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1.  Central pathways causing fatigue in neuro-inflammatory and autoimmune illnesses 
BMC Medicine  2015;13:28.
Background
The genesis of severe fatigue and disability in people following acute pathogen invasion involves the activation of Toll-like receptors followed by the upregulation of proinflammatory cytokines and the activation of microglia and astrocytes. Many patients suffering from neuroinflammatory and autoimmune diseases, such as multiple sclerosis, Parkinson’s disease and systemic lupus erythematosus, also commonly suffer from severe disabling fatigue. Such patients also present with chronic peripheral immune activation and systemic inflammation in the guise of elevated proinflammtory cytokines, oxidative stress and activated Toll-like receptors. This is also true of many patients presenting with severe, apparently idiopathic, fatigue accompanied by profound levels of physical and cognitive disability often afforded the non-specific diagnosis of chronic fatigue syndrome.
Discussion
Multiple lines of evidence demonstrate a positive association between the degree of peripheral immune activation, inflammation and oxidative stress, gray matter atrophy, glucose hypometabolism and cerebral hypoperfusion in illness, such as multiple sclerosis, Parkinson’s disease and chronic fatigue syndrome. Most, if not all, of these abnormalities can be explained by a reduction in the numbers and function of astrocytes secondary to peripheral immune activation and inflammation. This is also true of the widespread mitochondrial dysfunction seen in otherwise normal tissue in neuroinflammatory, neurodegenerative and autoimmune diseases and in many patients with disabling, apparently idiopathic, fatigue. Given the strong association between peripheral immune activation and neuroinflammation with the genesis of fatigue the latter group of patients should be examined using FLAIR magnetic resonance imaging (MRI) and tested for the presence of peripheral immune activation.
Summary
It is concluded that peripheral inflammation and immune activation, together with the subsequent activation of glial cells and mitochondrial damage, likely account for the severe levels of intractable fatigue and disability seen in many patients with neuroimmune and autoimmune diseases.This would also appear to be the case for many patients afforded a diagnosis of Chronic Fatigue Syndrome.
doi:10.1186/s12916-014-0259-2
PMCID: PMC4320458
Immune; Inflammation; Oxidative stress; Toll-like receptor; Fatigue; Mitochondria; Multiple sclerosis; Chronic fatigue syndrome; Parkinson’s disease
2.  The impact of maternal smoking during pregnancy on depressive and anxiety behaviors in children: the Norwegian Mother and Child Cohort Study 
BMC Medicine  2015;13:24.
Background
Maternal smoking during pregnancy (MSDP) is associated with multiple adverse childhood outcomes including externalizing behaviors. However, the association between MSDP and internalizing (anxiety and depressive) behaviors in offspring has received less investigation. We aimed to assess the association between MSDP and childhood internalizing (anxiety and depressive) behaviors in a very large, well-characterized cohort study.
Methods
We assessed the association between MSDP and internalizing behaviors in offspring utilizing information drawn from 90,040 mother-child pairs enrolled in the Norwegian Mother and Child Cohort Study. Mothers reported smoking information, including status and frequency of smoking, twice during pregnancy. Mothers also reported their child’s internalizing behaviors at 18 months, 36 months, and 5 years. Associations between MSDP and childhood internalizing behaviors, including dose-response and timing of smoking in pregnancy, were assessed at each time point.
Results
MSDP was associated with increased internalizing behaviors when offspring were aged 18 months (B = 0.11, P <0.001) and 36 months (B = 0.06, P <0.01), adjusting for numerous potential confounders. Higher rates of smoking (e.g., >20 cigarettes per day) were associated with higher levels of internalizing behaviors. Maternal smoking during early pregnancy appeared to be the critical period for exposure.
Conclusions
We found evidence supporting a potential role for MSDP in increasing internalizing (anxiety and depressive) behaviors in offspring. We also found evidence supportive of a possible causal relationship, including dose-dependency and support for a predominant role of early pregnancy exposure. Further investigation utilizing genetically informed designs are warranted to assess this association.
doi:10.1186/s12916-014-0257-4
PMCID: PMC4314755  PMID: 25644294
Anxiety; Depression; Cigarette smoking; Pregnancy; Obstetrics; Psychiatry
3.  Stearoyl-CoA desaturase plays an important role in proliferation and chemoresistance in human hepatocellular carcinoma 
The Journal of surgical research  2013;186(1):29-38.
Background
Hepatocellular carcinoma (HCC) is often diagnosed at an advanced stage, when it is not amenable for aggressive therapies such as surgical resection or liver transplantation. Current therapeutic options achieve clinical responses in only a small percentage of cases. As a consequence, effective approaches for prevention and treatment are greatly needed. Altered lipid metabolism has been recently linked to HCC pathogenesis. The aims of this study were to define the cellular and molecular mechanisms linking stearoyl-CoA desaturase (SCD), the rate-limiting enzyme and an essential regulator of lipid homeostasis in liver cells, to carcinogenesis in HCC.
Material and methods
HCC and normal liver specimens were collected. Human HCC cell lines: HepG2, Hep3B, and PLC/PLF/5 were used for immunoblot, cell viability, proliferation, and apoptosis assays. Small interfering RNAs were used for genetic inhibition, and 10, 12 conjugated linoleic acid was used for pharmacologic SCD inhibition.
