CBT + Antidepressants for Depression

(CANBIND6 Trial)

Overseen By Jill Cumby, RN

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: Nova Scotia Health Authority

Must not be taking: Antidepressants

Disqualifiers: Bipolar, Schizophrenia, 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: 28

Duration: 18 weeks

80 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial does not specify if you need to stop your current medications, but you cannot join if you've recently started a new antidepressant or increased your dose in the past 6 weeks.

What data supports the effectiveness of combining antidepressants with cognitive behavioral therapy for treating depression?

Research suggests that antidepressants, especially those affecting multiple neurotransmitters like venlafaxine, can be effective in treating depression. Combining these with therapies like cognitive behavioral therapy (CBT) may enhance treatment effectiveness, as targeting multiple aspects of depression can lead to better outcomes. ^{1 2 3 4 5}

Is the combination of CBT and antidepressants generally safe for humans?

Antidepressants like SSRIs and SNRIs are generally considered safe and have fewer side effects compared to older drugs like tricyclic antidepressants. However, all medications can have potential risks, so it's important to discuss these with a healthcare provider. ^{1 6 7 8 9}

How is the CBT + Antidepressants treatment for depression different from other treatments?

This treatment combines cognitive behavioral therapy (CBT), which helps change negative thought patterns, with antidepressants, which adjust brain chemicals to improve mood. This dual approach is unique because it addresses both the psychological and biological aspects of depression, potentially offering more comprehensive relief than using either method alone. ^{10 11 12 13 14}

What is the purpose of this trial?

Depression currently affects close to 2 million Canadians and is the leading cause of disability worldwide. Pharmacological treatments (antidepressant medication) and psychological treatments such as cognitive-behavioural therapy are available for depression, but the majority of those who receive treatment have an unsatisfactory response. On average, the combination of pharmacological and psychological treatment achieves better results than either treatment alone. However, the apparently superior results of combination treatment may be due to the fact that different individuals preferentially respond to pharmacological or psychological treatment. The invesitagtors have discovered several clinical factors and biomarkers that predict poor response to commonly used antidepressant medication: history of childhood maltreatment, loss of interest and reduced activity, a biomarker of systemic inflammation, and a genetic marker of sensitivity to environment. Indirect evidence suggests that the same factors may indicate the need for psychological treatment, but their usefulness as differential predictors of psychological and pharmacological treatment outcomes remains to be established. The investigators will test the hypothesis that a pre-determined clinical variables (history of childhood maltreatment, loss of interest and reduced activity) and biomarkers (serum C-reactive protein, a marker of systemic inflammation, and insulin resistence, an indicator of metabolic health) differentially predict response to antidepressants and to cognitive-behavioural psychotherapy with clinically significant accuracy. If this hypothesis is supported, the resulting predictor will allow personalized selection of treatment for depression, leading to improved outcomes and healthcare efficiency. Additional objectives include replication of additional predictors and integrative analyses aimed at refining the treatment choice algorithms.

Research Team

Rudolf Uher, MD

Principal Investigator

Nova Scotia Health Authority

Eligibility Criteria

This trial is for adults over 18 with depression lasting at least two months, diagnosed with Major Depressive Disorder (MDD) or Persistent Depressive Disorder (PDD), and a Hamilton Rating Scale for Depression score of 14+. They must see depression as their main issue and can consent. Excluded are those with psychosis, pregnancy, bipolar/schizophrenia spectrum disorders, recent substance abuse disorder, extensive recent CBT or non-response to study meds.

Inclusion Criteria

I have been diagnosed with major depression or persistent depressive disorder as my main health issue.

a minimum current severity of 14 on the 17-item Hamilton Rating Scale for Depression (HRSD-17)

I understand the information given to me and can make decisions about my health care.

Exclusion Criteria

You are currently experiencing symptoms of psychosis.

You are pregnant.

