compared to traditional oral antidepressants, based on a review of clinical trials from April 2015 to June 2020.

The treatment is self-administered under healthcare supervision, with a favorable safety profile; most adverse effects, such as sedation and increased blood pressure, occur during the 2-hour monitoring period after administration.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intranasal esketamine: A novel drug for treatment-resistant depression. Khorassani, F., Talreja, O.[2021]

Esketamine has been identified as a potent and long-lasting antidepressant that works by targeting NMDA receptors, offering a new approach to treating depression, especially for patients who do not respond to traditional antidepressants.

Despite its promising rapid effects in alleviating depression symptoms, the exact mechanism of action for esketamine is still unclear, and its clinical use remains limited.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Research progress of depression and the application of esketamine]. Lin, FB., Hou, DR., Tang, QP.[2020]

There is currently no standardized safety monitoring protocol for off-label use of generic ketamine, and safety monitoring for intranasal esketamine varies by jurisdiction, leading to potential gaps in patient safety.

The Ketamine Side Effect Tool (KSET) is recommended as a comprehensive tool for monitoring both acute and long-term side effects of ketamine and esketamine treatments, addressing the lack of agreed frameworks for safety monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Ketamine Side Effect Tool (KSET): A comprehensive measurement-based safety tool for ketamine treatment in psychiatry. Bayes, A., Short, B., Zarate, CA., et al.[2023]

Ketamine and esketamine are promising new treatments for adults with treatment-resistant depression, showing rapid-onset efficacy that differs from traditional monoamine-based antidepressants.

Despite their potential benefits, there are ongoing concerns regarding the safety and tolerability of these treatments, as well as uncertainties about their optimal use in clinical practice and the necessary infrastructure for safe administration.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation. McIntyre, RS., Rosenblat, JD., Nemeroff, CB., et al.[2022]

Patients with treatment-resistant depression (TRD) who initiated esketamine therapy had higher severity of major depressive disorder (MDD) and utilized more mental health resources compared to those receiving conventional therapies, indicating a more complex treatment history.

Esketamine users had significantly higher healthcare costs prior to therapy initiation, suggesting that early identification and treatment of TRD with effective options like esketamine could be beneficial for both patient outcomes and healthcare expenditures.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Characteristics of Real-world Commercially Insured Patients With Treatment-resistant Depression Initiated on Esketamine Nasal Spray or Conventional Therapies in the United States. Karkare, S., Zhdanava, M., Pilon, D., et al.[2022]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT06431386

Behavioural Activation Therapy and Esketamine for ... This is a randomized clinical trial to test the effectiveness of combining a proven psychological intervention called behavioural activation therapy ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11086269/

Protocol for a randomised controlled trial of ketamine versus ... This randomised controlled trial (RCT) seeks to establish the feasibility of evaluating repeated oral doses of ketamine and behavioural activation therapy (BAT ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12450024/

Spravato for Treatment-Resistant Depression: Efficacy and ... It can be concluded that esketamine has notable antidepressant and antisuicidal efficacy although it is undetermined whether this effect is a ...

4. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0165178123005358

Cognitive behavioral therapy following esketamine for ... A subsequent small, proof-of-concept trial showed that CBT could improve longer-term outcomes among patients treated with IV ketamine (Wilkinson et al., 2021).

5. psychiatryonline.org psychiatryonline.org/doi/10.1176/appi.ajp.20240515

Esketamine Treatment for Depression in Adults: A PRISMA ... Intranasal esketamine has been approved as an adjunctive therapy for treatment-resistant major depressive disorder with acute suicidal ideation and behavior.

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12021889/

Efficacy and safety of behavioural activation on depression ... Increased suicidal ideation affected 3.7% of the behavioural activation group and 7.4% of the enhanced usual care group. Unexpected physical health-related ...

7. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0005791624000727

An online group behavioral activation therapy for major ... A ten-session online group BAT program significantly reduced depressive symptoms in this pre-post trial. •Online group BAT increased behavioral activation ...

8. thelancet.com thelancet.com/journals/lancet/article/PIIS0140-6736(16)31140-0/fulltext

Cost and Outcome of Behavioural Activation versus ... We aimed to establish the clinical efficacy and cost-effectiveness of BA compared with CBT for adults with depression.

9. clinicaltrials.gov clinicaltrials.gov/study/NCT02297282

A Study to Assess the Effectiveness of Behavioural ... Behavioural activation is a therapy, which has been shown to be quite effective in the treatment of depression. Originally a component of cognitive therapy, ...

10. cochranelibrary.com cochranelibrary.com/cdsr/doi/10.1002/14651858.CD013305.pub2/full

Behavioural activation therapy for depression in adults We found moderate‐certainty evidence suggesting no evidence of a difference in short‐term treatment efficacy between behavioural activation and ...