Treatment Outcome in Major Depressive Disorder

NCT02869035 | Completed Phase 1 DMC

• 1 other identifier: NP1
• Study Type: interventional
• Target: 100
• Locations: 1 country
• Sites: 1

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.

Conditions

Major Depressive Disorder

Keywords

PET; Serotonin; 5-HT4R; MRI; fMRI; EEG; Cortisol awakening response; Oxidative stress; Mental health; 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

Outcome Measures

Primary Outcomes (25)

• Binary treatment outcome in terms of remission from depression.

  Treatment outcome defined as changes in HAMD-6 score after antidepressant treatment (remitters and non-responders as previously defined).

  Baseline to clinical follow-up at 8 weeks after antidepressant treatment.

• Baseline cerebral 5-HT4R binding as imaged by 11C-SB207145 PET.

  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.

  Baseline.

• Changes from baseline in cerebral 5-HT4R binding as imaged by 11C-SB207145 PET

  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.

  Baseline to follow-up scan at 8 weeks after antidepressant treatment.

• Baseline hippocampus volume

  Structural MRI scan in depressed patients and healthy controls.

  Baseline.

• Changes from baseline in hippocampus volume.

  Structural MRI in remitters and non-responders.

  Baseline to follow-up scan at 8 weeks after antidepressant treatment.

• Baseline fMRI BOLD response to an emotional faces paradigm

  fMRI (BOLD response) based assessment of brain activity to emotionally salient, relative to neutral, stimuli.

  Baseline

• Changes from baseline in fMRI BOLD response to an emotional faces paradigm

  fMRI (BOLD response) based assessment of brain activity to emotionally salient, relative to neutral, stimuli.

  Baseline to follow-up scan at 8 weeks after antidepressant treatment.

• Baseline fMRI BOLD response to reward paradigm.

  fMRI (BOLD response) based assessment of brain activity in response to reward, relative to non-reward, stimuli.

  Baseline

• Changes from baseline in fMRI BOLD response to reward paradigm

  fMRI (BOLD response) based assessment of brain activity in response to reward, relative to non-reward, stimuli.

  Baseline to follow-up scan at 8 weeks after antidepressant treatment.

• Baseline rsfMRI based spontaneous co-fluctuations in low frequency BOLD signal (functional connectivity)

  Assessed with rsfMRI scan in the resting state, i.e. non-goal oriented spontaneous thought and awake.

  Baseline

• Changes from baseline in rsfMRI spontaneous co-fluctuations in low frequency BOLD signal (functional connectivity)

  Assessed with rsfMRI scan in the resting state, i.e. non-goal oriented spontaneous thought and awake.

  Baseline to follow-up scan at 8 weeks after antidepressant treatment.

• Sexual function in depression

  Assessed with scores of self reported sexual function questionnaires in depressed patients and healthy controls.

  Baseline

• Changes in sexual function

  Questionnaire-based self-reported sexual function in remitters and non-responders

  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.

• Baseline EEG including event related potentials (ERP)

  Assessment of evoked gamma activity, alpha and theta cordance band activity in depressed patients and healthy controls.

  Baseline

• Changes in EEG including event related potentials (ERP)

  Assessment of evoked gamma activity, alpha and theta cordance band activity in remitters and non-responders.

  Baseline to follow-up examination at 8 weeks after antidepressant treatment.

• Cortisol awakening response

  Cortisol changes in response to awakening as measured in saliva from 0 to 60 minutes after awakening in depressed patients and healthy controls.

  Baseline

• Changes in cortisol awakening response (HPA-axis dynamics)

  Measured in remitters and non-responders.

  Baseline and follow-up examination at 8 weeks after antidepressant treatment.

• Systemic inflammation peripheral blood hsCRP and immunoactive cytokines

  Measured with peripheral blood markers in plasma by high-sensitivity (hs) methods.

  Baseline and follow-up examination at 8 weeks after antidepressant treatment.

• Changes in systemic inflammation peripheral blood hsCRP and immunoactive cytokines

  Measured with peripheral blood markers in plasma by high-sensitivity (hs) methods.

  Baseline and follow-up examination at 8 weeks after antidepressant treatment.

