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.
Nonalcoholic fatty liver disease (NAFLD); nonalcoholic steatohepatitis (NASH); inflammasome; caspases; inflammation; fibrosis
Linoleic acid (LA) is the most abundant polyunsaturated fatty acid in human diets, a major component of human tissues, and the direct precursor to the bioactive oxidized LA metabolites (OXLAMs), 9- and 13 hydroxy-octadecadienoic acid (9- and 13-HODE) and 9- and 13-oxo-octadecadienoic acid (9- and 13-oxoODE). These four OXLAMs have been mechanistically linked to pathological conditions ranging from cardiovascular disease to chronic pain. Plasma OXLAMs, which are elevated in Alzheimer’s dementia and non-alcoholic steatohepatitis, have been proposed as biomarkers useful for indicating the presence and severity of both conditions. Because mammals lack the enzymatic machinery needed for de novo LA synthesis, the abundance of LA and OXLAMs in mammalian tissues may be modifiable via diet. To examine this issue in humans, we measured circulating LA and OXLAMs before and after a 12-week LA lowering dietary intervention in chronic headache patients. Lowering dietary LA significantly reduced the abundance of plasma OXLAMs, and reduced the LA content of multiple circulating lipid fractions that may serve as precursor pools for endogenous OXLAM synthesis. These results show that lowering dietary LA can reduce the synthesis and/or accumulation of oxidized LA derivatives that have been implicated in a variety of pathological conditions. Future studies evaluating the clinical implications of diet-induced OXLAM reductions are warranted.
Linoleic acid; HODE; hydroxy-octadecadienoic acid; oxoODE; oxo-octadecadienoic acid; oxidation; OXLAM; PUFA; polyunsaturated fatty acid
The recent release of the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) by the American Psychiatric Association has led to much debate. For this forum article, we asked BMC Medicine Editorial Board members who are experts in the field of psychiatry to discuss their personal views on how the changes in DSM-5 might affect clinical practice in their specific areas of psychiatric medicine. This article discusses the influence the DSM-5 may have on the diagnosis and treatment of autism, trauma-related and stressor-related disorders, obsessive-compulsive and related disorders, mood disorders (including major depression and bipolar disorders), and schizophrenia spectrum disorders.
DSM-5; Psychiatry; Autism; PTSD; Mood disorders; Bipolar; Obsessive-compulsive disorders; Depression; Schizophrenia
We now know that depression is associated with a chronic, low-grade inflammatory response and activation of cell-mediated immunity, as well as activation of the compensatory anti-inflammatory reflex system. It is similarly accompanied by increased oxidative and nitrosative stress (O&NS), which contribute to neuroprogression in the disorder. The obvious question this poses is ‘what is the source of this chronic low-grade inflammation?’
This review explores the role of inflammation and oxidative and nitrosative stress as possible mediators of known environmental risk factors in depression, and discusses potential implications of these findings. A range of factors appear to increase the risk for the development of depression, and seem to be associated with systemic inflammation; these include psychosocial stressors, poor diet, physical inactivity, obesity, smoking, altered gut permeability, atopy, dental cares, sleep and vitamin D deficiency.
The identification of known sources of inflammation provides support for inflammation as a mediating pathway to both risk and neuroprogression in depression. Critically, most of these factors are plastic, and potentially amenable to therapeutic and preventative interventions. Most, but not all, of the above mentioned sources of inflammation may play a role in other psychiatric disorders, such as bipolar disorder, schizophrenia, autism and post-traumatic stress disorder.
Depression; Inflammation; Cytokines; Diet; Obesity; Exercise; Smoking; Vitamin D; Dental cares; Sleep; Atopic; Gut; Oxidative stress
Little is known about predictors of recovery from bipolar depression or moderators of treatment response. In the present study we investigated attributional style (a cognitive pattern of explaining the causes of life events) as a predictor of recovery from episodes of bipolar depression and as a moderator of response to psychotherapy for bipolar depression.
