Estimation of Control Before and After Treatment of a Depressive Episode With Serotonin Reuptake Inhibitors

The main questions it aims to answer are:

How do individuals with a depressive episode differ from healthy controls in their estimation of control over environmental events? How does antidepressant treatment (selective serotonin reuptake inhibitors) influence perceived control, cognitive performance, and depressive symptoms over time? Are changes in perceived control and symptoms associated with biological markers measured during the study?

Researchers will compare participants with a current depressive episode to healthy control participants, and examine changes over time in the depressed group before and after treatment initiation, in order to assess the effects of antidepressant treatment on cognition, perceived control, and symptoms.

Participants will:

• Complete 4 study sessions over approximately 8 weeks, including 2 in-person visits at the Centre de Recherche en Neurosciences de Lyon (CRNL) and 2 online sessions.
• Complete questionnaires assessing depressive symptoms, personality traits, and life events.
• Perform computerized behavioral tasks involving prediction, learning, memory, and decision-making in virtual environments.
• Complete tasks designed to assess perceived control over outcomes in different contexts.
• Undergo non-invasive physiological recordings during in-person sessions, including eye-tracking, heart rate monitoring, and muscle activity measurement.
• Perform short online versions of the cognitive tasks between visits.
• Healthy control participants will complete the same procedures, except for antidepressant treatment exposure, while the depressed group will be followed over time before and after treatment.

Inclusion criteria

- applicable to all participants:

• Affiliated with a social security or national health insurance system, or entitled to such coverage.
• Male or female, aged 18 to 55 years.
• Fluent in spoken and written French.
• Normal or corrected-to-normal vision.
• Access to a computer and an internet connection.
• Available for the 8-week study period following treatment initiation (patients) or the baseline visit (healthy controls).
• Willing to use an effective method of contraception (condom, oral contraceptive pill, abstinence, or intrauterine device).

Additional inclusion criteria for the depressed patient group:

• Eligible for antidepressant monotherapy with a selective serotonin reuptake inhibitor (SSRI: sertraline, fluoxetine, citalopram, or paroxetine) or a serotonin-norepinephrine reuptake inhibitor (SNRI: venlafaxine or duloxetine), with or without concomitant treatment with a short half-life benzodiazepine (<12 hours; e.g., oxazepam, lorazepam, or clotiazepam), for which the prescription has been issued but treatment has not yet been initiated.
• Montgomery-Åsberg Depression Rating Scale (MADRS) score >6 and <35 (corresponding to mild-to-moderate depression), assessed during the routine clinical visit with the treating physician.
• No evidence of suicidal ideation, high-risk behaviors, history of suicide attempt, or overt psychotic symptoms that could compromise participant safety.
• No severe medical condition or unstable physiological state considered incompatible with study participation by the referring physician, including but not limited to unstable chronic diseases (e.g., hypertension or diabetes), respiratory insufficiency, cardiovascular insufficiency, or renal insufficiency.

Exclusion criteria

applicable to all participants:

• History of a major depressive episode within the past 3 years.
• Use of antidepressants, mood stabilizers, or antipsychotic medication within the past 3 years.
• Diagnosis of a neurological or psychiatric disorder affecting central nervous system function (including bipolar disorder, schizophrenia, or other psychotic disorders according to DSM-5 criteria).
• Pregnancy or breastfeeding (self-reported).
• Individuals under legal protection (guardianship, curatorship, or judicial protection measures).
• Current participation in another interventional clinical trial or ongoing exclusion period following a previous clinical trial.
• Planned initiation during the study of a medication or substance known to interfere with serotonergic activity (including MDMA, LSD, psilocybin, ketamine, cocaine, 5-HT2A receptor antagonist antipsychotics, triptans, or lithium).
• Use of serotonin-acting recreational drugs within the previous 6 months (including cocaine, MDMA, or psychedelic substances).
• Refusal to be informed of the potential discovery of a clinically significant incidental finding.

Additional exclusion criteria for the depressed patient group

• Antidepressant treatment already initiated before study enrollment.
• Use of benzodiazepines within the 12 hours preceding an experimental session.
• Treatment with benzodiazepines other than oxazepam, lorazepam, or clotiazepam.
• Current hospitalization.
• Risk of suicidal behavior, defined as a score of ≥2 on the "zest for life" ("élan de vie") item of the Montgomery-Åsberg Depression Rating Scale (MADRS).
• Current treatment considered clinically incompatible with study participation by the physician responsible for recruitment.

Additional exclusion criteria for the healthy volunteer group :

Current or previous diagnosis of a depressive or anxiety disorder.