i-CBT + Ketamine for Depression

(Ket-CBT Trial)

Recruiting at 1 trial location

Overseen By Orly Lipsitz

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University Health Network, Toronto

Must not be taking: Benzodiazepines, MAOIs, Stimulants, Cannabis

Disqualifiers: Bipolar, Psychosis, Substance use, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 36

Duration: 13 weeks

110 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if combining internet-based cognitive behavioral therapy (i-CBT) with ketamine infusions can reduce suicidal thoughts and behaviors in people with depression. Participants will receive either i-CBT with ketamine (administered as an IV infusion) or i-CBT with midazolam (administered as an IV infusion) to compare the effectiveness of each combination. The trial targets individuals with depression who have recently experienced suicidal thoughts or behaviors and have not responded to other treatments. Participants must have reliable internet access and be comfortable using online resources. As a Phase 2 trial, this research focuses on assessing the treatment's effectiveness in an initial, smaller group of people.

Do I have to stop taking my current medications?

The trial requires stopping certain medications like other forms of ketamine, benzodiazepines, monoamine oxidase inhibitors, stimulants, or medical cannabis. All other medications are allowed. Also, you should not have changed your medication or non-CBT psychotherapy one month before joining the study.

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

Research shows that intravenous (IV) ketamine can quickly reduce suicidal thoughts in people with depression. In earlier studies, participants who received ketamine experienced a rapid decrease in these thoughts, with some reporting mild and temporary side effects such as nausea, dizziness, and increased blood pressure.

Internet-based cognitive behavioral therapy (i-CBT) is a well-accepted and effective treatment for depression. Research has found that many individuals complete i-CBT programs and see improvements in their symptoms. Typically, i-CBT has no serious side effects, making it a safe choice for most people.

This study tests the combination of i-CBT and IV ketamine to leverage the strengths of both treatments. Ketamine provides quick relief, while i-CBT offers long-term support. The goal is to determine if this combination can reduce suicidal thoughts more effectively than i-CBT alone. Past studies suggest that while ketamine might cause some mild side effects, both treatments are generally safe for most people. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for depression because they combine internet-based cognitive therapy (i-CBT) with either ketamine or midazolam infusions, which offer unique benefits. Ketamine, unlike traditional antidepressants that often take weeks to work, can produce rapid improvements in mood, sometimes within hours or days. This rapid action is especially crucial for patients with severe depression who need quick relief. Meanwhile, midazolam serves as an active comparator and is used for its sedative properties, offering a different mechanism of action compared to standard antidepressants. Both approaches integrate i-CBT, a flexible and accessible therapy method that can be done online, making it easier for patients to receive comprehensive treatment.

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

Studies have shown that cognitive behavioral therapy (CBT) can help reduce suicidal thoughts and actions. When offered online as i-CBT, it becomes more accessible, though it may take longer to reduce suicidal thoughts. In this trial, one group of participants will receive i-CBT combined with IV ketamine. Research has shown that ketamine can quickly reduce suicidal thoughts, though it might not immediately change behaviors. Another group will receive i-CBT combined with IV midazolam. The combination of i-CBT with IV ketamine could be more effective by quickly lowering suicidal thoughts and potentially maintaining these benefits over time, leveraging ketamine's fast effects and i-CBT's long-term support. ^{1 2 3 5 6}

Who Is on the Research Team?

Rodrigo Mansur

Principal Investigator

University Health Network, Toronto

Are You a Good Fit for This Trial?

This trial is for individuals with treatment-resistant depression who have had recent suicidal thoughts or behaviors. Participants must not have responded to previous treatments and are willing to undergo internet-based cognitive therapy and receive IV drug treatments.

Inclusion Criteria

Provide written, voluntary informed consent prior to study enrollment. Substitute decision makers will not be allowed to consent to study on a potential patient's behalf

I am experiencing a severe depressive episode.

Access to reliable internet for the entire study period and an internet-based device (i.e., a smartphone, laptop, desktop or tablet)

Exclusion Criteria

I am currently experiencing symptoms of mania or hypomania.

I have not had major neurological issues or strokes in the last year.

Current symptoms of psychosis or a substance use disorder within the past 3 months. Past history of psychotic features during a mood episode will not be excluded. Other secondary psychiatric comorbidities (e.g. anxiety disorders, trauma related disorders, etc.) will not be excluded

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive internet-based cognitive therapy (i-CBT) for 13 weeks. During the first 4 weeks, they also receive 6 infusions of either IV ketamine or IV midazolam.

13 weeks

Weekly i-CBT sessions, 6 infusions in the first 4 weeks

Follow-up

Participants are monitored for changes in suicidal thoughts and behaviors, as well as other secondary outcomes.

4 weeks

Assessments at Day 30 and Day 91

What Are the Treatments Tested in This Trial?

