Predicting Treatment Outcome in Major Depressive Disorder
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 100
- 试验地点
- 1
- 主要终点
- Changes from baseline in hippocampus volume.
研究概览
简要总结
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.
详细描述
Study population and study program:
Patients will be recruited through a unique new central referral site for "depression packages" in The Mental Health Services in the Capital Region of Denmark. 100 patients with MDD, 18-65 years of age, with moderate to severe single or recurrent episode of MDD (Hamilton 17 item (HAMD-17) score > 17) will be recruited through this portal. All diagnoses will be confirmed by a specialist in psychiatry.
Before initiation of pharmacological antidepressant treatment with escitalopram, patients will receive baseline examinations as follows: 1) 5-HT4R imaging with 11C-SB207145 PET-scan, 2) EEG examinations, 3) structural MRI, 4) functional MRI , 5) neuropsychological testing, 6) peripheral markers of immune-active cell responses, oxidative stress, cortisol-levels, RNA, genotypes and epigenetic factors will be measured in urine, saliva and peripheral blood at baseline and across the study period. Repeated measures across the study period include: 7) psychometrics by using self-reported questionnaires covering trait and state, including mental distress related to depression and other psychopathology, 8) neuropsychological examinations as well as 9) clinical follow-up with interview based ratings of mental status.
Patients will be treated with escitalopram at flexible doses of 10-20 mg/day adjusted depending on effects and side effects, and participate in clinical follow-up sessions at week 1, 2, 4 and 8. Patients with no response to escitalopram after 4 weeks will be shifted to a secondary pharmacological treatment (duloxetine). A final visit to determine longer-term clinical outcome will be performed at week 12. Compliance, side-effects to antidepressant treatment, and depressive symptoms will be monitored at each follow-up session.
The Hamilton 6 items (HAMD-6) subscale has recently shown to be more sensitive to antidepressant response (Østergaard et al), and will be used to identify treatment response in patients. Patients with > 50 % reduction in HAMD-6 after 4 weeks will be defined as early responders, and those with additional < 5 points on the HAMD-6 scale after 8 weeks will be considered in remission. Patients with >25% response at week 4 and < 50% reduction in HAMD-6 after full intervention will be considered non-responders. The assessment program including brain imaging with PET 11C-SB207145 will be conducted before drug intervention is initiated and, depending on treatment outcome, again after 8 weeks of antidepressant treatment in 20 patients in remission (remitters) and 20 non-responding patients (non-responders).
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Single Group
- 主要目的
- Other
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Moderate to severe depression
- •Age 18-65 years
- •No previous antidepressant treatment the last 2 months
- •Informed and signed consent
排除标准
- •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
研究组 & 干预措施
Treatment of MDD patients
Treatment of MDD patients with escitalopram
干预措施: Escitalopram (Drug)
Shift of treatment for MDD patients
Treatment of MDD patients with duloxetine
干预措施: Duloxetine (Drug)
结局指标
主要结局
Changes from baseline in hippocampus volume.
时间窗: Baseline to follow-up scan at 8 weeks after antidepressant treatment.
Structural MRI in remitters and non-responders.
Baseline fMRI BOLD response to an emotional faces paradigm
时间窗: Baseline
fMRI (BOLD response) based assessment of brain activity to emotionally salient, relative to neutral, stimuli.
Changes from baseline in fMRI BOLD response to an emotional faces paradigm
时间窗: 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.
Binary treatment outcome in terms of remission from depression.
时间窗: 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).
Baseline cerebral 5-HT4R binding as imaged by 11C-SB207145 PET.
时间窗: 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.
Changes from baseline in cerebral 5-HT4R binding as imaged by 11C-SB207145 PET
时间窗: 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.
Baseline hippocampus volume
时间窗: Baseline.
Structural MRI scan in depressed patients and healthy controls.
Baseline fMRI BOLD response to reward paradigm.
时间窗: Baseline
fMRI (BOLD response) based assessment of brain activity in response to reward, relative to non-reward, stimuli.
Changes from baseline in fMRI BOLD response to reward paradigm
时间窗: 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.
