NCAM1, TACR1 and NOS Genes and Temperament: A Study on Suicide Attempters and Controls

Suicide, one of the leading causes of death among young adults, seems to be plausibly modulated by both genetic and personality factors. The aim of this study was to dissect the potential association between genetics and temperament in a sample of 111 suicide attempters and 289 healthy controls. We focused on 4 genes previously investigated in association with suicide on the same sample: the nitric oxide synthase 1 and 3 (NOS1 and NOS3), the neuronal cell adhesion molecule 1 (NCAM1), and the tachykinin receptor 1 (TACR1) genes. In particular, we investigated whether a set of genetic variants in these genes (NOS1 : rs2682826, rs1353939, rs693534; NOS3 : rs2070744, rs1799983, rs891512; NCAM1 : rs2301228, rs1884, rs1245113, rs1369816, rs2196456, rs584427; TACR1 : rs3771810, rs3771825, rs726506, rs1477157) were associated with temperamental traits at the Temperament and Character Inventory (TCI). No strong evidence was found for the association between TCI personality traits and the polymorphisms considered in the 4 genes, with the exception of an association between reward dependence trait and the rs2682826 SNP in NOS1 in the healthy sample. However, this result could be plausibly interpreted as a false-positive finding. In conclusion, our study did not support the thesis of a direct modulation of these genes on temperament; however, further studies on larger samples are clearly required in order to confirm our preliminary findings and to exclude any possible minor influence. Copyright (C) 2011 S. Karger AG, Base

Influence of short- and long-term exposure to a hot environment on rumen passage rate and diet digestibility by Friesian heifers.

Effects of short- and long-term exposure to a hot environment on diet digestibility and rumen passage rate were studied in four, 10-mo-old Friesian heifers housed in a climatic chamber. The trial lasted 65 d. Twenty-five days were spent under thermal comfort (temperature-humidity index = 64), and 40 d were spent under hot conditions (temperature-humidity index = 84). Three digestibility and rumen passage rate trials were performed during the 65 d. Chromium oxide was used as an external marker. The first digestibility and rumen passage rate trial (trial 1) was performed under thermal comfort; trials 2 and 3 were performed under hot conditions. Exposure to the hot environment reduced dry matter intake and increased water intake and rectal temperature compared with those during the thermal comfort period. Digestibility coefficients for dry matter, organic matter, neutral detergent fiber, and acid detergent fiber were higher in trial 2 than in trials 1 and 3. No statistical differences were found between trials 1 and 3 for these variables. Rumen passage rate was more rapid in trial 1 than in trials 2 and 3. No difference was observed between trials 2 and 3. These results indicated that exposure to a hot environment can affect digestibility in a time-dependent fashion, suggesting an adaptation of the digestive tract to hot environments

Tyrosine Hydroxylase and DOPA Decarboxylase Gene Variants in Personality Traits

Personality influences several characteristics of normal and pathologic behaviors and it is associated with neurotransmitter systems that are under genetic control. The dopaminergic system has been proposed to play a role in the modulation of personality traits. In the present study, variants of the tyrosine hydroxylase (TH) and DOPA decarboxylase (DDC) genes (for TH: rs3842727, rs6356; for DDC: rs1451371, rs1470750, rs998850) were investigated in 111 suicide attempters and 289 healthy subjects to assess the involvement of the dopaminergic synthesis pathway in personality traits. No strong evidence was found for the associations between personality and TH or DDC in overall tests. An interaction effect of genotype and diagnosis was present, with TH and DDC SNPs having a greater effect on the respective personality dimensions in the group of suicide attempters. Because of the risk of false positives, these findings should be interpreted with highest caution. Direct replication attempts within independent groups of suicide attempters will help to resolve this question. Copyright (C) 2009 S. Karger AG, Base

The dilemma of polypharmacy in psychosis: is it worth combining partial and full dopamine modulation?

