JAK Signaling in Depression and Cognition in Male Football Players (JAK DC in Play)

실험적: Baricitinib

Participants will receive 1 tablet/d of 2 mg baricitinib at baseline. For participants who do not exhibit a clinical response at 4 Weeks (a 50% reduction in HAM-D scores), the dose will be increased to 4 mg/day (2 tablets/d of baricitinib), as tolerated.

의약품: Baricitinib

Baricitinib is an orally administered, selective inhibitor of Janus kinase (JAK) 1 and 2. It reduces cytokine-mediated signaling involved in inflammation and immune activation. Baricitinib is FDA-approved for rheumatoid arthritis (RA), atopic dermatitis, and alopecia areata. It has also been authorized for the treatment of COVID-19 in hospitalized patients. Baricitinib will be dispensed every other week at the Week 2, 4, and 6 study visits. Participants who do not exhibit a clinical response (50% reduction in HAM-D scores from baseline) at Week 4 will be increased to 4 mg/day of baricitinib (2 x 2 mg tablets). A virtual follow-up visit will be conducted at Week 1 to assess safety and tolerability in all patients, and at Week 5 in patients who increase the dose.

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Monetary Incentive Delay (MID) Task functional magnetic resonance imaging (fMRI)

Resting-state and task-based MID Task functional magnetic resonance imaging (fMRI). The MID Task is a specialized behavioral paradigm used during functional magnetic resonance imaging (fMRI). It isolates and measures the neural mechanisms of reward processing, specifically motivational salience, anticipation, and outcome feedback. fMRI blood oxygen level-dependent (BOLD) for resting and task-based functional connectivity: A multi-echo (ME) ep2 BOLD sequence will be optimized to provide a high signal-to-noise ratio in regions of interest that is maintained during minor incidences of head motion. Resting ME BOLD will be acquired over ~10 min, and task fMRI will involve two ~10 min scans. For resting bold, a single acquisition of phase-encoding in the opposite polarity (anterior-posterior) for distortion correction over ~30 seconds.

Effort-Expenditure for Rewards Task (EEFRT)

The EEfRT is a widely used, multi-trial task measuring motivation for rewards as an assessment of anhedonia, as anhedonia is specifically associated with decreased motivation for rewards.

Participants are given an opportunity to choose between two different task difficulty levels in order to obtain monetary rewards by repeated manual button presses within a short time. Button presses raise a virtual ''bar'' viewed onscreen. If they raise the bar to the ''top'' within the prescribed time, they are eligible to win the allotted money. Each trial presents the subject with a choice between two levels of task difficulty, a 'hard task' and an 'easy task,' and 3 probabilities of winning. Subjects participate in the task for 20 minutes, and the first 50 trials are analyzed by calculating the proportion of hard-task choices across each level of probability. Lower proportions of hard task choices indicate decreased motivation.

Finger Tapping Test (FTT)

The Finger Tapping Test (FTT) is a simple neuropsychological assessment that measures fine motor speed, coordination, and nervous system health. This task uses a specially adapted tapper that the subject is asked to tap as fast as possible using the index finger. The subject is given 5 consecutive 10-second trials for both the preferred and non-preferred hands. The finger tapping score is the mean of the 5 trials and is computed for each hand.

Normal/Average: 45-60 taps. Mild Slowing / Potential Impairment: 30-45 taps. Significant Motor Impairment / Fatigue: Fewer than 30 taps

Trail-Making Test (TMT)

The Trail-Making Test (TMT) is a common neuropsychological assessment measuring processing speed, visual attention, and task-switching ability. The test is typically administered using a paper-and-pencil format (or digital equivalent) and has two primary sections: Part A: Patients connect 25 randomly distributed circles containing numbers in ascending order (1, 2, 3...) as quickly as possible. This measures baseline processing speed, motor speed, and visual scanning. Part B: Patients connect 25 circles containing both numbers and letters, strictly alternating between them in ascending order (1-A-2-B-3-C...). This places a much higher cognitive demand on mental flexibility, set-shifting, and working memory. Evaluators record the total time (in seconds) taken to complete each part. Longer times generally indicate poorer cognitive function.

