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Treatment Outcome in Major Depressive Disorder

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ClinicalTrials.gov Identifier: NCT02869035
Recruitment Status : Recruiting
First Posted : August 16, 2016
Last Update Posted : June 2, 2017
Sponsor:
Collaborators:
Center for Integrated Molecular Brain Imaging, Copenhagen, Denmak
Psychiatric Centre Copenhagen
Central Visitation, Region Hovedstaden
Information provided by (Responsible Party):
Gitte Moos Knudsen, Rigshospitalet, Denmark

Brief Summary:
Major Depressive Disorder (MDD) is one of the most severe and frequently occurring brain disorders worldwide. It has been linked to serotonergic dysfunction, sexual dysfunction, vulnerability to stress and neuro-inflammation. However, at the same time the etiological understanding is limited. Most antidepressants act on the serotonin (5- HT) system, yet between 30-50 % of patients with MDD does not respond successfully to 5-HT acting drugs. Recent experimental models from our group suggest that cerebral 5-HT levels in vivo can be indexed through molecular brain imaging of the 5-HT 4 receptor (5-HT4R) with a novel Positron Emission Tomography (PET) ligand (11C-SB207145). Also, our human studies have confirmed that cerebral synaptic 5-HT is inversely related to 5-HT4R binding and this technique thus can be used to investigate the role of 5-HT tone in the brain in MDD with differential responses to standard antidepressant treatment. By using multimodal neuroimaging technology, we aim to determine the status of the 5-HT system prior to and after either successful or failed neuropharmacological intervention in a non-randomized longitudinal open clinical trial. 100 untreated patients with moderate to severe MDD will be included. Data collection from various neurobiological domains (i.e, 5-HT4R PET imaging, Magnetic Resonance Imaging (MRI), functional MRI (fMRI), electroencephalogram (EEG), psychometrics, neuropsychological tests, and peripheral biomarkers) will be conducted before, during and after 12 weeks of antidepressant treatment. The objective is to identify predictors of pharmacological antidepressant treatment response in depressed individuals before and after 8 weeks of antidepressant treatment.

Condition or disease Intervention/treatment Phase
Major Depressive Disorder Drug: Escitalopram Drug: Duloxetine Phase 1

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 100 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Other
Official Title: Predicting Treatment Outcome in Major Depressive Disorder
Study Start Date : August 2016
Estimated Primary Completion Date : July 2019
Estimated Study Completion Date : July 2019

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Treatment of MDD patients
Treatment of MDD patients with escitalopram
Drug: Escitalopram
Patients will be treated with an antidepressant drug (escitalopram) at flexible standard doses for 12 weeks. If no response after 4 weeks; shift to duloxetine arm.

No Intervention: Healthy controls
No treatment.
Experimental: Shift of treatment for MDD patients
Treatment of MDD patients with duloxetine
Drug: Duloxetine
Patients who at 4 weeks of escitalopram have not responded will be shifted to duloxetine at flexible standard dosages.




Primary Outcome Measures :
  1. Binary treatment outcome in terms of remission from depression. [ Time Frame: Baseline to clinical follow-up at 8 weeks after antidepressant treatment. ]
    Treatment outcome defined as changes in HAMD-6 score after antidepressant treatment (remitters and non-responders as previously defined).

  2. Baseline cerebral 5-HT4R binding as imaged by 11C-SB207145 PET. [ Time Frame: Baseline. ]
    Latent variable construct of 5-HT4R level based on quantification of 5-HT4R binding in primary volumes of interest; neocortex, nucleus caudatus, putamen and hippocampus. Assessed in depressed patients and healthy controls.

  3. Changes from baseline in cerebral 5-HT4R binding as imaged by 11C-SB207145 PET [ Time Frame: Baseline to follow-up scan at 8 weeks after antidepressant treatment. ]
    Difference in latent variable construct of 5-HT4R level based on quantification of 5-HT4R binding in primary volumes of interest; neocortex, nucleus caudatus, putamen and hippocampus. Measured in remitters and non-responders.

  4. Baseline hippocampus volume [ Time Frame: Baseline. ]
    Structural MRI scan in depressed patients and healthy controls.

  5. Changes from baseline in hippocampus volume. [ Time Frame: Baseline to follow-up scan at 8 weeks after antidepressant treatment. ]
    Structural MRI in remitters and non-responders.

  6. Baseline fMRI BOLD response to an emotional faces paradigm [ Time Frame: Baseline ]
    fMRI (BOLD response) based assessment of brain activity to emotionally salient, relative to neutral, stimuli.

