Peripheral inflammatory effects of different interventions for treatment-resistant depression: A systematic review

Immune-related mechanisms are increasingly recognised as important in the pathophysiology of depression, particularly treatment-resistant depression (TRD). Preliminary evidence suggests that people with TRD may benefit from anti-inflammatory interventions; however, the relative anti-inflammatory effects of therapies currently recommended for TRD have not been integrated in a specific evidence synthesis. A systematic search was performed to identify articles published up to February 8, 2021. Results from databases (Pubmed, Embase) and handsearches were reviewed to include any longitudinal study examining circulating marker(s) of inflammation in humans before and after treatment with electroconvulsive therapy (ECT), ketamine, bupropion, lithium, aripiprazole, or quetiapine. We undertook a narrative synthesis of results and risk of bias assessment to incorporate and interpret the evidence. Of 57 included studies, 34 assessed the effects of ketamine and 12 of ECT, with other medications examined in ≤5 studies each. Results were highly heterogeneous. Numerically, more frequent increases than decreases in pro-inflammatory markers were reported after ketamine, quetiapine and lithium (although more frequent significant decreases were observed for lithium). Findings for ECT and bupropion were even more inconsistent. Two studies consistently reported inflammatory reductions (significant/non-significant) after aripiprazole. Treatment effects on inflammatory proteins are confounded by several factors: ketamine, in most studies, was co-administered with other surgical procedures, while ketamine and ECT findings are also obscured by variable post-procedure assessment timing. The evidence base for other treatments is scant. Greater examination is warranted to establish whether inflammatory biomarkers could be used to stratify TRD patients to a ‘most appropriate’ intervention.