***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: Objectives The safety and efficacy of sirukumab , an anti-interleukin-6 ( IL-6 ) monoclonal antibody , were evaluated in a 2-part , placebo-controlled phase II study of patients with active rheumatoid arthritis ( RA ) despite methotrexate therapy . Methods In Part A ( proof-of-concept ) , 36 patients were r and omised to placebo or sirukumab 100 mg every 2 weeks ( q2w ) through week 10 , with crossover treatment during weeks 12–22 . In Part B ( dose finding ) , 151 patients were r and omised to sirukumab ( 100 mg q2w , 100 mg q4w , 50 mg q4w , or 25 mg q4w ) through week 24 , or placebo through week 10 with crossover to sirukumab 100 mg q2w ( weeks 12–24 ) . The proportion of patients with an American College of Rheumatology 50 ( ACR50 ) response and the change from baseline in the 28-joint count disease activity score using C-reactive protein ( DAS28-CRP ) were determined . Safety was evaluated through week 38 in both parts . Results The primary endpoint ( ACR50 at week 12 in Part B ) was achieved only with sirukumab 100 mg q2w versus placebo ( 26.7 % vs 3.3 % ; p=0.026 ) . Greater improvements in mean DAS28-CRP at week 12 were observed with sirukumab 100 mg q2w versus placebo in Parts A ( 2.1 vs 0.6 , p<0.001 ) and B ( 2.2 vs 1.1 ; p<0.001 ) . The incidence of adverse events ( AEs ) was similar for sirukumab-treated and placebo-treated patients through week 12 in Part A ( 70.6 % and 63.2 % , respectively ) and B ( 67.8 % and 66.7 % , respectively ) . Infections were the most common type of AE ; one death occurred ( Part B , sirukumab 100 mg q2w , brain aneurysm ) . Conclusions Sirukumab-treated patients experienced improvements in the signs/symptoms of RA . Safety results through 38 weeks were consistent with other IL-6 inhibitors . Trial registration number NCT00718718 CONTEXT Increased concentrations of inflammatory biomarkers predict antidepressant nonresponse , and inflammatory cytokines can sabotage and circumvent the mechanisms of action of conventional antidepressants . OBJECTIVES To determine whether inhibition of the inflammatory cytokine tumor necrosis factor ( TNF ) reduces depressive symptoms in patients with treatment-resistant depression and whether an increase in baseline plasma inflammatory biomarkers , including high-sensitivity C-reactive protein ( hs-CRP ) , TNF , and its soluble receptors , predicts treatment response . DESIGN Double-blind , placebo-controlled , r and omized clinical trial . SETTING Outpatient infusion center at Emory University in Atlanta , Georgia . PARTICIPANTS A total of 60 medically stable out patients with major depression who were either on a consistent antidepressant regimen ( n = 37 ) or medication-free ( n = 23 ) for 4 weeks or more and who were moderately resistant to treatment as determined by the Massachusetts General Hospital Staging method . INTERVENTIONS Three infusions of the TNF antagonist infliximab ( 5 mg/kg ) ( n = 30 ) or placebo ( n = 30 ) at baseline and weeks 2 and 6 of a 12-week trial . MAIN OUTCOME MEASURES The 17-item Hamilton Scale for Depression ( HAM-D ) scores . RESULTS No overall difference in change of HAM-D scores between treatment groups across time was found . However , there was a significant interaction between treatment , time , and log baseline hs-CRP concentration ( P = .01 ) , with change in HAM-D scores ( baseline to week 12 ) favoring infliximab-treated patients at a baseline hs-CRP concentration greater than 5 mg/L and favoring placebo-treated patients at a baseline hs-CRP concentration of 5 mg/L or less . Exploratory analyses focusing on patients with a baseline hs-CRP concentration greater than 5 mg/L revealed a treatment response ( ≥50 % reduction in HAM-D score at any point during treatment ) of 62 % ( 8 of 13 patients ) in infliximab-treated patients vs 33 % ( 3 of 9 patients ) in placebo-treated patients ( P = .19 ) . Baseline concentrations of TNF and its soluble receptors were significantly higher in infliximab-treated responders vs nonresponders ( P < .05 ) , and infliximab-treated responders exhibited significantly greater decreases in hs-CRP from baseline to week 12 compared with placebo-treated responders ( P < .01 ) . Dropouts and adverse events were limited and did not differ between groups . CONCLUSIONS This proof-of-concept study suggests that TNF antagonism does not have generalized efficacy in treatment-resistant depression but may improve depressive symptoms in patients with high baseline inflammatory biomarkers . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00463580 Rationale Premature discontinuation of antidepressant drugs is a frequent clinical problem . Adverse effects are common , occur early on in treatment and are reported to be one of the main reasons for discontinuation of antidepressant treatment . Objectives To investigate the association between adverse effects occurring in the first 2 weeks of antidepressant treatment and discontinuation by 6 weeks as the outcome . To investigate the time profile of adverse effects induced by the selective serotonin reuptake inhibitor citalopram and the noradrenaline reuptake inhibitor reboxetine over 12 weeks of treatment . Methods Six hundred and one depressed individuals were r and omly allocated to either citalopram ( 20 mg daily ) or reboxetine ( 4 mg twice daily ) . A modified version of the Toronto Side Effects Scale was used to measure 14 physical symptoms at baseline ( medication free ) and at 2 , 6 and 12 weeks after r and omisation . Results Individuals r and omised to reboxetine reported a greater number of adverse effects and were more likely to