To the Editor We read with interest the meta-analysis of randomized clinical trials providing support for anti-inflammatory treatment of depression that was published in JAMA Psychiatry by Köhler and colleagues.1 The meta-analysis highlighted the heterogeneity of results across studies, and it is unclear how anti-inflammatory treatment achieves its antidepressant effects. Given the well-established concurrence of depression and fatigue, one hypothesis is that the beneficial effect of anti-inflammatory treatment on depression may be mediated at least in part by treatment effects to reduce fatigue. Patients who feel less fatigued are likely to report less depression, particularly as measured by depression inventories with items that conflate the 2 constructs. Indeed, nonsteroidal anti-inflammatory drug treatment (aspirin) effectively lowers fatigue in patients with relapsing-remitting multiple sclerosis, even when controlling for depression.2