The bipolar depression rating scale (BDRS) : its development, validation and utility

Objectives: Unipolar and bipolar depression differ neurobiologically and in clinical presentation. Existing depression rating instruments, used in bipolar depression, fail to capture the necessary phenomenological nuances, as they are based on and skewed towards the characteristics of unipolar depression. Both clinically and in research there is a growing need for a new observer-rated scale that is specifically designed to assess bipolar depression.

Methods: An instrument reflecting the characteristics of bipolar depression was drafted by the authors, and administered to 122 participants aged 18–65 (44 males and 78 females) with a diagnosis of DSM-IV bipolar disorder, who were currently experiencing symptoms of depression. The Bipolar Depression Rating Scale (BDRS) was administered together with the Hamilton Depression Rating Scale (HAM-D), Montgomery Asberg Depression Rating Scale (MADRS) and Young Mania Rating Scale (YMRS).

Results: The BDRS has strong internal consistency (Cronbach's alpha = 0.917), and robust correlation coefficients with the MADRS (r = 0.906) and HAM-D (r = 0.744), and the mixed subscale correlated with the YMRS (r = 0.757). Exploratory factor analysis showed a three-factor solution gave the best account of the data. These factors corresponded to depression (somatic), depression (psychological) and mixed symptom clusters.

Conclusions: This study provides evidence for the validity of the BDRS for the measurement of depression in bipolar disorder. These results suggest good internal validity, provisional evidence of inter-rater reliability and strong correlations with other depression rating scales.

Bovine Muc1 is a highly polymorphic gene encoding an extensively glycosylated mucin that binds bacteria

The bovine Muc1 protein is synthesized by mammary epithelial cells and shed into milk as an integral component of the milk fat globule membrane; however, the structure and functions of this mucin, particularly in relation to lactation, are poorly defined. The objectives of this investigation were to investigate the Muc1 gene and protein structures in the context of lactation and to test the hypothesis that Muc1 has a role in innate immune defense. Polymerase chain reaction analysis of genomic DNA from 630 cattle revealed extensive polymorphism in the variable number of tandem repeats (VNTR) in the bovine Muc1 gene. Nine allelic
variants spanning 7 to 23 VNTR units, each encoding 20 AA, were identified. Three alleles, containing 11, 14, and 16 VNTR units, respectively, were predominant. In addition, a polymorphism in one of the VNTR units has the potential to introduce a unique site for N-linked glycosylation. Statistical analysis indicated weak associations between the VNTR alleles and milk protein and fat percentages in a progeny-tested population of Holstein-Friesian dairy cattle. No association with somatic cell count could be demonstrated. Bovine Muc1 was purified from milk fat globule membranes and characterized. The protein was highly glycosylated, primarily with O-linked sialylated T-antigen [Neu5Ac(α2–3)-Gal(β1–3)-GalNAcα1] and, to a lesser extent, with N-linked oligosaccharides, which together accounted for approximately 60% of the apparent mass of Muc1. Purified bovine Muc1 directly bound fluorescently labeled Escherichia coli BioParticles (Invitrogen, Mount Waverley, Australia) and inhibited their binding to bovine mammary epithelial cells grown in vitro.

