Study of the Neural Circuits Underlying the Negative Emotional Bias of Depressive Disorders and Their Response to Ketamine

Official title

Translational Study of the Neural Circuits Underlying the Negative Emotional Bias of Depressive Disorders and Their Response to Ketamine

Overview

Major depressive disorder is the leading cause of disability worldwide, affecting up to 300 million people each year, and one in five people will experience depression at least once in their lives. Emotional bias is an essential component of characterized depressive episodes, leading depressed patients to attribute a more negative valence to emotional stimuli. On the basis of recent and robust neuroscientific data revisiting the role of the cerebral amygdala as an essential essential structure for encoding the negative and positive valences and of emotional stimuli, the team has shown in mice that a depressive phenotype induced by a chronic administration of corticosterone, a well-known model of depression, is associated with a change in hedonic value allocation, i.e. pleasant odors become less pleasant, and aversive odors become even more unpleasant, mimicking what happens in humans (identical data in humans). It assumes that: 1. There is a negative emotional bias in depressed patients compared with control subjects, evidenced by the assignment of more negative valences when viewing images. 2. In depressed subjects, compared with controls subjects, there is greater activation of the basolateral amygdala/ventral hippocampus pathway (the level of imaging resolution of imaging does not allow to study the basolateral amygdala/central amygdala pathway in humans) and less of the basolateral amygdala/nucleus accumbens pathway. 3. In depressed subjects, improvement in negative emotional bias correlated with a good response after after 4 weeks of treatment with esketamine (Spravato) measured by a 50% reduction in the Montgomery-Åsberg Depression Rating Scale. 4. In depressed patients, early improvement of emotional bias (after a single administration) is predictive of response to treatment at 4 weeks. 5. In depressed patients with a good response to a single 4-weeks course of esketamine (Spravato), a normalization of activation of basolateral amygdala/ventral hippocampus and basolateral amygdala/nucleus accumbens pathways is observed. 6. Depressed subjects have different immunoinflammatory and RNA editing patterns different from control subjects. 7. In depressed patients, clinical improvement correlates with normalization of patients; inflammatory profile and certain mRNA editing 8. Some clinical features of major depressive disorder are associated with greater negative emotional bias significant

Interventions

• Behavioral fMRI with emotional task and pupillometry
  Anatomical and functional magnetic resonance imaging (fMRI) imaging sequences with pupillometry (\~90 min) A functional sequence - Task (\~20min): * Emotional task in fMRI: Instructions: simply look images, then evaluate the emotions triggered at the end of each block; rating on a valence and intensity scale and intensity (arousal) scale. * Experimental conditions: positive, negative and neutral * Paradigm: block validated image banks: IAPS, GAPED, EMOPICS, OASIS, etc. Pupillometry: In order t
• Behavioral Behavioral task with emotional facial expressions
  Description of the recognized emotion joy - sadness. Test to assess the hedonic value of an olfactory stimulus (10 min)
• Genetic Biological investigation
  Standard biological assessment, immuno-inflammatory profile and the association of 8 mRNA editing variants

Primary outcome measures

• Significant difference in negative emotional bias measured by an image perception task before vs. after esketamine treatment [Time frame: 1 month]

Secondary outcome measures (12)

