After adjustment for relevant covariates, the association between depressive symptoms and Type 2 diabetes was heterogenous in our population-based study. In subjects with undiagnosed diabetes, however, depressive symptoms were less frequent in men. Co-morbidities and psychosocial conditions are strongly associated with depressive symptoms.

Objective Electroconvulsive therapy (ECT) is the most robust acute treatment for severe major depressive disorder, yet clinical response is variable. Inflammation is associated with depression, especially in women, and levels of C-reactive protein (CRP) and interleukin-6 (IL-6) predict response to antidepressant medications. This study evaluated whether markers of inflammation predicted response to electroconvulsive therapy (ECT) in patients with treatment resistant depression, and to what extent this association differed between men and women. Methods In patients (n=29) with a current major depressive episode diagnosed using DSM-IV-TR criteria, undergoing ECT at an academic referral center, levels of CRP, IL-6, IL-8, tumor necrosis factor (TNF)-α, and severity of depressive symptoms (Montgomery-Asberg Depression Rating Scale, MADRS) were prospectively evaluated before ECT treatment, after the second ECT session, and again at the completion of the index treatment series. Data were collected between 12/2011 and 12/2014. The primary outcome was end-of-treatment MADRS score. Results In multivariate analyses, higher levels of IL-6 at baseline, but not other inflammatory markers or clinical variables, were associated with lower end-of-treatment MADRS score (p=0.01). When stratified by sex, IL-6 remained a significant predictor of end-of-treatment MADRS for women (p=0.02) but not men (p=0.1), and CRP emerged as a significant predictor for women (p=0.04) but not men (p=0.66). CRP and IL-6 increased from baseline to the second ECT session (p’s<0.01) and returned to baseline levels at end of treatment; these changes did not relate to MADRS score over the course of ECT. Conclusions Levels of IL-6 prior to ECT treatment may be useful in identifying those depressed patients most likely to benefit from ECT treatment. In contrast, acute changes in IL-6 and CRP may reflect spikes in inflammatory response related to the initiation of seizure therapy, but not mood. Assessment of pre-treatment inflammatory biomarkers, especially in women, might be useful in guiding treatment decision-making in treatment resistant depression.

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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.

Inflammation has an important physiological influence on mood and behavior. Kynurenine metabolism is hypothesized to be a pathway linking inflammation and depressed mood, in part through the impact of kynurenine metabolites on glutamate neurotransmission in the central nervous system. This study evaluated whether the circulating concentrations of kynurenine and related compounds change acutely in response to an inflammatory challenge (endotoxin administration) in a human model of inflammation-induced depressed mood, and whether such metabolite changes relate to mood change. Adults (n = 115) were randomized to receive endotoxin or placebo. Mood (Profile of Mood States), plasma cytokine (interleukin-6, tumor necrosis factor-α) and metabolite (kynurenine, tryptophan, kynurenic acid, quinolinic acid) concentrations were repeatedly measured before the intervention, and at 2 and 6 h post-intervention. Linear mixed models were used to evaluate relationships between mood, kynurenine and related compounds, and cytokines. Kynurenine, kynurenic acid, and tryptophan (but not quinolinic acid) concentrations changed acutely (p's all < 0.001) in response to endotoxin as compared to placebo. Neither kynurenine, kynurenic acid nor tryptophan concentrations were correlated at baseline with cytokine concentrations, but all three were significantly correlated with cytokine concentrations over time in response to endotoxin. Quinolinic acid concentrations were not correlated with cytokine concentrations either before or following endotoxin treatment. In those who received endotoxin, kynurenine (p = 0.049) and quinolinic acid (p = 0.03) positively correlated with depressed mood, although these findings would not survive correction for multiple testing. Changes in tryptophan and kynurenine pathway metabolites did not mediate the relationship between cytokines and depressed mood. Further work is necessary to clarify the pathways leading from inflammation to depressed mood in humans.