Integrity of the circadian time-keeping system in chronic fatigue syndrome

Chronic Fatigue Syndrome (CFS) is a debilitating condition in which severe, ongoing fatigue is the most prominent of a complex of somatic, psychological and neuropsychological symptoms. The aetiology of CFS remains uncertain and, to date, efforts to distinguish a clear pathophysiological profile for the disorder have been unsuccessful. Current evidence suggests that, rather than being a discrete disease entity with a single cause, CFS is a clinical condition resulting from the interaction of a number of pathophysiological factors, including acute infections, stress and psychiatric disorder. Recently, there has been some interest in the proposition that disordered circadian time-keeping may contribute to the development and/or course of the illness. The rationale for the investigation of circadian factors in CFS is based on the fact that disorders known to be associated with circadian dysregulation, such as jet lag and shiftwork related syndromes have a high degree of symptomatological overlap with CFS. Also, the presence of circadian disturbance could account, in part, for other phenomenological aspects of CFS, including the high rates of comorbid affective disturbance, and the reports of low-level immune dyregulation among sufferers. While several recent studies have produced some evidence of chronobiological dysregulation in CFS patients, much work remains before conclusions can be drawn about the presence, nature and clinical significance of circadian disturbance in CFS. This thesis describes a series of studies that were designed to systematically investigate: 1. whether CFS is associated with a state of circadian dysregulation, and 2. whether circadian dysregulation contributes significantly to the symptomatology of CFS. The first of the 5 studies reported here compared the circadian patterns of sleep-activity of CFS sufferers with those of healthy controls. Results indicated that CFS patients' sleep-activity cycles were significantly phase delayed compared to controls, and that some aspects of their circadian profiles of sleep-activity were related to some measures of sleep-disturbance and well-being. Studies 2 and 3 investigated the relationship between rhythms of sleep-wake and core temperature in CFS patients and healthy controls. The major finding from these studies was that sleep-wake and core temperature rhythms appear to be less effectively synchronised. Further evidence was collected that suggested that there was a relationship between circadian parameters and symptom measures in the CFS group. While this indicated that circadian dysregulation is linked in some way to the symptoms of CFS, assessment of the actual clinical significance of circadian disturbances required the use of a prospective methodology. The final two studies, therefore, report on a placebo-controlled trial of clinical interventions that were designed to restore circadian integrity to CFS patients, in order to see whether this would lead to a reduction in symptom number or severity. Results indicated that, although patients experienced improvements across a range of measures of symptoms and functional capacity, these were small in magnitude, of unlikely clinical significance, and no greater, in general, to improvements reported by patients who underwent placebo treatment. These results, along with those of the earlier studies, are discussed with respect to their implications regarding the presence and significance of circadian dysregulation. It is concluded that, while they provide evidence that CFS is associated with a degree of both internal and external circadian desynchrony, these findings suggest that circadian dysregulation is likely to be only a peripheral, contributor to the processes that generate and maintain the symptom complex. These findings are discussed with respect to how they contribute to our overall understanding of this multi-dimensional condition, and the implications they have for the continuing effort to investigate the causes and treatment of CFS.

Depression and pain : an overview

Background: Depression and pain are both burdensome ailments that affect a major proportion of the population. It is evident that depression and pain frequently coexist, with treatment and outcome implications.

Objective: To review the literature on the nature, prevalence and co-morbidity of depression and pain, the biological and psychological mechanisms involved and treatment options, thus presenting a broad overview of the current information available.

Methods: Relevant sources were identified from PubMed and Medline databases using a combination of keywords including depression, pain, prevalence, co-morbidity, biological and psychological mechanisms, serotonin (5-HT), norepinephrine (NE), hypothalamic-pituitary-adrenal (HPA) axis, amygdala, functional magnetic resonance imaging (fMRI), antidepressant and psychological therapy.

Results: It is evident from the research that depression and pain are common co-morbidities. Pain as a physical symptom of depression affects approximately 65% of patients, leading to less favourable outcomes and greater health care utilization. Moreover, depression is a common feature in chronic pain patients and can affect pain threshold and tolerance. Evidence from biological and psychological studies has revealed mechanisms that link chronic pain to depression. Several classes of anti-depressants and psychological interventions have been used successfully in the treatment of somatic symptoms of depression and for a variety of pain syndromes.

Conclusions: Pain and depression are linked by overlapping phenomenology, neurobiology and therapy. They are mutually interacting, and the interaction has significant treatment and outcome implications.

