Metyrapone and fluoxetine suppress enduring behavioral but not cardiac effects of subchronic stress in rats

In humans, chronic stressors have long been recognized as potential causes for cardiac dysregulation. Despite this, the underlying mechanistic links responsible for this association are still poorly understood. The purpose of this study was to determine whether exposure to a paradigm of subchronic stress can provoke enduring changes on the heart rate of experimental rats and, if so, to reveal the autonomic and neural mechanisms that mediate these effects. The study was conducted on adult male Sprague-Dawley rats instrumented for telemetric recording of heart rate and locomotor activity. Animals were submitted to a subchronic stress protocol, consisting of a 1-h foot shock session on five consecutive days. Heart rate and locomotor activity were recorded continuously for 3 days before and for 6 days after the subchronic stress period. Subchronic foot shock produced significant and enduring reduction in heart rate both during the dark/active [Δ= −23 ± 3 beats per minute (bpm)] and light/inactive (Δ= −20 ± 3 bpm) phases of the circadian cycle, and a reduction in locomotor activity during the dark/active phase [Δ= −54 ± 6 counts per hour (cph)]. The bradycardic effect of subchronic stress was not related to a reduced locomotion. Selective sympathetic (atenolol) and vagal (methyl-scopolamine) blockades were performed to reveal which autonomic component was responsible for this effect. We found that the fall in heart rate persisted after subchronic stress in animals treated with atenolol (active phase Δ= −16 ± 3 bpm, inactive phase Δ= −19 ± 2 bpm), whereas vagal blockade with scopolamine transiently prevented this effect, suggesting that the bradycardia following subchronic stress was predominantly vagally mediated. Fluoxetine (selective serotonin reuptake inhibitor) and metyrapone (inhibitor of corticosterone synthesis) treatments did not affect heart rate changes but prevented the reduction in locomotion. We conclude that subchronic stress exposure in rats reduces heart rate via a rebound in vagal activation and that this effect is serotonin- and corticosterone-independent.

Can phylogeny predict chemical diversity and potential medicinal activity of plants? A case study of amaryllidaceae

Background During evolution, plants and other organisms have developed a diversity of chemical defences, leading to the evolution of various groups of specialized metabolites selected for their endogenous biological function. A correlation between phylogeny and biosynthetic pathways could offer a predictive approach enabling more efficient selection of plants for the development of traditional medicine and lead discovery. However, this relationship has rarely been rigorously tested and the potential predictive power is consequently unknown.
Results We produced a phylogenetic hypothesis for the medicinally important plant subfamily Amaryllidoideae (Amaryllidaceae) based on parsimony and Bayesian analysis of nuclear, plastid, and mitochondrial DNA sequences of over 100 species. We tested if alkaloid diversity and activity in bioassays related to the central nervous system are significantly correlated with phylogeny and found evidence for a significant phylogenetic signal in these traits, although the effect is not strong.
Conclusions Several genera are non-monophyletic emphasizing the importance of using phylogeny for interpretation of character distribution. Alkaloid diversity and in vitro inhibition of acetylcholinesterase (AChE) and binding to the serotonin reuptake transporter (SERT) are significantly correlated with phylogeny. This has implications for the use of phylogenies to interpret chemical evolution and biosynthetic pathways, to select candidate taxa for lead discovery, and to make recommendations for policies regarding traditional use and conservation priorities.

ABCB1 polymorphism predicts escitalopram dose needed for remission in major depression

The ATP-binding cassette family of transporter proteins, subfamily B (MDR/TAP), member 1 (ABCB1) (P-glycoprotein) transporter is a key component of the blood–brain barrier. Many antidepressants are subject to ABCB1 efflux. Functional polymorphisms of ABCB1 may influence central nervous system bioavailability of antidepressants subject to efflux. Single-nucleotide polymorphisms (SNPs) at rs1045642 (C3435T) of ABCB1 have been associated with efflux pump efficiency. This may explain part of the interindividual variation in antidepressant dose needed to remit. Individuals (N=113) with DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) major depressive disorder (MDD) were treated with escitalopram (ESC) or venlafaxine (VEN) over 8 weeks. The17-item Hamilton Depression Rating Scale was assessed serially, blind to genotype. SNP rs1045642 of ABCB1 along with two SNPs previously reported to be in linkage disequilibrium with it (rs2032582 and rs1128503) were genotyped. Demographic features, clinical features, P450 metabolizer status and 5-HTTLPR (serotonin-transporter-linked promoter region) genotype were controlled for. Carriers of rs1045642 TT needed on average 11 mg of ESC to remit, whereas TC and CC carriers required 24 and 19 mg, respectively (P=0.0001). This equates to a 2.0- (95% confidence interval=1.5–3.4; P<0.001) fold greater ESC dose needed to remit for C carriers compared with TT carriers at rs1045642. Of VEN-treated subjects carrying TT genotype at rs1045642, 73.3% remitted compared with 12.5% for CC genotype (odds ratio=6.69; 95% confidence interval=1.72–25.9, P=0.006). These data suggest that antidepressant dose needed to remit can be predicted by an ABCB1 SNP. This has the potential clinical translation implications for dose selection and remission from MDD.

