Treatment Outcome in Major Depressive Disorder
Condition: Major Depressive Disorder
MeSH terms: Depressive Disorder; Depression; Depressive Disorder, Major
Study type: Interventional
Phase: Phase 1

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.
    

Detailed description: 
      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).

      UPDATE: As per April 3, 2017 the rescanned group has been expanded to include various
      response patterns in order to capture rescan data from patients on a spectrum from poor to
      excellent treatment response, since out of the first 17 included patients only 1 patient
      fulfilled the non-responder criterion defined above. Accordingly, the clinical outcome
      parameter in the context will be changes in HAM-D6 from baseline at week 8.

      Healthy controls:

      From previous studies conducted at the Neurobiological Research Unit, there is access to
      brain imaging data and baseline PET-SB207145 brain images among healthy controls as well as
      an associated biobank with stored blood specimens. During the trial, additional healthy
      controls will be included and will receive baseline examinations and repeated
      neuropsychological testing after 12 weeks.

      Hypotheses:

        1. 5-HT4R binding (as imaged by 11C-SB207145 PET) before treatment will predict
           antidepressant treatment outcome (remission vs non-response) in depressed patients;
           higher binding at baseline is hypothesized to be associated with a better treatment
           outcome. Likewise, secondary, 5-HT4R binding (as imaged by 11C-SB207145 PET) before
           treatment is expected to be associated with the magnitude of change from baseline in
           Hamilton score (HAMD-6) at 8 weeks.

        2. Remitters will display a greater reduction in 5-HT4R binding (as imaged by 11C-SB207145
           PET) after antidepressant treatment relative to non-responders.

        3. Patients with MDD will have a higher 5-HT4R binding (as imaged by 11C-SB207145 PET)
           relative to healthy controls.

        4. High amygdala reactivity in an "emotional faces" fMRI paradigm before treatment predicts
           remission in response to antidepressant treatment.

        5. Amygdala response to exposure to negative emotional faces (fear and anger) and cerebral
           5-HT4R binding is expected to be associated, both in cross-sectional comparison before
           treatment and with regard to longitudinal changes (changes from baseline).

        6. In resting state fMRI (rsfMRI), we expect that changes from baseline in a functional
           network centered around dorsomedial prefrontal cortex and other networks centered around
           anterior cingulate cortex and posterior cingulate cortex (default mode network)
           respectively will predict treatment outcome.

        7. Low activity in a brain network engaged in reward processing (as assessed by fMRI) will
           predict antidepressant treatment response (i.e. positive association between low
           activity and remitter- relative to non-responder group) both in cross-sectional
           comparison before treatment and with regard to longitudinal changes (changes from
           baseline).

        8. We expect reduced evoked gamma-activity measured with EEG and "Event-related-potentials"
           (ERP) in MDD patients compared to controls.

        9. Using EEG/ERP, we expect reduced alpha and theta cordance and higher theta band activity
           among remitters measured at baseline.

       10. Higher levels of systemic inflammation will predict poor cognitive function at baseline,
           and a poor antidepressant treatment outcome.

       11. A blunted cortisol awakening response (CAR) at baseline will predict a positive
           antidepressant treatment outcome.

       12. Restored HPA-axis dynamics (increased CAR compared to baseline) at week 8 will be
           associated with a positive treatment outcome.

       13. There will be a significant association between functional networks found by EEG and
           fMRI, both at baseline and as contrast between remitters and non-responders after 8
           weeks.

       14. Hippocampal volume will predict treatment outcome.

       15. Patients with a low 5-HT4R binding (as imaged by 11C-SB207145 PET) at baseline before
           treatment will have a lower libido relative to patients with a high binding.

       16. Patients who respond to antidepressant treatment with the most pronounced changes in
           5-HT4R binding (as imaged by 11C-SB207145) will experience a larger degree of sexual
           side-effects; i.e., the magnitude of 5-HT4R binding changes from baseline will be
           positively associated with the degree of sexual side-effects.

       17. Childhood abuse (defined by a composite measure of early life stress questionnaires) and
           anxious depression (defined as anxiety/somatization factor score in HAMD-17 > 7)
           predicts poor antidepressant treatment outcome.

       18. We expect urinary markers of oxidatively generated DNA/RNA damage to increase more in
           responders than in non-responders.

       19. With an exploratory approach it will be possible to identify a set of predictors of
           antidepressant treatment outcome. This explorative analysis includes genetics,
           epigenetics, peripheral and central neurobiological characteristics, neuropsychology
           testing outcomes, psychometry including self-reported mental distress, both
           cross-sectional at baseline and as longitudinal measures.

      Ethical Aspects:

      The study protocol complies with the Declaration of Helsinki II and approval by all relevant
      authorities will be obtained before initiation. All human volunteers will receive oral and
      written information about the given study and provide written informed consent before
      enrolment. The trial is monitored by a Good Clinical Practise unit for the relevant domains.
    

Intervention name(s): Escitalopram; Duloxetine
Intervention type(s): Drug; Drug
Intervention description(s): 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.; Patients who at 4 weeks of escitalopram have not responded will be shifted to duloxetine at flexible standard dosages.
Intervention MeSH terms: Duloxetine Hydrochloride; Escitalopram
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Other
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