• Measure of the blood oxygenation level with the Blood-Oxygen-Level Dependent (BOLD) signal obtained at the functional magnetic resonance imaging (fMRI) task in depressed patients and in control subjects [Time frame: patients: at baseline (Day 0) and at the end-of study visit (6 weeks); control subjects: at baseline (Day 0)]
• Measure of the functional connectivity obtained at the resting-state functional magnetic resonance imaging (fMRI) in depressed patients and in control subjects [Time frame: patients: at baseline (Day 0) and at the end-of study visit (6 weeks); control subjects: at baseline (Day 0)]
• Measure of the gray matter integrity obtained at the High-resolution anatomical (T1) magnetic resonance imaging (MRI) in depressed patients and in control subjects [Time frame: Patients: at baseline (Day 0) and at the end-of study visit (6 weeks); control subjects: at baseline (Day 0)]
• Measure of the white matter integrity obtained at the diffusion imaging in depressed patients and in control subjects [Time frame: Patients: at baseline (Day 0) and at the end-of study visit (6 weeks); control subjects: at baseline (Day 0)]
• Measure of the depression severity in patients and control subjects thanks to the Montgomery-Åsberg Depression Rating Scale score [Time frame: Patients: at baseline (Day 0), Day 7, Week 2 (2 times), Week 3 (2 times), Week 4 (2 times), Week 5 (2 times) and at the end-of-study visit (Week 6); control subjects: at baseline (Day 0)]
• Assessment of the emotional bias measured by an image perception task [Time frame: Patients: at baseline (Day 0) and at the end-of-study visit (Week 6); control subjects: at baseline (Day 0)]
• Measure of the suicidality score in depressed patients thanks to the Columbia-Suicide Severity Rating Scale [Time frame: At baseline (Day 0) and at the end-of-study visit (Week 6)]
• Measure of anhedonia score in depressed patients thanks to the Snaith-Hamilton Pleasure Scale [Time frame: At baseline (Day 0) and at the end-of-study visit (Week 6)]
• Measure of the anxiety score in depressed patients thanks to the Beck anxiety scale [Time frame: At baseline (Day 0) and at the end-of-study visit (Week 6)]
• Measure of the emotional reactivity in depressed patients and control subjects thanks to the Multidimensional Assessment of Thymic States scale [Time frame: Patients: at baseline (Day 0), Day 7, Week 2 (2 times), Week 3 (2 times), Week 4 (2 times), Week 5 (2 times) and at the end-of-study visit (Week 6); control subjects: at baseline (Day 0).]
• Measure of the mania score in depressed patients and control subjects thanks to the Young Mania Rating Scale [Time frame: Patients: at baseline (Day 0), Day 7, Week 2 (2 times), Week 3 (2 times), Week 4 (2 times), Week 5 (2 times) and at the end-of-study visit (Week 6); control subjects: at baseline (Day 0)]
• Assessment of the severity and improvement of the clinical condition using the Clinical Global Impression Severity scale [Time frame: Patients: at baseline (Day 0), Day 7, Week 2 (2 times), Week 3 (2 times), Week 4 (2 times), Week 5 (2 times) and at the end-of-study visit (Week 6); control subjects: at baseline (Day 0)]

Eligibility criteria

Inclusion criteria

Patient inclusion criteria :

• Age over 18
• Patient hospitalized or consulting at GHU Paris Psychiatrie et Neurosciences
• Patient with EDC (unipolar or bipolar) diagnosed according to the DSM-5 CRITERIA
• With MADRS score > 20
• For whom a course of esketamine has been decided by the psychiatrist of the patient
• Patient having given written informed consent
• Patient covered by a social security plan

Inclusion criteria for control subjects :

• Over 18 years old
• No EDC assessed by MADRS < 8

Exclusion criteria

Patient non-inclusion criteria:

• Psychiatric comorbidities: schizophrenic disorder or schizoaffective disorder, history of recreational use of ketamine
• Protected adults, persons under legal protection
• Contraindications to MRI, including refusal to be informed of the discovery of a clinically significant abnormality on MRI
• Pregnant or breast-feeding women
• Usual contraindications to esketamine :

• Neurological comorbidity: epilepsy, neurodegenerative disease, cerebrovascular disease with recent history (< 3 months) of stroke or ischemic attack or transient ischemic attack
• Cardiological co-morbidity: vascular aneurysm, ischemic heart disease with acute elements or stent within the previous 12 months, uncontrolled hypertension, heart failure, rhythm or conduction disorders on ECG
• History of cirrhosis (or ALAT, ASAT or bilirubin greater than 2 N)
• Severe chronic respiratory insufficiency

Exclusion criteria for control subjects:

• MADRS <8
• Contraindications to MRI, including refusal to be informed of a clinically significant clinically significant abnormality on MRI

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Allocation

Non-randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

France · 1 center

• - Groupe hospitalo-universitaire Paris Psychiatrie et Neurosciences — Paris

Identifiers

NCT: NCT06630065 · D22-P015

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