Nine differentially expressed genes from a post mortem study and their association with suicidal status in a sample of suicide completers, attempters and controls.

Several lines of evidence indicate that suicidal behaviour is partly heritable, with multiple genes implicated in its aetiology. We focused on nine genes (S100A13, EFEMP1, PCDHB5, PDGFRB, CDCA7L, SCN2B, PTPRR, MLC1 and ZFP36) which we previously detected as differentially expressed in the cortex of suicide victims compared to controls. We investigated 84 variants within these genes in 495 suicidal subjects (299 completers and 196 attempters) and 1513 controls (109 post-mortem and 1404 healthy). We evaluated associations with: 1) suicidal phenotype; 2) possible endophenotypes for suicidal behaviour. Overall positive results did not survive the correction threshold. However, we found a nominally different distribution of EFEMP1 genotypes, alleles and haplotypes between suicidal subjects and controls, results that were partially replicated when we separately considered the subgroup of suicide completers and post-mortem controls. A weaker association emerged also for PTPRR. Both EFEMP1 and PTPRR genes were also related to possible endophenotypes for suicidal behaviour such as anger, depression-anxiety and fatigue. Because of the large number of analyses performed and the low significance values further replication are mandatory. Nevertheless, neurotrophic gene variants, in particular EFEMP1 and PTPRR, may have a role in the pathogenesis of suicidal behaviour.

Temperament and Character Inventory in Bipolar Disorder versus Healthy Controls and Modulatory Effects of 3 Key Functional Gene Variants.

BACKGROUND: Bipolar disorder (BD) has been associated with temperamental and personality traits, although the relationship is still to be fully elucidated. Several studies investigated the genetic basis of temperament and character, identifying catechol-O-methyltransferase (COMT), brain derived neurotrophic factor (BDNF), and serotonin transporter (5-HTT) gene variants as strong candidates. METHODS: In the GECO-BIP study, 125 BD patients and 173 HC were recruited. Subjects underwent to a detailed assessment and the temperament and character inventory 125 items (TCI) was administrated. Three functional genetic variants within key candidate genes (COMT rs4680, BDNF rs6265, and the serotonin-transporter-linked polymorphic region (5-HTTLPR)) were genotyped. Univariate and multivariate analyses were performed. RESULTS: Compared to HC, BD patients showed higher scores in novelty seeking (NS; p = 0.001), harm avoidance (HA; p < 0.001), and self transcendence (St; p < 0.001), and lower scores in self directness (p < 0.001) and cooperativeness (p < 0.001) TCI dimensions. Concerning the genetic analyses, COMT rs4680 was associated with NS in the total sample (p = 0.007) and in the male subsample (p = 0.022). When performing the analysis in the HC and BD samples, the association was confirmed only in HC (p = 0.012), and in the HC male subgroup in particular (p = 0.004). BDNF rs6265 was associated with St in the BD group (p = 0.017). CONCLUSION: COMT rs4680 may modulate NS in males in the general population. This effect was not detected in BD patients, probably because BD alters the neurobiological basis of some TCI dimensions. BDNF rs6265 seems to modulate St TCI dimension only in BD patients, possibly modulating the previously reported association between rs6265 and BD treatment response. Further studies are needed to confirm our findings.

Epistatic Interactions between CREB and CREM Variants in Affective Disorder.

The aim of the present work is to investigate the existence of epistatic interactions possibly influencing psychotropic agents' response between rs6740584 within Cyclic adenosine monophosphate Response Element Binding (CREB) and rs12775799 within cAMP response element-modulator (CREM) variants in bipolar disorder (BD) and major depressive disorder (MDD). All BD and MDD patients were administered with the Young Mania Rating Scale (YMRS) and Hamilton Depression Rating Scale (HAMD) at baseline and at endpoint, respectively. A multiple regression model was employed to investigate the existence of possible epistatic interactions between the two variants and diverse clinical factors including drug response in affective disorders. No significant epistatic interaction was observed between rs6740584 within CREB and rs12775799 within CREM on both symptom improvement and other clinical factors in affective disorders. Our preliminary results suggest that no epistatic interaction between rs6740584 within CREB and rs12775799 within CREM should exist on clinical improvement and clinical factors in affective disorders.

