***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: OBJECTIVE This study aim ed to explore effects of adjunctive N-acetylcysteine ( NAC ) treatment on inflammatory and neurogenesis markers in unipolar depression . METHODS We embarked on a 12-week clinical trial of NAC ( 2000 mg/day compared with placebo ) as an adjunctive treatment for unipolar depression . A follow-up visit was conducted 4 weeks following the completion of treatment . We collected serum sample s at baseline and the end of the treatment phase ( week 12 ) to determine changes in interleukin-6 ( IL6 ) , C-reactive protein ( CRP ) and brain-derived neurotrophic factor ( BDNF ) following NAC treatment . RESULTS NAC treatment significantly improved depressive symptoms on the Montgomery-Asberg Depression Rating Scale ( MADRS ) over 16 weeks of the trial . Serum levels of IL6 were associated with reductions of MADRS scores independent of treatment response . However , we found no significant changes in IL6 , CRP and BDNF levels following NAC treatment . CONCLUSION Overall , this suggests that our results failed to support the hypothesis that IL6 , CRP and BDNF are directly involved in the therapeutic mechanism of NAC in depression . IL6 may be a useful marker for future exploration of treatment response Given evidence of chronic inflammation in bipolar disorder ( BD ) , we tested the efficacy of aspirin and minocycline as augmentation therapy for bipolar depression . Ninety-nine depressed out patients with BD were enrolled in a 6 week , double-blind , placebo-controlled trial , and r and omized to one of four groups : active minocycline ( 100 mg b.i.d . ) + active aspirin ( 81 mg b.i.d . ) ( M + A ) ; active minocycline + placebo aspirin ( M + P ) ; placebo-minocycline + active aspirin ( A + P ) ; and placebo-minocycline + placebo aspirin ( P + P ) . A blinded interim analysis mid-way through the study led to the dropping of the M + P and A + P arms from further enrollment giving numbers per group who were included in the final analysis of : 30 ( M + A ) , 18 ( M + P ) , 19 ( A + P ) , and 28 ( P + P ) . When the study started , there were three primary outcome measures . Based on the results of the interim analysis , the primary outcome variable , response to treatment as defined by > 50 % decrease in Montgomery – Äsberg Depression Rating Scale ( MADRS ) score was maintained . The other two ( i.e. , the change in mean MADRS score from baseline to end of study and the remission rate , with remission being defined as a score of < 11 on the MADRS ) were reduced to exploratory outcome measures because the interim analysis indicated that the study was adequately powered to test differences in response rate but not the mean change in MADRS scores or remission rates . CRP and IL-6 were assayed to measure inflammation . Urinary thromboxane B2 ( 11-D-TXB2 ) concentrations , which were significantly increased at baseline in the combined BD sample ( n = 90 ) vs. a healthy control group ( n = 27 ) , served as an indirect marker of cyclooxygenase ( COX ) activity . In a two-group analysis , the M + A group showed a greater response rate than the P + P group ( p(one-tailed ) = 0.034 , OR = 2.93 , NNT = 4.7 ) . When all four arms were included in the analysis , there was a main effect of aspirin on treatment response that was driven by both the M + A and the A + P groups ( p(two-tailed ) = 0.019 , OR = 3.67 , NNT = 4.0 ) . Additionally , there was a significant 3-way interaction between aspirin , minocycline , and IL-6 , indicating that response to minocycline was significantly greater in participants in the M + P group with higher IL-6 concentrations . Further , participants in the M + P group who responded to treatment had significantly greater decreases in IL-6 levels between baseline and visit 7 vs. non-responders . Regarding the exploratory outcomes , there was a main effect for aspirin on the remission rate ( χ12 = 4.14 , p(2 t ) = 0.04 , OR = 2.52 , NNT = 8.0 ) . There was no significant main effect of aspirin or minocycline on the mean change in MADRS score across  visits . Aspirin and minocycline may be efficacious adjunctive treatments for bipolar depression . Given their potential import , additional studies to confirm and extend these findings are warranted Background : Evidence suggests that anti-inflammatory medication may be effective in the treatment of depressive symptoms . In this study , we aim ed to investigate whether minocycline added to treatment as usual ( TAU ) for 3 months in patients with treatment-resistant depression will lead to an improvement in depressive symptoms . Methods : Multi-site , 12-week , double-blind , placebo-controlled , pilot trial of minocycline added to TAU for patients suffering from DSM-5 major depressive disorder , whose current episode has failed to respond to at least two antidepressants . The primary outcome measure was mean change in Hamilton Depression Rating Scale ( HAMD-17 ) scores from baseline to week 12 . Secondary measures were the Clinical Global Impression scale ( CGI ) , Patient Health Question naire-9 ( PHQ-9 ) , the Generalised Anxiety Disorder scale ( GAD-7 ) and EuroQoL ( EQ-5D ) quality -of-life question naire . Side-effect checklists were also used . Minocycline was started at 100 mg once daily ( OD ) and increased to 200 mg after 2 weeks . Results : A total of 41 participants were r and omised , with 21 in the minocycline group and 20 in the placebo group . A large decrease in HAMD scores was observed in the minocycline group compared to the placebo group ( st and ardised effect size ( ES ) –1.21 , p < 0.001 ) . CGI scores in the minocycline group also showed a large improvement compared with placebo ( odds ratio ( OR ) : 17.6 , p < 0.001 ) . PHQ-9 , GAD-7 and EQ-5D total showed more moderate improvements ( ES ~ 0.4–0.5 ) . Conclusion : The findings indicate that adjunctive minocycline leads to improvement in symptoms of treatment-resistant depression . However , our findings require replication in a larger sample . Trial Registration : Clinical Trials.gov identifier : NCT02263872 , registered October 2014 There is increasing evidence that both immune and neurochemical alterations are involved in the pathogenesis of bipolar disorder ; however , their precise role remains unclear . In this study , we aim ed to evaluate  neuro‐immune changes  in a prospect i ve study on children of patients with bipolar disorder Major depressive disorder ( MDD ) in general , and anxious-depression in particular , are characterized by poor rates of remission with first-line treatments , contributing to the chronic illness burden suffered by many patients . Prospect i ve research is needed to identify the biomarkers predicting nonremission prior to treatment initiation . We collected blood sample s from a discovery cohort of 34 adult MDD patients with co-occurring anxiety and 33 matched , nondepressed controls at baseline and after 12 weeks ( of citalopram plus psychotherapy treatment for the depressed cohort ) . Sample s were processed on gene arrays and group differences in gene expression were investigated . Exploratory analyses suggest that at pretreatment baseline , nonremitting patients differ from controls with gene function and transcription factor analyses potentially related to elevated inflammation and immune activation . In a second phase , we applied an unbiased machine learning prediction model and corrected for model- selection bias . Results show that baseline gene expression predicted nonremission with 79.4 % corrected accuracy with a 13-gene model . The same gene-only model predicted nonremission after 8 weeks of citalopram treatment with 76 % corrected accuracy in an independent validation cohort of 63 MDD patients treated with citalopram at another institution . Together , these results demonstrate the potential , but also the limitations , of baseline peripheral blood-based gene expression to predict nonremission after citalopram treatment . These results not only support their use in future prediction tools but also suggest that increased accuracy may be obtained with the inclusion of additional predictors ( eg , genetics and clinical scales ) OBJECTIVE Major depressive disorder has been linked with inflammatory processes , but it is unclear whether individual differences in levels of inflammatory biomarkers could help match patients to treatments that are most likely to be beneficial . The authors tested the hypothesis that C-reactive protein ( CRP ) , a commonly available marker of systemic inflammation , predicts differential response to escitalopram ( a serotonin reuptake inhibitor ) and nortriptyline ( a norepinephrine reuptake inhibitor ) . METHOD The hypothesis was tested in the Genome-Based Therapeutic Drugs for Depression ( GENDEP ) study , a multicenter open-label r and omized clinical trial . CRP was measured with a high-sensitivity method in serum sample s from 241 adult men and women with major depressive disorder r and omly allocated to 12-week treatment with escitalopram ( N=115 ) or nortriptyline ( N=126 ) . The primary outcome measure was the score on the Montgomery-Åsberg Depression Rating Scale ( MADRS ) , administered weekly . RESULTS CRP level at baseline differentially predicted treatment outcome with the two antidepressants ( CRP-drug interaction : β=3.27 , 95 % CI=1.65 , 4.89 ) . For patients with low levels of CRP ( < 1 mg/L ) , improvement on the MADRS score was 3 points higher with escitalopram than with nortriptyline . For patients with  higher CRP levels , improvement on the MADRS