Psychiatry - Research Publications
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ItemNo Preview AvailableCaspase-1-mediated regulation of fibrogenesis in diet-induced steatohepatitis(NATURE PUBLISHING GROUP, 2012-05)Non-alcoholic steatohepatitis (NASH) is typically associated with pro-apoptotic caspase activation. A potential role for pro-inflammatory caspases remains incompletely understood. Our aims were to examine a potential role of caspase-1 in the development of liver damage and fibrosis in NASH. C57BL/6 wild type (WT) developed marked steatohepatitis, activation, fibrosis and increased hepatic caspase-1 and interleukin-1β expression when placed on the methionine- and choline-deficient (MCD) diet. Marked caspase-1 activation was detected in the liver of MCD-fed mice. Hepatocyte and non-parenchymal fractionation of the livers further demonstrated that caspase-1 activation after MCD feeding was mainly localized to non-parenchymal cells. Caspase-1-knockout (Casp1(-/-)) mice on the MCD diet showed marked reduction in mRNA expression of genes involved in inflammation and fibrogenesis (tumor necrosis factor-α was 7.6-fold greater in WT vs Casp1(-/-) MCD-fed mice; F4/80 was 1.5-fold greater in WT vs Casp1(-/-) MCD-fed mice; α-smooth muscle actin was 3.2-fold greater in WT vs Casp1(-/-) MCD-fed mice; collagen 1-α was 7.6-fold greater in WT vs Casp1(-/-) MCD-fed mice; transforming growth factor-β was 2.4-fold greater in WT vs Casp1(-/-) MCD-fed mice; cysteine- and glycine-rich protein 2 was 3.2-fold greater in WT vs Casp1(-/-) MCD-fed mice). Furthermore, Sirius red staining for hepatic collagen deposition was significantly reduced in Casp1(-/-) MCD-fed mice compared with WT MCD-fed animals. However, serum alanine aminotransferase levels, caspase-3 activity and terminal deoxynucleotidyl transferase dUTP nick-end labeling-positive cells were similar in Casp1(-/-) and WT mice on the MCD diet. Selective Kupffer cell depletion by clodronate injection markedly suppressed MCD-induced caspase-1 activation and protected mice from fibrogenesis and fibrosis associated with this diet. The conclusion of this study is that it uncovers a novel role for caspase-1 in inflammation and fibrosis during NASH development.
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ItemCo-prescription of medication for bipolar disorder and diabetes mellitus: a nationwide population-based study with focus on gender differences(BMC, 2012-11-27)BACKGROUND: Studies have shown a correlation between bipolar disorder and diabetes mellitus. It is unclear if this correlation is a part of common pathophysiological pathways, or if medication for bipolar disorder has negative effects on blood sugar regulation. METHODS: The Norwegian prescription database was analyzed. Prescriptions for lithium, lamotrigine, carbamazepine and valproate were used as proxies for bipolar disorder. Prescriptions for insulin and oral anti-diabetic agents were used as proxies for diabetes mellitus. We explored the association between medication for bipolar disorder and diabetes medication by logistic regression RESULTS: We found a strong association between concomitant use of medication to treat diabetes mellitus and mood stabilizers for the treatment of bipolar disorder. Females had a 30% higher risk compared to men of being treated for both disorders. Persons using oral anti-diabetic agents had higher odds of receiving valproate than either lithium or lamotrigine. Use of insulin as monotherapy seemed to have lower odds than oral anti-diabetic agents of co-prescription of mood stabilizers, compared to the general population. CONCLUSIONS: This study showed a strong association between the use of mood stabilizers and anti-diabetic agents. The association was stronger among women than men.
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ItemUsing lithium as a neuroprotective agent in patients with cancer(BMC, 2012-11-02)Neurocognitive impairment is being increasingly recognized as an important issue in patients with cancer who develop cognitive difficulties either as part of direct or indirect involvement of the nervous system or as a consequence of either chemotherapy-related or radiotherapy-related complications. Brain radiotherapy in particular can lead to significant cognitive defects. Neurocognitive decline adversely affects quality of life, meaningful employment, and even simple daily activities. Neuroprotection may be a viable and realistic goal in preventing neurocognitive sequelae in these patients, especially in the setting of cranial irradiation. Lithium is an agent that has been in use for psychiatric disorders for decades, but recently there has been emerging evidence that it can have a neuroprotective effect.This review discusses neurocognitive impairment in patients with cancer and the potential for investigating the use of lithium as a neuroprotectant in such patients.
