Table 2 Exclusion criteria

 1. Prior diagnosis within ICD-10 F20-39

All potential patients are screened for and excluded in the case of a history of psychotic or affective disorders, since we aim to include patients with first-time depression only.

 2. Contraindications against lumbar puncture

To minimize the risk of serious side effects potential participants with contraindication against lumbar puncture will not be included. Contraindications includes increased risk of bleeding (known International Normalized Ratio (INR) > 1.5, blood platelets < 40 × 10⁹/L, blood thinning treatment), signs of increased intracranial pressure (postural headache, recent onset morning headache, nausea) [36] or fever.

 3. Known organic psychiatric disorder or severe neurological disorder

To minimize the impact of other sources of neuroinflammation, patients with known organic cause to their symptoms (e.g. encephalitis), and/or known organic psychiatric disorder (ICD-10 F0), and/or known severe neurological disorder(s), including brain tumor, stroke, multiple sclerosis, epilepsy (with seizures within the past 10 years), and/or severe head injury within the past 3 months are not considered eligible.

 4. Severe somatic disease

To reduce the impact of other sources of inflammation, participants with diseases known to have major impact on the immune system (including active infection, cancer, autoimmune disorders (e.g. inflammatory bowel disease, or systemic lupus erythematosus), hypothyroidism or hyperthyroidism) are not considered eligible. However, participants with mild asthmatic bronchitis, allergy, or other common, mild somatic disorders will be included in both groups in order to avoid selection bias.

 5. Regular use of anti-inflammatory medication

To reduce the impact of medication impacting the immune system all participants are screened for the use of anti-inflammatory or immunosuppressive drugs (including Non-steroidal Anti-inflammatory Drugs, cortisone treatment (orally or intravenous), monoclonal antibody therapy of any kind and plasmapheresis). The participant can be included after a quarantine period of 14 days if still fulfilling the remaining eligibility criteria.

 6. Current electroshock therapy (ECT)

ECT is known to induce a proinflammatory response [37] and current ECT will lead to exclusion to avoid interference with results. After a 3-month quarantine the participant can be included if still fulfilling the inclusion criteria.

 7. Current abuse of alcohol or drugs

Potential participants who full-fill the criteria of a F1 diagnosis will not be included to avoid interference with results, however, recreational use will be accepted, also among healthy participants, since we aim for highly translational results. If the use of alcohol or drugs could have caused the current psychiatric illness or if the use is on regular (daily) basis, the participant will not be included.

 8. Not being able to participate in SCAN interview

Patients with minor psychiatric co-morbidity (e.g. anxiety) can be included, but if the participant has psychiatric co-morbidity complicating SCAN interview (e.g. severe autism or mental retardation), they will not be included. Participants who cannot participate in a (full) SCAN interview due to their depressive state will still be included.

 9. Language barrier

We aim for a thorough characterization of psychopathology in this study, and it will be individually evaluated whether a participant should be excluded due to language barrier, however, the participant should be capable of answering the questions of the SCAN interview. The interview will be conducted in either Danish or English.

 10. Pregnancy

As a precautionary principle, pregnant women are not allowed to participate. Furthermore, pregnancy is known to impact the female body in multiple ways including alterations of the immune system [38]. Female participants are asked routinely about their menstrual cycle and hormonal contraception, and a risk of pregnancy or known pregnancy leads to exclusion from the study. Lactating women can participate.

 11. Any psychiatric disorder (or former psychiatric disorder)

All healthy controls are screened for prior psychiatric disorders. Initially by phone, but also during the SCAN interview carried out before blood samples and lumbar puncture. The SCAN interview is based on the past 28 days, but all participants will be asked if they ever experienced any of the symptoms, and if the interview reveals possible former psychiatric disorder the healthy control is excluded. Furthermore, individuals treated with psychotropic medication for any reason will be excluded from the healthy control group.