  7. Changes from baseline in fMRI BOLD response to an emotional faces paradigm [ Time Frame: Baseline to follow-up scan at 8 weeks after antidepressant treatment. ]
    fMRI (BOLD response) based assessment of brain activity to emotionally salient, relative to neutral, stimuli.

  8. Baseline fMRI BOLD response to reward paradigm. [ Time Frame: Baseline ]
    fMRI (BOLD response) based assessment of brain activity in response to reward, relative to non-reward, stimuli.

  9. Changes from baseline in fMRI BOLD response to reward paradigm [ Time Frame: Baseline to follow-up scan at 8 weeks after antidepressant treatment. ]
    fMRI (BOLD response) based assessment of brain activity in response to reward, relative to non-reward, stimuli.

  10. Baseline rsfMRI based spontaneous co-fluctuations in low frequency BOLD signal (functional connectivity) [ Time Frame: Baseline ]
    Assessed with rsfMRI scan in the resting state, i.e. non-goal oriented spontaneous thought and awake.

  11. Changes from baseline in rsfMRI spontaneous co-fluctuations in low frequency BOLD signal (functional connectivity) [ Time Frame: Baseline to follow-up scan at 8 weeks after antidepressant treatment. ]
    Assessed with rsfMRI scan in the resting state, i.e. non-goal oriented spontaneous thought and awake.

  12. Sexual function in depression [ Time Frame: Baseline ]
    Assessed with scores of self reported sexual function questionnaires in depressed patients and healthy controls.

  13. Changes in sexual function [ Time Frame: Baseline to clinical follow-up at 8 or 12 weeks after antidepressant treatment, and baseline to follow-up scan at 8 weeks after antidepressant treatment. ]
    Questionnaire-based self-reported sexual function in remitters and non-responders

  14. Baseline EEG including event related potentials (ERP) [ Time Frame: Baseline ]
    Assessment of evoked gamma activity, alpha and theta cordance band activity in depressed patients and healthy controls.

  15. Changes in EEG including event related potentials (ERP) [ Time Frame: Baseline to follow-up examination at 8 weeks after antidepressant treatment. ]
    Assessment of evoked gamma activity, alpha and theta cordance band activity in remitters and non-responders.

  16. Cortisol awakening response [ Time Frame: Baseline ]
    Cortisol changes in response to awakening as measured in saliva from 0 to 60 minutes after awakening in depressed patients and healthy controls.

  17. Changes in cortisol awakening response (HPA-axis dynamics) [ Time Frame: Baseline and follow-up examination at 8 weeks after antidepressant treatment. ]
    Measured in remitters and non-responders.

  18. Systemic inflammation peripheral blood hsCRP and immunoactive cytokines [ Time Frame: Baseline and follow-up examination at 8 weeks after antidepressant treatment. ]
    Measured with peripheral blood markers in plasma by high-sensitivity (hs) methods.

  19. Changes in systemic inflammation peripheral blood hsCRP and immunoactive cytokines [ Time Frame: Baseline and follow-up examination at 8 weeks after antidepressant treatment. ]
    Measured with peripheral blood markers in plasma by high-sensitivity (hs) methods.

  20. Systemic oxidative stress in terms of 8-oxodG and 8-oxoGuo in urine [ Time Frame: Baseline ]
    8-oxodG and 8-oxoGuo measured with mass spectrometry in spot-urine and normalized to urinary creatinine, in depressed patients and healthy controls.

  21. Changes in systemic oxidative stress in terms of 8-oxodG and 8-oxoGuo in urine [ Time Frame: Baseline and follow-up examinations at 8 weeks after antidepressant treatment. ]
    8-oxodG and 8-oxoGuo measured with mass spectrometry in spot-urine and normalized to urinary creatinine, in remitters and non-responders.

  22. Early life Stress [ Time Frame: Baseline ]
    Self-reported early life stress with the Children Abuse and Trauma Scale (CATS) questionnaire.

  23. Performance on Verbal Affective Memory Tasks (VAMT-26). [ Time Frame: From baseline to follow-up after 12 weeks of treatment with antidepressant treatment. ]
    Differences between healthy controls and depressed patients at baseline and week 12 follow-up, as well as longitudinal alterations to treatment response in MDD patients.

  24. Performance on Moral Judgement Task [ Time Frame: From baseline to follow-up after 12 weeks of treatment with antidepressant treatment. ]
    Differences between healthy controls and depressed patients at baseline and week 12 follow-up, as well as longitudinal alterations to treatment response in MDD patients.

  25. Performance on Letter-Number Sequence Task. [ Time Frame: From baseline to follow-up after 12 weeks of treatment with antidepressant treatment. ]
    Differences between healthy controls and depressed patients at baseline and week 12 follow-up, as well as longitudinal alterations to treatment response in MDD patients.


