https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(15)00234-2.pdf

Suicide and suicidal behaviour

5-HT1A Receptor Function in Major Depressive Disorder

Objectives: 
To provide an evidence-based perspective on the prognostic value of novel markers in localised prostate cancer and to identify the best prognostic model including the three classical markers and investigate whether models incorporating novel markers are better. 

Data sources:
 
Eight electronic bibliographic databases were searched during March–April 2007. The reference lists of relevant articles were checked and various health services research-related resources consulted via the internet. The search was restricted to publications from 1970 onwards in the English language. 

Methods:
 
Selected studies were assessed, data extracted using a standard template, and quality assessed using an adaptation of published criteria. Because of the heterogeneity regarding populations, outcomes and study type, meta-analyses were not undertaken and the results are presented in tabulated format with a narrative synthesis of the results. 

Results:
 
In total 30 papers met the inclusion criteria, of which 28 reported on prognostic novel markers and five on prognostic models. A total of 21 novel markers were identified from the 28 novel marker studies. There was considerable variability in the results reported, the quality of the studies was generally poor and there was a shortage of studies in some categories. The marker with the strongest evidence for its prognostic significance was prostate-specific antigen (PSA) velocity (or doubling time). There was a particularly strong association between PSA velocity and prostate cancer death in both clinical and pathological models. In the clinical model the hazard ratio for death from prostate cancer was 9.8 (95% CI 2.8–34.3, pE<E0.001) in men with an annual PSA velocity of more than 2Eng/ml versus an annual PSA velocity of 2Eng/ml or less; similarly, the hazard ratio was 12.8 (95% CI 3.7–43.7, pE<E0.001) in the pathological model. The quality of the prognostic model studies was adequate and overall better than the quality of the prognostic marker studies. Two issues were poorly dealt with in most or all of the prognostic model studies: inclusion of established markers and consideration of the possible biases from study attrition. Given the heterogeneity of the models, they cannot be considered comparable. Only two models did not include a novel marker, and one of these included several demographic and co-morbidity variables to predict all-cause mortality. Only two models reported a measure of model performance, the C-statistic, and for neither was it calculated in an external data set. It was not possible to assess whether the models that included novel markers performed better than those without. 

Conclusions:
 
This review highlighted the poor quality and heterogeneity of studies, which render much of the results inconclusive. It also pinpointed the small proportion of models reported in the literature that are based on patient cohorts with a mean or median follow-up of at least 5 years, thus making long-term predictions unreliable. PSA velocity, however, stood out in terms of the strength of the evidence supporting its prognostic value and the relatively high hazard ratios. There is great interest in PSA velocity as a monitoring tool for active surveillance but there is as yet no consensus on how it should be used and, in particular, what threshold should indicate the need for radical treatment.

/pdf/the-harmful-health-effects-of-recreational-ecstasy-a-azxs1t7w9u.pdf

The harmful health effects of recreational ecstasy: a systematic review of observational evidence

Although recent years have seen large decreases in the overall global rate of suicide fatalities, this trend is not reflected everywhere. Suicide and suicidal behaviour continue to present key challenges for public policy and health services, with increasing suicide deaths in some countries such as the USA. The development of suicide risk is complex, involving contributions from biological (including genetics), psychological (such as certain personality traits), clinical (such as comorbid psychiatric illness), social and environmental factors. The involvement of multiple risk factors in conveying risk of suicide means that determining an individual’s risk of suicide is challenging. Improving risk assessment, for example, by using computer testing and genetic screening, is an area of ongoing research. Prevention is key to reduce the number of suicide deaths and prevention efforts include universal, selective and indicated interventions, although these interventions are often delivered in combination. These interventions, combined with psychological (such as cognitive behavioural therapy, caring contacts and safety planning) and pharmacological treatments (for example, clozapine and ketamine) along with coordinated social and public health initiatives, should continue to improve the management of individuals who are suicidal and decrease suicide-associated morbidity. Suicide and suicidal behaviour continue to present key challenges for public policy and health services. This Primer discusses the global burden of suicide and suicidal behaviours, and provides an overview of our current understanding of the mechanisms of suicide, including risk factors for suicidal ideation and the transition from ideation to suicide attempt.

/pdf/suicide-and-suicide-risk-2mwsvcppvb.pdf

Suicide and suicide risk

Environmental influence on developmental plasticity impacts a wide diversity of animal life from insects to humans. We now understand the epigenetic basis for many of these altered phenotypes. The five environmental factors of nutrition, behavior, stress, toxins, and stochasticity work individually and in concert to affect the developing epigenome. During early embryogenesis, epigenetic marks, such as DNA methylation, are reset at specific times. Two waves of global demethylation and reestablishment of methylation frame the sensitive times for early environmental influences and will be the focus of this review. Gene transcription, translation, and post-translational modification of chromatin remodeling complexes are three mechanisms affected by developmental exposure to environmental factors. To illustrate how changes in the early environment profoundly affect these mechanisms, we provide examples throughout the animal kingdom. Herein we review the history, time points, and mechanisms of epigenetic gene-e...

https://www.tandfonline.com/doi/pdf/10.4161/epi.6.7.16209

Timing is everything: the when and how of environmentally induced changes in the epigenome of animals.

