Interleukin-6 as a Biomarker in Major Depressive Disorder Angelos Halaris, MD, Edwin Meresh MD, Jawed Fareed, PhD, Debra Hoppensteadt PhD, Paula Olivieri MA, and James Sinacore PhD Departments of Psychiatry, Pathology and Epidemiology, Loyola University Chicago Stritch School of Medicine Introduction Methods Results Discussion A cohort of 48 patients with MDD and 23 healthy control subjects were analyzed from two consecutively run studies of identical design. Subjects met DSM-IV criteria for primary MDD, first or recurrent episode, with an index episode of at least one month duration. Screening included structured psychiatric interviews, physical exam, and laboratory studies. Subjects with medical illness or co-morbid Axis-I diagnoses (with the exception of Generalized Anxiety Disorder) were excluded from the study. Severity of depression was assessed using the HAM-D7 and HAM-D17 rating scales. Anxiety was assessed with the HAM-A and perceived stress was assessed with the PSS-14. Patients in the first study were treated for 12 weeks with escitalopram with flexible dosing (10-40 mg/day) at the discretion of the treating physician. In the second study, patients received quetiapine XR for 12 weeks with flexible dosing (range 50-300 mg/day). Although an atypical anti-psychotic, quetiapine has been used as an antidepressant at low doses. Its antidepressant activity is attributed to the inhibition of norepinephrine reuptake by quetiapine’s active metabolite, norquetiapine. Blood samples were obtained via venipuncture at baseline and weeks 8 and 12. Plasma IL-6 was measured using a compact biochip array system (Randox Technologies; Evidence Investigator TM). The data for IL-6 was not normally distributed, so non-parametric tests were used for statistical analyses. Patients with MDD (n=48) had significantly higher baseline serum IL-6 than healthy controls (n=20) (p=0.05). Serum IL-6 failed to normalize with either escitalopram or quetiapine after treatment. Treatment response (≥50% reduction or ≤7 in HAM-D17 score) did not correlate with the baseline level of IL-6. There was a significant correlation between baseline IL-6 level and depression severity as measured by HAMD-7 (p=0.05). This significance was lost with the HAMD-17 scale. There were no correlations between baseline IL-6 and severity of anxiety or perceived stress. Sex, BMI, smoking status, ethnicity, and menopausal status had no significant effect on baseline IL-6. Age did affect serum IL-6 as younger MDD patients (<39yrs) had higher IL-6 than healthy controls (p=0.01). Over the last few decades an abundance of research has focused on the relationship between psychiatric disorders and the immune system. When a person is exposed to the physical and mental stress of medical illness, certain cells release pro-inflammatory cytokines into the periphery and CNS. The process of inflammation and repair are closely intertwined, and the body will normally balance the actions of pro- and anti-inflammatory substances, notably cytokines, as it attempts to regain homeostasis. Dysregulation of this process occurs in the setting of chronic inflammatory conditions, such as autoimmune disorders, cancer, and cardiovascular disease. A similar response occurs when the individual is faced with chronic psychological stress. Interleukin-6 is a pro-inflammatory cytokine that stimulates the activity of the HPA-axis, sympathetic nervous system, and production of acute-phase reactants. Abnormal elevations of IL-6 have consistently been determined in patients with Major Depressive Disorder (MDD). Further studies have suggested that IL-6 is a specific indicator of the severity of symptoms, especially suicidality, or the likelihood of treatment response. As a result, depressive illness is increasingly considered a disease of inflammation that is triggered by chronic psychological stress. The specific aims of this study were the following: Confirm that serum IL-6 is higher in patients with MDD than healthy control subjects Examine the relationship between serum IL-6 and the severity of depression, anxiety, and perceived stress Evaluate whether IL-6 values normalized after monotherapy treatment with either Escitalopram, a selective-serotonin reuptake inhibitor, or Quetiapine, an atypical anti-psychotic Assess whether abnormal IL-6 specifically correlated with treatment resistant depression As predicted, patients with MDD had elevated serum IL-6. In contrast to previous studies, we did not find that this elevation was specific to treatment non-responders. Baseline IL-6 did correlate with depression severity as measured by HAM-D7. This scale