You have been diagnosed with a mental illness such as bipolar disorder, schizophrenia, or schizoaffective disorder, or you are currently struggling with alcohol or drug addiction.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either cognitive-behavioural therapy or antidepressant medication based on predictive scores

18 weeks

Visits every 2 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

34 weeks

Medium-term follow-ups at 26 and 52 weeks

Treatment Details

Interventions

• Antidepressants
• Cognitive Behavioral Therapy

Trial Overview The trial tests if certain clinical factors and biomarkers predict better outcomes in treating depression with Cognitive Behavioral Therapy versus antidepressants. It aims to personalize treatment by identifying who responds best to which therapy based on childhood maltreatment history, activity levels, inflammation markers (C-reactive protein), and genetic markers.

Participant Groups

Group I: Psychotherapy Experimental Treatment 1 Intervention

Cognitive Behavioral Therapy

Group II: Pharmacotherapy Experimental Treatment 1 Intervention

Antidepressant medication

Antidepressants is already approved in European Union, United States, Canada, Japan, China, Switzerland for the following indications:

Approved in European Union as Antidepressants for:

• Major Depressive Disorder (MDD)
• Persistent Depressive Disorder (PDD)
• Anxiety Disorders
• Post-Traumatic Stress Disorder (PTSD)

Approved in United States as Antidepressants for:

• Major Depressive Disorder (MDD)
• Persistent Depressive Disorder (PDD)
• Anxiety Disorders
• Post-Traumatic Stress Disorder (PTSD)
• Obsessive-Compulsive Disorder (OCD)

Approved in Canada as Antidepressants for:

• Major Depressive Disorder (MDD)
• Persistent Depressive Disorder (PDD)
• Anxiety Disorders
• Post-Traumatic Stress Disorder (PTSD)

Approved in Japan as Antidepressants for:

• Major Depressive Disorder (MDD)
• Anxiety Disorders

Approved in China as Antidepressants for:

• Major Depressive Disorder (MDD)
• Anxiety Disorders

Approved in Switzerland as Antidepressants for:

• Major Depressive Disorder (MDD)
• Persistent Depressive Disorder (PDD)
• Anxiety Disorders

Who Is Running the Clinical Trial?

Nova Scotia Health Authority

Lead Sponsor

Trials

302

Recruited

95,300+

University Health Network, Toronto

Collaborator

Trials

1,555

Recruited

526,000+

Kingston Health Sciences Centre

Collaborator

Trials

312

Recruited

112,000+

Queen's University

Collaborator

Centre for Addiction and Mental Health

Collaborator

Trials

388

Recruited

84,200+

Queen's University

Collaborator

Trials

382

Recruited

122,000+

Findings from Research

The search for effective treatments for major depression has evolved from tricyclic antidepressants to selective serotonin reuptake inhibitors (SSRIs), but concerns about tolerability and efficacy have prompted the exploration of new alternatives.

Venlafaxine, a serotonin and norepinephrine reuptake inhibitor, shows promise with potentially faster onset of action and higher remission rates compared to SSRIs, suggesting that drugs targeting multiple neurotransmitter systems may enhance treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mechanism of action of antidepressants. Artigas, F., Nutt, DJ., Shelton, R.[2022]

Antidepressants can be categorized into seven classes based on their distinct pharmacologic mechanisms, which influence both their therapeutic effects and side effects.

The most commonly prescribed antidepressants are SSRIs, but other classes like venlafaxine and bupropion offer different mechanisms of action, such as dual reuptake inhibition and norepinephrine/dopamine reuptake inhibition, respectively.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Basic psychopharmacology of antidepressants, part 1: Antidepressants have seven distinct mechanisms of action. Stahl, SM.[2022]

Despite improvements in treatment outcomes for depression with newer antidepressants, some doctors still prefer older tricyclic antidepressants for severely depressed patients due to mixed reports on the effectiveness of newer options like selective serotonin reuptake inhibitors (SSRIs).

Research suggests that longer trials and higher doses of newer antidepressants could improve remission rates in severe depression, and venlafaxine, which targets both serotonin and norepinephrine, may provide additional benefits for these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antidepressant effectiveness in severe depression and melancholia. Schatzberg, AF.[2022]

Citalopram, an SSRI, was linked to hair thinning in a 76-year-old woman after 3.5 months of treatment, highlighting a rare but distressing side effect of this medication.