stop treatment than individuals receiving citalopram . Dizziness ( OR 1.83 ; 95 % CI 1.09 , 3.09 ; p = 0.02 ) and the total number of adverse effects ( OR 1.12 ; 95 % CI 1.00 , 1.25 ; p = 0.06 ) reported at 2 weeks were associated with discontinuation from overall antidepressant treatment by 6 weeks . Reports of adverse effects tended to reduce throughout the 12 weeks for both antidepressants . Conclusions The majority of adverse effects were not individually associated with discontinuation from antidepressant treatment . Reports of physical symptoms tended to reduce over time . The physical symptoms that did not reduce over time may represent symptoms of depression rather than antidepressant-induced adverse effects 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 OBJECTIVE Sirukumab ( CNTO 136 ) is a human mAb with high affinity and specificity for binding to interleukin-6 . This Phase 1 study evaluated the pharmacokinetics , immunogenicity , safety , and tolerability of sirukumab following a single subcutaneous ( s.c . ) administration in healthy male Japanese and Caucasian subjects . METHODS Japanese and Caucasian subjects were r and omized to placebo or 25 , 50 , or 100 mg sirukumab . Blood sample s were collected to measure serum sirukumab concentration and antibodies to sirukumab . Noncompartmental analysis and population pharmacokinetic modeling were conducted to characterize sirukumab pharmacokinetics . Adverse events were monitored at each visit . RESULTS 25 Japanese and 24 Caucasian subjects received sirukumab and were included in the pharmacokinetic evaluation . Mean Cmax and AUC0-∞of sirukumab increased in an approximately dose-proportional manner in both Japanese and Caucasian subjects . Median tmax was 3 -5 days after s.c . administration of sirukumab . Mean t1/2 was 15 -16 days in Japanese and 15 -18 days in Caucasian subjects . A one-compartment population pharmacokinetic model adequately described sirukumab pharmacokinetics following s.c . administration . The estimated population means for CL/F , V/F , and Ka were 0.54 ±0.03 l/day , 12.2 ±0.55 l , and 0.77 ±0.07 day-1 , respectively . Race was not a significant covariate on CL/F or V/F. No subject was positive for antibodies to sirukumab . Adverse events were generally mild and did not appear to be dose-related or lead to study discontinuation . CONCLUSIONS Sirukumab pharmacokinetics following subcutaneous administration was linear at doses ranging 25 -100 mg and was comparable between Japanese and Caucasian subjects . A single subcutaneous administration of 25 , 50 , or 100 mg sirukumab appeared to be well tolerated by both Japanese and Caucasian healthy male subjects In a controlled study , such immunological parameters as whole blood production of the cytokines interleukin-6 ( IL-6 ) and tumor-necrosis factor-α ( TNF-α ) were assessed in 24 in patients with a major depressive disorder ( MDD ) both before and again under treatment . After a 6-week treatment period with amitriptyline , patients were classified as responders or nonresponders according to their psychopathological outcome as evaluated by the Hamilton and the Montgomery – Asberg Depression Rating Scales . Pre-treatment levels of c-reactive protein ( CRP ) were significantly higher in both patient subgroups than in the control subjects . In comparison to the controls , unstimulated pretreatment production of IL-6 was significantly decreased in the responders ; whereas it was significantly increased in the nonresponder subgroup . Post-treatment values did not differ significantly among the patient and control groups . Pretreatment levels of TNF-α were increased in both patient subgroups , with a significant decrease during treatment only in the responder subgroup . Pretreatment levels of IL-6/105 mononuclear cells and the ratio between lymphocytes and monocytes acted as independent variables with regard to the clinical response . Our data indicate that unstimulated secretion of TNF-α is related to the psychopathological improvement ; whereas , IL-6 levels might dichotomize the patients into subsequent responders and nonresponders already at admission OBJECTIVE We undertook a 2-part , phase I , double-blind , placebo-controlled study to evaluate the safety and pharmacokinetics of multiple intravenous infusions of sirukumab , a human anti-interleukin-6 monoclonal antibody , in patients with cutaneous lupus erythematosus ( CLE ) or systemic lupus erythematosus ( SLE ) . METHODS In part A , patients with histologically confirmed CLE were r and omized to 4 infusions of placebo or 1 , 4 , or 10 mg/kg sirukumab every 2 weeks . In part B , SLE patients diagnosed according to American College of Rheumatology criteria with a score of 5 - 12 on the Safety of Estrogens in Lupus Erythematosus National Assessment version of the SLE Disease Activity Index were r and omized to 4 infusions of placebo or 10 mg/kg sirukumab every 2 weeks . RESULTS We 
    Output:
    
Overall , sirukumab has been reported to be a safe and well-tolerated agent , capable of modulating the immune response in healthy population s as well as in subjects with inflammatory disorders ( e.g. , rheumatoid arthritis ) .
Amongst individuals with complex brain-based disorders ( e.g. , mood disorders ) , the dimensions/domains most likely to benefit with sirukumab are negative valence disturbances ( e.g. , anxiety , depression , rumination ) , positive valence disturbances ( e.g. , anhedonia ) as well as general cognitive processes .
We suggest that sirukumab represents a prototype and possibly a proof-of-concept that agents that engage IL-6 targets have salutary effects in psychiatry