106 depressed outpatients with DSM-IV bipolar I or II disorder enrolled in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) were randomized to intensive psychotherapy for depression (n=62), or collaborative care (n=44), a minimal psychoeducational intervention. The primary outcome was recovery status at each study visit as measured by the Clinical Monitoring Form. Attributional style was measured at baseline using the Attributional Style Questionnaire. Data were collected between 1998 and 2005.
All analyses were by intention to treat. Extreme attributions predicted a lower likelihood of recovery (p=.01, OR=0.93, 95% CI=.88-.98) and longer time until recovery (p<.01, OR=0.96, 95% CI=.93-.99), independent of the effects of initial depression severity. Among individuals with more pessimistic attributional styles, initial depression severity predicted a lower likelihood of recovery (p=.01, OR=0.64, 95% CI=.45-.91) and longer time until recovery (p<.001, OR=0.76, 95% CI=.66-.88). There was no difference in recovery rates between intensive psychotherapy and collaborative care (OR=0.90, 95% CI=0.40-2.01) in the full sample.
These results suggest that extreme, rigid attributions may be associated with a more severe course of depression, and that evaluating attributional style may help clinicians to identify patients who are at risk for experiencing a more severe course of depression.
Psychopathology seems to play a role in reflux pathogenesis and vice versa, yet few population-based studies have systematically investigated the association between gastro-oesophageal reflux disease (GORD) and psychopathology. We thus aimed to investigate the relationship between GORD-related symptoms and psychological symptomatology, as well as clinically diagnosed mood and anxiety disorders in a randomly selected, population-based sample of adult women.
This study examined data collected from 1084 women aged 20-93 yr participating in the Geelong Osteoporosis Study. Mood and anxiety disorders were identified using the Structured Clinical Interview for DSM-IV-TR Research Version, Non-patient edition (SCID-I/NP), and psychological symptomatology was assessed using the General Health Questionnaire (GHQ-12). GORD-related symptoms were self-reported and confirmed by medication use where possible and lifestyle factors were documented.
Current psychological symptomatology and mood disorder were associated with increased odds of concurrent GORD-related symptoms (adjusted OR 2.1, 95% CI 1.3-3.5, and OR 3.0, 95% CI 1.7-5.6, respectively). Current anxiety disorder also tended to be associated with increased odds of current GORD-related symptoms (p = 0.1). Lifetime mood disorder was associated with a 1.6-fold increased odds of lifetime GORD-related symptoms (adjusted OR 1.6, 95% CI 1.1-2.4) and lifetime anxiety disorder was associated with a 4-fold increased odds of lifetime GORD-related symptoms in obese but not non-obese participants (obese, age-adjusted OR 4.0, 95% CI 1.8-9.0).
These results indicate that psychological symptomatology, mood and anxiety disorders are positively associated with GORD-related symptoms. Acknowledging this common comorbidity may facilitate recognition and treatment, and opens new questions as to the pathways and mechanisms of the association.
Mood disorder; Anxiety disorder; Gastro-oesophageal reflux disease (GORD); Psychological symptoms; Comorbidity; Depression; Gastrointestinal tract; Somatic; Comorbidity
Bipolar disorder is associated with extreme mood symptoms, disability and suicide risk. Close family or friends often have a primary role in supporting an adult with bipolar disorder. However, not all support is helpful and there is little publicly accessible evidence-based information to guide caregivers. Caregiver burden increases the risk of caregiver depression and health problems. To help fill the information gap, expert clinicians, caregivers and consumers contributed to the development of guidelines for caregivers of adults with bipolar disorder using the Delphi consensus method. This paper reports on an evaluation of the acceptability and usefulness of the online version of the guidelines, http://www.bipolarcaregivers.org.
Visitors to the website responded to an initial online survey about the usefulness of the information (N = 536). A more detailed follow-up feedback survey was emailed to web users who were adult caregivers of adults with bipolar disorder a month later (N = 121). The feedback was analyzed quantitatively and qualitatively to establish user appraisals of the online information, whether and how caregivers applied the information and ways it could be improved.