Results
SCD was strongly expressed in surgically resected HCC (n = 64) and various human HCC cell lines (HepG2, Hep3B, and PLC/PLF/5). The levels of SCD negatively correlated with degree of tumor differentiation (P < 0.01). Treatment of these HCC cell lines with a panel of chemotherapeutic drugs resulted in a time-dependent, phosphatidylinositol 3 kinase- and c-Jun N-terminal kinases1/2–mediated upregulation of SCD expression, which paralleled the degree of resistance to drug-induced apoptosis. Specific genetic or pharmacologic SCD suppression resulted in inhibition of cell proliferation (P < 0.001) and significantly increased sensitivity to chemotherapy-induced apoptosis.
Conclusions
Our data suggest that increased SCD expression plays an important role in HCC development and resistance to chemotherapy-induced apoptosis, and this is in part mediated by phosphatidylinositol 3 kinase/c-Jun N-terminal kinases activation. Specific targeted interruption of this pathway in HCC could be a desirable approach in designing novel therapeutic strategies.
doi:10.1016/j.jss.2013.07.001
PMCID: PMC3923502  PMID: 24135379
Lipid metabolism; Apoptosis; Stearoyl-CoA desaturase; Carcinogenesis; Chemotherapy
4.  Construct validity of the Experiences of Therapy Questionnaire (ETQ) 
BMC Psychiatry  2014;14(1):369.
Background
The Experiences of Therapy Questionnaire (ETQ) is a reliable measure of adverse effects associated with psychotherapy. The measure has not been subject to validity analyses. This study sought to examine the validity of the ETQ by comparison against a measure of therapist satisfaction.
Methods
Participants were recruited from the Black Dog Institute’s website and completed all measures online, at two time points (two weeks apart). Correlational analyses compared scale scores on the ETQ with related constructs of the Therapist Satisfaction Scale (TSS). To exclude any impact of current depression on ratings, we examined correlations between salient ETQ and TSS scales after controlling for depression severity.
Results
Forty-six participants completed all the measures at both time points. Hypothesised associations between the ETQ and TSS scales were supported, irrespective of current depression severity.
Conclusions
The validity of the ETQ is supported; however limitations of the study are noted, including generalizability due to sample characteristics.
doi:10.1186/s12888-014-0369-6
PMCID: PMC4299478  PMID: 25551579
Therapy; Psychotherapy; Measure; Validity; Side-effects; Psychology; Questionnaire
5.  OxNASH Score Correlates with Histologic Features and Severity of Nonalcoholic Fatty Liver Disease 
Digestive diseases and sciences  2014;59(7):1617-1624.
Background and Aims
Oxidative stress is a core abnormality responsible for disease progression in nonalcoholic fatty liver disease (NAFLD). By employing a highly sensitive liquid chromatography-tandem mass spectrometry (LC/MS/MS) approach we recently were able to define the circulating profile of bioactive lipid peroxidation products characteristic of patients with nonalcoholic steatohepatitis (NASH) and developed the OxNASH score for NASH diagnosis. The aims of this study were to assess the utility of OxNASH as a predictor of NASH and study the association between OxNASH and specific histological features of NAFLD.
Methods
Our cohort consisted of 122 patients undergoing liver biopsy for clinical suspicion of NAFLD. The NAFLD activity score (NAS) calculated for each patient. Levels of fatty acid oxidation products were quantified using stable isotope dilution LC/MS/MS and OxNASH was calculated.
Results
The mean age was 49.3 (± 11.6) years and the mean BMI was 31.5 (± 4.8) kg/m2. The majority of patients were Caucasian (82%) and 48% were female. OxNASH correlated with NAS and its individual histologic features (steatosis, inflammation, and ballooning. P <0.05) with the strongest association being with inflammation [rho (95% CI) = 0.40 (0.23–0.57), p < 0.001]. Furthermore, there was a correlation between the stage of fibrosis and OxNASH (p = 0.001). These associations remained statistically significant after adjusting for multiple confounders.
Conclusions
In adult patients with NAFLD, OxNASH correlates with histologic features of NASH and appears to be a promising noninvasive marker.
doi:10.1007/s10620-014-3031-8
PMCID: PMC4279921  PMID: 24464211
Nonalcoholic steatohepatitis; oxidative stress; lipid peroxidation; noninvasive
6.  The effects of escitalopram on myocardial apoptosis and the expression of Bax and Bcl-2 during myocardial ischemia/reperfusion in a model of rats with depression 
BMC Psychiatry  2014;14(1):349.
Background
Major depressive disorder (MDD) is an independent risk factor for coronary heart disease (CHD), and influences the occurrence and prognosis of cardiovascular events. Although there is evidence that antidepressants may be cardioprotective after acute myocardial infarction (AMI) comorbid with MDD, the operative pathophysiological mechanisms remain unclear. Our aim was therefore to explore the molecular mechanisms of escitalopram on myocardial apoptosis and the expression of Bax and Bcl-2 in a rat model of depression during myocardial ischemia/reperfusion (I/R).
Methods
Rats were divided randomly into 3 groups (n = 8): D group (depression), DI/R group (depression with myocardial I/R) and escitalopram + DI/R group. The rats in all three groups underwent the same chronic mild stress and separation for 21 days, at the same time, in the escitalopram + DI/R group, rats were administered escitalopram by gavage (10 mg/kg/day). Ligation of the rat’s left anterior descending branch was done in the myocardial I/R model. Following which behavioral tests were done. The size of the myocardial infarction was detected using 1.5% TTC dye. The Tunel method was used to detect apoptotic myocardial cells, and both the Rt-PCR method and immunohistochemical techniques were used to detect the expression of Bcl–2 and Bax.