Managing panic disorder in general practice

BACKGROUND: Panic disorder (PD) is common in the community and contributes to significant distress and decreased quality of life for people who suffer from it. Most people with PD will present in the first instance to their general practitioner or hospital emergency department for assistance, often with a focus on somatic symptoms and concerns.

OBJECTIVE: This article aims to assist the GP to manage this group of patients by providing an outline of aetiology, approaches to assessment, and common management strategies.

DISCUSSION Although GPs have an important role to play in ruling out any causal organic basis for panic symptoms, the diagnosis of PD can usually be made as a positive diagnosis on the basis of careful history taking. Thorough and empathic education is a vital step in management. The prognosis for PD can be improved by lifestyle changes, specific psychological techniques, and the judicious use of pharmacotherapy.

Patterns of memory dysfunction in current and 2-year abstinent MDMA users

The popular recreational drug MDMA or “ecstasy” is a selective serotonin neurotoxin in many species and has been found to be associated with memory dysfunction in human beings. Recent studies suggest that this impairment persists after cessation of use for periods up to at least one year. However, there is no clear indication as yet concerning which stage of memory processing is impaired as a result of MDMA use. In the current study, 31 current MDMA users and 30 MDMA users who had been abstinent for more than two years were compared with 30 controls on the WMS-III. The results suggest that MDMA use is associated with memory dysfunction and that this dysfunction persists for up to two years after cessation of use. Importantly, the findings suggest that this memory dysfunction may be due to interference at the encoding stage of memory processing.

Anxiety disorders : assessment and management in general practice

Background: Anxiety is a normal physiological response to a threat. Anxiety disorders occur when this normal physiological response is associated with high levels of autonomic arousal, erroneous cognitions and dysfunctional coping strategies. Anxiety disorders are highly prevalent and present commonly to general practice. Anxiety disorders are often comorbid with other psychiatric and medical disorders and may be associated with significant morbidity.

Objective: This article describes the diagnosis, assessment and management of anxiety disorders in the general practice setting.

Discussion: Assessment in patients presenting with anxiety symptoms involves excluding a medical cause, identifying features of specific anxiety disorders as well as other coexisting psychiatric disorders, and assessing the degree of distress. Management options include psychoeducation, psychological treatments (particularly cognitive behaviour therapy) and pharmacological treatments. Patients with a diagnosis of an anxiety disorder can access Medicare funded psychological care under a number of Australian government initiatives. Selective serotonin reuptake inhibitors and serotonin norepinephrine reuptake inhibitors are the first line pharmacological agents used to treat anxiety disorders. Regular review is vital to monitor for clinical improvement and more complex presentations may require specialist psychological or psychiatric referral.

Distribution of Gaba in the nerve ganglia of haliotis asinina linnaeus

Gamma-aminobutyric acid (GABA) is a major neurotransmitter and effective settlement inducer in abalone aquaculture. This study aimed to explore the distribution of GABA within neural tissues of Haliotis asinina. Gamma-aminobutyric acid was found in neuronal cell type 1 of 3 major ganglia (i.e., cerebral, pleuropedal, and visceral ganglia) of both sexes. The distribution of GABA-immunoreactive (-ir) cells in the cerebral ganglion was concentrated mostly in the cortex region of the dorsal horn, whereas it was scattered throughout the pleuropedal ganglion, with more in the upper half. Gamma-aminobutyric acid-ir nerve fibers were found throughout the neuropils of the ganglia. The visceral ganglion had the least numbers of GABA-ir neurons compared with the other 2 ganglia. The cells were distributed mainly in the dorsal horn. We also observed GABA to be colocalized with 2 other neurotransmitters: serotonin (5-HT) and dopamine (DA). In the cerebral ganglion, fluorescence double staining of GABA and 5-HT, and GABA and DA showed immunoreactivity in separate cells and was also colocalized in the same cells. In the pleuropedal ganglion, the staining pattern was similar to the cerebral ganglion, but positive-staining cells were less numerous. In the visceral ganglion, GABA and DA, and GABA and 5-HT were colocalized in the same cell types. Overall, we found that GABAergic cells were most numerous in the cerebral ganglion of H. asinina. Further studies are required to determine the functions of these neurotransmitters in relation to their distribution.

The international society for bipolar disorders (ISBD) task force report on antidepressant use in bipolar diosrders

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.

Biological phenotypes underpin the physio-somatic symptoms of somatization, depression, and chronic fatigue syndrome

Objective
Somatization is a symptom cluster characterized by ‘psychosomatic’ symptoms, that is, medically unexplained symptoms, and is a common component of other conditions, including depression and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). This article reviews the data regarding the pathophysiological foundations of ‘psychosomatic’ symptoms and the implications that this has for conceptualization of what may more appropriately be termed physio-somatic symptoms.

