Treatment-resistant depression and peripheral C-reactive protein.

BACKGROUND: C-reactive protein (CRP) is a candidate biomarker for major depressive disorder (MDD), but it is unclear how peripheral CRP levels relate to the heterogeneous clinical phenotypes of the disorder.AimTo explore CRP in MDD and its phenotypic associations. METHOD: We recruited 102 treatment-resistant patients with MDD currently experiencing depression, 48 treatment-responsive patients with MDD not currently experiencing depression, 48 patients with depression who were not receiving medication and 54 healthy volunteers. High-sensitivity CRP in peripheral venous blood, body mass index (BMI) and questionnaire assessments of depression, anxiety and childhood trauma were measured. Group differences in CRP were estimated, and partial least squares (PLS) analysis explored the relationships between CRP and specific clinical phenotypes. RESULTS: Compared with healthy volunteers, BMI-corrected CRP was significantly elevated in the treatment-resistant group (P = 0.007; Cohen's d = 0.47); but not significantly so in the treatment-responsive (d = 0.29) and untreated (d = 0.18) groups. PLS yielded an optimal two-factor solution that accounted for 34.7% of variation in clinical measures and for 36.0% of variation in CRP. Clinical phenotypes most strongly associated with CRP and heavily weighted on the first PLS component were vegetative depressive symptoms, BMI, state anxiety and feeling unloved as a child or wishing for a different childhood. CONCLUSIONS: CRP was elevated in patients with MDD, and more so in treatment-resistant patients. Other phenotypes associated with elevated CRP included childhood adversity and specific depressive and anxious symptoms. We suggest that patients with MDD stratified for proinflammatory biomarkers, like CRP, have a distinctive clinical profile that might be responsive to second-line treatment with anti-inflammatory drugs.Declaration of interestS.R.C. consults for Cambridge Cognition and Shire; and his input in this project was funded by a Wellcome Trust Clinical Fellowship (110049/Z/15/Z). E.T.B. is employed half time by the University of Cambridge and half time by GlaxoSmithKline; he holds stock in GlaxoSmithKline. In the past 3 years, P.J.C. has served on an advisory board for Lundbeck. N.A.H. consults for GlaxoSmithKline. P.d.B., D.N.C.J. and W.C.D. are employees of Janssen Research & Development, LLC., of Johnson & Johnson, and hold stock in Johnson & Johnson. The other authors report no financial disclosures or potential conflicts of interest.This work was funded by a Wellcome Trust strategy award to the Neuroimmunology of Mood Disorders and Alzheimer’s Disease (NIMA) Consortium which is also funded by Janssen, GlaxoSmithKline, Lundbeck and Pfizer. Recruitment of patients was supported by the National Institute of Health Research (NIHR) Clinical Research Network: Kent, Surrey and Sussex & Eastern. SRC consults for Cambridge Cognition and Shire; and his input in this project was funded by a Wellcome Trust Clinical Fellowship (110049/Z/15/Z). ETB is employed half-time by the University of Cambridge and half-time by GlaxoSmithKline; he holds stock in GSK. In the last three years PJC has served on an advisory board for Lundbeck. NAH consults for GSK. PdB, DJ and WCD are employees of Janssen Research & Development, LLC., of Johnson & Johnson, and hold stock in Johnson & Johnson

Peripheral Blood Cell-Stratified Subgroups of Inflamed Depression.

