A Randomized Controlled Trial of the Tumor Necrosis Factor Antagonist Infliximab for Treatment-Resistant Depression

Inhibition of tumor necrosis factor improves sleep continuity in patients with treatment resistant depression and high inflammation.

Transcriptional signatures related to glucose and lipid metabolism predict treatment response to the tumor necrosis factor antagonist infliximab in patients with treatment-resistant depression.

176. The tumor necrosis factor-alpha antagonist infliximab reduces depressive symptoms in patients with treatment resistant depression and high inflammation

New mood stabilizers are needed that possess efficacy for all phases of bipolar disorder. This study was designed to provide preliminary evidence for the safety and efficacy of a new anticonvulsant, lamotrigine, in adult patients with bipolar disorder who had been inadequately responsive to or intolerant of prior pharmacotherapy. A 48-week, open-label, prospective trial was conducted in 75 patients with bipolar I or bipolar II disorder. Lamotrigine was used as adjunctive therapy (N = 60) or monotherapy (N = 15) in patients presenting in depressed, hypomanic, manic, or mixed states. Of the 40 depressed patients included in the efficacy analysis, 48% exhibited a marked response and 20% a moderate response as measured by reductions in 17-item Hamilton Depression Rating Scale scores. Of the 31 with a hypomanic, manic, or mixed state, 81% displayed a marked response and 3% a moderate response on the Mania Rating Scale. From baseline to endpoint, the depressed patients exhibited a 42% decrease in Hamilton depression scale scores, and the patients presenting with hypomania, mania, or a mixed state exhibited a 74% decrease in Mania Rating Scale scores. The most common drug-related adverse events were dizziness, tremor, somnolence, headache, nausea, and rash. Rash was the most common adverse event resulting in drug discontinuation (9% of patients); one patient developed a serious rash and required hospitalization. These open-label data provide preliminary evidence that lamotrigine may be an effective treatment option for patients with refractory bipolar disorder; however, potential benefits must be weighed against potential side effects, including rash.

Patients undergoing chronic dialysis often display sustained elevations of inflammation markers and also have a high prevalence of depressive symptoms. Although multiple studies demonstrated cross-sectional associations between inflammation markers and depressive symptoms in this patient group, longitudinal associations have not been examined. We therefore investigated whether longitudinal associations exist between inflammation markers and depressive symptoms in chronic dialysis patients. Data of three consecutive measurements of an observational, prospective cohort study among chronic dialysis patients were used. At baseline, 6-month, and 12-month follow-up, patients completed the Beck Depression Inventory, and inflammation markers (high-sensitivity C-reactive protein [HsCRP], interleukin (IL)-1β, IL-6, IL-10, and tumor necrosis factor α) were measured. We examined cross-sectional associations between inflammation markers and depressive symptoms using linear regression models. The longitudinal association between inflammation and depressive symptoms was assessed using a linear mixed model analyses. A total of 513 patients were included. Cross-sectional associations were found between HsCRP and depressive symptoms at baseline (β = 0.9, confidence interval [CI] = 0.4-1.4) and 6-month follow-up (β = 1.1, CI = 0.3-2.0), and between IL-1β and depressive symptoms at 6-month follow-up (β = 1.3, CI = 0.8-1.8) and 12-month follow-up (β = 1.2, CI = 0.4-1.9). Inflammation makers (HsCRP, IL-6, IL-1β, IL-10, and tumor necrosis factor α) at baseline were not associated with depressive symptoms at follow-up and vice versa. We confirmed the presence of cross-sectional associations between inflammation markers and depressive symptoms in chronic dialysis patients, but with our longitudinal data, we found no longitudinal associations. This supports an associative instead of a causal relationship between inflammation and depressive symptoms.