Discontinuing citalopram led to the patient regaining most of her hair, emphasizing the importance of recognizing and addressing drug-induced side effects promptly to improve patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Citalopram-Associated Alopecia: A Case Report and Brief Literature Review. Hekmatjah, J., Tareen, K., Tareen, RS.[2020]

Monoamine-based therapies that focus on serotonin, norepinephrine, or dopamine are effective for treating depression, but many patients do not fully recover with these single-target treatments.

Exploring treatment strategies that target multiple neurotransmitters—through methods like combination therapies or developing new medications that affect several neurotransmitters—could lead to better outcomes for patients who do not respond to traditional antidepressants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Can monoamine-based therapies be improved? Demitrack, MA.[2015]

In a meta-analysis of 15 clinical trials involving 2458 patients, serotonin-norepinephrine reuptake inhibitors (SNRIs) demonstrated the highest remission rate for major depressive disorder at 49.0%, outperforming tricyclic antidepressants (TCAs) at 44.1% and selective serotonin-reuptake inhibitors (SSRIs) at 37.7%.

SNRIs also had the lowest dropout rates due to adverse drug reactions (ADRs) and lack of efficacy (LoE), indicating a better safety profile compared to TCAs and SSRIs, which suggests that SNRIs may be a more effective and tolerable treatment option for patients with major depression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Remission, dropouts, and adverse drug reaction rates in major depressive disorder: a meta-analysis of head-to-head trials. Machado, M., Iskedjian, M., Ruiz, I., et al.[2022]

SSRIs and SNRIs are commonly prescribed for anxiety and mild to moderate depression due to their favorable side effect profiles, including fewer issues with orthostatic hypotension and cognitive impairment.

Tricyclic antidepressants remain important for severe depression treatment, while drugs like mianserin and trazodone are effective for specific conditions like delirium, highlighting the need for careful selection based on pharmacologic profiles to minimize adverse effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Review of pharmacological efficacies and side effects of antidepressants]. Ikenouchi-Sugita, A., Yoshimura, R., Nakamura, J.[2013]

Selective serotonin reuptake inhibitors (SSRIs) are generally considered a safer treatment for depression compared to older tricyclic antidepressants, but they still carry potential safety risks, especially in patients with a history of stroke or myocardial infarction.

Patients with cardiovascular issues may face increased risks of adverse events, such as QT prolongation and bleeding, when prescribed SSRIs, highlighting the importance of considering individual health conditions and medications when initiating treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety considerations for prescribing SSRI antidepressants to patients at increased cardiovascular risk. Mortensen, JK., Andersen, G.[2022]

Modern antidepressants, including selective serotonin reuptake inhibitors and norepinephrine-dopamine reuptake inhibitors, are safer and better tolerated than older medications like tricyclic antidepressants, making them the first-line treatments for major depressive disorder (MDD).

Despite the advancements in antidepressant therapies, there is still no one-size-fits-all solution for MDD, highlighting the importance of ongoing assessment of treatment response and management of side effects for effective disease management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-line pharmacotherapies for depression - what is the best choice? Koenig, AM., Thase, ME.[2022]

Combination therapies for depression, such as pairing anxiolytics or neuroleptics with antidepressants, can offer benefits and drawbacks in clinical practice, highlighting the need for careful consideration in treatment plans.

Recent medications like nomifensin, viloxazin, amineptin, and mianserin are noted for their ability to interact with fewer neurotransmitters, which may enhance their safety and efficacy in combination therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Drug combinations in the treatment of depression]. des Lauriers, A., Puech, A., Allilaire, JF.[2006]

The study involving 14 patients with major depressive disorder (MDD) found that combining transcranial direct current stimulation (tDCS) with computer-based cognitive behavioral therapy (CBT) is feasible and well-tolerated, with most side effects being mild.

