IL-6 inhibition in patients with depression and low-grade inflammation: the Insight study

INTERVENTION: 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. CONDITION: Specialty: Mental Health, Primary sub‐specialty: Depression; UKCRC code/ Disease: Mental Health/ Mood [affective] disorders ; Mental and Behavioural Disorders ; Depressive episode, unspecified PRIMARY OUTCOME: Change in total somatic symptoms score from baseline assessment to around day 14 post‐infusion. Somatic symptom score will be constructed by summing scores for seven relevant 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). Somatic symptoms will be measured using BDI‐II at baseline, day 7, 14 and 28 post‐infusion. SECONDARY OUTCOME: Secondary outcome measure:; Change in total depression severity score from baseline assessment to around day 14 post‐infusion assessed by BDI‐II. Depression severity will be measured using BDI‐II at baseline, day 7, 14 and 28 post‐infusion.; ; Tertiary/exploratory outcome measures:; ; Behavioural measures: ; 1. Fatigue, assessed by Multi‐dimensional Fatigue Inventory (MFI) at baseline, day 7, 14 and 28 post‐infusion; 2. Anhedonia, assessed by Snaith‐Hamilton Pleasure Scale Questionnaire at baseline, day 7, 14 and 28 post‐infusion; ; Cognitive measures:; 1. Psychomotor speed, assessed by CANTAB Reaction Time (RTI) test or a similar test (computerised) and Digit Symbol Substitution Test (pen and paper) or a similar test at baseline and day 14 post‐infusion; 2. Attention, assessed by CANTAB Rapid Visual Information Processing (RVP) test or a similar test (computerised) at baseline and day 14 post‐infusion; 3. Memory, assessed by CANTAB Paired Associates Learning (PAL) test or a similar test (computerised) at baseline and day 14 post‐infusion; 4. Emotional processing, assessed by Emotional categorization and recall task or a similar task (computerised) at baseline and day 14 post‐infusion; ; Blood biomarkers will be measured using appropriate tests at baseline and post‐infusion follow‐up. These include but are not limited to inflammatory markers, cortisol, cardio‐metabolic markers, and phenotyping of peripheral blood mononuclear cell populations (PBMC).; ; Genetic analysis of blood samples will be carried out using appropriate methods at baseline and post‐infusion follow‐up. INCLUSION CRITERIA: 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 receivi