Precision Medicine in the Depression Treatment

Depressive Disorder, Major Clinical Trial

— BDD  

Official title:

The BrainDrugs-Depression Study: A Prospective Precision Psychiatry Cohort Study in the Treatment of Depression

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05616559
• Other study ID #: H-20083013
• Status: Recruiting
• Start date: June 15, 2021
• Est. completion date: May 2026

Study information

• Verified date: November 2022
• Source: Rigshospitalet, Denmark
• Contact: Kristian HR Jensen, MD
• Phone: +45 35456720
• Email: kristian.reveles.jensen[@]nru.dk
• Is FDA regulated: No
• Study type: Observational [Patient Registry]

Clinical Trial Summary

The BrainDrugs-D study uses multimodal neuroimaging combined with self-report measures, clinical and molecular markers to identify clinically relevant predictors that can identify subtypes of major depressive disorder (MDD) and, in a naturalistic setting, predict treatment response to standard antidepressive treatment. The cohorts are followed in nationwide health registries.

Description:

BrainDrugs-D is a cohort study of patients with major depressive disorder (MDD) who are deeply phenotyped with demographic, clinical, genetic, biochemical and neuroimaging modalities. These features are subsequently examined for their ability to identify subtypes of MDD and to predict treatment response.

Treatment and study population All participants are phenotyped before initiating a standardized 'treatment package' in out-patient clinics within the Mental Health Services in the Capital Region of Denmark. The goal is to recruit a total of 800 patients with non-psychotic MDD. We use broad inclusion criteria to enable recruitment of representative adult out-patients with non-psychotic MDD who receive standard treatment in practice.

As the study is designed with a high degree of ecological validity, it will not interfere with or delay the standard treatment package for depression. The treatment package is a national uniform package designed by Mental Health Services in the Capital Region, it has been in use since 2017, after several preceding years of clinical use and patient experience. Treatment for first-episode depression has a manualized group Cognitive-behavioural therapy (CBT) as the backbone: 2-3 hours of initial workup followed by 6 hours of individual therapy or 12 sessions of 2 hours of group therapy (8 patients per group), 1-2 hours of engagement and psychoeducation of relatives, 1-5 hours of medication clinic and 2 hours of relapse prevention. Antidepressant medication and individual psychotherapy are instituted, as needed.

Groups The study comprises three groups: The entire cohort (n=800) will have basic clinical, cognitive, psychometric, and biological data available. A subgroup (Subcohort I, n=600) provided expanded clinical, cognitive, psychometric, and biological data as well as Magnetic Resonance Imaging (MRI) and Electroencephalogram (EEG). Subcohort II, (n=60) will be exclusively for patients unmedicated at initiation, consisting of the same investigation, and contributing Positron Emission Tomography imaging with the [11C]-UCB-J tracer of synaptic density.

Follow-up All cohorts receive questionnaires assessing depression symptom severity, level of functioning, and QoL at the three follow-up time points. We also assess the side effects of psychological treatment and medication at the end of the treatment package. The cohorts are also followed in nationwide health registries.

Outcomes The primary outcome is remission (QIDS ≤5) and clinical improvement (≥50% reduction in QIDS) after 6 months.

Secondary endpoints include remission status 12 and 18 months after treatment start and change in QIDS, SCL10, WHO-5, and SDS scores from baseline to follow-ups.

Analysis We will use machine learning algorithms to determine a combination of baseline characteristics that best predict treatment outcomes and statistical models to investigate the association between individual and clinical outcomes. We will also assess associations between patient characteristics, treatment choices, and clinical outcomes using path analysis, enabling us to estimate the effect of treatment choices and timing on the clinical outcome.

Hypotheses for the whole cohort:

Primary hypotheses:

1.1 Clinical, cognitive, psychometric, genetic, and blood biomarker measures at inclusion can predict clinical remission (defined as QIDS≤5) at the first follow-up.

1.2 Clinical, cognitive, psychometric, genetic, and blood biomarker measures at inclusion can predict clinical improvement (a ≥50% reduction in QIDS from pretreatment) at the first follow-up.

Secondary hypotheses:

1.3 Composite scores across a range of clinical, cognitive, psychometric, genetic, and blood biomarker measures at inclusion can cluster patients into MDD subgroups associated with treatment trajectories and outcomes.

1.4 Clinical, cognitive, psychometric, genetic, and blood biomarker measures at inclusion are associated with clinical outcome defined as a change in QIDS.

1.5 Path analysis of baseline patient characteristics and treatment tracks can uncover causal paths for clinical improvements, i.e., estimate the effect of treatment on clinical outcomes.

Hypotheses for Subcohort I

Primary hypotheses:

2.1 MRI, fMRI, and EEG patterns at inclusion may be associated with depressive phenotypes.

2.2 Adding EEG, MRI, and fMRI measures at inclusion to the classifier model (defined in hypotheses 1.1 and 1.2) may significantly improve the prediction of clinical remission and improvement.

Secondary hypotheses:

2.3 Adding EEG, MRI, and fMRI measures at inclusion to the composite score (defined in hypothesis 1.3) may significantly improve the clustering of patients into MDD subgroups.

Hypotheses for Subcohort II

Primary hypotheses:

3.1 Cerebral [11C]-UCB-J binding is lower in patients with MDD than in healthy controls.

3.2 Domain-specific cognitive function correlates positively with [11C]-UCB-J binding in associated cortical and subcortical areas.