Results
Compared with the D and DI/R groups, rats in Escitalopram + DI/R group showed significantly increased movements and sucrose consumption (P < .01). Compared with the DI/R group, the myocardial infarct size in the escitalopram + DI/R group was significantly decreased (P < .01). Compared with the D group, there were significantly increased apoptotic myocardial cells in the DI/R and escitalopram + DI/R groups (P < .01); however compared with the DI/R group, apoptotic myocardial cell numbers in the escitalopram + DI/R group were significantly decreased (P < .01). Compared with the DI/R group, there was a down-regulated Bax:Bcl-2 ratio in the escitalopram + DI/R group (P < .01).
Conclusions
These results suggest that in patients with AMI comorbid with MDD, there is an increase in pro-apoptotic pathways that is reversed by escitalopram. This suggests that clinically escitalopram may have a direct cardioprotective after acute myocardial infarction.
doi:10.1186/s12888-014-0349-x
PMCID: PMC4259089  PMID: 25471226
Escitalopram; Depression; Myocardial infarction; Bax; Bcl-2
7.  Statin use and risk of depression: a Swedish national cohort study 
BMC Psychiatry  2014;14(1):348.
Background
Statin medications, used to prevent heart disease by reducing cholesterol, also reduce inflammation and protect against oxidative damage. As inflammation and oxidative stress occur in depression, there is interest in their potential to reduce depression risk. We investigated whether use of statin medications was associated with a change in the risk of developing depression in a very large Swedish national cohort (n = 4,607,990).
Methods
National register data for adults ≥40yr was analyzed to obtain information about depression diagnoses and prescriptions of statin medications between 2006 and 2008. Associations were tested using logistic regression.
Results
Use of any statin was shown to reduce the odds of depression by 8% compared to individuals not using statin medications (OR = 0.92, 95% CI, 0.89-0.96; p < 0.001). Simvastatin had a protective effect (OR = 0.93, 95% CI, 0.89-0.97; p = 0.001), whereas atorvastatin was associated with increased risk of depression (OR = 1.11, 95% CI, 1.01-1.22; p = 0.032). There was a stepwise decrease in odds ratio with increasing age (OR ≥ 40 years = 0.95, OR ≥ 50 years = 0.91, OR ≥ 60 years = 0.85, OR ≥ 70 years = 0.81).
Conclusions
The use of any statin was associated with a reduction in risk of depression in individuals over the age of 40. Clarification of the strength of these protective effects, the clinical relevance of these effects and determination of which statins are most effective is needed.
doi:10.1186/s12888-014-0348-y
PMCID: PMC4266881  PMID: 25471121
Statins; Atorvastatin; Simvastatin; Depression; Aetiology; Inflammation; Oxidative stress
8.  Excessive Daytime Sleepiness and Body Composition: A Population-Based Study of Adults 
PLoS ONE  2014;9(11):e112238.
Background
Excessive daytime sleepiness (EDS) is often associated with increased adiposity, particularly when assessed in the context of samples of sleep-disordered patients; however, it is unclear if this relationship is sustained among non-clinical, population-based cohorts. This study aimed to investigate the relationship between EDS and a number of body composition markers among a population-based sample of men and women.
Methods
This study assessed 1066 women aged 21–94 yr (median = 51 yr, IQR 35–66), and 911 men aged 24–92 yr (median = 60 yr, IQR 46–73) who participated in the Geelong Osteoporosis Study (GOS) between the years 2001 and 2008. Total body fat mass was determined from whole body dual-energy X-ray absorptiometry scans, and anthropometric parameters (weight, height, and waist circumference) were measured. Lifestyle and health information was collected via self-report. Sleepiness was assessed using the Epworth Sleepiness Scale (ESS). Scores of ≥10 were considered indicative of EDS.
Results
Women: After adjusting for age, alcohol intake, antidepressant medication use and physical activity, EDS was associated with greater waist circumference and body mass index (BMI). EDS was also associated with 1.5–1.6-fold increased odds of being overweight or obese. Men: After adjusting for age, alcohol use, physical activity and smoking status, EDS was associated with greater BMI. These findings were not explained by the use of sedative or antidepressant medication. EDS was also associated with 1.5-fold increased likelihood of being obese, independent of these factors. No differences in lean mass, %body fat, or %lean mass were detected between those with and without EDS for men or women.
Conclusions
These data suggest that EDS is associated with several anthropometric adiposity profiles, independent of associated lifestyle and health factors. Among women, symptoms of EDS are pervasive at both overweight and obese BMI classifications; suggesting a need for further clinical examination to assess possible temporal associations with underlying sleep pathology.
doi:10.1371/journal.pone.0112238
PMCID: PMC4226485  PMID: 25383556
9.  The addition of fluoxetine to cognitive behavioural therapy for youth depression (YoDA-C): study protocol for a randomised control trial 
Trials  2014;15(1):425.
Background
The aim of the Youth Depression Alleviation–Combined Treatment (YoDA-C) study is to determine whether antidepressant medication should be started as a first-line treatment for youth depression delivered concurrently with psychotherapy. Doubts about the use of medication have been raised by meta-analyses in which the efficacy and safety of antidepressants in young people have been questioned, and subsequent treatment guidelines for youth depression have provided only qualified support.
Methods/Design
YoDA-C is a double-blind, randomised controlled trial funded by the Australian government’s National Health and Medical Research Council. Participants between the ages of 15 and 25 years with moderate to severe major depressive disorder will be randomised to receive either (1) cognitive behavioural therapy (CBT) and fluoxetine or (2) CBT and placebo. The treatment duration will be 12 weeks, and follow-up will be conducted at 26 weeks. The primary outcome measure is change in the Montgomery-Åsberg Depression Rating Scale (MADRS) after 12 weeks of treatment. The MADRS will be administered at baseline and at weeks 4, 8, 12 and 26. Secondary outcome measures will address additional clinical outcomes, functioning, quality of life and safety.
