Elsevier

Brain, Behavior, and Immunity

Volume 23, Issue 8, November 2009, Pages 1096-1103
Brain, Behavior, and Immunity

In-hospital levels of C-reactive protein and IL-6 predict post-operative depressive symptoms among patients undergoing total knee replacement surgery

https://doi.org/10.1016/j.bbi.2009.06.148Get rights and content

Abstract

Behavioral changes observed following immune system activation are similar to many of the hallmark symptoms of major depressive disorder (MDD), including appetite change, lethargy, fatigue, negative mood and anhedonia. Acute phase proteins, such as interleukin-6 (IL-6) and C-reactive protein (CRP) have been implicated in the production of sickness behavior, and research has revealed significant differences in the levels of these acute phase proteins between depressed and non-depressed individuals. The current study examined whether early post-operative IL-6 and CRP levels predicted subsequent depressive symptoms in 110 patients undergoing total knee replacement surgery (TKR). In-hospital levels of IL-6 and CRP predicted depressive symptoms at three-months following surgery, as indicated by significant main effects and a significant interaction term. Specifically, lower levels of in-hospital CRP and higher levels of IL-6 in-hospital predicted more depressive symptoms three-months following surgery. The finding that levels of acute phase proteins soon after surgery predict subsequent depressive symptoms, if replicated, extends prior research on the relationships between IL-6, CRP, and depression. Further, this predictive relationship suggests the possibility of early identification of individuals at risk for the subsequent development of post-operative depression.

Introduction

A growing body of literature has implicated immune system activity in the development and course of depression (e.g., Alesci et al., 2005, Lanquillon et al., 2000, Miller et al., 2002, Maes et al., 1997, Maes et al., 1995, Penninx et al., 2003). Although the findings are somewhat mixed, the majority of extant research supports a positive correlation between levels of acute phase proteins, such as interleukin-6 (IL-6) or C-reactive protein (CRP), and depressive symptoms (e.g., Alesci et al., 2005, Lanquillon et al., 2000, Miller et al., 2002, Maes et al., 1997, Maes et al., 1995, Penninx et al., 2003). The current study examined whether inflammatory markers can longitudinally predict depressive symptoms among individuals undergoing total knee replacement (TKR) surgery.

Activation of the innate immune system triggers the release of inflammatory proteins that produce a behavioral profile (i.e., sickness behavior), which has been compared to symptoms of depression (e.g., Anisman and Merali, 2002, Maier and Watkins, 1998, Yirmiya, 1996). Specifically, appetite change, lethargy, fatigue, negative mood, and anhedonia are behavioral consequences of immune system activation, but are also commonly associated with major depressive disorder (MDD) (for review see Maier and Watkins, 1998). Further support for this behavioral similarity can be drawn from animal research which has shown that pretreatment with antidepressants can attenuate immune system-induced behavioral change (Castanon et al., 2001, Shen et al., 1999, Yirmiya, 1996).

Due to the similar behavioral manifestations of sickness behavior and depression, researchers have examined acute phase proteins in an effort to understand causes, course, and cues to the severity of MDD. Initial research in this area reported that individuals diagnosed with clinical depression have higher levels of IL-6 and CRP compared to non-depressed controls (Lanquillon et al., 2000, Maes et al., 1995, Miller et al., 2002). Similar trends have been reported in large community samples, such that individuals with high levels of IL-6 and CRP were more likely to report depressed mood than those with low levels of IL-6 and CRP, independent of clinical diagnosis (Gimeno et al., 2009, Penninx et al., 2003). Further research has revealed that levels of IL-6 correlate positively with the components of negative affect typically associated with MDD (e.g., guilt, low self-esteem, sadness, and suicidal ideation; Alesci et al., 2005) and predict treatment-resistant cases (Lanquillon et al., 2000, Maes et al., 1997). Although the majority of the extant literature documents a positive correlation between indices of immune activity and depressive symptoms, there are exceptions. Whooley and colleagues (2007) found that lower levels of inflammatory proteins (e.g., CRP and IL-6) were associated with current MDD among men with a history of coronary heart disease. In addition, Matthews and colleagues (2007) reported that there was no significant relationship between CRP and depressive symptoms among pre- and early perimenopausal women.

Although prior research makes a strong case for the existence of a relationship between inflammatory proteins and depression, these studies have largely focused on cross-sectional relationships primarily within clinical populations (e.g., Kling et al., 2007, Maes et al., 1995, Maes et al., 1997, Miller et al., 2002, Whooley et al., 2007). Due to the cross-sectional nature of these studies, baseline assessments of either inflammatory markers or depressive symptoms are often absent (e.g., Penninx et al., 2003, Whooley et al., 2007). In addition, these studies have typically relied on small sample sizes of less than 50 individuals (Alesci et al., 2005, Kling et al., 2007, Lanquillon et al., 2000, Maes et al., 1997).