BACKGROUND: Depression has been associated with increased inflammatory proteins, but changes in circulating immune cells are less well defined. METHODS: We used multiparametric flow cytometry to count 14 subsets of peripheral blood cells in 206 depression cases and 77 age- and sex-matched controls (N = 283). We used univariate and multivariate analyses to investigate the immunophenotypes associated with depression and depression severity. RESULTS: Depression cases, compared with controls, had significantly increased immune cell counts, especially neutrophils, CD4+ T cells, and monocytes, and increased inflammatory proteins (C-reactive protein and interleukin-6). Within-group analysis of cases demonstrated significant associations between the severity of depressive symptoms and increased myeloid and CD4+ T-cell counts. Depression cases were partitioned into 2 subgroups by forced binary clustering of cell counts: the inflamed depression subgroup (n = 81 out of 206; 39%) had increased monocyte, CD4+, and neutrophil counts; increased C-reactive protein and interleukin-6; and more severe depression than the uninflamed majority of cases. Relaxing the presumption of a binary classification, data-driven analysis identified 4 subgroups of depression cases, 2 of which (n = 38 and n = 100; 67% collectively) were associated with increased inflammatory proteins and more severe depression but differed in terms of myeloid and lymphoid cell counts. Results were robust to potentially confounding effects of age, sex, body mass index, recent infection, and tobacco use. CONCLUSIONS: Peripheral immune cell counts were used to distinguish inflamed and uninflamed subgroups of depression and to indicate that there may be mechanistically distinct subgroups of inflamed depression.This work was supported by the Wellcome Trust [104025]. M Lynall was supported by a fellowship and grant from Addenbrooke’s Charitable Trust, Cambridge and a fellowship from the Medical Research Council (MR/S006257/1). M. R. Clatworthy is supported by the NIHR Cambridge Biomedical Research Centre (Transplant and Regenerative Medicine), NIHR Blood and Transplant Research Unit, MRC New Investigator Research Grant, MR/N024907/1; Arthritis Research UK Cure Challenge Research Grant, 21777), and an NIHR Research Professorship (RP-2017-08-ST2-002). E. T. Bullmore and C. M. Pariante are each supported by a NIHR Senior Investigator award. This work was also supported by the NIHR Cambridge Biomedical Research Centre (Mental Health) and the Cambridge NIHR BRC Cell Phenotyping Hub, as well as the NIHR BRC at the South London and Maudsley NHS Foundation Trust and King's College London, London

Methamphetamine Activates Reward Circuitry in Drug Naïve Human Subjects

Amphetamines are highly addictive drugs that have pronounced effects on emotional and cognitive behavior in humans. These effects are mediated through their potent dopaminergic agonistic properties. Dopamine has also been implicated in the modulation of responses of the 'reward circuit' in animal and human studies. In this study we use functional magnetic resonance imaging (fMRI) to identify the brain circuitry involved in the psychostimulant effect of methamphetamine in psychostimulant-naïve human subjects. Seven healthy volunteers were scanned in a 3T MR imaging system. They received single-blind intravenous infusions of methamphetamine (0.15 mg/kg), and rated their experience of 'mind-racing' on a button press throughout the experiment. Data were analyzed with statistical parametric mapping methods. Amphetamine administration activated the medial orbitofrontal cortex, the rostral part of the anterior cingulate cortex, and the ventral striatum. Ratings of 'mind-racing' after methamphetamine infusion correlated with activations in the rostral part of the anterior cingulate cortex and in the ventral striatum. In addition, activations in the medial orbitofrontal cortex were independent of motor and related responses involved in making the ratings. These findings indicate that the first administration of a psychostimulant to human subjects activates classical reward circuitry. Our data also support recent hypotheses suggesting a central role for the orbitofrontal cortex in drug reinforcement and the development of addiction

Early Life History and Fisheries Oceanography: New Questions in a Changing World

In the past 100 years since the birth of fisheries oceanography, research on the early life history of fishes, particularly the larval stage, has been extensive, and much progress has been made in identifying the mechanisms by which factors such as feeding success, predation, or dispersal can influence larval survival. However, in recent years, the study of fish early life history has undergone a major and, arguably, necessary shift, resulting in a growing body of research aimed at understanding the consequences of climate change and other anthropogenically induced stressors. Here, we review these efforts, focusing on the ways in which fish early life stages are directly and indirectly affected by increasing temperature; increasing CO₂ concentrations, and ocean acidification; spatial, temporal, and magnitude changes in secondary production and spawning; and the synergistic effects of fishing and climate change. We highlight how these and other factors affect not only larval survivorship, but also the dispersal of planktonic eggs and larvae, and thus the connectivity and replenishment of fish subpopulations. While much of this work is in its infancy and many consequences are speculative or entirely unknown, new modeling approaches are proving to be insightful by predicting how early life stage survival may change in the future and how such changes will impact economically and ecologically important fish populations

Correction: Whole-blood expression of inflammasome- and glucocorticoid-related mRNAs correctly separates treatment-resistant depressed patients from drug-free and responsive patients in the BIODEP study

We have corrected this Article post-publication, because Dr. Cattaneo’s affiliation details were originally incorrect (she was affiliated with three institutions but is in fact only linked to one: Biological Psychiatry Unit, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia). These changes reflect in both the PDF and HTML versions of this Article

Enhancement of individual and community competence: The older adult as community worker

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44012/1/10464_2004_Article_BF00896496.pd

A leaky umbrella has little value: evidence clearly indicates the serotonin system is implicated in depression.