Trial registration
Australian and New Zealand Clinical Trials Registry ID: ACTRN12612001281886 (registered on 11 December 2012)
doi:10.1186/1745-6215-15-425
PMCID: PMC4230740  PMID: 25370185
Adolescence; Antidepressants; Cognitive behavioural therapy; Depression; Fluoxetine; Selective serotonin reuptake inhibitors; Youth
10.  The International Society for Bipolar Disorders (ISBD) Task Force Report on Antidepressant Use in Bipolar Disorders 
The American journal of psychiatry  2013;170(11):1249-1262.
Objective
The risk-benefit profile of antidepressant medications in bipolar disorder is controversial. When conclusive evidence is lacking, expert consensus can guide treatment decisions. The International Society for Bipolar Disorders (ISBD) convened a task force to seek consensus recommendations on the use of antidepressants in bipolar disorders.
Method
An expert task force iteratively developed consensus through serial consensus-based revisions using the Delphi method. Initial survey items were based on systematic review of the literature. Subsequent surveys included new or reworded items and items that needed to be rerated. This process resulted in the final ISBD Task Force clinical recommendations on antidepressant use in bipolar disorder.
Results
There is striking incongruity between the wide use of and the weak evidence base for the efficacy and safety of antidepressant drugs in bipolar disorder. Few well-designed, long-term trials of prophylactic benefits have been conducted, and there is insufficient evidence for treatment benefits with antidepressants combined with mood stabilizers. A major concern is the risk for mood switch to hypomania, mania, and mixed states. Integrating the evidence and the experience of the task force members, a consensus was reached on 12 statements on the use of antidepressants in bipolar disorder.
Conclusions
Because of limited data, the task force could not make broad statements endorsing antidepressant use but acknowledged that individual bipolar patients may benefit from antidepressants. Regarding safety, serotonin reuptake inhibitors and bupropion may have lower rates of manic switch than tricyclic and tetracyclic antidepressants and norepinephrine-serotonin reuptake inhibitors. The frequency and severity of antidepressant-associated mood elevations appear to be greater in bipolar I than bipolar II disorder. Hence, in bipolar I patients antidepressants should be prescribed only as an adjunct to mood-stabilizing medications.
doi:10.1176/appi.ajp.2013.13020185
PMCID: PMC4091043  PMID: 24030475
11.  Lipid-induced toxicity stimulates hepatocytes to release angiogenic microparticles that require Vanin-1 for uptake by endothelial cells 
Science signaling  2013;6(296):ra88.
Angiogenesis is a key pathological feature of experimental and human steatohepatitis, a common chronic liver disease that is associated with obesity. We demonstrated that hepatocytes generated a type of membrane-bound vesicle, microparticles, in response to conditions that mimicked the lipid accumulation that occurs in the liver in some forms of steatohepatitis and that these microparticles promoted angiogenesis. When applied to an endothelial cell line, medium conditioned by murine hepatocytes or a human hepatocyte cell line exposed to saturated free fatty acids induced migration and tube formation, two processes required for angiogenesis. Medium from hepatocytes in which caspase 3 was inhibited or medium in which the microparticles were removed by ultracentrifugation lacked proangiogenic activity. Isolated hepatocyte-derived microparticles induced migration and tube formation of an endothelial cell line in vitro and angiogenesis in mice, processes that depended on internalization of microparticles. Microparticle internalization required the interaction of the ectoenzyme Vanin-1 (VNN1), an abundant surface protein on the microparticles, with lipid raft domains of endothelial cells. Large quantities of hepatocyte-derived microparticles were detected in the blood of mice with diet-induced steatohepatitis, and microparticle quantity correlated with disease severity. Genetic ablation of caspase 3 or RNA interference directed against VNN1 protected mice from steatohepatitis-induced pathological angiogenesis in the liver and resulted in a loss of the proangiogenic effects of microparticles. Our data identify hepatocyte-derived microparticles as critical signals that contribute to angiogenesis and liver damage in steatohepatitis and suggest a therapeutic target for this condition.
doi:10.1126/scisignal.2004512
PMCID: PMC4016801  PMID: 24106341
Obesity; hepatic steatosis; apoptosis; free fatty acids; fibrosis
12.  Extreme Attributions Predict Transition from Depression to Mania or Hypomania in Bipolar Disorder 
Journal of psychiatric research  2013;47(10):1329-1336.
Background
Relatively little is known about psychological predictors of the onset of mania among individuals with bipolar disorder, particularly during episodes of depression. In the present study we investigated attributional style as a predictor of onset of hypomanic, manic or mixed episodes among bipolar adults receiving psychosocial treatment for depression. We hypothesized that “extreme” (i.e., excessively pessimistic or optimistic) attributions would predict a greater likelihood of developing an episode of mood elevation.
Method
Outpatients with DSM-IV bipolar I or II disorder (N=105) enrolled in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) were randomly allocated to one of three types of intensive psychotherapy for depression or a brief psychoeducational intervention. Patients completed a measure of attributional style at baseline and were followed prospectively for up to one year. All analyses were by intent to treat.