Participants showed significant improvement in depression symptoms, with a 28.98% overall change on the Hamilton Depression Rating Scale (HAMD-21), indicating that this combination treatment may enhance the effects of CBT, although the study was too small to definitively assess the differences between active and sham tDCS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Feasibility of Computerized Cognitive-Behavioral Therapy Combined With Bifrontal Transcranial Direct Current Stimulation for Treatment of Major Depression. Welch, ES., Weigand, A., Hooker, JE., et al.[2022]

In a study involving 106 patients with chronic depression, the cognitive behavioral analysis system of psychotherapy (CBASP) was found to be significantly more effective than treatment-as-usual (TAU) in reducing depressive symptoms, indicating its potential as a strong treatment option.

Mindfulness-based cognitive therapy (MBCT) showed mixed results, being no more effective than TAU overall, but it did demonstrate some effectiveness at one treatment site, suggesting that its efficacy may vary based on specific contexts or populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomized controlled trial on the efficacy of mindfulness-based cognitive therapy and a group version of cognitive behavioral analysis system of psychotherapy for chronically depressed patients. Michalak, J., Schultze, M., Heidenreich, T., et al.[2018]

In a study of 10 patients with major depressive disorder (MDD) who did not respond to fluoxetine treatment, adding cognitive-behavioral therapy (CBT) resulted in a 100% response rate and a 70% remission rate, indicating significant efficacy of this combined approach.

Patients reported improved satisfaction and quality of life after CBT augmentation, with significant improvements measured by various scales, suggesting that CBT can enhance the effectiveness of fluoxetine in treating MDD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cognitive-behavioral therapy added to fluoxetine in major depressive disorder after 4 weeks of fluoxetine-treatment: 16-week open label study. Maneeton, N., Thongkam, A., Maneeton, B.[2022]

Trazodone, particularly in its extended-release formulation, is highlighted as a potentially effective treatment for major depressive disorder, offering a balance of efficacy and tolerability compared to other antidepressants.

The article emphasizes that while antidepressant monotherapy is typically the first-line treatment for moderate to severe depression, trazodone's once-a-day dosing may enhance patient compliance and overall treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Practical guidance for prescribing trazodone extended-release in major depression. Goracci, A., Forgione, RN., De Giorgi, R., et al.[2022]

References

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

Mechanism of action of antidepressants. [2022]

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

Basic psychopharmacology of antidepressants, part 1: Antidepressants have seven distinct mechanisms of action. [2022]

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

Antidepressant effectiveness in severe depression and melancholia. [2022]

4. United Arab Emirates pubmed.ncbi.nlm.nih.gov

Citalopram-Associated Alopecia: A Case Report and Brief Literature Review. [2020]

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

Can monoamine-based therapies be improved? [2015]

6. England pubmed.ncbi.nlm.nih.gov

Remission, dropouts, and adverse drug reaction rates in major depressive disorder: a meta-analysis of head-to-head trials. [2022]

7. Japan pubmed.ncbi.nlm.nih.gov

[Review of pharmacological efficacies and side effects of antidepressants]. [2013]

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

Safety considerations for prescribing SSRI antidepressants to patients at increased cardiovascular risk. [2022]

9. Poland pubmed.ncbi.nlm.nih.gov

First-line pharmacotherapies for depression - what is the best choice? [2022]

10. France pubmed.ncbi.nlm.nih.gov

[Drug combinations in the treatment of depression]. [2006]

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

Feasibility of Computerized Cognitive-Behavioral Therapy Combined With Bifrontal Transcranial Direct Current Stimulation for Treatment of Major Depression. [2022]

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

A randomized controlled trial on the efficacy of mindfulness-based cognitive therapy and a group version of cognitive behavioral analysis system of psychotherapy for chronically depressed patients. [2018]

13. Thailand pubmed.ncbi.nlm.nih.gov

Cognitive-behavioral therapy added to fluoxetine in major depressive disorder after 4 weeks of fluoxetine-treatment: 16-week open label study. [2022]

14. England pubmed.ncbi.nlm.nih.gov

Practical guidance for prescribing trazodone extended-release in major depression. [2022]