Interventions

• i-CBT
• IV Ketamine
• IV Midazolam

Trial Overview

The study tests if combining i-CBT (internet-delivered Cognitive Behavioural Therapy) with IV ketamine reduces suicidality more effectively than i-CBT with a control, Midazolam. Half the participants will get ketamine; the other half will get Midazolam, alongside weekly i-CBT sessions for 13 weeks.

How Is the Trial Designed?

Group I: i-CBT and IV ketamine Experimental Treatment 2 Interventions

Participants will receive internet-based cognitive therapy (i-CBT) for 13 weeks. During the first 4 weeks of i-CBT, participants will also be administered 6 infusions of ketamine intravenously. The first two infusions will be dosed at 0.5 mg/kg over a period of 40 mins. For infusions 3 and 4, patients will be flexibly-dosed between 0.5 mg/kg to 0.75 mg/kg, depending on clinical response to first two infusions. For infusions 5 and 6, patients will be flexibly-dosed between 0.5-0.85 mg/kg, depending on the clinical response to the first 4 infusions.

Group II: i-CBT and IV midazolam Active Control 2 Interventions

Participants will receive internet-based cognitive therapy (i-CBT) for 13 weeks. During the first 4 weeks of i-CBT, participants will also be administered 6 infusions of midazolam intravenously. The first two infusions will be dosed at 0.02 mg/kg over a period of 40 mins. For infusions 3 and 4, patients will be flexibly-dosed between 0.02 mg/kg to 0.03 mg/kg, depending on clinical response to first two infusions. For infusions 5 and 6, patients will be flexibly-dosed between 0.02 mg/kg to 0.035 mg/kg, depending on the clinical response to the first 4 infusions.

Who Is Running the Clinical Trial?

University Health Network, Toronto

Lead Sponsor

Trials

1,555

Recruited

526,000+

Ontario Shores Centre for Mental Health Sciences

Collaborator

Trials

15

Recruited

2,400+

Published Research Related to This Trial

In a review of 28 clinical trials involving 7,120 participants, only 10.5% experienced a significant increase in cotinine levels (>50% above baseline) while using nicotine replacement therapy (NRT), indicating that high nicotine exposure is relatively uncommon.

Adverse events related to nicotine overdose, such as nausea, vomiting, and palpitations, were reported infrequently (0.2% to 0.5% of subjects), supporting the overall safety of NRT for smoking cessation or reduction.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Symptoms of nicotine toxicity in subjects achieving high cotinine levels during nicotine replacement therapy. Tonstad, S., Gustavsson, G., Kruse, E., et al.[2018]

A study involving 1,093 university students with subthreshold depression found that all participants experienced significant reductions in depression symptoms after 8 weeks of internet-based cognitive-behavioral therapy (iCBT), regardless of which specific skills were included in their treatment.

No specific iCBT component (like self-monitoring, behavioral activation, cognitive restructuring, assertiveness training, or problem-solving) showed a clear advantage over others in reducing depression, indicating that the overall iCBT approach is effective but the individual components may not be critical for success.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Components of smartphone cognitive-behavioural therapy for subthreshold depression among 1093 university students: a factorial trial. Sakata, M., Toyomoto, R., Yoshida, K., et al.[2023]

A study involving 141 participants with major depressive disorder found that both clinician-assisted and technician-assisted internet-based cognitive behavioral therapy (iCBT) led to significant reductions in depression scores, demonstrating large effect sizes comparable to traditional face-to-face treatments.

At a 4-month follow-up, participants in the technician-assisted group showed further improvements and had significantly lower depression scores than those in the clinician-assisted group, suggesting that technician guidance can be as effective as clinician guidance in iCBT for depression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Internet treatment for depression: a randomized controlled trial comparing clinician vs. technician assistance. Titov, N., Andrews, G., Davies, M., et al.[2022]

A systematic review of 76 randomized controlled trials involving 11,704 participants found that behavioral activation in internet cognitive behavioral therapy (iCBT) may significantly reduce depression severity, while relaxation techniques could potentially be harmful.

Combining human and automated encouragement in iCBT programs was shown to decrease dropout rates, suggesting that support mechanisms are crucial for maintaining engagement in treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dismantling, optimising, and personalising internet cognitive behavioural therapy for depression: a systematic review and component network meta-analysis using individual participant data. Furukawa, TA., Suganuma, A., Ostinelli, EG., et al.[2022]

In a study of 390 smokers with schizophrenia, varenicline was found to significantly increase abstinence rates compared to placebo, with a number needed to treat (NNT) similar to that of a control group without psychiatric illness.