Specificity profile of venlafaxine and sertraline in major depression: metaregression of double-blind, randomized clinical trials.

Despite the well-known efficacy of selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) in the treatment of major depressive disorder, there is a lack of indications for each drug in different groups of patients. The aim of this study is to investigate the possible role of clinical sociodemographic factors as moderators of clinical response to venlafaxine (SNRI) and sertraline (SSRI). Research was performed on Medline and EMBASE for randomized control trials in English focused on sertraline and venlafaxine in the treatment of major depressive disorder and 59 studies were included. Clinical efficacy of each treatment was assessed on the basis of Hamilton Depressive Rating Scale and Montgomery-Asberg Depression Rating Scale. A metaregression analysis was performed to evaluate the role of clinical and sociodemographic factors as moderators of outcome, calculating the effect of each variable with the random-effects method. Gender, ethnicity and duration of depressive episode could have a role in prediction of clinical response to both antidepressants. Venlafaxine seems to have better effects in females and in Caucasian patients. Sertraline seems to be more efficacious in the treatment of females. Both drugs were more efficacious in patients who suffered a shorter episode of illness. Our results could represent an interesting point of view in the perspective of choosing the most suitable therapy based on clinical and social features for each patient. Metaregression is a retrospective analysis, based on the cumulative results of previous studies, so the lack of original data could represent the main limitation in this report and in the interpretation of the results obtained.

The 5-HTTLPR polymorphism and posttraumatic stress disorder: a meta-analysis.

Environmental and genetic factors contribute to the development of posttraumatic stress disorder (PTSD). Variation in the 5-HTTLPR polymorphism of the serotonin transporter gene has been hypothesized to affect risk for PTSD. With the aim of investigating this association, we conducted a meta-analysis to shed light on prior controversial results and increase statistical power to detect smaller effect sizes. PubMed and ISI databases were searched for studies published until December 2012. Twelve studies have been included, all based on trauma-exposed samples. Data were analyzed with Cochrane Collaboration Review Manager Software (Version 5). Quality and publication bias were assessed. Metaregressions were performed using Comprehensive Meta-Analysis software, Version 2. Taking into account all studies, no association was found between 5-HTTLPR and PTSD (p = .10), with evidence of between-study heterogeneity, which could be partly explained by gender differences. In sensitivity analyses, we found an association between SS genotype and PTSD in high trauma-exposed participants (p < .001). To be a carrier of the SS genotype seems to represent a risk factor for PTSD in high trauma exposure. Further studies focusing on Gene × Environment interactions are needed to better understand the role of this polymorphism in PTSD.

Social adjustment among treatment responder patients with mood disorders.

BACKGROUND: Patients with major depression (MD) show reduced social adjustment when compared with healthy controls. However, even among treatment responders, significant differences in social adjustment occur. The main aim of the present work is to study several socio-demographic and clinical variables possibly influencing social adjustment in MD patients who responded to treatment. METHODS: Two hundred and eleven MD patients experiencing a depressive episode who responded to their current treatment were recruited within the context of a large European multicentre project. Our primary outcome measure was the association between 19 socio-demographic and clinical variables and total social adjustment scores, as measured with the Social Adjustment Scale (SAS). Secondary outcome measures included the associations between the same variables and SAS sub-scales, and the associations between these variables and self-esteem, as measured with the Rosenberg Self-Esteem Scale. RESULTS: A co-morbidity with anxiety disorders and the severity of residual depression symptoms were the strongest independent factors associated with poorer social adjustment, in terms of total and most sub-areas' SAS scores. Other variables associated with total and sub-areas' SAS scores were identified as well, although some variations across different areas were observed. LIMITATIONS: The cross-sectional design, the retrospective assessment of data and the lack of a placebo control group. CONCLUSIONS: Our results confirm that a co-morbidity with anxiety disorders and higher residual depression symptoms could reduce social adjustment among responder MD patients. Further longitudinal studies are needed to confirm our results.