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ItemIs diagnosis enough to guide interventions in mental health? Using case formulation in clinical practice COMMENTARY(BMC, 2012-09-27)While diagnosis has traditionally been viewed as an essential concept in medicine, particularly when selecting treatments, we suggest that the use of diagnosis alone may be limited, particularly within mental health. The concept of clinical case formulation advocates for collaboratively working with patients to identify idiosyncratic aspects of their presentation and select interventions on this basis. Identifying individualized contributing factors, and how these could influence the person's presentation, in addition to attending to personal strengths, may allow the clinician a deeper understanding of a patient, result in a more personalized treatment approach, and potentially provide a better clinical outcome.
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ItemPathways to new drug discovery in neuropsychiatry(BMC, 2012-11-29)There is currently a crisis in drug discovery for neuropsychiatric disorders, with a profound, yet unexpected drought in new drug development across the spectrum. In this commentary, the sources of this dilemma and potential avenues to redress the issue are explored. These include a critical review of diagnostic issues and of selection of participants for clinical trials, and the mechanisms for identifying new drugs and new drug targets. Historically, the vast majority of agents have been discovered serendipitously or have been modifications of existing agents. Serendipitous discoveries, based on astute clinical observation or data mining, remain a valid option, as is illustrated by the suggestion in the paper by Wahlqvist and colleagues that treatment with sulfonylurea and metformin reduces the risk of affective disorder. However, the identification of agents targeting disorder-related biomarkers is currently proving particularly fruitful. There is considerable hope for genetics as a purist, pathophysiologically valid pathway to drug discovery; however, it is unclear whether the science is ready to meet this promise. Fruitful paradigms will require a break from the orthodoxy, and creativity and risk may well be the fingerprints of success.See related article http://www.biomedcentral.com/1741-7015/10/150.
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ItemDepression and sickness behavior are Janus-faced responses to shared inflammatory pathways(BIOMED CENTRAL LTD, 2012-06-29)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.
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ItemA Prospective Study of Diet Quality and Mental Health in Adolescents(PUBLIC LIBRARY SCIENCE, 2011-09-21)OBJECTIVES: A number of cross-sectional and prospective studies have now been published demonstrating inverse relationships between diet quality and the common mental disorders in adults. However, there are no existing prospective studies of this association in adolescents, the onset period of most disorders, limiting inferences regarding possible causal relationships. METHODS: In this study, 3040 Australian adolescents, aged 11-18 years at baseline, were measured in 2005-6 and 2007-8. Information on diet and mental health was collected by self-report and anthropometric data by trained researchers. RESULTS: There were cross-sectional, dose response relationships identified between measures of both healthy (positive) and unhealthy (inverse) diets and scores on the emotional subscale of the Pediatric Quality of Life Inventory (PedsQL), where higher scores mean better mental health, before and after adjustments for age, gender, socio-economic status, dieting behaviours, body mass index and physical activity. Higher healthy diet scores at baseline also predicted higher PedsQL scores at follow-up, while higher unhealthy diet scores at baseline predicted lower PedsQL scores at follow-up. Improvements in diet quality were mirrored by improvements in mental health over the follow-up period, while deteriorating diet quality was associated with poorer psychological functioning. Finally, results did not support the reverse causality hypothesis. CONCLUSION: This study highlights the importance of diet in adolescence and its potential role in modifying mental health over the life course. Given that the majority of common mental health problems first manifest in adolescence, intervention studies are now required to test the effectiveness of preventing the common mental disorders through dietary modification.
