Depression treatment response to ketamine: sex-specific role of interleukin-8, but not other inflammatory markers

Inflammation plays a role in depression pathophysiology and treatment response, with effects varying by sex and therapeutic modality. Lower levels of interleukin(IL)-8 predict depression response to antidepressant medication and to electroconvulsive therapy (ECT), although ECT effects are specific to females. Whether IL-8 predicts depression response to ketamine and in a sex-specific manner is not known. Here, depressed patients (n=46; female, n=17) received open label infusion of ketamine (0.5mg/kg over 40min; NCT02165449). Plasma levels of IL-8 were evaluated at baseline and post-treatment. Baseline levels of IL-8 had a trending association with response to ketamine, depending upon sex (responder status x sex interaction: p=0.096), in which lower baseline levels of IL-8 in females (p=0.095) but not males (p=0.96) trended with treatment response. Change in levels of IL-8 from baseline to post-treatment differed significantly by responder status (defined as >= 50% reduction in Hamilton Depression Rating Scale [HAM-D] Score), depending upon sex (responder status x sex x time interaction: F(1,42)=6.68, p=0.01). In addition, change in IL-8 interacted with sex to predict change in HAM-D score (beta=-0.63, p=0.003); increasing IL-8 was associated with decreasing HAM-D score in females (p=0.08) whereas the inverse was found in males (p=0.02). Other inflammatory markers (IL-6, IL-10, tumor necrosis factor-alpha, C-reactive protein) were explored with no significant relationships identified. Given these preliminary findings, further evaluation of sex differences in the relationship between IL-8 and treatment response is warranted to elucidate mechanisms of response and aid in the development of personalized approaches to depression treatment.