The majority of users (86.4% to 97.4%) found the various sections of the website useful. At follow-up, nearly 93% of caregivers reported that the information was relevant to them and 96% thought it would help others. Most respondents said that the information was supportive and encouraged adaptive control appraisals. However, a few respondents who were experiencing complex family problems, or who cared for a person with severe chronic bipolar disorder did not appraise it as positively. Nevertheless, over two-thirds of the caregivers reported using the information. Optional interactive features were recommended to maximize benefits.
Overall, http://www.bipolarcaregivers.org was appraised positively and used. It appears useful to close family and friends seeking basic information and reassurance, and may be an inexpensive way to disseminate guidelines for caregivers. Those who care for people with more severe and chronic bipolar disorder, or who have complex family problems might benefit from more specialized interventions, suggesting the importance of a stepped-care approach to supporting caregivers. The potential of evidence-based, collaboratively developed information websites to enhance caregiver and consumer outcomes merits further investigation.
Bipolar disorder; Caregiver burden; Caregivers; Control appraisals; Disseminate guidelines; Evaluation by users; Guidelines for caregivers; Information website; Website evaluation; Website for caregivers
Depression is an independent risk factor for coronary artery disease. Autonomic instability may play a mediating or moderating role in this relationship; however this is not well understood. The objective of this study was to explore cardiac autonomic function and cardiac arrhythmia in depression, the correlation between depression severity and Heart Rate Variability (HRV) related indices, and the prevalence of arrhythmia.
Individuals (n = 53) with major depression as assessed by the Diagnostic and Statistical Manual of Mental Disorders, who had a Hamilton Rating Scale for Depression (HAMD) score ≥20 and a Zung Self-Rating Depression Scale score > 53 were compared to 53 healthy individuals, matched for age and gender. Multichannel Electrocardiograph ECG-92C data were collected over 24 hours. Long-term changes in HRV were used to assess the following vagally mediated changes in autonomic tone, expressed as time domain indices: Standard deviation of the NN intervals (SDNN), standard deviation of 5 min averaged NN intervals (SDANN), Root Mean Square of the Successive Differences (RMSSD) and percentage of NN intervals > 50 ms different from preceding interval (pNN50). Pearson’s correlations were conducted to explore the strength of the association between depression severity (using the SDS and HRV related indices, specifically SDNN and low frequency domain / high frequency domain (LF/HF)).
The values of SDNN, SDANN, RMSSD, PNN50 and HF were lower in the depression group compared to the control group (P<.05). The mean value of the LF in the depression group was higher than the in control group (P<.05). Furthermore the ratio of LF/HF was higher among the depression group than the control group (P<.05). A linear relationship was shown to exist between the severity of the depression and HRV indices. In the depression group, the prevalence of arrhythmia was significantly higher than in the control group (P<.05), particularly supraventricular arrhythmias.
Our findings suggest that depression is accompanied by dysfunction of the cardiac autonomic nervous system, and further, that depression severity is linked to severity of this dysfunction. Individuals with depression appear to be susceptible to premature atrial and/or ventricular disease.
Depression; Cardiac autonomic nervous system; Heart rate variability; Arrhythmia; Vagus; Cardiovascular disorders
Recent evidence suggests that diet modifies key biological factors associated with the development of depression; however, associations between diet quality and depression are not fully understood. We performed a systematic review to evaluate existing evidence regarding the association between diet quality and depression.
A computer-aided literature search was conducted using Medline, CINAHL, and PsycINFO, January 1965 to October 2011, and a best-evidence analysis performed.
Twenty-five studies from nine countries met eligibility criteria. Our best-evidence analyses found limited evidence to support an association between traditional diets (Mediterranean or Norwegian diets) and depression. We also observed a conflicting level of evidence for associations between (i) a traditional Japanese diet and depression, (ii) a “healthy” diet and depression, (iii) a Western diet and depression, and (iv) individuals with depression and the likelihood of eating a less healthy diet.
To our knowledge, this is the first review to synthesize and critically analyze evidence regarding diet quality, dietary patterns and depression. Further studies are urgently required to elucidate whether a true causal association exists.