Clinical features and drug induced side effects in early versus late antidepressant responders.

Early antidepressant response (2nd week) has been reported as the result of a true antidepressant effect and a predictor of subsequent stable response. With the purpose to study the clinical profile of early response/remission (2nd week) compared to late response/remission (4th-6th weeks), two independent major depressive disorder (MDD) samples (the Sequenced Treatment Alternatives to Relieve Depression or STAR*D n=1922 and an Italian sample n=171) were investigated. Patients were treated with citalopram in the STAR*D while in a naturalistic setting in the Italian sample. Depressive symptomatology was assessed by the Hamilton Depressive Rating Scale weekly in the Italian sample and biweekly by the Quick Inventory of Depressive Symptomatology Clinician Rated in the STAR*D. Logistic regression was used to investigate possible predictors of early response and the Bonferroni correction was applied. In the STAR*D, higher levels of baseline core depressive symptoms (Bech subscale) were associated with early response (p=0.00017), as well as lower baseline insomnia (p=0.003) and higher work and social functioning (p=0.001). In the Italian sample none of these variables were associated with the phenotype, but a non significant trend of lower baseline quality of life (p=0.078) was observed in late remitters. In the STAR*D late responders reported higher levels of antidepressant induced side effects, especially difficulty in sleeping (p=5.68e-13), with a non significant trend in the same direction in the Italian sample (p=0.09). The identification of late versus early antidepressant responders at the beginning of the treatment may be useful to guide therapeutic choices in clinical settings.

Association between Sirtuin 2 gene rs10410544 polymorphism and depression in Alzheimer's disease in two independent European samples.

Among the several genes associated with late-onset Alzheimer's disease (LOAD), recently, Sirtuin genes have roused a growing interest because of their involvement in metabolic homeostasis and in brain aging. Particularly SIRT2 gene has been associated with Alzheimer's disease (AD) as well as with mood disorders. The aim of this study is to investigate the possible associations between Sirtuin 2 gene (SIRT2) rs10410544 polymorphism and AD as well as depression in AD. In addition, we performed some exploratory analyses to investigate possible associations between the rs10410544 genotype and clinical features. We investigated these associations in two independent samples: the first one was composed of 275 Greek inhabitants and 117 patients; the second sample counted 181 Italian people and 43 patients. All patients were affected by LOAD. We failed to find any association between rs10410544 genotype and AD in the two samples. On the other hand, we found an association between the single nucleotide polymorphism (SNP) and depressive symptomatology (in the total sample p = 0.002), which was modulated by the tumor necrosis factor (TNF) values. Particularly, TT genotype seems to be protective versus depression. Finally, in the exploratory analyses, we found that the TT genotype was associated with earlier AD onset and a longer duration of the illness. In conclusion, we confirmed the association between SIRT2 gene and mood disturbances, although in AD patients. Further, we provided evidence that the TT genotype may be protective versus depressive symptoms, allowing an easier and thus earlier diagnosis of AD. This awareness may lead to a more detailed approach to these patients concerning diagnosis and therapy.

Genetics of serotonin receptors and depression: state of the art.