Stimulatory effects of egg-laying hormone and gonadotropin-releasing hormone on reproduction of the tropical abalone, Haliotis asinina linnaeus

Egg-laying hormone (ELH) is a neuropeptide hormone that stimulates ovulation of gastropods, including Aplysia californica and Lymnaea stagnalis. Other neuropeptides, gonadotropin releasing hormones (GnRHs), also play important roles in controlling reproduction in both vertebrates and invertebrates. In the current study, the effects of abalone ELH (aELH) and several GnRHs on somatic growth, sex differentiation, gonad maturation, and spawning of Haliotis asinina were investigated in 3 experiments. In experiment 1, groups of 4-mo-old juveniles (11.8 ±  0.03 mm shell length (SL) and 0.33 ± 0.04 g body weight (BW)) were injected with aELH and GnRHs, including buserelin (mammalian GnRH analogue), octopus GnRH (octGnRH), and tunicate GnRH-I (tGnRH-I), at doses of 20 ng/g BW and 200 ng/g BW. The aELH induced early sex differentiation with a bias toward females, but with normal somatic growth, whereas the different isoforms of GnRH had no effect on sexual differentiation or somatic growth. In experiment 2, groups of 1-y-old-abalone (SL, 4.04 ± 0.02 cm; BW, 20.15 ± 0.25 g) were injected with aELH and the 3 isoforms of GnRH including buserelin, octGnRH, and lamprey GnRH (1GnRH-I) at doses of 500 ng/g BW and 1,000 ng/g BW, and all produced stimulatory effects. For each peptide treatment, the gonads reached full maturation within 5- 6 wk and spawning occurred, whereas control groups took 8 wk to reach maturity. In experiment 3, injections of ripe abalone with aELH stimulated spawning of both sexes in a dose-dependent manner. Buserelin had a lesser effect on inducing spawning, and octGnRH had no apparent effect. The gametes released from induced spawnings by aELH and GnRH showed normal fertilization and development of larvae. Altogether, these findings provide further knowledge on manipulating abalone reproduction, which is important in improving abalone aquaculture.

Suppressor of cytokine signaling 1 regulates embryonic myelopoiesis independently of its effects on T cell development

Suppressor of cytokine signaling 1 (SOCS1) has been shown to play important roles in the immune system. It acts as a key negative regulator of signaling via receptors for IFNs and other cytokines controlling T cell development, as well as Toll receptor signaling in macrophages and other immune cells. To gain further insight into SOCS1, we have identified and characterized the zebrafish socs1 gene, which exhibited sequence and functional conservation with its mammalian counterparts. Initially maternally derived, the socs1 gene showed early zygotic expression in mesodermal structures, including the posterior intermediate cell mass, a site of primitive hematopoiesis. At later time points, expression was seen in a broad anterior domain, liver, notochord, and intersegmental vesicles. Morpholino-mediated knockdown of socs1 resulted in perturbation of specific hematopoietic populations prior to the commencement of lymphopoiesis, ruling out T cell involvement. However, socs1 knockdown also lead to a reduction in the size of the developing thymus later in embryogenesis. Zebrafish SOCS1 was shown to be able to interact with both zebrafish Jak2a and Stat5.1 in vitro and in vivo. These studies demonstrate a conserved role for SOCS1 in T cell development and suggest a novel T cell-independent function in embryonic myelopoiesis mediated, at least in part, via its effects on receptors using the Jak2-Stat5 pathway.

Depression and sickness behavior are Janus-faced responses to shared inflammatory pathways