Depression; Diet; Food habits; Adults; Systematic review
Hydrogen gas is a bioactive molecule that has a diversity of effects, including anti-apoptotic, anti-inflammatory and anti-oxidative properties; these overlap with the process of neuroprogression in major psychiatric disorders. Specifically, both bipolar disorder and schizophrenia are associated with increased oxidative and inflammatory stress. Moreover, lithium which is commonly administered for treating bipolar disorder has effects on oxidative stress and apoptotic pathways, as do valproate and some atypical antipsychotics for treating schizophrenia. Molecular hydrogen has been studied pre-clinically in animal models for the treatment of some medical conditions including hypoxia and neurodegenerative disorders, and there are intriguing clinical findings in neurological disorders including Parkinson’s disease. Therefore, it is hypothesized that administration of hydrogen molecule may have potential as a novel therapy for bipolar disorder, schizophrenia, and other concurrent disorders characterized by oxidative, inflammatory and apoptotic dysregulation.
We report on the prospective association between smoking and depression and health-related quality of life (HRQOL) in patients with coronary artery disease (CAD).
Prospective study of 193 patients with assessment of depression occurring 3-, 6- and 9- months (T1, 2, and 3, respectively) following discharge from hospital for a cardiac event. HRQOL was assessed at T3. T1 depression was assessed by clinical interview; T2 and T3 depression was assessed by self-report. Smoking at time of cardiac event was assessed by self-report. Multivariate analyses controlled for known demographic, psychosocial and clinical correlates of depression.
Smoking at the time of index cardiac event increased the likelihood of being diagnosed with Major Depressive Disorder (MDD) at T1 by 4.30 [95% CI, 1.12-16.46; p < .05]. The likelihood of receiving a diagnosis of minor depression, dysthymia or MDD as a combined group was increased by 8.03 [95% CI, 2.35-27.46; p < .01]. Smoking did not reliably predict depression at T2 or T3 and did not reliably predict persistent depression. Smoking increased the likelihood of being classified as depressed according to study criteria at least once during the study period by 5.19 [95% CI, 1.51-17.82; p < .01]. Smoking independently predicted worse mental HRQOL.
The findings support a role for smoking as an independent predictor of depression in CAD patients, particularly in the first 3 months post-cardiac event. The well-established imperative to encourage smoking cessation in these patients is augmented and the findings may add to the evidence for smoking cessation campaigns in the primary prevention of depression.
Coronary artery disease; Depression; Smoking; Quality of life
Cigarette smoking is increased in people with trait anxiety and anxiety disorders, however no longitudinal data exist illuminating whether smoking in adolescence can influence the developmental trajectory of anxiety symptoms from early vulnerability in infancy to adult anxiety expression. Using The Tracing Opportunities and Problems in Childhood and Adolescence (TOPP) Study, a community-based cohort of children and adolescents from Norway who were observed from the age of 18months to age 18–19years, we explored the relationship between adolescent smoking, early vulnerability for anxiety in infancy (e.g. shyness, internalizing behaviors, emotional temperaments) and reported early adult anxiety.
Structural equation modeling demonstrated that adolescent active smoking was positively associated with increased early adulthood anxiety (β = 0.17, p<0.05), after controlling for maternal education (proxy for socioeconomic status). Adolescent anxiety did not predict early adult smoking. Adolescent active smoking was a significant effect modifier in the relationship between some infant vulnerability factors and later anxiety; smoking during adolescence moderated the relationship between infant internalizing behaviors (total sample: active smokers: β = 0.85,p<0.01, non-active smokers: ns) and highly emotional temperament (total sample: active smokers: β = 0.55,p<0.01,non-active smokers: ns), but not shyness, and anxiety in early adulthood. The results support a model where smoking acts as an exogenous risk factor in the development of anxiety, and smoking may alter the developmental trajectory of anxiety from infant vulnerability to early adult anxiety symptom expression. Although alternative non-mutually exclusive models may explain these findings, the results suggest that adolescent smoking may be a risk factor for adult anxiety, potentially by influencing anxiety developmental trajectories. Given the known adverse health effects of cigarette smoking and significant health burden imposed by anxiety disorders, this study supports the importance of smoking prevention and cessation programs targeting children and adolescence.
