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

Abstract

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 (0.5 mg/kg over 40 min; 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 × 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 × sex × 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 (β = -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-α, 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.

Inflammatory signaling mechanisms in bipolar disorder

“…As follows, ketamine’s anti-inflammatory function in affective disorder patients remains elusive. Temporal associations between inflammatory changes and treatment response are at best, unclear [ 177 – 182 ]. Likewise, elevation in baseline inflammation appears to predict treatment response in some studies [ 177 , 180 ] but not in others [ 178 , 179 , 183 ].…”

“…Thus, rather than focusing on the role of inflammation in initial treatment response, it would seem prudent to delineate the contribution of immune signaling to ketamine’s inability to sustain anti-depressant responses. Classically, elevated baseline inflammation is associated with treatment resistance to most antidepressant strategies, apart from ECT and targeted anti-inflammatory medications, where the inverse is true [ 32 , 182 ]. Unlike those therapies, ketamine appears to temporarily modulate (rather than purely suppress) inflammation.…”

Peripheral biomarkers in Repeated Ketamine Infusions Trial

“…In this study plasma CRP did not significantly change with repeated infusions throughout the clinical trial and higher pre-treatment CRP did not predict change in depressive symptoms with ketamine treatment. While this is the first study investigating the effect of repeated ketamine infusions on CRP, two studies have measured CRP before and after a single subanesthetic ketamine infusion and found no significant change (Chen et al, 2018b;Kruse et al, 2021). Thus, there is no current evidence that single or repeated ketamine infusions are associated with changes in CRP levels despite reported effects of ketamine treatment on other immune factors including IL-6 (Chen et al, 2018b;Yang et al, 2015), IL-1ß (Yang et al, 2015), IL-8 (Kruse et al, 2021) and TNF- (Yang et al, 2015).…”

“…While this is the first study investigating the effect of repeated ketamine infusions on CRP, two studies have measured CRP before and after a single subanesthetic ketamine infusion and found no significant change (Chen et al, 2018b;Kruse et al, 2021). Thus, there is no current evidence that single or repeated ketamine infusions are associated with changes in CRP levels despite reported effects of ketamine treatment on other immune factors including IL-6 (Chen et al, 2018b;Yang et al, 2015), IL-1ß (Yang et al, 2015), IL-8 (Kruse et al, 2021) and TNF- (Yang et al, 2015). As previously mentioned however, these findings have not been consistently replicated and thus, the relationship between ketamine treatment and inflammation still remains unclear (Cui et al, 2019).…”

“…Given the antiinflammatory properties of ketamine (Loix et al, 2011), it is hypothesized that elevated pretreatment CRP levels will also predict antidepressant response to ketamine. Thus far however, two studies have investigated the effects of a single ketamine infusion on CRP and found that there was no significant change in CRP after treatment and that CRP was not predictive of treatment response (Chen et al, 2018b;Kruse et al, 2021). However, these studies were limited as CRP levels were only examined for up to 7 days after a single ketamine infusion.…”