Secondary Outcome Measures :
  1. Changes from baseline in HAMD-6 score [ Time Frame: Baseline to follow-up at 8 and 12 weeks ]
    Score indexing changes in severity of the depressed state

  2. HAMD-6 score after 8 and 12 weeks of antidepressant treatment [ Time Frame: Week 8 and 12 of treatment period ]
    Score indexing severity of the depressed state

  3. Regional 5-HT4R binding [ Time Frame: Measured at baseline and after 8 weeks of antidepressant treatment. ]
    Measurement of 5-HT4R binding in (a) striatum (caudate nuclei and putamen), (b) a pooled limbic region (amygdala, hippocampus, thalamus, anterior- and posterior cingulate cortex,) (c) a pooled neocortex region (parietal cortex, occipital cortex, lateral temporal cortex, insula, orbito-frontal and lateral-frontal cortex).

  4. Sexual side-effects from antidepressant treatment [ Time Frame: 8 weeks of antidepressant treatment ]
    Perceived side effects from self reported questionnaires

  5. Baseline latent variable construct of self-reported mental state [ Time Frame: Baseline ]
    Composed by latent variable structural equation modelling of self-reported mental state from questionnaires score of: Becks Depression Inventory -II (BDI-II), Perceived Stress Scale (PSS), Snaith-Hamilton Pleasure Scale (SHAPS), Rumination Response Scale (RRS), Pittsburgh Sleep Quality Index (PSQI), Generalized Anxiety Distress Assessment 10 item (GAD-10), Activity level, Profile of Mood States (POMS), Visual Analogue Scale for mental distress (VAS) and Brief symptom Inventory-53 item (BSI-53)) in depressed patients and healthy controls.

  6. Baseline self reported family history of mood disorders [ Time Frame: Baseline ]
    Family History Assessment Module (OS-FHAM) in depressed patients and healthy controls.

  7. Changes from baseline in self-reported mental state questionnaire-based latent variable construct [ Time Frame: At baseline and repeated across the study period to last follow-up after 12 weeks of antidepressant treatment. ]
    Composed by latent variable structural equation modelling of changes from baseline in self-reported mental state from questionnaires score of: Becks Depression Inventory -II (BDI-II), Perceived Stress Scale (PSS), Snaith-Hamilton Pleasure Scale (SHAPS), Rumination Response Scale (RRS), Pittsburgh Sleep Quality Index (PSQI), Generalized Anxiety Distress Assessment 10 item (GAD-10), Activity level, Profile of Mood States (POMS) and Brief symptom Inventory-53 item (BSI-53) in remitters and non-responders.

  8. Total daily cortisol output [ Time Frame: Baseline (before treatment) ]
    Area under curve of 8 serial measures of salivary cortisol concentrations during an assessment day

  9. Changes in total daily cortisol output [ Time Frame: Baseline (before treatment) to 8 weeks of antidepressant treatment ]
    Difference in area under curve of 8 serial measures of salivary cortisol concentrations during an assessment day

  10. Parental bonding quality [ Time Frame: Baseline ]
    Self-reported parental bonding quality as assessed in baseline by parental bonding interview (PBI)

  11. 5-HTTLPR genotype status [ Time Frame: Baseline ]
    5-HTTLPR genotype status (binary), i.e. high-expressing LALA vs low-expressing (S or LG) variants

  12. Epigenetic FK506-binding protein 51 (FKBP5) status at baseline [ Time Frame: Baseline ]
    Methylation of the FKBP5 gene

  13. Changes in epigenetic FKBP5 status from baseline [ Time Frame: Baseline to 8 and 12 weeks of intervention ]
    Changes in methylation status of the FKBP5 gene

  14. Epigenetic 5-HTTLPR status at baseline [ Time Frame: Baseline ]
    Methylation status of the 5-HTTLPR gene

  15. Changes in epigenetic 5-HTTLPR status from baseline [ Time Frame: Baseline to 8 and 12 weeks of intervention ]
    Changes in methylation status of the 5-HTTLPR gene

  16. Epigenetic spindle and kinetochore associated complex subunit 2 (SKA2) status at baseline [ Time Frame: Baseline to 8 and 12 weeks of intervention ]
    Methylation status of the SKA2 gene

  17. Changes in epigenetic SKA2 status from baseline [ Time Frame: Baseline to 8 and 12 weeks of intervention ]
    Changes in methylation status of the SKA2 gene

  18. Performance on Face and Eyes Emotion Recognition Task [ Time Frame: From baseline to follow-up after 12 weeks of treatment with antidepressant treatment. ]
    Differences between healthy controls and depressed patients at baseline and week 12 follow-up, as well as longitudinal alterations to treatment response in MDD patients.