Results
Logistic regressions and Cox proportional hazards models indicated that extreme (both positively- and negatively-valenced) attributions predicted a higher likelihood of (and shorter time until) transition from depression to a (hypo)manic or mixed episode (ps < .04), independent of the effects of manic or depressive symptom severity at baseline. Extreme attributions were also retrospectively associated with more lifetime episodes of (hypo)mania and depression (ps < .05).
Conclusions
Evaluating extreme attributions may help clinicians to identify patients who are at risk for experiencing a more severe course of bipolar illness, and who may benefit from treatments that introduce greater cognitive flexibility.
doi:10.1016/j.jpsychires.2013.05.016
PMCID: PMC3743936  PMID: 23791456
attributional style; cognitive style; cognitive vulnerability; mania; hypomania; manic switch
13.  Assessing Regional Cerebral Blood Flow in Depression Using 320-Slice Computed Tomography 
PLoS ONE  2014;9(9):e107735.
While there is evidence that the development and course of major depressive disorder (MDD) symptomatology is associated with vascular disease, and that there are changes in energy utilization in the disorder, the extent to which cerebral blood flow is changed in this condition is not clear. This study utilized a novel imaging technique previously used in coronary and stroke patients, 320-slice Computed-Tomography (CT), to assess regional cerebral blood flow (rCBF) in those with MDD and examine the pattern of regional cerebral perfusion. Thirty nine participants with depressive symptoms (Hamilton Depression Rating Scale 24 (HAMD24) score >20, and Self-Rating Depression Scale (SDS) score >53) and 41 healthy volunteers were studied. For all subjects, 3 ml of venous blood was collected to assess hematological parameters. Trancranial Doppler (TCD) ultrasound was utilized to measure parameters of cerebral artery rCBFV and analyse the Pulsatility Index (PI). 16 subjects (8 =  MDD; 8 =  healthy) also had rCBF measured in different cerebral artery regions using 320-slice CT. Differences among groups were analyzed using ANOVA and Pearson's tests were employed in our statistical analyses. Compared with the control group, whole blood viscosity (including high\middle\low shear rate)and hematocrit (HCT) were significantly increased in the MDD group. PI values in different cerebral artery regions and parameters of rCBFV in the cerebral arteries were decreased in depressive participants, and there was a positive relationship between rCBFV and the corresponding vascular rCBF in both gray and white matter. rCBF of the left gray matter was lower than that of the right in MDD. Major depression is characterized by a wide range of CBF impairments and prominent changes in gray matter blood flow. 320-slice CT appears to be a valid and promising tool for measuring rCBF, and could thus be employed in psychiatric settings for biomarker and treatment response purposes.
doi:10.1371/journal.pone.0107735
PMCID: PMC4175469  PMID: 25251476
14.  Atypical antipsychotic agents; Peas in a pod or chalk and cheese? 
BMC Medicine  2014;12(1):126.
With escalating health expenditure and a shrinking purse, there is increased focus on the cost efficacy of still patented versus generic medications in general, and for atypical antipsychotics in particular. In a recent BMC Medicine article, Godman and colleagues presented data indicating poor uptake of the off patent atypical antipsychotic risperidone, arguing for authorities to mandate its greater use. This is under the assumption of clinical equivalence of atypical antipsychotics. This commentary argues that there are clinically meaningful differences between atypical antipsychotics and important inter-individual heterogeneity in clinical response and tolerability. Access to a broad range of atypical antipsychotics enables clinicians to tailor care, taking consideration of differential efficacy and adverse effects profile in order to meet the needs of individual patients with improved real world effectiveness of treatment. Restriction of agent choice risks detracting from optimal clinical care, with possible poorer outcomes and greater costs of care. A balance between encouraging use of cheapest in class agent and allowing access to various atypical agents for tailored care is likely to produce optimal health outcomes.
Please see related article: http://www.biomedcentral.com/1741-7015/12/98.
doi:10.1186/s12916-014-0126-1
PMCID: PMC4243724
Atypical antipsychotics; Risperidone; Bipolar; Schizophrenia; Generic; Health economics
15.  Pop, heavy metal and the blues: secondary analysis of persistent organic pollutants (POP), heavy metals and depressive symptoms in the NHANES National Epidemiological Survey 
BMJ Open  2014;4(7):e005142.
Objectives
Persistent environmental pollutants, including heavy metals and persistent organic pollutants (POPs), have a ubiquitous presence. Many of these pollutants affect neurobiological processes, either accidentally or by design. The aim of this study was to explore the associations between assayed measures of POPs and heavy metals and depressive symptoms. We hypothesised that higher levels of pollutants and metals would be associated with depressive symptoms.
Setting
National Health and Nutrition Examination Survey (NHANES).
Participants
A total of 15 140 eligible people were included across the three examined waves of NHANES.
Primary and secondary outcome measures
Depressive symptoms were assessed using the nine-item version of the Patient Health Questionnaire (PHQ-9), using a cut-off point of 9/10 as likely depression cases. Organic pollutants and heavy metals, including cadmium, lead and mercury, as well as polyfluorinated compounds (PFCs), pesticides, phenols and phthalates, were measured in blood or urine.
Results
Higher cadmium was positively associated with depression (adjusted Prevalence Ratios (PR)=1.48, 95% CI 1.16 to 1.90). Higher levels of mercury were negatively associated with depression (adjusted PR=0.62, 95% CI 0.50 to 0.78), and mercury was associated with increased fish consumption (n=5500, r=0.366, p<0.001). In addition, several PFCs (perfluorooctanoic acid, perfluorohexane sulfonic acid, perfluorodecanoic acid and perfluorononanoic acid) were negatively associated with the prevalence of depression.