It is of considerable translational importance whether depression is a form or a consequence of sickness behavior. Sickness behavior is a behavioral complex induced by infections and immune trauma and mediated by pro-inflammatory cytokines. It is an adaptive response that enhances recovery by conserving energy to combat acute inflammation. There are considerable phenomenological similarities between sickness behavior and depression, for example, behavioral inhibition, anorexia and weight loss, and melancholic (anhedonia), physio-somatic (fatigue, hyperalgesia, malaise), anxiety and neurocognitive symptoms. In clinical depression, however, a transition occurs to sensitization of immuno-inflammatory pathways, progressive damage by oxidative and nitrosative stress to lipids, proteins, and DNA, and autoimmune responses directed against self-epitopes. The latter mechanisms are the substrate of a neuroprogressive process, whereby multiple depressive episodes cause neural tissue damage and consequent functional and cognitive sequelae. Thus, shared immuno-inflammatory pathways underpin the physiology of sickness behavior and the pathophysiology of clinical depression explaining their partially overlapping phenomenology. Inflammation may provoke a Janus-faced response with a good, acute side, generating protective inflammation through sickness behavior and a bad, chronic side, for example, clinical depression, a lifelong disorder with positive feedback loops between (neuro)inflammation and (neuro)degenerative processes following less well defined triggers.

IgM-mediated autoimmune responses directed against anchorage epitopes are greater in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) than in major depression

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and depression are considered to be neuro-immune disorders (Maes and Twisk, BMC Medicine 8:35, 2010). There is also evidence that depression and ME/CFS are accompanied by oxidative and nitrosative stress (O&NS) and by increased autoantibodies to a number of self-epitopes some of which have become immunogenic due to damage by O&NS. The aim of this study is to examine IgM-mediated autoimmune responses to different self-epitopes in ME/CFS versus depression. We examined serum IgM antibodies to three anchorage molecules (palmitic and myristic acid and S-farnesyl-L-cysteine); acetylcholine; and conjugated NO-modified adducts in 26 patients with major depression; 16 patients with ME/CFS, 15 with chronic fatigue; and 17 normal controls. Severity of fatigue and physio-somatic (F&S) symptoms was measured with the Fibromyalgia and Chronic Fatigue Syndrome Rating Scale. Serum IgM antibodies to the three anchorage molecules and NO-phenylalanine were significantly higher in ME/CFS than in depression. The autoimmune responses to oxidatively, but not nitrosatively, modified self-epitopes were significantly higher in ME/CFS than in depression and were associated with F&S symptoms. The autoimmune activity directed against conjugated acetylcholine did not differ significantly between ME/CFS and depression, but was greater in the patients than controls. Partially overlapping pathways, i.e. increased IgM antibodies to a multitude of neo-epitopes, underpin both ME/CFS and depression, while greater autoimmune responses directed against anchorage molecules and oxidatively modified neo-epitopes discriminate patients with ME/CFS from those with depression. These autoimmune responses directed against neoantigenic determinants may play a role in the dysregulation of key cellular functions in both disorders, e.g. intracellular signal transduction, cellular differentiation and apoptosis, but their impact may be more important in ME/CFS than in depression.

Somatization, but not depression, is characterized by disorders in the tryptophan catabolite (TRYCAT) pathway, indicating increased indoleamine 2,3-dioxygenase and lowered kynurenine aminotransferase activity

BACKGROUND: Reduced plasma tryptophan occurs in depression and somatization. Induction of indoleamine 2,3-dioxygenase (IDO) with consequent synthesis of tryptophan catabolites (TRYCATs) and lowered tryptophan are associated with the onset of depression in the puerperium and during interferon-alpha treatment. Depression is accompanied by lowered kynurenic acid, a neuroprotectant, or increased kynurenine, a neurotoxic TRYCAT.

AIMS AND METHODS: To examine plasma tryptophan; kynurenine; kynurenic acid; the kynurenine / tryptophan (KY/TRP) ratio, indicating IDO activity; and the kynurenine / kynurenic acid (KY/KA) ratio, indicating kynurenine aminotransferase (KAT) activity, in somatization; depression; somatization + depression; and controls. Illness severity is measured by the Somatic Symptom Index (SSI), the Screening for Somatoform Symptoms (SOMS), and the Beck Depression Inventory (BDI).

