Depressive episode
A proof-of-concept, randomized, double blind, placebo-controlled experiment based on approximately 50 depressed participants (intervention cohort) who have evidence of low-grade inflammation (i.e., serum/plasma high sensitivity C-reactive protein (hsCRP) level > = 3mg/L). Randomisation will be done by an external agency (i.e. Sealed Envelope). Participants will be randomly assigned to tocilizumab or normal saline group ensuring the two groups are comparable to each other on depression severity and sex using minimisation. Participants will receive a single intravenous infusion of normal saline (placebo) or tocilizumab (a drug that inhibits IL-6 signalling and is licensed in the UK for treatment of rheumatoid arthritis) (8 mg/kg; max 800 mg in total). Behavioural data and blood samples will be collected at baseline and after infusion around day 7, 14 and 28. Cognitive tasks will be performed at baseline and after infusion around day 14. Approximately 50 depressed participants without low-grade inflammation (serum/plasma hsCRP level < 3mg/L) will complete the same baseline assessments as the intervention cohort to fulfil the secondary objective of the study.
Inclusion criteria for all participants: 1. Able and willing to give informed consent, including consent to share information with the participant’s General Practitioner (GP) and to access GP records 2. Able to understand written and spoken English 3. Able to consent to blood sampling 4. Willing to abstain from strenuous exercise for 72 hours before the assessment visits 5. Age: 20-65 years (inclusive) at the time of eligibility assessment 6. Diagnosis of depression: meet ICD-10 criteria for diagnosis of depression at the time of eligibility assessment 7. Somatic symptom score: ≥7 at the time of eligibility assessment based on Beck depression inventory II (BDI-II) items 4=lack of pleasure, 15=loss of energy, 16=changes in sleeping pattern, 18=changes in appetite, 19=concentration difficulty, 20=tiredness or fatigue, and 21=loss of interest in sex 8. History of non/slow response to antidepressant: at the time of eligibility assessment receiving treatment with an antidepressant at adequate dose (according to BNF) for at least four weeks Additional inclusion criteria for intervention cohort: 1. Inflamed: serum/plasma hsCRP level ≥3mg/L
Exclusion criteria for all participants: 1. Current or lifetime diagnosis of bipolar disorder, psychotic disorder, personality disorder or eating disorder 2. Current suicidal thoughts (BDI II item 9=suicidal thoughts or wishes score 2 or more) or history of suicide attempt, deliberate self-harm, overdose within six months prior to eligibility assessment 3. History of alcohol or substance use disorder (abuse/dependence) within six months prior to eligibility assessment (nicotine and caffeine dependence are not exclusionary) 4. Pregnant or breastfeeding 5. History of serious allergic reaction after any infusion 6. Current use of medication likely to compromise interpretation of immunological data (including, but not limited to, antibiotics, non-steroidal anti-inflammatory drugs, oral/injectable corticosteroids – or any other substances to be determined by the Chief Investigator) 7. Any major episode of infection requiring hospitalization or treatment with IV antibiotics within 4 weeks of eligibility assessment 8. Known active current or history of recurrent bacterial, viral, fungal, mycobacterial or other opportunistic infections 9. Unstable cardiac, pulmonary, renal, hepatic, endocrine, hematologic, or active infectious disease, including current or prior malignancy 10. Rheumatic autoimmune disease, mixed connective tissue disease, scleroderma, polymyositis, or significant systemic involvement secondary to rheumatoid arthritis 11. Uncontrolled hypertension defined as systolic blood pressure > 170 or diastolic blood pressure > 110 12. No history of chickenpox infection or no history of varicella zoster vaccination Additional exclusion criteria for intervention cohort: 1. Current or past infection with TB, Hepatitis B, Hepatitis C, VZV or HIV confirmed by blood/other test. Chest X-ray will be also done to exclude TB 2. Pregnancy test (for female participants) 3. History of severe allergic or anaphylactic reactions to human, humanized or murine monoclonal antibodies