  19. Performance on Intensity Morphing Task [ Time Frame: From baseline to follow-up after 12 weeks of treatment with antidepressant treatment. ]
    Differences between healthy controls and depressed patients at baseline and week 12 follow-up, as well as longitudinal alterations to treatment response in MDD patients.

  20. Performance on Social Information Preference Task [ Time Frame: From baseline to follow-up after 12 weeks of treatment with antidepressant treatment. ]
    Differences between healthy controls and depressed patients at baseline and week 12 follow-up, as well as longitudinal alterations to treatment response in MDD patients.

  21. Performance on Simple Reaction Time. [ Time Frame: From baseline to follow-up after 12 weeks of treatment with antidepressant treatment. ]
    Differences between healthy controls and depressed patients at baseline and week 12 follow-up, as well as longitudinal alterations to treatment response in MDD patients.



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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Moderate to severe depression
  • Age 18-65 years
  • No previous antidepressant treatment the last 2 months
  • Informed and signed consent

Exclusion Criteria:

  • More than one previous attempt with antidepressant drugs
  • Duration of current depression more than 2 years
  • Current or previous psychiatric severe co-morbidity
  • Acute suicidal ideation
  • Psychotic
  • Previous non-response to Selective Serotonin Reuptake Inhibitor (SSRI)
  • Contraindication for SSRI treatment
  • More suitable with treatment of alternative anti-depressive drug.
  • Severe somatic co-morbidity
  • Somatic medicine that can influence the trial
  • Contraindications for MR-scanning
  • Previous exposure to radioactivity > 10 milli sievert (mSv) within the last year
  • Alcohol or drug abuse
  • Previous severe head trauma
  • Pregnancy
  • Breast-feeding
  • Insufficient Danish skills

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02869035


Contacts
Contact: Vibe G Frokjaer, MD, PhD vibe.frokjaer@nru.dk
Contact: Martin B Joergensen, MD,Prof. martin.balslev.joergensen@regionh.dk

Locations
Denmark
Neurobiology Research Unit, Rigshospitalet Recruiting
Copenhagen, Denmark, 2100
Contact: Gitte M Knudsen, DMSc    +45 35456720    gmk@nru.dk   
Sponsors and Collaborators
Rigshospitalet, Denmark
Center for Integrated Molecular Brain Imaging, Copenhagen, Denmak
Psychiatric Centre Copenhagen
Central Visitation, Region Hovedstaden
Investigators
Principal Investigator: Gitte M Knudsen, MD,Prof. Neurobiology Research Unit

Publications:
Responsible Party: Gitte Moos Knudsen, Chair, Professor, MD, DMSc, Rigshospitalet, Denmark
ClinicalTrials.gov Identifier: NCT02869035     History of Changes
Other Study ID Numbers: NP1
First Posted: August 16, 2016    Key Record Dates
Last Update Posted: June 2, 2017
Last Verified: May 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Via database of Center for Integrated Molecular Brain Imaging (Knudsen et al 2016, NeuroImage) data will be available for neuroscience research community contingent on approval by scientific board.

Keywords provided by Gitte Moos Knudsen, Rigshospitalet, Denmark:
Mental health
PET
Serotonin
5-HT4R
MRI
fMRI
EEG
Cortisol awakening response
Oxidative stress
Prediction of treatment response
Inflammation
5-HTTLPR
Brain imaging
Early life stress
Selective Serotonin Reuptake Inhibitor
Escitalopram
Psychometrics
Moderate depression
Severe depression
ERP
rsfMRI
11C-SB207145
Sexual function
MDD
Affective cognition
Cold cognition
Social cognition
Anxiety

Additional relevant MeSH terms:
Disease
Depressive Disorder
Depression
Depressive Disorder, Major
Pathologic Processes
Mood Disorders
Mental Disorders
Behavioral Symptoms
Citalopram
Serotonin Uptake Inhibitors
Duloxetine Hydrochloride
Dexetimide
Serotonin
Neurotransmitter Uptake Inhibitors
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Neurotransmitter Agents
Serotonin Agents
Physiological Effects of Drugs
Antidepressive Agents, Second-Generation
Antidepressive Agents
Psychotropic Drugs
Antiparkinson Agents
Anti-Dyskinesia Agents
Parasympatholytics
Autonomic Agents
Peripheral Nervous System Agents
Muscarinic Antagonists
Cholinergic Antagonists
Cholinergic Agents