Neuroinflammation and depression: the role of indoleamine 2,3-dioxygenase (IDO) as a molecular pathway.

Major depression is associated with neuroendocrine and neuroimmune abnormalities, including hyperactivity of the hypothalamic-pituitary-adrenal axis (1); brain astroglia loss and microglia activation (2); and increased circulating levels of inflammation markers such as C-reactive protein (CRP) levels (3) and proinflammatory cytokines, as well as their soluble receptors, including interleukin 2 (IL-2), soluble IL-2 receptor, IL-1b, IL-1 receptor antagonist, IL-6, soluble IL-6 receptor, interferon F (IFN-F), and tumor necrosis factor > (4Y7). Moreover, administering proinflammatory cytokines such as IFN-> for therapeutic or experimental purposes can induce depression (8), and major depression is highly comorbid with medical illnesses with an inflammatory component, such as cardiac disease (9). The enzyme indoleamine 2,3-dioxygenase (IDO) can be seen as a pivot point between the regulation of immune processes and monoaminergic systems involved in depression. IDO is activated by proinflammatory cytokines and functions as a catalyst for the formation of kynurenine (KYN) from tryptophan (TRP) (10). Two hypotheses have been put forward for the putative effects of elevated IDO-mediated KYN formation on depression (Fig. 1). a) The first is the serotonergic (TRP depletion) hypothesis, which posits that siphoning TRP in the direction of KYN formationmay decrease the production of serotonin (11,12). This idea has face value in that low serotonergic functioning (13) and low TRP levels (14) are both associated with depression. In addition, experimentally induced TRP depletion causes abnormalities in emotional processing among young healthy volunteers with a family history of depression (15) and depressive relapse among remitted depressed individuals (16), even in the continued presence of antidepressant medications. This override of antidepressant effects may be medication specific (17) or may depend on the magnitude of the TRP depletion (16). Reemergence of depressive symptoms induced by TRP depletion also has been correlated with functional changes in brain regions involved in mood regulation and dysregulation (18), and both the increased symptoms (19) and brain metabolic changes (20) are differentially associated with the s/s variant of the serotonin transporter gene promoter polymorphism (5HTTLPR). b) The second is the glutamatergic (neurotoxic/neurodegenerative) hypothesis, according to which, increased levels of downstream KYN metabolites may contribute to inducing and perpetuating depression. This contention is supported by findings in IFN-FYinduced depression that severity of depression symptoms is correlated with measures of IDO activity but not with measures of TRP availability to the brain (8) and that elevated cerebrospinal fluid KYN metabolites are not associated with depleted cerebrospinal fluid TRP (21). KYN is metabolized through two main pathways (reviewed in Myint et al. (22)). The major, rate-limiting pathway, in glial cells, produces the N-methyl-D-aspartate receptor agonist and potentially neurotoxic compound quinolinic acid (QUIN); a secondary pathway, in astrocytes, produces kynurenic acid (KYNA), an N-methyl-D-aspartate antagonist thought to be neuroprotective. Dominance of QUIN over KYNA production would be consistent with the neurotoxic/neurodegenerative hypothesis of depression (23), and thus, it is relevant to investigate the relative proportion of QUIN and KYNA metabolites. Myint et al. (22) have calculated a surrogate neuroprotective ratio (plasma KYNA 1000 / plasma KYN) and found it to be lower in depressed patients compared with healthy controls, which they interpret as catabolic activity of KYN, leading primarily to increased formation of QUIN. The role of IDO in depression also has been modeled in animal studies, in which depressive-like behaviors are induced by stimulating IDO (24Y26), are not induced when IDO is blocked (27), and are not inducible with inflammatory stimuli in IDO-knockout animals (27). In humans, IDO up-regulation has been implicated in disturbances of quality of life in patients with colorectal cancer (28), in peripartum depression (29), and in postpartum blues (30). The KYN pathway has also has been hypothesized to play a role in suicide risk. Among patients with major depressive disorder, higher levels of plasma KYN but not lower levels of TRP were observed in patients who had made suicide attempts compared with nonattempters (31). Furthermore, in suicide attempters only, a positive correlation was seen between the increased KYN-to-TRP ratio and plasma levels of the cytokine activation marker neopterin (31), consistent with other reports of altered cytokine regulation associated with suicidal behavior and other forms of self-directed violence (32Y35). Moreover, postmortem, in patients with severe unipolar or bipolar depression who died through suicide, in comparison with controls with no neuropsychiatric illness, microglial QUIN immunohistochemistry is elevated in areas of the brain previously implicated in mood dysregulation, such as the subgenual prefrontal cortex and anterior midcingulate cortex (36). In this issue of Psychosomatic Medicine, Elovainio and colleagues (37) have examined the value of KYN/TRP ratio as a predictor of future depression. In a prospective longitudinal design, the calculated KYN/TRP ratio was used as an estimate of IDO activity at baseline, and clinical status was assessed 6 years later in a large cohort of men and women aged 24 to 39 years (n = 986) as part of the Young Finns Study. Because this was a community sample, not a psychiatrically ill cohort, they used a modified, previously validated version of the Beck Depression Inventory that allowed for finer detection of subthreshold depressive symptoms (38). DOI: 10.1097/PSY.0b013e318268de9f EDITORIAL COMMENT