i-CBT + Ketamine for Depression

(Ket-CBT Trial)

Recruiting at 1 trial location

Overseen By Lee Phan, MSc

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

Trial Summary

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.

What data supports the idea that i-CBT + Ketamine for Depression is an effective treatment?

The available research shows that Internet-based Cognitive Behavioural Therapy (i-CBT) is effective for treating depression, especially when guided by a clinician. It is also noted that i-CBT can be easily distributed and is acceptable to both patients and clinicians. However, the research provided does not specifically mention the combination of i-CBT with Ketamine for depression, so there is no direct data supporting the effectiveness of this combined treatment from the information given. ^{1 2 3 4 5}

What safety data exists for i-CBT and Ketamine treatment for depression?

The provided research does not contain safety data for i-CBT or Ketamine treatment for depression. It focuses on the safety and efficacy of smoking cessation aids like varenicline, bupropion, and nicotine replacement therapy in various populations, including those with psychiatric disorders. ^{6 7 8 9 10}

Is i-CBT a promising treatment for depression?

Yes, i-CBT is a promising treatment for depression. It is effective in delivering therapy online, making it more accessible and affordable. It can be guided by a clinician for better results, and it helps people learn skills to manage their depression. ^{1 3 11 12 13}

What is the purpose of this trial?

Approximately four thousand Canadians die by suicide every year, and suicide is the second leading cause of death in youth and young adults (15-34 years). Most people with depression experience thoughts of suicide and many will also plan and/or attempt suicide at some time in their life. There is an urgent need for new scalable treatments that can effectively reduce suicidality in people with depression. Cognitive behavioural therapy (CBT) reduces suicidal thoughts and behaviours, and can be delivered through the internet (i-CBT) making it more accessible and scalable. However, i-CBT has not been shown to rapidly reduce suicidal thoughts and behaviours (suicidality), such as within 24 hours. IV ketamine on the other hand has been shown to rapidly reduce thoughts of suicide, but not suicidal behaviours. Therefore, combining i-CBT with IV ketamine may be more effective reducing suicidality than i-CBT treatment with a control treatment. The investigators propose a 13-week, multi-site, study that looks at how combining i-CBT and IV ketamine treatment will affect suicidality in individuals with depression who have recently experienced suicidal thoughts and/or behaviours, but have not responded to previous treatment. All 110 participants will receive a weekly session of i-CBT for 13 weeks, but half will be randomly assigned to also receive six IV ketamine treatments or six IV midazolam treatments (control treatment) over the first initial 30 days. The investigators will measure changes in suicidal thoughts and behaviours before drug treatment and at the primary endpoint (i.e.,day 30), and after 3 months (i.e. Day 91) of the starting treatment.

Research Team

Rodrigo Mansur

Principal Investigator

University Health Network, Toronto

Eligibility Criteria

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 have been diagnosed with Major Depressive Disorder without psychosis.

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

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]

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 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]

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 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]

References

1. United States pubmed.ncbi.nlm.nih.gov

Internet treatment for depression: a randomized controlled trial comparing clinician vs. technician assistance. [2022]

2. England 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. [2022]

3. England 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. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

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

5. Canada 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. [2021]

6. United States 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. [2020]

7. United States pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Pharmacotherapeutic Smoking Cessation Aids in Schizophrenia Spectrum Disorders: Subgroup Analysis of EAGLES. [2023]

8. England pubmed.ncbi.nlm.nih.gov

Adverse effects with use of nicotine replacement therapy among quitline clients. [2015]

9. England pubmed.ncbi.nlm.nih.gov

High-dose transdermal nicotine replacement for tobacco cessation. [2019]

10. England pubmed.ncbi.nlm.nih.gov

Symptoms of nicotine toxicity in subjects achieving high cotinine levels during nicotine replacement therapy. [2018]

11. England pubmed.ncbi.nlm.nih.gov

Components of smartphone cognitive-behavioural therapy for subthreshold depression among 1093 university students: a factorial trial. [2023]

12. United States 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. [2022]

13. Netherlands 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. [2023]