Conclusions
Cadmium was associated with an increased likelihood of depression. Contrary to hypotheses, many of persistent environmental pollutants were not associated or negatively associated with depression. While the inverse association between mercury and depressive symptoms may be explained by a protective role for fish consumption, the negative associations with other pollutants remains unclear. This exploratory study suggests the need for further investigation of the role of various agents and classes of agents in the pathophysiology of depression.
doi:10.1136/bmjopen-2014-005142
PMCID: PMC4120423  PMID: 25037643
MENTAL HEALTH
16.  SLC6A4 STin2 VNTR genetic polymorphism is associated with tobacco use disorder, but not with successful smoking cessation or smoking characteristics: a case control study 
BMC Genetics  2014;15:78.
Background
The aim of this study was to determine if variable number of tandem repeats (VNTR) in the second intron (STin2) of the serotonin transporter (SLC6A4) gene was associated with tobacco use disorder, successful smoking cessation, or smoking characteristics. In this case–control study, patients with current tobacco use disorder, diagnosed according to DSM IV criteria (n = 185), and never-smokers, diagnosed according to CDC criteria (n = 175), were recruited and received 52 weeks of combined pharmacotherapy and cognitive therapy. Successful smoking cessation was defined as exhaled carbon monoxide < 6 ppm. SLC6A4 gene STin2 VNTR polymorphism was assessed using a Multiplex-PCR-based method. At baseline, participants were evaluated using the Fagerström Test for Nicotine Dependence (FTND) and the ASSIST scale.
Results
The STin2.12 allele (OR = 2.45; 95% CI = 1.44-4.15, p < 0.001) was associated with an increased risk for tobacco use disorder, while the STin2.10/10 genotype (OR = 0.42; 95% CI 0.25-0.71, p < 0.001) decreased risk. There were no significant associations between tobacco use disorder and the STin2.10 or STin2.9 alleles or the other genotypes (STin2.12/12, 12/10, 12/9, 10/9 or 9/9). There were no significant associations between the STin2 genotypes and alleles and successful smoking cessation, smoking characteristics and increased alcohol or sedative use risk.
Conclusions
Our results suggest that the STin2.10/10 genotype and STin2.12 allele are associated with tobacco use disorder or nicotine dependence, but not with treatment response or severity of dependence. It is hypothesized that the ST2in.12 allele by modulating the metabolism of serotonin may participate in the pathophysiology of tobacco use disorder or nicotine dependence.
doi:10.1186/1471-2156-15-78
PMCID: PMC4114164  PMID: 24968820
STin2 VNTR; Tobacco use disorder; Smoking cessation; Serotonin; Inflammation; Oxidative stress; Polymorphism; Genetic
17.  Food policies for physical and mental health 
BMC Psychiatry  2014;14:132.
Noncommunicable diseases (NCDs) account for the largest burden of early mortality and are predicted to cost the global community more than US $30 trillion over the next 20 years. Unhealthy dietary habits, in large part driven by substantial changes to global food systems, are recognised as major contributors to many of the common NCDs, including cardiovascular disease, cancer and diabetes. Recent evidence now indicates that unhealthy diets are also risk factors for mental disorders, particularly depression and dementia. This affords substantial scope to leverage on the established and developing approaches to the nutrition-related NCDs to address the large global burden of these mental disorders and reinforces the imperative for governments take substantial actions in regards to improving the food environment and consequent population health via policy initiatives.
doi:10.1186/1471-244X-14-132
PMCID: PMC4026829  PMID: 24884515
18.  Lifestyle medicine for depression 
BMC Psychiatry  2014;14:107.
The prevalence of depression appears to have increased over the past three decades. While this may be an artefact of diagnostic practices, it is likely that there are factors about modernity that are contributing to this rise. There is now compelling evidence that a range of lifestyle factors are involved in the pathogenesis of depression. Many of these factors can potentially be modified, yet they receive little consideration in the contemporary treatment of depression, where medication and psychological intervention remain the first line treatments. “Lifestyle Medicine” provides a nexus between public health promotion and clinical treatments, involving the application of environmental, behavioural, and psychological principles to enhance physical and mental wellbeing. This may also provide opportunities for general health promotion and potential prevention of depression. In this paper we provide a narrative discussion of the major components of Lifestyle Medicine, consisting of the evidence-based adoption of physical activity or exercise, dietary modification, adequate relaxation/sleep and social interaction, use of mindfulness-based meditation techniques, and the reduction of recreational substances such as nicotine, drugs, and alcohol. We also discuss other potential lifestyle factors that have a more nascent evidence base, such as environmental issues (e.g. urbanisation, and exposure to air, water, noise, and chemical pollution), and the increasing human interface with technology. Clinical considerations are also outlined. While data supports that some of these individual elements are modifiers of overall mental health, and in many cases depression, rigorous research needs to address the long-term application of Lifestyle Medicine for depression prevention and management. Critically, studies exploring lifestyle modification involving multiple lifestyle elements are needed. While the judicious use of medication and psychological techniques are still advocated, due to the complexity of human illness/wellbeing, the emerging evidence encourages a more integrative approach for depression, and an acknowledgment that lifestyle modification should be a routine part of treatment and preventative efforts.