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ItemA consensus statement for safety monitoring guidelines of treatments for major depressive disorder(SAGE PUBLICATIONS LTD, 2011-09)OBJECTIVE: This paper aims to present an overview of screening and safety considerations for the treatment of clinical depressive disorders and make recommendations for safety monitoring. METHOD: Data were sourced by a literature search using MEDLINE and a manual search of scientific journals to identify relevant articles. Draft guidelines were prepared and serially revised in an iterative manner until all co-authors gave final approval of content. RESULTS: Screening and monitoring can detect medical causes of depression. Specific adverse effects associated with antidepressant treatments may be reduced or identified earlier by baseline screening and agent-specific monitoring after commencing treatment. CONCLUSION: The adoption of safety monitoring guidelines when treating clinical depression is likely to improve overall physical health status and treatment outcome. It is important to implement these guidelines in the routine management of clinical depression.
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ItemPrevalence of mood and anxiety disorder in self reported irritable bowel syndrome (IBS). An epidemiological population based study of women(BMC, 2010-08-05)BACKGROUND: Irritable bowel syndrome (IBS) is commonly regarded as a functional disorder, and is hypothesized to be associated with anxiety and depression. This evidence mainly rests on population-based studies utilising self-report screening instruments for psychopathology. Other studies applying structured clinical interviews are generally based on small clinical samples, which are vulnerable to biases. The extant evidence base for an association between IBS and psychopathology is hence not conclusive. The aim of this study was therefore to re-examine the hypothesis using population-based data and psychiatric morbidity established with a structured clinical interview. METHODS: Data were derived from a population-based epidemiological study (n = 1077). Anxiety and mood disorders were established using the Structured Clinical Interview for DSM-IV-TR (SCID-I/NP) and the General Health Questionnaire (GHQ-12). Current and lifetime IBS was self-reported. Hypertension and diabetes were employed as comparison groups as they are expected to be unrelated to mental health. RESULTS: Current IBS (n = 69, 6.4%) was associated with an increased likelihood of current mood and/or anxiety disorders (OR = 2.62, 95%CI 1.49 - 4.60). Half the population reporting a lifetime IBS diagnosis also had a lifetime mood or anxiety disorder. Exploratory analyses demonstrated an increased prevalence of IBS across most common anxiety and mood disorders, the exception being bipolar disorder. The association with IBS and symptoms load (GHQ-12) followed a curved dose response pattern. In contrast, hypertension and diabetes were consistently unrelated to psychiatric morbidity. CONCLUSIONS: IBS is significantly associated with anxiety and mood disorders. This study provides indicative evidence for IBS as a disorder with a psychosomatic aspect.
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ItemAbnormalities in Osteoclastogenesis and Decreased Tumorigenesis in Mice Deficient for Ovarian Cancer G Protein-Coupled Receptor 1(PUBLIC LIBRARY SCIENCE, 2009-05-28)Ovarian cancer G protein-coupled receptor 1 (OGR1) has been shown to be a proton sensing receptor in vitro. We have shown that OGR1 functions as a tumor metastasis suppressor gene when it is over-expressed in human prostate cancer cells in vivo. To examine the physiological functions of OGR1, we generated conditional OGR1 deficient mice by homologous recombination. OGR1 deficient mice were viable and upon gross-inspection appeared normal. Consistent with in vitro studies showing that OGR1 is involved in osteoclastogenesis, reduced osteoclasts were detected in OGR1 deficient mice. A pH-dependent osteoclasts survival effect was also observed. However, overall abnormality in the bones of these animals was not observed. In addition, melanoma cell tumorigenesis was significantly inhibited in OGR1 deficient mice. OGR1 deficient mice in the mixed background produced significantly less peritoneal macrophages when stimulated with thioglycolate. These macrophages also showed altered extracellular signal-regulated kinases (ERK) activation and nitric oxide (NO) production in response to lipopolysaccharide. OGR1-dependent pH responses assessed by cAMP production and cell survival in macrophages or brown fat cells were not observed, presumably due to the presence of other proton sensing receptors in these cells. Our results indicate that OGR1's role in osteoclastogenesis is not strong enough to affect overall bone development and its role in tumorigenesis warrants further investigation. The mice generated can be potentially used for several disease models, including cancers or osteoclast-related diseases.