Event Abstract Back to Event C-REACTIVE PROTEIN EFFECTS IN PATIENTS WITH BIPOLAR DEPRESSION TREATED WITH LURASIDONE: AN EXPLORATORY ANALYSIS OF A PLACEBO-CONTROLLED TRIAL Charles L. Raison1, Andrei Pikalov2*, Cynthia Siu3, Joyce Tsai2, Kenneth Koblan2 and Antony Loebel2 1 University of Wisconsin System, United States 2 Sunovion (United States), United States 3 COS and Associates Ltd. (Hong Kong), Hong Kong, SAR China Objective Bipolar depressive episodes are challenging to treat and greater understanding of factors that might predict outcome in patient subgroups is much needed. As is the case with unipolar depression, bipolar depression is associated with elevated levels of C-reactive protein (CRP). While elevated CRP has been associated with reduced response to standard antidepressant therapy, Raison et al. (2013) showed that tumor necrosis factor (TNF) antagonism (using infliximab) improved depressive symptoms in patients with treatment-resistant depression (TRD) and high baseline CRP, while not benefiting patients with TRD and lower levels of CRP. The objective of the current study was to evaluate the influence of pre-treatment CRP levels on response to lurasidone in patients with bipolar depression. Methods The study population included outpatients who met DSM-IV-TR criteria for bipolar I depression and who received double-blind treatment with lurasidone 20-60 mg/day (n =161), lurasidone 80–120 mg/day (n = 162) or placebo (N=162) for 6 weeks (Loebel et al., 2014). The primary efficacy endpoint was change from baseline to week 6 in Montgomery-Åsberg Depression Rating Scale (MADRS) score. A wide-range CRP assay (wr-crp, equivalent to high sensitivity CRP assay) was utilized as an inflammatory marker. Mixed model for longitudinal data analyses and statistical interaction tests were applied to investigate the moderating effects of pre-treatment wr-CRP level on change in MADRS scores. Results A total of 118 (24.5%) patients had elevated wr-CRP (>5.0 mg/L) prior to treatment. A significant interaction was observed between pre-treatment wr-CRP and the impact of lurasidone (20-60 mg/d or 80-120 mg/d) on change in MADRS score from baseline to week 6, with increased wr-CRP predicting a larger antidepressant response to lurasidone when compared to placebo. Patients with pre-treatment hs-CRP levels >5 mg/L had a placebo-corrected effect size favoring lurasidone of d=0.95, whereas patients with hs-CRP <5 mg/L had an effect size of d =0.35. These effects remained significant after adjustment for baseline BMI and weight change from baseline. There were significant interactions between pre-treatment wr-CRP and lurasidone treatment for the following MADRS items: “lassitude”, “apparent sadness”, “reported sadness”, and “pessimistic thoughts” (all P< 0.05), with improvement in these symptoms all favoring lurasidone in patients with higher baseline wr-CRP level. Conclusion Our findings, based on results of a placebo-controlled trial, suggest that baseline levels of the inflammatory marker wr-CRP predict the therapeutic efficacy of lurasidone for the treatment of bipolar depressive symptoms, with larger effect sizes observed in patients with elevated levels of wr-CRP at study baseline. These findings suggest that the efficacy of lurasidone in patients with bipolar depression may in part be linked to the inflammatory status of patients prior to treatment. If confirmed in prospective investigations, wr-CRP may prove useful as a predictive biomarker that could help optimize the use of lurasidone for the treatment of patients with bipolar depression. Acknowledgements This study was supported and sponsored by Sunovion Pharmaceuticals Inc. References Raison, C. L. et al. A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: the role of baseline inflammatory biomarkers. JAMA