Anhedonia Subscale of the Inventory of Depressive Symptoms-Self Reported (IDSSR)

Anhedonia is assessed with a 3-item subscale of the Inventory of Depressive Symptomatology Self-Report (IDS-SR). Each of the three items is rated on a 4-point severity scale from 0 to 3, where 0 indicates no impairment, and 3 indicates maximum severity. Scores range from 0 to 9, with higher scores reflecting a greater severity of anhedonia, meaning a stronger loss of interest, motivation, and ability to experience pleasure.

Behavior Rating Inventory of Executive Function, Second Edition (BRIEF2A)

BRIEF2A is a standardized rating scale that allows adults and knowledgeable informants (caregivers, adult children, partners/spouses) to rate executive function or self-regulation in that adult's day-to-day setting. Scoring relies on T-scores (Mean = 50, Standard Deviation = 10).

< 60 T-score: Within Normal Limits. 60 - 64 T-score: Subclinical difficulties; subtle but generally manageable challenges.

65 - 69 T-score: Mildly elevated; noticeable executive function deficits. 70 - 74 T-score: Moderately elevated; significant executive dysfunction affecting daily life.

>= 75 T-score: Highly elevated; severe impairment.

Snaith-Hamilton Pleasure Scale-Clinician (SHAPS-C)

The Snaith-Hamilton Pleasure Scale-Clinician (SHAPS-C) is a 14-item validated clinician-administered assessment tool used to measure hedonic capacity and evaluate anhedonia (the inability to experience pleasure). The clinician asks the patient about their expected or actual ability to feel pleasure over the past few days, translating the standard self-report questions into a guided clinical interview. Responses are typically evaluated using a 4-point Likert scale (Strongly Disagree, Disagree, Agree, Strongly Agree). Total scores range from 0 to 14, with higher scores indicating greater difficulty experiencing pleasure or a higher level of anhedonia.

Hamilton Depression (HAM-D) Rating Scale

Hamilton Depression (HAM-D) Rating Scale is the most widely used clinician-administered depression assessment scale. It evaluates symptoms such as mood, guilt, insomnia, anxiety, and weight loss over the previous week.

Scores are tallied to estimate the severity of the depression, although context and clinical judgment are always required. Maximum score is 52 0 to 7: Normal/Remission 8 to 16: Mild Depression 17 to 23: Moderate Depression 24 or higher: Severe Depression

Columbia Suicide Severity Rating Scale (CSSR)

The Columbia-Suicide Severity Rating Scale (C-SSRS) evaluates both suicidal ideation and suicidal behavior.

Minimum 0 (no ideation) to Max: 5 (active suicidal ideation with a specific plan and intent).

Meaning of Scores:0: No suicidal ideation reported.

1. (Wish to be Dead): Endorses thoughts about a wish to be dead or not alive.
2. (Non-Specific Thoughts): General, non-specific thoughts of wanting to end life, without methods or plans.
3. (Method, No Intent/Plan): Thoughts of suicide with a specific method in mind, but no intent or actual plan to act.
4. (Some Intent, No Plan): Thoughts of suicide and some intent to act, but without fully mapped-out details.
5. (Specific Plan and Intent): Fully or partially worked-out details of a suicide plan with intent to carry it out.

Phosphorylated Signal Transducer and Activator of Transcription 3 (pSTAT3)

Intracellular pSTAT3 in peripheral blood immune cells will be assessed by flow cytometric methods.

Plasma inflammatory biomarkers

CRP, IL-6, TNF-alpha and IL-1beta. High-sensitivity (hs) CRP will be assayed using an immunoturbidometric assay with a Beckman AU480 chemistry analyzer and Ultra WR CRP kit (Sekisui Diagnostics). Inflammatory cytokines (IL-1, IL-6, TNF) and their soluble receptors will be analyzed by multiplex bead-based assays, previously validated against individual ELISA.