doi:10.1186/1471-244X-14-107
PMCID: PMC3998225  PMID: 24721040
Lifestyle; Depression; Exercise; Diet; Smoking; Alcohol; Prevention; Treatment
19.  Stress, Inflammation, and Cellular Vulnerability during Early Stages of Affective Disorders: Biomarker Strategies and Opportunities for Prevention and Intervention 
The mood disorder prodrome is conceptualized as a symptomatic, but not yet clinically diagnosable stage of an affective disorder. Although a growing area, more focused research is needed in the pediatric population to better characterize psychopathological symptoms and biological markers that can reliably identify this very early stage in the evolution of mood disorder pathology. Such information will facilitate early prevention and intervention, which has the potential to affect a person’s disease course. This review focuses on the prodromal characteristics, risk factors, and neurobiological mechanisms of mood disorders. In particular, we consider the influence of early-life stress, inflammation, and allostatic load in mediating neural mechanisms of neuroprogression. These inherently modifiable factors have known neuroadaptive and neurodegenerative implications, and consequently may provide useful biomarker targets. Identification of these factors early in the course of the disease will accordingly allow for the introduction of early interventions which augment an individual’s capacity for psychological resilience through maintenance of synaptic integrity and cellular resilience. A targeted and complementary approach to boosting both psychological and physiological resilience simultaneously during the prodromal stage of mood disorder pathology has the greatest promise for optimizing the neurodevelopmental potential of those individuals at risk of disabling mood disorders.
doi:10.3389/fpsyt.2014.00034
PMCID: PMC3988376  PMID: 24782789
prodrome; depression; bipolar; biomarker; stress; inflammation; cellular resilience; plasticity
20.  Risk stratification using data from electronic medical records better predicts suicide risks than clinician assessments 
BMC Psychiatry  2014;14:76.
Background
To date, our ability to accurately identify patients at high risk from suicidal behaviour, and thus to target interventions, has been fairly limited. This study examined a large pool of factors that are potentially associated with suicide risk from the comprehensive electronic medical record (EMR) and to derive a predictive model for 1–6 month risk.
Methods
7,399 patients undergoing suicide risk assessment were followed up for 180 days. The dataset was divided into a derivation and validation cohorts of 4,911 and 2,488 respectively. Clinicians used an 18-point checklist of known risk factors to divide patients into low, medium, or high risk. Their predictive ability was compared with a risk stratification model derived from the EMR data. The model was based on the continuation-ratio ordinal regression method coupled with lasso (which stands for least absolute shrinkage and selection operator).
Results
In the year prior to suicide assessment, 66.8% of patients attended the emergency department (ED) and 41.8% had at least one hospital admission. Administrative and demographic data, along with information on prior self-harm episodes, as well as mental and physical health diagnoses were predictive of high-risk suicidal behaviour. Clinicians using the 18-point checklist were relatively poor in predicting patients at high-risk in 3 months (AUC 0.58, 95% CIs: 0.50 – 0.66). The model derived EMR was superior (AUC 0.79, 95% CIs: 0.72 – 0.84). At specificity of 0.72 (95% CIs: 0.70-0.73) the EMR model had sensitivity of 0.70 (95% CIs: 0.56-0.83).
Conclusion
Predictive models applied to data from the EMR could improve risk stratification of patients presenting with potential suicidal behaviour. The predictive factors include known risks for suicide, but also other information relating to general health and health service utilisation.
doi:10.1186/1471-244X-14-76
PMCID: PMC3984680  PMID: 24628849
Suicide risk; Electronic medical record; Predictive models
21.  Do Comorbid Anxiety Disorders Moderate the Effects of Psychotherapy for Bipolar Disorder? Results From STEP-BD 
The American journal of psychiatry  2014;171(2):178-186.
Objective
At least 50% of individuals with bipolar disorder have a lifetime anxiety disorder. Individuals with both bipolar disorder and a co-occurring anxiety disorder experience longer illness duration, greater illness severity, and poorer treatment response. The study explored whether comorbid lifetime anxiety in bipolar patients moderates psychotherapy treatment outcome.
Method
In the Systematic Treatment Enhancement Program randomized controlled trial of psychotherapy for bipolar depression, participants received up to 30 sessions of intensive psychotherapy (family-focused therapy, interpersonal and social rhythm therapy, or cognitive-behavioral therapy) or collaborative care, a three-session comparison treatment, plus pharmacotherapy. Using the number needed to treat, we computed effect sizes to analyze the relationship between lifetime anxiety disorders and rates of recovery across treatment groups after 1 year.
Results
A total of 269 patients (113 women) with a comorbid lifetime anxiety disorder (N=177) or without a comorbid lifetime anxiety disorder (N=92) were included in the analysis. Participants with a lifetime anxiety disorder were more likely to recover with psychotherapy than with collaborative care (66% compared with 49% recovered over 1 year; number needed to treat=5.88, small to medium effect). For patients without a lifetime anxiety disorder, there was no difference between rates of recovery in psychotherapy compared with collaborative care (64% compared with 62% recovered; number needed to treat=50, small effect). Participants with one lifetime anxiety disorder were likely to benefit from intensive psychotherapy compared with collaborative care (84% compared with 53% recovered; number needed to treat=3.22, medium to large effect), whereas patients with multiple anxiety disorders exhibited no difference in response to the two treatments (54% compared with 46% recovered; number needed to treat=12.5, small effect).
Conclusions
Depressed patients with bipolar disorder and comorbid anxiety may be in particular need of additional psychotherapy for treating acute depression. These results need to be replicated in studies that stratify bipolar patients to treatments based on their anxiety comorbidity status.
doi:10.1176/appi.ajp.2013.13020225
PMCID: PMC3946300  PMID: 24077657
22.  Depression following fracture in women: a study of age-matched cohorts 
BMJ Open  2014;4(2):e004226.