Context: Brain-derived neurotrophic factor (BDNF) plays a pivotal role in the pathophysiology of suicidal behavior andBDNF levels are decreased in the brain and plasma of suicide subjects. So far, the mechanisms leading to downregulation of BDNF expression are poorly understood. Objectives: To test the hypothesis that alterations of DNA methylation could be involved in the dysregulation of BDNF gene expression in the brain of suicide subjects. Design: Three independent quantitative methylation techniques were performed on postmortem samples of brain tissue. BDNF messenger RNA levels were determined by quantitative real-time polymerase chain reaction. Setting: Academic medical center. Patients or Other Participants: Forty-four suicide completers and 33 nonsuicide control subjects of white ethnicity.

https://jamanetwork.com/journals/jamapsychiatry/articlepdf/210623/yoa90071_258_267.pdf

Increased BDNF promoter methylation in the Wernicke area of suicide subjects.

In Europe, the countries with the highest suicide rates form a so-called J-curve, which starts in Finland and extends down to Slovenia-a country with one of the world's highest suicide rates. So far, the strongest association between suicide and genes has been shown for the serotonergic system. A functional polymorphism 68G>C (Cys23Ser) and a promoter polymorphism-995G>A of serotonin receptor 2C (HTR2C) have already been investigated, but no associations with suicide were determined. In the present study 334 suicide victims and 211 controls of Slovenian origin were genotyped for the above-mentioned polymorphisms using standard methods. In the case of the polymorphism-995G>A no association with suicide was found. However, a significant association was observed between female suicide victims and polymorphism 68G>C. The significance remained when we combined alleles of female and male populations. An excess of GG genotype and allele G was observed. However, no statistically important differences were present when only males were analyzed. Haplotype analysis on female population showed marginal association of haplotype G-C with suicide. The present study speaks for the plausible implication of the HTR2C in suicide susceptibility.

Promoter and functional polymorphisms of HTR2C and suicide victims.

Several studies have been carried out to investigate how genetic variants of gene encoding for the serotonin transporter (5-HTT) may confer susceptibility to suicide. It was demonstrated that polymorphisms in the promoter region (5-HTTLPR) and in the second intron (VNTR) have functional consequences and are for this reason of particular interest in relation to various psychiatric disorders. In our study, we analyzed 5-HTTLPR and VNTR polymorphisms in 235 suicide victims and 233 controls in a Slovenian population to find a possible association of the polymorphisms and suicidal behavior. No statistically important differences between genotypes of controls and suicide group (5-HTTLPR: Pearson's chi2=1.597, df=2, P=0.455; VNTR: Pearson's chi=1.961, df=4, P=0.744), as well as no differences in allele distribution (5-HTTLPR: Pearson's chi2=0.598, df=1, P=0.467; VNTR: Pearson's chi2=0.837, df=2, P=0.654) were found, although a slightly higher frequency of LL genotype and of L allele was observed in the suicide group. Haplotype frequency analysis showed no excess of particular haplotypes between the two groups. Our study showed no association of serotonin transporter polymorphisms and suicide. The study, however, was performed on a population with a very high suicide rate (27.1 victims/100,000 citizens) and the role of 5-HTTLPR polymorphisms may be different in other populations.

Serotonin transporter gene promoter (5-HTTLPR) and intron 2 (VNTR) polymorphisms: a study on Slovenian population of suicide victims.

Fingerprint recovery from human skin surfaces.

A number of molecular genetic studies have investigated if serotonin (5-HT) receptor subtypes are involved in the pathogenesis of depression, suicidal behavior, aggression, and impulsive behavior. Existence of many receptor subtypes for a single transmitter permits a great diversity of signaling raising the possibility that they may serve as genetic markers for suicidal behavior. Most previous studies of suicide have analyzed polymorphisms of the receptors 5-HT(1A), 5-HT(1B), 5-HT(2A), fewer have examined 5-HT(1F). We report a study of possible association between the polymorphisms in the 5-HT receptor genes (1A, 1B, 1F, and 2A) and suicidal behavior on a sample of 226 suicide victims and 225 healthy control subjects. No significant differences in genotype frequency distributions between the suicide victims and healthy control subjects were observed for four polymorphisms; three were not polymorphic. A single polymorphism, C-1420T in gene 5-HT(2A), showed a slight association with suicide (chi(2) = 4.94, df = 2, P = 0.067), but the correlation was not statistically significant. None of the tested genetic variants of serotonin receptors appears to be associated with suicidal behavior in the Slovenian population which has a relatively high suicide rate. Language: en

Joze Balazic

Papers

Increased BDNF promoter methylation in the Wernicke area of suicide subjects.

Promoter and functional polymorphisms of HTR2C and suicide victims.

Serotonin transporter gene promoter (5-HTTLPR) and intron 2 (VNTR) polymorphisms: a study on Slovenian population of suicide victims.

Fingerprint recovery from human skin surfaces.

Association study of seven polymorphisms in four serotonin receptor genes on suicide victims