Psychiatry 70, 31–41 (2013). Loebel, A., Cucchiaro, J., Silva, R., Kroger H., Hsu J., Sarma K., Sachs G., 2014a. Lurasidone monotherapy in the treatment of bipolar I depression, a randomized, double-blind, placebo-controlled study. Am. J. Psychiatry 171, 160-168. Keywords: Bipolar depression, Inflammatory marker, C-reactive protein (CRP), lurasidone, treatment outcome Conference: ISAD LONDON 2017: Perspectives on Mood and Anxiety Disorders: Looking to the future, London, United Kingdom, 6 Jul - 7 Jul, 2017. Presentation Type: Oral Topic: Comorbidity between mood disorders and other psychiatric disorders Citation: Raison CL, Pikalov A, Siu C, Tsai J, Koblan K and Loebel A (2019). C-REACTIVE PROTEIN EFFECTS IN PATIENTS WITH BIPOLAR DEPRESSION TREATED WITH LURASIDONE: AN EXPLORATORY ANALYSIS OF A PLACEBO-CONTROLLED TRIAL. Front. Psychiatry. Conference Abstract: ISAD LONDON 2017: Perspectives on Mood and Anxiety Disorders: Looking to the future. doi: 10.3389/conf.fpsyt.2017.48.00029 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 26 May 2017; Published Online: 25 Jan 2019. * Correspondence: MD, PhD. Andrei Pikalov, Sunovion (United States), Marlborough, United States, andrei.pikalov@sunovion.com Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Charles L Raison Andrei Pikalov Cynthia Siu Joyce Tsai Kenneth Koblan Antony Loebel Google Charles L Raison Andrei Pikalov Cynthia Siu Joyce Tsai Kenneth Koblan Antony Loebel Google Scholar Charles L Raison Andrei Pikalov Cynthia Siu Joyce Tsai Kenneth Koblan Antony Loebel PubMed Charles L Raison Andrei Pikalov Cynthia Siu Joyce Tsai Kenneth Koblan Antony Loebel Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Depressive symptoms in patients with cancer are associated with poor quality of life and decreased survival. Although inflammation is reliably associated with depression in otherwise healthy individuals, the association in patients with cancer remains unclear. Given the high prevalence of cancer-related inflammation, the authors aimed to establish the relationship between inflammation and depression in cancer patients based on extant literature. A systematic review and meta-analysis was performed using Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines and registered under Prospero ID CRD42021226743. Three databases were searched including PubMed, the Cochrane Library, and PsycINFO using the following criteria for inclusion: 1) measurement of a peripheral inflammatory marker, 2) use of a validated tool/scale to measure depression, and 3) a cancer diagnosis. Risk of publication bias was assessed by Funnel plot and Egger test. Seventy-three studies were included in the systematic review and 54 studies (n=5017) were included in meta-analyses. Associations with depressive symptoms were significant for peripheral blood interleukin (IL)-6 (standardized mean difference [SMD] = 0.59; 95% confidence interval [CI], 0.35-0.82), I2 =57.9%; tumor necrosis factor (TNF) (SMD=0.73; 95% CI, 0.35-1.11), I2 =74.1%; and C-reactive protein (CRP) (SMD=0.57; 95% CI, 0.27-0.87), I2 =0%. IL-5, IL-13, albumin, and neutrophil-to-lymphocyte ratio were associated with depressive symptoms but based on fewer studies. Most cancer settings were represented; the number of studies per inflammatory marker varied from 1 to 52. Although peripheral inflammatory markers were unevenly studied, the most studied markers (IL-6, TNF, and CRP) were associated with depressive symptoms in cancer patients and may be useful for management of depressive symptoms in the cancer setting. Peripheral blood inflammatory markers (IL-6, TNF, and CRP) were associated with depressive symptoms in various cancer settings. Although further studies are warranted, these findings may help identify and manage depressive symptoms in patients with cancer.