Major depression (MD) is a major health problem, partly due to the incomplete understanding of the pathogenic mechanisms of the disease. Research efforts have mainly focused on alterations in monoaminergic neurotransmission, especially in relation to the serotonergic system, due to its key role in the regulation of mood and related biological functions. Given the high heritability of MD (estimated between 31% and 42% for unipolar depression), genes coding for key regulators of the serotonergic neurotransmission have been considered as optimal candidates. The present review is focused on the role of genes coding for serotonin receptors in MD pathogenesis, since the serotonin transporter and enzymes involved in serotonin metabolism have been reviewed elsewhere. Despite the large number of candidate gene studies focusing on genes coding for serotonin receptors, results have been inconsistent. The most replicated findings are the associations between rs6295 (HTR1A gene) G allele or G/G genotype and rs6311 (HTR2A gene) A allele or A/A genotype and MD or depressive symptoms. Preclinical and imaging/post-mortem studies in humans provide strong support for the involvement of HTR1A and HTR2A genes in MD. Nevertheless, the inconsistency across previous studies clearly suggests that innovative approaches should be designed in order to overcome the limitations of candidate gene studies. To date, the most appealing methodologies seem to be full exome or genome sequencing, genome-wide pathway analyses, endophenotypes, and epigenetic biomarkers. The reported tools may assist in the detection of multiple-loci models, which could potentially explain the high percentage of MD susceptibility ascribed to genetic factors.

Effects of SORL1 gene on Alzheimer's disease. Focus on gender, neuropsychiatric symptoms and pro-inflammatory cytokines.

It was suggested that the gene encoding for sorLa, (SORL1) may affect Alzheimer's disease (LOAD) through a female-specific mechanism. The aims of this study were to confirm the role of gender in modulating the association between SORL1 and LOAD and to ascertain the influence of SORL1 on cognitive impairment, neuropsychiatric symptoms (BPSD) and secretion of pro-inflammatory cytokines. Ninety six outpatients with LOAD and 120 unrelated controls were genotyped for APOE and three SNPs at the 5' end of SORL1(intron 6): SNP 8 (rs668387); SNP 9 (rs68902); SNP 10 (rs641120). Clinical evaluation was made with the MMSE, Neuropsychiatric Inventory (NPI) and Cornell Scale for Depression in Dementia (CDDS). ELISPOT assays were used to measure pro-inflammatory cytokine (TNF-alpha; IL-6; IL-1beta; IFN-gamma) production in peripheral blood mononuclear cell (PBMC) supernatant from AD patients. SORL1 SNPs were not associated with LOAD in overall sample. Instead the G-alleles at SNPs 9 (p=0.015) and 10 (p=0.015) and the CGG haplotype (p=0.02) were associated with LOAD in the women subgroup. The TAA haplotype was marginally protective in AD patients being associated with lower BPSD scores (p=0.01). The same haplotype was also associated with higher IL-1beta (p=0.01) production. These genetic effects were not modified by APOE4 allele and controlled for illness duration and treatment. In conclusion, SORL1 does not appear to be a major risk factor for LOAD. Its contribution could be underestimated in our small sample. Sex-specific factors could modulate the association between SORL1 and AD. The influence of SORL1 variants on production of inflammatory cytokines warrants further investigation.

Antidepressants in elderly: metaregression of double-blind, randomized clinical trials.

BACKGROUND: Depression is common in the elderly and in the last few years this led to a significant increase in antidepressant prescription rates. However, little is known about antidepressant efficacy profile in relation with socio-demographic and clinical features in this population. The aim of the present study was to define the most suitable socio-demographic and clinical profile for the use of antidepressant treatments in late-life depression. METHODS: MEDLINE, EMBASE and PsycINFO were searched for randomized controlled trials (RCTs) focused on efficacy of antidepressants of all classes in major depressed elderly subjects (>60 years old). Reviews and meta-analyses focusing on this topic have been considered as well. Thirty-four RCTs were included and socio-demographic and clinical features were investigated via meta-regression analysis as moderators of efficacy measures (standardized mean difference based on Hamilton Depressive Rating Scale and Montgomery-Asberg Depression Rating Scale). RESULTS: A lower rate of response to antidepressants of all classes was found in patients of male gender, of older age, and with a longer mean duration of the current episode. On the contrary, a higher rate of response was found in patients with a higher baseline severity and at their first episode of illness. Subsamples treated with selective serotonin reuptake inhibitors alone yielded similar results. LIMITATIONS: RCTs only have been included. CONCLUSIONS: A number of socio-demographic and clinical features have been found to moderate antidepressant efficacy in elderly population. Those variables could help clinicians for a more individualized treatment.