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Cytokine imbalance in the pathophysiology of major depressive disorder.

OBJECTIVE: A substantial body of evidence indicates that dysregulation of the immune system is associated with Major Depressive Disorder (MDD). Because most cytokines have pleiotropic effects, we measured various subsets of cytokines to examine the association between immune response and MDD. METHODS: Forty-eight hospitalized MDD patients and 63 normal controls were recruited. We measured in vitro monocytic (IL-6 and tumor necrosis factor (TNF)-alpha), Th1 (interferon (IFN)-gamma and interleukin (IL)-2), Th2 (IL-4), and Treg (transforming growth factor (TGF)-beta1) cytokine production as well as IL-2/IL-4 and IFN-gamma/IL-4 ratios for both groups. Depressive symptoms were assessed by Hamilton Depression Rating Scale. Patients were evaluated before and after 6 weeks of antidepressant treatment. RESULTS: At admission, IL-6, TNF-alpha, TGF-beta1 production, and IFN-gamma/IL-4 ratio were significantly higher, whereas IFN-gamma, IL-2, and IL-4 were significantly lower in MDD patients. After treatment, IL-6 and TGF-beta1 production were significantly lower than before treatment. CONCLUSION: We suggest that activation of monocytic proinflammatory cytokines, and inhibition of both Th1 and Th2 cytokines may be associated with immunological dysregulation in MDD. TGF-beta1 may be associated with the regulation of monocytic cytokines as well as Th1 and Th2 cytokines in MDD.

Prog Neuropsychopharmacol Biol Psychiatry. 2007 Jun 30;31(5):1044-53

Cytokines and late-life depression.

Cytokines are peripherally and centrally produced proteins that regulate immune and immunological responses. They also have neurochemical, neuroendocrine and behavioral effects similar to those seen in patients with depression. A review of the literature reveals several cytokines, including IL-1beta, IL-2, IL-6 and IFN, have been shown to be elevated in plasma of working-age adults with depression and dysthymia. A more detailed review of the literature also reveals similar associations between cytokines and late-life depression, with IL-1beta, IL-6 and TNF-alpha all being reported to be elevated in both depression and dysthymia. It has been hypothesized that cytokines provide the link between depression, neurochemical changes and the altered HPA axis that are known to occur in this disease, and evidence is presented that supports this view. However, the evidence that antidepressants may have effects on cytokines is conflicting. Increased cytokine levels may also serve as an explanation for the increased risk for vascular disease that has been associated with depression, and a possible mechanism for this is discussed.

Essent Psychopharmacol. 2006;7(1):42-52

Plasma cytokine profiles in depressed patients who fail to respond to selective serotonin reuptake inhibitor therapy.

OBJECTIVE: Approximately 30% of patients with depression fail to respond to a selective serotonin reuptake inhibitor (SSRI). Few studies have attempted to define these patients from a biological perspective. Studies suggest that overall patients with depression show increased production of proinflammatory cytokines. We examined pro- and anti-inflammatory cytokine levels in patients who were SSRI resistant. METHODS: Plasma concentrations of IL-6, IL-8, IL-10, TNF-alpha and sIL-6R were measured with enzyme linked immunosorbent assays (ELISA) in DSM-1V major depressives who were SSRI resistant, in formerly SSRI resistant patients currently euthymic and in healthy controls. RESULTS: Patients with SSRI-resistant depression had significantly higher production of the pro-inflammatory cytokines IL-6 (p=0.01) and TNF-alpha (p=0.004) compared to normal controls. Euthymic patients who were formerly SSRI resistant had proinflammatory cytokine levels which were similar to the healthy subject group. Anti-inflammatory cytokine levels did not differ across the 3 groups. CONCLUSION: Suppression of proinflammatory cytokines does not occur in depressed patients who fail to respond to SSRIs and is necessary for clinical recovery.

J Psychiatr Res. 2007 Apr-Jun;41(3-4):326-31

Antidepressant therapy and C-reactive protein levels.

BACKGROUND: Major depression is associated with activation of the inflammatory response. AIMS: To examine C-reactive protein levels in depression and to determine the impact of selective serotonin reuptake inhibitor (SSRI) therapy. METHOD: A two-part study. In study 1, which used a between-subjects design, C-reactive protein was measured in 32 patients (20 currently depressed, 12 euthymic) with a history of DSM-IV major depression, all of whom were treated with an SSRI, and in a healthy comparison group (n = 20). Study 2 employed a within-subject design: C-reactive protein was measured in 20 patients with major depression both before and after SSRI treatment. RESULTS: In study 1, C-reactive protein levels did not differ between the group with depressive disorder (either currently depressed or euthymic) treated with SSRIs and the healthy group.In study 2 the protein levels dropped significantly following treatment with antidepressant medication. CONCLUSIONS: Following SSRI treatment for major depression there is a significant drop in C-reactive protein concentrations whether or not the depression resolves. These findings indicate that antidepressants induce an anti-inflammatory response independent of antidepressant action.

Br J Psychiatry. 2006 May;188:449-52

Plasma levels of adiponectin and tumor necrosis factor-alpha in patients with remitted major depression receiving long-term maintenance antidepressant therapy.