score was 3 points higher with nortriptyline than with escitalopram . CRP and its interaction with medication explained more than 10 % of individual-level variance in treatment outcome . CONCLUSIONS An easily accessible peripheral blood biomarker may contribute to improvement in outcomes of major depressive disorder by personalizing treatment choice Although stress-induced increases in inflammation have been implicated in several major disorders , including cardiovascular disease and depression , the neurocognitive pathways that underlie inflammatory responses to stress remain largely unknown . To examine these processes , we recruited 124 healthy young adult participants to complete a laboratory-based social stressor while markers of inflammatory activity were obtained from oral fluids . A subset of participants ( n = 31 ) later completed an fMRI session in which their neural responses to social rejection were assessed . As predicted , exposure to the laboratory-based social stressor was associated with significant increases in two markers of inflammatory activity , namely a soluble receptor for tumor necrosis factor-α ( sTNFαRII ) and interleukin-6 ( IL-6 ) . In the neuroimaging sub sample , greater increases in sTNFαRII ( but not IL-6 ) were associated with greater activity in the dorsal anterior cingulate cortex and anterior insula , brain regions that have previously been associated with processing rejection-related distress and negative affect . These data thus eluci date a neurocognitive pathway that may be involved in potentiated inflammatory responses to acute social stress . As such , they have implication s for underst and ing how social stressors may promote susceptibility to diseases with an inflammatory component OBJECTIVE To compare the efficacy of plasma level-targeted dose imipramine and high-dose venlafaxine in depressed in patients in a r and omized double-blind study . METHODS The study included 85 patients with a diagnosis of major depressive episode according to the DSM IV criteria and a 17-item Hamilton Rating Scale for Depression ( HAM-D ) score ≥ 17 . Patients were r and omized to imipramine or venlafaxine .  The dose of imipramine was adjusted for each patient to a predefined blood level of 200 - 300 ng/ml . The dose of venlafaxine was increased gradually to 300 - 375 mg/day . Efficacy was evaluated after 7 weeks of treatment . RESULTS The mean age of the study group was 54.5 ( range 29 - 82 ) years . There was no significant difference according to the primary outcome criterion of a ≥50 % reduction on the HAM-D score : 17 of 43 ( 39.5 % ) patients on imipramine were responders compared to 21 of 42 ( 50 % ) patients on venlafaxine . When considering remission as outcome criterion ( HAM-D score ≤ 7 ) , 10 of 43 ( 23.3 % ) patients on imipramine  were remitters compared to 15 of 42 ( 35.7 % ) patients on venlafaxine ; again , no significant difference . When analysing a sub population of patients without psychotic features , with remission as outcome criterion , a significant difference was found : 5 of 34 ( 14.7 % ) patients on imipramine were remitters compared to 12 of 31 ( 38.7 % ) patients on venlafaxine . CONCLUSIONS The present study used optimal doses in depressed in patients and showed that venlafaxine is at least equal in efficacy to imipramine . The results in the subgroup without psychotic features indicate a possible superiority of venlafaxine Background Research ers turn to citation tracking to find the most influential articles for a particular topic 
    Output:
    
Results : Collectively , the literature and original data showed that : 1 ) raised serum levels of pro-inflammatory compounds ( in particular of CRP/IL-6 ) characterize an inflammatory form of MDD with poor responsiveness to predominately serotonergic agents , but a better responsiveness to antidepressant regimens with a ) ( add-on ) noradrenergic , dopaminergic , or glutamatergic action or b ) ( add-on ) anti-inflammatory agents such as infliximab , minocycline , or eicosapentaenoic acid , showing — next to anti-inflammatory — dopaminergic or lipid corrective action ; 2 ) these successful anti-inflammatory ( add-on ) agents , when used in patients with low serum levels of CRP/IL-6 , decreased response rates in comparison to placebo .
Add-on aspirin , in contrast , improved responsiveness in such “ non-inflammatory ” patients ; 3 ) patients with increased inflammatory gene expression in circulating leukocytes had a poor responsiveness to serotonergic/noradrenergic agents .
However , at present , insufficient data exist to design protocol s with reliable inflammation parameter cutoff points to guide such therapies , the more since detrimental outcomes are possible of anti-inflammatory agents in “ non-inflamed ” patients