• Systemic oxidative stress in terms of 8-oxodG and 8-oxoGuo in urine

  8-oxodG and 8-oxoGuo measured with mass spectrometry in spot-urine and normalized to urinary creatinine, in depressed patients and healthy controls.

  Baseline

• Changes in systemic oxidative stress in terms of 8-oxodG and 8-oxoGuo in urine

  8-oxodG and 8-oxoGuo measured with mass spectrometry in spot-urine and normalized to urinary creatinine, in remitters and non-responders.

  Baseline and follow-up examinations at 8 weeks after antidepressant treatment.

• Early life Stress

  Self-reported early life stress with the Children Abuse and Trauma Scale (CATS) questionnaire.

  Baseline

• Performance on Verbal Affective Memory Tasks (VAMT-26).

  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.

  From baseline to follow-up after 12 weeks of treatment with antidepressant treatment.

• Performance on Moral Judgement Task

  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.

  From baseline to follow-up after 12 weeks of treatment with antidepressant treatment.

• Performance on Letter-Number Sequence Task.

  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.

  From baseline to follow-up after 12 weeks of treatment with antidepressant treatment.

Secondary Outcomes (21)

• Changes from baseline in HAMD-6 score

  Baseline to follow-up at 8 and 12 weeks

• HAMD-6 score after 8 and 12 weeks of antidepressant treatment

  Week 8 and 12 of treatment period

• Regional 5-HT4R binding

  Measured at baseline and after 8 weeks of antidepressant treatment.

• Sexual side-effects from antidepressant treatment

  8 weeks of antidepressant treatment

• Baseline latent variable construct of self-reported mental state

  Baseline

Study Arms (3)

Treatment of MDD patients

EXPERIMENTAL

Treatment of MDD patients with escitalopram

Drug: Escitalopram

Healthy controls

NO INTERVENTION

No treatment.

Shift of treatment for MDD patients

EXPERIMENTAL

Treatment of MDD patients with duloxetine

Drug: Duloxetine

Interventions

Escitalopram DRUG

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.

Treatment of MDD patients

Duloxetine DRUG

Patients who at 4 weeks of escitalopram have not responded will be shifted to duloxetine at flexible standard dosages.

Shift of treatment for MDD patients

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

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

You may not qualify if:

• 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

Sponsors & Collaborators

• Rigshospitalet, Denmark: lead
• Center for Integrated Molecular Brain Imaging, Copenhagen, Denmak: collaborator
• Psychiatric Centre Copenhagen: collaborator
• Central Visitation, Region Hovedstaden: collaborator

Study Sites (1)

Neurobiology Research Unit, Rigshospitalet

Copenhagen, 2100, Denmark

Location

Related Publications (9)

• Ostergaard SD, Bech P, Miskowiak KW. Fewer study participants needed to demonstrate superior antidepressant efficacy when using the Hamilton melancholia subscale (HAM-D(6)) as outcome measure. J Affect Disord. 2016 Jan 15;190:842-845. doi: 10.1016/j.jad.2014.10.047. Epub 2014 Nov 7.

  PMID: 25487682 BACKGROUND

• Jensen KHR, Aarestrup MR, Larsen SV, Kohler-Forsberg K, Knudsen GM, Jorgensen MB, Frokjaer VG. Psychoneuroendocrine profiles of unmedicated men with major depressive disorder and associations to treatment effects and sexual side-effects. Neurosci Appl. 2024 Feb 23;3:104050. doi: 10.1016/j.nsa.2024.104050. eCollection 2024.

  PMID: 40656082 DERIVED

• Sankar A, Ozenne B, Dam VH, Svarer C, Jorgensen MB, Miskowiak KW, Frokjaer VG, Knudsen GM, Fisher PM. Association between brain serotonin 4 receptor binding and reactivity to emotional faces in depressed and healthy individuals. Transl Psychiatry. 2023 May 11;13(1):165. doi: 10.1038/s41398-023-02440-3.

