Add-on Treatment with Curcumin Has Antidepressive Effects in Thai Patients with Major Depression: Results of a Randomized Double-Blind Placebo-Controlled Study

Many studies have explored the association between soluble interleukin-2 receptor (sIL-2R), cytokines and major depressive disorder (MDD). However, the results of these studies were not consistent. The aim of our study is to compare the levels of sIL-2R and cytokines in the blood between MDD patients and controls by a meta-analysis and to identify moderators accounting for potential heterogeneity in the levels of sIL-2R and cytokines in MDD patients versus controls by meta-regression analyses. A comprehensive literature search was performed to identify studies comparing the levels of sIL-2R and cytokines between MDD patients and controls. We pooled the effect sizes for standardized mean differences (SMD) of the levels of sIL-2R and cytokines. We also performed meta-regression and sensitivity analyses to investigate the roles of age, gender, sample type, ethnic origin and selected studies' quality in explaining potential heterogeneity and differences in results respectively. Twenty-nine studies were selected for this analysis. The levels of sIL-2R, TNF-α and IL-6 in MDD patients were significantly higher than those of healthy controls (SMD=0.555, p<0.001, SMD=0.567, p=0.010; SMD=0.680, p<0.001). Mean age of all subjects was a significant moderator to explain the high heterogeneity of IL-6. Sensitivity analysis found that European but not non-European subjects have higher levels difference of sIL-2R, TNF-α and IL-1β between MDD patients and controls. The severity of MDD was not considered. The blood levels of sIL-2R, TNF-α and IL-6 were significantly higher in MDD patients than controls. Age, samples source and ethnic origins may play a potential role in heterogeneity. Copyright © 2011 Elsevier B.V. All rights reserved.

Several studies have reported antidepressant effects of anti-inflammatory treatment; however, the results have been conflicting and detrimental adverse effects may contraindicate the use of anti-inflammatory agents. To systematically review the antidepressant and possible adverse effects of anti-inflammatory interventions. Trials published prior to December, 31, 2013, were identified searching Cochrane Central Register of Controlled Trials, PubMed, EMBASE, PsychINFO, Clinicaltrials.gov, and relevant review articles. Randomized placebo-controlled trials assessing the efficacy and adverse effects of pharmacologic anti-inflammatory treatment in adults with depressive symptoms, including those who fulfilled the criteria for depression. Data were extracted by 2 independent reviewers. Pooled standard mean difference (SMD) and odds ratios (ORs) were calculated. Depression scores after treatment and adverse effects. Ten publications reporting on 14 trials (6262 participants) were included: 10 trials evaluated the use of nonsteroidal anti-inflammatory drugs (NSAIDs) (n=4,258) and 4 investigated cytokine inhibitors (n=2,004). The pooled effect estimate suggested that anti-inflammatory treatment reduced depressive symptoms (SMD, -0.34; 95% CI, -0.57 to -0.11; I2=90%) compared with placebo. This effect was observed in studies including patients with depression (SMD, -0.54; 95% CI, -1.08 to -0.01; I2=68%) and depressive symptoms (SMD, -0.27; 95% CI, -0.53 to -0.01; I2=68%). The heterogeneity of the studies was not explained by differences in inclusion of clinical depression vs depressive symptoms or use of NSAIDs vs cytokine inhibitors. Subanalyses emphasized the antidepressant properties of the selective cyclooxygenase 2 inhibitor celecoxib (SMD, -0.29; 95% CI, -0.49 to -0.08; I2=73%) on remission (OR, 7.89; 95% CI, 2.94 to 21.17; I2=0%) and response (OR, 6.59; 95% CI, 2.24 to 19.42; I2=0%). Among the 6 studies reporting on adverse effects, we found no evidence of an increased number of gastrointestinal or cardiovascular events after 6 weeks or infections after 12 weeks of anti-inflammatory treatment compared with placebo. All trials were associated with a high risk of bias owing to potentially compromised internal validity. Our analysis suggests that anti-inflammatory treatment, in particular celecoxib, decreases depressive symptoms without increased risks of adverse effects. However, a high risk of bias and high heterogeneity made the mean estimate uncertain. This study supports a proof-of-concept concerning the use of anti-inflammatory treatment in depression. Identification of subgroups that could benefit from such treatment might be warranted.

This paper reviews the body of evidence that not only tryptophan and consequent 5-HT depletion, but also induction of indoleamine 2,3-dioxygenase (IDO) and the detrimental effects of tryptophan catabolites (TRYCATs) play a role in the pathophysiology of depression. IDO is induced by interferon (IFN)γ, interleukin-6 and tumor necrosis factor-α, lipopolysaccharides and oxidative stress, factors that play a role in the pathophysiology of depression. TRYCATs, like kynurenine and quinolinic acid, are depressogenic and anxiogenic; activate oxidative pathways; cause mitochondrial dysfunctions; and have neuroexcitatory and neurotoxic effects that may lead to neurodegeneration. The TRYCAT pathway is also activated following induction of tryptophan 2,3-dioxygenase (TDO) by glucocorticoids, which are elevated in depression. There is evidence that activation of IDO reduces plasma tryptophan and increases TRYCAT synthesis in depressive states and that TDO activation may play a role as well. The development of depressive symptoms during IFNα-based immunotherapy is strongly associated with IDO activation, increased production of detrimental TRYCATs and lowered levels of tryptophan. Women show greater IDO activation and TRYCAT production following immune challenge than men. In the early puerperium, IDO activation and TRYCAT production are associated with the development of affective symptoms. Clinical depression is accompanied by lowered levels of neuroprotective TRYCATs or increased levels or neurotoxic TRYCATs, and lowered plasma tryptophan, which is associated with indices of immune activation and glucocorticoid hypersecretion. Lowered tryptophan and increased TRYCATs induce T cell unresponsiveness and therefore may exert a negative feedback on the primary inflammatory response in depression. It is concluded that activation of the TRYCAT pathway by IDO and TDO may be associated with the development of depressive symptoms through tryptophan depletion and the detrimental effects of TRYCATs. Therefore, the TRYCAT pathway should be a new drug target in depression. Direct inhibitors of IDO are less likely to be useful drugs than agents, such as kynurenine hydroxylase inhibitors; drugs which block the primary immune response; compounds that increase the protective effects of kynurenic acid; and specific antioxidants that target IDO activation, the immune and oxidative pathways, and 5-HT as well. Copyright © 2010 Elsevier Inc. All rights reserved.