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

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

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

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