Tuesday, September 04, 2012

Jill Leslie Littrell - Taking the Perspective that a Depressive State Reflects Inflammation: Implications for the Use of Antidepressants

From Frontiers in Psychology for Clinical Settings, this new study is an important piece in our understanding of depression (increasing evidence suggests it is an inflammatory disorder) and of antidepressants may work or, more importantly, not work.

In essence, antidepressants work as anti-inflammatory agents in the short term, but in the long term they become pro-inflammatory, which may explain why most of them stop working after six months or so.

Taking the perspective that a depressive state reflects inflammation: implications for the use of antidepressants

  • School of Social Work, Georgia State University, Atlanta, GA, USA
This paper reviews both the evidence that supports the characterization of depression as an inflammatory disorder and the different biochemical mechanisms that have been postulated for the connection between inflammation and depression. This association offers credible explanation for the short term efficacy of antidepressants, which have short term anti-inflammatory effects. Evidence for those anti-inflammatory effects is discussed. Evidence of the contrary long-term effects of antidepressants, which increase rather than decrease inflammation, is also reviewed. It is argued that this increase in inflammation would predict an increase in chronicity among depressed patients that have been treated with antidepressants drugs, which has been noted in the literature. A brief discussion of alternatives for decreasing inflammation, some of which have demonstrated efficacy in ameliorating depression, is presented.

Littrell JL (2012) Taking the perspective that a depressive state reflects inflammation: implications for the use of antidepressants. Front. Psychology 3:297. doi: 10.3389/fpsyg.2012.00297

Here are a few paragraphs from the beginning of the paper that offer a little background.

Depressive Behaviors Involve Inflammation

The association between stress, systemic inflammation, and behavioral signs of depression has been recognized for over a decade (Raison et al., 2006; Capuron et al., 2008; Dantzer et al., 2011). Depressed and anxious persons display elevations in blood levels of inflammatory cytokines [Interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α)] as well as other markers of an inflammatory state [e.g., C-reactive protein (CRP), soluble intracellular adhesion molecule-1 (ICAM-1), and macrophage chemoattractant protein-1; Rajagopalan et al., 2001; Zorrilla et al., 2001; Schiepers et al., 2005; Raison et al., 2006; Howren et al., 2009; Dowlati et al., 2010], and given a social stressor, depressed individuals exhibit greater elevations in inflammatory cytokines, such as IL-6 (Pace et al., 2006). Depressed persons also exhibit lower levels of anti-inflammatory cytokines (Li et al., 2011).

In addition to the findings for persons exhibiting behavioral signs of depression, the immune system function of individuals undergoing stress has been evaluated. In examining the leukocytes from individuals who reported loneliness, Cole et al. (2007, 2011) found increased transcriptional activity of Nuclear Factor-κB (NF-κB), a marker of inflammatory activation. The spouses of Alzheimer patients and caregivers for cancer patients are characterized by high levels of inflammatory cytokines such as IL-6 (Kiecolt-Glaser et al., 2003; von Kanel et al., 2006) and higher levels of NF-κB activity (Miller et al., 2008). Persons who are under stress at work exhibit elevations in ICAM-1, inflammatory cytokines, and acute phase proteins such as fibrinogen (von Kanel et al., 2001; Steptoe et al., 2003; Ramachandruni et al., 2004; Hong et al., 2006).

Investigating Causal Connections

Relatively early in these investigations, Maier and Watkins (1998) advanced the hypothesis that undergoing psychological stress or provoking inflammation in the periphery induces an equivalent state of systemic inflammation. According to Maier and Watkins, systemic inflammation correlates with changes in the brain. Regardless of the initiating event, whether an infection or a psychological stressor, behavioral manifestations of depression emerge that are driven by synonymous changes in the brain. Maier and Watkins speculated that during evolution, an immune system for fighting pathogens emerged first. When multi-celled organisms needed a mechanism for responding to an external psychological threat, the body recruited the already existing immune system for responding to external threat. Similar ideas were proposed by Maes et al. (1999). With regard to the evolutionary connection between psychological stressors and inflammatory activation, Pace et al. (2012) have suggested that given a psychological threat, such as attack by a predator, preparing the immune system to fight infection resulting from a predatory attack could be adaptive.

Manipulating psychological stress

Given the association between subjective distress and markers of systematic inflammation, researchers investigated the direction of a possible causal relationship. Learned helplessness is an animal model of depression. To induce learned helplessness, researchers subject animals to bouts of uncontrollable shock. The animal cannot escape or avoid the shock. Subsequent to this stressor, the animal appears depressed. The animal fails to drink sucrose, displays less locomotion, fails to explore new environments, and, even when subsequently given an opportunity to avoid an aversive stimulus, fails to escape or avoid. Animals subjected to helplessness inductions also have elevated levels of IL-1, in their hippocampus and hypothalamus (Maier and Watkins, 1998). Moreover, when an antagonist for the IL-1 is placed in the hippocampi of animals exposed to uncontrollable shock, the animal no longer exhibits depressed behavior, and no longer fails to escape aversive stimuli (Maier and Watkins, 1995; Johnson et al., 2004; Koo and Duman, 2008; Arakawa et al., 2009). Thus, IL-1 in the hippocampus seems to play a causal role in mediating behavioral manifestations of depression.

Another way to make an animal exhibit signs of depression is to expose the animal to repeated episodes of social defeat. After exposure to rounds of social defeat the animal avoids other animals, displays reduced preference for sucrose, and appears more depressed on tests such as the forced swim test and the tail suspension test. Concomitant with behavioral signs of depression, animals display elevation in inflammatory cytokines in plasma (Merlot et al., 2004; Kinsey et al., 2007, 2008; Avitsur et al., 2009).

In addition to the work with animals showing that stressing the animal will induce signs of systemic inflammation, there is also experimental work in humans. Persons who are subjected to laboratory stressors exhibit activation of NF-κB (Bierhaus et al., 2003) as well as an increase in inflammatory cytokines such as IL-6 in plasma (Pace et al., 2006). In those individuals who are low on chronic stress, increases in NF-κB activity are correlated with perceived intensity of the laboratory stressor (Wolf et al., 2009). A study by Slavich et al. (2010) examined how a social stressors inducing elevations in inflammatory cytokines changes brain function. Following the social stressor, those with elevations in the soluble receptor for TNF-α exhibited greater activation in the dorsal anterior cingulate and the anterior insula, two areas involved in processing negative affect.
 Read the whole paper.
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