Antipsychotic polypharmacy in psychotic disorders is widespread despite international guidelines favoring monotherapy. Previous evidence indicates the utility of low-dose partial dopamine agonist (PDAs) add-ons to mitigate antipsychotic-induced metabolic adverse effects or hyperprolactinemia. However, clinicians are often concerned about using PDAs combined with high-potency, full dopaminergic antagonists (FDAs) due to the risk of psychosis relapse. We, therefore, conducted a literature review to find studies investigating the effects of combined treatment with PDAs (i.e. aripiprazole, cariprazine and brexpiprazole) and FDAs having a strong D-2 receptor binding affinity. Twenty studies examining the combination aripiprazole - high-potency FDAs were included, while no study was available on combinations with cariprazine or brexpiprazole. Studies reporting clinical improvement suggested that this may require a relatively long time (similar to 11 weeks), while studies that found symptom worsening observed this happening in a shorter timeframe (similar to 3 weeks). Patients with longer illness duration who received add-on aripiprazole on ongoing FDA monotherapy may be at greater risk for symptomatologic worsening. Especially in these cases, close clinical monitoring is therefore recommended during the first few weeks of combined treatment. These indications may be beneficial to psychiatrists who consider using this treatment strategy. Well-powered randomized clinical trials are needed to derive more solid clinical recommendations. Copyright (C) 2022 The Author(s). Published by Wolters Kluwer Health, Inc

A model to incorporate genetic testing (5-HTTLPR) in pharmacological treatment of major depressive disorders.

none5Objective. To evaluate the benefit of pharmacogenetics in antidepressant treatment. Methods. In a simulated trial 100,000 subjects in a current episode of major depressive disorder (MDD) received citalopram or bupropion based on the clinician's decision (algorithm A) or following indications from 5-HTTLPR genetic testing (algorithm B), which effect size of was estimated from a meta-analysis of pharmacogenetic trials. A and B were compared in a cost-utility analysis (12 weeks). Costs (international $, 2010) were drawn from official sources. Treatment effects were expressed as quality-adjusted life weeks (QALWs). Outcome was incremental cost-effectiveness ratio (ICER). Results. Under base-case conditions, genetic test use was associated with increases in antidepressant response (0.062 QALWs) and tolerability (0.016 QALWs) but cost benefit was not acceptable (ICER =$2,890; $1,800-$4,091). However, when the joint effect on antidepressant response and tolerability was analyzed in two recurrent episodes, ICER dropped to $1,392 ($837-$1,982). Cost-effectiveness acceptability curve (CEAC) showed a >80% probability that ICER value fell below the commonly accepted 3 times Gross Domestic Product (GDP) threshold (World Health Organization) and therefore suggesting cost-effectiveness. Conclusion. Notwithstanding some caveats (exclusion of gene-gene and gene-environment interactions; simple 5-HTTLPR architecture), this simulation is favourable to incorporate pharmacogenetic test in antidepressant treatment.openA. Serretti; P. Olgiati; E. Bajo; M. Bigelli; D. De RonchiA. Serretti; P. Olgiati; E. Bajo; M. Bigelli; D. De Ronch

No association of a set of candidate genes on haloperidol side effects.

We previously investigated a sample of patients during an active phase of psychosis in the search for genetic predictors of haloperidol induced side effects. In the present work we extend the genetic association analysis to a wider panel of genetic variations, including 508 variations located in 96 genes. The original sample included 96 patients. An independent group of 357 patients from the CATIE study served as a replication sample. Outcomes in the investigation sample were the variation through time of: 1) the ESRS and UKU total scores 2) ESRS and UKU subscales (neurologic and psychic were included) related to tremors and 3) ESRS and UKU subscales that do not relate to tremors. Outcome in the replication sample was the presence vs absence of motoric side effects from baseline to visit 1 (~ one month of treatment) as assessed by the AIMS scale test. Rs2242480 located in the CYP3A4 was associated with a different distribution of the UKU neurologic scores through time (permutated p = 0.047) along with a trend for a different haloperidol plasma levels (lower in CC subjects). This finding was not replicated in the CATIE sample. In conclusion, we did not find conclusive evidence for a major association between the investigated variations and haloperidol induced motoric side effects