Baseline rsfMRI based spontaneous co-fluctuations in low frequency BOLD signal (functional connectivity)
时间窗: Baseline
Assessed with rsfMRI scan in the resting state, i.e. non-goal oriented spontaneous thought and awake.
Changes from baseline in rsfMRI spontaneous co-fluctuations in low frequency BOLD signal (functional connectivity)
时间窗: 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.
Sexual function in depression
时间窗: Baseline
Assessed with scores of self reported sexual function questionnaires in depressed patients and healthy controls.
Changes in sexual function
时间窗: 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
Baseline EEG including event related potentials (ERP)
时间窗: Baseline
Assessment of evoked gamma activity, alpha and theta cordance band activity in depressed patients and healthy controls.
Changes in EEG including event related potentials (ERP)
时间窗: 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.
Cortisol awakening response
时间窗: Baseline
Cortisol changes in response to awakening as measured in saliva from 0 to 60 minutes after awakening in depressed patients and healthy controls.
Changes in cortisol awakening response (HPA-axis dynamics)
时间窗: Baseline and follow-up examination at 8 weeks after antidepressant treatment.
Measured in remitters and non-responders.
Systemic inflammation peripheral blood hsCRP and immunoactive cytokines
时间窗: Baseline and follow-up examination at 8 weeks after antidepressant treatment.
Measured with peripheral blood markers in plasma by high-sensitivity (hs) methods.
Changes in systemic inflammation peripheral blood hsCRP and immunoactive cytokines
时间窗: Baseline and follow-up examination at 8 weeks after antidepressant treatment.
Measured with peripheral blood markers in plasma by high-sensitivity (hs) methods.
Systemic oxidative stress in terms of 8-oxodG and 8-oxoGuo in urine
时间窗: Baseline
8-oxodG and 8-oxoGuo measured with mass spectrometry in spot-urine and normalized to urinary creatinine, in depressed patients and healthy controls.
Changes in systemic oxidative stress in terms of 8-oxodG and 8-oxoGuo in urine
时间窗: 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.
Early life Stress
时间窗: Baseline
Self-reported early life stress with the Children Abuse and Trauma Scale (CATS) questionnaire.
Performance on Verbal Affective Memory Tasks (VAMT-26).
时间窗: 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.
Performance on Moral Judgement Task
时间窗: 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.
Performance on Letter-Number Sequence Task.
时间窗: 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.
次要结局
- 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)
- Baseline self reported family history of mood disorders(Baseline)
- Changes from baseline in self-reported mental state questionnaire-based latent variable construct(At baseline and repeated across the study period to last follow-up after 12 weeks of antidepressant treatment.)
- Total daily cortisol output(Baseline (before treatment))
- Changes in total daily cortisol output(Baseline (before treatment) to 8 weeks of antidepressant treatment)
- Parental bonding quality(Baseline)
- 5-HTTLPR genotype status(Baseline)
- Epigenetic FK506-binding protein 51 (FKBP5) status at baseline(Baseline)
- Changes in epigenetic FKBP5 status from baseline(Baseline to 8 and 12 weeks of intervention)
- Epigenetic 5-HTTLPR status at baseline(Baseline)
- Changes in epigenetic 5-HTTLPR status from baseline(Baseline to 8 and 12 weeks of intervention)
- Epigenetic spindle and kinetochore associated complex subunit 2 (SKA2) status at baseline(Baseline to 8 and 12 weeks of intervention)
- Changes in epigenetic SKA2 status from baseline(Baseline to 8 and 12 weeks of intervention)
- Performance on Face and Eyes Emotion Recognition Task(From baseline to follow-up after 12 weeks of treatment with antidepressant treatment.)
- Performance on Intensity Morphing Task(From baseline to follow-up after 12 weeks of treatment with antidepressant treatment.)
- Performance on Social Information Preference Task(From baseline to follow-up after 12 weeks of treatment with antidepressant treatment.)
- Performance on Simple Reaction Time.(From baseline to follow-up after 12 weeks of treatment with antidepressant treatment.)
研究者
Gitte Moos Knudsen
Chair, Professor, MD, DMSc
Rigshospitalet, Denmark