The furore preceding the release of the new edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) is in contrast to the incremental changes to several diagnostic categories, which are derived from new research since its predecessor’s birth in 1990. While many of these changes are indeed controversial, they do reflect the intrinsic ambiguity of the extant literature. Additionally, this may be a mirror of the frustration of the field’s limited progress, especially given the false hopes at the dawn of the “decade of the brain”. In the absence of a coherent pathophysiology, the DSM remains no more than a set of consensus based operationalized adjectives, albeit with some degree of reliability. It does not cleave nature at its joints, nor does it aim to, but neither does alternate systems. The largest problem with the DSM system is how it’s used; sometimes too loosely by clinicians, and too rigidly by regulators, insurers, lawyers and at times researchers, who afford it reference and deference disproportionate to its overt acknowledged limitations.
DSM-V; Diagnosis; Pathophysiology; DSM-V; Symptoms; Classification
Multiple studies have demonstrated an association between cigarette smoking and increased anxiety symptoms or disorders, with early life exposures potentially predisposing to enhanced anxiety responses in later life. Explanatory models support a potential role for neurotransmitter systems, inflammation, oxidative and nitrosative stress, mitochondrial dysfunction, neurotrophins and neurogenesis, and epigenetic effects, in anxiety pathogenesis. All of these pathways are affected by exposure to cigarette smoke components, including nicotine and free radicals. This review critically examines and summarizes the literature exploring the role of these systems in increased anxiety and how exposure to cigarette smoke may contribute to this pathology at a biological level. Further, this review explores the effects of cigarette smoke on normal neurodevelopment and anxiety control, suggesting how exposure in early life (prenatal, infancy, and adolescence) may predispose to higher anxiety in later life. A large heterogenous literature was reviewed that detailed the association between cigarette smoking and anxiety symptoms and disorders with structural brain changes, inflammation, and cell-mediated immune markers, markers of oxidative and nitrosative stress, mitochondrial function, neurotransmitter systems, neurotrophins and neurogenesis. Some preliminary data were found for potential epigenetic effects. The literature provides some support for a potential interaction between cigarette smoking, anxiety symptoms and disorders, and the above pathways; however, limitations exist particularly in delineating causative effects. The literature also provides insight into potential effects of cigarette smoke, in particular nicotine, on neurodevelopment. The potential treatment implications of these findings are discussed in regards to future therapeutic targets for anxiety. The aforementioned pathways may help mediate increased anxiety seen in people who smoke. Further research into the specific actions of nicotine and other cigarette components on these pathways, and how these pathways interact, may provide insights that lead to new treatment for anxiety and a greater understanding of anxiety pathogenesis.
Anxiety; anxiety disorder; cigarette; epigenetic; inflammation; mitochondria; neurodevelopment; neurotransmitters; neurotrophins; nicotine; nitrosative stress; oxidative stress
The mind-body nexus has been a topic of growing interest. Further data are however required to understand the specific relationship between mood and anxiety disorders and individual physical health conditions, and to verify whether these psychiatric disorders are linked to overall medical burden.
This study examined data collected from 942 men, 20 to 97 years old, participating in the Geelong Osteoporosis Study. A lifetime history of mood and anxiety disorders was identified using the Structured Clinical Interview for DSM-IV-TR Research Version, Non-patient edition (SCID-I/NP). The presence of medical conditions (lifetime) was self-reported and confirmed by medical records, medication use or clinical data. Anthropometric measurements and socioeconomic status (SES) were determined and information on medication use and lifestyle was obtained via questionnaire. Logistic regression models were used to test the associations.
After adjustment for age, socioeconomic status, and health risk factors (body mass index, physical activity and smoking), mood disorders were associated with gastro oesophageal reflux disease (GORD), recurrent headaches, blackouts and/or epilepsy, liver disorders and pulmonary disease in older people, whilst anxiety disorders were significantly associated with thyroid, GORD and other gastrointestinal disorders, and psoriasis. Increased odds of high medical burden were associated with both mood and anxiety disorders.