Objectives
High levels of disability, functional impairment and mortality are independently associated with fracture and depression, however the relationship between fracture and depression is uncertain. The aim of this study was to investigate whether fracture is associated with subsequent depressive symptoms in a population-based sample of women.
Design
A study of age-matched fracture versus non-fracture cohorts of women.
Setting
Barwon Statistical Division, southeastern Australia.
Participants
Two samples of women aged ≥35 years were drawn from the Geelong Osteoporosis Study (GOS). The fracture cohort included women with incident fracture identified from radiology reports and the non-fracture cohort were randomly selected from the electoral roll during 1994–1996.
Outcome measure
Symptoms of depression for women with and without fracture during the 12-month period 2000–2001 were identified by self-report questionnaire based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria.
Results
A total of 296 women with fracture (12 hip, 48 vertebral, 91 wrist/forearm, 17 upper arm, 7 pelvis, 11 rib, 62 lower leg and 48 other fractures) and 590 women without fracture were included. Associations between fracture and depression differed between younger (≤65 years) and older (>65 years) women. Age and weight-adjusted odds ratio for depression following fracture among younger women was 0.62 (0.35 to 1.11, p=0.12) and 3.33 (1.24 to 8.98, p=0.02) for older women. Further adjustment for lifestyle factors did not affect the results.
Conclusions
This study demonstrated that differences in mood status exist between older and younger women following fracture and that fracture is associated with increased depression in older women. Assessment of mood status in both the short and long term following fracture in the elderly seems justified, with early detection and treatment likely to result in improved outcomes.
doi:10.1136/bmjopen-2013-004226
PMCID: PMC3931986  PMID: 24561497
Epidemiology; Geriatric Medicine
23.  Clock Face Drawing Test Performance in Children with ADHD 
Introduction
The utility and discriminatory pattern of the clock face drawing test in ADHD is unclear. This study therefore compared Clock Face Drawing test performance in children with ADHD and controls.
Methods
95 school children with ADHD and 191 other children were matched for gender ratio and age. ADHD symptoms severities were assessed using DSM-IV ADHD checklist and their intellectual functioning was assessed. The participants completed three clock-drawing tasks, and the following four functions were assessed: Contour score, Numbers score, Hands setting score, and Center score.
Results
All the subscales scores of the three clock drawing tests of the ADHD group were lower than that of the control group. In ADHD children, inattention and hyperactivity/ impulsivity scores were not related to free drawn clock test scores. When pre-drawn contour test was performed, inattentiveness score was statistically associated with Number score while none of the other variables of age, gender, intellectual functioning, and hand use preference were associated with that kind of score. In pre-drawn clock, no association of ADHD symptoms with any CDT subscales found significant. In addition, more errors are observed with free drawn clock and Pre-drawn contour than pre-drawn clock.
Discussion
Putting Numbers and Hands setting are more sensitive measures to screen ADHD than Contour and Center drawing. Test performance, except Hands setting, may have already reached a developmental plateau. It is probable that Hand setting deficit in children with ADHD may not decrease from age 8 to 14 years. Performance of children with ADHD is associated with complexity of CDT.
PMCID: PMC4202561  PMID: 25337328
Attention Deficit Disorder with; Hyperactivity; Clock Face Drawing Test; Diagnosis; Psychometrics; Assessment
24.  Caspase 1-mediated regulation of fibrogenesis in diet-induced steatohepatitis 
Nonalcoholic 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, HSC activation, fibrosis, and increased hepatic caspase 1 and IL-1β expression when placed on the methioninecholine 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 (TNFα 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-SMA was 3.2-fold greater in WT vs. Casp1−/− MCD-fed mice; Collagen 1-alpha was 7.6–fold greater in WT vs. Casp1−/− MCD-fed mice; TGFβ was 2.4-fold greater in WT vs. Casp1−/− MCD-fed mice; CRP2 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−/− mice MCD-fed mice compared to WT MCD-fed animals. However, serum aminotransferase (ALT) levels, caspase 3 activity and TUNEL 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. Conclusion: this study uncovers a novel role for caspase 1 in inflammation and fibrosis during NASH development.
doi:10.1038/labinvest.2012.45
PMCID: PMC3808241  PMID: 22411067
Nonalcoholic fatty liver disease (NAFLD); nonalcoholic steatohepatitis (NASH); inflammasome; caspases; inflammation; fibrosis
25.  Emerging pharmacotherapy for cancer patients with cognitive dysfunction 
BMC Neurology  2013;13:153.
Advances in the diagnosis and multi-modality treatment of cancer have increased survival rates for many cancer types leading to an increasing load of long-term sequelae of therapy, including that of cognitive dysfunction. The cytotoxic nature of chemotherapeutic agents may also reduce neurogenesis, a key component of the physiology of memory and cognition, with ramifications for the patient’s mood and other cognition disorders. Similarly radiotherapy employed as a therapeutic or prophylactic tool in the treatment of primary or metastatic disease may significantly affect cognition. A number of emerging pharmacotherapies are under investigation for the treatment of cognitive dysfunction experienced by cancer patients. Recent data from clinical trials is reviewed involving the stimulants modafinil and methylphenidate, mood stabiliser lithium, anti-Alzheimer’s drugs memantine and donepezil, as well as other agents which are currently being explored within dementia, animal, and cell culture models to evaluate their use in treating cognitive dysfunction.
doi:10.1186/1471-2377-13-153
PMCID: PMC4015674  PMID: 24156319
Cancer; Cognitive impairment; Chemotherapy; Cognitive dysfunction; Pharmacotherapy

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