No treatment, including varenicline, bupropion, or nicotine replacement therapy, was associated with a higher incidence of neuropsychiatric adverse events compared to placebo, indicating that these treatments are safe for smokers with schizophrenia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Pharmacotherapeutic Smoking Cessation Aids in Schizophrenia Spectrum Disorders: Subgroup Analysis of EAGLES. Evins, AE., West, R., Benowitz, NL., et al.[2023]

Self-guided internet-based cognitive behavioral therapy (iCBT) significantly reduces depressive symptoms compared to control groups, with a moderate effect size indicating its efficacy as a treatment option.

The study analyzed data from 3876 participants across 13 trials, showing that adherence to iCBT is linked to better treatment outcomes, suggesting that engagement with the program is crucial for effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of Self-guided Internet-Based Cognitive Behavioral Therapy in the Treatment of Depressive Symptoms: A Meta-analysis of Individual Participant Data. Karyotaki, E., Riper, H., Twisk, J., et al.[2022]

In a study of 33,690 smokers using nicotine replacement therapy (NRT) through the New York State Smokers' Quitline, about 25% reported adverse effects at 2 weeks, which increased to 42% at 3 months, but most effects were mild.

Only a small percentage (4.4%-5.4%) discontinued NRT due to these adverse effects, indicating that NRT is generally safe for users when proper screening is conducted.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse effects with use of nicotine replacement therapy among quitline clients. Ossip, DJ., Abrams, SM., Mahoney, MC., et al.[2015]

High-dose transdermal nicotine-replacement therapy (NRT) at doses of 42 mg or more daily appears to be safe, with most trials reporting no serious adverse events, although a dose-response relationship for adverse events was noted.

While high-dose NRT showed a numerically higher abstinence rate in most trials, none achieved statistically significant differences in final abstinence rates, indicating that more extensive studies are needed to confirm its efficacy and identify suitable patient populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High-dose transdermal nicotine replacement for tobacco cessation. Brokowski, L., Chen, J., Tanner, S.[2019]

In a study involving 1,093 Japanese university students with subthreshold depression, higher baseline PHQ-9 scores were associated with greater improvements in depressive symptoms after 8 weeks of internet-cognitive behavioral therapy (iCBT), indicating that those with more severe symptoms may benefit more from this treatment.

Exercise habits were identified as an effect modifier for the self-monitoring component of iCBT, suggesting that individuals who exercise more frequently may experience less benefit from self-monitoring, highlighting the need for personalized approaches in iCBT treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prognostic factors and effect modifiers for personalisation of internet-based cognitive behavioural therapy among university students with subthreshold depression: A secondary analysis of a factorial trial. Toyomoto, R., Sakata, M., Yoshida, K., et al.[2023]

In a study of 241 participants who completed internet-delivered cognitive-behavioral therapy (iCBT) for anxiety and depression, 70.8% remained in remission at 9 months post-treatment, while 29.2% experienced a relapse during that period.

Key predictors of relapse included younger age, having a long-term condition, and residual anxiety symptoms at the end of treatment, highlighting factors that may influence the durability of iCBT outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durability of treatment effects following internet-delivered cognitive behavioural therapy for depression and anxiety delivered within a routine care setting. Palacios, JE., Enrique, A., Mooney, O., et al.[2022]

In a study involving 4092 participants with psychiatric disorders, varenicline, bupropion, and nicotine patches were found to be well tolerated and effective for smoking cessation, with no significant increase in neuropsychiatric adverse events compared to placebo.

Varenicline demonstrated superior continuous abstinence rates compared to bupropion, nicotine patches, and placebo, indicating its effectiveness across various psychiatric diagnoses without varying efficacy based on the type of disorder.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neuropsychiatric Safety and Efficacy of Varenicline, Bupropion, and Nicotine Patch in Smokers With Psychotic, Anxiety, and Mood Disorders in the EAGLES Trial. Evins, AE., Benowitz, NL., West, R., et al.[2020]

The Thrive internet-based cognitive behavior therapy (iCBT) intervention significantly reduced depression and anxiety symptoms over 12 months, with improvements in work and social functioning and resilience, as evidenced by substantial reductions in scores on various mental health scales.

Higher adherence to the Thrive program, indicated by more logins and completed lessons, was associated with greater reductions in depression and anxiety symptoms, suggesting that engagement with the program enhances its effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Twelve-Month Follow-Up to a Fully Automated Internet-Based Cognitive Behavior Therapy Intervention for Rural Adults With Depression Symptoms: Single-Arm Longitudinal Study. Schure, M., McCrory, B., Tuchscherer Franklin, K., et al.[2021]

Internet-delivered automated cognitive behavior therapy (iCBT) is an effective treatment for adults with Major Depressive Disorder, providing a scalable solution to improve access to mental health care.

The review indicates that iCBT is not only effective but also acceptable to both patients and clinicians, addressing concerns about its implementation in clinical practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Up-scaling clinician assisted internet cognitive behavioural therapy (iCBT) for depression: A model for dissemination into primary care. Andrews, G., Williams, AD.[2022]

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