Our study provides further population-based evidence supporting the link between mental and physical illness in men. Understanding these associations is not only necessary for individual management, but also to inform the delivery of health promotion messages and health care.
Mood disorder; Anxiety disorder; Comorbidity; Medical burden; Population-based study; Physical illness
Despite increased investment in its recognition and treatment, depression remains a substantial health and economic burden worldwide. Current treatment strategies generally focus on biological and psychological pathways, largely neglecting the role of lifestyle. There is emerging evidence to suggest that diet and nutrition play an important role in the risk, and the genesis, of depression. However, there are limited data regarding the therapeutic impact of dietary changes on existing mental illness. Using a randomised controlled trial design, we aim to investigate the efficacy and cost-efficacy of a dietary program for the treatment of Major Depressive Episodes (MDE).
One hundred and seventy six eligible participants suffering from current MDE are being randomised into a dietary intervention group or a social support group. Depression status is assessed using the Montgomery–Åsberg Depression Rating Scale (MADRS) and Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders (Non Patient Edition) (SCID-I/NP). The intervention consists of 7 individual nutrition consulting sessions (of approximately 60 minutes), delivered by an Accredited Practising Dietitian (APD). Sessions commence within one week of baseline assessment. The intervention focuses on advocating a healthy diet based on the Australian Dietary Guidelines and the Dietary Guidelines for Adults in Greece. The control condition comprises a befriending protocol using the same visit schedule and length as the diet intervention. The study is being conducted at two locations in Victoria, Australia (a metropolitan and regional centre). Data collection occurs at baseline (pre-intervention), 3-months (post-intervention) and 6– months. The primary endpoint is MADRS scores at 3 months. A cost consequences analysis will determine the economic value of the intervention.
If efficacious, this program could provide an alternative or adjunct treatment strategy for the management of this highly prevalent mental disorder; the benefits of which could extend to the management of common co-morbidities including cardiovascular disease (CVD), obesity, and type 2 diabetes.
Diet; Nutrition; Depression; Mental health; Social support
There is compelling evidence to support an aetiological role for inflammation, oxidative and nitrosative stress (O&NS), and mitochondrial dysfunction in the pathophysiology of major neuropsychiatric disorders, including depression, schizophrenia, bipolar disorder, and Alzheimer's disease (AD). These may represent new pathways for therapy. Aspirin is a non-steroidal anti-inflammatory drug that is an irreversible inhibitor of both cyclooxygenase (COX)-1 and COX-2, It stimulates endogenous production of anti-inflammatory regulatory 'braking signals', including lipoxins, which dampen the inflammatory response and reduce levels of inflammatory biomarkers, including C-reactive protein, tumor necrosis factor-α and interleukin (IL)--6, but not negative immunoregulatory cytokines, such as IL-4 and IL-10. Aspirin can reduce oxidative stress and protect against oxidative damage. Early evidence suggests there are beneficial effects of aspirin in preclinical and clinical studies in mood disorders and schizophrenia, and epidemiological data suggests that high-dose aspirin is associated with a reduced risk of AD. Aspirin, one of the oldest agents in medicine, is a potential new therapy for a range of neuropsychiatric disorders, and may provide proof-of-principle support for the role of inflammation and O&NS in the pathophysiology of this diverse group of disorders.
aspirin; depression; schizophrenia; dementia; inflammation; cytokines; neuroprogression; treatment; COX
The aim of this paper was to delineate the impact of gender on premorbid history, onset, and 18 month outcomes of first episode psychotic mania (FEPM) patients.
Medical file audit assessment of 118 (male = 71; female = 47) patients with FEPM aged 15 to 29 years was undertaken on clinical and functional measures.