Depressive symptoms and measures of disability: a prospective study

Insufficient treatment response and resulting chronicity constitute a major problem in depressive disorders. Remission rates range as low as 15% to 40% and treatment-resistant depression (TRD) is associated with low-grade inflammation, suggesting anti-inflammatory interventions as a rational treatment strategy. Minocycline, which inhibits microglial activation, represents a promising repurposing candidate in the treatment of TRD. To determine whether 6 weeks of minocycline as add-on to antidepressant treatment as usual can significantly reduce depressive symptoms in patients with TRD. The study was conducted in Germany and designed as a multicenter double-blind randomized clinical trial (RCT) of 200 mg/d minocycline treatment over a course of 6 weeks with a 6-month follow-up. Participants were recruited from January 2016 to August 2020 at 9 university hospitals that served as study sites. Key inclusion criteria were a diagnosis of major depressive disorder (according to Diagnostic and Statistical Manual of Mental Disorders [Fifth Edition] criteria), severity of depressive symptoms on the Hamilton Depression Rating Scale (HAMD-17) greater than or equal to 16 points, aged 18 to 75 years, body mass index 18 to 40, Clinical Global Impression Scale (CGI-S) greater than or equal to 4, failure to adequately respond to an initial antidepressant standard medication as per Massachusetts General Hospital Antidepressant Treatment History Questionnaire, and stable medication for at least 2 weeks. A total of 258 patients were screened, of whom 173 were randomized and 168 were included into the intention-to-treat population. Statistical analysis was performed from April to November 2020. Participants were randomized (1:1) to receive adjunct minocycline (200 mg/d) or placebo for 6 weeks. Primary outcome measure was the change in Montgomery-Åsberg Depression Rating Scale (MADRS) score from baseline to week 6 analyzed by intention-to-treat mixed model repeated measures. Secondary outcome measures were response, remission, and various other clinical rating scales. Of 173 eligible and randomized participants (84 randomized to minocycline and 89 randomized to placebo), 168 formed the intention-to-treat sample (79 [47.0%] were women, 89 [53.0%] were men, 159 [94.6%] were White, 9 [6.4%] were of other race and ethnicity, including Asian and unknown ethnicity), with 81 in the minocycline group and 87 in the placebo group. The mean (SD) age was 46.1 (13.1) years, and the mean (SD) MADRS score at baseline was 26.5 (5.0). There was no difference in rates of completion between the minocycline (83.3% [70 of 81]) and the placebo group (83.1% [74 of 87]). Minocycline treatment did not alter the course of depression severity compared with placebo as assessed by a decrease in MADRS scores over 6 weeks of treatment (1.46 [-1.04 to 3.96], P = .25). Minocycline treatment also exhibited no statistically significant effect on secondary outcomes. In this large randomized clinical trial with minocycline at a dose of 200 mg/d added to antidepressant treatment as usual for 6 weeks, minocycline was well tolerated but not superior to placebo in reducing depressive symptoms in patients with TRD. The results of this RCT emphasize the unmet need for therapeutic approaches and predictive biomarkers in TRD. EU Clinical Trials Register Number: EudraCT 2015-001456-29.

Glucose and lipid-related biomarkers and the antidepressant response to infliximab in patients with treatment-resistant depression

Background: Psoriasis is a chronic skin disease associated with psychiatric co-morbidities, especially depression. Early detection of psychological vulnerability in patients with psoriasis seems to be of great clinical importance and significantly impacts the quality of life of the patients.Objectives: We sought to clarify the association between psoriasis and depressive symptoms in patients with moderate-to-severe psoriasis, and to determine the risk factors for depressive symptoms and analyze the effect of ustekinumab on the symptoms. We also aimed to evaluate the changes in glucose metabolism using 18fluorodeoxyglucose (FDG) positron emission tomography (FDG-PET).Methods: Fifteen patients with moderate-to-severe psoriasis scheduled to be treated with ustekinumab were enrolled. At baseline and after achieving a 75% reduction in the Psoriasis Area and Severity Index (PASI) score (PASI75), all patients underwent a psychiatric interview and FDG-PET. Fifteen healthy volunteers were enrolled for comparison.Results: Patients with moderate-to-severe psoriasis were more depressed than those in the control group were (p < .05). The severity of psoriasis at baseline did not correlate with the depression symptoms. Treatment with ustekinumab significantly reduced the depressive symptoms, as verified using Beck Depression Inventory and Hamilton Depression Rating Scale psychiatric interviews (p < .05). However, FDG-PET of the brain showed no significant difference before and after PASI75 achievement using ustekinumab injection.Conclusions: Patients with moderate-to-severe psoriasis are at an increased risk for depressive symptoms, and treatment with ustekinumab may be beneficial. FDG-PET does not reflect the changes in depressive symptoms in such patients.