RESULTS: Tryptophan is significantly lower in patients than in controls and lower in somatization than in depression. KY/TRP is significantly increased in somatization. Kynurenic acid is significantly lower in patients than in controls, and lower in somatization than in depression. KY/KA is significantly higher in somatization and somatization + depression than in depression and controls. There are significant correlations between the severity of somatization, but not depression, and KY/TRP and KY/KA (positive) and tryptophan (negative). Kynurenine and kynurenic acid are significantly correlated in controls, somatization + depression, and depression, but not in somatization.

CONCLUSIONS: Somatization is characterized by increased IDO activity and disorders in KAT activity and an increased neurotoxic potential. The TRYCAT pathway may play a role in the pathophysiology of somatizing and “psychosomatic” symptoms through effects on pain, gut motility, the autonomic nervous system, peripheral NMDA receptors, etc. Even more, biological disorders, such as aberrations in the TRYCAT pathway, which are considered to be a hallmark for depression, are in fact attributable to somatization rather than to depression per se. Future research in depression on the TRYCAT pathway should always control for the possible effects of somatization.

Depression's multiple comorbidities explained by (neuro)inflammatory and oxidative & nitrosative stress pathways

There is now evidence that depression, as characterized by melancholic symptoms, anxiety, and fatigue and somatic (F&S) symptoms, is the clinical expression of peripheral cell-mediated activation, inflammation and induction of oxidative and nitrosative stress (IO&NS) pathways and of central microglial activation, decreased neurogenesis and increased apoptosis. This review gives an explanation for the multiple “co-morbidities” between depression and a large variety of a) brain disorders related to neurodegeneration, e.g. Alzheimer’s, Parkinson’s and Huntington’s disease, multiple sclerosis and stroke; b) medical disorders, such as cardiovascular disorder, chronic fatigue syndrome, chronic obstructive pulmonary disease, rheumatoid arthritis, psoriasis, systemic lupus erythematosus, inflammatory bowel disease, irritable bowel syndrome, leaky gut, diabetes type 1 and 2, obesity and the metabolic syndrome, and HIV infection; and c) conditions, such as hemodialysis, interferon-α-based immunotherapy, the postnatal period and psychosocial stressors. The common denominator of all those disorders/conditions is the presence of microglial activation and/or activation of peripheral IO&NS pathways. There is evidence that shared peripheral and / or central IO&NS pathways underpin the pathophysiology of depression and the previously mentioned disorders and that activation of these IO&NS pathways contributes to shared risk. The IO&NS pathways function as a smoke sensor that detect threats in the peripheral and central parts of the body and signal these threats as melancholic, anxiety, and fatigue and somatic (F&S) symptoms. The presence of concomitant depression is strongly associated with a lower quality of life and increased morbidity and mortality in medical disorders. This may be explained since depression contributes to increased (neuro)inflammatory burden and may therefore drive the inflammatory and degenerative progression. It is concluded that the activation of peripheral and / or central IO&NS pathways may explain the co-occurrence of depression with the above disorders. This shows that depression belongs to the spectrum of inflammatory and degenerative disorders.

Human brain structural change related to acute single exposure to sarin

Objective This study aimed to identify persistent morphological changes subsequent to an acute single-time exposure to sarin, a highly poisonous organophosphate, and the neurobiological basis of long-lasting somatic and cognitive symptoms in victims exposed to sarin.

Methods Thirty-eight victims of the 1995 Tokyo subway sarin attack, all of whom had been treated in an emergency department for sarin intoxication, and 76 matched healthy control subjects underwent T1-weighted and diffusion tensor magnetic resonance imaging (DTI) in 2000 to 2001. Serum cholinesterase (ChE) levels measured immediately and longitudinally after the exposure and the current severity of chronic reports in the victims were also evaluated.

Results The voxel-based morphometry exhibited smaller than normal regional brain volumes in the insular cortex and neighboring white matter, as well as in the hippocampus in the victims. The reduced regional white matter volume correlated with decreased serum cholinesterase levels and with the severity of chronic somatic complaints related to interoceptive awareness. Voxel-based analysis of diffusion tensor magnetic resonance imaging further demonstrated an extensively lower than normal fractional anisotropy in the victims. All these findings were statistically significant (corrected p < 0.05).