More recent research has focused on medical populations in whom alterations of inflammatory proteins and depression might confer additional health risk. Positive relationships between CRP and depressive symptoms have been reported in stroke patients (Arbelaez et al., 2007), pregnant women (Scrandis et al., 2008), and individuals undergoing gastric bypass surgery (Emery et al., 2007). While these studies often employ a longitudinal design, they often report only significant cross-sectional findings (e.g., Arbelaez et al., 2007; Scrandis et al., 2008).

Few studies have examined the dynamic relationship that may occur between inflammatory proteins and depressive symptoms assessed before and after a surgical procedure. However, one exception examined this relationship in patients undergoing gastric bypass surgery (Emery et al., 2007). In this study, Emery and colleagues (2007) report a significant bivariate correlation between change scores for depressive symptoms and CRP from baseline to 12 months following surgery. However, these analyses did not control for health characteristics (e.g., BMI, body fat, etc.), that could impact this relationship. Further, despite a longitudinal design, no mention was made of any significant predictive relationships between CRP, IL-6, and depressive symptoms.

As an elective and scheduled surgical procedure, total knee replacement surgery (TKR) provides researchers the opportunity to conduct baseline (pre-surgical) assessments. In addition, patients undergoing TKR are relatively healthy, as they must pass a pre-admission screening in advance of the procedure. Further, TKR is a relatively standardized surgical procedure, considered to induce similar levels of physical trauma across patients (Aarons et al., 1996). Surgery also stimulates the immune system, thereby providing the opportunity to examine the relationship between inflammatory proteins and depressive symptoms within a baseline and reactive context.

Joint replacement surgery stimulates the secretion of CRP and IL-6 (Hall et al., 2000, Moreschini et al., 2001, Shah et al., 2009), resulting in significantly higher levels of these proteins 24–48 h following surgery compared to baseline assessments. Prior research has attributed elevated levels of CRP and IL-6 to the tissue damage associated with surgery (Hall et al., 2000, Larsson et al., 1992). Even in uncomplicated cases, these increases in CRP and IL-6 persist for several days following surgery, (e.g., Hall et al., 2000). However, the extant literature concerning the secretion of acute phase proteins within a surgical context has focused on its relationship to post-operative infections or other complications (e.g., Andres et al., 2003, Larsson et al., 1992, Moreschini et al., 2001, Shah et al., 2009), rather than its possible relationship to psychological constructs.

Another reason for examining TKR patients is that depression following orthopedic surgery is prevalent and is associated with increased mortality rates and impaired or prolonged functional recovery (Caracciolo and Giaquinto, 2005, Faller et al., 2003, Voshaar et al., 2007). Following TKR, patients must actively participate in physical therapy to optimize their functional recovery (Rohr and Hungerford, 1992). Depressive symptoms may significantly interfere with or prolong patients’ recovery. Specifically, depressed patients are more likely to complain and less willing to undergo passive flexion of the operated joint than non-depressed patients (Caracciolo and Giaquinto, 2005). Understanding the mechanisms through which depression develops following surgery could lead to early identification of patients at risk for depression and worse recovery outcomes, as well as inform the development of novel post-operative interventions for at-risk patients.

Section snippets

The present study

The current study aimed to examine the extent to which levels of IL-6 and CRP assessed at varying points before and after TKR surgery predicted post-surgical depressive symptoms. The present analyses were conducted on a larger dataset concerning psychophysiological variables that predict outcome following TKR (Cremeans-Smith et al., 2006, Cremeans-Smith et al., 2009). Based on previous research (e.g., Alesci et al., 2005, Lanquillon et al., 2000, Maes et al., 1997, Maes et al., 1995, Miller et

Participants

Participants consisted of 123 consecutive unilateral TKR patients recruited from August 2002 to March 2003 through the Department of Orthopedics at Summa Health System (Akron, OH). Potential participants were initially approached by their surgeons, who briefly described the research protocol. Subsequent letters describing the study were mailed to patients indicating an interest, and letters were followed up with phone contact initiated by members of the research team. Potential participants

Results

The majority of patients undergoing TKR scored less than 15 on the CESD at one- and three-months following surgery (66.4% and 78.8%, respectively). A little more than half of the patients reported an increase in depressive symptoms between baseline and one-month following surgery (51.96%; 43.14% reported a decrease; 4.90% reported no change). In contrast, a majority of patients reported a decrease in depressive symptoms between baseline and three-months following surgery (55.00%; 37.00%

Discussion

In summary, our results reveal that early post-operative levels of IL-6 and CRP, reflecting patients’ reactivity to surgical trauma, are significant predictors of depressive symptoms one- and three-months following surgery. Lower levels of in-hospital CRP predicted more depressive symptoms at both one- and three-months following surgery. In contrast, greater levels of IL-6 in-hospital predicted more depressive symptoms three-months following surgery. Further, the interaction between IL-6 and

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    Preparation of this manuscript was supported, in part, by National Institutes of Mental Health Grants R34 MH 71201 and R34 MH73014. Funding for this study was provided by a grant from the Kent-Summa Center for the Treatment and Study of Traumatic Stress.

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