Gayle Wittenberg

Ketamine and Imipramine Reverse Transcriptional Signatures of Susceptibility and Induce Resilience-Specific Gene Expression Profiles

BACKGROUND Examining transcriptional regulation by antidepressants in key neural circuits implicated in depression and understanding the relation to transcriptional mechanisms of susceptibility and natural resilience may help in the search for new therapeutic agents. Given the heterogeneity of treatment response in human populations, examining both treatment response and nonresponse is critical. METHODS We compared the effects of a conventional monoamine-based tricyclic antidepressant, imipramine, and a rapidly acting, non-monoamine-based antidepressant, ketamine, in mice subjected to chronic social defeat stress, a validated depression model, and used RNA sequencing to analyze transcriptional profiles associated with susceptibility, resilience, and antidepressant response and nonresponse in the prefrontal cortex (PFC), nucleus accumbens, hippocampus, and amygdala. RESULTS We identified similar numbers of responders and nonresponders after ketamine or imipramine treatment. Ketamine induced more expression changes in the hippocampus; imipramine induced more expression changes in the nucleus accumbens and amygdala. Transcriptional profiles in treatment responders were most similar in the PFC. Nonresponse reflected both the lack of response-associated gene expression changes and unique gene regulation. In responders, both drugs reversed susceptibility-associated transcriptional changes and induced resilience-associated transcription in the PFC. CONCLUSIONS We generated a uniquely large resource of gene expression data in four interconnected limbic brain regions implicated in depression and its treatment with imipramine or ketamine. Our analyses highlight the PFC as a key site of common transcriptional regulation by antidepressant drugs and in both reversing susceptibility- and inducing resilience-associated molecular adaptations. In addition, we found region-specific effects of each drug, suggesting both common and unique effects of imipramine versus ketamine.

MicroRNAs 146a/b-5 and 425-3p and 24-3p are markers of antidepressant response and regulate MAPK/Wnt-system genes

Antidepressants (ADs) are the most common treatment for major depressive disorder (MDD). However, only ∼30% of patients experience adequate response after a single AD trial, and this variability remains poorly understood. Here, we investigated microRNAs (miRNAs) as biomarkers of AD response using small RNA-sequencing in paired samples from MDD patients enrolled in a large, randomized placebo-controlled trial of duloxetine collected before and 8 weeks after treatment. Our results revealed differential expression of miR-146a-5p, miR-146b-5p, miR-425-3p and miR-24-3p according to treatment response. These results were replicated in two independent clinical trials of MDD, a well-characterized animal model of depression, and post-mortem human brains. Furthermore, using a combination of bioinformatics, mRNA studies and functional in vitro experiments, we showed significant dysregulation of genes involved in MAPK/Wnt signalling pathways. Together, our results indicate that these miRNAs are consistent markers of treatment response and regulators of the MAPK/Wnt systems.

Replicable and Coupled Changes in Innate and Adaptive Immune Gene Expression in Two Case-Control Studies of Blood Microarrays in Major Depressive Disorder

Background Peripheral inflammation is often associated with major depressive disorder (MDD), and immunological biomarkers of depression remain a focus of investigation. Methods We used microarray data on whole blood from two independent case-control studies of MDD: the GlaxoSmithKline–High-Throughput Disease-specific target Identification Program [GSK-HiTDiP] study (113 patients and 57 healthy control subjects) and the Janssen–Brain Resource Company study (94 patients and 100 control subjects). Genome-wide differential gene expression analysis (18,863 probes) resulted in a p value for each gene in each study. A Bayesian method identified the largest p-value threshold (q = .025) associated with twice the number of genes differentially expressed in both studies compared with the number of coincidental case-control differences expected by chance. Results A total of 165 genes were differentially expressed in both studies with concordant direction of fold change. The 90 genes overexpressed (or UP genes) in MDD were significantly enriched for immune response to infection, were concentrated in a module of the gene coexpression network associated with innate immunity, and included clusters of genes with correlated expression in monocytes, monocyte-derived dendritic cells, and neutrophils. In contrast, the 75 genes underexpressed (or DOWN genes) in MDD were associated with the adaptive immune response and included clusters of genes with correlated expression in T cells, natural killer cells, and erythroblasts. Consistently, the MDD patients with overexpression of UP genes also had underexpression of DOWN genes (correlation > .70 in both studies). Conclusions MDD was replicably associated with proinflammatory activation of the peripheral innate immune system, coupled with relative inactivation of the adaptive immune system, indicating the potential of transcriptional biomarkers for immunological stratification of patients with depression.

SAT0182 Improvement in Measures of Depressed Mood and Anhedonia, and Fatigue, In a Randomized, Placebo-Controlled, Phase 2 Study of Sirukumab, A Human Anti-Interleukin-6 Antibody, In Patients with Rheumatoid Arthritis