Adiponectin, an adipose tissue-specific plasma protein, is involved in insulin sensitization and has anti-atherosclerotic properties, whereas tumor necrosis factor-alpha (TNF-alpha), a pro-inflammatory protein, plays important roles in inflammatory endothelial injury and atherosclerotic changes. It has been reported that adiponectin and TNF-alpha inhibit each other’s expression and production in adipocytes. Several in vitro studies indicated that antidepressant medications decreased the production of pro-inflammatory cytokines including TNF-alpha, but the effect of antidepressants on the expression of adiponectin is still unknown. We examined the plasma levels of TNF-alpha and adiponectin in patients with remitted depression receiving maintenance antidepressant therapy for longer than half a year, and compared the levels with those in healthy controls. The plasma levels of TNF-alpha and adiponectin in the remitted depression group were significantly lower and higher than those in the control group, respectively. This preliminary cross-sectional study suggests the possibility that maintenance antidepressant therapy may have anti-inflammatory effects and prevent the development of atherosclerosis.

Prog Neuropsychopharmacol Biol Psychiatry. 2006 Aug 30;30(6):1159-62

Evidence for low-grade systemic proinflammatory activity in patients with posttraumatic stress disorder.

Posttraumatic stress disorder (PTSD) may increase cardiovascular risk but the psychophysiological mechanisms involved are elusive. We hypothesized that proinflammatory activity is elevated in patients with PTSD as diagnosed by the Clinician Administered PTSD Scale (CAPS) interview. Plasma levels of proinflammatory C-reactive protein (CRP), interleukin (IL)-1beta, IL-6, and tumor necrosis factor (TNF)-alpha, and of anti-inflammatory IL-4 and IL-10 were measured in 14 otherwise healthy PTSD patients and in 14 age- and gender-matched healthy non-PTSD controls. Levels of TNF-alpha (p=0.038; effect size Cohen’s d=0.58) and of IL-1beta (p=0.075, d=0.68) were higher in patients than in controls. CRP (d=0.10), IL-6 (d=0.18), IL-4 (d=0.42), and IL-10 (d=0.37) were not significantly different between groups. Controlling for traditional cardiovascular risk factors, mood, and time since trauma revealed lower IL-4 in patients than in controls (p=0.029) and rendered group differences in TNF-alpha and IL-1beta insignificant. In all subjects, TNF-alpha correlated with total (frequency and intensity) PTSD symptom cluster of re-experiencing (r=0.49, p=0.008), avoidance (r=0.37, p=0.050), and hyperarousal (r=0.42, p=0.026), and with PTSD total symptom score (r=0.37, p=0.054). Controlling for time since trauma attenuated these associations. The correlation between IL-1beta and total avoidance symptoms (r=0.42, p=0.028) became insignificant when controlling for anxiety and depression. IL-4 correlated with total hyperarousal symptoms (r=-0.38, p=0.047), and after controlling for systolic blood pressure and smoking status, with PTSD total symptom score (r=-0.41, p=0.035). PTSD patients showed a low-grade systemic proinflammatory state, which, moreover, was related to PTSD symptom levels suggesting one mechanism by which PTSD could contribute to atherosclerotic disease.

J Psychiatr Res. 2007 Nov;41(9):744-52

Specific brain regions of female rats are differentially depleted of docosahexaenoic acid by reproductive activity and an (n-3) fatty acid-deficient diet.

Low tissue levels of (n-3) PUFA, particularly docosahexaenoic acid [DHA, 22:6(n-3)], are implicated in postpartum depression. Brain DHA content is depleted in female rats undergoing pregnancy and lactation when the diet supplies inadequate (n-3) PUFA. In this study, the effects of DHA depletion as a result of reproductive activity and an (n-3) PUFA-deficient diet were examined in 8 specific brain regions of female rats after undergoing 2 sequential reproductive cycles. Virgin females, fed the alpha-linolenic acid (ALA)-containing or deficient (low-ALA) diets for a commensurate duration (13 wk) served as a control for reproduction. Total phospholipid composition of each brain region was determined at weaning (postnatal d 21) by TLC/GC. The regional PUFA composition of ALA virgins was similar to that previously measured in male rats. All brain regions examined were affected by reproductive activity and/or the low-ALA diet; however, the magnitude of the loss of DHA and compensatory incorporation of docosapentaenoic acid [(n-6) DPA, 22:5(n-6)] varied among brain regions. In low-ALA parous dams, frontal cortex (77% of ALA virgin) and temporal lobe (83% of ALA virgin), regions involved in cognition and affect, were among those exhibiting the greatest depletion of DHA. Caudate-putamen also exhibited significant depletion of DHA (82% of ALA virgin), whereas only (n-6) DPA levels were altered in ventral striatum, hypothalamus, hippocampus, and cerebellum. This pattern of changes in regional DHA and (n-6) DPA content suggests that specific neuronal systems may be differentially affected by depletion of brain DHA in the postpartum organism.

J Nutr. 2007 Jan;137(1):130-4

Omega-3 polyunsaturated essential fatty acid status as a predictor of future suicide risk.

OBJECTIVE: Low levels of docosahexaenoic acid, a polyunsaturated fatty acid, and elevated ratios of omega-6/omega-3 fatty acids are associated with major depression and, possibly, suicidal behavior. Predicting risk of future suicidal behaviors by essential fatty acid status merits examination. METHOD: Plasma polyunsaturated fatty acid levels in phospholipids were measured in 33 medication-free depressed subjects monitored for suicide attempt over a 2-year period. Survival analysis examined the association of plasma polyunsaturated fatty acid status and pathological outcome. RESULTS: Seven subjects attempted suicide on follow-up. A lower docosahexaenoic acid percentage of total plasma polyunsaturated fatty acids and a higher omega-6/omega-3 ratio predicted suicide attempt. CONCLUSIONS: A low docosahexaenoic acid percentage and low omega-3 proportions of lipid profile predicted risk of suicidal behavior among depressed patients over the 2-year period. If confirmed, this finding would have implications for the neurobiology of suicide and reduction of suicide risk.

Am J Psychiatry. 2006 Jun;163(6):1100-2