A recent “umbrella” review examined various biomarkers relating to the serotonin system, and concluded there was no consistent evidence implicating serotonin in the pathophysiology of depression. We present reasons for why this conclusion is overstated, including methodological weaknesses in the review process, selective reporting of data, over-simplification, and errors in the interpretation of neuropsychopharmacological findings. We use the examples of tryptophan depletion and serotonergic molecular imaging, the two research areas most relevant to the investigation of serotonin, to illustrate this

A leaky umbrella has little value:evidence clearly indicates the serotonin system is implicated in depression

A recent “umbrella” review examined various biomarkers relating to the serotonin system, and concluded there was no consistent evidence implicating serotonin in the pathophysiology of depression. We present reasons for why this conclusion is overstated, including methodological weaknesses in the review process, selective reporting of data, over-simplification, and errors in the interpretation of neuropsychopharmacological findings. We use the examples of tryptophan depletion and serotonergic molecular imaging, the two research areas most relevant to the investigation of serotonin, to illustrate this

Effect of Virulence Factors on the Photodynamic Inactivation of Cryptococcus neoformans

Opportunistic fungal pathogens may cause an array of superficial infections or serious invasive infections, especially in immunocompromised patients. Cryptococcus neoformans is a pathogen causing cryptococcosis in HIV/AIDS patients, but treatment is limited due to the relative lack of potent antifungal agents. Photodynamic inactivation (PDI) uses the combination of non-toxic dyes called photosensitizers and harmless visible light, which produces singlet oxygen and other reactive oxygen species that produce cell inactivation and death. We report the use of five structurally unrelated photosensitizers (methylene blue, Rose Bengal, selenium derivative of a Nile blue dye, a cationic fullerene and a conjugate between poly-L-lysine and chlorin(e6)) combined with appropriate wavelengths of light to inactivate C. neoformans. Mutants lacking capsule and laccase, and culture conditions that favoured melanin production were used to probe the mechanisms of PDI and the effect of virulence factors. The presence of cell wall, laccase and melanin tended to protect against PDI, but the choice of the appropriate photosensitizers and dosimetry was able to overcome this resistance.Fundação de Amparo à Pesquisa do Estado de São Paulo (2010/13313–9

Disturbed sex hormone milieu in males and females with major depressive disorder and low-grade inflammation

Sex hormones have biological effects on inflammation, and these might contribute to the sex-specific features of depression. C-reactive protein (CRP) is the most widely used inflammatory biomarker and consistent evidence shows a significant proportion (20–30 %) of patients with major depressive disorder (MDD) have CRP levels above 3 mg/L, a threshold indicating at least low-grade inflammation. Here, we investigate the interplay between sex hormones and CRP in the cross-sectional, observational Biomarkers in Depression Study. We measured serum high-sensitivity (hs-)CRP, in 64 healthy controls and 178 MDD patients, subdivided into those with hs-CRP below 3 mg/L (low-CRP; 53 males, 72 females) and with hs-CRP above 3 mg/L (high-CRP; 19 males, 34 females). We also measured interleukin-6, testosterone, 17-β-estradiol (E2), progesterone, sex-hormone binding globulin (SHBG), follicle-stimulating and luteinising hormones, and calculated testosterone-to-E2 ratio (T/E2), free androgen and estradiol indexes (FAI, FEI), and testosterone secretion index. In males, high-CRP patients had lower testosterone than controls (p = 0.001), and lower testosterone (p = 0.013), T/E2 (p < 0.001), and higher FEI (p = 0.015) than low-CRP patients. In females, high-CRP patients showed lower SHGB levels than controls (p = 0.033) and low-CRP patients (p = 0.034). The differences in testosterone, T/E2 ratio, and FEI levels in males survived the Benjamini-Hochberg FDR correction. In linear regression analyses, testosterone (β = −1.069 p = 0.033) predicted CRP concentrations (R2 = 0.252 p = 0.002) in male patients, and SHBG predicted CRP levels (β = −0.628 p = 0.009, R2 = 0.172 p = 0.003) in female patients. These findings may guide future research investigating interactions between gonadal and immune systems in depression, and the potential of hormonal therapies in MDD with inflammation