was adapted from the HAM-D17 and includes the items with the greatest frequency of occurrence and sensitivity to treatment. It emphasizes the core features of depression such as depressed mood, guilt, and anhedonia. Thus, IL-6 appears to have a stronger association with the prototypical cognitive symptoms than the somatic-vegetative symptoms of depression. Patients in both studies experienced high rates of treatment response, but neither escitalopram nor quetiapine normalized IL-6 levels. Thus, inflammation persisted despite the improvement in mood symptoms. One explanation for this observation is that the length of treatment may have been inadequate to reverse the pro-inflammatory state. Alternatively, it is possible that IL-6 levels would fail to fully normalize regardless of treatment length. Antidepressants have been shown to inhibit the production and/or release of pro-inflammatory cytokines and to stimulate production of anti-inflammatory cytokines. Although current therapies may attenuate inflammation, they may not sufficiently resolve it. The monoamine theory of mood disorders has guided our understanding of major depression since the 1960s. The emerging inflammation hypothesis of depression elaborates upon a possible mechanism for the pathophysiology of depression. Depressive symptoms are associated with dysfunction of neurotransmitters like serotonin. Under healthy conditions, serotonin is produced from its precursor tryptophan and is available at neural synapses. Under conditions of psychological stress, tryptophan is preferentially metabolized through the kynurenine pathway (Figure 1). Upregulation of Indoleamine 2,3 (IDO) deprives serotonin production of its essential substrate and leads to symptoms of depression. Some metabolites of the IDO-mediated pathway are neurotoxic and contribute to neurodegeneration in areas, such as the hypothalamus, hippocampus, and cortex. This model explains both the immediate symptoms of depression and the associated long-term negative cognitive deficits. The above mechanism is a useful construct from which to expand the goal of antidepressant therapy. The ideal standard of treatment is to achieve remission of depression symptoms. Remission is clinically defined by a significant reduction in a depression rating scale. Patients that meet remission criteria may be prematurely discontinued from the medications when they actually retain subthreshold symptoms and persistent inflammation. Incomplete remission is associated Kynurenine Pathway with greater risk for recurrence, sustained suicidality, substance dependence, and increased risk of developing treatment-resistant depression. Assessing remission with depression rating scales can be valuable in quantifying and tracking patients’ subjective symptoms, but it can be an inadequate guide for treatment decisions. In order to prevent the poor outcomes associated with undertreating depressed patients, it would be useful to refer to a biological marker like IL-6 as an adjunctive measurement tool. Median Serum IL-6 at Baseline References Janelidze S, et al. Cytokine Levels in the Blood May Distinguish Suicide Attempters from Depressed Patients. Brain, Behavior, and Immunity. 2011; 25(2): 335-339. Janeway C, Travers P, Walport M, Shlomchik MJ. (2004) Immunobiology, 6th edition. Garland Science, New York, p.76-87. Kumar V, Fausto N, Abbas A. (2005) Robbins & Cotran Pathologic Basis of Disease, 7th edition. Elsevier Saunders, Philadelphia, p.48. Keller MB. Remission Versus Response: The New Gold Standard of Antidepressant Care. Journal of Clinical Psychiatry. 2004;65 (suppl4): 53-59. Lanquillon S, Krieg JC, Bening-Abu SV, Vedders H. Cytokine Production and Treatment Response in Major Depressive Disorder. Neuropsychopharmacology. 2000; 22:370-379. Leonard, BE. 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These cytokines induce the expression of Kynurenine 3-mono-oxygenase (K3MO) and Indoleamine 2,3 dioxygenase (IDO), an enzyme that metabolizes tryptophan to kynuerenine. Overactivity of IDO decreases produnction of serotonin. Tryptophan Dioxygenase (TDO) also diverts tryptophan down this pathway. TDO is induced by glucocorticoids which are also increased in the stressed state. Kynuerenine is ultimately metabolized to kynurenate and qunolinic acid. Whereas Kynurenate is a neuroprotective end-product, Quinolinic acid causes NMDA glutamate excitotoxicity. This causes neuronal apoptosis and decreased production of key neurotrophic factors. The buildup of quinolinic acid is thought to contribute to the structural changes observed in the brain of patients with chronic depression.