Method
This narrative review used papers published in PubMed, Scopus, and Google Scholar electronic databases using the keywords: depression and chronic fatigue, depression and somatization, somatization and chronic fatigue syndrome, each combined with inflammation, inflammatory, tryptophan, and cell-mediated immune (CMI).

Results
The physio-somatic symptoms of depression, ME/CFS, and somatization are associated with specific biomarkers of inflammation and CMI activation, which are correlated with, and causally linked to, changes in the tryptophan catabolite (TRYCAT) pathway. Oxidative and nitrosative stress induces damage that increases neoepitopes and autoimmunity that contribute to the immuno-inflammatory processes. These pathways are all known to cause physio-somatic symptoms, including fatigue, malaise, autonomic symptoms, hyperalgesia, intestinal hypermotility, peripheral neuropathy, etc.

Conclusion
Biological underpinnings, such as immune-inflammatory pathways, may explain, at least in part, the occurrence of physio-somatic symptoms in depression, somatization, or myalgic encephalomyelitis/chronic fatigue syndrome and thus the clinical overlap among these disorders.

Role of immune-inflammatory and oxidative and nitrosative stress pathways in the etiology of depression: therapeutic implications

Accumulating data have led to a re-conceptualization of depression that emphasizes the role of immuneinflammatory processes, coupled to oxidative and nitrosative stress (O&NS). These in turn drive the production of neuroregulatory tryptophan catabolites (TRYCATs), driving tryptophan away from serotonin, melatonin, and Nacetylserotonin production, and contributing to central dysregulation. This revised perspective better encompasses the diverse range of biological changes occurring in depression and in doing so provides novel and readily attainable treatment targets, as well as potential screening investigations prior to treatment initiation. We briefly review the role that immune-inflammatory, O&NS, and TRYCAT pathways play in the etiology, course, and treatment of depression. We then discuss the pharmacological treatment implications arising from this, including the potentiation of currently available antidepressants by the adjunctive use of immune- and O&NS- targeted therapies. The use of such a frame of reference and the treatment benefits attained are likely to have wider implications and utility for depression-associated conditions, including the neuroinflammatory and (neuro)degenerative disorders.

Protocol for a collaborative meta-analysis of 5-HTTLPR, stress, and depression

Background: Debate is ongoing about what role, if any, variation in the serotonin transporter linked polymorphic region (5-HTTLPR) plays in depression. Some studies report an interaction between 5-HTTLPR variation and stressful life events affecting the risk for depression, others report a main effect of 5-HTTLPR variation on depression, while others find no evidence for either a main or interaction effect. Meta-analyses of multiple studies have also reached differing conclusions.

Methods/Design: To improve understanding of the combined roles of 5-HTTLPR variation and stress in the development of depression, we are conducting a meta-analysis of multiple independent datasets. This coordinated approach utilizes new analyses performed with centrally-developed, standardized scripts. This publication documents the protocol for this collaborative, consortium-based meta-analysis of 5-HTTLPR variation, stress, and depression.

Study eligibility criteria: Our goal is to invite all datasets, published or unpublished, with 5-HTTLPR genotype and assessments of stress and depression for at least 300 subjects. This inclusive approach is to minimize potential impact from publication bias.

Data sources: This project currently includes investigators from 35 independent groups, providing data on at least N = 33,761 participants.  The analytic plan was determined prior to starting data analysis. Analyses of individual study datasets will be performed by the investigators who collected the data using centrally-developed standardized analysis scripts to ensure a consistent analytical approach across sites. The consortium as a group will review and interpret the meta-analysis results.

Discussion: Variation in 5-HTTLPR is hypothesized to moderate the response to stress on depression. To test specific hypotheses about the role of 5-HTTLPR variation on depression, we will perform coordinated meta-analyses of de novo results obtained from all available data, using variables and analyses determined a priori. Primary analyses, based on the original 2003 report by Caspi and colleagues of a GxE interaction will be supplemented by secondary analyses to help interpret and clarify issues ranging from the mechanism of effect to heterogeneity among the contributing studies. Publication of this protocol serves to protect this project from biased reporting and to improve the ability of readers to interpret the results of this specific meta-analysis upon its completion.

Application of the gradient boosted method in randomised clinical trials: participant variables that contribute to depression treatment efficacy of duloxetine, SSRIs or placebo

Randomised, placebo-controlled trials of treatments for depression typically collect outcomes data but traditionally only analyse data to demonstrate efficacy and safety. Additional post-hoc statistical techniques may reveal important insights about treatment variables useful when considering inter-individual differences amongst depressed patients. This paper aims to examine the Gradient Boosted Model (GBM), a statistical technique that uses regression tree analyses and can be applied to clinical trial data to identify and measure variables that may influence treatment outcomes.