Males with FEPM had increased likelihood of substance use (OR = 13.41, p <.001) and forensic issues (OR = 4.71, p = .008), whereas females were more likely to have history of sexual abuse trauma (OR = 7.12, p = .001). At service entry, males were more likely to be using substances, especially cannabis (OR = 2.15, p = .047), had more severe illness (OR = 1.72, p = .037), and poorer functioning (OR = 0.96, p = .045). During treatment males were more likely to decrease substance use (OR = 5.34, p = .008) and were more likely to be living with family (OR = 4.30, p = .009). There were no gender differences in age of onset, psychopathology or functioning at discharge.
Clinically meaningful gender differences in FEPM were driven by risk factors possibly associated with poor outcome. For males, substance use might be associated with poorer clinical presentation and functioning. In females with FEPM, the impact of sexual trauma on illness course warrants further consideration.
Gender; Mania; Psychosis; Bipolar disorder
It is of importance whether myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a variant of sickness behavior. The latter is induced by acute infections/injury being principally mediated through proinflammatory cytokines. Sickness is a beneficial behavioral response that serves to enhance recovery, conserves energy and plays a role in the resolution of inflammation. There are behavioral/symptomatic similarities (for example, fatigue, malaise, hyperalgesia) and dissimilarities (gastrointestinal symptoms, anorexia and weight loss) between sickness and ME/CFS. While sickness is an adaptive response induced by proinflammatory cytokines, ME/CFS is a chronic, disabling disorder, where the pathophysiology is related to activation of immunoinflammatory and oxidative pathways and autoimmune responses. While sickness behavior is a state of energy conservation, which plays a role in combating pathogens, ME/CFS is a chronic disease underpinned by a state of energy depletion. While sickness is an acute response to infection/injury, the trigger factors in ME/CFS are less well defined and encompass acute and chronic infections, as well as inflammatory or autoimmune diseases. It is concluded that sickness behavior and ME/CFS are two different conditions.
CFS; chronic fatigue; depression; inflammation; ME; oxidative stress; sickness behavior
There is an increased incidence of major depressive disorder (MDD) in individuals after myocardial infarction (MI), but the pathophysiological processes mediating this association are unclear. Our previous study demonstrated an increase in pro-apoptotic pathways in the myocardium and hippocampus in MDD, which was reversed by venlafaxine. This study aimed to attempt to confirm the effects of apoptosis vulnerability markers on the myocardium in a model of depression after myocardial infarction.
Rats were divided into four groups: sham (N = 8), depression (N = 8, chronic mild unpredictable stress and separation were used in the depression group), MI (N = 13) and post-MI depression (N = 7). The rats in all four groups underwent the same open field and sucrose preference behavioral tests. Evan Blue staining was used to determine the area at risk of myocardial infarction in the left ventricle, and 2,3,5-triphenyl tetrazolium chloride (1.5% TTC) dye was used to detect the size of the myocardial infarction. The expression of bax and bcl-2 protein in the myocardium was investigated by immunohistochemistry, and the mRNA expression of bax, bcl-2 and caspase-3 in the myocardium was investigated by real time RT-PCR. Apoptosis was estimated in the myocardium by measuring the Bax:Bcl-2 ratio.
In the depression and post-MI depression rats, there were significantly decreased movements and total sucrose consumption, modeling behavioral deficits and an anhedonic-like state. In terms of myocardial infarction size, no difference was seen between the MI and post-MI depression groups. There was an up-regulated Bax:Bcl-2 ratio in the depression, MI and post-MI depression groups. Furthermore, in the latter group, there was a greater up-regulated Bax:Bcl-2 ratio. However, caspase-3 did not differ among the four groups.
These results of this animal model suggest that active pro-apoptotic pathways may be involved in the nexus between myocardial infarction and depression. This mechanism may be germane to understanding this relationship in humans.
major depressive disorder; myocardial infarction; apoptosis; myocardium; stress; cardiac; comorbidity.
Although bipolar disorder has high heritability, the onset occurs during several decades of life, suggesting that social and environmental factors may have considerable influence on disease onset. This study examined the association between the age of onset and sunlight at the location of onset.