Interpretation Sarin intoxication might be associated with structural changes in specific regions of the human brain, including those surrounding the insular cortex, which might be related to elevated subjective awareness of internal bodily status in exposed individuals.

Ontogeny of energy allocation reveals selective pressure promoting risk-taking behaviour in young fish cohorts

Given limited food, prey fishes in a temperate climate must take risks to acquire sufficient reserves for winter and/or to outgrow vulnerability to predation. However, how can we distinguish which selective pressure promotes risk-taking when larger body size is always beneficial? To address this question, we examined patterns of energy allocation in populations of age-0 trout to determine if greater risk-taking corresponds with energy allocation to lipids or to somatic growth. Trout achieved maximum growth rates in all lakes and allocated nearly all of their acquired energy to somatic growth when small in early summer. However, trout in low-food lakes took greater risks to achieve this maximal growth, and therefore incurred high mortality. By late summer, age-0 trout allocated considerable energy to lipids and used previously risky habitats in all lakes. These results indicate that: (i) the size-dependent risk of predation (which is independent of behaviour) promotes risk-taking behaviour of age-0 trout to increase growth and minimize time spent in vulnerable sizes; and (ii) the physiology of energy allocation and behaviour interact to mediate growth/mortality trade-offs for young animals at risk of predation and starvation.

The nocebo effect : a clinicians guide

Objective: This paper aims to provide an overview on the nocebo effect, focusing on recognition — its phenomenology, at-risk demographic profiles, clinical situations and personality factors, as well as discriminating somatic symptoms in the general population from treatment-related adverse effects. Lastly, the paper addresses available evidence-based strategies for management and minimisation of the nocebo effect.

Method: Data for this paper were identified by searching PubMed using the search terms "nocebo" and “nocebo effect”, augmented by a manual search of the references of the key papers and the related literature.

Results: The nocebo effect refers to non-pharmacodynamic, harmful or undesirable effects occurring after inactive treatment, a phenomenon that also occurs in the context of active therapy. Known drivers include classical conditioning and negative expectations concerning treatment. Recent meta-analyses have reported a considerable prevalence, ranging from 18% in the symptomatic treatment of migraine, to more than 74% in multiple sclerosis. Recognition of the nocebo-driven adverse effects presents a challenge, especially because of its non-specific nature and the similarity to the active medication’s expected profile. Traits such as neuroticism, pessimism and type A personalities may predispose individuals to this phenomenon. Clinical management of the nocebo effect includes awareness and recognition, changing the manner of disclosure of potential drug-related adverse effects, shaping patients’ expectations and enhancing the treatment alliance.

Conclusion: The nocebo effect is a common, clinically significant, yet covert driver of clinical outcomes. Increased awareness of its features, as well as knowledge of strategies on how to manage it, are fundamental so that clinicians can mitigate its impact on clinical practice.

Moving towards a population health approach to the primary prevention of common mental disorders

There is a need for the development of effective universal preventive approaches to the common mental disorders, depression and anxiety, at a population level. Poor diet, physical inactivity and smoking have long been recognized as key contributors to the high prevalence noncommunicable diseases. However, there are now an increasing number of studies suggesting that the same modifiable lifestyle behaviors are also risk factors for common mental disorders. In this paper we point to the emerging data regarding lifestyle risk factors for common mental disorders, with a particular focus on and critique of the newest evidence regarding diet quality. On the basis of this most recent evidence, we consequently argue for the inclusion of depression and anxiety in the ranks of the high prevalence noncommunicable diseases influenced by habitual lifestyle practices. We believe that it is both feasible and timely to begin to develop effective, sustainable, population-level prevention initiatives for the common mental illnesses that build on the established and developing approaches to the noncommunicable somatic diseases.