Secondary hypotheses:

3.1 Depression severity, anxiety, and anhedonia correlate with [11C]-UCB-J binding in associated cortical and subcortical areas.

3.2 Addition of [11C]-UCB-J binding, EEG, and MRI measures at inclusion to the composite score (defined in hypotheses 2.1) can significantly improve the prediction of clinical improvement and remission beyond clinical, cognitive, psychometric, fluid biomarker, EEG, and MRI measures in antidepressant naïve patients.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 800
• Est. completion date: May 2026
• Est. primary completion date: June 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

Inclusion Criteria:

• Age between 18 and 65 years

• Fulfilment of International Classification of Diseases version 10 diagnostic criteria for a primary depressive episode (i.e., not secondary to known organic or other psychiatric disorder).

• Referral to a treatment package for single-episode depression.

Exclusion Criteria:

• Psychosis or psychotic symptoms

• History of severe head trauma

• Somatic disease associated with morphological brain changes (e.g., brain tumour)

• Insufficient Danish language skills to complete questionnaires and cognitive testing

Additional exclusion criteria for Cohort II:

• Severe somatic disease

• Contraindications for MRI (e.g., metal implants, claustrophobia or back problems)

Additional exclusion criteria for Cohort III:

• Severe somatic disease

• Contraindications for MRI

• Exposure to radioactivity >10 mSv within the last year

• Pregnancy or breastfeeding

• Use of psychotropic drugs

Related Conditions & MeSH terms

• Antidepressive Agents
• Cognitive Behavioral Therapy
• Cognitive Dysfunction
• Depression
• Depressive Disorder
• Depressive Disorder, Major
• Treatment Outcome

Intervention

Combination Product:
• Treatment Package for First-Episode Depression
The outpatient 'treatment package' for first episode depression is a national uniform package designed by Mental Health Services in the Capital Region. The treatment package for first-episode depression is a program with manualized group CBT, psychoeducation of patients and relatives, and relapse prevention. Antidepressant medication and individual psychotherapy are available as needed.

Locations

Country	Name	City	State
Denmark	Neurobiology Research Unit, Rigshospitalet	Copenhagen

Sponsors (4)

Lead Sponsor	Collaborator
Rigshospitalet, Denmark	Center for Integrated Molecular Brain Imaging, Copenhagen, Denmak, Lundbeck Foundation, Mental Health Centre Copenhagen

Country where clinical trial is conducted

Denmark, 

References & Publications (3)

Cipriani A, Furukawa TA, Salanti G, Chaimani A, Atkinson LZ, Ogawa Y, Leucht S, Ruhe HG, Turner EH, Higgins JPT, Egger M, Takeshima N, Hayasaka Y, Imai H, Shinohara K, Tajika A, Ioannidis JPA, Geddes JR. Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis. Lancet. 2018 Apr 7;391(10128):1357-1366. doi: 10.1016/S0140-6736(17)32802-7. Epub 2018 Feb 21. Review. — View Citation

Kessler RC, van Loo HM, Wardenaar KJ, Bossarte RM, Brenner LA, Ebert DD, de Jonge P, Nierenberg AA, Rosellini AJ, Sampson NA, Schoevers RA, Wilcox MA, Zaslavsky AM. Using patient self-reports to study heterogeneity of treatment effects in major depressive disorder. Epidemiol Psychiatr Sci. 2017 Feb;26(1):22-36. doi: 10.1017/S2045796016000020. Epub 2016 Jan 26. Review. — View Citation

Trevino K, McClintock SM, McDonald Fischer N, Vora A, Husain MM. Defining treatment-resistant depression: a comprehensive review of the literature. Ann Clin Psychiatry. 2014 Aug;26(3):222-32. Review. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Medication side-effects	Patient Reported Inventory of Side-Effects (PRISE)	Baseline to 6 months after treatment start
Other	Adverse and unwanted events in psychotherapy	Negative Effects Questionnaire (NEQ) to assess adverse and unwanted events in psychological treatment	Baseline to 6 months after treatment start
Other	Psychosocial remission	Defined as either a WHO-5 score of >49, an SCL-10 score of <26 or an mSDS score of <10.	Baseline to 6, 12 and 18 months after treatment start
Primary	Clinical remission	Quick Inventory of Depressive Symptomatology (QIDS) score of =5	Baseline to 6 months after treatment start
Primary	Clinical improvement	=50% reduction in QIDS score.	Baseline to 6 months after treatment start
Secondary	Changes in depression severity	Changes in depression severity by QIDS (range from 0 to 27, higher score indicating greater severity)	Baseline to 6, 12 and 18 months after treatment start
Secondary	Changes in symptomatology	Changes on the Brief Symptom Inventory 18 (BSI-18, range 0-72, higher score indicating greater psychological distress)	Baseline to 6, 12 and 18 months after treatment start
Secondary	Changes in depression and anxiety symptomatology	Changes on the 10-item depression and anxiety symptom checklist (SCL-10, range 0-100 higher score indicating greater symptomatology)	Baseline to 6, 12 and 18 months after treatment start
Secondary	Change in wellbeing	Changes measured by the WHO-5 well-being Index (range 0-100, with 0 representing the worst imaginable well-being and 100 representing the best imaginable well-being).	Baseline to 6, 12 and 18 months after treatment start
Secondary	Change in disability	Changes measured by modified S. Disability Scale (mSDS) scores (range 0-30, with greater score indicating greater disability)	Baseline to 6, 12 and 18 months after treatment start

External Links

•   Description of treatment package (in Danish)