Data were obtained from 2414 patients with a diagnosis of bipolar I disorder, according to DSM-IV criteria. Data were collected at 24 sites in 13 countries spanning latitudes 6.3 to 63.4 degrees from the equator, including data from both hemispheres. The age of onset and location of onset were obtained retrospectively, from patient records and/or direct interviews. Solar insolation data, or the amount of electromagnetic energy striking the surface of the earth, were obtained from the NASA Surface Meteorology and Solar Energy (SSE) database for each location of onset.
The larger the maximum monthly increase in solar insolation at the location of onset, the younger the age of onset (coefficient= −4.724, 95% CI: −8.124 to −1.323, p = 0.006), controlling for each country’s median age. The maximum monthly increase in solar insolation occurred in springtime. No relationships were found between the age of onset and latitude, yearly total solar insolation, and the maximum monthly decrease in solar insolation. The largest maximum monthly increases in solar insolation occurred in diverse environments, including Norway, arid areas in California, and Chile.
The large maximum monthly increase in sunlight in springtime may have an important influence on the onset of bipolar disorder.
PMID: 22612720 CAMSID: cams2451
age of onset; bipolar disorder; solar insolation; sunlight
The Bipolar Comprehensive Outcomes Study (BCOS) is a 2-year, prospective, non-interventional, observational study designed to explore the clinical and functional outcomes associated with ‘real-world’ treatment of participants with bipolar I or schizoaffective disorder. All participants received treatment as usual. There was no study medication.
Participants prescribed either conventional mood stabilizers (CMS; n = 155) alone, or olanzapine with, or without, CMS (olanzapine ± CMS; n = 84) were assessed every 3 months using several measures, including the Young Mania Rating Scale, 21-item Hamilton Depression Rating Scale, Clinical Global Impressions Scale – Bipolar Version, and the EuroQol Instrument. This paper reports 24-month longitudinal clinical, pharmacological, functional, and socioeconomic data.
On average, participants were 42 (range 18 to 79) years of age, 58%; were female, and 73%; had a diagnosis of bipolar I. Polypharmacy was the usual approach to pharmacological treatment; participants took a median of 5 different psychotropic medications over the course of the study, and spent a median proportion of time of 100%; of the study on mood stabilizers, 90%; on antipsychotics, 9%; on antidepressants, and 5%; on benzodiazepines/hypnotics. By 24 months, the majority of participants had achieved both symptomatic and syndromal remission of both mania and depression. Symptomatic relapse rates were similar for both the CMS alone (65%;) and the olanzapine ± CMS (61%;) cohorts.
Participants with bipolar I or schizoaffective disorder in this study were receiving complex medication treatments that were often discordant with recommendations made in contemporary major treatment guidelines. The majority of study participants demonstrated some clinical and functional improvements, but not all achieved remission of symptoms or syndrome.
Cholesterol-lowering medications such as statins have anti-inflammatory and antioxidant properties, which may be beneficial for treating depression and improving mood. However, evidence regarding their effects remains inconsistent, with some studies reporting links to mood disturbances. We aimed to conduct a meta-analysis to determine the impact of statins on psychological wellbeing of individuals with or without hypercholesterolemia.
Articles were identified using medical, health, psychiatric and social science databases, evaluated for quality, and data were synthesized and analyzed in RevMan-5 software using a random effects model.
The 7 randomized controlled trials included in the analysis represented 2,105 participants. A test for overall effect demonstrated no statistically significant differences in psychological wellbeing between participants receiving statins or a placebo (standardized mean difference (SMD) = -0.08, 95% CI -0.29 to 0.12; P = 0.42). Sensitivity analyses were conducted to separately analyze depression (n = 5) and mood (n = 2) outcomes; statins were associated with statistically significant improvements in mood scores (SMD = -0.43, 95% CI -0.61 to -0.24).
Our findings refute evidence of negative effects of statins on psychological outcomes, providing some support for mood-related benefits. Future studies could examine the effects of statins in depressed populations.
anti-inflammatory; cytokines; depression; hypercholesterolemia; mood; oxidative; statins
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
depression; bipolar disorder; diabetes; treatment; drug discovery; pathophysiology
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.
Anxiety; etiology; common mental disorders; diet; depression; lifestyle; physical activity; prevention; risk; smoking