Background Interleukin-6 (IL-6) is among the known neuroactive cytokines involved in stress coping and neuronal plasticity. Clinical and preclinical studies suggest a role for IL-6 in the pathophysiology of depression; it is unclear whether peripheral anti-IL-6 treatment can directly alleviate depressive symptoms. Depressive symptoms and fatigue commonly affect RA patients, particularly those with high disease activity. Objectives To assess the effects of sirukumab, a human IL6 antibody, on measures of depressed mood and anhedonia, and fatigue from a Ph2 trial in patients with active RA. Methods This was a post-hoc analysis of the SF-36 Mental Health and Vitality domain items from a Ph2, multicenter, randomized, double-blind, placebo-controlled study evaluating efficacy and safety of 4 dose regimens of sirukumab (25mg q4wks up to 100mg q2wks) administered SC in patients with active RA despite MTX. Serum CRP ≥10mg/L was required for enrollment, and history of an uncontrolled psychiatric or emotional disorder that was of sufficient severity to interfere with study participation was excluded. Patients using anti-depressants were excluded from analysis. Patients were grouped by presence or absence of prevalent depressed mood and anhedonia (PDMA) at entry, defined as self-reported depressed mood and anhedonia on the SF-36 with >1 item designated “most of the time” and the other at least “some of the time” for 4wks. Sirukumab treatment was defined as receiving any sirukumab regimen. Change from baseline in PDMA and fatigue at wk12 were analyzed unadjusted and adjusted for baseline and wk12 DAS28-CRP score; to investigate the relationship between depressive symptoms improvement and RA clinical response, change in PDMA symptoms was also investigated separately in ACR50 responders and non-responders Results At entry, about 26% of patients were classified as having PDMA. This group also experienced significantly more fatigue and nervousness than those without PDMA. The severity of PDMA symptoms in this group was not significantly correlated with RA chronicity or severity, or with baseline serum levels of inflammatory biomarkers. Clinical efficacy of sirukumab on RA disease symptoms as measured with the DAS28-CRP occurred in patients with and without PDMA at entry. Patients in the PDMA group receiving sirukumab but not PBO achieved significant improvements at wk12 in PDMA symptoms (p=0.0006), and fatigue (p=0.0157). In patients with PDMA, significant improvements on PDMA symptoms upon sirukumab treatment, but not PBO, were observed in both ACR50 responders (p=0.0024) and non-responders (p=0.0014). In patients with PDMA treated with sirukumab, baseline soluble IL-6 receptor (sIL-6R) level significantly correlated with improvement at wk12 in PDMA symptoms (Spearman r=0.44, p=0.015). Conclusions These novel findings link IL-6 signaling pathway dysregulation to depressive symptoms and fatigue, and suggest that peripheral anti-IL-6 treatment can improve depressive symptoms in RA patients independently of clinical response. References Hodes GE et al,PNAS 2014;111(45):16136-16141. Smolen JS et al,ARD 2014;73:1616-1625. Disclosure of Interest B. Hsu Employee of: Janssen, D. Wang Employee of: Janssen, Y. Sun Employee of: Janssen, G. Salvadore Employee of: Janssen, J. Singh Employee of: Janssen, M. Curran Employee of: Janssen, I. Caers Employee of: Janssen, W. Drevets Employee of: Janssen, G. Wittenberg Employee of: Janssen, G. Chen Employee of: Janssen

Identifying amyloid pathology–related cerebrospinal fluid biomarkers for Alzheimer's disease in a multicohort study

The dynamic range of cerebrospinal fluid (CSF) amyloid β (Aβ1–42) measurement does not parallel to cognitive changes in Alzheimers disease (AD) and cognitively normal (CN) subjects across different studies. Therefore, identifying novel proteins to characterize symptomatic AD samples is important.

Repeated exposure to systemic inflammation and risk of new depressive symptoms among older adults

Evidence on systemic inflammation as a risk factor for future depression is inconsistent, possibly due to a lack of regard for persistency of exposure. We examined whether being inflamed on multiple occasions increases risk of new depressive symptoms using prospective data from a population-based sample of adults aged 50 years or older (the English Longitudinal Study of Ageing). Participants with less than four of eight depressive symptoms in 2004/05 and 2008/09 based on the Eight-item Centre for Epidemiologic Studies Depression scale were analysed. The number of occasions with C-reactive protein ⩾3 mg l−1 over the same initial assessments (1 vs 0 occasion, and 2 vs 0 occasions) was examined in relation to change in depressive symptoms between 2008/09 and 2012/13 and odds of developing depressive symptomology (having more than or equal to four of eight symptoms) in 2012/13. In multivariable-adjusted regression models (n=2068), participants who were inflamed on 1 vs 0 occasion showed no increase in depressive symptoms nor raised odds of developing depressive symptomology; those inflamed on 2 vs 0 occasions showed a 0.10 (95% confidence intervals (CIs)=−0.07, 0.28) symptom increase and 1.60 (95% CI=1.00, 2.55) times higher odds. In further analyses, 2 vs 0 occasions of inflammation were associated with increased odds of developing depressive symptoms among women (odds ratio (OR)=2.75, 95% CI=1.53, 4.95), but not among men (OR=0.70, 95% CI=0.29, 1.68); P-for-sex interaction=0.035. In this cohort study of older adults, repeated but not transient exposure to systemic inflammation was associated with increased risk of future depressive symptoms among women; this subgroup finding requires confirmation of validity.

Neuropathological subtypes among subjects with Alzheimer's disease

SUBJECTS WITH ALZHEIMER’S DISEASE Alexey Nefedov, Juan Toledo, Yuk Yee Leung, Nandini Raghavan, Sharon Xie, Robi Polikar, Michael Farnum, Tim Schultz, Young Baek, Victor Lobanov, Allitia DiBernardo, Vaibhav Narayan, Virginia Lee, Steven Arnold, John Trojanowski, Li-San Wang, Gayle Wittenberg, 1 University of Pennsylvania, Philadelphia, Pennsylvania, United States; 2 University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States; University of Pennsylvania, Philadelphia, Pennsylvania, United States; Janssen Pharmaceuticals, Raritan, New Jersey, United States; 5 University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States; 6 Rowan University, Glassboro, New Jersey, United States; Janssen Pharmaceuticals, Spring House, Pennsylvania, United States; Janssen Pharmaceuticals, Spring House, Pennsylvania, United States; 9 Janssen Pharmaceuticals, Titusville, New Jersey, United States; Janssen Pharmaceuticals, Titusville, Pennsylvania, United States.