Clinical trial NCT05616559: Precision Medicine in the Depression Treatment
Official title: The BrainDrugs-Depression Study: A Prospective Precision Psychiatry Cohort Study in the Treatment of Depression
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Depressive Disorder, Major
Treatment Outcome
Cognitive Dysfunction
Cognitive Behavioral Therapy
Antidepressive Agents
Keywords: PET
MRI
fMRI
EEG
Prediction of treatment response
Early life stress
Selective Serotonin Reuptake Inhibitor
Psychometrics
MDD
Cold cognition
Social cognition
Anxiety
Lead sponsor: Rigshospitalet, Denmark
Sponsor class: OTHER
Collaborators: name: Mental Health Services in the Capital Region, Denmark
name: Center for Integrated Molecular Brain Imaging, Copenhagen, Denmak
name: Lundbeck Foundation
First posted: 2022-11-15
Enrollment: 800
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: The Capital Region of Denmark is the most urban area of Denmark and has a population of 1.6 million people. Patients in the Capital Region of Denmark are referred from their general practitioner or other treatment providers for treatment within the mental health services in the region. All six clinics in the region provide treatment packages for first-episode depression.

Brief 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.

Detailed 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.

Eligibility criteria: 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

Primary outcomes:
measure: Clinical remission
timeFrame: Baseline to 6 months after treatment start
measure: Clinical improvement
timeFrame: Baseline to 6 months after treatment start
Secondary outcomes:
measure: Changes in depression severity
timeFrame: Baseline to 6, 12 and 18 months after treatment start
measure: Changes in symptomatology
timeFrame: Baseline to 6, 12 and 18 months after treatment start
measure: Changes in depression and anxiety symptomatology
timeFrame: Baseline to 6, 12 and 18 months after treatment start
measure: Change in wellbeing
timeFrame: Baseline to 6, 12 and 18 months after treatment start
measure: Change in disability
timeFrame: Baseline to 6, 12 and 18 months after treatment start
Other outcomes:
measure: Medication side-effects
timeFrame: Baseline to 6 months after treatment start
measure: Adverse and unwanted events in psychotherapy
timeFrame: Baseline to 6 months after treatment start
measure: Psychosocial remission
timeFrame: Baseline to 6, 12 and 18 months after treatment start
Locations:
city: Copenhagen
country: Denmark
facility: Neurobiology Research Unit, Rigshospitalet
Study officials:
affiliation: Psychiatric Center Copenhagen
name: Martin B Jørgensen, DMSc
role: PRINCIPAL_INVESTIGATOR
affiliation: Neurobiology Research Unit, Rigshospitalet
name: Gitte MK Knudsen, DMSc
role: STUDY_DIRECTOR
References:
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