Although quality of life (QoL) has become an important aspect of cancer rehabilitation, psychometric studies on thyroid cancer patients are rare. We performed a case-controlled study on QoL in patients with differentiated thyroid carcinoma (DTC). QoL was evaluated in 61 patients with a history of DTC diagnosed from < 1 to 23 yr earlier. An undetectable thyroglobulin (Tg) level after recombinant human TSH (rhTSH) testing was considered the best predictor of cure. QoL was evaluated by means of a general psychiatric interview, the self-rating Kellner Symptoms Questionnaire (KSQ) and the Hamilton Depression Scale (HDS). QoL was also evaluated in a control group of subjects on L-T4 therapy with a non-toxic multinodular goiter diagnosed from < 1 to 25 yr earlier. DTC and control subjects were similar in age, male-female distribution and concomitant psychiatric therapies. Per-week dosage of L-T4 was higher in DTC patients than in controls (p < 0.01). In neither group of subjects was there any correlation between current TSH levels or interval from diagnosis and KSQ or HDS scores. Only in DTC patients was there a positive correlation between age and KSQ (p < 0.05) or HDS (p < 0.01) scores. There was a significant difference in overall KSQ scores between DTC (33.4 +/- 2.1) and control (24.5 +/- 1.9; p < 0.01) subjects. The subscales of KSQ showed a significant inter-group difference. HDS scores were higher in DTC subjects (35.8 +/- 1.0) than in controls (30.0 +/- 1.1; p < 0.01). HDS score was significantly (p = 0.02) higher in female than in male DTC patients. In patients with papillary carcinoma there was a positive correlation between the MACIS (metastases, age, completeness, invasiveness, size) score and KSQ (p = 0.01) or HDS (p < 0.01) scores. After rhTSH testing, detectable Tg levels were found in 13% of DTC patients. In Tg-positive patients, KSQ and HDS scores were not different from those of Tg-negative patients. After an 8-14 month period, a significant decrease in the KSQ scale somatization (p = 0.02) was found in a sub-set of 31 DTC patients. In conclusion, even in the age of rhTSH testing, DTC patients suffer an impairment of their QoL, as noted when short-term L-T4 withdrawal was the gold standard. Longitudinal evaluation seems to indicate a slight improvement in QoL when safe rhTSH testing is extensively used in the management of the disease.

Anti-Inflammatory May Benefit Treatment-Resistant Depression

The objective of the study was to explore the risk factors for depressive symptoms in patients with gout and to construct and validate a nomogram model. From October 2022 to July 2023, a total of 469 gout patients from a Class iii Grade A hospital in Northeast China were selected as the research objects by the convenience sampling method. The General Information Questionnaire, Self-Rating Depression Scale, Gout Knowledge Questionnaire, Self-Efficacy Scale for Managing Chronic Disease (SEMCD), and Social Support Rating Scale were used to conduct the survey. Univariate and multivariate logistic regression analyses were used to establish a depression risk prediction model and construct a nomogram. The bootstrap method was used to verify the performance of the model. The detection rate of depressive symptoms in gout patients was 25.16%. Binary logistic regression analysis showed that male, the number of tophi, acute attack period, lack of knowledge about gout, the number of attacks in the past year, and the duration of the last attack were independent risk factors for post-gout depression. Female, interictal period, chronic arthritis period, knowledge of gout, and social support were protective factors for post-gout depression (p < 0.05). The calibration (χ2 = 11.348, p = 0.183, p > 0.05) and discrimination (AUC = 0.858, 95%CI: 0.818-0.897) of the nomogram model for depressive symptoms in gout patients were good. The prevalence of depressive symptoms in gout patients is high, and it is affected by gender, current disease stage, number of tophi, gout knowledge level, the number of attacks in the past year, and the last attack days. The nomogram model is scientific and practical for predicting the occurrence of depressive symptoms in gout patients.

Effects of Home-Based Supportive Care on Improvements in Physical Function and Depressive Symptoms in Patients With Stroke: A Meta-Analysis