  PMID: 37169780 DERIVED

• Ip CT, Ganz M, Ozenne B, Olbrich S, Beliveau V, Dam VH, Kohler-Forsberg K, Jorgensen MB, Frokjaer VG, Knudsen GM. Association between the loudness dependence of auditory evoked potential, serotonergic neurotransmission and treatment outcome in patients with depression. Eur Neuropsychopharmacol. 2023 May;70:32-44. doi: 10.1016/j.euroneuro.2023.02.008. Epub 2023 Feb 28.

  PMID: 36863106 DERIVED

• Weber S, Frokjaer VG, Armand S, Nielsen JH, Knudsen GM, Joergensen MB, Stenbaek DS, Giraldi A. Sexual function improves as depressive symptoms decrease during treatment with escitalopram: results of a naturalistic study of patients with major depressive disorder. J Sex Med. 2023 Feb 14;20(2):161-169. doi: 10.1093/jsxmed/qdac016.

  PMID: 36763929 DERIVED

• Dam VH, Stenbaek DS, Kohler-Forsberg K, Cheng Ip, Ozenne B, Sahakian BJ, Knudsen GM, Jorgensen MB, Frokjaer VG. Evaluating cognitive disturbances as treatment target and predictor of antidepressant action in major depressive disorder: A NeuroPharm study. Transl Psychiatry. 2022 Nov 8;12(1):468. doi: 10.1038/s41398-022-02240-1.

  PMID: 36347845 DERIVED

• Fisher PM, Ozenne B, Ganz M, Frokjaer VG, Dam VN, Penninx BW, Sankar A, Miskowiak K, Jensen PS, Knudsen GM, Jorgensen MB. Emotional faces processing in major depressive disorder and prediction of antidepressant treatment response: A NeuroPharm study. J Psychopharmacol. 2022 May;36(5):626-636. doi: 10.1177/02698811221089035. Epub 2022 May 13.

  PMID: 35549538 DERIVED

• Ip CT, Olbrich S, Ganz M, Ozenne B, Kohler-Forsberg K, Dam VH, Beniczky S, Jorgensen MB, Frokjaer VG, Sogaard B, Christensen SR, Knudsen GM. Pretreatment qEEG biomarkers for predicting pharmacological treatment outcome in major depressive disorder: Independent validation from the NeuroPharm study. Eur Neuropsychopharmacol. 2021 Aug;49:101-112. doi: 10.1016/j.euroneuro.2021.03.024. Epub 2021 Apr 25.

  PMID: 33910154 DERIVED

• Kohler-Forsberg K, Jorgensen A, Dam VH, Stenbaek DS, Fisher PM, Ip CT, Ganz M, Poulsen HE, Giraldi A, Ozenne B, Jorgensen MB, Knudsen GM, Frokjaer VG. Predicting Treatment Outcome in Major Depressive Disorder Using Serotonin 4 Receptor PET Brain Imaging, Functional MRI, Cognitive-, EEG-Based, and Peripheral Biomarkers: A NeuroPharm Open Label Clinical Trial Protocol. Front Psychiatry. 2020 Jul 23;11:641. doi: 10.3389/fpsyt.2020.00641. eCollection 2020.

  PMID: 32792991 DERIVED

MeSH Terms

Conditions

Depressive Disorder, Major; Psychological Well-Being; Inflammation; Stress, Psychological; Depression; Anxiety Disorders

Interventions

Escitalopram; Duloxetine Hydrochloride

Condition Hierarchy (Ancestors)

Depressive Disorder; Mood Disorders; Mental Disorders; Personal Satisfaction; Behavior; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Behavioral Symptoms

Intervention Hierarchy (Ancestors)

Propylamines; Amines; Organic Chemicals; Nitriles; Benzofurans; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Thiophenes; Sulfur Compounds; Heterocyclic Compounds, 1-Ring

Study Officials

• Gitte M Knudsen, MD,Prof.

  Neurobiology Research Unit

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: OTHER
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Chair, Professor, MD, DMSc

Study Record Dates

• First Submitted: July 29, 2016
• First Posted: August 16, 2016
• Study Start: August 1, 2016
• Primary Completion: July 1, 2019
• Study Completion: July 1, 2019
• Last Updated: October 16, 2019

Record last verified: 2019-10

Data Sharing

• IPD Sharing: Will share

Locations

DK (1)